WO2002046192A2 - Thioether substituted imidazoquinolines - Google Patents

Thioether substituted imidazoquinolines Download PDF

Info

Publication number
WO2002046192A2
WO2002046192A2 PCT/US2001/046697 US0146697W WO0246192A2 WO 2002046192 A2 WO2002046192 A2 WO 2002046192A2 US 0146697 W US0146697 W US 0146697W WO 0246192 A2 WO0246192 A2 WO 0246192A2
Authority
WO
WIPO (PCT)
Prior art keywords
imidazo
butyl
amine
alkyl
quinolin
Prior art date
Application number
PCT/US2001/046697
Other languages
French (fr)
Other versions
WO2002046192A3 (en
Inventor
Joseph F. Dellaria
Bryon A. Merrill
Matthew R. Radmer
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
Priority to KR10-2003-7007534A priority Critical patent/KR20030070049A/en
Priority to HU0400710A priority patent/HUP0400710A2/en
Application filed by 3M Innovative Properties Company filed Critical 3M Innovative Properties Company
Priority to BR0116026-5A priority patent/BR0116026A/en
Priority to NZ526087A priority patent/NZ526087A/en
Priority to SK710-2003A priority patent/SK287264B6/en
Priority to CA2436846A priority patent/CA2436846C/en
Priority to EP01987297A priority patent/EP1341791B1/en
Priority to AU2002239530A priority patent/AU2002239530B2/en
Priority to JP2002547929A priority patent/JP2004515500A/en
Priority to IL15590401A priority patent/IL155904A0/en
Priority to DK01987297T priority patent/DK1341791T3/en
Priority to AU3953002A priority patent/AU3953002A/en
Priority to EEP200300275A priority patent/EE200300275A/en
Priority to DE60111076T priority patent/DE60111076T2/en
Priority to SI200130382T priority patent/SI1341791T1/en
Priority to PL366330A priority patent/PL207340B1/en
Priority to AT01987297T priority patent/ATE296301T1/en
Priority to MXPA03004975A priority patent/MXPA03004975A/en
Publication of WO2002046192A2 publication Critical patent/WO2002046192A2/en
Publication of WO2002046192A3 publication Critical patent/WO2002046192A3/en
Priority to NO20032595A priority patent/NO20032595D0/en
Priority to CY20051101024T priority patent/CY1105586T1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • 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
    • A61P31/08—Antibacterial agents for leprosy
    • 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
    • A61P31/10—Antimycotics
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • 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
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to imidazoquinoline compounds that have thioether functionality at the 1 -position, and to pharmaceutical compositions containing such compounds.
  • a further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
  • this invention provides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have a thioether containing substituent at the 1 -position.
  • the compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula:
  • the compounds of formulas (I) and (II) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
  • the invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I) or (II) to the animal.
  • the invention provides methods of synthesizing the compounds of the invention.
  • Imidazoquinoline compounds of the invention which have thioether functionality at the 1 -position are represented by Formula (I):
  • Ri is selected from the group consisting of:
  • R 2 is selected from the group consisting of:
  • each R 3 is independently H or Ci-io alkyl; each t is independently alkyl or alkenyl; each Y is independently -O- or -S(0)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Cj-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • the invention also includes tetrahydroimidazoquinoline compounds that bear a thioether containing substituent at the 1 -position.
  • tetrahydroimidazoquinoline compounds are represented by Formula (II):
  • Z is -S-, -SO-, or -S0 2 -;
  • Ri is selected from the group consisting of: -alkyl;
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl;
  • each R 3 is independently H or Ci-io alkyl; each R-j is independently alkyl or alkenyl; each Y is independently -O- or -S(0)o- 2 -; n is 0 to 4; and each R present is independently selected from the group consisting of C-.io alkyl, d-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
  • a 4-chloro-3-nitroquinoline of Formula X is reacted with an amine of formula HO-X-NH 2 to provide a 3-nitroquinolin-4-amine of Formula XI.
  • the reaction can be carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as chloroform or dichloromethane in the presence of triethylamine and optionally heating.
  • a suitable solvent such as chloroform or dichloromethane
  • Many quinolines of Formula X are known compounds (see for example, U.S. Patent 4,689,338 and references cited therein).
  • Many amines of formula HO-X-NH 2 are commercially available; others can be readily prepared using known synthetic routes.
  • step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XI is chlorinated to provide a 3-nitroquinolin-4-amine of Formula XII.
  • Conventional chlorinating agents can be used.
  • the reaction is carried out by combining a compound of Formula XI with thionyl chloride in a suitable solvent such as dichloromethane and heating. Alternatively the reaction may be run neat.
  • step (3) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XII is reduced to provide a quinoline-3,4-diamine of Formula XIII.
  • the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
  • the reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
  • a quinoline-3,4-diamine of Formula XIII is reacted with a carboxylic acid or an equivalent thereof to provide a lH-imidazo[4,5- cjquinoline of Formula XIV.
  • Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates.
  • the carboxylic acid or equivalent is selected such that it will provide the desired R 2 substituent in a compound of Formula XIV.
  • triethyl orthoformate will provide a compound where R 2 is hydrogen and trimethyl orthovalerate will provide a compound where R 2 is butyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as toluene.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • step (4) can be carried out by (i) reacting the diamine of Formula
  • acyl halide of Formula R 2 C(0)C1 or R 2 C(0)Br is added to a solution of the diamine in a suitable solvent such as pyridine.
  • a suitable solvent such as pyridine.
  • the reaction can be carried out at ambient temperature.
  • the product of part (i) is heated in pyridine in the presence of pyridine hydrochloride.
  • a lH-imidazo[4,5-c]quinoline of Formula XIV is oxidized to provide a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides.
  • a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature.
  • step (6) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XVI.
  • Step (6) involves (i) reacting a compound of Formula XV with an acylating agent and then (ii) reacting the product with an aminating agent.
  • Part (i) of step (6) involves reacting an N-oxide of Formula XV with an acylating agent.
  • Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Para- toluenesulfonyl chloride is most preferred.
  • Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent.
  • Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate).
  • Ammonium hydroxide is preferred.
  • the reaction is preferably carried out by dissolving the N-oxide of Formula XV in an inert solvent such as dichloromethane or chloroform, adding the aminating agent to the solution, and then slowly adding the acylating agent.
  • an inert solvent such as dichloromethane or chloroform
  • XVI is reacted with a compound of Formula Ri-SNa to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XVII which is a subgenus of Formula I.
  • the reaction can be carried out by combining a compound of Formula XVI with a compound of formula RiSNa in a suitable solvent such as N,N-dimethylformamide or dimethyl sulfoxide and heating (60-80°C).
  • a suitable solvent such as N,N-dimethylformamide or dimethyl sulfoxide and heating (60-80°C).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (8) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-4-amine of Formula
  • XVII is oxidized using a conventional oxidizing agent to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I.
  • a solution of a compound of Formula XVII in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature.
  • the degree of oxidation is controlled by adjusting the amount of 3-chloroperoxybenzoic acid used in the reaction; i.e., using approximately one equivalent will provide the sulfoxide whereas using two equivalents will provide the sulfone.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XII is reacted with a compound of the Formula Rj-SNa using the method of step (7) of Reaction Scheme I to provide a 3-nitroquinolin-4-amine of Formula XIX.
  • step (2) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XIX is reduced using the method of step (3) of Reaction Scheme I to provide a quinoline-3,4- diamine of Formula XX.
  • step (3) of Reaction Scheme II a quinoline-3,4-diamine of Formula XX is cyclized using the method of step (4) of Reaction Scheme I to provide a lH-imidazo[4,5- cjquinoline of Formula XXI.
  • a lH-imidazo[4,5-c]quinoline of Formula XXI is oxidized to provide a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII using a conventional oxidizing agent.
  • a solution of a compound of Formula XXI in a suitable solvent such as chloroform or dichloromethane is treated with at least three equivalents of 3-chloroperoxybenzoic acid at ambient temperature.
  • step (5) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII is aminated using the method of step (6) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme III a 3-nitro-4-amino-quinolin-l-yl alcohol of Formula XI is protected with a tert-butyldimethylsilyl group using conventional methods.
  • a compound of Formula XI is combined with tert-butyldimethylsilyl chloride in a suitable solvent such as chloroform in the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine.
  • step (2) of Reaction Scheme III a protected 3-nitro-4-amino-quinolin-l-yl alcohol of Formula XXIII is reduced using the method of step (3) of Reaction Scheme I to provide a protected 3 , 4-diamino-quinolin- 1 -yl alcohol of Formula XXIV.
  • step (3) of Reaction Scheme III a protected 3,4-diamino-quinolin-l-yl alcohol of Formula XXIV is cyclized using the method of step (4) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinoline of Formula XXV.
  • step (4) of Reaction Scheme III a lH-imidazo[4,5-c]quinoline of Formula XXV is oxidized using the method of step (5) of Reaction Scheme I to provide a 1H- imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI.
  • step (5) of Reaction Scheme III a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI is aminated using the method of step (6) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVII.
  • step (6) of Reaction Scheme III the protecting group is removed from a 1H- imidazo[4,5-c]quinolin-4-amine of Formula XXVII to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXVIII.
  • a solution of a compound of Formula XXVII in a suitable solvent such as tetrahydrofuran is treated with tetrabutylammonium fluoride.
  • a suitable solvent such as tetrahydrofuran
  • tetrabutylammonium fluoride Some compounds of Formula XXVIII are known, see for example, Gerster, U.S. Patent No. 4,689,338 and Gerster et al., U.S. Patent 5,605,899.
  • a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is chlorinated using conventional methods to provide a lH-imidazo[4,5- c]quinoIin-4-amine of Formula XVI.
  • a compound of Formula XXVIII can be heated neat with thionyl chloride.
  • phosphorous oxychloride can be added in a controlled fashion to a solution of a compound of Formula XXVIII in a suitable solvent such as N,N-dimethyIformamide in the presence of triethylamine.
  • Steps (8) and (9) of Reaction Scheme III can be carried out in the same manner as steps (7) and (8) respectively of Reaction Scheme I.
  • step (1) of Reaction Scheme IV the hydroxy group of a 6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-l-yl alcohol of Formula XXIX is protected with a tert- butyldimethylsilyl group using the method of step (1) of Reaction Scheme III.
  • step (2) of Reaction Scheme IV the amino group of a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXX is protected using conventional methods to provide a protected lH-imidazo[4,5-c]quinoline of Formula XXXI.
  • a compound of Formula XXX is treated with di-tert-butyl dicarbonate in a suitable solvent such as tetrahydrofuran in the presence of triethylamine and 4-dimethylaminopyridine.
  • the reaction can be run at an elevated temperature (60°C).
  • step (3) of Reaction Scheme IV the te;-t-butyldimethylsilyl protecting group of a compound of Formula XXXI is removed using the method of step (6) of Reaction Scheme III to provide a lH-imidazo[4,5-c]quinolin-lyl alcohol of Formula XXXII.
  • step (4) of Reaction Scheme IV a lH-imidazo[4,5-c]quinolin-lyl alcohol of Formula XXXII is converted to a methanesulfonate of Formula XXXIII.
  • a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of triethylamine.
  • the reaction can be run at a reduced temperature (-10°C).
  • step (5) of Reaction Scheme IV a methanesulfonate of Formula XXXIII is reacted with a thiol of formula RiS ⁇ to provide a thioether of Formula XXXIV.
  • a solution of a compound of Formula XXXIII in a suitable solvent such as N, N-dimethylformamide is treated with the thiol in the presence of triethylamine.
  • the reaction can be run at an elevated temperature (80°C).
  • step (6) of Reaction Scheme IV the tert-butoxycarbonyl protecting groups are removed by hydrolysis under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-4- amine of Formula XXXV which is a subgenus of Formula II.
  • a solution of a compound of Formula XXXIV in a suitable solvent such as dichloromethane is treated at ambient temperature with a solution of hydrochloric acid in dioxane.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (7) of Reaction Scheme IV a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme V a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin- 1-yl alcohol of Formula XXIX is chlorinated using the method of step (7) of Reaction Scheme III to provide a compound of Formula XXXVII.
  • step (2) of Reaction Scheme V a compound of Formula XXXVII is reacted with a compound of formula Ri-SNa using the method of step (7) of Reaction Scheme I to provide a thioether of Formula XXXV which is a subgenus of Formula II.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (3) of Reaction Scheme V a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • alkyl As used herein, the terms "alkyl”, “alkenyl” 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 groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 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 and adamantyl.
  • the alkyl and alkenyl portions of-X- groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the groups consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
  • haloalkyl is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N).
  • Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
  • Heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring hetero atom (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, mo ⁇ holinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
  • the aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, 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, heteroarylcarbon
  • preferred X groups include ethylene and n-butylene and preferred Rj groups are alkyl and aryl, with phenyl or substituted phenyl a preferred aryl group. Preferably no R substituents are present (i.e., n is 0).
  • Preferred R 2 groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl.
  • preferred substituents if present, can be present in the compounds of the invention in any combination.
  • the invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymo ⁇ hs, and the like.
  • isomers e.g., diastereomers and enantiomers
  • salts e.g., sodium bicarbonate
  • solvates e.g., sodium bicarbonate
  • polymo ⁇ hs e.g., sodium bicarbonate
  • polymo ⁇ hs e.g., sodium bicarbonate
  • the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
  • compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity.
  • the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg, of the compound to the subject.
  • Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • the compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
  • the compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
  • Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon- ⁇ (IFN- ⁇ ) and/or tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL).
  • Cytokines whose biosynthesis may be induced by compounds of the invention include IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • Certain compounds of the invention have been found to preferentially induce the expression of IFN- ⁇ in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
  • PBMCs peripheral blood mononuclear cells
  • pDC2 cells precursor dendritic cell-type 2
  • the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
  • Compounds of the invention also have an effect on the acquired immune response.
  • the production of the T helper type 1 (Thl) cytokine IFN- ⁇ is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.
  • This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thl response and/or downregulation of the Th2 response is desired.
  • the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • atopic diseases e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • the immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN- ⁇ and/or TNF- ⁇ , the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such
  • Hepatitis C He ⁇ es Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
  • Candida aspergillus, and cryptococcal meningitis
  • neoplastic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g.
  • Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia areata; the inhibition of Keloid formation after surgery and other types of post-surgical scars.
  • these compounds could enhance or stimulate the healing of wounds, including chronic wounds.
  • the compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • a Parr vessel was charged with N-(4- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ butyl)-3- nitroquinolin-4-amine (6.05 g, 16.11 mmol), 5% platinum on carbon (3.0 g), and toluene (32 mL).
  • the vessel was placed on a Parr shaker and pressurized to 50 psi (3.5 Kg/cm 2 ) hydrogen. After shaking for one hour, more catalyst (3.0 g) and toluene (15 mL) were added and the vessel was pressurized to 50 psi (3.5 Kg/cm 2 ) hydrogen and shaking continued. The reaction was judged to be complete after one hour.
  • the catalyst was removed by filtration through fluted paper.
  • ⁇ PLC analysis indicated no starting material and a 3:1 mixture of 2-butyl-4-chloro-l-[4-(phenylthio)butyl]-lH-imidazo[4,5- c]quinoline and 2-butyl-4-(phenylthio)-l-[4-(phenylthio)butyl]-lH-imidazo[4,5- cjquinoline.
  • the solution was cooled and then partitioned between ethyl acetate and aqueous saturated sodium bicarbonate.
  • Part B A round bottom flask was charged with a magnetic stir bar, a 3: 1 mixture of 2- butyl-l-(2- ⁇ [tert-butyl(dimethyl)silyl]oxy ⁇ ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine and 2-butyl-N-[tert-butyl(dimethyl)silylJ-l-(2- ⁇ [tert- butyl(dimethyl)silylJoxy ⁇ ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-cJquinolin-4-amine (1.6 g) and a 1 M solution of acetic acid in dichloromethane (85 mL) to provide a homogenous solution.
  • the reaction mixture was heated to 60 °C to give a homogeneous solution that was maintained at 60 °C for 5 hours at which time the starting material was completely consumed.
  • the volatiles were removed under reduced pressure to give a dark brown oil.
  • the material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (lx).
  • the resulting solution was heated to 100 °C to give a homogeneous solution that was maintained at 100 °C for 90 hours at which time the starting materials were completely consumed.
  • the solution was cooled and then partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark yellow gum.
  • the material was dissolved in methanol (20 mL) and a 4 M solution of hydrochloric acid in dioxane (3.02 mL, 12.1 mmol). The light orange solution was stirred at ambient temperature for 12 hours at which time the reaction was judged to be complete.
  • the volatiles were removed under reduced pressure to give a light yellow gum.
  • the material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (lx). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid.
  • the material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to give an off-white solid.
  • the solid (0.63 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.6 g) was added and the resulting mixture was heated at reflux for 5 minutes.
  • the reaction mixture was heated to 60 °C to give a homogeneous solution that was maintained at 60 °C for 16 hours at which time the starting material was completely consumed.
  • the solution was cooled and then partitioned between chloroform and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were extracted with chloroform (l ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark brown oil.
  • the material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a light yellow solid.
  • the material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide an off-white solid.
  • the solid was recrystallized from acetonitrile and water to give 2- butyl-l-[4-(methylsulfonyl)butyl]-l ⁇ -imidazo[4,5-c]quinolin-4-amine (0.61 g, 1.63 mmol) as off-white needles, m.p. 164-165 °C.
  • the material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a fine white powder which was recrystallized from acetonitrile to give l-[4-(phenylsulfonyl)butylJ-lH- imidazo[4,5-cJquinolin-4-amine (0.32 g, 0.84 mmol) as white needles, m. p. 175-177 °C.
  • Example 6 Part B Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.46 mmol) was converted to l-[4-(phenylthio)butyl]-l ⁇ -imidazo[4,5-c]quinolin-4- amine.
  • the resulting solid (1.53 g) was dissolved in acetonitrile (90 mL) and brought to reflux. Activated charcoal (0,9 g) was added and the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution.
  • the title compound (0.86 g, 2.47 mmol) was isolated as white needles, m.p 158-160 °C.
  • N-(5-chloropentyl)-3- nitroquinolin-4-amine (2.0 g, 6.80 mmol) was reduced to provide N*-(5- chloropentyl)quinoline-3,4-diamine (1.79 g, 6.80 mmol) which was isolated as a brown oil and used without further purification.
  • the material was used without further purification.
  • CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor ( ⁇ ) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In “Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995). Blood Cell Preparation for Culture
  • PBMCs Peripheral blood mononuclear cells
  • Histopaque®-1077 The PBMCs are washed twice with Hank's Balanced Salts Solution and then are suspended at 3-4 x 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sulfoxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • the compounds are generally tested initially at concentrations ranging from 0.12 to 30 ⁇ M. Compounds showing activity at 0.12 ⁇ M may then be tested at lower concentrations.
  • Incubation The solution of test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 ⁇ M).
  • the final concentration of PBMC suspension is 1.5-2 X 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere. Separation
  • Interferon ( ⁇ ) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
  • Tumor necrosis factor ( ⁇ ) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg/mL.

