WO2005016275A2 - Formulations containing an immune response modifier - Google Patents

Formulations containing an immune response modifier Download PDF

Info

Publication number
WO2005016275A2
WO2005016275A2 PCT/US2004/025277 US2004025277W WO2005016275A2 WO 2005016275 A2 WO2005016275 A2 WO 2005016275A2 US 2004025277 W US2004025277 W US 2004025277W WO 2005016275 A2 WO2005016275 A2 WO 2005016275A2
Authority
WO
WIPO (PCT)
Prior art keywords
amines
alkyl
imidazo
substituted
quinolin
Prior art date
Application number
PCT/US2004/025277
Other languages
French (fr)
Other versions
WO2005016275A3 (en
Inventor
David M. Hammerbeck
Cynthia A. Guy
Suzanne S. Leung
Original Assignee
3M Innovative Properties Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 3M Innovative Properties Company filed Critical 3M Innovative Properties Company
Priority to US10/595,049 priority Critical patent/US8221771B2/en
Priority to CA2534313A priority patent/CA2534313C/en
Priority to JP2006522714A priority patent/JP2007501252A/en
Priority to AU2004264336A priority patent/AU2004264336B2/en
Priority to EP04780166A priority patent/EP1651190B1/en
Publication of WO2005016275A2 publication Critical patent/WO2005016275A2/en
Publication of WO2005016275A3 publication Critical patent/WO2005016275A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention is directed to pharmaceutical formulations that include at least one immune response modifier, such as those chosen from imidazoquinolme amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, and thiazolonaphthyridine amines, for example.
  • at least one immune response modifier such as those chosen from imidazoquinolme amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazo
  • IRM'' immune response modifier
  • the mechanism for the immunostimulatory activity of these IRM compounds is thought to be due in substantial part to enhancement of the immune response by induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.).
  • cytokines e.g., interferons, interleukins, tumor necrosis factor, etc.
  • Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to secrete antibodies, which play an important role in these IRM compounds' activities.
  • One of the predominant immunostimulating responses to these compounds is the induction of interferon (LFN)- ⁇ production, which is believed to be very important in the acute antiviral and antitumor activities seen.
  • LFN interferon
  • TNF tumor necrosis factor
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • IL-12 also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds.
  • TNF tumor necrosis factor
  • IL-1 Interleukin-1
  • IL-6 Interleukin-6
  • IL-12 also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds.
  • the present invention is directed to aqueous formulations and methods of use.
  • such formulations are sprayable.
  • Such formulations include: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 Centipoise (cps) at room temperature.
  • Formulations of the present invention can provide desirable vehicles for immune response modifier compounds and can allow for easier manufacture and increased residence time of the immune response modifier, particularly on mucosal tissue.
  • the present invention provides an aqueous sprayable formulation that includes: an immune response modifier selected from the group consisting of imidazoquinolme amines, tetrahydroimidazoqumolme amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H- imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthy
  • the present invention also provides methods of using the formulations of the present invention.
  • the present invention provides a method for delivering an immune response modifier to a nasal passage of a subject.
  • the method includes: selecting a formulation that includes: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherem the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature; and applying the selected formulation into a nasal passage.
  • Other methods of the present invention are directed to methods of treating and/or preventing allergic rhinitis by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human).
  • Other methods of the present invention are directed to methods of treating and/or preventing a viral infection by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human).
  • Other methods of the present invention are directed to methods of treating and/or preventing sinusitis by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human).
  • Other methods of the present invention are directed to methods of treating and/or preventing asthma by applying (e.g., spraying) a formulation of the present invention into the respiratory tract of a subject (typically, an animal, preferably, a mammal, and more preferably, a human).
  • the present invention also provides a method of desensitizing a subject to an antigen.
  • the method involves administering to the subject an IRM compound in a formulation of the present invention, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen.
  • the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen.
  • solution refers to a combination of two or more substances uniformly dispersed throughout a single phase, so that the combination is homogeneous at the molecular or ionic level.
  • the terms “comprises” and variations thereof do not have a limiting meaning where these terms appear in the description and claims. As used herein, "a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably.
  • an aqueous formulation that comprises "an” immune response modifier can be interpreted to mean that the formulation includes “one or more” immune response modifiers.
  • a formulation comprising "a” hydrophilic viscosity enhancing agent can be interpreted to mean that the formulation includes “one or more” hydrophilic viscosity enhancing agents.
  • the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
  • Fig. 1 is a bar graph comparing viral titers in rats after treatment with vehicle, LFN- ⁇ , or IRM compound four hours before viral challenge.
  • Fig. 2 is a bar graph comparing viral titers in rats after treatment with vehicle, LFN- ⁇ , or IRM compound twenty-four hours and again at four hours before viral challenge.
  • the present invention provides aqueous (preferably, sprayable) formulations and methods of use.
  • Such formulations include: an immune response modifier (IRM); water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature.
  • Such formulations are in solution form at room temperature (i.e., 25°C-30°C).
  • the formulations include two or more substances uniformly dispersed throughout a single phase, so that the combination is homogeneous at the molecular or ionic level. Also, such formulations are sufficiently low in viscosity (less than 100 centipoise (cps)) at room temperature. At such low viscosity level, the compositions are typically and preferably sprayable.
  • sprayable means the formulation can be delivered using a conventional pump spray device, such as those described in Encyclopedia of Pharmaceutical Technology, Second Edition, 856-860, Marcel Dekker, Inc., 2002. Although preferred formulations are sprayable solutions, they do not have to be administered to a subject by spraying.
  • formulations of the present invention can be administered to a subject (e.g., mammal, particularly a human) in various ways by spraying, injection, inhalation, etc. They can be administered, for example, intranasally, intraperitoneally, topically, orally, intratracheally via inhalation (e.g., from a nebulizer or spray pump atomizer), or subcutaneously.
  • formulations of the present invention are administered intranasally by spraying into the nasal passages of a mammal.
  • the therapeutic effect of the IRM compound may extend only to the superficial layers of the nasal passages or to tissues below the surface.
  • the above-described formulations are particularly advantageous for application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absorption of the IRM.
  • the immune response modifier is a positively charged immune response modifier.
  • the hydrophilic viscosity enhancing agent is negatively charged.
  • IRM Compounds Preferred IRM compounds suitable for use in the formulations of the invention preferably include compounds having a 2-aminopyridine fused to a five membered nitrogen-containing heterocyclic ring.
  • Other small organic molecules known to function as IRM compounds are also suitable for use in the formulations of the invention.
  • Certain IRMs are small organic molecules (e.g., molecular weight under about 1000 Daltons, preferably under about 500 Daltons, as opposed to large biologic protein, peptides, and the like) such as those disclosed in, for example, U.S. Patent Nos. 4,689,338;
  • IRM compounds suitable for use in the invention preferably include compounds having a 2-aminopyridine fused to a five membered nitrogen-containing heterocyclic ring.
  • Such compounds include, for example, imidazoquinolme amines, including but not limited to, substituted imidazoquinolme amines such as, for example, amide substituted imidazoquinolme amines, sulfonamide substituted imidazoquinolme amines, urea substituted imidazoquinolme amines, aryl ether substituted imidazoquinolme amines, heterocyclic ether substituted imidazoquinolme amines, amido ether substituted imidazoquinolme amines, sulfonamido ether substituted imidazoquinolme amines, urea substituted imidazoquinolme ethers, thioether substituted imidazoquinolme amines, and 6- , 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinolme amines; tetrahydroimidazoquinoline amines, including but not limited to, amide substituted tetrahydroimid
  • IRM compound can be chosen from lH-imidazo[4,5-c]quinolin-4-amines defined by one of Formulas I-V below:
  • R ⁇ is selected from alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms; R 21 is selected from hydrogen, alkyl of one to eight carbon atoms, benzyl,
  • R 12 is selected from straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from straight chain or branched chain alkyl containing one to four carbon atoms and cycloalkyl containing three to six carbon atoms; and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; and R is selected from hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl containing one to four carbon atoms, straight chain or branched
  • R 2 is selected from hydrogen, straight chain or branched chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy of one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R is independently selected from straight chain or branched chain alkoxy of one to four carbon atoms, halogen, and straight chain or branched chain alkyl of one to four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R 3 groups together
  • R 14 is -CHR x R y wherein R y is hydrogen or a carbon-carbon bond, with the proviso that when R y is hydrogen R x is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1 -alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, or 2-, 3-, or 4-pyridyl, and with the further proviso that when R y is a carbon-carbon bond R y and R x together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms; R 24 is selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein
  • R 1 is selected from hydrogen; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to
  • R T are independently selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen;
  • X is selected from alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-py ⁇ olidino, alkylthio of one to four carbon atoms; and R 5 is selected from hydrogen, straight chain
  • R ⁇ 6 is selected from hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing
  • Z is selected from -(CH 2 ) P - wherein p is 1 to 4; -(CH 2 )a-C(R ⁇ RE)(CH 2 ) b -, wherein a and b are integers and a+b is 0 to 3, RD is hydrogen or alkyl of one to four carbon atoms, and R E is selected from alkyl of one to four carbon atoms, hydroxy, -ORp wherein R F is alkyl of one to four carbon atoms, and -NR G R' G wherein R G and R' G are independently hydrogen or alkyl of one to four carbon atoms; and -(CH 2 ) a -(Y)-(CH 2 ) b - wherein a and b are integers and a+b is 0 to 3, and Y is O, S, or -NR J - wherein R is hydrogen or alkyl of one to four carbon atoms; q is O or 1; and R 8 is selected from alkyl of
  • the IRM compound can be chosen from thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, thiazolonaphthyridine amines and oxazolonaphthyridine amines defined by Formula IX below:
  • R 19 is selected from oxygen, sulfur and selenium;
  • R 29 is selected from -hydrogen; -alkyl; -alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-N(R 59 ) 2 ; -alkyl-N 3 ; -alkyl-O-C(O)-N(R 59 ) 2 ; -heterocyclyl; -alkyl-X-heterocyclyl; -alkenyl-X-heterocyclyl; -aryl; -alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl; and -alkenyl-X
  • R 110 is selected from: - hydrogen; -C 1-20 alkyl or C 2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-C ⁇ -20 alkyl; -O-(C 1-20 alkyl) 0-1 -aryl; -O-(C 1-2 o alky ⁇ o-i-heteroaryl; -O-(C 1-2 o alkyl)o- ⁇ -heterocyclyl; -CO-O-C ⁇ -20 alkyl; -S(O)o -2 -C ⁇ -20 alkyl; -S(O) 0-2 -(C 1-2 o alkyl) 0-1 -ary
  • R 21 o is selected from: -hydrogen; -Ci-io alkyl; -C 2-10 alkenyl; -aryl; -C ⁇ -10 alkyl-O-C ⁇ -io alkyl; -C 1-10 alkyl-O-C 2-10 alkenyl; and -C 1-10 alkyl or C 2 .
  • each R 310 is independently selected from hydrogen and C 1-10 alkyl; and each R is independently selected from hydrogen, C 1-10 alkyl, C 1-10 alkoxy, halogen and trifluoromethyl;
  • B is -NR-C(R) 2 -C(R) 2 -C(R) 2 -; -C(R) 2 -NR-C(R) 2 -C(R) 2 -; -C(R) 2 -C(R) 2 -NR-C(R) 2 - or -C(R) 2 -C(R) 2 -C(R) 2 -NR-;
  • R ⁇ i is selected from: - hydrogen; -C 1-2 o alkyl or C 2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-C ⁇ -20 alkyl; -O-(C 1-20 alkyl) 0-1 -aryl; -O-(C 1-20 alkyl) 0-1 -heteroaryl; -O-(C 1-20 alkyl) 0-1 -hetero
  • the IRM compound can be chosen from lH-imidazo[4,5- c]quinolin-4-amines and tetrahydro- lH-imidazo[4,5-c]quinolin-4-amines defined by Formulas XII, XIII and XIV below:
  • R 112 is -alkyl-NR ⁇ -CO-Rm or -alkenyl-NR 312 -CO- R412 wherein R 12 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -alkynyl; -(alkyl) 0-1 -aryl; -(alkyl)o- ⁇ -(substituted aryl); -(alkyl)o -1 -heteroaryl; -(alky ⁇ o- ⁇ -(substituted heteroaryl); -O-alkyl; -O-(alkyl) 0-1 -aryl; -O-(alkyl) 0-1 -(substituted aryl); -O-(alkyl) 0-1 -heteroaryl; -O-(al
  • R ⁇ i3 is -alkyl-NR 313 - SO 2 -X-R413 or -alkenyl-NR 313 - SO 2 -X-R413 ;
  • X is a bond or -NR 513 -;
  • R 413 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl)o- ⁇ -aryl; -O-(alkyl)o- ⁇ -substituted aryl; -O-(alky
  • R 2 i 3 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; - alkyl-O-alkyl; - alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R 3 ⁇ 3 ) 2 ; -CO-N(R 313 ) 2 ; -CO-C 1-10 alkyl; -CO-O-Ci-io alkyl; -N 3 ; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substituted ary
  • X is a bond, -CO- or -SO 2 -;
  • R 41 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyi) 0- i-aryl; -O-(alkyl) 0- -substituted aryl; -O
  • the IRM compound can be chosen from lH-imidazo[4,5- c]quinolin-4-amines and tetrahydro- lH-imidazo[4,5-c]quinolin-4-amines defined by Formulas XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, and XXVI below:
  • X is -CHR 515 -, -CHR 515 -alkyl-, or -CHR 515 -alkenyl-;
  • R 5 is selected from: -R4i 5 -CR 31 5-Z-R 615 — alkyl; -R 4 is-CR 315 -Z-R 615 — alkenyl; -R 415 -CR 315 -Z-R 615 — aryl; -R 415 -CR 315 -Z-R 615 — heteroaryl; -R 15 -CR 315 -Z-R 615 — heterocyclyl; -R 415 -CR 315 -Z-H; -R4 15 -NR 715 -CR315-R615— alkyl; -R 4 ⁇ 5 -NR 715 -CR 315 -R 615 -aryl; -R 4 i 5 -NR 7 i 5 -CR3i5-R 6 i
  • R 116 is selected from: -R 416 -CR 316 -Z-R 616 — alkyl; -Ru ⁇ -CRsi ⁇ -Z-R ⁇ i ⁇ — alkenyl; -R 416 -CR 316 -Z-R 616 — aryl; -R 4 6 -CR 316 -Z-R 616 — heteroaryl; -R 416 -CR 316 -Z-R 616 — heterocyclyl; -R 416 — CR 316 -Z— H; -R4ie-NR.7i6 -CR 316 -R6 16 — alkyl; -R416- R716 -CR 3 i6-R6i ⁇ — lkenyl; -R 416 -NR 7 ⁇ 6 -CR 316
  • X is -CHR 317 -, -CHR 317 -alkyl-, or -CHR 31 -alkenyl-;
  • R 11 is selected from: -alkenyl; -aryl; and
  • R 217 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl- Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R 3 ⁇ 7 ) 2 ; -CO-N(R 317 ) 2 ; -CO-Ci-io alkyl; -CO-O-C 1-10 alkyl; -N 3 ; -aryl; -heteroaryl; -
  • X is -CHR 3 ⁇ 8 -, -CHR 3 s-alkyl-, or -CHR 3 ⁇ 8 -alkenyl- ;
  • R 118 is selected from: -aryl; -alkenyl; and
  • R 218 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y-aryl; - alkyl-Y- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R 318 ) 2 ; -CO-N(R 318 ) 2 ; -CO-C 1-10 alkyl; -CO-O-C 1-10 alkyl; -N 3 ; -aryl; -heteroaryl;
  • X is -CHR 3 ⁇ 9 ⁇ , -CHR 319 -alkyl-, or -CHR 3 ⁇ 9 -alkenyl-;
  • R 119 is selected from: -heteroaryl; -heterocyclyl; -R 419 - heteroaryl; and -R ⁇ g-heterocyclyl;
  • R 219 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl- Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R 319 ) 2 ; -CO-N(R 319 ) 2 ; -CO-C 1-10 alkyl; -CO-
  • X is -CHR 320 -, -CHR 320 -alkyl-, or -CHR 320 -alkenyl-;
  • R 120 is selected from: -heteroaryl; -heterocyclyl; -R ⁇ - heteroaryl; and -R 2o-heterocyclyl;
  • R 22 Q is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R 320 ) 2 ; -CO-N(R 320 ) 2 ; -CO-Ci-io alkyl; -CO-O-Ci-
  • each R 320 is independently H or C 1-10 alkyl; each Y is independently -O- or -S(O) 0-2 -; v is 0 to 4; and each R 2 o present is independently selected from C 1-10 alkyl, C 1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
  • X is -CHR 5 21-, -CHR 521 -alkyl-, or -CHR 521 -alkenyl-;
  • R 12 ⁇ is selected from: -R 42 i—NR 321 —SO 2 —R 621 — alkyl; -R421— NR321 — SO2— R ⁇ 2 ⁇ — alkenyl; -R 42 ⁇ -NR 321 -SO 2 -R 621 -aryl; -R 4 ⁇ -NR 321 -SO 2 -R 621 -heteroaryl; -R 421 -NR 321 -SO 2 -R 621 -heterocyclyl; -R421— NR 32 ⁇ — SO 2 — R-721 ; -R 421 -NR 32 ⁇ -SO 2 -NR 52 i-R 62 i-alkyl; -R 421 -NR 321 -SO 2 -NR 52 ⁇ -
  • R 122 is selected from: -R 422 —NR 322 —S ⁇ 2 —R 622 — alkyl; -R42 2 — NR 3 22 — SO 2 — R ⁇ 22 — alkenyl; -R 422 -NR 322 -S0 2 -R 622 -aryl; -R 422 -NR 322 -SO 2 -R 622 -heteroaryl; 5 -R 422 -NR 322 -SO 2 -R 622 -heterocyclyl; -R422 — NR322 — S O 2 — 7 2 2 ; -R 422 -NR 322 -SO 2 -NR 522 -R 622 -alkyl; -R 422 -NR 322 -SO 2 -NR 522 ;
  • X is -CHR 323 -, -CHR 323 -alkyl-, or -CHR 323 -alkenyl- Z is -S-, -SO-, or-SO 2 -;
  • R 123 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R 423 -aryl; -R 423 - heteroaryl; and -R 23 -heterocyclyl;
  • R2 23 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl-Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen;
  • X is -CHR 32 -, -CHR 324 -alkyl-, or -CHR 324 -alkenyl-;
  • Z is -S-, -SO-, or -SO 2 -;
  • Ri 2 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R ⁇ -aryl; -R 42 - heteroaryl; and -R 424 -heterocyclyl;
  • R 224 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen
  • X is -CHR 525 -, -CHR 525 -alkyl-, or -CHR 525 -alkenyl-;
  • R ⁇ 5 is selected from: -R 425 -NR 825 -CR 325 — NR 525 -Z-R 625 -alkyl; -R 25 -NR 82S -CR S25 — NR 525 -Z-R 625 -alkenyl; -R 425 -NR 825 -CR 325 — NR 525 -Z-R 62 s-aryl; -R 425 -NR 825 -CR 325 — NR 525 -Z-R 625 -heteroaryl; -R 25 -NRs 25 -CR 3 2 5 — NR 52 5-Z-R 6 2s-heterocycryl; -R425-NR 825 — CR 325 — NR 525 R72 5 ; -R 4
  • X is -CHR 526 -, -CHR 52 ⁇ -alkyl-, or -CHR 526 -alkenyl-;
  • R ⁇ 2 6 is selected from: -R 426 -NR 826 -CR 326 — NR 526 -Z-R 626 -alkyl; -R 426 -NR 826 -CR 326 — NR 526 -Z-R 626 -alkenyl; -R 426 -NR 826 -CR 326 — R 526 -Z-R 626 -aryl; -R 426 -NR 8 2 6 -CR 326 — NR 526 -Z-R62 6 -heteroaryl; -R 426 -NR 826 -CR 326 — NR 526 -Z-R 626 -heterocyclyl; -R426— NR 826 — CR 326 — NR 526 R 7 2 6 ;
  • R 626 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups;
  • R 726 is H or C MO alkyl which may be interrupted by a hetero atom, or R 726 can join with R 526 to form a ring;
  • R 826 is H, C MO alkyl, or arylalkyl; or R 26 and R 826 can join together to form a ring;
  • R 926 is C O alkyl which can join together with R 826 to form a ring;
  • each Y is independently -O- or -S(O) 0-2 -;
  • Z is a bond, -CO- or -SO 2 -;
  • v is 0 to 4;
  • each R 26 present is independently selected from C 1-10 alkyl, C 1-10 alkoxy, hydroxy, halogen, and trifluoromethyl; and pharmaceutically acceptable salts of any of the foregoing.
  • the IRM compound can be chosen from lH-imidazo[4,5- c]pyridin-4-amines defined by Formula XXVII below:
  • X is alkylene or alkenylene; Y is -CO- or-CS; Z is a bond, -O-, or -S-;
  • R 127 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl)o- ⁇ -aryl; -O-(alkyl)o -1 -(substituted aryl); 5 -O-(alkyl) 0-1 -heteroaryl; -O-(alkyl)
  • X is alkylene or alkenylene; Y is -SO2-; Z is a bond or -NR 628 -; R 128 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; 5 -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; 10 -O-(alkyl) 0-1 -aryl; -O-(alkyl)o- ⁇ -(substituted aryl); -O-(alkyl) 0-1 -heteroaryl; -O-(alkyl)o -1 -(
  • X is alkylene or alkenylene; Y is -CO- or -CS; Z is -NR 629 -, -NR 629 -CO-, -NR 629 -SO 2 -, or-NR 729 -; R 129 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl) 0-1 -aryl; -O-(alkyl)o-i-(substituted aryl); -O-(alkyl
  • X is -CH(R 530 )-, -CH(R 530 )-alkylene-, -CH(R 530 )-alkenylene-, or CH(R 530 )-alkylene-Y-alkylene-;
  • Y is -O-, or-S(O)o -2 -;
  • -W-R 13 o is selected from -O-R O ⁇ -S and -S(O)o -2 -R ⁇ 3 o-6;
  • Ri30- ⁇ - 5 is selected from -R 63 o-C(R 730 )-Z-R 830 — alkyl; -R 630 -C(R 730 )-Z-R 830 — alkenyl; -R 63 o-C(R 73 o)-Z-R 83 o— aryl; -R 630 -C(R 73 o) ⁇ Z-R 83 o— heteroaryl; -R
  • Q is a bond, -CO- or -SO 2 -;
  • A represents the atoms necessary to provide a 5- or 6-membered heterocyclic or heteroaromatic ring that contains up to three heteroatoms;
  • R 13 o -6 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R 630 -aryl; -R 63 o- heteroaryl; and -R 630 -heterocyclyl; each R 53 o is independently hydrogen, CMO alkyl, or C 2 - 10 alkenyl;
  • R 630 is alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups;
  • R 830 is a bond, alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups;
  • Ri03o is hydrogen or CMO alkyl; or R 930 and R 1030 can join together to form a ring selected from
  • R 1130 is CMO alkyl; or R 930 and R 1130 can join together to form a ring having the structure
  • R1 230 is C 2-7 alkylene which is straight chain or branched, wherein the branching does not prevent formation of the ring; and R2 3 o, R 330 and R 430 are independently selected from hydrogen and non-interfering substitutents; and pharmaceutically acceptable salts thereof.
  • Illustrative non-interfering R 230 substituents include: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkylene- Y-alkyl; -alkylene- Y- alkenyl; -alkylene- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R 530 ) 2 ; -C(O)-Cuo alkyl; -C(O)-O-Ci -10 alkyl; -N 3 ; -aryl; -heteroaryl; -heterocyclyl; -C(O)-aryl; and -C(O)-heteroaryl.
  • Illustrative non-interfering R 33 o and R 430 substitutents include: CM O alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, C 1-10 alkylthio, amino, alkylamino, dialkylamino, halogen, and nitro.
  • the IRM compound can be chosen from IH-imidazo dimers of the formula (XXXI): wherein: A is a divalent linking group selected from the group consisting of: straight or branched chain C -20 alkylene; straight or branched chain C 4-20 alkenylene; straight or branched chain C -20 alkynylene; and -Z-Y-W-Y-Z-; each Z is independently selected from the group consisting of: straight or branched chain C 2-2 o alkylene; straight or branched chain C -2 0 alkenylene; and straight or branched chain C 4- 2o alkynylene; any of which may be optionally interrupted by -O-, -N(R 531 )-, or -S(O) 2 -; each Y is independently selected from the group consisting of: a bond; -N(R 53 ⁇ )C(O)N(R 5 3i)-; -S(O) 2 N(R 53 ⁇ )-
  • each R is independently selected from the group consisting of C 1-4 alkyl, C ⁇ -4 alkoxy, and halogen; and Q is selected from the group consisting of a bond, -CH 2 -, and -O-;
  • R 31 is selected from the group consisting of: -hydrogen; -alkyl; -allcenyl; -aryl; -substituted aryl;
  • each R 631 is independently hydrogen or C MO alkyl; R 731 is C 3-8 alkylene; and X is -O- or -S-; with the proviso that if W is -C(O)-, -S(O) 2 -, -OC(O)O-, or -N(R 531 )C(O)N(R 53 ⁇ )- then each Y is a bond; and pharmaceutically acceptable salts thereof.
  • the IRM compound can be chosen from 6-, 7-, 8-, or imposition aryl or heteroaryl substituted lH-imidazo[4,5-c]quinolin-4-amines of the following Formula (XXXII):
  • R 32 is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; n is O or 1; Ri 32 and R 232 are independently selected from the group consisting of hydrogen and non-interfering substitutents; R 332 is selected from the group consisting of: -Z-Ar, -Z-Ar'-Y-R 432 , -Z-Ar'-X-Y-R 432 , -Z-Ar'-X-R 532 ; Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, aryl
  • Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene;
  • R 32 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of al
  • R 532 is selected from the group consisting of:
  • Q is selected from the group consisting of a bond, -C(R 63 2)-, -C(R 632 )-C(R 632 ), -S(O) 2 -, -C(R 632 )-N(R 832 )-W-, -S(O) 2 -N(R 832 )-, -C(R 632 )-O-, and -
  • V is selected from the group consisting of -C(R 632 )-, -O-C(R 632 )-, -N(R 8 3 2 )-C(R 63 2)-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and— S(O) 2 -; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7; and pharmaceutically acceptable salts thereof.
  • Illustrative non-interfering R 132 substituents include: -R432, -X-R 32 , -X-Y-X-Y-R4 32 , and -X-R 532 ; wherein: each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; each Y is independently selected from the group consisting of: -S(O) 0 -2-, -S(O) 2 -N(R 832 )-, -C(R 632 )-, -C(R 632 )-O-, -O-C(R 632 )-, -O-C(O)-O-, -N(R 832