Abstract

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain thioether functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

Description

Thioether Substituted Imidazoquinolines
Field of the Invention
This invention relates to imidazoquinoline compounds that have thioether functionality at the 1 -position, and to pharmaceutical compositions containing such compounds. A further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
Background of the Invention
The first reliable report on the lH-imidazo[4,5-c]quinoline ring system, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes the synthesis of l-(6-methoxy-8- quinolinyl)-2-methyl-lH-imidazo[4s5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted lH-imidazo[4,5-c] quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound l-[2-(4-piperidyl)ethyl]-lH-imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, 94362 (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Ηeterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5- c] quinolines.
Certain lH-imidazo[4,5-c]quinolin-4-amines and 1- and 2-substituted derivatives thereof were later found to be useful as antiviral agents, bronchodilators and immunomodulators. These are described in, inter alia, U.S. Patent Nos. 4,689,338; 4,698,348; 4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of which are incorporated herein by reference.
There continues to be interest in the imidazoquinoline ring system.
Certain lΗ-imidazo[4,5-c] naphthyridine-4-amines, lH-imidazo [4,5-c] pyridin-4- amines, and lH-imidazo [4,5-c] quinolin-4-amines having an ether containing substituent at the 1 position are known. These are described in U.S. Patent Nos. 5,268,376; 5,389,640; 5,494,916; and WO 99/29693. Despite these attempts to identify compounds that are useful as immune response modifiers, there is a continuing need for compounds that have the ability to modulate the immune response, by induction of cytokine biosynthesis or other mechanisms.
Summary of the Invention
We have found a new class of compounds that are useful in inducing cytokine biosynthesis in animals. Accordingly, this invention provides imidazoquinoline-4-amine and tetrahydroimidazoquinoline-4-amine compounds that have a thioether containing substituent at the 1 -position. The compounds are defined by Formulas (I) and (II), which are defined in more detail infra. These compounds share the general structural formula:
Figure imgf000003_0001
wherein X, Z, Rls R , and R are as defined herein for each class of compounds having formulas (I) and (II).
The compounds of formulas (I) and (II) are useful as immune response modifiers due to their ability to induce cytokine biosynthesis and otherwise modulate the immune response when administered to animals. This makes the compounds useful in the treatment of a variety of conditions such as viral diseases and tumors that are responsive to such changes in the immune response.
The invention further provides pharmaceutical compositions containing the immune response modifying compounds, and methods of inducing cytokine biosynthesis in an animal, treating a viral infection in an animal, and/or treating a neoplastic disease in an animal by administering a compound of Formula (I) or (II) to the animal. In addition, the invention provides methods of synthesizing the compounds of the invention. Detailed Description of the Invention
As mentioned earlier, we have found certain compounds that induce cytokine biosynthesis and modify the immune response in animals. Such compounds are represented by Formulas (I) and (II) as shown below.
Imidazoquinoline compounds of the invention, which have thioether functionality at the 1 -position are represented by Formula (I):
Figure imgf000004_0001
(I) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Z is -S-, -SO-, or-S02-; Ri is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
-R-t-aryl;
-Rj- heteroaryl;
-I^-heterocyclyl; R2 is selected from the group consisting of:
-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 the group consisting of: -OH; -halogen;
-N(R3)2; -CO-N(R3)2; -CO-Ci-io alkyl; -CO-O-Ci-io alkyl; -N3;
-aryl;
-heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R3 is independently H or Ci-io alkyl; each t is independently alkyl or alkenyl; each Y is independently -O- or -S(0)o-2-; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Cj-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear a thioether containing substituent at the 1 -position. Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
Figure imgf000006_0001
(II) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Z is -S-, -SO-, or -S02-; Ri is selected from the group consisting of: -alkyl;
-aryl;
-heteroaryl; -heterocyclyl; -alkenyl;
Figure imgf000006_0002
-R-r- heteroaryl; and -R-Hheterocyclyl; R2 is selected from the group consisting of: -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 the group consisting of: -OH; -halogen; -N(R3)2;
-CO-N(R3)2; -CO-d-io alkyl; -CO-0-CMo alkyl; -N3; -aryl;
-heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R3 is independently H or Ci-io alkyl; each R-j is independently alkyl or alkenyl; each Y is independently -O- or -S(0)o-2-; n is 0 to 4; and each R present is independently selected from the group consisting of C-.io alkyl, d-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
Preparation of the Compounds
Compounds of the invention can be prepared according to Reaction Scheme I where R, Ri, R2, X and n are as defined above.
In step (1) of Reaction Scheme I a 4-chloro-3-nitroquinoline of Formula X is reacted with an amine of formula HO-X-NH2 to provide a 3-nitroquinolin-4-amine of Formula XI. The reaction can be carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as chloroform or dichloromethane in the presence of triethylamine and optionally heating. Many quinolines of Formula X are known compounds (see for example, U.S. Patent 4,689,338 and references cited therein). Many amines of formula HO-X-NH2 are commercially available; others can be readily prepared using known synthetic routes.
In step (2) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XI is chlorinated to provide a 3-nitroquinolin-4-amine of Formula XII. Conventional chlorinating agents can be used. Preferably the reaction is carried out by combining a compound of Formula XI with thionyl chloride in a suitable solvent such as dichloromethane and heating. Alternatively the reaction may be run neat.
In step (3) of Reaction Scheme I a 3-nitroquinolin-4-amine of Formula XII is reduced to provide a quinoline-3,4-diamine of Formula XIII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as toluene.
In step (4) of Reaction Scheme I a quinoline-3,4-diamine of Formula XIII is reacted with a carboxylic acid or an equivalent thereof to provide a lH-imidazo[4,5- cjquinoline of Formula XIV. Suitable equivalents to a carboxylic acid include orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired R2 substituent in a compound of Formula XIV. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and trimethyl orthovalerate will provide a compound where R2 is butyl. The reaction can be run in the absence of solvent or in an inert solvent such as toluene. The reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
Optionally a catalyst such as pyridine hydrochloride can be included.
Alternatively, step (4) can be carried out by (i) reacting the diamine of Formula
XIII with an acyl halide of Formula R2C(0)C1 or R2C(0)Br and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in a suitable solvent such as pyridine. The reaction can be carried out at ambient temperature. In part (ii) the product of part (i) is heated in pyridine in the presence of pyridine hydrochloride.
In step (5) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline of Formula XIV is oxidized to provide a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV using a conventional oxidizing agent capable of forming N-oxides. Preferably a solution of a compound of Formula XIV in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature. In step (6) of Reaction Scheme I a lH-imidazo[4,5-c]quinoline-5N-oxide of Formula XV is aminated to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XVI. Step (6) involves (i) reacting a compound of Formula XV with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (6) involves reacting an N-oxide of Formula XV with an acylating agent. Suitable acylating agents include alkyl- or arylsulfonyl chlorides (e.g., benezenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred. Para- toluenesulfonyl chloride is most preferred. Part (ii) of step (6) involves reacting the product of part (i) with an excess of an aminating agent. Suitable aminating agents include ammonia (e.g., in the form of ammonium hydroxide) and ammonium salts (e.g., ammonium carbonate, ammonium bicarbonate, ammonium phosphate). Ammonium hydroxide is preferred. The reaction is preferably carried out by dissolving the N-oxide of Formula XV in an inert solvent such as dichloromethane or chloroform, adding the aminating agent to the solution, and then slowly adding the acylating agent. In step (7) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-4-amine of Formula
XVI is reacted with a compound of Formula Ri-SNa to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XVII which is a subgenus of Formula I. The reaction can be carried out by combining a compound of Formula XVI with a compound of formula RiSNa in a suitable solvent such as N,N-dimethylformamide or dimethyl sulfoxide and heating (60-80°C). The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (8) of Reaction Scheme I a lH-imidazo[4,5-c]quinolin-4-amine of Formula
XVII is oxidized using a conventional oxidizing agent to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I. Preferably a solution of a compound of Formula XVII in a suitable solvent such as chloroform or dichloromethane is treated with 3-chloroperoxybenzoic acid at ambient temperature. The degree of oxidation is controlled by adjusting the amount of 3-chloroperoxybenzoic acid used in the reaction; i.e., using approximately one equivalent will provide the sulfoxide whereas using two equivalents will provide the sulfone. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods. Reaction Scheme I
Figure imgf000010_0001
(3)
Figure imgf000010_0002
Compounds of the invention can be prepared according to Reaction Scheme II where R, Rj, R2, X and n are as defined above.
In step (1) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XII is reacted with a compound of the Formula Rj-SNa using the method of step (7) of Reaction Scheme I to provide a 3-nitroquinolin-4-amine of Formula XIX.
In step (2) of Reaction Scheme II a 3-nitroquinolin-4-amine of Formula XIX is reduced using the method of step (3) of Reaction Scheme I to provide a quinoline-3,4- diamine of Formula XX. In step (3) of Reaction Scheme II a quinoline-3,4-diamine of Formula XX is cyclized using the method of step (4) of Reaction Scheme I to provide a lH-imidazo[4,5- cjquinoline of Formula XXI.
In step (4) of Reaction Scheme II a lH-imidazo[4,5-c]quinoline of Formula XXI is oxidized to provide a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII using a conventional oxidizing agent. Preferably a solution of a compound of Formula XXI in a suitable solvent such as chloroform or dichloromethane is treated with at least three equivalents of 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme II a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXII is aminated using the method of step (6) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XVIII which is a subgenus of Formula I. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
Figure imgf000011_0001
(3)
Figure imgf000011_0002
Compounds of the invention can be prepared according to Reaction Scheme III where R, R , R2, X and n are as defined above.
In step (1) of Reaction Scheme III a 3-nitro-4-amino-quinolin-l-yl alcohol of Formula XI is protected with a tert-butyldimethylsilyl group using conventional methods. Preferably a compound of Formula XI is combined with tert-butyldimethylsilyl chloride in a suitable solvent such as chloroform in the presence of triethylamine and a catalytic amount of 4-dimethylaminopyridine.
In step (2) of Reaction Scheme III a protected 3-nitro-4-amino-quinolin-l-yl alcohol of Formula XXIII is reduced using the method of step (3) of Reaction Scheme I to provide a protected 3 , 4-diamino-quinolin- 1 -yl alcohol of Formula XXIV.
In step (3) of Reaction Scheme III a protected 3,4-diamino-quinolin-l-yl alcohol of Formula XXIV is cyclized using the method of step (4) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinoline of Formula XXV.
In step (4) of Reaction Scheme III a lH-imidazo[4,5-c]quinoline of Formula XXV is oxidized using the method of step (5) of Reaction Scheme I to provide a 1H- imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI.
In step (5) of Reaction Scheme III a lH-imidazo[4,5-c]quinolin-5N-oxide of Formula XXVI is aminated using the method of step (6) of Reaction Scheme I to provide a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVII. In step (6) of Reaction Scheme III the protecting group is removed from a 1H- imidazo[4,5-c]quinolin-4-amine of Formula XXVII to provide a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXVIII. Preferably a solution of a compound of Formula XXVII in a suitable solvent such as tetrahydrofuran is treated with tetrabutylammonium fluoride. Some compounds of Formula XXVIII are known, see for example, Gerster, U.S. Patent No. 4,689,338 and Gerster et al., U.S. Patent 5,605,899.
In step (7) of Reaction Scheme III a lH-imidazo[4,5-c]quinolin-4-amine of Formula XXVIII is chlorinated using conventional methods to provide a lH-imidazo[4,5- c]quinoIin-4-amine of Formula XVI. A compound of Formula XXVIII can be heated neat with thionyl chloride. Alternatively, phosphorous oxychloride can be added in a controlled fashion to a solution of a compound of Formula XXVIII in a suitable solvent such as N,N-dimethyIformamide in the presence of triethylamine. Steps (8) and (9) of Reaction Scheme III can be carried out in the same manner as steps (7) and (8) respectively of Reaction Scheme I.
Reaction Scheme III
Figure imgf000013_0001
Compounds of the invention can be prepared according to Reaction Scheme IV where R, Rl5 R2, X and n are as defined above and BOC is tert-butoxycarbonyl.
In step (1) of Reaction Scheme IV the hydroxy group of a 6,7,8,9-tetrahydro-lH- imidazo[4,5-c]quinolin-l-yl alcohol of Formula XXIX is protected with a tert- butyldimethylsilyl group using the method of step (1) of Reaction Scheme III.
Compounds of Formula XXIX are known or can be prepared using known synthetic methods, see for example, Nikolaides, et al., U.S. Patent No.5,352,784 and Lindstrom, U.S. Patent No. 5,693,811 and references cited therein.
In step (2) of Reaction Scheme IV the amino group of a lH-imidazo[4,5- c]quinolin-4-amine of Formula XXX is protected using conventional methods to provide a protected lH-imidazo[4,5-c]quinoline of Formula XXXI. Preferably a compound of Formula XXX is treated with di-tert-butyl dicarbonate in a suitable solvent such as tetrahydrofuran in the presence of triethylamine and 4-dimethylaminopyridine. The reaction can be run at an elevated temperature (60°C). In step (3) of Reaction Scheme IV the te;-t-butyldimethylsilyl protecting group of a compound of Formula XXXI is removed using the method of step (6) of Reaction Scheme III to provide a lH-imidazo[4,5-c]quinolin-lyl alcohol of Formula XXXII.
In step (4) of Reaction Scheme IV a lH-imidazo[4,5-c]quinolin-lyl alcohol of Formula XXXII is converted to a methanesulfonate of Formula XXXIII. Preferably a solution of a compound of Formula XXXII in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of triethylamine. The reaction can be run at a reduced temperature (-10°C).
In step (5) of Reaction Scheme IV a methanesulfonate of Formula XXXIII is reacted with a thiol of formula RiSΗ to provide a thioether of Formula XXXIV. Preferably a solution of a compound of Formula XXXIII in a suitable solvent such as N, N-dimethylformamide is treated with the thiol in the presence of triethylamine. The reaction can be run at an elevated temperature (80°C).
In step (6) of Reaction Scheme IV the tert-butoxycarbonyl protecting groups are removed by hydrolysis under acidic conditions to provide a lH-imidazo[4,5-c]quinolin-4- amine of Formula XXXV which is a subgenus of Formula II. Preferably a solution of a compound of Formula XXXIV in a suitable solvent such as dichloromethane is treated at ambient temperature with a solution of hydrochloric acid in dioxane. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (7) of Reaction Scheme IV a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
Figure imgf000015_0001
Compounds of the invention can be prepared according to Reaction Scheme V where R, Ri, R2, X and n are as defined above.
In step (1) of Reaction Scheme V a 6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin- 1-yl alcohol of Formula XXIX is chlorinated using the method of step (7) of Reaction Scheme III to provide a compound of Formula XXXVII.
In step (2) of Reaction Scheme V a compound of Formula XXXVII is reacted with a compound of formula Ri-SNa using the method of step (7) of Reaction Scheme I to provide a thioether of Formula XXXV which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
In step (3) of Reaction Scheme V a thioether of Formula XXXV is oxidized using the method of step (8) of Reaction Scheme I to provide a sulfone or sulfoxide of Formula XXXVI which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
Figure imgf000016_0001
N>R2
R„ I
X
SCO),.;
XXXVI As used herein, the terms "alkyl", "alkenyl" 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 groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 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 and adamantyl. In addition, the alkyl and alkenyl portions of-X- groups can be unsubstituted or substituted by one or more substituents, which substituents are selected from the groups consisting of alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl.
The term "haloalkyl" is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-". Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
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 term "heteroaryl" includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom (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, moφholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, isothiazolidinyl, and the like.
The aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, 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, aryloxycarbonyl, heteroaryloxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, alkanoylamino, arylcarbonyloxy, arylcarbonylthio, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, heteroaiylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylamino, arylalkylaminocarbonylamino, heteroarylaminocarbonylamino, heteroarylalkylcarbonylamino, 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.
Certain substituents are generally preferred. For example, preferred X groups include ethylene and n-butylene and preferred Rj groups are alkyl and aryl, with phenyl or substituted phenyl a preferred aryl group. Preferably no R substituents are present (i.e., n is 0). Preferred R2 groups include hydrogen, alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and cyclopropylmethyl), methoxyethyl, and ethoxymethyl. One or more of these preferred substituents, if present, can be present in the compounds of the invention in any combination.
The invention is inclusive of the compounds described herein in any of their pharmaceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), salts, solvates, polymoφhs, and the like. In particular, if a compound is optically active, the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers. Pharmaceutical Compositions and Biological Activity
Pharmaceutical compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier. The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity. Although the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg, of the compound to the subject. Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
The compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc. The compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders. Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon-α (IFN-α) and/or tumor necrosis factor-α (TNF-α) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
Certain compounds of the invention have been found to preferentially induce the expression of IFN-α in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
In addition to the ability to induce the production of cytokines, the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction. The compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes.
Compounds of the invention also have an effect on the acquired immune response. For example, although there is not believed to be any direct effect on T cells or direct induction of T cell cytokines, the production of the T helper type 1 (Thl) cytokine IFN-γ is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds. This activity means that the compounds are useful in the treatment of diseases where upregulation of the Thl response and/or downregulation of the Th2 response is desired. In view of the ability of compounds of the invention to inhibit the Th2 immune response, the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia. The immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN-α and/or TNF-α, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis
B; Hepatitis C; Heφes Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus; influenza; and para-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g. Candida, aspergillus, and cryptococcal meningitis; neoplastic diseases, e.g., basal cell carcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers; parasitic diseases, e.g. pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection, and leishmaniasis; and bacterial infections, e.g., tuberculosis, and mycobacterium avium. Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocythaemia; leprosy; multiple sclerosis; Ommen's syndrome; discoid lupus; Bowen's disease; Bowenoid papulosis; alopecia areata; the inhibition of Keloid formation after surgery and other types of post-surgical scars. In addition, these compounds could enhance or stimulate the healing of wounds, including chronic wounds. The compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN-α, TNF-α, IL-1, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals. The precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg. An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg.
The invention is further described by the following examples, which are provided for illustration only and are not intended to be limiting in any way.
Example 1
2-butyl-l-[4-(phenylthio)butyI]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000022_0001
Part A A round bottom flask was charged with a magnetic stir bar, 4-chloro-3- nitroquinoline (109.70 g, 525.87 mmol) and dichloromethane (500 mL). To the solution was added triethylamine (79.82 g, 788.81 mmol) and 4-amino-l-butanol (46.87 g, 525.87 mmol) to give a homogeneous, dark yellow solution. The reaction was judged to be complete after heating at reflux for 30 minutes. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated and the aqueous layer was extracted with chloroform (lx). The organic layers were combined and then concentrated under reduced pressure to afford of 4-[(3- nitroquinolin-4-yl)amino]butan-l-ol (104.67 g, 400.60 mmol) as a dark yellow solid. This material was used without further purification. Part B
A round bottom flask was charged with a magnetic stir bar, 4-[(3-nitroquinolin-4- yl)amino]butan-l-ol (5.0 g, 19.14 mmol), triethylamine (2.91 g, 28.71 mmol), tert- butyldimethylsilyl chloride (3.75 g, 24.9 mmol), 4-dimethylaminopyridine (0.10 g) and chloroform (40 mL) to give a dark yellow solution. The reaction was judged was to complete after stirring at ambient temperature for 2 hours. The solution was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-3-nitroquinolin-4-amine (6.05 g, 16.11 mmol) as a yellow-green solid. This material was used without further purification. MS (CI) for C]9H29Ν303Si m/z 376 (MH+), 342, 210. Part C
A Parr vessel was charged with N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-3- nitroquinolin-4-amine (6.05 g, 16.11 mmol), 5% platinum on carbon (3.0 g), and toluene (32 mL). The vessel was placed on a Parr shaker and pressurized to 50 psi (3.5 Kg/cm2) hydrogen. After shaking for one hour, more catalyst (3.0 g) and toluene (15 mL) were added and the vessel was pressurized to 50 psi (3.5 Kg/cm2) hydrogen and shaking continued. The reaction was judged to be complete after one hour. The catalyst was removed by filtration through fluted paper. The filter cake was washed with toluene (50 mL) and the filtrates were combined. The volatiles were removed under reduced pressure to afford N-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)quinoline-3,4-diamine (5.57 g, 16.11 mmol) as a dark oil. The material was used without further purification.
PartD
A round bottom flask was charged with a magnetic stir bar, N-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)quinoline-3,4-diamine (5.57 g, 16.11 mmol), trimethyl orthovalerate (5.23 g, 32.22 mmol) and toluene (47 mL). The reaction was heated to maintain a reflux that brought about a slow distillation to facilitate removal of the methanol byproduct. The reaction was judged to be complete after 15 hours at reflux. The reaction was cooled and the volatiles were removed under reduced pressure to afford of2-butyl-l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline (4.65 g, 11.30 mmol) as a thick, dark brown oil. The material was used without further purification. MS (CI) for C24Η37Ν3OSi m/z 412 (MH"1"), 298.
Part E
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline (4.65 g, 11.30 mmol) and chloroform (57 mL). Solid 3-chloroperbenzoic acid (2.78 g, 12.43 mmol) was added portion wise to the solution over 15 minutes and the reaction was stirred at ambient temperature for 1 hour. More 3-chloroperbenzoic acid (0.5g, 2.9 mmol) was added and after 30 minutes the starting material was completely consumed. The solution was partitioned between chloroform and aqueous saturated sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-butyl-l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH- imidazo[4,5-c]quinoline-5N-oxide (4.83 g, 11.30 mmol) as a dark oil. The material was used without further purification. Part F
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline-5N-oxide (11.30 mmol) and anhydrous dimethyl formamide (57 mL) under a nitrogen atmosphere. Phosphorus oxychloride (1.91 g, 12.43 mmol) was added to the reaction mixture in a drop wise fashion to give a homogeneous solution after complete addition. The reaction was judged to be complete after stirring for 1.5 hours at ambient temperature and was then partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated and the organic portion was washed with aqueous saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-butyl-4-chloro-l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinoline (3.65 g, 10.42 mmol) as a dark brown solid. The material was used without further purification. MS (CI) for Cι8Η21Cl2N3 m/z 350 (MH+), 314. Part G
A round bottom flask was charged with a magnetic stir bar, 2-butyl-4-chloro-l-(4- chlorobutyl)-lH-imidazo[4,5-c]quinoline (1.18 g, 3.37 mmol), benzenethiol (0.56 g, 5.05 mmol), triethylamine (0.68 g, 6.74 mmol), and dimethyl formamide (15 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C to give a homogeneous solution that was maintained at 80 °C for 2.5 hours. ΗPLC analysis indicated no starting material and a 3:1 mixture of 2-butyl-4-chloro-l-[4-(phenylthio)butyl]-lH-imidazo[4,5- c]quinoline and 2-butyl-4-(phenylthio)-l-[4-(phenylthio)butyl]-lH-imidazo[4,5- cjquinoline. The solution was cooled and then partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a 3:1 mixture of the products named above (1.43 g). The material was used without further purification.
Part H
A 3:1 mixture of 2-butyl-4-chloro-l-[4-(phenylthio)butyl]-lH-imidazo[4,5- cjquinoline to 2-butyl-4-(phenylthio)-l-[4-(phenylthio)butyl]-lH-imidazo[4,5-c]quinoline
(1.38 g) and a solution of 7% ammonia in methanol (30 mL) were combined in a bomb and heated to 150 °C. The reaction was judged to be complete after 5 hours. The volatiles were removed under reduced pressure and the resulting residue was stirred in water and made basic (pΗ 10) with solid sodium carbonate. The aqueous mixture was extracted with chloroform (3x). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow crystalline solid. The solid (0.8 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.4 g) was added; the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-l-[4-(phenylthio)butyl]-lH- imidazo[4,5-c]quinolin-4-amine (0.51 g, 1.25 mmol) as white needles, m.p. 118-120 °C. Analysis. Calculated for C24Η28N4S: %C 71.25; %H, 6.98; %N, 13.85. Found %C 71.12; %H, 6.81; %N, 13.62 -NMR (300 MHz, DMSO) δ 8.02 (d, J = 8.3 Hz, 1H), δ 7.61 (d, J = 8.3 Hz, 1H), δ 7.41 (t, J *= 8.3 Hz, 1H), δ 7.16-7.30 (m, 6H), δ 6.46 (bs, 2H), δ 4.52 (t, J = 7.6 Hz, 2H), δ 3.02 (t, J = 7.3 Hz, 2H), δ 2.89 (t, J = 7.8 Hz, 2H), δ 1.95 (m, 2H), δ 1.75 (m, 4H), δ 1.43 (sextet, J = 7.3 Hz, 2H), δ 0.94 (t, J = 7.3 Hz, 3H) MS (CI) for C24H28N4S m/z 405 (MH+), 282, 241
Example 2 2-butyl-l-[2-(ρhenylthio)ethyl]-6,7,8,9-tetrahydro- lH-imidazo[4,5-c]quinolin-4-amine hydrochloride
Figure imgf000026_0001
Part A
A round bottom flask was charged with a magnetic stir bar, 2-(4-amino-2-butyl- 6,7,8,9-te1xahydro-lH-imidazo[4,5-c]quinolin-l-yl)ethanol (1.0 g, 3.47 mmol), tert- butyldimethylsilyl chloride (1.62 g, 10.75 mmol), triethylamine (1.58 g, 15.62 mmol), 4- dimethylaminopyridine (0.1 g), and chloroform (30 mL) to give a heterogeneous reaction mixture. The reaction was judged to be complete after stirring at 60 °C for 2 hours. The solution was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a 3:1 mixture of 2-butyl-l-(2-{[tert- butyl(dimethyl)silyl]oxy} ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine and 2-butyl-N-[tert-butyl(dimethyl)silyl]-l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)- 6,7,8,9-tetrahydro-lH-imidazo[4,5-cJquinolin-4-amine (1.79 g) as a dark brown oil. The material was used without further purification. Part B A round bottom flask was charged with a magnetic stir bar, a 3: 1 mixture of 2- butyl-l-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-amine and 2-butyl-N-[tert-butyl(dimethyl)silylJ-l-(2-{[tert- butyl(dimethyl)silylJoxy}ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-cJquinolin-4-amine (1.6 g) and a 1 M solution of acetic acid in dichloromethane (85 mL) to provide a homogenous solution. The reaction was judged to be complete after stirring at ambient temperature for 30 minutes. The solution was partitioned between chloroform and brine. The layers were separated and the organic layer was washed with aqueous saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark brown oil. The material was purified by chromatography over silica gel (95/4/1 dichloromethane/methanol/ammonium hydroxide [14.8 M in water]) to provide 2-butyl-l-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine
(1.24 g, 3.10 mmol) as a colorless oil. Part C
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-(2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine (0.83 g, 2.06 mmol), di-tert-butyl dicarbonate (1.79 g, 8.24 mmol), triethylamine (0.52 g,
5.15 mmol), 4-dimethylaminopyridine (0.1 g), and anhydrous tetrahydrofuran (21 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60 °C to give a homogeneous solution that was maintained at 60 °C for 2.5 hours at which time the reaction was judged to be complete. The solution was cooled to ambient temperature and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2.27 mL, 2.27 mmol) was added. The reaction was judged to be complete after stirring at ambient temperature for 30 minutes. The solution was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide di(tert-butyl) 2-butyl-l-(2-hydroxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5- c]quinolin-4-ylimidodicarbonate (0.55 g, 1.13 mmol) as a clear gum. Part D A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl- l-(2-hydroxyethyl)-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.55 g, 1.13 mmol) and anhydrous dichloromethane (11 L) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to -10 °C in a methanol/ice bath. To the cooled solution was added triethylamine (0.23 g, 2.26 mmol) and methanesulfonyl chloride (0.19 g, 1.70 mmol). The reaction was judged to be complete after stirring at -10 °C for 15 minutes and was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-{4- [bis(tert-butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l- yl} ethyl methanesulfonate (0.61 g, 1.08 mmol) as a gummy yellow solid. The material was used without further purification. MS (CI) for C27Η 2N407S m/z 567 (MH+), 467,
367, 271. Part E
A round bottom flask was charged with a magnetic stir bar, 2-{4-[bis(tert- butoxycarbonyl)amino]-2-butyl-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-l-yl}ethyl methanesulfonate (0.61 g, 1.08 mmol), benzenethiol (0.21 g, 1.88 mmol), triethylamine
(0.25 g, 2.43 mmol) and anhydrous dimethyl formamide (11 mL) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C to give a dark yellow, homogeneous solution that was maintained at 80 °C for 2.5 hours at which time the reaction was judged to be complete. The solution was cooled and then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide di(tert-butyl) 2-butyl-l-[2- (phenylthio)ethyl]-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-ylimidodicarbonate
(0.54 g, 0.93 mmol) as a light yellow oil. MS (CI) for C32Η44N404S m/z 581 (MH+), 481,
381, 245.
Part F
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl- l-[2-(phenylthio)ethylJ-6,7,8,9-tetrahydro-lH-imidazo[4,5---Jquinolin-4- ylimidodicarbonate (0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5 mL), and dichloromethane (5 mL). The reaction was judged to be complete after stirring at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford an off white solid. The material was recrystallized from acetonitrile to provide 2- butyl-l-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine hydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237-238 °C. Analysis. Calculated for C22H28N4S -(H20)ι/4 - (HC1)2: %C 57.70; %H, 6.71; %N, 12.23. Found %C 57.62; %H, 6.57; %N, 12.41
Η-NMR (300 MHz, DMSO) δ 7.81 (bs, 2H), δ 7.22-7.39 (m, 5H), δ 4.64 (t, J = 6.8 Hz, 2H), δ 3.40 (t, J = 6.8 Hz, 2H), δ 2.75 (m, 6H), δ 1.71 (m, 6H), δ 1.34 (sextet, J = 7.3 Hz, 2H), δ 0.89 (t, J = 7.3 Hz, 3H)
MS (CI) for C22H28N4S (H20)ι 4(HC1)2 m/z 381 (MH+), 245, 137
Example 3 2-butyl-l-[4-(phenylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000029_0001
Part A
Using the general method of Example 1 Part E, 2-butyl-l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline (16.0 g, 38.87 mmol) was oxidized to 2-butyl-l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5- c]quinoline-5N-oxide (16.61g, 38.87 mmol) which was isolated without purification as a tan solid. Part B
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline-5N-oxide (16.61 g, 38.87 mmol), a 14.8 M solution of ammonium hydroxide in water (75 mL) and chloroform (200 mL). To the rapidly stirring solution was added -toluenesulfonyl chloride (8.15 g, 42.76 mmol) in a portion wise fashion resulting in a mild exotherm. The reaction was judged to be complete after stirring at ambient temperature for 10 minutes. The solution was partitioned between chloroform and aqueous saturated sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford an off-white solid. The material was triturated with ethyl ether and collected by filtration to provide 2-butyl-l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)- lH-imidazo[4,5-c]quinolin-4-amine (9.3 g, 21.80 mmol) as a fine white powder. The material was used without further purification.
Part C
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinolin-4-amine (9.2 g, 21.56 mmol), a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (23.72 mL, 23.72 mmol), and anhydrous tetrahydrofuran (100 mL) to give a homogeneous, light orange solution. The reaction was judged to be complete after stirring at ambient temperature for 1 hour. While stirring, water (100 mL) was added and resulted in a mild exotherm. The volatiles were removed under reduced pressure until a solid precipitated out of solution. The solid was collected by filtration and washed with water (20 mL) and acetone (20 mL) to afford a white solid. The material was triturated with ethyl ether (50 mL) and collected by filtration to provide 4-(4-amino-2-butyl-lH-imidazo[4,5-c]quinolin-l-yl)butan-l-ol (6.12 g, 19.59 mmol) as a fine white solid, m.p. 184-186 °C.
Analysis. Calculated for Cι8Η24N4O: %C 69.20; %H, 7.74; %N, 17.93. Found %C 69.05; %H, 8.02; %N, 18.03 MS (CI) for C]8H24N40 m z 313 (MH+)
Part D
A round bottom flask was charged with a magnetic stir bar, 4-(4-amino-2-butyl- lH-imidazo[4,5-c]quinolin-l-yl)butan-l-ol (7.3 g, 23.37 mmol), triethylamine (3.55 g, 35.06 mmol), and anhydrous dimethyl formamide (93 mL) under a nitrogen atmosphere. To the stirred solution was added phosphorus oxychloride (3.94 g, 25.70 mmol) in a drop wise fashion resulting in an exotherm to give a dark yellow heterogeneous reaction mixture. The reaction mixture was heated to 60 °C to give a homogeneous solution that was maintained at 60 °C for 5 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure to give a dark brown oil. The material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (lx). The organic layers were combined and the volatiles removed under reduced pressure to afford a 2:1 mixture ofN-[2-butyl-l-(4-chlorobutyl)-lH-imidazo[4,5- c]quinolin-4-yl]-N,N-dimethylimidoformamide and 2-butyl-l-(4-chlorobutyl)-lH- imidazo[4,5-c]quinolin-4-amine (7.70 g) as an off-white solid. The material was used without further purification. Part E
A round bottom flask was charged with a magnetic stir bar, a 2: 1 mixture of Λ"-[2- butyl-l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamide and 2-butyl-l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (1.3 g), benzenesulfinic acid sodium salt (1.67 g, 10.11 mmol), and anhydrous dimethyl formamide (15 mL) under a nitrogen atmosphere. The resulting solution was heated to 100 °C to give a homogeneous solution that was maintained at 100 °C for 90 hours at which time the starting materials were completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark yellow gum. The material was dissolved in methanol (20 mL) and a 4 M solution of hydrochloric acid in dioxane (3.02 mL, 12.1 mmol). The light orange solution was stirred at ambient temperature for 12 hours at which time the reaction was judged to be complete. The volatiles were removed under reduced pressure to give a light yellow gum. The material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (lx). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to give an off-white solid. The solid (0.63 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.6 g) was added and the resulting mixture was heated at reflux for 5 minutes. The charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-l-[4-(phenylsulfonyl)butyl]-lΗ-imidazo[4,5-c]quinoIin-4-amine (0.37 g, 0.85 mmol) as a white fluffy solid, m.p. 179-180 °C. Analysis. Calculated for C24H28Ν 02S: %C 66.03; %H, 6.46; %N, 12.83. Found %C 65.88; %H, 6.49; %N, 12.76 !H-NMR (300 MHz, DMSO) δ 7.98 (d, J = 8.3 Hz, 1H), δ 7.82 (m, 2H) δ 7.73 (d, J = 7.3 Hz, 1H), δ 7.62 (m, 3H) δ 7.41 (t, J = 7.6 Hz, 1H), δ 7.22 (t, J = 7.6 Hz, 1H), δ 6.45 (bs, 2H), δ 4.51 (t, J = 7.3 Hz, 2H), δ 3.90 (t, J = 7.8 Hz, 2H), δ 2.86 (t, J = 7.6 Hz, 3H), δ 1.69-1.90 (m, 6H), δ 1.43 (sextet, J - 7.3 Hz, 2H), δ 0.95 (t, J = 7.3 Hz, 3H) MS (CI) for C24H28N402S m/z 437 (MH+), 295
Example 4 2-butyl-l^[4-(methylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000032_0001
Part A