  • alkyl 32 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, hal
  • R 532 is selected from the group consisting of:
  • R 432 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen
  • V is selected from the group consisting of -C(R 632 )-, -O-C(R 63 2)-, -N(R 83 2)-C(R 632 )-, and -S(O) 2 -;
  • W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is ⁇ 7;
  • non-interfering means that the ability of the compound or salt to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substituent.
  • alkyl alkenyl
  • alkynyl alkynyl
  • alk- alk-
  • these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms.
  • Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms.
  • Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl.
  • alkylene", “alkenylene”, and “alkynylene” are the divalent fonris of the "alkyl", “alkenyl", and “alkynyl” groups defined above.
  • alkylenyl alkenylenyl
  • alkynylenyl are the divalent forms of the "alkyl”, “alkenyl”, and “alkynyl” groups defined above.
  • an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached.
  • haloalkyl is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix "halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • fluoroalkyl is inclusive of groups that are substituted by one or more fluorine atoms, including perfluorinated groups (e.g., trifluoromethyl) .
  • aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • the te ⁇ n "heteroatom” refers to the atoms O, S, or N.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N).
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, rriazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on.
  • heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like.
  • arylene is the divalent forms of the "aryl,” “heteroaryl,” and “heterocyclyl” groups defined above.
  • arylenyl is the divalent forms of the "aryl,” “heteroaryl,” and “heterocyclyl” groups defined above.
  • an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached. Unless otherwise specified, the aryl, heteroaryl, and heterocyclyl groups of
  • Formulas IX - XXX can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbon
  • any other groups are identified as being “substituted” or “optionally substituted”, then those groups can also be substituted by one or more of the above enumerated substituents.
  • each group or substituent or variable is independently selected, whether explicitly stated or not.
  • each R 631 group is independently selected.
  • an R2 3 2 and an R 332 group both contain an R- 132 group, each R 32 group is independently selected.
  • more than one Y group is present (i.e.
  • R 232 and R 332 both contain a Y group) and each Y group contains one or more Rs 32 groups, then each Y group is independently selected, and each R 832 group is independently selected.
  • the immune response modifier is selected from the group consisting of imidazoquinolme amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, IH- imidazo dimers
  • the immune response modifier is selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, and combinations thereof.
  • the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinoline amines, amide substituted tetrahydroimidazoquinoline amines, amide substitute
  • the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, thioether substituted imidazoquinoline amines, 7-aryl substituted imidazoquinoline amines, 7-heteroaryl substituted imidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, and combinations thereof.
  • the immune response modifier is a sulfonamide substituted imidazoquinoline amine.
  • the immune response modifier is selected from the group consisting of: N 1 - ⁇ 4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yljbutyl ⁇ -4-fluoro- 1 -benzenesulfonamide,
  • the immune response modifier is selected from the group consisting of:
  • the immune response modifier is N- ⁇ 2-[4-amino-2- (ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l-dimethylethyl ⁇ methanesulfonamide and pharmaceutically acceptable salts thereof.
  • the IRM compounds and salts thereof described herein include any of their pharmaceutically acceptable forms, such as isomers (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like.
  • the invention specifically includes the use of each of the compound's enantiomers as well as racemic combinations of the enantiomers.
  • the immune response modifier can, for example, be a salt of an acid selected from the group consisting of a carboxylic acid, a halo acid, sulfuric acid, phosphoric acid, dicarboxylic acid, tricarboxylic acid, and combinations thereof.
  • the salt of the immune response modifier can be a salt of an acid selected from the group consisting of hydrobromic acid, hydrochloric acid, lactic acid, glutamic acid, gluconic acid, tartaric acid, succinic acid, and combinations thereof.
  • the immune response modifier is substantially completely dissolved at a therapeutic level (i.e., therapeutically effective amount) in the foraiulation at room temperature. This amount is effective to treat and/or prevent a specified condition (e.g., allergic rhinitis, a viral infection, sinusitis, asthma).
  • the amount of the IRM compound present in an aqueous (preferably, sprayable) formulation of the invention will be an amount effective to provide a desired physiological effect, e.g., to treat a targeted condition (e.g., reduce symptoms of allergic rhinitis), to prevent recu ⁇ ence of the condition, or to promote immunity against the condition.
  • a targeted condition e.g., reduce symptoms of allergic rhinitis
  • an amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more manifestations of viral infections, such as viral load, rate of virus production, or mortality as compared to untreated control animals.
  • the amount of an IRM compound that will be therapeutically effective in a specific situation will depend on such things as the activity of the particular compound, the dosing regimen, the application site, the particular formulation and the condition being treated.
  • the amount or concentration of the IRM compound (or combinations of IRMs) is at least 0.0001% by weight (wt-%), in other embodiments, at least 0.001 wt-%, in other embodiments at least 0.01 wt-%, in other embodiments at least 0.1 wt-%, in other embodiments at least 0.5 wt- %, in other embodiments at least 1.0 wt-%, and in other embodiments at least 1.5 wt-%, based on the total formulation weight.
  • the amount of the IRM compound (or combinations of IRMs) is at most 5.0 wt-%, and in other embodiments at most 3.0 wt-%, based on the total formulation weight.
  • Formulations of the invention include a hydrophilic viscosity enhancing agent, preferably one that is a mucoadhesive.
  • hydrophilic means the agent is water soluble or water dispersible.
  • hydrophilic viscosity enhancing agents include: cellulose ethers such as hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, and carboxymethylcellulose sodium; polysaccharide gums such as xanthan gum and carrageenan; and acrylic acid polymers (i.e., homopolymers and copolymers) made from acrylic acid crosslinked with, for example, allyl sucrose or allyl pentaerythriol such as those polymers designated as carbomers in the United States Pha ⁇ nacopoeia. Various combinations of these can be used if desired.
  • Certain embodiments of the present invention include an acrylic acid polymer (i.e., polyacrylic acid polymer), carboxymethylcellulose sodium, xanthan gum, and combinations thereof.
  • carboxymethylcellulose sodium i.e., polyacrylic acid polymer
  • carboxymethylcellulose sodium i.e., polyacrylic acid polymer
  • xanthan gum i.e., polyacrylic acid polymer
  • carboxymethylcellulose sodium i.e., polyacrylic acid polymer
  • carboxymethylcellulose sodium i.e., polyacrylic acid polymer
  • xanthan gum i.e., xanthan gum
  • Various grades of carboxymethylcellulose sodium are commercially available that have differing aqueous viscosities. Aqueous 1% weight by volume (w/v) solutions with viscosities of 5-13,000 cps may be obtained.
  • Examples include carboxymethylcellulose sodium, high viscosity, USP (CA194); carboxymethylcellulose sodium, medium viscosity, USP (CA192); and carboxymethylcellulose sodium, low viscosity, USP (CA193); all of which are available from Spectrum Chemicals and Laboratory Products, Inc., Gardena, CA, USA; and AKUCELL AF 3085 (high viscosity), AKUCELL AF 2785 (medium viscosity), and AKUCELL AF 0305 (low viscosity), all of which are available from Akzo Nobel Functional Chemicals, Amersfoort, The Netherlands.
  • grades of carboxymethylcellulose sodium having a low aqueous viscosity are prefened.
  • the hydrophilic viscosity enhancing agent is negatively charged. These include carboxymethylcellulose sodium, xanthan gum, and the carbomers. In some embodiments of the invention, the hydrophilic viscosity enhancing agent includes carboxylic acid and/or carboxylate groups. Examples of such agents include carboxymethylcellulose sodium, xanthan gum, and the acrylic acid polymers. In some embodiments of the invention the hydrophilic viscosity enhancing agent is uncrosslinked. Examples of such agents include cellulose ethers and xanthan gum.
  • the hydrophilic viscosity enhancing agent is present in formulations of the invention in an amount sufficient to bring the viscosity to a level of less than 100 centipoise (cps), preferably less than about 50 cps, more preferably less than about 20 cps, and most preferably less than about 10 cps.
  • the viscosity is determined at 20 ⁇ 0.1 °C 1 1 using a double-gap concentric cylinder at a controlled strain rate of 10 s " to 1000 s " .
  • the amount or concentration of the hydrophilic viscosity enhancing agent is at least 0.01 wt-%, in other embodiments at least 0.025 wt-%, in other embodiments at least 0.05 wt-%, and in other embodiments at least 0.1 wt-%, based on the total formulation weight. In certain embodiments, the amount of the viscosity enhancing agent (or combinations of such agents) is at most 2.0 wt-%, in other embodiments at most 1.0 wt-%, in other embodiments at most 0.5 wt-%, and in other embodiments at most 0.25 wt-%, based on the total formulation weight.
  • pH Adjusting Agents and Buffers Formulations of the invention can additionally include a pharmaceutically acceptable pH adjusting agent to adjust the pH of the formulation to the desired range.
  • the pH is at least 4.
  • the pH is no greater than 8, usually no greater than 7, and in some cases no greater than 6.
  • the pH adjusting agent may be any pharmaceutically acceptable acid or base. Examples of suitable pH adjusting agents include hydrochloric acid, sodium hydroxide, tromethamine, and potassium hydroxide. Combinations of such agents can be used if desired.
  • the formulations of the invention can additionally include a pharmaceutically acceptable buffer to maintain the pH of the formulations in the desired range (generally, 4 to 8, usually, 4 to 7, and often, 4 to 6).
  • the buffer maybe any pharmaceutically acceptable buffer that provides one or more of the desired pH ranges.
  • suitable buffers include buffers containing lactic acid, tartaric acid, citric acid, and succinic acid. Combinations of buffers can be used if desired.
  • the buffers can also function as tonicity adjusting agents.
  • Cosolvents The formulations of the invention can additionally include a water-miscible cosolvent.
  • the water-miscible cosolvent assists in dissolving the immune response modifier or a salt thereof.
  • the cosolvent can be a single component or a combination.
  • cosolvents examples include propylene glycol, glycerin, polyethylene glycol 400, diethylene glycol monoethyl ether, and combinations thereof.
  • the cosolvent (or combination of cosolvents) is present in an amount of at least 5 wt-%, in other embodiments at least 10 wt-%, and in other embodiments at least 15 wt-%, based on the total weight of the formulation.
  • the cosolvent (or combination of cosolvents) is present in an amount of at most 25 wt-%, and in other embodiments at most 20 wt-%, based on the total weight of the formulation. In certain preferred formulations, the cosolvent is present in an amount of 5 wt-% to 15 wt-%. In certain embodiments, if a cosolvent is used, then water is present in an amount of at least 75 wt-%, and in other embodiments at least 80 wt-%, based on the total weight of the formulation. In certain embodiments, if a cosolvent is used, then water is present in an amount of at least 90 wt-%, and in other embodiments at least 95 wt-%, based on the total weight of the formulation.
  • the formulations of the invention can additionally include a preservative.
  • the preservative includes one or more compounds that inhibit microbial growth (e.g., fungal and bacterial growth) within the composition.
  • Suitable preservatives include benzalkonium chloride, benzethonium chloride, methylparaben, propylparaben, phenyl ethyl alcohol, and combinations thereof.
  • the preservative is benzalkonium chloride.
  • Certain water-miscible cosolvents, such as glycerin or propylene glycol also have antimicrobial properties when present in amounts greater than 15 wt-%.
  • the preservative (or combination of preservatives) is present in an amount of at least 0.005 wt-%, in other embodiments at least 0.01 wt-%, and in other embodiments at least 0.02 wt-%, based on the total weight of the formulation, hi certain embodiments, the preservative (or combination of preservatives) is present in an amount of at most 0.5 wt-%, and in other embodiments at most 0.2 wt-%, based on the total weight of the formulation.
  • Chelating agents can additionally include a chelating agent.
  • Chelating agents are compounds that complex metal ions.
  • suitable chelating agents include ethylenediaminetetracetic acid (EDTA) and derivatives thereof such as the disodium salt, and ethylenediaminetetracetic acid disodium salt dihydrate.
  • EDTA ethylenediaminetetracetic acid
  • the chelating agent is ethylenediaminetetracetic acid disodium salt dihydrate (edetate disodium).
  • the chelating agent (or combination of chelating agents) is present in an amount of at least 0.005 wt-%, in other embodiments at least 0.01 wt-%, in other embodiments at least 0.02 wt-%, and in other embodiments at least 0.05 wt-%, based on the total weight of the formulation. In certain embodiments, the chelating agent (or combination of chelating agents) is present in an amount of at most 0.5 wt-%, and in other embodiments at most 0.2 wt-%, based on the total weight of the formulation.
  • Formulations of the invention can be applied to the respiratory tract (e.g., nasal passages) of a subject (particularly, e.g., a mammal).
  • the therapeutic effect of the IRM compound may extend only to the superficial layers of the respiratory tract (e.g., nasal passages) or to tissues below the surface.
  • another aspect of the present invention is directed to a method for the treatment of a nasal-associated condition by applying (preferably by spraying) one of the foregoing formulations into the nasal passages.
  • a "nasal-associated condition” is defined as a condition in which an extrinsic protein (i.e., allergen, viral, bacterial, fungal) contacts the nasal mucosa creating an allergic and/or flu-like immune response. Examples include allergic rhinitis, sinusitis, asthma, and influenza.
  • Allergic rhinitis is a nasal-associated condition in which a subject is sensitized to one or more antigens (i.e., allergens). When a sensitized subject is re-exposed to an antigen, mediators are released quickly leading to rhino ⁇ hea, increased nasal mucosal secretions, increased vascular permeability and vasodilation in the subject's nasal mucosa.
  • IRMs have the ability to desensitize a subject to one or more antigens. As can be seen in
  • Example 61 which contains IRM 22, when dosed at 0.375 wt- %, was able to inhibit 95% of nasal perfusion of Evan's blue when the sensitized subjects were re-exposed to the antigen ovalbumin.
  • the present invention includes use of the formulations described herein for treating and/or preventing allergic rhinitis, treating and/or preventing a viral infection, treating and or preventing sinusitis, and treating and/or preventing asthma.
  • the formulations would generally be delivered to the lung via inhalation, e.g., by a nebulizer or spray.
  • the present invention also provides a method of desensitizing a subject to an antigen, the method involves administering to the subject an IRM compound in a formulation of the present invention, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen.
  • the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen.
  • the formulations of the present invention can also be used administered together
  • the methods of the present invention include administering sufficient formulation to provide a dose of IRM compound of, for example, from 100 ng kg to 50 mg/kg to the subject, although in some embodiments the methods may be performed by administering IRM compound in concentrations outside this range.
  • the method includes administering sufficient formulation to provide a dose of IRM compound of from 10 ⁇ g/kg to 5 mg/kg to the subject, for example, a dose of from 100 ⁇ g/kg to 1 mg/kg.
  • the above-described formulations are particularly advantageous for application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic abso ⁇ tion of the IRM.
  • IRM COMPOUNDS The IRM compounds that were used to prepare the aqueous formulations are shown in Table 1 below. Table 1
  • IRM 21 N- ⁇ 2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro- U.S. 6,331,539* lH-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl ⁇ methanesulfonamide
  • IRM 32 N- ⁇ 2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- U.S. 6,573,273" c] quinolin- 1 -yl] -1,1 -dimethylethyl ⁇ -N'-cyclohexylurea
  • IRM 33 N- ⁇ 2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- U.S. 6,756,382 w c] quinolin- 1 -yl] -1,1- dimethylethyl ⁇ cyclohexanecarboxamide
  • IRM 37 N- ⁇ 2-[4-amino-2-(ethoxymethyl)-6,7-dimethyl- 1H- U.S. 6,545,017# imidazo[4,5-c]pyridin-l -yl]- 1 , 1 -dimethylethyl ⁇ -N'- phenylurea
  • Carboxymethylcellulose sodium, low viscosity, USP (CMC) Carboxymethylcellulose sodium, low viscosity, USP (CMC)
  • Hydroxypropyl methylcellulose (hypromellose, 2910, 50 cps, USP; HPMC) Acetic acid, NF
  • Ethylenediaminetetraacetic acid disodium salt dihydrate (Edetate disodium, USP) 1 N Sodium hydroxide, NF (1 N NaOH)
  • the aqueous formulations were prepared using the following general method.
  • the hydrophilic viscosity enhancing agent was hydrated in water (about 50% of total) for about 20 minutes with stirring.
  • the edetate sodium was added and mixed until dissolved.
  • the resulting solution was mixed with the benzalkonium chloride.
  • the buffering agent (if used) and the cosolvent (if used) were mixed with water; the IRM compound was added to this combination and stirred. The two combinations were combined and mixed.
  • a pH adjuster was added, as necessary, to adjust each formulation to the desired pH. Finally, water was added to each formulation to adjust to the final formulation weight.
  • a drug solution or vehicle (control groups) is administered by nasal instillation.
  • Nasal instillation is performed by lightly anesthetizing an animal with a combination of a solution consisting of 10 mL of ketamine HCI (100 mg/mL) and acepromazine (10 mg/mL) dosed at a rate of 60-90 mg/Kg.
  • a solution of drug or vehicle is instilled in a drop-by-drop manner (each drop is cleared from the nasal passage before the next drop is administered) to each nare (10 ⁇ L/nare) for a total of 20 ⁇ L/animal. Ophthalmic ointment will be used in conjunction with the ketamine/xylazine combination.
  • the animal is placed back into the cage and becomes fully alert within 1-2 hours. Twenty (20) hours later the animal is dosed a second time using the same procedure. Four (4) hours after the second dosing, animals are placed inside an inverted desiccator jar, which is placed onto a Plexiglas platform forming a chamber with a diameter of 6 inches (15 cm) and a height of 6 inches (15 cm).
  • the platform has several ports which allow for aerosolization, for monitoring breathing patterns, for exhausting aerosolized particles and for providing a constant flow of air into the chamber from a continuous air source to prevent hypoxia.
  • Aerosolization of H 2 O, ovalbumin ( ⁇ 100 mg/mL) is done using a DeVilbiss Ultra-Neb large volume ultrasonic nebulizer system for 10-30 minutes in duration. Following ovalbumin aerosol challenge, the animals are returned to their cages. Twenty-four (24) hours after the ovalbumin challenge, the animals are initially anesthetized using a combination of 10 mL of ketamine HCI (100 mg/mL) and 2 mL of acepromazine maleate (10 mg/mL) dosed intraperitoneally at ⁇ 60-90 mg/Kg (dose to effect).
  • lidocaine is injected subcutaneously over the trachea and surrounding neck area. An incision is made midline over the trachea and the internal or external jugular vein is exposed and cannulated (INTRAMEDIC polyethylene tubing size
  • PE50 is used with a 23g luer stub adapter). The trachea is exposed and a modified tracheotomy is performed (a longitudinal incision about 5 mm long). A 6f-tracheal catheter is inserted caudally and a catheter (PE40-60) inserted cranally. Both tubes are tied in place and the animal is hooked up to a HARVARD small animal respirator ( ⁇ 58 breaths/min, 4cc stroke volume). At this point the animal is given 0.1-0.25 mL of a solution consisting of 0.3 mL sodium pentobarbital and 0.7 mL saline (dose to effect). Animals in the drug treatment groups and in the ovalbumin control group receive an additional challenge with ovalbumin.
  • a nasal perfusion line is attached to a HARVARD compact infusion pump set to deliver 0.2 mL/min and a 10% solution of ovalbumin in saline is manually "pushed” through the nasal infusion catheter slowly until 1 or 2 drops of the ovalbumin solution is expressed through the nose.
  • the line is attached to the infusion pump, the pump is turned on and allowed to run for 3 min at a rate of 0.2 mL/min. Animals in the saline control group are treated with saline alone. After the 3 minute exposure period the ovalbumin solution is flushed out of the line and nasal cavities with air.
  • the nasal infusion catheter is then filled with pH adjusted PBS (about pH 5) and PBS is manually "pushed” through the nasal perfusion catheter slowly until 1 or 2 drops of PBS is expressed through the nose.
  • the line is attached to the infusion pump and the pump is allowed to run for 3 min.
  • Evans Blue dye (1 mL of 1.0%) is injected intravenously; the infusion pump is turned on and a timer is started for a 40 min collection period.
  • the nasal perfusate is collected in a 15 mL-collection tube.
  • One sample is collected (8 mLs for 40 min).
  • the amount of Evans blue dye in the sample is determined spectrophotometrically (610 nm wavelength). The percent inhibition is calculated using the equation below: n / ⁇ , ., J. .
  • Examples 18 - 23 A series of aqueous formulations containing IRM 2 were prepared and tested in a model of allergic rhinitis using the test method described above. Table 5 shows the composition of each formulation and the test result.
  • Examples 24 - 131 A series of aqueous formulations containing IRMs were prepared and tested in a model of allergic rhinitis using the test method described above. Each IRM was formulated using one or more of the vehicles shown in Table 6. Table 7 shows the composition of each formulation and the test result.
  • Example 132 IRM 1 was prepared as a 0.375% solution formulation capable of being nasally administered via a spray pump.
  • the formulation vehicle was prepared as follows:
  • Carboxymethylcellulose sodium, low viscosity, USP was hydrated in water (about 50% of total) for 20 minutes with stirring.
  • the EDTA was added and dissolved.
  • the CMC/EDTA solution was mixed with the benzalkonium chloride to form a CMC/EDTA/BAC solution.
  • the lactic acid and PEG 400 were mixed with water.
  • IRM 1 formulation IRM 1 was dissolved into the lactic acid/PEG 400 solution.
  • the CMC/EDTA/BAC solution was mixed with lactic acid/PEG 400 solution to prepare the Vehicle formulation.
  • the CMC/EDTABAC solution was mixed with lactic acid/PEG 400/IRM 1 solution to prepare the IRM 1 formulation.
  • Fisher 344 rats (Charles River Laboratories, Raleigh, NC) were divided into six treatment groups. Rats in each group were infected intranasally with humanized, non-lethal influenza virus. 24 hours after infection, viral titers were measured in nasal lavage fluid and whole lung homogenates. The influenza virus and methods for measuring viral titers are described in Burleson, Gary L., "Influenza Virus Host Resistance Model for Assessment of hnmunotoxicity,
  • *lx one dose of treatment provided four hours before viral infection. **2x: one dose of treatment 24 hours (Day -1) before viral infection, second treatment four hours before viral infection (Day 0).
  • Example 133 A formulation containing 4-amino- ⁇ , ⁇ -dimethyl-2-ethoxymethyl-lH- imidazo[4,5-c]quinoline-l-ethanol (U.S. Pat. No. 5,389,640; Example 99) was prepared using the method described above. The composition is shown in Table 11 below.
  • the viscosity of the formulation was measured using a controlled stress step test.
  • Rheometer ⁇ aake RSI 50; sensor: double-gap concentric cylinder (DG41); gap: 5.100 mm; sample size: sufficient to fill the sample holder; temperature 20.0 ⁇ 0.1 °C; initial stress: 0.10 Pa; final stress: 1.20 Pa.
  • Three (3) separate samples were measured. The measured viscosity was 1.4 cps for each of the samples.