A round bottom flask was charged with a magnetic stir bar, a 2: 1 mixture of N-[2- butyl-l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamide and 2-butyl-l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (6.17 g), a 4 M solution of hydrochloric acid in dioxane (21.15 mL, 84.56 mmol), and methanol (200 mL) to provide a light orange solution. The reaction was judged to be complete after stirring at ambient temperature for 43 hours. The volatiles were removed under reduced pressure and the resulting light yellow solid was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (l ). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-butyl-l-
(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (4.65 g, 14.05 mmol) as an off-white solid. The material was used without further purification. MS (CI) for Cι8Η23ClΝ m/z 331 (MH+), 295. Part B A round bottom flask was charged with a magnetic stir bar, 2-butyl-l -(4- chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (1.5 g, 4.53 mmol), sodium thiomethoxide (0.48 g, 6.80 mmol), and anhydrous dimethyl formamide (18 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60 °C to give a homogeneous solution that was maintained at 60 °C for 16 hours at which time the starting material was completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were extracted with chloroform (l ). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark brown oil. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a light yellow solid. The solid was recrystallized from dimethyl formamide and water to give 2-butyl-l-[4-(methylthio)butyl]-lH- imidazo[4,5-c]quinolin-4-amine (0.83 g, 2.42 mmol) as light yellow needles, m.p. 127-130
°C.
Analysis. Calculated for Cι9Η26N4S: %C 66.63; %H, 7.65; %N, 16.36. Found %C 66.68;
%H, 7.53; %N, 16.35 Η-NMR (500 MHz, DMSO) δ 8.04 (d, J = 8.3 Hz, 1H), δ 7.61 (d, J = 8.3 Hz, 1H), δ 7.41
(t, J = 8.3 Hz, 1H), δ 7.25 (t, J = 8.3 Hz, 1H), δ 6.43 (bs, 2H), δ 4.52 (t, J = 7.6 Hz, 2H), δ 2.92 (t, J = 7.8 Hz, 2H), δ 2.53 (t, J = 7.3 Hz, 2H), δ 2.01 (s, 3H), δ 1.90 (m, 2H) δ 1.80 (p, J = 7.8 Hz, 2H) δ 1.71 (p, J = 7.3 Hz, 2H) δ 1.46 (sextet, J = 7.3 Hz, 2H), δ 0.96 (t, J = 7.3 Hz, 3H) MS (CI) for C19H26N4S m/z 343 (MH+), 295, 241
Example 5 2-butyl-l-[4-(methylsulfonyl)butyl]-lH-imidazo[4,5-cJquinolin-4-amine
Figure imgf000034_0001
Part A A round bottom flask was charged with a magnetic stir bar, 2-butyl-l-[4-
(methylthio)butylJ-lH-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.50 mmol), and chloroform (18 mL). Solid 3-chloroperbenzoic acid (1.72 g, 7.71 mmol) was added to the resulting solution portion wise over 15 minutes. The reaction was judged to be complete after stirring at ambient temperature for 5 minutes. The solution was partitioned between chloroform and 1% aqueous sodium carbonate. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light brown solid. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide an off-white solid. The solid was recrystallized from acetonitrile and water to give 2- butyl-l-[4-(methylsulfonyl)butyl]-lΗ-imidazo[4,5-c]quinolin-4-amine (0.61 g, 1.63 mmol) as off-white needles, m.p. 164-165 °C.
Analysis. Calculated for Cι9H26N402S: %C 60.94; %H, 7.00; %N, 14.96. Found %C 60.71; %H, 6.94; %N, 14.94 1H-NMR (300 MHz, DMSO) δ 8.03 (d, J = 8.3 Hz, IH), δ 7.61 (d, J = 8.3 Hz, IH), δ 7.42 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.46 (bs, 2H), δ 4.56 (t, J = 7.6 Hz, 2H), δ
3.21 (t, J = 7.3 Hz, 2H), δ 2.96 (s, 3H), δ 2.93 (t, J = 7.8 Hz, 2H), δ 1.91 (m, 4H), δ 1.81 (p, J = 7.3 Hz, 2H), δ 1.45 (sextet, J = 7.3 Hz, 2H), δ 0.96 (t, J = 7.3 Hz, 3H) MS (CI) for Cι9H26N402S m/z 375 (MH+), 295 Example 6 l-[2-(phenylthio)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000035_0001
Part A A round bottom flask was charged with a magnetic stir bar, 2-(4-amino-lH- imidazo[4,5-c]quinolin-l-yl)ethanol (8.46 g, 37.06 mmol), and thionyl chloride (68.99 g, 57.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C to give a heterogeneous reaction mixture that was maintained at 80 °C for 2 hours at which time the starting material was completely consumed. The solution was cooled and quenched by the addition of water (400 mL). To the stirred solution was added solid sodium carbonate until the pΗ reached 10 at which time a solid precipitated out of solution. The solid was collected by filtration to afford l-(2-chloroethyι)-lH-imidazo[4,5- c]quinolin-4-amine (7.86 g, 31.86 mmol) as an off-white solid. The material was used without further purification. Part B
A round bottom flask was charged with a magnetic stir bar, l-(2-chloroethyl)-lH- imidazo[4,5-cJquinolin-4-amine (2.0 g, 8.11 mmol), sodium benzenethiolate (1.79 g, 12.16 mmol), and anhydrous dimethyl sulfoxide (40 mL) under a nitrogen atmosphere. The reaction mixture was heated to 100 °C to give a homogeneous solution that was maintained at 100 °C for 30 minutes at which time the starting material was completely consumed. The hot solution was poured into rapidly stirred water (300 mL) which caused a solid to precipitate out of solution. The solid was collected by filtration to afford an off- white solid. The material was triturated with acetonitrile and collected by filtration to give l-[2-(phenylthio)ethyl]-lH-imidazo[4,5-c]quinolin-4-amine (2.08 g, 6.49 mmol) as an off- white powder, m. p. 233-235 °C. Analysis. Calculated for C18Hι6N4S: %C 67.47; %H, 5.03; %N, 17.49. Found: %C 67.20; %H, 4.95; %N, 17.52
!H-NMR (300 MHz, DMSO) δ 8.14 (s, IH), δ 7.76 (d, J = 8.3 Hz, IH), δ 7.60 (t, J = 8.3 Hz, IH), δ 7.28-7.44 (m, 6H), δ 7.12 (t, J = 8.3 Hz, IH), δ 6.58 (bs, 2H), δ 4.79 (t, J = 6.8 Hz, 2H), δ 3.48 (t, J = 6.8 Hz, 2H)
MS (CI) for Cι8Hι6N4S m/z 321 (MH+), 185, 137
Example 7 l-[4-(phenylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000036_0001
Part A
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-lH- imidazo[4,5-c]quinolin-4-amine (20.0 g, 55.04 mmol), sodium hydride (3.3 g, 60% dispersion, 82.56 mmol), and anhydrous dimethyl formamide (275 mL) under a nitrogen atmosphere. After the reaction mixture had stirred at ambient temperature for 2 hours, 4- chloro-1-iodobutane (19.23 g, 88.06 mmol) was added and the resulting homogeneous solution was stirred at ambient temperature for 48 hours at which time the starting material was consumed. The solution was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was recrystallized from ethyl acetate and hexanes to give N,N-dibenzyl-l-(4-chlorobutyl)-lH-imidazo[4,5- c]quinolin-4-amine (20.7 g, 45.49 mmol) as white needles. MS (CI) for C28Η27C1Ν4 m/z 455 (MH+), 365, 329, 239 Part B
A round boftom flask was charged with a magnetic stir bar, N,N-dibenzyl-l-(4- chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (7.0 g, 15.38 mmol), sodium benzenethiolate (3.46 g, 26.15 mmol), and anhydrous dimethyl formamide (77 mL) under a nitrogen atmosphere. The reaction mixture was heated to 60 °C to give a heterogeneous mixture that was maintained at 60 °C for 4 hours at which time the starting material was completely consumed. The cooled solution was partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a colorless oil. The material was purified by chromatography over silica gel (80/20 hexanes/ethyl acetate) to provide N,N-dibenzyl- l-[4-(phenylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine (7.5 g, 14.19 mmol) as a colorless oil. MS (CI) for C34Η32Ν S m/z 529 (MH+), 439, 349 Part C A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-l-[4-
(phenylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine (3.64 g, 6.88 mmol) and chloroform (34 mL). Solid 3-chloroperbenzoic acid (3.39 g, 15.14 mmol) was added portion wise to the resulting solution over 5 minutes. The reaction was judged to be complete after stirring at ambient temperature for 5 minutes. The solution was partitioned between chloroform and 1% aqueous sodium carbonate. The layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a red gum. The material was purified by chromatography over silica gel (dichloromethane) to provide N,N-dibenzyl-l-[4- (phenylsulfonyl)butylJ-lH-imidazo[4,5-c]quinolin-4-amine (2.85 g, 5.08 mmol) as a light pink gum. MS (CI) for C34Η32Ν402S m/z 561 (MH+), 471, 381
PartD
A round bottom flask was charged with a magnetic stir bar, N,N-dibenzyl-l-[4- (phenylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine (1.0 g, 1.78 mmol), triflic acid (2.68 g, 17.83 mmol), and anhydrous dichloromethane (14 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at ambient temperature for 24 hours. The solution was partitioned between chloroform and excess aqueous sodium hydroxide (20%). The layers were separated. The aqueous layer was extracted with chloroform (3x). The organic layers were combined and then concentrated under reduced pressure to afford a light brown solid. The material was purified by chromatography over silica gel (90/10 dichloromethane/methanol) to provide a fine white powder which was recrystallized from acetonitrile to give l-[4-(phenylsulfonyl)butylJ-lH- imidazo[4,5-cJquinolin-4-amine (0.32 g, 0.84 mmol) as white needles, m. p. 175-177 °C.
Analysis. Calculated for C20H20N4O2S: %C 63.14; %H, 5.30; %N, 14.73. Found: %C 63.14; %H, 5.24; %N, 14.77
Η-NMR (300 MHz, DMSO) δ 8.15 (s, IH), δ 8.01 (d, J = 8.3 Hz, IH), δ 7.80 (m, 2H), δ 7.71 (m, IH), δ 7.60 (m, 3H), δ 7.44 (t, J = 8.3 Hz, IH), δ 7.24 (t, J *= 8.3 Hz, IH), δ 6.59 (bs, 2H), δ 4.59 (t, J = 6.8 Hz, 2H), δ 3.38 (t, J = 7.8 Hz, 2H), δ 1.93 (m, 2H), δ 1.58 (m,
2H) MS (CI) for C20H20N4O2S m/z 381 (MH+), 239
Example 8 l-[4-(methylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000038_0001
Part A
Using the general method of Example 7 Part B, N,N-dibenzyl-l-(4-chlorobutyl)- lH-imidazo[4,5-c]quinolin-4-amine (5.0 g, 10.99 mmol) was converted to N,N-dibenzyl- l-[4-(methylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine using sodium thiomethoxide
(1.16 g, 16.48 mmol). The material was purified by chromatography over silica gel (80/20 hexanes/ethyl acetate) to provide the product (4.91 g, 10.52 mmol) as a colorless oil. MS
(CI) for C29Η30Ν4S m/z 467 (MH+), 377, 287, 185
Part B Using the general method of Example 7 Part C, N,N-dibenzyl-l-[4-
(methylthio)butyl]-lH-imidazo[4,5-cJquinolin-4-amine (4.91 g, 15.52 mmol) was oxidized to N,N-dibenzyl-l-[4-(methylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine which was purified by chromatography over silica gel (80/20 hexanes/ethyl acetate) to provide the product (4.53 g, 9.08 mmol) as a light orange solid. MS (CI) for C29H30N4O2S m/z 499 (MH+), 409, 319 Part C Using the general method of Example 7 Part D, N,N-dibenzyl-l-[4-
(methylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine (4.53 g, 9.08 mmol) was converted to l-[4-(methylsulfonyl)butyl]-lΗ-imidazo[4,5-c]quinolin-4-amine. The material was recrystallized from methanol and water to afford the title compound (1.33 g, 4.18 mmol) as white needles, m.p. 203-204 °C. Analysis. Calculated for Cι5Hι8Ν402S: %C 56.58; %H, 5.70; %N, 17.60. Found: %C
56.33; %H, 5.63; %N, 17.41
Η-NMR (300 MHz, DMSO) δ 8.22 (s, IH), δ 8.06 (d, J = 8.3 Hz, IH), δ 7.62 (d, J = 8.3 Hz, IH), δ 7.45 (t, J = 8.3 Hz, IH), δ 7.27 (t, J = 8.3 Hz, IH), δ 6.59 (bs, 2H), δ 4.65 (t, J * 6.8 Hz, 2H), δ 3.19 (t, J = 7.8 Hz, 2H), δ 2.93 (s, 3H), δ 1.99 (m, 2H), δ 1.74 (m, 2H) MS (CI) for C]5H]8N402S m/z 319 (MH+), 239
Example 9 l-[4-(phenylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000039_0001
Part A
Using the general method of Example 1 Part D, N-(4-{[tert- butyl(dimethyl)silylJoxy}butyl)quinoline-3,4-diamine (101.21 g, 292.90 mmol) was cyclized to l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline using triethyl orthoformate (65.11 g, 439.35 mmol). The product (75.0 g, 210.93 mmol) was isolated as a brown oil and used without further purification. Part B
Using the general method of Example 1 Part E, l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline (42.2 g, 118.69 mmol) was oxidized to l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-cJquinoline-5N- oxide (44.10 g, 118.69 mmol) which was isolated without further purification as a tan solid. Part C
Using the general method of Example 3 Part B, l-(4-{[tert- butyl(dimethyl)silyl]oxy}butyl)-lH-imidazo[4,5-c]quinoline-5N-oxide (44.10 g, 118.69 mmol) was aminated to provide l-(4-{[tert-butyl(dimethyl)silyl]oxy}butyl)-lH- imidazo[4,5-c]quinolin-4-amine. The material was triturated with ethyl ether and collected by filtration to afford the product (21.54 g, 58.12 mmol) as a light brown solid which was used without further purification. Part D Using the general method of Example 3 Part C, l-(4-{[tert- butyl(dimethyI)siIyl]oxy}butyl)-lH-imidazo[4,5-c]quinolin-4-amine (21.5 g, 58.02 mmol) was converted to 4-(4-amino-lH-imidazo[4,5-cJquinolin-l-yl)butan-l-ol. The material was triturated with cold methanol (0 °C) and collected by filtration to afford the product (13.92 g, 54.30 mmol) which was used without further purification. MS (CI) for C,4ΗI6N40 m/z 257 (MH+), 185
Part E
Using the general method of Example 6 Part A, 4-(4-amino-lH-imidazo[4,5- c]quinolin-l-yl)butan-l-ol (5.0 g, 19.51 mmol) was chlorinated to provide l-(4- chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (4.92 g, 17.91 mmol) which was isolated without further purification as an off-white solid.
Part F
Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.46 mmol) was converted to l-[4-(phenylthio)butyl]-lΗ-imidazo[4,5-c]quinolin-4- amine. The resulting solid (1.53 g) was dissolved in acetonitrile (90 mL) and brought to reflux. Activated charcoal (0,9 g) was added and the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The title compound (0.86 g, 2.47 mmol) was isolated as white needles, m.p 158-160 °C.
Analysis. Calculated for C20H20N4S: %C 68.94; %H, 5.79; %N, 16.08. Found: %C 68.70; %H, 5.74; %N, 16.08 -H-NMR (300 MHz, DMSO) δ 8.18 (s, IH), δ 8.05 (d, J = 8.3 Hz, IH), δ 7.63 (d, J = 8.3
Hz, IH), δ 7.45 (t, J = 8.3 Hz, IH), δ 7.26 (m, 5H), δ 7.14-7.19 (m, IH), δ 6.60 (bs, 2H), δ 4.62 (t, J = 6.8 Hz, 2H), δ 3.00 (t, J = 7.3 Hz, 2H), δ 2.00 (m, 2H), δ 1.61 (m, 2H) MS (CI) for C20H20N4S m/z 349 (MH+), 185
Example 10
1 -[4-(methylthio)butyl]- lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000041_0001
Part A
Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, l-(4-chlorobutyl)-lH-imidazo[4,5-c]quinolin-4-amine
(1.5 g, 5.46 mmol) was converted to l-[4-(methylthio)butyl]-lΗ-imidazo[4,5-c]quinolin- 4-amine using sodium thiomethoxide (0.88 g, 12.56 mmol) in lieu of sodium benzenethiolate. The resulting solid (1.26 g) was dissolved in acetonitrile (40 mL) and brought to reflux. Activated charcoal (0.7 g) was added, the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from acetonitrile. The title compound (0.66 g, 2.30 mmol) was isolated as white needles, m.p 163-164 °C. Analysis. Calculated for Cι5Hι8N4S: %C 62.91; %H, 6.34; %N, 19.56. Found: %C 62.70; %H, 6.19; %N, 19.45 Η-NMR (300 MHz, DMSO) δ 8.21 (s, IH), δ 8.06 (d, J = 8.3 Hz, IH), δ 7.62 (d, J = 8.3 Hz, IH), δ 7.44 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.59 (bs, 2H), δ 4.62 (t, J = 7.6 Hz, 2H), δ 2.50 (t, J = 6.8 Hz, 2H), δ 1.99 (s, 3H), δ 1.95 (p, J = 7.3 Hz, 2H), δ 1.59 (p, J = 7.3 Hz, 2H) MS (CI) for Cι5Hι8N4S m/z 287 (MH1"), 185
Example 11 2-butyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000042_0001
Part A
Using the general method of Example 1 Part A, 4-chloro-3-nitroquinoline (107.7 g, 525.87 mmol) was converted to 5-[(3-nitroquinolin-4-yl)amino]pentan-l-ol using 5- amino-1-pentanol (79.82 g, 788.81 mmol) in lieu of 4-amino-butanol. The product (117.22 g, 425.77 mmol) was used without further purification as a dark yellow solid. MS (CI) for Cι4Η N303 m z 276 (MH+), 224
Part B
A round bottom flask was charged with a magnetic stir bar, 5-[(3-nitroquinolin-4- yl)amino]pentan-l-ol (5.0 g, 18.16 mmol), and thionyl chloride (40.78 g, 0.34 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 80 °C to give a homogeneous solution that was maintained at 80 °C for 1 hour at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting oil stirred in water made basic (pH 10) with solid sodium carbonate. The resulting solid was collected by filtration to afford N-(5-chloropentyl)-3-nitroquinolin-4- amine (4.80 g, 16.34 mmol) which was used without further purification. Part C
Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, N-(5-chloropentyl)-3-nitroquinolin-4-amine (4.75 g, 16.17 mmol) was converted to N-[5-(methylthio)pentyl]-3-nitroquinolin-4-amine using sodium thiomethoxide (1.43 g, 19.40 mmol) in lieu of sodium benzenethiolate. The product (3.28 g, 10.74 mmol) was isolated without further purification as a light yellow solid. MS (CI) for C15Hι9Ν302S m/z 306 (MH+), 272, 117
Part D
Using the general method of Example 1 Part C, N-[5-(methylthio)pentyl]-3- nitroquinolin-4-amine (3.20 g, 10.48 mmol) was reduced to N4-^-
(methylthio)pentyl]quinoline-3,4-diamine (2.89 g, 10.48 mmol) which was isolated without further purification as a brown oil.
Part E
Using the general method of Example 1 Part D, N -^- (methylthio)pentyl]quinoline-3,4-diamine (2.89 g, 10.48 mmol) was cyclized to provide 2- butyl-l-[5-(methylthio)pentyl]-lH-imidazo[4,5-c]quinoline. The material was purified by chromatography over silica gel (ethyl acetate) to afford the product (2.10 g, 6.15 mmol) as a light brown oil. Part F A round bottom flask was charged with a magnetic stir bar, 2-butyl-l -[5-
(methylthio)pentylJ-lH-imidazo[4,5-c]quinoline (2.1 g, 6.15 mmol) and chloroform (31 mL). Solid 3-chloroperbenzoic acid (4.41 g, 19.68 mmol) was added portion wise to the solution over 10 minutes and the reaction was stirred at ambient temperature for 30 minutes at which time the starting material was completely consumed. The solution was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-butyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5- c]quinoline-5Ν-oxide (2.40 g, 6.15 mmol) as a tan solid. The material was used without further purification. Part G
Using the general method of Example 3 Part B, 2-butyl-l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (2.40 g, 6.15 mmol) was aminated to provide 2-butyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4- amine. The resulting solid (2.24 g) was dissolved in acetonitrile (40 mL) and brought to reflux. Activated charcoal (1 g) was added and the resulting mixture was heated at reflux for 5 minutes and then the charcoal was removed by filtration through fluted paper to provide a light brown solution. Upon cooling 2-butyl-l-[5-(methylsulfonyl)pentyl]-lH- imidazo[4,5-c]quinolin-4-amine (0.90 g, 2.32 mmol) was isolated as white needles, m.p. 173-175 °C.
Analysis. Calculated for C20Η28N4O2S: %C 61.83; %H, 7.26; %N, 14.42. Found: %C 61.58; %H, 7.27; %N, 14.36
!H-NMR (300 MHz, DMSO) δ 8.01 (d, J = 8.3 Hz, IH), δ 7.61 (d, J = 8.3 Hz, IH), δ 7.41 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.45 (bs, 2H), δ 4.51 (t, J = 7.6 Hz, 2H), δ 3.10 (t, J = 7.8 Hz, 2H), δ 2.92 (s, 3H), δ 2.92 (t, J = 7.3 Hz, 2H), δ 1.76 (m, 6H), δ 1.54
(m, 2H), δ 1.46 (sextet, J = 7.3 Hz, 2H), δ 0.99 (t, J = 7.3 Hz, 3H) MS (CI) for C20H28N4O2S m/z 389 (MH+)
Example 12 2-methyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000044_0001
Part A
Using the general method of Example 1 Part D, N*-[5- (methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) was cyclized to provide 2- methyl-l-[5-(methylthio)pentyl]-lH-imidazo[4,5-cJquinoline using 1,1,1- trimethoxyethane (2.95 g, 24.6 mmol) and pyridine hydrochloride (0.1 g). The material was triturated with ethyl ether and collected by filtration to afford the product (3.78 g, 12.62 mmol) as a light brown solid which was used without further purification. Part B
Using the general method of Example 11 Part F, 2-methyl-l-[5- (methylthio)pentyl]-lH-imidazo[4,5-c]quinoline (3.78 g, 12.62 mmol) was oxidized to 2- methyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (4.38 g, 12.62 mmol) which was isolated as a tan solid and used without purification. Part C
Using the general method of Example 3 Part B, 2-methyl-l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (4.38 g, 12.62 mmol) was aminated to provide 2-methyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4- amine. The resulting solid was triturated with acetonitrile and collected by filtration to afford the title compound (0.8 g, 2.31 mmol) as an off-white solid, m.p. 235-240 °C. Analysis. Calculated for Cι7Η22N402S: %C 58.94; %H, 6.40; %N, 16.17. Found: %C 58.77; %H, 6.34; %N, 16.39
Η-NMR (300 MHz, DMSO) δ 8.02 (d, J = 8.3 Hz, IH), δ 7.60 (d, J = 8.3 Hz, IH), δ 7.41 (t, J = 8.3 Hz, IH), δ 7.25 (t, J = 8.3 Hz, IH), δ 6.49 (bs, 2H), δ 4.50 (t, J = 7.3 Hz, 2H), δ 3.12 (t, J = 7.8 Hz, 2H), δ 2.92 (s, 3H), δ 2.61 (s, 3H), δ 1.86 (m, 2H), δ 1.74 (m, 2H), δ 1.53 (m, 2H) MS (CI) for Cι7H22N402S m/z 347 (MH+), 267
Example 13 2-ethyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-cJquinolin-4-amine
Figure imgf000046_0001
Part A Using the general method of Example 1 Part D, N4-^-
(methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) was cyclized to 2-ethyl-l- [5-(methylthio)pentyl]-lH-imidazo[4,5-c]quinoline using triethyl orthopropionate (4.3 g, 24.56 mmol) and pyridine hydrochloride (0.1 g). The material was triturated with ethyl ether and collected by filtration to afford the product (3.25 g, 10.37 mmol) as an off-white powder which was used without further purification.
Part B
Using the general method of Example 11 Part F, 2-ethyl-l-[5-(methylthio)pentyl]- lH-imidazo[4,5-c]quinoline (3.25 g, 10.37 mmol) was oxidized to 2-ethyl-l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5Ν-oxide (3.75 g, 10.37 mmol) which was isolated as a tan solid and used without purification.
Part C
Using the general method of Example 3 Part B, 2-ethyl-l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (3.75 g, 10.37 mmol) was aminated to provide 2-ethyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4- amine. The resulting solid was recrystallized sequentially from ethanol and acetonitrile to afford the title compound (1.4 g, 3.88 mmol) as off-white needles, m.p. 189-191 °C. Analysis. Calculated for Cι8Η24N402S: %C 59.98; %H, 6.71; %N, 15.54. Found: %C 59.71; %H, 6.68; %N, 15.64 Η-NMR (300 MHz, DMSO) δ 8.01 (d, J = 8.3 Hz, IH), δ 7.61 (d, J = 8.3 Hz, IH), δ 7.42 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.45 (bs, 2H), δ 4.50 (t, J = 7.6 Hz, 2H), δ 3.10 (t, J = 7.8 Hz, 2H), δ 2.95 (q, J = 7.3 Hz, 2H), δ 2.92 (s, 3H), δ 1.85 (m, 2H), δ 1.74 (m, 2H), δ 1.55 (m, 2H), δ 1.38 (t, J = 7.3 Hz, 3H) MS (CI) for C18H24N402S m/z 361 (MH+), 281
i Example 14 l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000047_0001
Part A
Using the general method of Example 1 Part D, N*-[5- (methylthio)pentyl]quinoline-3,4-diamine (4.53 g, 16.37 mmol) was cyclized to l-[5-
(methylthio)pentyl]-lH-imidazo[4,5-c]quinoline using triethyl orthoformate (3.64 g, 24.56 mmol) and pyridine hydrochloride (0.1 g). The product (4.05 g, 14.19 mmol) was isolated as a brown oil and used without further purification. Part B Using the general method of Example 11 Part F, l-[5-(methylthio)pentyl]-lH- imidazo[4,5-c]quinoline (4.05 g, 14.19 mmol) was oxidized to l-[5- (methylsulfonyl)pentylJ-lH-imidazo[4,5-c]quinoline-5Ν-oxide (4.73 g, 14.19 mmol) which was isolated as a tan solid and used without further purification. Part C Using the general method of Example 3 Part B, l-[5-(methylsulfonyl)pentyl]-lH- imidazo[4,5-cJquinoline-5N-oxide (4.73 g, 14.19 mmol) was aminated to provide l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to afford a light yellow solid. The solid was recrystallized from dimethyl formamide to give the title compound (0.43 g, 1.29 mmol) as a light yellow, granular solid, m.p. 199-201 °C. Analysis. Calculated for Cι6H20N O2S: %C 57.81; %H, 6.06; %N, 16.85. Found: %C 57.01; %H, 6.06; %N, 16.70
Η-NMR (300 MHz, DMSO) δ 8.20 (S, IH), δ 8.04 (d, J = 8.3 Hz, IH), δ 7.62 (d, J == 8.3 Hz, IH), δ 7.44 (t, J = 8.3 Hz, IH), δ 7.27 (t, J = 8.3 Hz, IH), δ 6.57 (bs, 2H), δ 4.61 (t, J = 6.8 Hz, 2H), δ 3.09 (t, J = 7.8 Hz, 2H), δ 2.92 (s, 3H), δ 1.91 (p, J = 7.6 Hz, 2H), δ 1.73
(m, 2H), δ l.45 (m, 2H) MS (CI) for Cι6H20N4O2S m/z 333 (MH+)
Example 15 2-hexyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000048_0001
Part A
A round bottom flask was charged with a magnetic stir bar, N -^- (methylthio)pentyl]quinoline-3,4-diamine (3.17 g, 11.46 mmol) and anhydrous pyridine (46 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to
0 °C in an ice-water bath. To the cooled solution was added neat heptanoyl chloride (1.87 g, 12.61 mmol). The reaction was judged to be complete after stirring at ambient temperature for 1 hour. The volatiles were removed under reduced pressure and the resulting oil was partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford N-(4-{[5-(methylthio)pentylJamino}quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol) which was isolated as a brown oil and used without further purification. Part B A round bottom flask was charged with a magnetic stir bar, N-(4- {[5-
(methylthio)pentylj amino }quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol), pyridine hydrochloride (0.13 g, 1.15 mmol), and anhydrous pyridine (50 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at reflux for 1.5 hours. The solution was cooled and partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-hexyl-l-[5-(methylthio)pentyl]-lH-imidazo[4,5-c]quinoline (4.0 g, 10.82 mmol) as a brown oil which was used without further purification. Part C
Using the general method of Example 11 Part F, 2-hexyl-l-[5-(methylthio)pentylJ- lH-imidazo[4,5-cJquinoline (4.0 g, 10.82 mmol) was oxidized to 2-hexyl-l-[5-
(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (4.52 g, 10.82 mmol) which was isolated as a tan solid and used without further purification.
Part D
Using the general method of Example 3 Part B 2-hexyl-l-[5- (methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (4.0 g, 10.82 mmol) was aminated to provide 2-hexyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4- amine. The material was recrystallized from acetonitrile to afford the title compound (2.25 g, 5.40 mmol) as off-white needles, m.p. 168-171 °C. Analysis. Calculated for C22Η32N402S: %C 63.43; %H, 7.74; %N, 13.45. Found: %C 63.06; %H, 7.66; %N, 13.81
1H-NMR (300 MHz, DMSO) δ 8.01 (d, J = 8.3 Hz, IH), δ 7.62 (d, J = 8.3 Hz, IH), δ 7.42 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.51 (bs, 2H), δ 4.51 (t, J = 7.3 Hz, 2H), δ 3.10 (t, J = 7.8 Hz, 2H), δ 2.93 (s, 3H), δ 2.93 (t, J = 7.3 Hz, 2H), δ 1.71-1.87 (m, 6H), δ 1.54 (m, 2H), δ 1.44 (m, 2H), δ 1.33 (m, 4H), δ 0.89 (t, J = 7.3 Hz, 3H) MS (CI) for C22H32N402S m z 417 (MH+), 337
Example 16 2-(2-methoxyethyl)-l-[5-(methylsulfonyl)pentyl]- lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000050_0001
Part A
A round bottom flask was charged with a magnetic stir bar, ^-[5- (methylthio)pentyl]quinoline-3,4-diamine (3.56 g, 12.93 mmol) and anhydrous pyridine (52 mL) under a nitrogen atmosphere. The resulting homogeneous solution was cooled to 0 °C in an ice-water bath. To the cooled solution was added neat 3-methoxypropionyl chloride (2.74 g, 22.36 mmol). After addition of the acid chloride, the reaction was heated to reflux for 14 hours at which time the acylated intermediate was completely consumed. The solution was cooled and then partitioned between chloroform and saturated aqueous ammonium chloride. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-(2-methoxyethyl)-l -[5-
(methylthio)pentyl]-lH-imidazo[4,5-c]quinoline (3.0 g, 8.73 mmol) which was isolated as a brown oil and used without further purification.
Part B
Using the general method of Example 11 Part F, 2-(2-methoxyethyl)-l-[5- (methylthio)pentyl]-lH-imidazo[4,5-c]quinoline (3.0 g, 8.73 mmol) was oxidized to 2-(2- methoxyethyl)-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinoline-5N-oxide (3.41 g, 8.73 mmol) which was isolated as a tan solid and used without further purification. Part C
Using the general method of Example 3 Part B, 2-(2-methoxyethyl)-l-[5- (methylsulfonyl)pentylJ-lH-imidazo[4,5-cJquinoline-5N-oxide (3.41 g, 8.73 mmol) was aminated to provide 2-(2-methoxyethyl)-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5- c]quinolin-4-amine. The resulting solid was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide a gummy solid. The solid was recrystallized from acetonitrile to give the title compound (0.54 g, 1.38 mmol) as an off-white powder, m.p. 158-160 °C. Analysis. Calculated for Cι9H26N403S: %C 58.44; %H, 6.71; %N, 14.35. Found: %C
58.24; %H, 6.76; %N, 14.70
1H-NMR (300 MHz, DMSO) δ 8.02 (d, J = 8.3 Hz, IH), δ 7.62 (d, J = 8.3 Hz, IH), δ 7.42 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.50 (bs, 2H), δ 4.53 (t, J = 7.6 Hz, 2H), δ 3.83 (t, J = 6.8 Hz, 2H), δ 3.30 (s, 3H), δ 3.19 (t, J = 6.8 Hz, 2H), δ 3.11 (t, J = 7.8 Hz, 2H), δ 2.93 (s, 3H), δ 1.85 (m, 2H), δ 1.76 (m, 2H), δ 1.57 (m, 2H)
MS (CI) for Cι9H26N403S m z 391 (MH+), 359
Example 17 2-butyl-l-[5-(methylthio)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000051_0001
Part A
Using the general method of Example 1 Part C, N-(5-chloropentyl)-3- nitroquinolin-4-amine (2.0 g, 6.80 mmol) was reduced to provide N*-(5- chloropentyl)quinoline-3,4-diamine (1.79 g, 6.80 mmol) which was isolated as a brown oil and used without further purification.
Part B
Using the general method of Example 1 Part D, / -(S-chloropenty^quinoline-S^- diamine (1.79 g, 6.80 mmol) was cyclized to 2-butyl-l-(5-chloropentyl)-lH-imidazo[4,5- cjquinoline using trimethyl orthovalerate (2.55 g, 15.72 mmol) and pyridine hydrochloride (0.079 g). The product (1.95 g, 5.91 mmol) was isolated as an off-white solid and used without further purification. Part C
Using the general method of Example 1 Part E, 2-butyl-l-(5-chloropentyl)-lH- imidazo[4,5-c]quinoline (1.95 g, 5.91 mmol) was oxidized to 2-butyl-l -(5-chloropentyl)- lH-imidazo[4,5-c]quinoline-5N-oxide (2.04 g, 5.91 mmol) which was isolated as a tan solid and used without further purification.
Part D
Using the general method of Example 3 Part B, 2-butyl-l -(5-chloropentyl)-lH- imidazo[4,5-c]quinoline-5N-oxide (2.04 g, 5.91 mmol) was aminated to provide 2-butyl-l- (5-chloropentyl)-lΗ-imidazo[4,5-c]quinolin-4-amine. The resulting solid was recrystallized from ethanol to afford the product (0.85 g, 2.46 mmol) as a fine white powder, m.p. 144-146 °C.
Analysis. Calculated for C19H25C1N4: %C 66.17; %H, 7.31; %N, 16.24. Found: %C 66.44; %H, 7.55; %N, 16.29 MS (CI) for Cι9H25ClN4 m z 345 (MH+), 309 Part E
Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, 2-butyl-l-(5-chloropentyl)-lH-imidazo[4,5-c]quinolin- 4-amine (2.0 g, 5.80 mmol) was converted to 2-butyl-l-[5-(methylthio)pentyl]-lΗ- imidazo[4,5-c]quinolin-4-amine using sodium thiomethoxide (0.68 g, 8.70 mmol) in lieu of sodium benzenethiolate. The resulting solid was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a white solid. The material was recrystallized from acetonitrile to give the title compound (1.91 g, 5.36 mmol) as a fine white solid, m.p. 112- 114 °C.
Analysis. Calculated for C20H28N4S: %C 67.38; %H, 7.92; %N, 15.71. Found: %C 67.26; %H, 8.08; %N, 15.74
Η-NMR (300 MHz, DMSO) δ 8.01 (d, J = 8.3 Hz, IH), δ 7.61 (d, J = 8.3 Hz, IH), δ 7.41 (t, J = 8.3 Hz, IH), δ 7.25 (t, J = 8.3 Hz, IH), δ 6.45 (bs, 2H), δ 4.50 (t, J = 7.8 Hz, 2H), δ 2.92 (t, J = 7.6 Hz, 2H), δ 2.46 (t, J = 7.3 Hz, 2H), δ 2.01 (s, 3H), δ 1.80 (m, 4H), δ 1.42-
1.61 (m, 6H), δ 0.96 (t, J = 7.3 Hz, 3H) MS (CI) for C20H28N4S m z 357 (MH+), 309 Example 18 2-butyl-l-[5-(methylsulfinyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000053_0001
A round bottom flask was charged with a magnetic stir bar, 2-butyl-l -[5- (methylthio)pentyIJ-lΗ-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.80 mmol) and chloroform (14 mL). Solid 3-chloroperbenzoic acid (0.69 g, 3.09 mmol) was added portion wise over 5 minutes and the reaction was stirred at ambient temperature for 20 minutes at which time the starting material was completely consumed. The solution was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford an off-white solid which was shown by 1H-NMR to be the 3- chlorobenzoic acid salt of the desired product. The solid was stirred in water and then made basic (pH 10) by addition of solid sodium carbonate. The resulting free base was collected by filtration to provide a white solid which was recrystallized from acetonitrile to give 2-butyl-l-[5-(methylsulfinyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine (0.40 g, 1.07 mmol) as a white powder, m.p. 119-121 °C. Analysis. Calculated for C20Η28N4OS (H20)_: %C 61.51; %H, 7.74; %N, 14.35. Found:
%C 61.64; %H, 7.82; %N, 14.32
!H-NMR (300 MHz, DMSO) δ 8.01 (d, J = 8.3 Hz, IH), δ 7.60 (d, J = 8.3 Hz, IH), δ 7.41 (t, J = 8.3 Hz, IH), δ 7.26 (t, J = 8.3 Hz, IH), δ 6.44 (bs, 2H), δ 4.51 (t, J = 7.6 Hz, 2H), δ 2.92 (t, J = 7.8 Hz, 2H), δ 2.57-2.74 (m, 2H), δ 2.50 (s, 3H), δ 1.80 (m, 4H), δ 1.66 (m, 2H), δ 1.55 (m, 2H), δ 1.48 (m, 2H), δ 0.96 (t, J = 7.3 Hz, 3H)
MS (CI) for C20H28N4OS (H20)ι m/z 373 (MH+), 309, 253 Example 19 2-butyl-l-[3-(methylsulfonyl)propyl]-lH-imidazo[4,5-c]quinolin-4-amine
Figure imgf000054_0001
Part A
A round bottom flask was charged with a magnetic stir bar, 3-[(3-nitroquinolin-4- yl)amino]propan-l-ol (20.75 g, 83.93 mmol), thionyl chloride (15.0 g, 125.89 mmol), and dichloromethane (420 mL). The bright yellow, homogeneous solution was stirred at ambient temperature for 2 hours at which time the starting material was completely consumed. The volatiles were removed under reduced pressure and the resulting solid stirred in water (400 mL) made basic (pH 10) with solid sodium carbonate. A bright yellow solid was collected by filtration to afford N-(3-chloropropyl)-3-nitroquinolin-4- amine (21.63 g, 81.41 mmol) which was used without further purification. Part B Using the general method of Example 1 Part C, N-(3-chloropropyl)-3- nitroquinolin-4-amine (10.0 g, 37.63 mmol) was reduced to provide N4-^- chloropropyl)quinoline-3,4-diamine (8.87 g, 37.63 mmol) which was isolated as a brown oil and used without further purification. Part C Using the general method of Example 1 Part D, .Ap-chloropropyrjquinoline-S^- diamine (8.87 g, 37.63 mmol) was cyclized to provide 2-butyl-l -(3 -chloropropyl)-lH- imidazo[4,5-c]quinoline using trimethyl orthovalerate (7.33 g, 45.16 mmol) and pyridine hydrochloride (0.43 g). The resulting solid was triturated with ethyl ether and collected by filtration to afford the product (9.00 g, 29.82 mmol) as an off-white solid. The material was used without further purification. Part D
Using the general method of Example 1 Part E, 2-butyl-l-(3-chloropropyl)-lH- imidazo[4,5-c]quinoline (9.0 g, 29.82 mmol) was oxidized to 2-butyl-l-(3-chloropropyl)- lH-imidazo[4,5-c]quinoline-5N-oxide (9.48 g, 29.82 mmol) which was isolated as a tan solid and used without purification.
Part E
Using the general method of Example 3 Part B, 2-butyl-l -(3-chloropropyl)-lH- imidazo[4,5-c]quinoline-5N-oxide (9.48 g, 29.82 mmol) was aminated to provide 2-butyl- l-(3-chloropropyl)-lH-imidazo[4,5-c]quinolin-4-amine. The resulting solid was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide the product (6.4 g, 20.20 mmol) as a tan solid.
Part F
Using the general method of Example 6 Part B, except that the reaction temperature was lowered to 80 °C, 2-butyl-l-(3-chloropropyl)-lH-imidazo[4,5-c]quinolin- 4-amine (2.0 g, 6.31 mmol) was converted to 2-butyl-l-[3-(methylthio)propyl]-lH- imidazo[4,5-cJquinolin-4-amine using sodium thiomethoxide (0.74 g, 9.47 mmol) in lieu of sodium benzenethiolate. The resulting solid was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford the title compound (2.0 g, 6.09 mmol) as a white solid.
The material was used without further purification.
Part G
Using the general method of Example 5 Part A, 2-butyl-l- [3 -(methylthio)propylj- lH-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.09 mmol) was oxidized to 2-butyl-l -[3- (methylsulfonyl)propyl]-lΗ-imidazo[4,5-c]quinolin-4-amine. The resulting solid was triturated with methanol and collected by filtration to afford the title compound (0.96 g,
2.66 mmol) as an off-white powder, m.p. 233-236 °C.
Analysis. Calculated for C-8H24N402S: %C 59.98; %H, 6.71; %N, 15.54. Found: %C
59.71; %H, 6.65; %N, 15.43 1H-NMR (300 MHz, DMSO) δ 8.10 (d, J = 8.3 Hz, IH), δ 7.61 (d, J = 8.3 Hz, IH), δ 7.42
(t, J = 8.3 Hz, IH), δ 7.25 (t, J = 8.3 Hz, IH), δ 6.47 (bs, 2H), δ 4.66 (t, J = 7.8 Hz, 2H), δ 3.40 (t, J = 7.3 Hz, 2H), δ 3.01 (s, 3H), δ 2.94 (t, J = 7.8 Hz, 2H), δ 2.22 (m, 2H), δ 1.80 (m, 2H), δ 1.46 (sextet, J = 7.3 Hz, 2H), δ 0.96 (t, J = 7.3 Hz, 3H) MS (CI) for Cι8H24N402S m/z 361 (MH+), 281, 235
> Example 20
2-butyl-l-[3-(phenylsulfonyl)propyl]-lH-imidazo[4,5-cJquinolin-4-amine
Figure imgf000056_0001
Part A
A round bottom flask was charged with a magnetic stir bar, benzenethiol (0.68 g, 6.21 mmol), sodium hydride (0.25 g, 60% dispersion, 6.21 mmol), and anhydrous dimethyl formamide (28 mL) under a nitrogen atmosphere. After the reaction mixture had stiπed at ambient temperature for 30 minutes, 2-butyl-l-(3-chloropropyl)-lH-imidazo[4,5- c]quinolin-4-amine (1.64 g, 5.18 mmol) was added and the resulting cloudy solution was heated to 80 °C and maintained at 80 °C for 2.5 hours at which time the starting material was completely consumed. The hot solution was poured into rapidly stiπed water (200 mL). The resulting mixture was extracted with chloroform (2x). The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow oil. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to provide 2-butyl-l-[3-(phenylthio)propyl]-lH-imidazo[4,5- c]quinolin-4-amine (1.38 g, 3.53 mmol) as a white solid. Part B
Using the general method of Example 5 Part A, 2-butyl-l -[3 -(phenylthio)propylj- lH-imidazo[4,5-c]quinolin-4-amine (1.38 g, 3.53 mmol) was oxidized to 2-butyl-l-[3- (phenylsulfonyl)propylJ-lH-imidazo[4,5-c]quinolin-4-amine. The resulting solid was recrystallized from ethanol to provide the title compound (0.85 g, 2.01 mmol) as an off- white powder, m.p. 224-227 °C. Analysis. Calculated for C23H26N402S: %C 65.38; %H, 6.20; %N, 13.26. Found: %C 65.25; %H, 6.23; %N, 13.20
Η-NMR (300 MHz, DMSO) δ 7.96 (d, J = 8.3 Hz, IH), δ 7.89 (m, 2H), δ 7.73 (m, IH), δ 7.63 (m, 3H), δ 7.40 (t, J = 8.3 Hz, IH), δ 7.17 (t, J = 8.3 Hz, IH), δ 6.46 (bs, 2H), δ 4.60 (t, J = 7.8 Hz, 2H), δ 3.66 (t, J = 7.3 Hz, 2H), δ 2.86 (t, J = 7.8 Hz, 2H), δ 2.04 (m, 2H), δ 1.73 (p, J = 7.6 Hz, 2H), δ 1.39 (sextet, J = 7.3 Hz, 2H), δ 0.92 (t, J = 7.3 Hz, 3H) MS (CI) for C23H26N402S m/z 423 (MH+), 322, 281
CYTOKINE INDUCTION IN HUMAN CELLS An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon and tumor necrosis factor (α) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In "Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995). Blood Cell Preparation for Culture
Whole blood from healthy human donors is collected by venipuncture into EDTA vacutainer tubes. Peripheral blood mononuclear cells (PBMCs) are separated from whole blood by density gradient centrifugation using Histopaque®-1077. The PBMCs are washed twice with Hank's Balanced Salts Solution and then are suspended at 3-4 x 106 cells/mL in RPMI complete. The PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound. Compound Preparation
The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells. The compounds are generally tested initially at concentrations ranging from 0.12 to 30 μM. Compounds showing activity at 0.12 μM may then be tested at lower concentrations. Incubation The solution of test compound is added at 60 μM to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells. The PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 μM). The final concentration of PBMC suspension is 1.5-2 X 106 cells/mL. The plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere. Separation
Following incubation the plates are centrifuged for 5-10 minutes at 1000 m (~200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transfeπed to sterile polypropylene tubes. Samples are maintained at -30 to -70°C until analysis. The samples are analyzed for interferon (α) and for tumor necrosis factor (α) by ELISA Interferon (α) and Tumor Necrosis Factor ( ) Analysis by ELISA
Interferon (α) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
Tumor necrosis factor (α) (TNF)concentration is determined using ELISA kits available from Genzyme, Cambridge, MA; R&D Systems, Minneapolis, MN; or Pharmingen, San Diego, CA. Results are expressed in pg/mL.
The table below lists the lowest concentration found to induce interferon and the lowest concentration found to induce tumor necrosis factor for each compound. A "*" indicates that no induction was seen at any of the tested concentrations (0.12, 0.37, 1.11, 3.33, 10 and 30 μM).
Figure imgf000058_0001
Figure imgf000059_0001