Abstract

Pharmaceutical formulations in an aqueous (preferably, sprayable) formulaiton including an immune response modifier (IRM), such as those chosen from imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridine amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, and 1H-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, are provided. In one embodiment, the aqueous formulations are advantageous for treatment and/or prevention of allergic rhinitis, viral infections, sinusitis, and asthma.

Description

FORMULATIONS CONTAINING AN IMMUNE RESPONSE MODIFIER
CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application Serial No. 60/493,109, filed August 5, 2003, which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention is directed to pharmaceutical formulations that include at least one immune response modifier, such as those chosen from imidazoquinolme amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, and thiazolonaphthyridine amines, for example. Embodiments of the present invention are directed to aqueous (preferably sprayable) solutions. Other embodiments of the present invention are directed to various methods of use of the aqueous formulations.
BACKGROUND Many imidazoquinolme amine, imidazopyridine amine, 6,7-fused cycloalkylimidazopyridme amine, 1,2-bridged imidazoquinolme amine, thiazoloquinoline amine, oxazoloquinoline amine, thiazolopyridine amine, oxazolopyridine amine, imidazonaphthyridine amine, imidazotetrahydronaphthyridine amine, and thiazolonaphthyridine amine compounds have demonstrated potent immunostimulating, antiviral and antitumor (including anticancer) activity, and have also been shown to be useful as vaccine adjuvants and treatment of TH2 -mediated diseases. These compounds are hereinafter collectively referred to as "IRM'' (immune response modifier) compounds. The mechanism for the immunostimulatory activity of these IRM compounds is thought to be due in substantial part to enhancement of the immune response by induction of various important cytokines (e.g., interferons, interleukins, tumor necrosis factor, etc.). Such compounds have been shown to stimulate a rapid release of certain monocyte/macrophage-derived cytokines and are also capable of stimulating B cells to secrete antibodies, which play an important role in these IRM compounds' activities. One of the predominant immunostimulating responses to these compounds is the induction of interferon (LFN)-α production, which is believed to be very important in the acute antiviral and antitumor activities seen. Moreover, up regulation of other cytokines such as, for example, tumor necrosis factor (TNF), Interleukin-1 (IL-1), IL-6, and IL-12 also have potentially beneficial activities and are believed to contribute to the antiviral and antitumor properties of these compounds. Although some of the beneficial effects of IRMs are known, the ability to provide therapeutic benefit via topical application of an IRM compound for treatment of a particular condition at a particular location may be hindered by a variety of factors. These factors include irritation of the dermal or mucosal surface to which the formulation is applied, ciliary clearance of the formulation, formulation wash away, insolubility and/or degradation of the IRM compound in the formulation, physical instability of the formulation (e.g., separation of components, thickening, precipitation/agglomerization of active ingredient, and the like), and poor permeation, for example. Accordingly, there is a continuing need for new methods and formulations to provide the greatest therapeutic benefit from this class of compounds.
SUMMARY The present invention is directed to aqueous formulations and methods of use. Preferably, such formulations are sprayable. Such formulations include: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 Centipoise (cps) at room temperature. Formulations of the present invention can provide desirable vehicles for immune response modifier compounds and can allow for easier manufacture and increased residence time of the immune response modifier, particularly on mucosal tissue. In another embodiment, the present invention provides an aqueous sprayable formulation that includes: an immune response modifier selected from the group consisting of imidazoquinolme amines, tetrahydroimidazoqumolme amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, 1H- imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; water; and a hydrophilic viscosity enhancing agent selected from the group consisting of cellulose ethers, polysaccharide gums, acrylic acid polymers, and combinations thereof; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature. The present invention also provides methods of using the formulations of the present invention. In one embodiment, the present invention provides a method for delivering an immune response modifier to a nasal passage of a subject. The method includes: selecting a formulation that includes: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherem the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature; and applying the selected formulation into a nasal passage. Other methods of the present invention are directed to methods of treating and/or preventing allergic rhinitis by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human). Other methods of the present invention are directed to methods of treating and/or preventing a viral infection by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human). Other methods of the present invention are directed to methods of treating and/or preventing sinusitis by applying (e.g., spraying) a formulation of the present invention into a nasal passage of a subject (typically, an animal, preferably, a mammal, and more preferably, a human). Other methods of the present invention are directed to methods of treating and/or preventing asthma by applying (e.g., spraying) a formulation of the present invention into the respiratory tract of a subject (typically, an animal, preferably, a mammal, and more preferably, a human). The present invention also provides a method of desensitizing a subject to an antigen. The method involves administering to the subject an IRM compound in a formulation of the present invention, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen. Preferably, the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen. The term "solution" refers to a combination of two or more substances uniformly dispersed throughout a single phase, so that the combination is homogeneous at the molecular or ionic level. The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, an aqueous formulation that comprises "an" immune response modifier can be interpreted to mean that the formulation includes "one or more" immune response modifiers. Similarly, a formulation comprising "a" hydrophilic viscosity enhancing agent can be interpreted to mean that the formulation includes "one or more" hydrophilic viscosity enhancing agents. Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.). The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments, m several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a bar graph comparing viral titers in rats after treatment with vehicle, LFN- α, or IRM compound four hours before viral challenge. Fig. 2 is a bar graph comparing viral titers in rats after treatment with vehicle, LFN- α, or IRM compound twenty-four hours and again at four hours before viral challenge.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The present invention provides aqueous (preferably, sprayable) formulations and methods of use. Such formulations include: an immune response modifier (IRM); water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature. Such formulations are in solution form at room temperature (i.e., 25°C-30°C). That is, the formulations include two or more substances uniformly dispersed throughout a single phase, so that the combination is homogeneous at the molecular or ionic level. Also, such formulations are sufficiently low in viscosity (less than 100 centipoise (cps)) at room temperature. At such low viscosity level, the compositions are typically and preferably sprayable. In this context, "sprayable" means the formulation can be delivered using a conventional pump spray device, such as those described in Encyclopedia of Pharmaceutical Technology, Second Edition, 856-860, Marcel Dekker, Inc., 2002. Although preferred formulations are sprayable solutions, they do not have to be administered to a subject by spraying. That is, formulations of the present invention can be administered to a subject (e.g., mammal, particularly a human) in various ways by spraying, injection, inhalation, etc. They can be administered, for example, intranasally, intraperitoneally, topically, orally, intratracheally via inhalation (e.g., from a nebulizer or spray pump atomizer), or subcutaneously. Preferably, formulations of the present invention are administered intranasally by spraying into the nasal passages of a mammal. Depending on the particular IRM compound, IRM compound concentration, and formulation composition, the therapeutic effect of the IRM compound may extend only to the superficial layers of the nasal passages or to tissues below the surface. In some embodiments, the above-described formulations are particularly advantageous for application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absorption of the IRM. hi certain embodiments the immune response modifier is a positively charged immune response modifier. Analogously, in certain embodiments, the hydrophilic viscosity enhancing agent is negatively charged.
IRM Compounds Preferred IRM compounds suitable for use in the formulations of the invention preferably include compounds having a 2-aminopyridine fused to a five membered nitrogen-containing heterocyclic ring. Other small organic molecules known to function as IRM compounds are also suitable for use in the formulations of the invention. Certain IRMs are small organic molecules (e.g., molecular weight under about 1000 Daltons, preferably under about 500 Daltons, as opposed to large biologic protein, peptides, and the like) such as those disclosed in, for example, U.S. Patent Nos. 4,689,338;
4,929,624; 4,988,815; 5,037,986 5,175,296 5,238,944 5,266,575 5,268,376; 5,346,905; 5,352,784; 5,367,076; 5,389,640 5,395,937 5,446,153 5,482,936 5,693,811; 5,741,908; 5,756,747; 5,939,090; 6,039,969 6,083,505 6,110,929 6,194,425 6,245,776; 6,331,539; 6,376,669; 6,451,810; 6,525,064 6,545,016 6,545,017 6,558,951 6,573,273; 6,656,938; 6,660,735; 6,660,747; 6,664,260 6,664,264 6,664,265 6,667,312 6,670,372; 6,677,347; 6,677,348; 6,677,349; 6,683,088 6,756,382; European Patent 0 394 026; U.S. Patent
Publication Nos. 2002/0016332; 2002/0055517; 2002/0110840; 2003/0133913; 2003/0199538; and 2004/0014779; and International Patent Publication No. WO 04/058759. IRM compounds suitable for use in the invention preferably include compounds having a 2-aminopyridine fused to a five membered nitrogen-containing heterocyclic ring. Such compounds include, for example, imidazoquinolme amines, including but not limited to, substituted imidazoquinolme amines such as, for example, amide substituted imidazoquinolme amines, sulfonamide substituted imidazoquinolme amines, urea substituted imidazoquinolme amines, aryl ether substituted imidazoquinolme amines, heterocyclic ether substituted imidazoquinolme amines, amido ether substituted imidazoquinolme amines, sulfonamido ether substituted imidazoquinolme amines, urea substituted imidazoquinolme ethers, thioether substituted imidazoquinolme amines, and 6- , 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinolme amines; tetrahydroimidazoquinoline amines, including but not limited to, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines, heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, and thioether substituted tetrahydroimidazoquinoline amines; imidazopyridine amines, including but not limited to, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers, and thioether substituted imidazopyridine amines; 1,2-bridged imidazoquinolme amines; 6,7-fused cycloalkylimidazopyridme amines; imidazonaphthyridine amines; imidazotetrahydronaphthyridine amines; oxazoloquinoline amines; thiazoloquinoline amines; oxazolopyridine amines; thiazolopyridine amines; oxazolonaphthyridine amines; thiazolonaphthyridine amines; and lH-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines.
Exemplary IRM Compounds In certain embodiments of the present invention the IRM compound can be chosen from lH-imidazo[4,5-c]quinolin-4-amines defined by one of Formulas I-V below:
Figure imgf000009_0001
I wherein Rπ is selected from alkyl of one to ten carbon atoms, hydroxyalkyl of one to six carbon atoms, acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, benzyl, (phenyl)ethyl and phenyl, said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that if said benzene ring is substituted by two of said moieties, then said moieties together contain no more than six carbon atoms; R21 is selected from hydrogen, alkyl of one to eight carbon atoms, benzyl,
(phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms and halogen, with the proviso that when the benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and each R is independently selected from alkoxy of one to four carbon atoms, halogen, and alkyl of one to four carbon atoms, and n is an integer from 0 to 2, with the proviso that if n is 2, then said R\ groups together contain no more than six carbon atoms;
Figure imgf000010_0001
II wherein R12 is selected from straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from straight chain or branched chain alkyl containing one to four carbon atoms and cycloalkyl containing three to six carbon atoms; and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; and R is selected from hydrogen, straight chain or branched chain alkyl containing one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl containing one to four carbon atoms, straight chain or branched chain alkoxy containing one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R2 is independently selected from straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R2 groups together contain no more than six carbon atoms;
Figure imgf000011_0001
III wherein R2 is selected from hydrogen, straight chain or branched chain alkyl of one to eight carbon atoms, benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from straight chain or branched chain alkyl of one to four carbon atoms, straight chain or branched chain alkoxy of one to four carbon atoms, and halogen, with the proviso that when the benzene ring is substituted by two such moieties, then the moieties together contain no more than six carbon atoms; and each R is independently selected from straight chain or branched chain alkoxy of one to four carbon atoms, halogen, and straight chain or branched chain alkyl of one to four carbon atoms, and n is an integer from zero to 2, with the proviso that if n is 2, then said R3 groups together contain no more than six carbon atoms;
Figure imgf000011_0002
TV wherein R14 is -CHRxRy wherein Ry is hydrogen or a carbon-carbon bond, with the proviso that when Ry is hydrogen Rx is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1 -alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, or 2-, 3-, or 4-pyridyl, and with the further proviso that when Ry is a carbon-carbon bond Ry and Rx together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms; R24 is selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; and 4 is selected from hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms;
Figure imgf000012_0001
V wherein R1 is selected from hydrogen; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms;
Figure imgf000013_0001
wherein Rs and RT are independently selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; X is selected from alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, hydroxyalkyl of one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherein the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyπolidino, alkylthio of one to four carbon atoms; and R5 is selected from hydrogen, straight chain or branched chain alkoxy containing one to four carbon atoms, halogen, and straight chain or branched chain alkyl containing one to four carbon atoms; and pharmaceutically acceptable salts of any of the foregoing. In another embodiment, the IRM compound can be chosen from 6,7 fused cycloalkylimidazopyridme amines defined by Formula VI below:
Figure imgf000013_0002
VI wherein m is 1, 2, or 3; Rι6 is selected from hydrogen; cyclic alkyl of three, four, or five carbon atoms; straight chain or branched chain alkyl containing one to ten carbon atoms and substituted straight chain or branched chain alkyl containing one to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; fluoro- or chloroalkyl containing from one to ten carbon atoms and one or more fluorine or chlorine atoms; straight chain or branched chain alkenyl containing two to ten carbon atoms and substituted straight chain or branched chain alkenyl containing two to ten carbon atoms, wherein the substituent is selected from cycloalkyl containing three to six carbon atoms and cycloalkyl containing three to six carbon atoms substituted by straight chain or branched chain alkyl containing one to four carbon atoms; hydroxyalkyl of one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to four carbon atoms or benzoyloxy, and the alkyl moiety contains one to six carbon atoms, with the proviso that any such alkyl, substituted alkyl, alkenyl, substituted alkenyl, hydroxyalkyl, alkoxyalkyl, or acyloxyalkyl group does not have a fully carbon substituted carbon atom bonded directly to the nitrogen atom; benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenyl substituent being optionally substituted on the benzene ring by one or two moieties independently selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, with the proviso that when said benzene ring is substituted by two of said moieties, then the moieties together contain no more than six carbon atoms; and -CHRxRy wherein Ry is hydrogen or a carbon-carbon bond, with the proviso that when Ry is hydrogen Rx is alkoxy of one to four carbon atoms, hydroxyalkoxy of one to four carbon atoms, 1- alkynyl of two to ten carbon atoms, tetrahydropyranyl, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, 2-, 3-, or 4-pyridyl, and with the further proviso that when Ry is a carbon-carbon bond Ry and Rx together form a tetrahydrofuranyl group optionally substituted with one or more substituents independently selected from hydroxy and hydroxyalkyl of one to four carbon atoms; R26 is selected from hydrogen; straight chain or branched chain alkyl containing one to eight carbon atoms; straight chain or branched chain hydroxyalkyl containing one to six carbon atoms; morpholinoalkyl; benzyl; (phenyl)ethyl; and phenyl, the benzyl, (phenyl)ethyl, or phenyl substituent being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and -C(Rs)(Rτ)(X) wherein Rs and RT are independently selected from hydrogen, alkyl of one to four carbon atoms, phenyl, and substituted phenyl wherein the substituent is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen; X is selected from alkoxy containing one to four carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to four carbon atoms, haloalkyl of one to four carbon atoms, alkylamido wherem the alkyl group contains one to four carbon atoms, amino, substituted amino wherein the substituent is alkyl or hydroxyalkyl of one to four carbon atoms, azido, alkylthio of one to four carbon atoms, and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; and R6 is selected from hydrogen, fluoro, chloro, straight chain or branched chain alkyl containing one to four carbon atoms, and straight chain or branched chain fluoro- or chloroalkyl containing one to four carbon atoms and at least one fluorine or chlorine atom; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from imidazopyridine amines defined by Formula VII below:
Figure imgf000015_0001
VII wherein R1 is selected from hydrogen; -CH2Rw wherein Rw is selected from straight chain, branched chain, or cyclic alkyl containing one to ten carbon atoms, straight chain or branched chain alkenyl containing two to ten carbon atoms, straight chain or branched chain hydroxyalkyl containing one to six carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms, and phenylethyl; and -CH=CRzRz wherein each Rz is independently straight chain, branched chain, or cyclic alkyl of one to six carbon atoms; R2 is selected from hydrogen; straight chain or branched chain alkyl containing one to eight carbon atoms; straight chain or branched chain hydroxyalkyl containing one to six carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one to four carbon atoms and the alkyl moiety contains one to six carbon atoms; benzyl, (phenyl)ethyl and phenyl, the benzyl, (phenyl)ethyl and phenyl being optionally substituted on the benzene ring by a moiety selected from methyl, methoxy, and halogen; and morpholinoalkyl wherein the alkyl moiety contains one to four carbon atoms; R6 and R are independently selected from hydrogen and alkyl of one to five carbon atoms, with the proviso that R6 and R taken together contain no more than six carbon atoms, and with the further proviso that when R is hydrogen then R67 is other than hydrogen and R2 is other than hydrogen or morpholinoalkyl, and with the further proviso that when R67 is hydrogen then R 7 and R27 are other than hydrogen; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from 1,2 bridged imidazoquinolme amines defined by Formula VIII below:
Figure imgf000016_0001
VIII wherein Z is selected from -(CH2)P- wherein p is 1 to 4; -(CH2)a-C(RϋRE)(CH2)b-, wherein a and b are integers and a+b is 0 to 3, RD is hydrogen or alkyl of one to four carbon atoms, and RE is selected from alkyl of one to four carbon atoms, hydroxy, -ORp wherein RF is alkyl of one to four carbon atoms, and -NRGR'G wherein RG and R'G are independently hydrogen or alkyl of one to four carbon atoms; and -(CH2)a-(Y)-(CH2)b- wherein a and b are integers and a+b is 0 to 3, and Y is O, S, or -NRJ- wherein R is hydrogen or alkyl of one to four carbon atoms; q is O or 1; and R8 is selected from alkyl of one to four carbon atoms, alkoxy of one to four carbon atoms, and halogen, and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from thiazoloquinoline amines, oxazoloquinoline amines, thiazolopyridine amines, oxazolopyridine amines, thiazolonaphthyridine amines and oxazolonaphthyridine amines defined by Formula IX below:
Figure imgf000017_0001
IX wherein: R19 is selected from oxygen, sulfur and selenium; R29 is selected from -hydrogen; -alkyl; -alkyl-OH; -haloalkyl; -alkenyl; -alkyl-X-alkyl; -alkyl-X-alkenyl; -alkenyl-X-alkyl; -alkenyl-X-alkenyl; -alkyl-N(R59)2; -alkyl-N3; -alkyl-O-C(O)-N(R59)2; -heterocyclyl; -alkyl-X-heterocyclyl; -alkenyl-X-heterocyclyl; -aryl; -alkyl-X-aryl; -alkenyl-X-aryl; -heteroaryl; -alkyl-X-heteroaryl; and -alkenyl-X-heteroaryl; R and R49 are each independently: -hydrogen; -X-alkyl; -halo; -haloalkyl; 1 -N(R59)2; or when taken together, R39 and R^ form a fused aromatic, heteroaromatic, cycloalkyl or heterocyclic ring; X is selected from-O-, -S-, -NR59- -C(O)-, -C(O)O- -OC(O)-, and a bond; and each R59 is independently H or C1-8alkyl; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from imidazonaphthyridine amines and imidazotetrahydronaphthyridine amines defined by Formulas X and XI below:
Figure imgf000018_0001
X wherein A is =N-CR=CR-CR=; =CR-N=CR-CR=; =CR-CR=N-CR=; or =CR-CR=CR-N=; R110 is selected from: - hydrogen; -C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-Cι-20 alkyl; -O-(C1-20 alkyl)0-1-aryl; -O-(C1-2o alky^o-i-heteroaryl; -O-(C1-2o alkyl)o-ι -heterocyclyl; -CO-O-Cι-20 alkyl; -S(O)o-2 -Cι-20 alkyl; -S(O)0-2-(C1-2o alkyl)0-1-aryl; -S(O)0-2 -(C1-20 alkyl)0-i -heteroaryl; -S(O)o-2 -(C1-20 alkyl)0-1 -heterocyclyl; -N(R310) ; -N3; oxo; -halogen; -NO2; -OH; and -SH; and -Cι-20 alkyl-NR31o-Q-X-R io or -C -20
Figure imgf000019_0001
wherein Q is -CO- or-SO2-; X is a bond, -O- or -NR310- and R410 is aryl; heteroaryl; heterocyclyl; or -C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-C1-20 alkyl; -O-(C1-20 alkyl)0-i-aryl; -O-(C1-20 alkyl)0-1-heteroaryl; -O-(C1-20 alkyl)o-ι-heterocyclyl; -CO-O-C1-20 alkyl; -S(O)0-2 -C1-20 alkyl; -S(O)o-2-(C1.20 alkyl)0-1-aryl; -S(O)0-2 -(C1-2o alkyl)0-1-heteroaryl; -S(O)0-2 -(C1-20 alkyl)0-i -heterocyclyl; -N(R3ιo)2; -NR31o-CO-O-C1-20 alkyl; -N3; oxo; -halogen; -NO2; -OH; and -SH; or R 10 is
Figure imgf000020_0001
wherein Y is -N- or -CR-; R21o is selected from: -hydrogen; -Ci-io alkyl; -C2-10 alkenyl; -aryl; -Cι-10 alkyl-O-Cϊ-io alkyl; -C1-10 alkyl-O-C2-10 alkenyl; and -C1-10 alkyl or C2.10 alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R310)2; -CO-N(R310)2; -CO-C1-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R310 is independently selected from hydrogen and C1-10 alkyl; and each R is independently selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen and trifluoromethyl;
Figure imgf000021_0001
XI wherein B is -NR-C(R)2-C(R)2-C(R)2-; -C(R)2-NR-C(R)2-C(R)2-; -C(R)2-C(R)2-NR-C(R)2- or -C(R)2-C(R)2-C(R)2-NR-; Rπi is selected from: - hydrogen; -C1-2o alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-Cι-20 alkyl; -O-(C1-20 alkyl)0-1-aryl; -O-(C1-20 alkyl)0-1-heteroaryl; -O-(C1-20 alkyl)0-1-heterocyclyl; -CO-O-C1-20 alkyl; -S(O)o-2 -Cι-2o alkyl; -S(O)0-2-(C1-20 alkyl)0-1-aryl; -S(O)o-2 -(C1-20 alkyl)0-1 -heteroaryl; -S(O)0-2 -(C1-20 alkyl)0-1 -heterocyclyl; -N(R3U)2; -N3; oxo; -halogen; -NO2; -OH; and -SH; and -C1-20 alkyl-NR3π-Q-X-R4π or -C2-2o alkenyl-NR311-Q-X-R411 wherein Q is -CO- or -SO2-; X is a bond, -O- or -NR311- and R411 is aryl; heteroaryl; heterocyclyl; or -C1-20 alkyl or C2-20 alkenyl that is unsubstituted or substituted by one or more substituents selected from: -aryl; -heteroaryl; -heterocyclyl; -O-C1-20 alkyl; -O-(Ci_2o alkyl)0-1-aryl; -O-(C1-20 alkyl)0-ι -heteroaryl; -O-(C 1 _20 alkyl)o-ι -heterocyclyl; -CO-O-C1.20 alkyl; -S(O)o-2 -Cι.2o alkyl; -S(O)o-2-(Cι.2o alkyl)0-1-aryl; -S(O)o-2 -(C1-20 alkyl)0-i -heteroaryl; -S(O)0-2 -(C1.20 alkyl)0-1 -heterocyclyl; -N(R3n)2; -NR311-CO-O-C1.20 alkyl; -N3; oxo; -halogen; -NO2; -OH; and -SH; or R π is
Figure imgf000023_0001
wherein Y is -N- or -CR-; R211 is selected from: -hydrogen; -Cι-10 alkyl; -C2-10 alkenyl; -aryl; -C1-10 alkyl -O-Cno-alkyl; -C1-10 alkyl-O-C2-1o alkenyl; and -C1-10 alkyl or C2-10 alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R3π)2; -CO-N(R311)2; -CO-Cι-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R311 is independently selected from hydrogen and C1-10 alkyl; and each R is independently selected from hydrogen, C1-10 alkyl, C1-10 alkoxy, halogen, and trifluoromethyl; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from lH-imidazo[4,5- c]quinolin-4-amines and tetrahydro- lH-imidazo[4,5-c]quinolin-4-amines defined by Formulas XII, XIII and XIV below:
Figure imgf000024_0001
wherein R112 is -alkyl-NR^-CO-Rm or -alkenyl-NR312-CO- R412 wherein R 12 is aryl, heteroaryl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -alkynyl; -(alkyl)0-1-aryl; -(alkyl)o-ι -(substituted aryl); -(alkyl)o-1 -heteroaryl; -(alky^o-ϊ -(substituted heteroaryl); -O-alkyl; -O-(alkyl)0-1-aryl; -O-(alkyl)0-1 -(substituted aryl); -O-(alkyl)0-1 -heteroaryl; -O-(alkyl)0-1-(substituted heteroaryl); -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; -CO-(substituted heteroaryl); -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)o-2 -alkyl; -S(O)0-2-(alkyl)0-1-aryl; -S(O)o-2 -(alkyl)0-1-(substituted aryl); -S(O)o-2 -(alkyl)0-1-heteroaryl; -S(O)o-2-(alkyl)o-1-(substituted heteroaryl); -P(O)(OR312)2; -NR312-CO-O-alkyl; -N3; -halogen; -NO2; -CN; -haloalkyl; -O-haloalkyl; -CO-haloalkyl; -OH; -SH; and in the case that R 12 is alkyl, alkenyl, or heterocyclyl, oxo; or R4ι2 is
Figure imgf000025_0001
wherein R512 is an aryl, (substituted aryl), heteroaryl, (substituted heteroaryl), heterocyclyl or (substituted heterocyclyl) group; R212 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -(substituted aryl); -heteroaryl; -(substituted heteroaryl); -heterocyclyl; -(substituted heterocyclyl); -alkyl-O-alkyl; -alkyl-O-alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R312)2; -CO-N(R312)2; -CO-C1-10 alkyl; -CO-O-C1-10 alkyl; -N3; -aryl; -(substituted aryl); -heteroaryl; -(substituted heteroaryl); -heterocyclyl; -(substituted heterocyclyl); -CO-aryl; and -CO-heteroaryl; each R312 is independently selected from hydrogen; C1-10 alkyl-heteroaryl; C1-10 alkyl-(substituted heteroaryl); CM0 alkyl-aryl; Cι-10 alkyl-(substituted aryl) and C1-10 alkyl; v is 0 to 4; and each R^ present is independently selected from C1-10 alkyl, C1-10 alkoxy, halogen, and trifluoromethyl;
Figure imgf000026_0001
wherein Rιi3 is -alkyl-NR313- SO2 -X-R413 or -alkenyl-NR313- SO2 -X-R413 ; X is a bond or -NR513-; R413 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl)o-ι-aryl; -O-(alkyl)o-ι-substituted aryl; -O-(alkyl)o-ι -heteroaryl; -O-(alkyl)o-ι-substituted heteroaryl; -O-(alkyl)o-i -heterocyclyl; -©-(alkyl rsubstituted heterocyclyl; -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)o-2 -alkyl; -S(O)0-2-(alkyl)0-1-aryl; -S(O)o-2 -(aUcyl)0-1 -substituted aryl; -S(O)o-2 -(alkyl)0-1 -heteroaryl; -S(O)o-2 -(alkyl)0-1 -substituted heteroaryl; -S(O)o-2 -(alkyl)0-1 -heterocyclyl; -S(O)0-2-(alkyl)0-1 -substituted heterocyclyl; -(alkyl)o-ι-NR313R313; -(alkyl)0-1-NR313-CO-O-alkyl; -(alkyl)0-1-NR3ι3-CO-alkyl; -(alkyl)0-1-NR3ι3-CO-aryl; -(alkyl)0-rNR3ι3-CO-substituted aryl; -(alkyl)0-1-NR313-CO-heteroaryl; -(alky^o-rNRsB-CO-substituted heteroaryl; -N3; -halogen; -haloalkyl; -haloalkoxy; -CO-haloalkyl; -CO-haloalkoxy; -NO2; -CN; -OH; -SH; and in the case that R413 is alkyl, alkenyl, or heterocyclyl, oxo;
R2i3 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; - alkyl-O-alkyl; - alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R3ι3)2; -CO-N(R313)2; -CO-C1-10 alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); each R 13 is independently selected from hydrogen and C1-10 alkyl; or when X is a bond R313 and 413 can join to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; R5 3 is selected from hydrogen and C1-10 alkyl, or R413 and R5ι3 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4; and each R13 present is independently selected from C1-10 alkyl, C1-10 alkoxy, halogen, and trifluoromethyl;
Figure imgf000029_0001
xrv wherein Rn4 is -alkyl-NR314-CY-NR514-X-R414 or -alkenyl-NR314-CY- NR51 -X- R41 wherein Y is =O or =S; X is a bond, -CO- or -SO2-; R41 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyi)0-i-aryl; -O-(alkyl)0- -substituted aryl; -O-(alkyl)o-1-heteroaryl; -O-(alkyl)0-1-substituted heteroaryl; -©-(alky^o-rheterocyclyl; -O-(alkyl)0-ι-substituted heterocyclyl; -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)0-2 -alkyl; -S(O)0-2-(alkyl)0-1-aryl; -S(O)0-2 -(alkyl)0-1 -substituted aryl; -S(O)o-2 -(alkyl)0-1 -heteroaryl; -S(O)0-2 -(alkyl)0-1 -substituted heteroaryl;
Figure imgf000030_0001
-S(O)0-2 -(alkyl)0-1 -substituted heterocyclyl; -(alkyl)0-1-NR314R314; -(alkyl)0-1-NR314-CO-O-alkyl; -(alkyl)0-1-NR314-CO-alkyl; -(alkyl)0-1-NR314-CO-aryl; -(alkyl)o-ι -NR314-CO-substituted aryl; -(alkyl)o-ι-NR31 -CO-heteroaryl; -(alkyl)0-1-NR314-CO-substituted heteroaryl; -N3; -halogen; -haloalkyl; -haloalkoxy; -CO-haloalkoxy; -NO2; -CN; -OH; -SH; and, in the case that R 14 is alkyl, alkenyl or heterocyclyl, oxo; with the proviso that when X is a bond R4i4 can additionally be hydrogen; R21 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -alkyl-O-alkyl; -alkyl-O- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R3ι4)2; -CO-N(R314)2; -CO-Ci-io alkyl; -CO-O-C1-10 alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; 1 -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substiruted heteroaryl); each R314 is independently selected from hydrogen and C1-10 alkyl; R514 is selected from hydrogen and C1-10 alkyl, or R41 and R51 can combine to form a 3 to 7 membered heterocyclic or substituted heterocyclic ring; v is 0 to 4; and each Rι present is independently selected from C1-10 alkyl, C1-10 alkoxy, halogen, and trifluoromethyl; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from lH-imidazo[4,5- c]quinolin-4-amines and tetrahydro- lH-imidazo[4,5-c]quinolin-4-amines defined by Formulas XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, and XXVI below:
Figure imgf000032_0001
XV
wherein: X is -CHR515-, -CHR515-alkyl-, or -CHR515-alkenyl-; R 5 is selected from: -R4i5-CR315-Z-R615 — alkyl; -R4is-CR315-Z-R615 — alkenyl; -R415-CR315-Z-R615— aryl; -R415-CR315-Z-R615 — heteroaryl; -R 15-CR315-Z-R615— heterocyclyl; -R415-CR315-Z-H; -R415-NR715 -CR315-R615— alkyl;
Figure imgf000033_0001
-R4ι5-NR715-CR315-R615-aryl; -R4i5-NR7i5-CR3i5-R6ir-heteroaryl; -R 15-NR715-CR315-R6ι5-heterocyclyl; and -R-πs-NRzis -CR3ιs-R8i5; Z is - R515-, -O-, or -S-; R215 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl- Y-alkyl; -alkyl-Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R515)2; -CO-N(R5ι5)2; -CO-Cι-10 alkyl; -CO-O-Ci.io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R315 is =O or =S; R415 is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R515 is independently H or C1-10 alkyl; R615 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups; R715 is H, C1-10 alkyl, or arylalkyl; or R415 and R715 can join together to form a ring; R815 is H or C1-10 alkyl; or R715 and R815 can join together to form a ring; Y is -O- or-S(O)0-2-; v is 0 to 4; and each R15 present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000034_0001
wherein: X is -CHR516-, -CHR516-alkyl-, or -CHR516-alkenyl-; R116 is selected from: -R416-CR316-Z-R616— alkyl; -Ruβ-CRsiβ-Z-Rβiβ— alkenyl; -R416-CR316-Z-R616— aryl; -R4 6-CR316-Z-R616 — heteroaryl; -R416-CR316-Z-R616— heterocyclyl; -R416— CR316-Z— H; -R4ie-NR.7i6 -CR316-R616— alkyl; -R416- R716 -CR3i6-R6iβ— lkenyl; -R416-NR7ι6-CR316-R616-aryl; -R4i6-NR716-CR316-R616-heteroaryl; -R416-NR716-CR316-R616-heterocyclyl; and -R4i6-NR7ι6 -CR316-R816; Z is -NR5ι6-, -O-, or -S-; R216 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl- Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R516)2; -CO-N(R5ι6)2; -CO-CMO alkyl; -CO-O-C1-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R316 is =O or =S; R416 is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R5 6 is independently H or Cwo alkyl; R616 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups; R716 is H, C1-10 alkyl, arylalkyl; or R416 and R716 can join together to form a ring; R816 is H or C1-10 alkyl; or R716 and R816 can join together to form a ring; Y is -O- or-S(O)0-2-; v is 0 to 4; and each R16 present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000036_0001
XVII
wherein: X is -CHR317-, -CHR317-alkyl-, or -CHR31 -alkenyl-; R11 is selected from: -alkenyl; -aryl; and
Figure imgf000036_0002
R217 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl- Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R3ι7)2; -CO-N(R317)2; -CO-Ci-io alkyl; -CO-O-C1-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R417 is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R3ι7 is independently H or C1-10 alkyl; each Y is independently -O- or -S(Q)o-2-; v is 0 to 4; and each Rι7 present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000037_0001
XVIII
wherein: X is -CHR3 \ 8-, -CHR3 s-alkyl-, or -CHR3 \ 8-alkenyl- ; R118 is selected from: -aryl; -alkenyl; and
Figure imgf000038_0001
R218 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y-aryl; - alkyl-Y- alkenyl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R318)2; -CO-N(R318)2; -CO-C1-10 alkyl; -CO-O-C1-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R418 is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R31g is independently H or Cι-10 alkyl; each Y is independently -O- or -S(O)0-2-; v is 0 to 4; and each R18 present is independently selected C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000039_0001
wherein: X is -CHR3ι9~, -CHR319-alkyl-, or -CHR3ι9-alkenyl-; R119 is selected from: -heteroaryl; -heterocyclyl; -R419- heteroaryl; and -R^g-heterocyclyl; R219 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl- Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R319)2; -CO-N(R319)2; -CO-C1-10 alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R419 is alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R31 is independently H or C1-10 alkyl; each Y is independently -O- or -S(O)o-2-; v is 0 to 4; and each R19 present is independently selected from C1-10 alkyl, Cno alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000040_0001
XX
wherein: X is -CHR320-, -CHR320-alkyl-, or -CHR320-alkenyl-; R120 is selected from: -heteroaryl; -heterocyclyl; -R^σ- heteroaryl; and -R 2o-heterocyclyl; R22Q is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R320)2; -CO-N(R320)2; -CO-Ci-io alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; R420 is alkyl or alkenyl, which may be interrupted by one or more
-O- groups; each R320 is independently H or C1-10 alkyl; each Y is independently -O- or -S(O)0-2-; v is 0 to 4; and each R2o present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000042_0001
XXI
wherein: X is -CHR521-, -CHR521 -alkyl-, or -CHR521-alkenyl-; R12ι is selected from: -R42i—NR321—SO2—R621— alkyl; -R421— NR321 — SO2— Rό2ι — alkenyl; -R42ι-NR321-SO2-R621-aryl; -R4 ι-NR321-SO2-R621-heteroaryl; -R421-NR321-SO2-R621-heterocyclyl; -R421— NR32ι— SO2— R-721 ; -R421-NR32ι-SO2-NR52i-R62i-alkyl; -R421-NR321 -SO2-NR52ι -Rffli -alkenyl; -R42i-NR321-SO2-NR521-R621-aryl; -R421-NR321-Sθ2-NR52i-R62i-heteroaryl; -R421-NR321-Sθ2-NR52i-R62i-heterocyclyl; and
Figure imgf000042_0002
R221 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R52ι)2; -CO-N(R52i)2; -CO-Ci-io alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; Y is -O- or -S(O)0-2-; R321 is H, C1-10 alkyl, or arylalkyl; each R 21 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R32ι and R421 can join together to form a ring; each R521 is independently H, CMO alkyl, or C2-10 alkenyl; R6 1 is a bond, alkyl, or allcenyl, which may be interrupted by one or more ■ O- groups; R721 is CMO alkyl; or R 21 and R721 can join together to form a ring; v is 0 to 4; and each R21 present is independently selected from C1-10 alkyl, Cι-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000043_0001
wherein: X is -CHR522-, -CHR522-alkyl-, or -CHR522-alkenyl-; R122 is selected from: -R422—NR322—Sθ2—R622— alkyl; -R422— NR322 — SO2 — Rβ22 — alkenyl; -R422-NR322-S02-R622-aryl; -R422-NR322-SO2-R622-heteroaryl; 5 -R422-NR322-SO2-R622-heterocyclyl; -R422 — NR322 — S O2 — 722 ; -R422-NR322-SO2-NR522-R622-alkyl; -R422-NR322-SO2-NR522-R622-alkenyl; -R422-NR322-SO2-NR522-R622-aryl; 10 -R422-NR322-SO2-NR522-R622-heteroaryl; -R422-NR322-SO2-NR522-R622-heterocyclyl; and
Figure imgf000044_0001
R222 is selected from: -hydrogen; 15 -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; 20 -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: 25 -OH; -halogen; -N(R522)2; -CO-N(R522)2; -CO-Cι-10 alkyl; 30 -CO-O-Cι-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; Y is -O- or -S(O)0-2-; R322 is H, Ci-io alkyl, or arylalkyl; each R42 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R322 and R422 can join together to form a ring; each R522 is independently H, C1-10 alkyl, or C2-10 alkenyl; R622 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups; R722 is C1-10 alkyl; or R322 and R722 can join together to form a ring; v is 0 to 4; and each R22 present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000045_0001
XXIII
wherein: X is -CHR323-, -CHR323-alkyl-, or -CHR323-alkenyl- Z is -S-, -SO-, or-SO2-; R123 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R423-aryl; -R423- heteroaryl; and -R 23-heterocyclyl; R223 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl-Y- alkenyl; -alkyl-Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R323)2; -CO-N(R323)2; -CO-Ci-io alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R323 is independently H or C1-10 alkyl; each R423 is independently alkyl or alkenyl; each Y is independently -O- or -S(O)o-2-; v is 0 to 4; and each R23 present is independently selected from Cι-10 alkyl, Cι-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000047_0001
xxrv
wherein: X is -CHR32 -, -CHR324-alkyl-, or -CHR324-alkenyl-; Z is -S-, -SO-, or -SO2-; Ri2 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R^-aryl; -R42 - heteroaryl; and -R424-heterocyclyl; R224 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; - alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R324)2; -CO-N(R324)2; -CO-C1-10 alkyl; -CO-O-Ci-io alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R324 is independently H or C1-10 alkyl; each _424 is independently alkyl or alkenyl; each Y is independently -O- or -S(O)0-2-; v is 0 to 4; and each R24 present is independently selected from C1-10 alkyl, -io alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000048_0001
wherein: X is -CHR525-, -CHR525-alkyl-, or -CHR525-alkenyl-; R^5 is selected from: -R425-NR825-CR325— NR525-Z-R625-alkyl; -R 25-NR82S-CRS25— NR525-Z-R625-alkenyl; -R425-NR825-CR325— NR525-Z-R62s-aryl; -R425-NR825-CR325— NR525-Z-R625-heteroaryl; -R 25-NRs25-CR325 — NR525-Z-R62s-heterocycryl; -R425-NR825— CR325— NR525R725; -R425-NR825-CR325— NR925-Z— R625-alkyl; -R425-NR825-CR325— NR925-Z— R625-alkenyl; -R425-NR825-CR325— NR925~Z— R625-aryl; -R425-NR825-CR325— NR925-Z— R625-heteroaryl; and -R425-NR825-CR325— NR925-Z— R625-heterocyclyl; R225 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R525)2; -CO-N(R525)2; -CO-C1-10 alkyl; -CO-O-CMO alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R325 is =O or =S; each R 25 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R525 is independently H or C1-10 alkyl; R625 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups; R725 is H or CMO alkyl which may be interrupted by a hetero atom, or R725 can join with R525 to form a ring; R825 is H, C1-10 alkyl, or arylalkyl; or R 25 and R825 can join together to form a ring; R925 is CMO alkyl which can join together with R825 to form a ring; each Y is independently -O- or -S(O)0-2-; Z is a bond, -CO-, or -SO2-; v is 0 to 4; and each R25 present is independently selected CMO alkyl, C O alkoxy, hydroxy, halogen, and trifluoromethyl;
Figure imgf000050_0001
XXVI
wherein: X is -CHR526-, -CHR52δ-alkyl-, or -CHR526-alkenyl-; RΪ26 is selected from: -R426-NR826-CR326— NR526-Z-R626-alkyl; -R426-NR826-CR326— NR526-Z-R626-alkenyl; -R426-NR826-CR326— R526-Z-R626-aryl; -R426-NR826-CR326— NR526-Z-R626-heteroaryl; -R426-NR826-CR326— NR526-Z-R626-heterocyclyl; -R426— NR826— CR326— NR526R726; -R426-NR826-CR326— NR926-Z— R626-alkyl; -R426-NR826-CR326— R926-Z— R626-alkenyl; -R426-NR826-CR326— NR926-Z— R626-aryl; -R 26-NR826-CR326 — NR926-Z — R626-heteroaryl; and -R426-NR826-CR326 — NR926-Z — R626-heterocyclyl; R226 is selected from: -hydrogen; -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkyl-Y-alkyl; -alkyl-Y- alkenyl; -alkyl- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R526)2; -CO-N(R526)2; -CO-CMO alkyl; -CO-O-CMO alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R326 is =O or =S; each R426 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; each R52g is independently H or C1-10 alkyl;
R626 is a bond, alkyl, or alkenyl, which may be interrupted by one or more - O- groups;
R726 is H or CMO alkyl which may be interrupted by a hetero atom, or R726 can join with R526 to form a ring; R826 is H, CMO alkyl, or arylalkyl; or R 26 and R826 can join together to form a ring; R926 is C O alkyl which can join together with R826 to form a ring; each Y is independently -O- or -S(O)0-2-; Z is a bond, -CO- or -SO2-; v is 0 to 4; and each R26 present is independently selected from C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl; and pharmaceutically acceptable salts of any of the foregoing. In another embodiment, the IRM compound can be chosen from lH-imidazo[4,5- c]pyridin-4-amines defined by Formula XXVII below:
Figure imgf000052_0001
XXVII
wherein X is alkylene or alkenylene; Y is -CO- or-CS; Z is a bond, -O-, or -S-; R127 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl)o-ι-aryl; -O-(alkyl)o-1 -(substituted aryl); 5 -O-(alkyl)0-1-heteroaryl; -O-(alkyl)o-1-(substituted heteroaryl); -O-(alkyl)o-1-heterocyclyl; -O-(alkyl)o-1-(substituted heterocyclyl); -COOH; 10 -CO-O-alkyl; -CO-alkyl; -S(O)0-2 -alkyl; -S^o^^alky^o- aryl; -S(O)o-2 -(alkyl)o-ι-(substituted aryl); 15 -S(O)0-2 -(alkyl)o-ι -heteroaryl; -S(O)o-2 -(alkyl)o-1-(substituted heteroaryl); -S(O)o-2 -(alkyl)0-1 -heterocyclyl; -S(O)o-2 -(alkyl)o-ι -(substituted heterocyclyl); -(alkyl)0-ι-N(R627)2; 20 -(alkyl)0-i-NR627-CO-O-alkyl; -(alkyl)0-ι-NR627-CO-alkyl; -(alkyl)0-i-NR627-CO-aryl; -(alkyl)o-1-NR627-CO-(substiruted aryl); -(alkyl)0-1 -NR627-CO-heteroaryl; 25 -(alkyl)0-1-NR627-CO-(substituted heteroaryl); -N3; -halogen; -haloalkyl; -haloalkoxy; 30 -CO-haloalkyl; -CO-haloalkoxy; -NO2; -CN; -OH; -SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo; R227 is selected from: 5 -hydrogen; -alkyl; -alkenyl; -aryl; -substituted aryl; 10 -heteroaryl; -substituted heteroaryl; -alkyl-O-alkyl; -alkyl-S-alkyl; -alkyl-O-aryl; 15 -alkyl-S-aryl: -alkyl-O- alkenyl; -alkyl-S- alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from: 20 -OH; -halogen; -N(R627)2;
Figure imgf000054_0001
-CS-N(R627)2; 25 -SO2-N(R627)2; -NR627-CO-CMO alkyl; -NR627-CS-C1-10 alkyl; -NR627-SO2-CMO alkyl; -CO-CMO alkyl; 30 -CO-O-CMO alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); R327 and R 27 are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; R527 is H or CMO alkyl, or R527 can join with X to form a ring that contains one or two heteroatoms; or when R127 is alkyl, R527 and R127 can join to form a ring; each R627 is independently H or CMoalkyl; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from lH-imidazo[4,5- c]pyridin-4-amines defined by Formula XXVIII below:
Figure imgf000055_0001
XXVIII
wherein X is alkylene or alkenylene; Y is -SO2-; Z is a bond or -NR628-; R128 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; 5 -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; 10 -O-(alkyl)0-1-aryl; -O-(alkyl)o-ι-(substituted aryl); -O-(alkyl)0-1 -heteroaryl; -O-(alkyl)o-1-(substituted heteroaryl); -O-(alkyl)0-1 -heterocyclyl; 15 -O-(alkyl)o-1-(substituted heterocyclyl); -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)0-2 -alkyl; 20 -S(O)o-2-(alkyl)0-1-aryl; -S(O)o-2 -(alkyl)0-1 -(substituted aryl); -S(O)0-2 -(alkyl)0-1 -heteroaryl; -S(O)o-2 -(alkyl)o-ι -(substituted heteroaryl); -S(O)o-2-(alkyl)o-1-heterocyclyl; 25 -S(O)0-2 -(alkyl)o-1-(substituted heterocyclyl); -(alkyl)o-ι-N(R628)2; -(alkyl)0-1-NR628-CO-O-alkyl; -(alkyl)0-1-NR628-CO-alkyl; -(alkyl)0-ι-NR628-CO-aryl; 30 -(alkyl)0-1-NR628-CO-(substituted aryl); -(alkyl)0-1 -NR628-CO-heteroaryl; -(alkyl)0-1 -NR628-CO-(substiruted heteroaryl); -N3; -halogen; -haloalkyl; -haloalkoxy; 5 -CO-haloalkyl; -CO-haloalkoxy; -NO2; -CN; -OH; 10 -SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo; R228 is selected from: -hydrogen; -alkyl; -alkenyl; 15 -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -alkyl-O-alkyl; 20 -alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl: -alkyl-O- alkenyl; -alkyl-S- alkenyl; and 25 -alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R628)2; 30 -CO-N(R628)2; -CS-N(R628)2; -SO2-N(R628)2; -NRωβ-CO-Ci-io alkyl; -NR628-CS-C1-10 alkyl; -NR628-SO2-C1-10 alkyl; -CO-CMO alkyl; -CO-O-CMO alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substiruted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); R328 and R428 are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; 528 is H or CMO alkyl, or R528 can join with X to form a ring; or when R128 is alkyl, R528 and R128 can join to form a ring; each R628 is independently H or C1-10alkyl; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from lH-imidazo[4,5- c]pyridin-4-arnines defined by Formula XXIX below:
Figure imgf000058_0001
XXIX
wherein X is alkylene or alkenylene; Y is -CO- or -CS; Z is -NR629-, -NR629-CO-, -NR629-SO2-, or-NR729-; R129 is aryl, heteroaryl, heterocyclyl, alkyl or alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -substituted cycloalkyl; -substituted aryl; -substituted heteroaryl; -substituted heterocyclyl; -O-alkyl; -O-(alkyl)0-1-aryl; -O-(alkyl)o-i-(substituted aryl);
Figure imgf000059_0001
-O-(alkyl)o-ι-(substituted heteroaryl); -O-(alkyl)0-1-heterocyclyl; -O-(alkyl)0-1 -(substituted heterocyclyl); -COOH; -CO-O-alkyl; -CO-alkyl; -S(O)0-2 -alkyl; -S(O)o-2-(alkyl)0-1-aryl; -S(O)o_2 -(alkyl)0-1 -(substituted aryl); -S(O)o-2 -(alkyl)0-1 -heteroaryl; -S(O)o-2 -(alkyl)o-ι-(substituted heteroaryl); -S(O)o-2 -(alkyl)o-ι-heterocyclyl; -S(O)o-2 -(alkyl)o-ι -(substituted heterocyclyl); -(alkyl)0-ι-N(R629)2; -(alkyl)0-ι-NR629-CO-O-alkyl; -(alkyl)0-1-NR629-CO-alkyl; -(alkyl)0-i-NR629-CO-aryl; -(alkyl)o-ι-NR62 -CO-(substituted aryl); 5 -(alkyl)0-1-NR629-CO-heteroaryl; -(alkyl)0-ι -NR629-CO-(substituted heteroaryl); -P(O)(O-alkyl)2; -N3; -halogen; 10 -haloalkyl; -haloalkoxy; -CO-haloalkyl; -CO-haloalkoxy; -NO2; 15 -CN; -OH; -SH; and in the case of alkyl, alkenyl, and heterocyclyl, oxo; R229 is selected from: -hydrogen; 20 -alkyl; -alkenyl; -aryl; -substituted aryl; -heteroaryl; 25 -substituted heteroaryl; -alkyl-O-alkyl; -alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl: 30 -alkyl-O- alkenyl; -alkyl-S- alkenyl; and -alkyl or alkenyl substituted by one or more substituents selected from: -OH; -halogen; -N(R6 9)2; -CO-N(R629)2; -CS-N(R629)2; -SO2-N(R629)2; -NR629-CO-CMO alkyl; -NR629-CS-Cι-10 alkyl; -NR629-SO2-C1-10 alkyl; -CO-Ci-io alkyl; -CO-O-CMO alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -CO-aryl; -CO-(substituted aryl); -CO-heteroaryl; and -CO-(substituted heteroaryl); R329 and R42 are independently selected from hydrogen, alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino, and alkylthio; R529 is H or CMO alkyl, or R52 can join with X to form a ring that contains one or two heteroatoms; each R629 is independently H or C1-10alkyl; R729 is H or CMO alkyl which may be interrupted by a heteroatom; or when R129 is alkyl, R729 and R12 can join to form a ring; and pharmaceutically acceptable salts thereof. In another embodiment, the J M compound can be chosen from 1 -position ether or thioether substituted lH-imidazo[4,5-c]pyridin-4-amines defined by Formula XXX below:
Figure imgf000062_0001
XXX
wherein: X is -CH(R530)-, -CH(R530)-alkylene-, -CH(R530)-alkenylene-, or CH(R530)-alkylene-Y-alkylene-; Y is -O-, or-S(O)o-2-; -W-R13o is selected from -O-R O^-S and -S(O)o-2-Rι3o-6; Ri30-ι-5 is selected from -R63o-C(R730)-Z-R830— alkyl; -R630-C(R730)-Z-R830— alkenyl; -R63o-C(R73o)-Z-R83o— aryl; -R630-C(R73o)~Z-R83o— heteroaryl; -R63o-C(R730)-Z-R83o— heterocyclyl; -R630-C(R73o)-Z-H; -R63o-N(R930)-C(R730)-R83o— lkyl; -R63o-N(R930)-C(R730)-R83o— alkenyl; -R630-N(R930)-C(R73o)-R83o-aryl; -R63o-N(R93o)-C(R730)-R83o-heteroaryl; -R63o-N(R930)-C(R730)-R8 o-heterocyclyl; -R630-N(R93o)-C(R730)-R1o3o; -R630—N(R930)—SO2—R83o— alkyl; -R63o—N(R93o)—SO2—R83o— alkenyl; -R630-N(R930)-SO2-R83o-aryl; -R63o-N(R93o)-SO2-R83o-heteroaryl; -R63o-N(R930)-SO2-R83o-heterocyclyl; -R63o— N(R930)— SO2— R1030; -R63o-N(R93o)-SO2-N(R530)-R83o-alkyl; -R63o-N(R930)-SO2-N(R53o)-R83o-alkenyl; -R63o-N(R93o)-SO2-N(R53o)-R83o-aryl; -R63o-N(R93o)-SO2-N(R530)-R830-heteroaryl; -R630-N(R93o)-SO2-N(R53o)-R83o-heterocyclyl; -R630-N(R930)-SO2-NH2; -R63o-N(R930)-C(R730)— N(R530)-Q-R830-alkyl; -R630-N(R930)-C(R730)— N(R530)-Q-R830-alkenyl; -R630-N(R93o)-C(R730)— N(R530)-Q-R830-aryl; -R63o-N(R930)- C(R730)— N(R530)-Q-R830-heteroaryl; -R630-N(R93o)- C(R73o)— N(R53o)-Q-R830-heterocyclyl; -R630-N(R930)— C(R730)— N(R530)2;
-R630-N(R930)-C(R730)- N A ;
-R630-N(R93o)-C(R73o)— N(R1130)-Q— Rsso-alkyl; -R63o-N(R930)-C(R73o)— N(Rπ30)-Q— R830-alkenyl; -R630-N(R930)-C(R73o)— N(R1130)-Q— Rsso-aryl; -R63o-N(R930)- C(R730)— N(R1130)-Q— R830-heteroaryl; -R630-N(R93o)- C(R730)— N(Ri 13o)-Q— Rs30-heterocyclyl; -R630-N(R930)- C(R730)— N( n3o)H; -alkenyl; -aryl; -R630-aryl; -heteroaryl; -heterocyclyl; -R63o- heteroaryl; and -R630-heterocyclyl; Z is-N(R53o)- -O-, or -S-;
Q is a bond, -CO- or -SO2-; A represents the atoms necessary to provide a 5- or 6-membered heterocyclic or heteroaromatic ring that contains up to three heteroatoms; R13o-6 is selected from: -alkyl; -aryl; -heteroaryl; -heterocyclyl; -alkenyl; -R630-aryl; -R63o- heteroaryl; and -R630-heterocyclyl; each R53o is independently hydrogen, CMO alkyl, or C2-10 alkenyl; R630 is alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups; R730 is =O or =S; R830 is a bond, alkylene, alkenylene, or alkynylene, which may be interrupted by one or more -O- groups; R93o is hydrogen, CMO alkyl, or arylalkyl; or R93o can join together with any carbon atom of R63o to form a ring of the formula
Figure imgf000064_0001
Ri03o is hydrogen or CMO alkyl; or R930 and R1030 can join together to form a ring selected from
Figure imgf000064_0002
R1130 is CMO alkyl; or R930 and R1130 can join together to form a ring having the structure
Figure imgf000064_0003
R1230 is C2-7 alkylene which is straight chain or branched, wherein the branching does not prevent formation of the ring; and R23o, R330 and R430 are independently selected from hydrogen and non-interfering substitutents; and pharmaceutically acceptable salts thereof. Illustrative non-interfering R230 substituents include: -alkyl; -alkenyl; -aryl; -heteroaryl; -heterocyclyl; -alkylene- Y-alkyl; -alkylene- Y- alkenyl; -alkylene- Y-aryl; and - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(R530)2; -C(O)-Cuo alkyl; -C(O)-O-Ci-10 alkyl; -N3; -aryl; -heteroaryl; -heterocyclyl; -C(O)-aryl; and -C(O)-heteroaryl. Illustrative non-interfering R33o and R430 substitutents include: CMO alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 alkylthio, amino, alkylamino, dialkylamino, halogen, and nitro. In another embodiment, the IRM compound can be chosen from IH-imidazo dimers of the formula (XXXI):
Figure imgf000066_0001
wherein: A is a divalent linking group selected from the group consisting of: straight or branched chain C -20 alkylene; straight or branched chain C4-20 alkenylene; straight or branched chain C -20 alkynylene; and -Z-Y-W-Y-Z-; each Z is independently selected from the group consisting of: straight or branched chain C2-2o alkylene; straight or branched chain C -20 alkenylene; and straight or branched chain C4-2o alkynylene; any of which may be optionally interrupted by -O-, -N(R531)-, or -S(O)2-; each Y is independently selected from the group consisting of: a bond;
Figure imgf000066_0002
-N(R53ι)C(O)N(R53i)-;
Figure imgf000066_0003
-S(O)2N(R53ι)-; -OC(O)O-; -OC(O)-; -C(O)O-; -N(R53ι)C(O)O-; and -OC(O)N(R531)-; W is selected from the group consisting of: straight or branched chain C2-2o alkylene; straight or branched chain C2-20 alkenylene; straight or branched chain C4-2o alkynylene; straight or branched chain perfluoro C2-20 alkylene; C1-4 alkylene-O-C1-4 alkylene; -C(O)-; -S(O)2-; -OC(O)O-; -N(R531)C(O)N(R531)-;
Figure imgf000067_0001
1,5-naphthylene; 2,6-pyridinylene; 1 ,2-cyclohexylene; 1,3-cyclohexylene; 1 ,4-cyclohexylene; trans- 1 ,4-cyclohexylene;
Figure imgf000067_0002
trans-5-norbornen-2,3-diyl; wherein n is 0 - 4; each R is independently selected from the group consisting of C1-4 alkyl, Cι-4 alkoxy, and halogen; and Q is selected from the group consisting of a bond, -CH2-, and -O-; R 31 is selected from the group consisting of: -hydrogen; -alkyl; -allcenyl; -aryl; -substituted aryl;
-heteroaryl; -substituted heteroaryl; -alkyl-X-alkyl; -alkyl-X-aryl; -alkyl-X- alkenyl; and
-alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH; -halogen; -N(Re31)2; -C(O)-N(R631)2; -C(S)-N(R631)2; -S(O)2-N(R631)2; -N(R63i)-C(O)-C1-10 alkyl; -N(R631)-C(S)-C1-10 alkyl; -N(R63i)- S(O)2-Cι-ιo alkyl; -C(O)-C1-10 alkyl; -C(O)-O-Cι-10 alkyl; -N3; -aryl; -substituted aryl; -heteroaryl; -substituted heteroaryl; -heterocyclyl; -substituted heterocyclyl; -C(O)-aryl; -C(O)-(substituted aryl); -C(O)-heteroaryl; and -C(O)-(substiruted heteroaryl); R331 and R^ are each independently selected from the group consisting of: -hydrogen; -halogen; -alkyl; -alkenyl; -X-alkyl; and -N(R631)2; or when taken together, R331 and R 31 form a fused aryl or heteroaryl ring that is unsubstituted or substituted by one or more substituents selected from the group consisting of: -halogen; -alkyl; -alkenyl; -X-alkyl; and -N(R631)2; or when taken together, R331 and R431 form a fused 5 to 7 membered saturated ring, containing 0 to 2 heteroatoms and unsubstituted or substituted by one or more substituents selected from the group consisting of: -halogen; -alkyl; -alkenyl; -X-alkyl; and -N(R631)2; each R531 is independently selected from the group consisting of: hydrogen; C1-6 alkyl; C3-7 cycloalkyl; and benzyl; or when Y is -N(R531)C(O)-, -C(O)N(R531)-, -N(R53ι)C(O)N(R531)-, -N(R531)S(O)2-, -S(O2)N(R53ι)-, -N(R531)C(O)O-, or -OC(O)N(R531)- and the nitrogen of the N(R531) group is bonded to Z, then R531 can join with Z to form a ring having the structure
Figure imgf000070_0001
each R631 is independently hydrogen or CMO alkyl; R731 is C3-8 alkylene; and X is -O- or -S-; with the proviso that if W is -C(O)-, -S(O)2-, -OC(O)O-, or -N(R531)C(O)N(R53ι)- then each Y is a bond; and pharmaceutically acceptable salts thereof. In another embodiment, the IRM compound can be chosen from 6-, 7-, 8-, or imposition aryl or heteroaryl substituted lH-imidazo[4,5-c]quinolin-4-amines of the following Formula (XXXII):
Figure imgf000070_0002
XXXII
wherein: R32 is selected from the group consisting of alkyl, alkoxy, hydroxy, and trifluoromethyl; n is O or 1; Ri32 and R232 are independently selected from the group consisting of hydrogen and non-interfering substitutents; R332 is selected from the group consisting of: -Z-Ar, -Z-Ar'-Y-R432, -Z-Ar'-X-Y-R432,
Figure imgf000071_0001
-Z-Ar'-X-R532; Ar is selected from the group consisting of aryl and heteroaryl both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, methylenedioxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; Ar' is selected from the group consisting of arylene and heteroarylene both of which can be unsubstituted or can be substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylalkoxy, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclyl, heterocyclylalkyl, amino, alkylamino, and dialkylamino; X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of: -S(O)o-2-, -S(O)2-N(R832)-, -C(R632)-, -C(R632)-O-, -O-C(R632)-, -O-C(O)-O-, -N(R832)-Q-,
Figure imgf000071_0002
-O-C(R632)-N(R832)-, -C(R632)-N(OR932)-,
Figure imgf000071_0003
Figure imgf000072_0001
Z is selected from the group consisting of a bond, alkylene, alkenylene, and alkynylene; R 32 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R532 is selected from the group consisting of:
-N C(R632)
Figure imgf000072_0002
Figure imgf000072_0003
each R632 is independently selected from the group consisting of =O and =S; each R 32 is independently C2-7 alkylene; each R832 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl; R932 is selected from the group consisting of hydrogen and alkyl; each RΪ032 is independently C3-8 alkylene; A is selected from the group consisting of-O-, -C(O)-, -S(O)o-2-, -CH2-, and -
Q is selected from the group consisting of a bond, -C(R632)-, -C(R632)-C(R632), -S(O)2-, -C(R632)-N(R832)-W-, -S(O)2-N(R832)-, -C(R632)-O-, and -
C(R632)-N(OR932)-; V is selected from the group consisting of -C(R632)-, -O-C(R632)-, -N(R832)-C(R632)-, and -S(O)2-; W is selected from the group consisting of a bond, -C(O)-, and— S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; and pharmaceutically acceptable salts thereof. Illustrative non-interfering R132 substituents include: -R432, -X-R 32,
Figure imgf000073_0001
-X-Y-X-Y-R432, and -X-R532; wherein: each X is independently selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; each Y is independently selected from the group consisting of: -S(O)0-2-, -S(O)2-N(R832)-, -C(R632)-, -C(R632)-O-, -O-C(R632)-, -O-C(O)-O-, -N(R832)-Q-, -C(R632)-N(R832)-, -O-C(R632)-N(R832)-, -C(R632)-N(OR932)-,
Figure imgf000074_0001
32 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,
(dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R532 is selected from the group consisting of:
-N - C(R632)
Figure imgf000074_0002
Figure imgf000074_0003
each R632 is independently selected from the group consisting of =O and =S; each R732 is independently C2-7 alkylene; each R8 2 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl; each R932 is independently selected from the group consisting of hydrogen and alkyl; each R1032 is independently C3-8 alkylene; A is selected from the group consisting of-O-, -C(O)-, -S(O)0-2-, -CH2-, and - each Q is independently selected from the group consisting of a bond, -C(R632)-, -C(R632)-C(R632)~, -S(O)2-, -C(R632)-N(R832)-W-, -S(O)2-N(R832)-, -C(R632)-O-, and -C(R632)-N(OR932)-; each V is independently selected from the group consisting of -C(R632)-, -O-C(R632)-, -N(R832)-C(R632)-, and -S(O)2-; each W is independently selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7; Illustrative non-interfering R232 substitutents include: -R4325 -X-R 32, -X-Y-R432, and -X-R532; wherein: X is selected from the group consisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene, and heterocyclylene wherein the alkylene, alkenylene, and alkynylene groups can be optionally interrupted or terminated with arylene, heteroarylene, or heterocyclylene, and optionally interrupted by one or more -O- groups; Y is selected from the group consisting of: -S(O)o-2-, -S(O)2-N(R832)-, -C(R632)-, -C(R632)-O-, -O-C(R632)-, -O-C(O)-O-, -N(R832)-Q-, -C(R632)-N(R832)-, -O-C(R632)-N(R832)-, -C(R632)-N(OR932)-,
Figure imgf000076_0001
-NN--RR773322--NN-- Q- V32
Figure imgf000076_0002
R432 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino, (dialkylamino) alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl, and heterocyclyl, oxo; R532 is selected from the group consisting of:
■ γN
Figure imgf000076_0003
each R632 is independently selected from the group consisting of =O and =S; each R732 is independently C2-7 alkylene; each R83 is independently selected from the group consisting of hydrogen, alkyl, alkoxyalkylenyl, and arylalkylenyl; R932 is selected from the group consisting of hydrogen and alkyl; each RΪ032 is independently C3-8 alkylene; A is selected from the group consisting of-O-, -C(O)-, -S(O)o-2~, -CH2-, and - N(EU32)-; Q is selected from the group consisting of a bond, -C(R632)-, -C(R632)-C(R632)-, -S(O)2-, -C(R632)-N(R832)-W-, -S(O)2-N(R832)-, -C(R632)-O-, and -
C(R632)-N(OR932)-; V is selected from the group consisting of -C(R632)-, -O-C(R632)-, -N(R832)-C(R632)-, and -S(O)2-; W is selected from the group consisting of a bond, -C(O)-, and -S(O)2-; and a and b are independently integers from 1 to 6 with the proviso that a + b is < 7;
Herein, "non-interfering" means that the ability of the compound or salt to modulate (e.g., induce or inhibit) the biosynthesis of one or more cytokines is not destroyed by the non-interfering substituent. As used herein, the terms "alkyl", "alkenyl", "alkynyl" and the prefix "alk-" are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to
20 carbon atoms, with alkenyl and alkynyl groups containing from 2 to 20 carbon atoms.
In some embodiments, these groups have a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6 carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, adamantyl, and substituted and unsubstituted bornyl, norbornyl, and norbornenyl. Unless otherwise specified, "alkylene", "alkenylene", and "alkynylene" are the divalent fonris of the "alkyl", "alkenyl", and "alkynyl" groups defined above. Likewise,
"alkylenyl", "alkenylenyl", and "alkynylenyl" are the divalent forms of the "alkyl", "alkenyl", and "alkynyl" groups defined above. For example, an arylalkylenyl group comprises an alkylene moiety to which an aryl group is attached. The term "haloalkyl" is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of other groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like. Similarly, the term "fluoroalkyl" is inclusive of groups that are substituted by one or more fluorine atoms, including perfluorinated groups (e.g., trifluoromethyl) . The term "aryl" as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl. The teπn "heteroatom" refers to the atoms O, S, or N. The term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, rriazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl, oxadiazolyl, thiadiazolyl, and so on. The term "heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring heteroatom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl, homopiperidinyl, homopiperazinyl, and the like. The terms "arylene," "heteroarylene," and "heterocyclylene" are the divalent forms of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. Likewise, "arylenyl," "heteroarylenyl," and "heterocyclylenyl" are the divalent forms of the "aryl," "heteroaryl," and "heterocyclyl" groups defined above. For example, an alkylarylenyl group comprises an arylene moiety to which an alkyl group is attached. Unless otherwise specified, the aryl, heteroaryl, and heterocyclyl groups of
Formulas IX - XXX can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, aroyloxy, aroylthio, aroylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, heteroarylaminocarbonyl, heteroarylalkylaminocarbonyl, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylaminocarbonylamino and, in the case of heterocyclyl, oxo. If any other groups are identified as being "substituted" or "optionally substituted", then those groups can also be substituted by one or more of the above enumerated substituents. When a group (or substituent or variable) is present more that once in any Fonnula described herein, each group (or substituent or variable) is independently selected, whether explicitly stated or not. For example, for the formula -N(R631)2 each R631 group is independently selected. In another example, when an R232 and an R332 group both contain an R-132 group, each R 32 group is independently selected. In a further example, when more than one Y group is present (i.e. R232 and R332 both contain a Y group) and each Y group contains one or more Rs32 groups, then each Y group is independently selected, and each R832 group is independently selected. In certain embodiments, the immune response modifier is selected from the group consisting of imidazoquinolme amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinolme amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, IH- imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof. hi certain embodiments, the immune response modifier is selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, and combinations thereof. In certain embodiments, the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinoline amines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines, heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazoquinoline amines, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers, thioether substituted imidazopyridine amines, and combinations thereof. In certain embodiments, the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, thioether substituted imidazoquinoline amines, 7-aryl substituted imidazoquinoline amines, 7-heteroaryl substituted imidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, and combinations thereof. hi certain embodiments, the immune response modifier is a sulfonamide substituted imidazoquinoline amine. In certain embodiments, the immune response modifier is selected from the group consisting of: N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yljbutyl} -4-fluoro- 1 -benzenesulfonamide,
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]mo holine-4- carboxamide,
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2,2- dimethylpropyl} -N'-phenylurea,
N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}methanesulfonamide,
2-butyl- 1 - [2-(propylsulfonyl)ethyl] - IH-imidazo [4,5-c] quinolin-4-amine,
N- {2- [4-amino-2-(ethoxymethyl)- 1 H-imidazo [4,5-c] quinolin- 1 -yl] -1,1 -dimethylethyl} -2- ethoxyacetamide,
N- {4- [4-amino-2-(cyclopropylmethyι)- 1 Η-imidazo [4,5-c] quinolin- 1 - yl]butyl}methanesulfonamide,
N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l-dimethylethyl}-N'- cyclohexylurea, N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}cyclohexanecarboxamide,
N-{2-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydrp-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}methanesulfonamide,
N- [3 -(4-amino-2-butyl- 1 H-imidazo [4, 5 -c] quinolin- 1 -yl)-2,2- dimethylpropyl]methanesulfonamide,
N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)-l,l- dimethylethyl]methanesulfonamide,
N-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l-yl]-
1 , 1 -dimethylethyljmethanesulfonamide, l-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-lH-imidazo[4,5- c]quinolin-l-yl]-2-methylpropan-2-ol, 1 - [4-amino-7-(3 -hydroxymethyphenyl)-2-(2-methoxyethyl)- IH-imidazo [4,5-c] quinolin- 1 - yl]-2-methylpropan-2-ol,
N-{3-[4-amino-l-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-lH-imidazo[4,5- c]quinolin-7-yl]phenyl}methanesulfonamide, {5 - [4-amino-2-(2-methoxyethyl)- 1 -(2-methylpropyl)- 1 H-imidazo [4,5-c] quinolm-7- yl]pyridin-3 -yl} methanol, l-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-l-yl]-2- methylpropan-2-ol, l-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-lH-imidazo[4,5- c]quinolin-l-yl}-2-methylpropan-2-ol,
N-(2-{4-amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy]-lΗ-imidazo[4,5- c] quinolin- 1 -yl} - 1 , 1 -dimethylethyl)methanesulfonamide,
N-(6-{[4-amino-2-ethoxymethyl-l-(2-methanesulfonylamino-2-methylpropyl)-lH- imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide, N- [2-(4-amino-2-ethoxymethyl- 1 -propyl- 1 H-imidazo [4, 5 -c] quinolin-7- yloxy)ethyl]methanesulfonamide, l-[4-amino-2-(ethoxymethyl)-7-(lH-pyrazol-4-yl)-lH-imidazo[4,5-c]quinolin-l-yl]-2- methylpropan-2-ol,
3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-lH-imidazo[4,5-c]quinolin-l-yl]propane- 1,2-diol, and combinations thereof In certain embodiments, the immune response modifier is selected from the group consisting of:
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]morpholine-4- carboxamide,
N- {3 - [4-amino-2-(2-methoxyethyl)- IH-imidazo [4, 5 -c] quinolin- 1 -yl] -2,2- dimethylpropyl} -N'-phenylurea,
N- {2- [4-amino-2-(ethoxymethyl)- 1 H-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl}methanesulfonamide, 2-butyl- 1 - [2-(propylsulfonyl)ethyl] - IH-imidazo [4, 5 -c] quinolin-4-amine,
N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l-dimethylethyl}-2- ethoxyacetamide, N- {2-[4-amino-2-(ethoxymethyl)- IH-imidazo [4,5-c] quinolin- 1 -yl] -1,1 -dimethylethyl} -N'- cyclohexylurea,
N-{2-[4-ammo-2-(ethox methyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}methanesulfonamide, N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)-l,l- dimethylethyljmethanesulfonamide,
N-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l-yl]-
1 , 1 -dimethylethyl}methanesulfonamide, l-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-lH-imidazo[4,5- c] quinolin- 1 -yl} -2-methylpropan-2-ol,
N-(6- { [4-amino-2-ethoxymethyl- 1 -(2-methanesulfonylamino-2-methylpropyl)- 1Η- imidazo [4,5-c] quinolin-7-yι] oxy} hexyl)acetamide, and combinations thereof. In certain embodiments, the immune response modifier is N-{2-[4-amino-2- (ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l-dimethylethyl}methanesulfonamide and pharmaceutically acceptable salts thereof. The IRM compounds and salts thereof described herein include any of their pharmaceutically acceptable forms, such as isomers (e.g., diastereomers and enantiomers), solvates, polymorphs, and the like. In particular, if a compound is optically active, the invention specifically includes the use of each of the compound's enantiomers as well as racemic combinations of the enantiomers. The immune response modifier can, for example, be a salt of an acid selected from the group consisting of a carboxylic acid, a halo acid, sulfuric acid, phosphoric acid, dicarboxylic acid, tricarboxylic acid, and combinations thereof. In certain embodiments, the salt of the immune response modifier can be a salt of an acid selected from the group consisting of hydrobromic acid, hydrochloric acid, lactic acid, glutamic acid, gluconic acid, tartaric acid, succinic acid, and combinations thereof. The immune response modifier is substantially completely dissolved at a therapeutic level (i.e., therapeutically effective amount) in the foraiulation at room temperature. This amount is effective to treat and/or prevent a specified condition (e.g., allergic rhinitis, a viral infection, sinusitis, asthma). In general, the amount of the IRM compound present in an aqueous (preferably, sprayable) formulation of the invention will be an amount effective to provide a desired physiological effect, e.g., to treat a targeted condition (e.g., reduce symptoms of allergic rhinitis), to prevent recuπence of the condition, or to promote immunity against the condition. For certain embodiments, an amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more manifestations of viral infections, such as viral load, rate of virus production, or mortality as compared to untreated control animals. The amount of an IRM compound that will be therapeutically effective in a specific situation will depend on such things as the activity of the particular compound, the dosing regimen, the application site, the particular formulation and the condition being treated. As such, it is generally not practical to identify specific administration amounts herein; however, those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to these compounds, and routine testing. In certain embodiments of the formulations of the invention, the amount or concentration of the IRM compound (or combinations of IRMs) is at least 0.0001% by weight (wt-%), in other embodiments, at least 0.001 wt-%, in other embodiments at least 0.01 wt-%, in other embodiments at least 0.1 wt-%, in other embodiments at least 0.5 wt- %, in other embodiments at least 1.0 wt-%, and in other embodiments at least 1.5 wt-%, based on the total formulation weight. In certain embodiments, the amount of the IRM compound (or combinations of IRMs) is at most 5.0 wt-%, and in other embodiments at most 3.0 wt-%, based on the total formulation weight.