Claims

WHAT IS CLAIMED IS:
1. A compound of the formula (I):
Figure imgf000060_0001
(I) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Z is -S-, -SO-, or-S02-; Ri is selected from the group consisting of:
-alkyl;
-aryl;
-heteroaryl;
-heterocyclyl;
-alkenyl;
-R-t-aryl;
-R-v- heteroaryl;
-RHtieterocyclyl; R2 is selected from the group consisting of:
-hydrogen;
-alkyl;
-alkenyl;
Figure imgf000060_0002
-heteroaryl;
-heterocyclyl;
-alkyl-Y-alkyl; - alkyl-Y- alkenyl; -alkyl-Y-aryl; and
- alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: -OH;
-halogen; -N(R3)2; -CO-N(R3)2; -CO-Ci-io alkyl; -CO-0-Cι-ιo alkyl;
-N3; -aryl;
-heteroaryl; -heterocyclyl; -CO-aryl; and
-CO-heteroaryl; each R3 is independently H or C--ιo alkyl; each i is independently alkyl or alkenyl; each Y is independently -O- or -S(O)0.2-; n is 0 to 4; and each R present is independently selected from the group consisting of Cι-ι0 alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein Z is -S-.
3. A compound of claim 1 wherein Z is -S02-
4. A compound of claim 1 wherein Ri is -alkyl.
5. A compound of claim 1 wherein Ri is -aryl.
6. A compound of claim 1 wherein Rj is phenyl.
7. A compound of claim 1 wherein Ri is heteroaryl.
8. A compound of claim 1 wherein X is -(CH2)2.6-
9. A compound of claim 1 wherein R2 is H.
10. A compound of claim 1 wherein R2 is -alkyl-O-alkyl.
11. A compound of claim 1 wherein R2 is -alkyl.
12. A compound selected from the group consisting of:
2-butyl-l-[4-(phenylthio)butyl]-lH-imidazo[4,5-c]quinolin-4-amine; 2-butyl-l-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-lH-imidazo[4,5-c]quinolin-4-amine;
2-butyl- 1 -[4-(phenylsulfonyl)butyl]- lH-imidazo[4,5-c]quinolin-4-amine;
2-butyl-l -[4-(methylthio)butyl]-lH-imidazo[4,5-cJquinolin-4-amine;
2-butyl-l-[4-(methylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine; l-[2-(phenylthio)ethylJ-lH-imidazo[4,5-c]quinolin-4-amine; l-[4-(phenylsulfonyl)butylJ-lH-imidazo[4,5-c]quinolin-4-amine; l-[4-(methylsulfonyl)butyl]-lH-imidazo[4,5-c]quinolin-4-amine;
1 -[4-(phenylthio)butylJ - 1 H-imidazo [4,5-c] quinolin-4-amine;
1 -[4-(methylthio)butyl] - 1 H-imidazo [4,5-c] quinolin-4-amine;
2-butyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-cJquinolin-4-amine; 2-methyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine;
2-ethyl-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine;
1 - [5 -(methylsulfonyl)pentyl] - 1 H-imidazo [4,5-c] quinolin-4-amine;
2-hexyl- 1 -[5-(methyIsulfonyl)pentyl]- lH-imidazo[4,5-c]quinolin-4-amine;
2-(2-methoxyethyl)-l-[5-(methylsulfonyl)pentyl]-lH-imidazo[4,5-cJquinolin-4-amine; 2-butyl-l-[5-(methylthio)pentyl]-lH-imidazo[4,5-c]quinolin-4-amine;
2-butyl-l-[5-(methylsulfinyl)pentylJ-lH-imidazo[4,5-c]quinolin-4-amine;
2-butyl- 1 - [3 -(methylsulfonyl)propylj - lH-imidazo [4, 5 -cj quinolin-4-amine; and 2-butyl-l -[3-(phenylsulfonyl)propyl]-lH-imidazo[4,5-c]quinolin-4-amine; or a pharmaceutically acceptable salt thereof.
13. A compound of the formula (II)
Figure imgf000063_0001
(II) wherein: X is -CHR3-, -CHR3-alkyl-, or -CHR3-alkenyl-;
Z is -S-, -SO-, or-S02-; Ri is selected from the group consisting of: -alkyl; -aryl;
-heteroaryl; -heterocyclyl; -alkenyl; -R-r-aryl; -R-r* heteroaryl; and
-Rr-heterocyclyl; R2 is selected from the group consisting of: -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 the group consisting of: -OH; -halogen; -N(R3)2;
-CO-N(R3)2; -CO-Ci-io alkyl; -CO-0-Cι-ιo alkyl; -N3; -aryl;
-heteroaryl; -heterocyclyl; -CO-aryl; and -CO-heteroaryl; each R3 is independently H or C-.io alkyl; each Rj is independently alkyl or alkenyl; each Y is independently -O- or -S(O)0.2-; n is 0 to 4; and each R present is independently selected from the group consisting of Ci-io alkyl, Ci-io alkoxy, hydroxy, halogen and trifluoromethyl; or a pharmaceutically acceptable salt thereof.
14. A compound of claim 13 wherein Ri is phenyl.
15. A compound of claim 13 wherein R2 is H or alkyl.
16. A compound of claim 13 wherein R2 is -alkyl-O-alkyl.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12 and a pharmaceutically acceptable carrier.
19. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound of claim 1 to the animal.
20. The method of claim 19 wherein the cytokine is IFN-α.
21. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound of claim 1 to the animal.
22. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound of claim 1 to the animal.
23. A method of inducing cytokine biosynthesis in an animal comprising administering a theraputically effective amount of a compound of claim 12 to the animal.
24. The method of claim 23 wherein the cytokine is IFN-α
25. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound of claim 12 to the animal.
26. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound of claim 12 to the animal.
27. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 13 and a pharmaceutically acceptable carrier.
28. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound of claim 13 to the animal.
29. The method of claim 29 wherein the cytokine is IFN-α.
30. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound of claim 13 to the animal.
31. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound of claim 13 to the animal.
PCT/US2001/046697 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines WO2002046192A2 (en)

Priority Applications (20)

Application Number Priority Date Filing Date Title
PL366330A PL207340B1 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
IL15590401A IL155904A0 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
BR0116026-5A BR0116026A (en) 2000-12-08 2001-12-06 Thioether-Replaced Imidazoquinolines
NZ526087A NZ526087A (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
SK710-2003A SK287264B6 (en) 2000-12-08 2001-12-06 Imidazoquinoline and tetrahydroimidazoquinoline derivatives, pharmaceutical compositions containing thereof and use thereof
CA2436846A CA2436846C (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
EP01987297A EP1341791B1 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
AU2002239530A AU2002239530B2 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
AU3953002A AU3953002A (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
KR10-2003-7007534A KR20030070049A (en) 2000-12-08 2001-12-06 Thioether Substituted Imidazoquinolines
DK01987297T DK1341791T3 (en) 2000-12-08 2001-12-06 Thioether-substituted imidazoquinolines
JP2002547929A JP2004515500A (en) 2000-12-08 2001-12-06 Thioether-substituted imidazoquinoline
EEP200300275A EE200300275A (en) 2000-12-08 2001-12-06 Thioether-substituted imidazoquinolines
DE60111076T DE60111076T2 (en) 2000-12-08 2001-12-06 THIOETHERSUBSTITUTED IMIDAZOCHINOLINE
SI200130382T SI1341791T1 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines
HU0400710A HUP0400710A2 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines, their use and pharmaceutical compositions containing them
AT01987297T ATE296301T1 (en) 2000-12-08 2001-12-06 THIOETHER SUBSTITUTED IMIDAZOCINOLINES
MXPA03004975A MXPA03004975A (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines.
NO20032595A NO20032595D0 (en) 2000-12-08 2003-06-06 Tioether-substituted imidazoquinolines
CY20051101024T CY1105586T1 (en) 2000-12-08 2005-08-24 THIOETHER SUBSTITUTED IMIDAZOQUINOLINES

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25421800P 2000-12-08 2000-12-08
US60/254,218 2000-12-08

Publications (2)

Publication Number Publication Date
WO2002046192A2 true WO2002046192A2 (en) 2002-06-13
WO2002046192A3 WO2002046192A3 (en) 2003-02-13

Family

ID=22963391

Family Applications (6)