Hydrophilic Viscosity Enhancing Agents Formulations of the invention include a hydrophilic viscosity enhancing agent, preferably one that is a mucoadhesive. In this context, hydrophilic means the agent is water soluble or water dispersible. Examples of suitable hydrophilic viscosity enhancing agents include: cellulose ethers such as hydroxypropyl methylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, and carboxymethylcellulose sodium; polysaccharide gums such as xanthan gum and carrageenan; and acrylic acid polymers (i.e., homopolymers and copolymers) made from acrylic acid crosslinked with, for example, allyl sucrose or allyl pentaerythriol such as those polymers designated as carbomers in the United States Phaπnacopoeia. Various combinations of these can be used if desired. Certain embodiments of the present invention include an acrylic acid polymer (i.e., polyacrylic acid polymer), carboxymethylcellulose sodium, xanthan gum, and combinations thereof. Various grades of carboxymethylcellulose sodium are commercially available that have differing aqueous viscosities. Aqueous 1% weight by volume (w/v) solutions with viscosities of 5-13,000 cps may be obtained. Examples include carboxymethylcellulose sodium, high viscosity, USP (CA194); carboxymethylcellulose sodium, medium viscosity, USP (CA192); and carboxymethylcellulose sodium, low viscosity, USP (CA193); all of which are available from Spectrum Chemicals and Laboratory Products, Inc., Gardena, CA, USA; and AKUCELL AF 3085 (high viscosity), AKUCELL AF 2785 (medium viscosity), and AKUCELL AF 0305 (low viscosity), all of which are available from Akzo Nobel Functional Chemicals, Amersfoort, The Netherlands. In some embodiments of the invention, grades of carboxymethylcellulose sodium having a low aqueous viscosity are prefened. In some embodiments of the invention, the hydrophilic viscosity enhancing agent is negatively charged. These include carboxymethylcellulose sodium, xanthan gum, and the carbomers. In some embodiments of the invention, the hydrophilic viscosity enhancing agent includes carboxylic acid and/or carboxylate groups. Examples of such agents include carboxymethylcellulose sodium, xanthan gum, and the acrylic acid polymers. In some embodiments of the invention the hydrophilic viscosity enhancing agent is uncrosslinked. Examples of such agents include cellulose ethers and xanthan gum. The hydrophilic viscosity enhancing agent is present in formulations of the invention in an amount sufficient to bring the viscosity to a level of less than 100 centipoise (cps), preferably less than about 50 cps, more preferably less than about 20 cps, and most preferably less than about 10 cps. The viscosity is determined at 20 ± 0.1 °C 1 1 using a double-gap concentric cylinder at a controlled strain rate of 10 s" to 1000 s" . In certain embodiments, the amount or concentration of the hydrophilic viscosity enhancing agent (or combinations of such agents) is at least 0.01 wt-%, in other embodiments at least 0.025 wt-%, in other embodiments at least 0.05 wt-%, and in other embodiments at least 0.1 wt-%, based on the total formulation weight. In certain embodiments, the amount of the viscosity enhancing agent (or combinations of such agents) is at most 2.0 wt-%, in other embodiments at most 1.0 wt-%, in other embodiments at most 0.5 wt-%, and in other embodiments at most 0.25 wt-%, based on the total formulation weight.
pH Adjusting Agents and Buffers Formulations of the invention can additionally include a pharmaceutically acceptable pH adjusting agent to adjust the pH of the formulation to the desired range. Generally, the pH is at least 4. Typically, the pH is no greater than 8, usually no greater than 7, and in some cases no greater than 6. The pH adjusting agent may be any pharmaceutically acceptable acid or base. Examples of suitable pH adjusting agents include hydrochloric acid, sodium hydroxide, tromethamine, and potassium hydroxide. Combinations of such agents can be used if desired. The formulations of the invention can additionally include a pharmaceutically acceptable buffer to maintain the pH of the formulations in the desired range (generally, 4 to 8, usually, 4 to 7, and often, 4 to 6). The buffer maybe any pharmaceutically acceptable buffer that provides one or more of the desired pH ranges. Examples of suitable buffers include buffers containing lactic acid, tartaric acid, citric acid, and succinic acid. Combinations of buffers can be used if desired. The buffers can also function as tonicity adjusting agents.
Cosolvents The formulations of the invention can additionally include a water-miscible cosolvent. The water-miscible cosolvent assists in dissolving the immune response modifier or a salt thereof. The cosolvent can be a single component or a combination.
Examples of suitable cosolvents include propylene glycol, glycerin, polyethylene glycol 400, diethylene glycol monoethyl ether, and combinations thereof. Certain water-miscible cosolvents, such as glycerin or propylene glycol, also add beneficial humectant properties to the formulations. hi certain embodiments, the cosolvent (or combination of cosolvents) is present in an amount of at least 5 wt-%, in other embodiments at least 10 wt-%, and in other embodiments at least 15 wt-%, based on the total weight of the formulation. In certain embodiments, the cosolvent (or combination of cosolvents) is present in an amount of at most 25 wt-%, and in other embodiments at most 20 wt-%, based on the total weight of the formulation. In certain preferred formulations, the cosolvent is present in an amount of 5 wt-% to 15 wt-%. In certain embodiments, if a cosolvent is used, then water is present in an amount of at least 75 wt-%, and in other embodiments at least 80 wt-%, based on the total weight of the formulation. In certain embodiments, if a cosolvent is used, then water is present in an amount of at least 90 wt-%, and in other embodiments at least 95 wt-%, based on the total weight of the formulation.
Preservatives The formulations of the invention can additionally include a preservative. The preservative includes one or more compounds that inhibit microbial growth (e.g., fungal and bacterial growth) within the composition. Suitable preservatives include benzalkonium chloride, benzethonium chloride, methylparaben, propylparaben, phenyl ethyl alcohol, and combinations thereof. Preferably, the preservative is benzalkonium chloride. Certain water-miscible cosolvents, such as glycerin or propylene glycol, also have antimicrobial properties when present in amounts greater than 15 wt-%. In certain embodiments, the preservative (or combination of preservatives) is present in an amount of at least 0.005 wt-%, in other embodiments at least 0.01 wt-%, and in other embodiments at least 0.02 wt-%, based on the total weight of the formulation, hi certain embodiments, the preservative (or combination of preservatives) is present in an amount of at most 0.5 wt-%, and in other embodiments at most 0.2 wt-%, based on the total weight of the formulation.
Chelating agents The formulations of the invention can additionally include a chelating agent. Chelating agents are compounds that complex metal ions. Examples of suitable chelating agents include ethylenediaminetetracetic acid (EDTA) and derivatives thereof such as the disodium salt, and ethylenediaminetetracetic acid disodium salt dihydrate. Preferably, the chelating agent is ethylenediaminetetracetic acid disodium salt dihydrate (edetate disodium). In certain embodiments, the chelating agent (or combination of chelating agents) is present in an amount of at least 0.005 wt-%, in other embodiments at least 0.01 wt-%, in other embodiments at least 0.02 wt-%, and in other embodiments at least 0.05 wt-%, based on the total weight of the formulation. In certain embodiments, the chelating agent (or combination of chelating agents) is present in an amount of at most 0.5 wt-%, and in other embodiments at most 0.2 wt-%, based on the total weight of the formulation.
Applications Formulations of the invention can be applied to the respiratory tract (e.g., nasal passages) of a subject (particularly, e.g., a mammal). Depending on the particular IRM compound, IRM compound concentration, and formulation composition, the therapeutic effect of the IRM compound may extend only to the superficial layers of the respiratory tract (e.g., nasal passages) or to tissues below the surface. Thus, another aspect of the present invention is directed to a method for the treatment of a nasal-associated condition by applying (preferably by spraying) one of the foregoing formulations into the nasal passages. As used herein, a "nasal-associated condition" is defined as a condition in which an extrinsic protein (i.e., allergen, viral, bacterial, fungal) contacts the nasal mucosa creating an allergic and/or flu-like immune response. Examples include allergic rhinitis, sinusitis, asthma, and influenza. Allergic rhinitis is a nasal-associated condition in which a subject is sensitized to one or more antigens (i.e., allergens). When a sensitized subject is re-exposed to an antigen, mediators are released quickly leading to rhinoπhea, increased nasal mucosal secretions, increased vascular permeability and vasodilation in the subject's nasal mucosa. IRMs have the ability to desensitize a subject to one or more antigens. As can be seen in
Table 7, the formulation of Example 61 which contains IRM 22, when dosed at 0.375 wt- %, was able to inhibit 95% of nasal perfusion of Evan's blue when the sensitized subjects were re-exposed to the antigen ovalbumin. Thus, when a subject is treated with an IRM prior to a re-exposure to an antigen, the IRM is capable of desensitizing subjects who have been sensitized to an antigen. Accordingly, the present invention includes use of the formulations described herein for treating and/or preventing allergic rhinitis, treating and/or preventing a viral infection, treating and or preventing sinusitis, and treating and/or preventing asthma. For treatment of asthma, the formulations would generally be delivered to the lung via inhalation, e.g., by a nebulizer or spray. The present invention also provides a method of desensitizing a subject to an antigen, the method involves administering to the subject an IRM compound in a formulation of the present invention, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen. Preferably, the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen. The formulations of the present invention can also be used administered together
(e.g., in one composition or separately but simultaneously) with a vaccine for enhanced vaccine effectivity. In some embodiments, the methods of the present invention include administering sufficient formulation to provide a dose of IRM compound of, for example, from 100 ng kg to 50 mg/kg to the subject, although in some embodiments the methods may be performed by administering IRM compound in concentrations outside this range. In some of these embodiments, the method includes administering sufficient formulation to provide a dose of IRM compound of from 10 μg/kg to 5 mg/kg to the subject, for example, a dose of from 100 μg/kg to 1 mg/kg. In some embodiments, the above-described formulations are particularly advantageous for application for a period of time sufficient to obtain a desired therapeutic effect without undesired systemic absoφtion of the IRM.
EXAMPLES Objects and advantages of this invention are further illustrated by the following examples, but the particular materials and amounts thereof recited in these examples, as well as other conditions and details, should not be construed to unduly limit this invention.
IRM COMPOUNDS The IRM compounds that were used to prepare the aqueous formulations are shown in Table 1 below.
Figure imgf000090_0001
Table 1
Compound Chemical Name Reference
IRM 21 N-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro- U.S. 6,331,539* lH-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl}methanesulfonamide
IRM 22 N- [2-(4-amino-2-butyl- 1 H-imidazo [4,5-c] quinolin- 1 -yl)- U.S. 6,677,349" 1 , 1 -dimethylethyljmethanesulfonamide
TRM 23 N-{4-[4-amino-2-(cyclopropylmethyl)-lH-imidazo[4,5- U.S. 6,677,349 c]quinolin-l-yl]butyl}methanesulfonamide Example 270
IRM 24 N-(2-{4-amino-2-ethoxvmethyl-7-[6- U.S. Ser. No. (methanesulfonylamino)hexyloxy]-lH-imidazo[4,5- 60/508634 cjquinolin- 1 -yl} - 1 , 1 -dimethylethyl)methanesulfonamide Example 45
IRM 25 N-(6- { [4-amino-2-ethoxymethyl- 1 -(2- U.S. Ser. No. methanesulfonylamino-2-methylpropyl)-lH-imidazo[4,5- 60/508634 c] quinolin-7-yl] oxy } hexyl)acetamide Example 46
IRM 26 1 - {4-amino-2-(ethoxymethyl)-7-[5- WO 04/058759 (hydroxymethyl)pyridin-3-yl]-lH-imidazo[4,5- Example 133 c] quinolin- 1 -yl} -2-methylpropan-2-ol
IRM 27 1 -(2-methylpropyl)- 1 H-imidazo [4,5-c] U.S. 6,194,425 [l,5]naphthyridin-4-amine Example 32
IRM 28 N- {4- [4-amino-2-(3 -phenoxypropyl)- 1 H-imidazo [4,5- U.S. 6,677,349 c]quinolin-l-yl]butyl}methanesulfonamide Example 262
TRM 29 2-butyl- 1 -[2-(propylsulfonyl)ethyl] - IH-imidazo [4,5- U.S. 6,667,312 c] quinolin-4-amine Example 62
IRM 30 N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5- U.S. 6,573,273 c]quinolin-l-yl]propyl}-N'-phenyl urea Example 161
IRM 31 4-amino-2-ethoxymethyl-α,α,6,7-tetramethyl-lH- U.S. 5,494,916 imidazo[4,5-c]pyridine-l-ethanol Example 47
IRM 32 N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- U.S. 6,573,273" c] quinolin- 1 -yl] -1,1 -dimethylethyl} -N'-cyclohexylurea
IRM 33 N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- U.S. 6,756,382 w c] quinolin- 1 -yl] -1,1- dimethylethyl}cyclohexanecarboxamide
IRM 34 N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5- U.S. 6,756,382 c]quinolin- 1 -yl]- 1 , 1 -dimethylethyl} -2-ethoxyacetamide Example 209
IRM 35 N-{2-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-lH- U.S. 6,677,349* imidazo[4,5-c]qumolin-l~yl]-l,l- dimethylethyl}methanesulfonamide
IRM 36 N-[4-(4-amino-2-propyl-lH-imidazo[4,5-c]quinolin-l- U.S. 6,677,349 yl)butyl]methanesulfonamide Example 235
IRM 37 N- {2-[4-amino-2-(ethoxymethyl)-6,7-dimethyl- 1H- U.S. 6,545,017# imidazo[4,5-c]pyridin-l -yl]- 1 , 1 -dimethylethyl} -N'- phenylurea
IRM 38 N- [4-(4-amino-2-ethyl- 1 H-imidazo [4,5-c] quinolin- 1 - U.S. 6,677,349 yl)butyl]methanesulfonamide Example 236
TRM 39 N- {8-[4-amino-2-(methoxyethyl)- lH-imidazo[4,5- U.S. 6,677,349 c] quinolin- 1 -yl] octyl } methanesulfonamide Example 243
Figure imgf000092_0001
# This compound is not specifically exemplified but can be readily prepared using the synthetic methods disclosed in the cited reference.
EXCIPIENTS The excipients that were used to prepare the aqueous sprayable formulations are shown in Table 2 below.
Table 2
Carboxymethylcellulose sodium, low viscosity, USP (CMC)
Hydroxypropyl methylcellulose (hypromellose, 2910, 50 cps, USP; HPMC) Acetic acid, NF
Citric acid, USP
L-Lactic acid
Succinic acid
L-Tartaric acid
Polyethylene glycol 400, NF (PEG 400),
Propylene glycol, USP
Glycerin, USP
Diethylene glycol monoethyl ether, NF
Benzalkonium chloride, Ph. Eur.
Ethylenediaminetetraacetic acid disodium salt dihydrate (Edetate disodium, USP) 1 N Sodium hydroxide, NF (1 N NaOH)
10 N Sodium hydroxide, NF (10 N NaOH)
IN Hydrochloric acid, NF (1 N HCI)
Water, USP
USP United States Pharmacopeia NF National Formulary (USA) Ph. Eur. European Pharmacopeia
PREPARATION OF THE FORMULATIONS The aqueous formulations were prepared using the following general method. The hydrophilic viscosity enhancing agent was hydrated in water (about 50% of total) for about 20 minutes with stirring. The edetate sodium was added and mixed until dissolved. The resulting solution was mixed with the benzalkonium chloride. Separately, the buffering agent (if used) and the cosolvent (if used) were mixed with water; the IRM compound was added to this combination and stirred. The two combinations were combined and mixed. A pH adjuster was added, as necessary, to adjust each formulation to the desired pH. Finally, water was added to each formulation to adjust to the final formulation weight.
TEST METHOD Inhibition of Ovalbumin-Induced Changes in Plasma Extravasation in a Model of Allergic Rhinitis in Brown-Norway Rats Formulations of the invention were tested for their ability to inhibit ovalbumin- induced changes in plasma extravasation using the following test method. Male Brown-Norway rats (150-250 g) are used to monitor pulmonary and nasal responses to aerosolized antigen challenge in conscious animals and establish late pulmonary responses which can be measured by various functional or cellular measures. Groups of rats (4 to 5 per group) are sensitized to ovalbumin (grade V or VI), 4 mg/Kg, with Al(OH)3, 400 mg/Kg in 0.9% saline by intraperitoneal administration on 3 consecutive days. At > 21 days a drug solution or vehicle (control groups) is administered by nasal instillation. Nasal instillation is performed by lightly anesthetizing an animal with a combination of a solution consisting of 10 mL of ketamine HCI (100 mg/mL) and acepromazine (10 mg/mL) dosed at a rate of 60-90 mg/Kg. A solution of drug or vehicle is instilled in a drop-by-drop manner (each drop is cleared from the nasal passage before the next drop is administered) to each nare (10 μL/nare) for a total of 20 μL/animal. Ophthalmic ointment will be used in conjunction with the ketamine/xylazine combination. The animal is placed back into the cage and becomes fully alert within 1-2 hours. Twenty (20) hours later the animal is dosed a second time using the same procedure. Four (4) hours after the second dosing, animals are placed inside an inverted desiccator jar, which is placed onto a Plexiglas platform forming a chamber with a diameter of 6 inches (15 cm) and a height of 6 inches (15 cm). The platform has several ports which allow for aerosolization, for monitoring breathing patterns, for exhausting aerosolized particles and for providing a constant flow of air into the chamber from a continuous air source to prevent hypoxia. Aerosolization of H2O, ovalbumin (<100 mg/mL) is done using a DeVilbiss Ultra-Neb large volume ultrasonic nebulizer system for 10-30 minutes in duration. Following ovalbumin aerosol challenge, the animals are returned to their cages. Twenty-four (24) hours after the ovalbumin challenge, the animals are initially anesthetized using a combination of 10 mL of ketamine HCI (100 mg/mL) and 2 mL of acepromazine maleate (10 mg/mL) dosed intraperitoneally at ~60-90 mg/Kg (dose to effect). Once the animal is exhibiting no response to external stimuli (toe pinch, eye reflex, etc.) about 1 mL of lidocaine is injected subcutaneously over the trachea and surrounding neck area. An incision is made midline over the trachea and the internal or external jugular vein is exposed and cannulated (INTRAMEDIC polyethylene tubing size
PE50 is used with a 23g luer stub adapter). The trachea is exposed and a modified tracheotomy is performed (a longitudinal incision about 5 mm long). A 6f-tracheal catheter is inserted caudally and a catheter (PE40-60) inserted cranally. Both tubes are tied in place and the animal is hooked up to a HARVARD small animal respirator (~ 58 breaths/min, 4cc stroke volume). At this point the animal is given 0.1-0.25 mL of a solution consisting of 0.3 mL sodium pentobarbital and 0.7 mL saline (dose to effect). Animals in the drug treatment groups and in the ovalbumin control group receive an additional challenge with ovalbumin. A nasal perfusion line is attached to a HARVARD compact infusion pump set to deliver 0.2 mL/min and a 10% solution of ovalbumin in saline is manually "pushed" through the nasal infusion catheter slowly until 1 or 2 drops of the ovalbumin solution is expressed through the nose. Once the air is flushed out of the line with ovalbumin solution the line is attached to the infusion pump, the pump is turned on and allowed to run for 3 min at a rate of 0.2 mL/min. Animals in the saline control group are treated with saline alone. After the 3 minute exposure period the ovalbumin solution is flushed out of the line and nasal cavities with air. The nasal infusion catheter is then filled with pH adjusted PBS (about pH 5) and PBS is manually "pushed" through the nasal perfusion catheter slowly until 1 or 2 drops of PBS is expressed through the nose.
Once the air is flushed out of the line with PBS, the line is attached to the infusion pump and the pump is allowed to run for 3 min. Evans Blue dye (1 mL of 1.0%) is injected intravenously; the infusion pump is turned on and a timer is started for a 40 min collection period. The nasal perfusate is collected in a 15 mL-collection tube. One sample is collected (8 mLs for 40 min). The amount of Evans blue dye in the sample is determined spectrophotometrically (610 nm wavelength). The percent inhibition is calculated using the equation below: n / τ , ., J.. ι i (μg Evans Blue)Dmg - (μg Evans Blue)saiine control \ ■> , ΛΛ % Inhibtion = { l- ^ - ^-≤ ) jxlOO (μg Evans Blue)ovAControi - (μg Evans Blue)saiine control Where the OVA control is the group of animals that is dosed with vehicle and receives an additional challenge with ovalbumin and the saline control is the group of animals that is dosed with vehicle and receives an additional challenge with saline. Examples 1 - 17 A series of aqueous formulations containing IRM 1 were prepared and tested in a model of allergic rhinitis using the test method described above. Tables 3 and 4 show the composition of each formulation and the test result.
Figure imgf000096_0001
Figure imgf000097_0001
Examples 18 - 23 A series of aqueous formulations containing IRM 2 were prepared and tested in a model of allergic rhinitis using the test method described above. Table 5 shows the composition of each formulation and the test result.
Figure imgf000098_0001
Examples 24 - 131 A series of aqueous formulations containing IRMs were prepared and tested in a model of allergic rhinitis using the test method described above. Each IRM was formulated using one or more of the vehicles shown in Table 6. Table 7 shows the composition of each formulation and the test result.
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Example 132 IRM 1 was prepared as a 0.375% solution formulation capable of being nasally administered via a spray pump. The formulation vehicle was prepared as follows:
Figure imgf000104_0001
Carboxymethylcellulose sodium, low viscosity, USP (CMC) was hydrated in water (about 50% of total) for 20 minutes with stirring. The EDTA was added and dissolved. The CMC/EDTA solution was mixed with the benzalkonium chloride to form a CMC/EDTA/BAC solution. Separately, the lactic acid and PEG 400 were mixed with water. For the IRM 1 formulation, IRM 1 was dissolved into the lactic acid/PEG 400 solution. The CMC/EDTA/BAC solution was mixed with lactic acid/PEG 400 solution to prepare the Vehicle formulation. The CMC/EDTABAC solution was mixed with lactic acid/PEG 400/IRM 1 solution to prepare the IRM 1 formulation. 1 N NaOH was added, as necessary, to adjust each formulation to a pH of 4.0. Finally, water was added to each formulation to adjust to the final formulation weight. Fisher 344 rats (Charles River Laboratories, Raleigh, NC) were divided into six treatment groups. Rats in each group were infected intranasally with humanized, non-lethal influenza virus. 24 hours after infection, viral titers were measured in nasal lavage fluid and whole lung homogenates. The influenza virus and methods for measuring viral titers are described in Burleson, Gary L., "Influenza Virus Host Resistance Model for Assessment of hnmunotoxicity,
Immunostimulation, and Antiviral Compounds," Methods in Immunology 2:181- 202, Wiley-Liss Inc., 1995.. Each of the six treatment groups received a different pre-infection treatment. Rats in each group received the treatment indicated in Table 10. The results are summarized in Figure 1 and Figure 2.
Figure imgf000105_0001
*lx: one dose of treatment provided four hours before viral infection. **2x: one dose of treatment 24 hours (Day -1) before viral infection, second treatment four hours before viral infection (Day 0).
Example 133 A formulation containing 4-amino-α,α-dimethyl-2-ethoxymethyl-lH- imidazo[4,5-c]quinoline-l-ethanol (U.S. Pat. No. 5,389,640; Example 99) was prepared using the method described above. The composition is shown in Table 11 below.
Figure imgf000105_0002
The viscosity of the formulation was measured using a controlled stress step test. Rheometer: Ηaake RSI 50; sensor: double-gap concentric cylinder (DG41); gap: 5.100 mm; sample size: sufficient to fill the sample holder; temperature 20.0 ± 0.1 °C; initial stress: 0.10 Pa; final stress: 1.20 Pa. Three (3) separate samples were measured. The measured viscosity was 1.4 cps for each of the samples.
The complete disclosures of the patents, patent documents, and publications cited herein are incorporated by reference in their entirety as if each were individually incorporated. Various modifications and alterations to this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention. It should be understood that this invention is not intended to be unduly limited by the illustrative embodiments and examples set forth herein and that such examples and embodiments are presented by way of example only with the scope of the invention intended to be limited only by the claims set forth herein as follows.

Claims

WHAT IS CLAIMED IS:
1. An aqueous formulation comprising: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature.
2. The aqueous formulation of claim 1 wherein the immune response modifier is a positively charged immune response modifier.
3. The aqueous formulation of claims 1 or 2 wherein the hydrophilic viscosity enhancing agent is negatively charged.
4. The aqueous formulation of any one of claims 1 through 3 wherein the hydrophilic viscosity enhancing agent is uncrosslinked.
5. The aqueous formulation of any one of claims 1 through 4 wherein the hydrophilic viscosity enhancing agent is selected from the group consisting of cellulose ethers, polysaccharide gums, acrylic acid polymers, and combinations thereof.
6. The aqueous formulation of claim 5 wherein the hydrophilic viscosity enhancing agent comprises carboxylic acid groups and/or carboxylate groups.
7. The aqueous formulation of claim 6 wherein the hydrophilic viscosity enhancing agent is selected from the group consisting of a acrylic acid polymer, carboxymethyl cellulose sodium, xanthan gum, and combinations thereof.
8. The aqueous formulation of any one of claims 1 through 7 wherein the hydrophilic viscosity enhancing agent is present in an amount of at least 0.01 wt-
%, based on the total weight of the formulation.
9. The aqueous formulation of any one of claims 1 through 8 wherein the immune response modifier is present in an amount of at least 0.0001 wt-%, based on the total weight of the formulation.
10. The aqueous formulation of any one of claims 1 through 9 wherein the immune response modifier is present in an amount of at most 5.0 wt-%, based on the total weight of the formulation.
11. The aqueous formulation of any one of claims 1 through 10 wherein the immune response modifier is a compound having a 2-aminopyridine fused to a five membered nitrogen-containing heterocyclic ring.
12. The aqueous formulation of claim 11 wherein the immune response modifier is selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, IH-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof.
13. The aqueous formulation of claim 12 wherein the immune response modifier is selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, and combinations thereof.
14. The aqueous formulation of claim 13 wherein the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, aryl ether substituted imidazoquinoline amines, heterocyclic ether substituted imidazoquinoline amines, amido ether substituted imidazoquinoline amines, sulfonamido ether substituted imidazoquinoline amines, urea substituted imidazoquinoline ethers, thioether substituted imidazoquinoline amines, 6-, 7-, 8-, or 9-aryl or heteroaryl substituted imidazoquinoline amines, amide substituted tetrahydroimidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline amines, aryl ether substituted tetrahydroimidazoquinoline amines, heterocyclic ether substituted tetrahydroimidazoquinoline amines, amido ether substituted tetrahydroimidazoquinoline amines, sulfonamido ether substituted tetrahydroimidazoquinoline amines, urea substituted tetrahydroimidazoquinoline ethers, thioether substituted tetrahydroimidazoquinoline amines, amide substituted imidazopyridine amines, sulfonamide substituted imidazopyridine amines, urea substituted imidazopyridine amines, aryl ether substituted imidazopyridine amines, heterocyclic ether substituted imidazopyridine amines, amido ether substituted imidazopyridine amines, sulfonamido ether substituted imidazopyridine amines, urea substituted imidazopyridine ethers, thioether substituted imidazopyridine amines, and combinations thereof.
15. The aqueous formulation of claim 14 wherein the immune response modifier is selected from the group consisting of amide substituted imidazoquinoline amines, sulfonamide substituted imidazoquinoline amines, urea substituted imidazoquinoline amines, thioether substituted imidazoquinoline amines, 7-aryl substituted imidazoquinoline amines, 7- heteroaryl substituted imidazoquinoline amines, sulfonamide substituted tetrahydroimidazoquinoline amines, and combinations thereof.
16. The aqueous formulation of claim 15 wherein the immune response modifier is a sulfonamide substituted imidazoquinoline amine.
17. The aqueous formulation of claim 15 wherein the immune response modifier is selected from the group consisting of: N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c] quinolin- 1 -yljbutyl } -4-fluoro- 1 -benzenesulfonamide, N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]morpholine-4- carboxamide,
N- {3 - [4-amino-2-(2-methoxyethyl)- IH-imidazo [4,5-c] quinolin- 1 -yl] -2,2- dimethylpropyl} -N'-phenylurea, N- {2- [4-amino-2-(ethoxymethyl)- IH-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl}methanesulfonamide,
2-butyl-l-[2-(propylsulfonyl)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine,
N- {2-[4-amino-2-(ethoxymethyl)- IH-imidazo [4,5-c]quinolin- 1 -yl] -1,1- dimethylethyl}-2-ethoxyacetamide, N- {4- [4-amino-2-(cyclopropylmethyl)- 1 Η-imidazo [4,5-c] quinolin- 1 - yl]butyl}methanesulfonamide,
N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}-N'-cyclohexylurea,
N- {2- [4-amino-2-(ethoxymethyl)- 1 H-imidazo [4,5-c] quinolin- 1 -yl] -1,1- dimethylethyl} cyclohexanecarboxamide,
N-{2-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-
1 -yl] -1,1 -dimethylethyl} methanesulfonamide,
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)-2,2- dimethylpropyljmethanesulfonamide, N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)-l,l- dimethylethyl]methanesulfonamide,
N-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c] quinolin- 1 -yl] -1,1 -dimethylethyl} methanesulfonamide, l-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-lH- imidazo[4,5-c]quinolin-l-yl]-2-methylpropan-2-ol, l-[4-amino-7-(3-hydroxymethyphenyl)-2-(2-methoxyethyl)-lH-imidazo[4,5- c] quinolin- 1 -yl] -2-methylpropan-2-ol,
N- {3-[4-amino-l -(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-lH- imidazo[4,5-c]quinolin-7-yl]phenyl} methanesulfonamide, {5-[4-amino-2-(2-methoxyethyl)-l-(2-methylpropyl)-lH-imidazo[4,5- c]quinolin-7-yl]pyridin-3-yl}methanol,
1 -[4-amino-2-(ethoxymethyl)-7-(pyridin-3 -yl)- IH-imidazo [4,5-c] quinolin- 1 -yl] -
2-methylpropan-2-ol, 1 - {4-amino-2-(ethoxymethyl)-7- [5 -(hydroxymethyl)p yridin-3 -yl] - 1H- imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol,
N-(2- {4-amino-2-ethoxymethyl-7-[6-(methanesulfonylamino)hexyloxy] - 1 Η- imidazo [4,5-c] quinolin- 1 -yl} - 1 , 1 -dimethylethyl)methanesulfonamide, N-(6- { [4-amino-2-ethoxymethyl- 1 -(2-methanesulfonylamino-2-methylpropyl)- 1 Η-imidazo [4, 5 -c] quinolin-7-yl] oxy } hexyl)acetamide, N- [2-(4-amino-2-ethoxymethyl- 1 -propyl- 1 Η-imidazo [4,5-c] quinolin-7- yloxy)ethyl]methanesulfonamide,
1 - [4-amino-2-(ethoxymethyl)-7-( 1 Η-p yrazol-4-yl)- 1 Η-imidazo [4,5-c] quinolin- 1 - yl]-2-methylpropan-2-ol,
3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-lΗ-imidazo[4,5-c]quinolin-l- yljpropane- 1 ,2-diol, and combinations thereof
18. The aqueous formulation of claim 17 wherein the immune response modifier is selected from the group consisting of:
N-[3-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)propyl]morpholine-4- carboxamide,
N-{3-[4-amino-2-(2-methoxyethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-2,2- dimethylpropyl}-N'-phenylurea,
N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]-l,l- dimethylethyl}methanesulfonamide,
2-butyl-l-[2-(propylsulfonyl)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine,
N- {2-[4-amino-2-(ethoxymethyl)- lH-imidazo[4,5-c]quinolin- 1 -yl] -1,1- dimethylethyl} -2-ethoxyacetamide,
N- {2-[4-amino-2-(ethoxymethyl)- lH-imidazo[4,5-c]quinolin- 1 -yl]-l , 1 - dimethylethyl}-N'-cyclohexylurea,
N-{2-[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-
1 -yl]-l , 1 -dimethylethyl} methanesulfonamide, N-[2-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin- 1 -yl)-l , 1 - dimethylethyl]methanesulfonamide,
N-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c] quinolin- 1 -yl] -1,1 -dimethylethyl} methanesulfonamide, 1 - {4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3 -yl] - 1H- imidazo[4,5-c]quinolin-l-yl}-2-methylpropan-2-ol,
N-(6- { [4-amino-2-ethoxymethyl- 1 -(2-methanesulfonylamino-2-methylpropyl)- lΗ-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)acetamide, and combinations thereof.
19. The aqueous formulation of claim 18 wherein the immune response modifier is N-{2-[4-amino-2-(ethoxymethyl)-lH-imidazo[4,5-c]quinolin-l-yl]- l,l-dimethylethyl}methanesulfonamide.
20. The aqueous formulation of claim 11 wherein the immune response modifier is a salt of an acid selected from the group consisting of a carboxylic acid, a halo acid, sulfuric acid, phosphoric acid, dicarboxylic acid, tricarboxylic acid, and combinations thereof.
21. The aqueous formulation of claim 20 wherein the salt of the immune response modifier is a salt of an acid selected from the group consisting of hydrobromic acid, hydrochloric acid, lactic acid, glutamic acid, gluconic acid, tartaric acid, succinic acid, and combinations thereof.
22. The aqueous formulation of any one of claims 1 through 21 having a pΗ of at least 4.
23. The aqueous formulation of claim 22 having a pΗ of no more than 8.
24. The aqueous formulation of any one of claims 1 through 23 further comprising a pΗ adjusting agent.
25. The aqueous formulation of claim 24 wherein the pΗ adjusting agent is selected from the group consisting of hydrochloric acid, sodium hydroxide, tromethamine, potassium hydroxide, and combinations thereof.
26. The aqueous formulation of any one of claims 1 through 25 further comprising a buffer.
27. The aqueous formulation of claim 26 wherein the buffer is selected from the group consisting of citric acid, lactic acid, succmic acid, tartaric acid, and combinations thereof.
28. The aqueous formulation of any one of claims 1 through 27 further comprising a preservative.
29. The aqueous formulation of claim 28 wherein the preservative is selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylparaben, propylparaben, phenyl ethyl alcohol, and combinations thereof.
30. The aqueous formulation of any one of claims 1 through 29 further comprising a chelating agent.
31. The aqueous formulation of claim 30 wherein the chelating agent is ethylenediaminetetraacetic acid disodium salt dihydrate.
32. The aqueous formulation of any one of claims 1 through 31 further comprising a water-miscible cosolvent.
33. The aqueous formulation of claim 32 wherein the cosolvent is selected from the group consisting of propylene glycol, glycerin, polyethylene glycol 400, diethylene glycol monoethyl ether, and combinations thereof.
34. The aqueous formulation of claims 32 or 33 wherein the cosolvent is present in an amount of 5 wt-% to 15 wt-%.
35. An aqueous sprayable formulation comprising: an immune response modifier selected from the group consisting of imidazoquinoline amines, tetrahydroimidazoquinoline amines, imidazopyridine amines, 6,7-fused cycloalkylimidazopyridme amines, 1,2-bridged imidazoquinoline amines, imidazonaphthyridine amines, imidazotetrahydronaphthyridine amines, oxazoloquinoline amines, thiazoloquinoline amines, oxazolopyridine amines, thiazolopyridine amines, oxazolonaphthyridine amines, thiazolonaphthyridine amines, IH-imidazo dimers fused to pyridine amines, quinoline amines, tetrahydroquinoline amines, naphthyridine amines, or tetrahydronaphthyridine amines, and combinations thereof; water; and a hydrophilic viscosity enhancing agent selected from the group consisting of cellulose ethers, polysaccharide gums, acrylic acid polymers, and combinations thereof; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature.
36. A method for delivering an immune response modifier to a nasal passage of a subject, the method comprising: selecting a formulation comprising: an immune response modifier; water; and a hydrophilic viscosity enhancing agent; with the proviso that the hydrophilic viscosity enhancing agent is not covalently bonded to the immune response modifier; wherein the formulation is a solution at room temperature and has a viscosity of less than 100 cps at room temperature; and applying the selected formulation into a nasal passage or a subject.
37. A method of treating and/or preventing allergic rhinitis, the method comprising applying the formulation of any one of claims 1 through 34 into a nasal passage or a subject.
38. A method of treating and/or preventing allergic rhinitis, the method comprising spraying the formulation of claim 35 into a nasal passage of a subject.
39. A method of treating and/or preventing a viral infection, the method comprising applying the formulation of any one of claims 1 through 34 into a nasal passage or a subject.
40. A method of treating and/or preventing a viral infection, the method comprising spraying the formulation of claim 35 into a nasal passage of a subject.
41. A method of treating and/or preventing sinusitis, the method comprising applying the formulation of any one of claims 1 through 34 into a nasal passage of a subject.
42. A method of treating and/or preventing sinusitis, the method comprising spraying the formulation of claim 35 into a nasal passage of a subject.
43. A method of treating and/or preventing asthma, the method comprising applying the formulation of any one of claims 1 through 34 into the respiratory tract of a subject.
44. A method of treating and/or preventing asthma, the method comprising spraying the formulation of claim 35 into the respiratory tract of a subject.
45. A method of desensitizing a subject to an antigen comprising: administering to the subject an IRM compound in the formulation of any one of claims 1 through 34, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen.
46. The method of claim 45 wherein the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen.
47. A method of desensitizing a subject to an antigen comprising: administering to the subject an IRM compound in the formulation of claim 35, after the subject has been sensitized to the antigen, in an amount effective to desensitize the subject to the antigen.
48. The method of claim 47 wherein the IRM compound is administered to the subject at least four hours prior to re-exposure of the subject to the antigen.
PCT/US2004/025277 2003-08-05 2004-08-05 Formulations containing an immune response modifier WO2005016275A2 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US10/595,049 US8221771B2 (en) 2003-08-05 2004-08-05 Formulations containing an immune response modifier
CA2534313A CA2534313C (en) 2003-08-05 2004-08-05 Formulations containing an immune response modifier
JP2006522714A JP2007501252A (en) 2003-08-05 2004-08-05 Formulation containing immune response modifier
AU2004264336A AU2004264336B2 (en) 2003-08-05 2004-08-05 Formulations containing an immune response modifier
EP04780166A EP1651190B1 (en) 2003-08-05 2004-08-05 Formulations containing an immune response modifier

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US49310903P 2003-08-05 2003-08-05
US60/493,109 2003-08-05

Publications (2)

Publication Number Publication Date
WO2005016275A2 true WO2005016275A2 (en) 2005-02-24
WO2005016275A3 WO2005016275A3 (en) 2005-04-14

Family

ID=34193164

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2004/025241 WO2005016273A2 (en) 2003-08-05 2004-08-05 Infection prophylaxis using immune response modifier compounds
PCT/US2004/025277 WO2005016275A2 (en) 2003-08-05 2004-08-05 Formulations containing an immune response modifier

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2004/025241 WO2005016273A2 (en) 2003-08-05 2004-08-05 Infection prophylaxis using immune response modifier compounds

Country Status (7)

Country Link
US (2) US8221771B2 (en)
EP (2) EP1651216A2 (en)
JP (2) JP2007501252A (en)
CN (1) CN1852711A (en)
AU (2) AU2004264330A1 (en)
CA (2) CA2534313C (en)
WO (2) WO2005016273A2 (en)

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060195067A1 (en) * 2003-08-25 2006-08-31 Wolter James T Delivery of immune response modifier compounds
EP1835915A2 (en) * 2004-12-30 2007-09-26 Coley Pharmaceutical Group, Inc. Immune response modifier formulations and methods
EP1687307A4 (en) * 2003-11-25 2009-06-17 3M Innovative Properties Co Substituted imidazo ring systems and methods
US7879849B2 (en) 2003-10-03 2011-02-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
US7897609B2 (en) 2004-06-18 2011-03-01 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US7897767B2 (en) 2003-11-14 2011-03-01 3M Innovative Properties Company Oxime substituted imidazoquinolines
US7897597B2 (en) 2003-08-27 2011-03-01 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
US8598192B2 (en) 2003-11-14 2013-12-03 3M Innovative Properties Company Hydroxylamine substituted imidazoquinolines
US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US8697873B2 (en) 2004-03-24 2014-04-15 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8735421B2 (en) 2003-12-30 2014-05-27 3M Innovative Properties Company Imidazoquinolinyl sulfonamides
US8802853B2 (en) 2003-12-29 2014-08-12 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US8883151B2 (en) 2010-01-15 2014-11-11 Kirin-Amgen, Inc. IL-17 receptor antibody formulation
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US10208122B2 (en) 2006-10-02 2019-02-19 Amgen K-A, Inc. IL-17 receptor A antigen binding proteins
US10675358B2 (en) 2016-07-07 2020-06-09 The Board Of Trustees Of The Leland Stanford Junior University Antibody adjuvant conjugates
US11400164B2 (en) 2019-03-15 2022-08-02 Bolt Biotherapeutics, Inc. Immunoconjugates targeting HER2

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6756382B2 (en) * 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6331539B1 (en) * 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6677347B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US20040265351A1 (en) 2003-04-10 2004-12-30 Miller Richard L. Methods and compositions for enhancing immune response
EP1617845A4 (en) * 2003-04-28 2006-09-20 3M Innovative Properties Co Compositions and methods for induction of opioid receptors
AU2004315876B2 (en) 2003-10-03 2011-05-26 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
US20090075980A1 (en) * 2003-10-03 2009-03-19 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and Analogs Thereof
US8541438B2 (en) 2004-06-18 2013-09-24 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US20090270443A1 (en) * 2004-09-02 2009-10-29 Doris Stoermer 1-amino imidazo-containing compounds and methods
WO2006063072A2 (en) * 2004-12-08 2006-06-15 3M Innovative Properties Company Immunomodulatory compositions, combinations and methods
CA2602083A1 (en) 2005-02-09 2006-08-09 Coley Pharmaceutical Group, Inc. Oxime and hydroxylamine substituted thiazolo(4,5-c) ring compounds and methods
AU2006212765B2 (en) 2005-02-09 2012-02-02 3M Innovative Properties Company Alkyloxy substituted thiazoloquinolines and thiazolonaphthyridines
US8658666B2 (en) 2005-02-11 2014-02-25 3M Innovative Properties Company Substituted imidazoquinolines and imidazonaphthyridines
CA2598639A1 (en) 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazonaphthyridines
US8158794B2 (en) 2005-02-23 2012-04-17 3M Innovative Properties Company Hydroxyalkyl substituted imidazoquinoline compounds and methods
CA2598695A1 (en) 2005-02-23 2006-09-21 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazoquinolines
EP1850849A2 (en) * 2005-02-23 2007-11-07 Coley Pharmaceutical Group, Inc. Method of preferentially inducing the biosynthesis of interferon
US8476292B2 (en) 2005-09-09 2013-07-02 3M Innovative Properties Company Amide and carbamate derivatives of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c] quinolin-1-Yl]-1,1-dimethylethyl}methanesulfonamide and methods
ZA200803029B (en) 2005-09-09 2009-02-25 Coley Pharm Group Inc Amide and carbamate derivatives of alkyl substituted /V-[4-(4-amino-1H-imidazo[4,5-c] quinolin-1-yl)butyl] methane-sulfonamides and methods
EP1948173B1 (en) 2005-11-04 2013-07-17 3M Innovative Properties Company Hydroxy and alkoxy substituted 1h-imidazoquinolines and methods
EP3085373A1 (en) 2006-02-22 2016-10-26 3M Innovative Properties Company Immune response modifier conjugates
WO2007106854A2 (en) * 2006-03-15 2007-09-20 Coley Pharmaceutical Group, Inc. Hydroxy and alkoxy substituted 1h-imidazonaphthyridines and methods
US8178539B2 (en) 2006-09-06 2012-05-15 3M Innovative Properties Company Substituted 3,4,6,7-tetrahydro-5H-1,2a,4a,8-tetraazacyclopenta[cd]phenalenes and methods
EP2477642A4 (en) * 2009-09-17 2013-03-13 Mutual Pharmaceutical Co Method of treating asthma with antiviral agents
HUE033901T2 (en) 2010-08-17 2018-01-29 3M Innovative Properties Co Lipidated immune response modifier compound compositions, formulations, and methods
JP6460789B2 (en) 2011-06-03 2019-01-30 スリーエム イノベイティブ プロパティズ カンパニー Heterobifunctional linker having polyethylene glycol segment and immune response modulating complex prepared from the linker
CA2838023C (en) 2011-06-03 2019-08-13 3M Innovative Properties Company Hydrazino 1h-imidazoquinolin-4-amines and conjugates made therefrom
CN107922416B (en) * 2015-08-31 2021-07-02 3M创新有限公司 Imidazo [4,5-c ] ring compounds containing substituted guanidine groups
EP3344622B1 (en) * 2015-08-31 2021-07-07 3M Innovative Properties Company Guanidine substituted, fused 1h-imidazo[4,5-c]pyridine compounds useful in the treatment of viral and neoplastic diseases
US11306083B2 (en) 2017-12-20 2022-04-19 3M Innovative Properties Company Amide substituted imidazo[4,5-C]quinoline compounds with a branched chain linking group for use as an immune response modifier

Family Cites Families (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3314941A (en) * 1964-06-23 1967-04-18 American Cyanamid Co Novel substituted pyridodiazepins
JPS4931814A (en) * 1972-07-26 1974-03-22
IL73534A (en) * 1983-11-18 1990-12-23 Riker Laboratories Inc 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds
ZA848968B (en) * 1983-11-18 1986-06-25 Riker Laboratories Inc 1h-imidazo(4,5-c)quinolines and 1h-imidazo(4,5-c)quinolin-4-amines
JPS61106509A (en) 1984-10-29 1986-05-24 Fujisawa Pharmaceut Co Ltd Pharmaceutical composition for nasal cavity application
DE3877904D1 (en) * 1987-11-13 1993-03-11 Asta Pharma Ag MEDICINAL PRODUCTS CONTAINING AZELASTIN FOR USE IN THE NOSE AND / OR EYE.
US5238944A (en) * 1988-12-15 1993-08-24 Riker Laboratories, Inc. Topical formulations and transdermal delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine
US5756747A (en) * 1989-02-27 1998-05-26 Riker Laboratories, Inc. 1H-imidazo 4,5-c!quinolin-4-amines
US4929624A (en) * 1989-03-23 1990-05-29 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo(4,5-c)quinolin-4-amines
US5037986A (en) * 1989-03-23 1991-08-06 Minnesota Mining And Manufacturing Company Olefinic 1H-imidazo[4,5-c]quinolin-4-amines
NZ232740A (en) 1989-04-20 1992-06-25 Riker Laboratories Inc Solution for parenteral administration comprising a 1h-imidazo(4,5-c) quinolin-4-amine derivative, an acid and a tonicity adjuster
US4988815A (en) * 1989-10-26 1991-01-29 Riker Laboratories, Inc. 3-Amino or 3-nitro quinoline compounds which are intermediates in preparing 1H-imidazo[4,5-c]quinolines
DK0553202T3 (en) * 1990-10-05 1995-07-03 Minnesota Mining & Mfg Process for the preparation of imidazo (4,5-c) quinoline-4-amines
US5389640A (en) * 1991-03-01 1995-02-14 Minnesota Mining And Manufacturing Company 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5175296A (en) * 1991-03-01 1992-12-29 Minnesota Mining And Manufacturing Company Imidazo[4,5-c]quinolin-4-amines and processes for their preparation
US5268376A (en) * 1991-09-04 1993-12-07 Minnesota Mining And Manufacturing Company 1-substituted 1H-imidazo[4,5-c]quinolin-4-amines
US5266575A (en) * 1991-11-06 1993-11-30 Minnesota Mining And Manufacturing Company 2-ethyl 1H-imidazo[4,5-ciquinolin-4-amines
IL105325A (en) * 1992-04-16 1996-11-14 Minnesota Mining & Mfg Immunogen/vaccine adjuvant composition
US5395937A (en) * 1993-01-29 1995-03-07 Minnesota Mining And Manufacturing Company Process for preparing quinoline amines
EP0622681B1 (en) * 1993-04-27 1997-10-01 Agfa-Gevaert N.V. Process for incorporation of a water-insoluble substance into a hydrophilic layer
CZ288182B6 (en) * 1993-07-15 2001-05-16 Minnesota Mining & Mfg Imidazo[4,5-c]pyridine-4-amines and pharmaceutical preparations based thereon
US5352784A (en) * 1993-07-15 1994-10-04 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
US6239116B1 (en) * 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US6207646B1 (en) * 1994-07-15 2001-03-27 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
ES2267100T5 (en) * 1994-07-15 2011-04-08 The University Of Iowa Research Foundation IMMUNOMODULATING OLIGONUCLEOTIDES.
US5482936A (en) * 1995-01-12 1996-01-09 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]quinoline amines
JPH09208584A (en) 1996-01-29 1997-08-12 Terumo Corp Amide derivative, pharmaceutical preparation containing the same, and intermediate for synthesizing the same
JPH09255926A (en) 1996-03-26 1997-09-30 Diatex Co Ltd Pressure-sensitive tape
US5693811A (en) * 1996-06-21 1997-12-02 Minnesota Mining And Manufacturing Company Process for preparing tetrahdroimidazoquinolinamines
US5741908A (en) * 1996-06-21 1998-04-21 Minnesota Mining And Manufacturing Company Process for reparing imidazoquinolinamines
EP0882727B9 (en) * 1996-07-03 2005-06-15 Sumitomo Pharmaceuticals Company, Limited Novel purine derivatives
US6387938B1 (en) * 1996-07-05 2002-05-14 Mochida Pharmaceutical Co., Ltd. Benzimidazole derivatives
CA2268957C (en) * 1996-10-25 2008-04-29 Minnesota Mining And Manufacturing Company Immune response modifier compounds for treatment of th2 mediated and related diseases
US5939090A (en) * 1996-12-03 1999-08-17 3M Innovative Properties Company Gel formulations for topical drug delivery
EP0894797A4 (en) * 1997-01-09 2001-08-16 Terumo Corp Novel amide derivatives and intermediates for the synthesis thereof
US6406705B1 (en) * 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
US6426334B1 (en) * 1997-04-30 2002-07-30 Hybridon, Inc. Oligonucleotide mediated specific cytokine induction and reduction of tumor growth in a mammal
US6113918A (en) * 1997-05-08 2000-09-05 Ribi Immunochem Research, Inc. Aminoalkyl glucosamine phosphate compounds and their use as adjuvants and immunoeffectors
US6303347B1 (en) * 1997-05-08 2001-10-16 Corixa Corporation Aminoalkyl glucosaminide phosphate compounds and their use as adjuvants and immunoeffectors
EP1003531B1 (en) * 1997-05-20 2007-08-22 Ottawa Health Research Institute Processes for preparing nucleic acid constructs
IS4516A (en) * 1997-07-01 1999-01-02 Gizurarson Sveinbjörn New pharmaceutical form
ES2205573T3 (en) * 1997-11-28 2004-05-01 Sumitomo Pharmaceuticals Company, Limited NEW HETEROCICLIC COMPOUNDS.
UA67760C2 (en) * 1997-12-11 2004-07-15 Міннесота Майнінг Енд Мануфакчурінг Компані Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines
TW572758B (en) * 1997-12-22 2004-01-21 Sumitomo Pharma Type 2 helper T cell-selective immune response inhibitors comprising purine derivatives
JPH11222432A (en) 1998-02-03 1999-08-17 Terumo Corp Preparation for external use containing amide derivative inducing interferon
US6110929A (en) * 1998-07-28 2000-08-29 3M Innovative Properties Company Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof
JP2000119271A (en) 1998-08-12 2000-04-25 Hokuriku Seiyaku Co Ltd 1h-imidazopyridine derivative
US6518280B2 (en) * 1998-12-11 2003-02-11 3M Innovative Properties Company Imidazonaphthyridines
US20020058674A1 (en) * 1999-01-08 2002-05-16 Hedenstrom John C. Systems and methods for treating a mucosal surface
CN1555264A (en) * 1999-01-08 2004-12-15 3M Formulations for treatment of mucosal associated conditions with an immune response modifier
US6558951B1 (en) * 1999-02-11 2003-05-06 3M Innovative Properties Company Maturation of dendritic cells with immune response modifying compounds
JP2000247884A (en) 1999-03-01 2000-09-12 Sumitomo Pharmaceut Co Ltd Arachidonic acid-induced skin disease-treating agent
US6331539B1 (en) * 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6451810B1 (en) * 1999-06-10 2002-09-17 3M Innovative Properties Company Amide substituted imidazoquinolines
US6573273B1 (en) * 1999-06-10 2003-06-03 3M Innovative Properties Company Urea substituted imidazoquinolines
US6756382B2 (en) * 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6541485B1 (en) * 1999-06-10 2003-04-01 3M Innovative Properties Company Urea substituted imidazoquinolines
WO2001012804A2 (en) * 1999-08-13 2001-02-22 Hybridon, Inc. MODULATION OF OLIGONUCLEOTIDE CpG-MEDIATED IMMUNE STIMULATION BY POSITIONAL MODIFICATION OF NUCLEOSIDES
US6376669B1 (en) * 1999-11-05 2002-04-23 3M Innovative Properties Company Dye labeled imidazoquinoline compounds
US20040023870A1 (en) * 2000-01-21 2004-02-05 Douglas Dedera Methods of therapy and diagnosis using targeting of cells that express toll-like receptor proteins
GB0001704D0 (en) * 2000-01-25 2000-03-15 Glaxo Group Ltd Protein
CA2403553A1 (en) * 2000-03-17 2001-09-27 David Johnson Novel amphipathic aldehydes and their use as adjuvants and immunoeffectors
US6894060B2 (en) * 2000-03-30 2005-05-17 3M Innovative Properties Company Method for the treatment of dermal lesions caused by envenomation
US6489338B2 (en) * 2000-06-13 2002-12-03 Bristol-Myers Squibb Company Imidazopyridine and imidazopyrimidine antiviral agents
US20020055517A1 (en) * 2000-09-15 2002-05-09 3M Innovative Properties Company Methods for delaying recurrence of herpes virus symptoms
JP2002145777A (en) 2000-11-06 2002-05-22 Sumitomo Pharmaceut Co Ltd Therapeutic agent for arachidonic acid-induced dermatosis
US6660747B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US6664260B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Heterocyclic ether substituted imidazoquinolines
US6545016B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Amide substituted imidazopyridines
UA75622C2 (en) * 2000-12-08 2006-05-15 3M Innovative Properties Co Aryl ether substituted imidazoquinolines, pharmaceutical composition based thereon
US6545017B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
US6525064B1 (en) * 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6667312B2 (en) * 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
EP1360486A2 (en) * 2000-12-08 2003-11-12 3M Innovative Properties Company Screening method for identifying compounds that selectively induce interferon alpha
US6677347B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US6660735B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
US6664264B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6664265B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US6677348B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Aryl ether substituted imidazoquinolines
DE60227794D1 (en) * 2001-04-26 2008-09-04 Eisai R&D Man Co Ltd NITROGENIC COMPOUND WITH CONDENSED RING AND PYRAZOLYL GROUP AS A SUBSTITUENT AND MEDICAL COMPOSITION THEREOF
US20030133913A1 (en) * 2001-08-30 2003-07-17 3M Innovative Properties Company Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules
AU2002360278A1 (en) * 2001-10-12 2003-11-11 Coley Pharmaceutical Gmbh Methods and products for enhancing immune responses using imidazoquinoline compounds
DK1719511T3 (en) * 2001-11-16 2009-04-14 Coley Pharm Group Inc N- [4- (4-amino-2-ethyl-1H-imidazo [4,5-c] quinolin-1-yl) butyl] methanesulfonamide, a pharmaceutical composition comprising the same, and use thereof
ES2312659T3 (en) 2001-11-29 2009-03-01 3M Innovative Properties Company PHARMACEUTICAL FORMULATIONS THAT INCLUDE A MODIFIER OF THE IMMUNE RESPONSE.
US6677349B1 (en) * 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6525028B1 (en) * 2002-02-04 2003-02-25 Corixa Corporation Immunoeffector compounds
JP2005518433A (en) * 2002-02-22 2005-06-23 スリーエム イノベイティブ プロパティズ カンパニー Methods for reducing and treating UVB-induced immunosuppression
GB0206461D0 (en) * 2002-03-19 2002-05-01 Glaxo Group Ltd Improvements in vaccination
GB0211649D0 (en) 2002-05-21 2002-07-03 Novartis Ag Organic compounds
AU2003233519A1 (en) * 2002-05-29 2003-12-19 3M Innovative Properties Company Process for imidazo(4,5-c)pyridin-4-amines
JP2005538057A (en) * 2002-06-07 2005-12-15 スリーエム イノベイティブ プロパティズ カンパニー Ether-substituted imidazopyridine
AU2003299863B2 (en) * 2002-08-15 2009-09-24 3M Innovative Properties Company Immunostimulatory compositions and methods of stimulating an immune response
AU2003299082A1 (en) * 2002-09-26 2004-04-19 3M Innovative Properties Company 1h-imidazo dimers
AU2003287324A1 (en) * 2002-12-11 2004-06-30 3M Innovative Properties Company Gene expression systems and recombinant cell lines
AU2003287316A1 (en) * 2002-12-11 2004-06-30 3M Innovative Properties Company Assays relating to toll-like receptor activity
AU2003301052A1 (en) * 2002-12-20 2004-07-22 3M Innovative Properties Company Aryl / hetaryl substituted imidazoquinolines
US7387271B2 (en) * 2002-12-30 2008-06-17 3M Innovative Properties Company Immunostimulatory combinations
WO2004071459A2 (en) * 2003-02-13 2004-08-26 3M Innovative Properties Company Methods and compositions related to irm compounds and toll-like receptor 8
US7485432B2 (en) * 2003-02-27 2009-02-03 3M Innovative Properties Company Selective modulation of TLR-mediated biological activity
AU2004218349A1 (en) * 2003-03-04 2004-09-16 3M Innovative Properties Company Prophylactic treatment of UV-induced epidermal neoplasia
CA2517655A1 (en) * 2003-03-07 2004-09-23 3M Innovative Properties Company 1-amino 1h-imidazoquinolines
MXPA05009694A (en) * 2003-03-13 2005-10-20 3M Innovative Properties Co Methods of improving skin quality.
CA2518445A1 (en) * 2003-03-13 2004-09-23 3M Innovative Properties Company Method of tattoo removal
WO2004080293A2 (en) * 2003-03-13 2004-09-23 3M Innovative Properties Company Methods for diagnosing skin lesions
US20040192585A1 (en) * 2003-03-25 2004-09-30 3M Innovative Properties Company Treatment for basal cell carcinoma
WO2004087049A2 (en) * 2003-03-25 2004-10-14 3M Innovative Properties Company Selective activation of cellular activities mediated through a common toll-like receptor
AU2004244962A1 (en) * 2003-04-10 2004-12-16 3M Innovative Properties Company Delivery of immune response modifier compounds using metal-containing particulate support materials
EP1617845A4 (en) * 2003-04-28 2006-09-20 3M Innovative Properties Co Compositions and methods for induction of opioid receptors
EP1658076B1 (en) 2003-08-27 2013-03-06 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
BRPI0414856A (en) 2003-10-03 2006-11-21 3M Innovative Properties Co alkoxy-substituted imidazoquinolines
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems and methods
AU2004315771A1 (en) 2003-12-04 2005-08-25 3M Innovative Properties Company Sulfone substituted imidazo ring ethers
WO2005094531A2 (en) 2004-03-24 2005-10-13 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
JP2009542668A (en) * 2006-06-27 2009-12-03 シェーリング−プラウ ヘルスケア プロダクツ，インコーポレイテッド Aerosol lotion

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
None
See also references of EP1651190A4

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8673932B2 (en) 2003-08-12 2014-03-18 3M Innovative Properties Company Oxime substituted imidazo-containing compounds
US8961477B2 (en) * 2003-08-25 2015-02-24 3M Innovative Properties Company Delivery of immune response modifier compounds
US20060195067A1 (en) * 2003-08-25 2006-08-31 Wolter James T Delivery of immune response modifier compounds
US7897597B2 (en) 2003-08-27 2011-03-01 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
US7923429B2 (en) 2003-09-05 2011-04-12 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
US7879849B2 (en) 2003-10-03 2011-02-01 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
US7897767B2 (en) 2003-11-14 2011-03-01 3M Innovative Properties Company Oxime substituted imidazoquinolines
US8598192B2 (en) 2003-11-14 2013-12-03 3M Innovative Properties Company Hydroxylamine substituted imidazoquinolines
EP1687307A4 (en) * 2003-11-25 2009-06-17 3M Innovative Properties Co Substituted imidazo ring systems and methods
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems and methods
EP1687307B1 (en) * 2003-11-25 2016-01-06 3M Innovative Properties Company Substituted imidazo ring systems and methods
US8802853B2 (en) 2003-12-29 2014-08-12 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
US8735421B2 (en) 2003-12-30 2014-05-27 3M Innovative Properties Company Imidazoquinolinyl sulfonamides
US8697873B2 (en) 2004-03-24 2014-04-15 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
US8017779B2 (en) 2004-06-15 2011-09-13 3M Innovative Properties Company Nitrogen containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
US7915281B2 (en) 2004-06-18 2011-03-29 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and method
US8026366B2 (en) 2004-06-18 2011-09-27 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
US7897609B2 (en) 2004-06-18 2011-03-01 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
US8034938B2 (en) 2004-12-30 2011-10-11 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
US7943609B2 (en) 2004-12-30 2011-05-17 3M Innovative Proprerties Company Chiral fused [1,2]imidazo[4,5-C] ring compounds
EP1835915A4 (en) * 2004-12-30 2010-02-24 Coley Pharm Group Inc Immune response modifier formulations and methods
JP2008526757A (en) * 2004-12-30 2008-07-24 スリーエム イノベイティブ プロパティズ カンパニー Immune response modulator formulation and method
EP1835915A2 (en) * 2004-12-30 2007-09-26 Coley Pharmaceutical Group, Inc. Immune response modifier formulations and methods
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US10071156B2 (en) 2005-02-04 2018-09-11 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US7943610B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company Pyrazolopyridine-1,4-diamines and analogs thereof
US7943636B2 (en) 2005-04-01 2011-05-17 3M Innovative Properties Company 1-substituted pyrazolo (3,4-C) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US7906506B2 (en) 2006-07-12 2011-03-15 3M Innovative Properties Company Substituted chiral fused [1,2] imidazo [4,5-c] ring compounds and methods
US10208122B2 (en) 2006-10-02 2019-02-19 Amgen K-A, Inc. IL-17 receptor A antigen binding proteins
US11180564B2 (en) 2006-10-02 2021-11-23 Amgen K-A, Inc. IL-17 Receptor A antigen binding proteins
US11858999B2 (en) 2006-10-02 2024-01-02 Amgen K-A, Inc. IL-17 receptor A antigen binding proteins
US10072085B2 (en) 2010-01-15 2018-09-11 Kirin-Amgen, Inc. Method of treating psoriasis using an IL-17 receptor antibody formulation
US8883151B2 (en) 2010-01-15 2014-11-11 Kirin-Amgen, Inc. IL-17 receptor antibody formulation
US10808033B2 (en) 2010-01-15 2020-10-20 Amgen K-A, Inc. IL-17 receptor antibody formulation
US11505612B2 (en) 2010-01-15 2022-11-22 Amgen K-A, Inc. Method of treating diseases using an IL-17 receptor antibody formulation
US10675358B2 (en) 2016-07-07 2020-06-09 The Board Of Trustees Of The Leland Stanford Junior University Antibody adjuvant conjugates
US11110178B2 (en) 2016-07-07 2021-09-07 The Board Of Trustees Of The Leland Standford Junior University Antibody adjuvant conjugates
US11547761B1 (en) 2016-07-07 2023-01-10 The Board Of Trustees Of The Leland Stanford Junior University Antibody adjuvant conjugates
US11400164B2 (en) 2019-03-15 2022-08-02 Bolt Biotherapeutics, Inc. Immunoconjugates targeting HER2

Also Published As

Publication number Publication date
AU2004264330A1 (en) 2005-02-24
WO2005016275A3 (en) 2005-04-14
US8221771B2 (en) 2012-07-17
CN1852711A (en) 2006-10-25
AU2004264336B2 (en) 2010-12-23
CA2534313A1 (en) 2005-02-24
WO2005016273A2 (en) 2005-02-24
EP1651190B1 (en) 2012-09-19
US20070292456A1 (en) 2007-12-20
AU2004264336A1 (en) 2005-02-24
US20050070460A1 (en) 2005-03-31
EP1651190A4 (en) 2009-07-15
EP1651190A2 (en) 2006-05-03
JP2007501251A (en) 2007-01-25
JP2007501252A (en) 2007-01-25
CA2534313C (en) 2013-03-19
WO2005016273A3 (en) 2005-12-29
EP1651216A2 (en) 2006-05-03
CA2534625A1 (en) 2005-02-24

Similar Documents

Publication Publication Date Title
AU2004264336B2 (en) Formulations containing an immune response modifier
EP1844201B1 (en) Aqueous gel formulations containing immune response modifiers
AU2005222995B2 (en) Immune response modifier formulations and methods
AU2005244260B2 (en) Methods, compositions, and preparations for delivery of immune response modifiers
US20080119508A1 (en) Multi-Route Administration Of Immune Response Modifier Compounds
ZA200405334B (en) Amide substituted imidazopyridines
EP1850849A2 (en) Method of preferentially inducing the biosynthesis of interferon
ZA200305273B (en) Sulfonamido ether substituted imidazoquinolines.
SK9542001A3 (en) Formulations comprising imiquimod or other immune response modifiers for treating mucosal conditions
JPWO2005011674A1 (en) Preventive and / or therapeutic agent for bronchial asthma

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 10595049

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2004780166

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2534313

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2004264336

Country of ref document: AU

Ref document number: 2006522714

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 2004264336

Country of ref document: AU

Date of ref document: 20040805

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004264336

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2004780166

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 10595049

Country of ref document: US