Application Number Title Priority Date Filing Date
PCT/US2001/046359 WO2002046188A2 (en) 2000-12-08 2001-12-06 Amido ether substituted imidazoquinolines
PCT/US2001/046704 WO2002046193A2 (en) 2000-12-08 2001-12-06 Heterocyclic ether substituted imidazoquinolines
PCT/US2001/046696 WO2002046191A2 (en) 2000-12-08 2001-12-06 Urea substituted imidazoquinoline ethers
PCT/US2001/046582 WO2002046190A2 (en) 2000-12-08 2001-12-06 Sulfonamido ether substituted imidazoquinolines
PCT/US2001/046581 WO2002046189A2 (en) 2000-12-08 2001-12-06 Aryl ether substituted imidazoquinolines
PCT/US2001/046697 WO2002046192A2 (en) 2000-12-08 2001-12-06 Thioether substituted imidazoquinolines

Family Applications Before (5)

Application Number Title Priority Date Filing Date
PCT/US2001/046359 WO2002046188A2 (en) 2000-12-08 2001-12-06 Amido ether substituted imidazoquinolines
PCT/US2001/046704 WO2002046193A2 (en) 2000-12-08 2001-12-06 Heterocyclic ether substituted imidazoquinolines
PCT/US2001/046696 WO2002046191A2 (en) 2000-12-08 2001-12-06 Urea substituted imidazoquinoline ethers
PCT/US2001/046582 WO2002046190A2 (en) 2000-12-08 2001-12-06 Sulfonamido ether substituted imidazoquinolines
PCT/US2001/046581 WO2002046189A2 (en) 2000-12-08 2001-12-06 Aryl ether substituted imidazoquinolines

Country Status (32)

Country Link
US (8) US6670372B2 (en)
EP (6) EP1341790B1 (en)
JP (7) JP2004515501A (en)
KR (6) KR20030070050A (en)
CN (6) CN1252070C (en)
AR (6) AR035664A1 (en)
AT (3) ATE296301T1 (en)
AU (12) AU2002230618B2 (en)
BR (6) BR0116047A (en)
CA (6) CA2431151A1 (en)
CY (2) CY1105586T1 (en)
CZ (6) CZ20031561A3 (en)
DE (3) DE60111076T2 (en)
DK (3) DK1343784T3 (en)
EE (6) EE200300272A (en)
ES (3) ES2281456T3 (en)
HK (3) HK1064383A1 (en)
HR (6) HRP20030462A2 (en)
HU (6) HUP0400704A2 (en)
IL (6) IL156044A0 (en)
MX (6) MXPA03004975A (en)
NO (6) NO20032449D0 (en)
NZ (6) NZ526106A (en)
PL (7) PL365883A1 (en)
PT (2) PT1341790E (en)
RU (6) RU2003116063A (en)
SI (1) SI1341790T1 (en)
SK (6) SK7152003A3 (en)
TW (3) TWI293300B (en)
UA (2) UA75622C2 (en)
WO (6) WO2002046188A2 (en)
ZA (6) ZA200305273B (en)

Cited By (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6525064B1 (en) 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6534654B2 (en) 1996-06-21 2003-03-18 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6545016B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Amide substituted imidazopyridines
US6545017B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
WO2003050121A1 (en) * 2001-12-06 2003-06-19 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6660735B2 (en) 2000-12-08 2003-12-09 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
US6664265B2 (en) 2000-12-08 2003-12-16 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6677349B1 (en) 2001-12-21 2004-01-13 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
US6677348B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Aryl ether substituted imidazoquinolines
US6699878B2 (en) 1997-12-11 2004-03-02 3M Innovative Properties Company Imidazonaphthyridines
US6780873B2 (en) 1999-06-10 2004-08-24 3M Innovative Properties Company Urea substituted imidazoquinolines
US6784188B2 (en) 1999-06-10 2004-08-31 3M Innovative Properties Company Urea substituted imidazoquinolines
US6797718B2 (en) 2002-06-07 2004-09-28 3M Innovative Properties Company Ether substituted imidazopyridines
US6818650B2 (en) 2002-09-26 2004-11-16 3M Innovative Properties Company 1H-imidazo dimers
US6825350B2 (en) 1999-06-10 2004-11-30 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines and methods for the treatment of periodontal disease using these and other immune response modifiers
US6916925B1 (en) 1999-11-05 2005-07-12 3M Innovative Properties Co. Dye labeled imidazoquinoline compounds
EP1653959A2 (en) * 2003-08-14 2006-05-10 3M Innovative Properties Company Lipid-modified immune response modifiers
JP2007512370A (en) * 2003-11-25 2007-05-17 スリーエム イノベイティブ プロパティズ カンパニー Substituted imidazo ring systems and methods
JP2007521317A (en) * 2003-08-14 2007-08-02 スリーエム イノベイティブ プロパティズ カンパニー Lipid-modified immune response modifier
US7299453B2 (en) 2001-12-20 2007-11-20 International Business Machines Corporation Testing measurements
US7393859B2 (en) 1999-06-10 2008-07-01 Coley Pharmaceutical Group, Inc. Amide substituted imidazoquinolines
US7427629B2 (en) 2002-08-15 2008-09-23 3M Innovative Properties Company Immunostimulatory compositions and methods of stimulating an immune response
US7696159B2 (en) 2003-03-25 2010-04-13 Graceway Pharmaceuticals, Llc Treatment for basal cell carcinoma
WO2010111485A1 (en) 2009-03-25 2010-09-30 The Board Of Regents Of The University Of Texas System Compositions for stimulation of mammalian innate immune resistance to pathogens
US7923560B2 (en) 2003-04-10 2011-04-12 3M Innovative Properties Company Delivery of immune response modifier compounds
US7968562B2 (en) 2001-11-29 2011-06-28 3M Innovative Properties Company Pharmaceutical formulations comprising an immune response modifier
US8110582B2 (en) 2003-03-04 2012-02-07 3M Innovative Properties Company Prophylactic treatment of UV-induced epidermal neoplasia
WO2013013055A1 (en) 2011-07-21 2013-01-24 Rubigo Therapeutics, Inc. System for drug delivery and monitoring
EP2572714A1 (en) 2002-12-30 2013-03-27 3M Innovative Properties Company Immunostimulatory Combinations
US8426457B2 (en) 2003-03-13 2013-04-23 Medicis Pharmaceutical Corporation Methods of improving skin quality
US8728486B2 (en) 2011-05-18 2014-05-20 University Of Kansas Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
WO2015103987A1 (en) 2014-01-10 2015-07-16 Shanghai Birdie Biotech, Inc. Compounds and compositions for treating her2 positive tumors
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
WO2016004875A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Combination therapy compositions and methods for treating cancers
US9248127B2 (en) 2005-02-04 2016-02-02 3M Innovative Properties Company Aqueous gel formulations containing immune response modifiers
WO2018087699A2 (en) 2016-11-09 2018-05-17 The Board Of Regents Of The University Of Texas System Methods and compositions for adaptive immune modulation
US10286065B2 (en) 2014-09-19 2019-05-14 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds
US10548988B2 (en) 2012-07-18 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
EP3632458A1 (en) 2013-07-26 2020-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of bacterial infections
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
WO2021116420A1 (en) 2019-12-13 2021-06-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of tlr7 and/or tlr8 agonists for the treatment of leptospirosis
US11046781B2 (en) 2016-01-07 2021-06-29 Birdie Biopharmaceuticals, Inc. Anti-HER2 combinations for treating tumors
US11053240B2 (en) 2017-04-27 2021-07-06 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
US11136397B2 (en) 2016-01-07 2021-10-05 Birdie Pharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
US11220552B2 (en) 2016-01-07 2022-01-11 Birdie Biopharmaceuticals, Inc. Anti-CD20 combinations for treating tumors
US11517567B2 (en) 2017-06-23 2022-12-06 Birdie Biopharmaceuticals, Inc. Pharmaceutical compositions

Families Citing this family (157)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3436512B2 (en) * 1999-12-28 2003-08-11 株式会社デンソー Accelerator device
US6660747B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Amido ether substituted imidazoquinolines
UA75622C2 (en) * 2000-12-08 2006-05-15 3M Innovative Properties Co Aryl ether substituted imidazoquinolines, pharmaceutical composition based thereon
US7226928B2 (en) * 2001-06-15 2007-06-05 3M Innovative Properties Company Methods for the treatment of periodontal disease
IL147953A (en) * 2002-02-01 2008-04-13 Meir Bialer Derivatives and pharmaceutical compositions of n-hydroxymethyl tetramethylcyclopropyl-
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
GB0211649D0 (en) 2002-05-21 2002-07-03 Novartis Ag Organic compounds
CA2491680C (en) * 2002-07-02 2012-04-17 Southern Research Institute Inhibitors of ftsz and uses thereof
AU2003301052A1 (en) 2002-12-20 2004-07-22 3M Innovative Properties Company Aryl / hetaryl substituted imidazoquinolines
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
US7163947B2 (en) * 2003-03-07 2007-01-16 3M Innovative Properties Company 1-Amino 1H-imidazoquinolines
CA2517655A1 (en) * 2003-03-07 2004-09-23 3M Innovative Properties Company 1-amino 1h-imidazoquinolines
WO2004080293A2 (en) * 2003-03-13 2004-09-23 3M Innovative Properties Company Methods for diagnosing skin lesions
CA2518445A1 (en) 2003-03-13 2004-09-23 3M Innovative Properties Company Method of tattoo removal
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
WO2004110992A2 (en) * 2003-06-06 2004-12-23 3M Innovative Properties Company Process for imidazo[4,5-c] pyridin-4-amines
WO2004110991A2 (en) * 2003-06-06 2004-12-23 3M Innovative Properties Company PROCESS FOR IMIDAZO[4,5-c]PYRIDIN-4-AMINES
WO2005016273A2 (en) * 2003-08-05 2005-02-24 3M Innovative Properties Company Infection prophylaxis using immune response modifier compounds
JP2007502288A (en) * 2003-08-12 2007-02-08 スリーエム イノベイティブ プロパティズ カンパニー Oxime-substituted imidazo-containing compounds
EP1660122A4 (en) * 2003-08-25 2007-10-24 3M Innovative Properties Co Immunostimulatory combinations and treatments
AU2004268616B2 (en) * 2003-08-25 2010-10-07 3M Innovative Properties Company Delivery of immune response modifier compounds
EP1658076B1 (en) 2003-08-27 2013-03-06 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted imidazoquinolines
JP2007504172A (en) * 2003-09-02 2007-03-01 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 treatment of mucosa related symptoms
AU2004270201A1 (en) * 2003-09-05 2005-03-17 3M Innovative Properties Company Treatment for CD5+ B cell lymphoma
EP1664342A4 (en) * 2003-09-17 2007-12-26 3M Innovative Properties Co Selective modulation of tlr gene expression
US7544697B2 (en) 2003-10-03 2009-06-09 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and analogs thereof
US20090075980A1 (en) * 2003-10-03 2009-03-19 Coley Pharmaceutical Group, Inc. Pyrazolopyridines and Analogs Thereof
AU2004315876B2 (en) 2003-10-03 2011-05-26 3M Innovative Properties Company Pyrazolopyridines and analogs thereof
WO2005041891A2 (en) * 2003-10-31 2005-05-12 3M Innovative Properties Company Neutrophil activation by immune response modifier compounds
CA2545774A1 (en) 2003-11-14 2005-06-02 3M Innovative Properties Company Oxime substituted imidazo ring compounds
WO2005048945A2 (en) * 2003-11-14 2005-06-02 3M Innovative Properties Company Hydroxylamine substituted imidazo ring compounds
CN1902200A (en) * 2003-11-21 2007-01-24 诺瓦提斯公司 1h-imidazoquinoline derivatives as protein kinase inhibitors
AR046845A1 (en) * 2003-11-21 2005-12-28 Novartis Ag DERIVATIVES OF 1H-IMIDAZO [4,5-C] QUINOLINE FOR THE TREATMENT OF PROTEIN-KINASE DEPENDENT DISEASES
US8778963B2 (en) * 2003-11-25 2014-07-15 3M Innovative Properties Company Hydroxylamine and oxime substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US8940755B2 (en) * 2003-12-02 2015-01-27 3M Innovative Properties Company Therapeutic combinations and methods including IRM compounds
AU2004315771A1 (en) * 2003-12-04 2005-08-25 3M Innovative Properties Company Sulfone substituted imidazo ring ethers
WO2005066170A1 (en) 2003-12-29 2005-07-21 3M Innovative Properties Company Arylalkenyl and arylalkynyl substituted imidazoquinolines
WO2005066172A1 (en) * 2003-12-29 2005-07-21 3M Innovative Properties Company Piperazine, [1,4]diazepane, [1,4]diazocane, and [1,5]diazocane fused imidazo ring compounds
EP1699398A4 (en) * 2003-12-30 2007-10-17 3M Innovative Properties Co Enhancement of immune responses
US8735421B2 (en) 2003-12-30 2014-05-27 3M Innovative Properties Company Imidazoquinolinyl sulfonamides
WO2005065678A1 (en) * 2003-12-30 2005-07-21 3M Innovative Properties Company Immunomodulatory combinations
CA2559607C (en) * 2004-03-15 2013-02-19 3M Innovative Properties Company Immune response modifier formulations and methods
WO2005094531A2 (en) 2004-03-24 2005-10-13 3M Innovative Properties Company Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines
AU2005244260B2 (en) * 2004-04-09 2010-08-05 3M Innovative Properties Company Methods, compositions, and preparations for delivery of immune response modifiers
US20050267145A1 (en) * 2004-05-28 2005-12-01 Merrill Bryon A Treatment for lung cancer
US20080015184A1 (en) * 2004-06-14 2008-01-17 3M Innovative Properties Company Urea Substituted Imidazopyridines, Imidazoquinolines, and Imidazonaphthyridines
WO2005123080A2 (en) 2004-06-15 2005-12-29 3M Innovative Properties Company Nitrogen-containing heterocyclyl substituted imidazoquinolines and imidazonaphthyridines
EP1765348B1 (en) * 2004-06-18 2016-08-03 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
US20070259881A1 (en) * 2004-06-18 2007-11-08 Dellaria Joseph F Jr Substituted Imidazo Ring Systems and Methods
WO2006009826A1 (en) 2004-06-18 2006-01-26 3M Innovative Properties Company Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines
WO2006038923A2 (en) 2004-06-18 2006-04-13 3M Innovative Properties Company Aryl substituted imidazonaphthyridines
WO2006065280A2 (en) 2004-06-18 2006-06-22 3M Innovative Properties Company Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods
US8541438B2 (en) 2004-06-18 2013-09-24 3M Innovative Properties Company Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines
CA2578975A1 (en) 2004-09-02 2006-03-16 3M Innovative Properties Company 2-amino 1h imidazo ring systems and methods
US20090270443A1 (en) * 2004-09-02 2009-10-29 Doris Stoermer 1-amino imidazo-containing compounds and methods
CA2578741C (en) * 2004-09-02 2014-01-14 3M Innovative Properties Company 1-alkoxy 1h-imidazo ring systems and methods
WO2006029223A2 (en) * 2004-09-08 2006-03-16 Children's Medical Center Corporation Method for stimulating the immune response of newborns
RU2415857C2 (en) * 2004-09-14 2011-04-10 Новартис Вэксинс Энд Диагностикс Инк. Imidazoquinoline compounds
WO2006042254A2 (en) * 2004-10-08 2006-04-20 3M Innovative Properties Company Adjuvant for dna vaccines
WO2006063072A2 (en) * 2004-12-08 2006-06-15 3M Innovative Properties Company Immunomodulatory compositions, combinations and methods
US8080560B2 (en) 2004-12-17 2011-12-20 3M Innovative Properties Company Immune response modifier formulations containing oleic acid and methods
WO2006074003A2 (en) * 2004-12-30 2006-07-13 3M Innovative Properties Company CHIRAL FUSED [1,2]IMIDAZO[4,5-c] RING COMPOUNDS
CA2594674C (en) 2004-12-30 2016-05-17 3M Innovative Properties Company Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds
ES2538498T3 (en) 2004-12-30 2015-06-22 Meda Ab Use of Imiquimod for the treatment of skin metastases from a breast cancer tumor
CA2592897A1 (en) * 2004-12-30 2006-07-13 Takeda Pharmaceutical Company Limited 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine ethanesulfonate and 1-(2-methylpropyl)-1h-imidazo[4,5-c][1,5]naphthyridin-4-amine methanesulfonate
US8436176B2 (en) * 2004-12-30 2013-05-07 Medicis Pharmaceutical Corporation Process for preparing 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine
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
US7968563B2 (en) 2005-02-11 2011-06-28 3M Innovative Properties Company Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods
US8658666B2 (en) 2005-02-11 2014-02-25 3M Innovative Properties Company Substituted imidazoquinolines and imidazonaphthyridines
WO2006089264A2 (en) 2005-02-18 2006-08-24 Novartis Vaccines And Diagnostics Inc. Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli
JP2008530245A (en) 2005-02-18 2008-08-07 ノバルティス ヴァクシンズ アンド ダイアグノスティクス， インコーポレイテッド Antigens from uropathogenic strains
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
CA2598639A1 (en) 2005-02-23 2006-08-31 Coley Pharmaceutical Group, Inc. Hydroxyalkyl substituted imidazonaphthyridines
AU2006223148A1 (en) 2005-03-14 2006-09-21 3M Innovative Properties Company Method of treating actinic keratosis
AU2006232375A1 (en) 2005-04-01 2006-10-12 Coley Pharmaceutical Group, Inc. 1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
EP1869043A2 (en) 2005-04-01 2007-12-26 Coley Pharmaceutical Group, Inc. Pyrazolopyridine-1,4-diamines and analogs thereof
JP2008539252A (en) * 2005-04-25 2008-11-13 スリーエム イノベイティブ プロパティズ カンパニー Immune activation composition
CA2615626A1 (en) 2005-07-18 2007-01-25 Novartis Ag Small animal model for hcv replication
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
US8889154B2 (en) 2005-09-15 2014-11-18 Medicis Pharmaceutical Corporation Packaging for 1-(2-methylpropyl)-1H-imidazo[4,5-c] quinolin-4-amine-containing formulation
CA2628328A1 (en) 2005-11-04 2007-05-10 Novartis Vaccines And Diagnostics S.R.L. Influenza vaccines including combinations of particulate adjuvants and immunopotentiators
US20090304742A1 (en) 2005-11-04 2009-12-10 Novartis Vaccines And Diagnostics Srl Influenza vaccines with reduced amount of emulsion adjuvant
CA2628424A1 (en) 2005-11-04 2007-05-10 Novartis Vaccines And Diagnostics S.R.L. Adjuvanted influenza vaccines including cytokine-inducing agents
EP1948173B1 (en) 2005-11-04 2013-07-17 3M Innovative Properties Company Hydroxy and alkoxy substituted 1h-imidazoquinolines and methods
HUE051122T2 (en) 2005-11-04 2021-03-01 Seqirus Uk Ltd Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture
PT2478916T (en) 2006-01-27 2020-07-03 Seqirus Uk Ltd Influenza vaccines containing hemagglutinin and matrix proteins
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
WO2007109813A1 (en) 2006-03-23 2007-09-27 Novartis Ag Imidazoquinoxaline compounds as immunomodulators
EP2010530A2 (en) * 2006-03-23 2009-01-07 Novartis AG Methods for the preparation of imidazole-containing compounds
CA2646891A1 (en) * 2006-03-23 2007-09-27 Novartis Ag Immunopotentiating compounds
EP2382987A1 (en) 2006-03-24 2011-11-02 Novartis Vaccines and Diagnostics GmbH Storage of influenza vaccines without refrigeration
CA2647942A1 (en) 2006-03-31 2007-11-08 Novartis Ag Combined mucosal and parenteral immunization against hiv
US20100015168A1 (en) 2006-06-09 2010-01-21 Novartis Ag Immunogenic compositions for streptococcus agalactiae
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
GB0614460D0 (en) 2006-07-20 2006-08-30 Novartis Ag Vaccines
US20100166788A1 (en) 2006-08-16 2010-07-01 Novartis Vaccines And Diagnostics Immunogens from uropathogenic escherichia coli
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
ES2536401T3 (en) 2006-09-11 2015-05-25 Novartis Ag Making vaccines against influenza viruses without using eggs
US20110045022A1 (en) 2006-12-06 2011-02-24 Theodore Tsai Vaccines including antigen from four strains of influenza virus
US20080149123A1 (en) 2006-12-22 2008-06-26 Mckay William D Particulate material dispensing hairbrush with combination bristles
GB0700562D0 (en) 2007-01-11 2007-02-21 Novartis Vaccines & Diagnostic Modified Saccharides
PT2185191E (en) 2007-06-27 2012-11-27 Novartis Ag Low-additive influenza vaccines
GB0714963D0 (en) 2007-08-01 2007-09-12 Novartis Ag Compositions comprising antigens
GB0810305D0 (en) 2008-06-05 2008-07-09 Novartis Ag Influenza vaccination
GB0818453D0 (en) 2008-10-08 2008-11-12 Novartis Ag Fermentation processes for cultivating streptococci and purification processes for obtaining cps therefrom
UA101339C2 (en) * 2008-01-15 2013-03-25 Меда Аб Treatment of colorectal diseases or prevention of colorectal cancer by means of imidazoquinoline derivatives
WO2009111337A1 (en) 2008-03-03 2009-09-11 Irm Llc Compounds and compositions as tlr activity modulators
EP2268309B1 (en) 2008-03-18 2015-01-21 Novartis AG Improvements in preparation of influenza virus vaccine antigens
AU2010220103A1 (en) 2009-03-06 2011-09-22 Novartis Ag Chlamydia antigens
SG175092A1 (en) 2009-04-14 2011-11-28 Novartis Ag Compositions for immunising against staphylococcus aerus
USH2283H1 (en) 2009-04-27 2013-09-03 Novartis Ag Vaccines for protecting against influenza
GB0907551D0 (en) * 2009-05-01 2009-06-10 Univ Dundee Treatment or prophylaxis of proliferative conditions
AU2013203591B2 (en) * 2009-05-01 2017-01-19 University Court Of The University Of Dundee Treatment or prophylaxis of proliferative conditions
SG178026A1 (en) 2009-07-15 2012-03-29 Novartis Ag Rsv f protein compositions and methods for making same
ES2526996T3 (en) 2009-07-16 2015-01-19 Novartis Ag Detoxified immunogens from Escherichia coli
GB0918392D0 (en) 2009-10-20 2009-12-02 Novartis Ag Diagnostic and therapeutic methods
GB0919690D0 (en) 2009-11-10 2009-12-23 Guy S And St Thomas S Nhs Foun compositions for immunising against staphylococcus aureus
GB201009861D0 (en) 2010-06-11 2010-07-21 Novartis Ag OMV vaccines
HUE033901T2 (en) * 2010-08-17 2018-01-29 3M Innovative Properties Co Lipidated immune response modifier compound compositions, formulations, and methods
JP5978225B2 (en) 2010-12-16 2016-08-24 大日本住友製薬株式会社 Imidazo [4,5-c] quinolin-1-yl derivatives useful for therapy
AU2012211278B2 (en) 2011-01-26 2016-11-10 Glaxosmithkline Biologicals Sa RSV immunization regimen
LT2707385T (en) 2011-05-13 2017-12-11 Glaxosmithkline Biologicals Sa Pre-fusion rsv f antigens
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
US9493517B2 (en) 2011-11-07 2016-11-15 Glaxosmithkline Biologicals Sa Conjugates comprising an antigen and a carrier molecule
WO2013108272A2 (en) 2012-01-20 2013-07-25 International Centre For Genetic Engineering And Biotechnology Blood stage malaria vaccine
EP2941233B1 (en) 2013-01-07 2020-10-07 The Trustees of the University of Pennsylvania Compositions and methods for treating cutaneous t cell lymphoma
AU2014347059B2 (en) 2013-11-05 2017-09-07 Solventum Intellectual Properties Company Sesame oil based injection formulations
EP2870974A1 (en) 2013-11-08 2015-05-13 Novartis AG Salmonella conjugate vaccines
KR102297357B1 (en) 2014-03-26 2021-09-02 글락소스미스클라인 바이오로지칼즈 에스.에이. Mutant staphylococcal antigens
CN105461767B (en) * 2014-08-07 2019-03-12 富力 A kind of chemical synthesis process of forsythin
JP6873980B2 (en) * 2015-09-14 2021-05-19 ファイザー・インク Novel imidazole [4,5-c] quinoline and imidazole [4,5-c] [1,5] naphthylidine derivatives as LRRK2 inhibitors
WO2017058996A1 (en) * 2015-09-29 2017-04-06 The University Of Chicago Polymer conjugate vaccines
US10526309B2 (en) 2015-10-02 2020-01-07 The University Of North Carolina At Chapel Hill Pan-TAM inhibitors and Mer/Axl dual inhibitors
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
JP2021512953A (en) 2018-02-02 2021-05-20 メイベリックス オンコロジー インコーポレイテッド Small molecule drug conjugate of gemcitabine monophosphate
EP3759107A1 (en) * 2018-02-28 2021-01-06 3M Innovative Properties Company Substituted imidazo[4,5-c]quinoline compounds with an n-1 branched group
KR20200128116A (en) 2018-02-28 2020-11-11 화이자 인코포레이티드 IL-15 variants and uses thereof
CA3100829A1 (en) 2018-05-23 2019-11-28 Pfizer Inc. Antibodies specific for gucy2c and uses thereof
EP3797121A1 (en) 2018-05-23 2021-03-31 Pfizer Inc Antibodies specific for cd3 and uses thereof
US11884662B2 (en) 2018-05-24 2024-01-30 3M Innovative Properties Company N-1 branched cycloalkyl substituted imidazo[4,5-c]quinoline compounds, compositions, and methods
WO2020023680A1 (en) * 2018-07-24 2020-01-30 Torque Therapeutics, Inc. Tlr7/8 agonists and liposome compositions
EP3887369A1 (en) * 2018-11-26 2021-10-06 3M Innovative Properties Company N-1 branched alkyl ether substituted imidazo[4,5-c]quinoline compounds, compositions, and methods
US20220370606A1 (en) 2018-12-21 2022-11-24 Pfizer Inc. Combination Treatments Of Cancer Comprising A TLR Agonist
WO2020163118A1 (en) * 2019-02-07 2020-08-13 Canwell Biotech Limited Phosphorus imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof
WO2020168017A1 (en) 2019-02-12 2020-08-20 Ambrx, Inc. Compositions containing, methods and uses of antibody-tlr agonist conjugates
US20220411421A1 (en) * 2019-10-29 2022-12-29 Prime Reach Trading Limited 4-amino-imidazoquinoline compounds and use thereof
MX2022006578A (en) 2019-12-17 2022-07-04 Pfizer Antibodies specific for cd47, pd-l1, and uses thereof.
JP2023533793A (en) 2020-07-17 2023-08-04 ファイザー・インク Therapeutic antibodies and their uses
EP4199968A1 (en) 2020-08-20 2023-06-28 Ambrx, Inc. Antibody-tlr agonist conjugates, methods and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015582A1 (en) * 1991-03-01 1992-09-17 Minnesota Mining And Manufacturing Company 1-SUBSTITUTED, 2-SUBSTITUTED 1H-IMIDAZO[4,5-c]QUINOLIN-4-AMINES
WO1995002598A1 (en) * 1993-07-15 1995-01-26 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines

Family Cites Families (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2135210A (en) * 1937-03-13 1938-11-01 John R Farrar Golf ball
US3314941A (en) 1964-06-23 1967-04-18 American Cyanamid Co Novel substituted pyridodiazepins
US3692907A (en) * 1970-10-27 1972-09-19 Richardson Merrell Inc Treating viral infections with bis-basic ethers and thioethers of fluorenone and fluorene and pharmaceutical compositons of the same
US3819190A (en) * 1972-10-02 1974-06-25 D Nepela Golf ball
US4284276A (en) * 1980-02-13 1981-08-18 Worst Joseph C Grooved golf ball
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
US4880779A (en) * 1987-07-31 1989-11-14 Research Corporation Technologies, Inc. Method of prevention or treatment of AIDS by inhibition of human immunodeficiency virus
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
US5037986A (en) 1989-03-23 1991-08-06 Minnesota Mining And Manufacturing Company Olefinic 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
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
US5054153A (en) * 1989-12-01 1991-10-08 Silliman Paul D Golf club cleaner
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
FR2692159B1 (en) * 1992-06-10 1996-10-11 Vartan Berberian BALL FOR BALL GAMES AND METHODS OF OBTAINING SUCH A BALL.
US5395937A (en) * 1993-01-29 1995-03-07 Minnesota Mining And Manufacturing Company Process for preparing quinoline amines
CZ288182B6 (en) 1993-07-15 2001-05-16 Minnesota Mining & Mfg Imidazo[4,5-c]pyridine-4-amines and pharmaceutical preparations based thereon
US5648516A (en) 1994-07-20 1997-07-15 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines
US5644063A (en) 1994-09-08 1997-07-01 Minnesota Mining And Manufacturing Company Imidazo[4,5-c]pyridin-4-amine intermediates
US5482936A (en) 1995-01-12 1996-01-09 Minnesota Mining And Manufacturing Company Imidazo[4,5-C]quinoline amines
JPH09116911A (en) * 1995-10-20 1997-05-02 Canon Inc Image pickup system
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
US5741908A (en) * 1996-06-21 1998-04-21 Minnesota Mining And Manufacturing Company Process for reparing imidazoquinolinamines
US5693811A (en) * 1996-06-21 1997-12-02 Minnesota Mining And Manufacturing Company Process for preparing tetrahdroimidazoquinolinamines
US5759109A (en) * 1996-09-09 1998-06-02 Martini; Byron Rocco Simulated golf ball instructional device
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
UA67760C2 (en) * 1997-12-11 2004-07-15 Міннесота Майнінг Енд Мануфакчурінг Компані Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines
JPH11222432A (en) 1998-02-03 1999-08-17 Terumo Corp Preparation for external use containing amide derivative inducing interferon
JPH11255926A (en) 1998-03-13 1999-09-21 Toray Ind Inc Silicone molding and its production
US6239965B1 (en) * 1998-05-22 2001-05-29 Matsushita Electric Industrial Co., Ltd. Electrolytic capacitor and method of producing the same
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
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
US6573273B1 (en) * 1999-06-10 2003-06-03 3M Innovative Properties Company Urea substituted imidazoquinolines
US6541485B1 (en) * 1999-06-10 2003-04-01 3M Innovative Properties Company Urea substituted imidazoquinolines
US6756382B2 (en) 1999-06-10 2004-06-29 3M Innovative Properties Company Amide substituted imidazoquinolines
US6451810B1 (en) 1999-06-10 2002-09-17 3M Innovative Properties Company Amide substituted imidazoquinolines
US6331539B1 (en) 1999-06-10 2001-12-18 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6376669B1 (en) * 1999-11-05 2002-04-23 3M Innovative Properties Company Dye labeled imidazoquinoline compounds
US6894060B2 (en) 2000-03-30 2005-05-17 3M Innovative Properties Company Method for the treatment of dermal lesions caused by envenomation
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
US6545017B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
US6667312B2 (en) * 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6664264B2 (en) * 2000-12-08 2003-12-16 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6677347B2 (en) * 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
EP1360486A2 (en) 2000-12-08 2003-11-12 3M Innovative Properties Company Screening method for identifying compounds that selectively induce interferon alpha
UA74593C2 (en) 2000-12-08 2006-01-16 3M Innovative Properties Co Substituted imidazopyridines
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
UA75622C2 (en) 2000-12-08 2006-05-15 3M Innovative Properties Co Aryl ether substituted imidazoquinolines, pharmaceutical composition based thereon
US6525064B1 (en) * 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6664260B2 (en) 2000-12-08 2003-12-16 3M Innovative Properties Company Heterocyclic ether substituted imidazoquinolines
US6660747B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US6660735B2 (en) * 2000-12-08 2003-12-09 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
US6545016B1 (en) * 2000-12-08 2003-04-08 3M Innovative Properties Company Amide substituted imidazopyridines
JP2005519849A (en) 2001-06-15 2005-07-07 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 modifier for the treatment of periodontal disease
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
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
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
AU2003287316A1 (en) 2002-12-11 2004-06-30 3M Innovative Properties Company Assays relating to toll-like receptor activity
AU2003287324A1 (en) 2002-12-11 2004-06-30 3M Innovative Properties Company Gene expression systems and recombinant cell lines
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
CA2518445A1 (en) 2003-03-13 2004-09-23 3M Innovative Properties Company Method of tattoo removal
MXPA05009694A (en) 2003-03-13 2005-10-20 3M Innovative Properties Co Methods of improving skin quality.
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
US7576068B2 (en) 2003-09-05 2009-08-18 Anadys Pharmaceuticals, Inc. Administration of TLR7 ligands and prodrugs thereof for treatment of infection by hepatitis C virus

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015582A1 (en) * 1991-03-01 1992-09-17 Minnesota Mining And Manufacturing Company 1-SUBSTITUTED, 2-SUBSTITUTED 1H-IMIDAZO[4,5-c]QUINOLIN-4-AMINES
WO1995002598A1 (en) * 1993-07-15 1995-01-26 Minnesota Mining And Manufacturing Company Fused cycloalkylimidazopyridines

Cited By (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6897314B2 (en) 1996-06-21 2005-05-24 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6534654B2 (en) 1996-06-21 2003-03-18 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6624305B2 (en) 1996-06-21 2003-09-23 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6613902B2 (en) 1996-06-21 2003-09-02 3M Innovative Properties Company Process for preparing imidazoquinolinamines
US6797716B2 (en) 1997-12-11 2004-09-28 3M Innovative Properties Company Imidazonaphthyridines
US6894165B2 (en) * 1997-12-11 2005-05-17 3M Innovative Properties Company Imidazonaphthyridines
US6699878B2 (en) 1997-12-11 2004-03-02 3M Innovative Properties Company Imidazonaphthyridines
US6747040B2 (en) 1997-12-11 2004-06-08 3M Innovative Properties Company Imidazonaphthyridines
US7393859B2 (en) 1999-06-10 2008-07-01 Coley Pharmaceutical Group, Inc. Amide substituted imidazoquinolines
US6825350B2 (en) 1999-06-10 2004-11-30 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines and methods for the treatment of periodontal disease using these and other immune response modifiers
US6784188B2 (en) 1999-06-10 2004-08-31 3M Innovative Properties Company Urea substituted imidazoquinolines
US6780873B2 (en) 1999-06-10 2004-08-24 3M Innovative Properties Company Urea substituted imidazoquinolines
US6916925B1 (en) 1999-11-05 2005-07-12 3M Innovative Properties Co. Dye labeled imidazoquinoline compounds
US6720333B2 (en) 2000-12-08 2004-04-13 3M Innovative Properties Company Amide substituted imidazopyridines
US6667312B2 (en) 2000-12-08 2003-12-23 3M Innovative Properties Company Thioether substituted imidazoquinolines
US6716988B2 (en) 2000-12-08 2004-04-06 3M Innovative Properties Company Urea substituted imidazopyridines
US6545016B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Amide substituted imidazopyridines
US6720334B2 (en) 2000-12-08 2004-04-13 3M Innovative Properties Company Urea substituted imidazopyridines
US6720422B2 (en) 2000-12-08 2004-04-13 3M Innovative Properties Company Amide substituted imidazopyridines
US6677348B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Aryl ether substituted imidazoquinolines
US6677347B2 (en) 2000-12-08 2004-01-13 3M Innovative Properties Company Sulfonamido ether substituted imidazoquinolines
US6545017B1 (en) 2000-12-08 2003-04-08 3M Innovative Properties Company Urea substituted imidazopyridines
US6696465B2 (en) 2000-12-08 2004-02-24 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6660735B2 (en) 2000-12-08 2003-12-09 3M Innovative Properties Company Urea substituted imidazoquinoline ethers
US6525064B1 (en) 2000-12-08 2003-02-25 3M Innovative Properties Company Sulfonamido substituted imidazopyridines
US6664265B2 (en) 2000-12-08 2003-12-16 3M Innovative Properties Company Amido ether substituted imidazoquinolines
US7968562B2 (en) 2001-11-29 2011-06-28 3M Innovative Properties Company Pharmaceutical formulations comprising an immune response modifier
WO2003050121A1 (en) * 2001-12-06 2003-06-19 3M Innovative Properties Company Thioether substituted imidazoquinolines
US7299453B2 (en) 2001-12-20 2007-11-20 International Business Machines Corporation Testing measurements
US6677349B1 (en) 2001-12-21 2004-01-13 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6924293B2 (en) 2001-12-21 2005-08-02 3M Innovative Properties Company Sulfonamide and sulfamide substituted imidazoquinolines
US6797718B2 (en) 2002-06-07 2004-09-28 3M Innovative Properties Company Ether substituted imidazopyridines
US7427629B2 (en) 2002-08-15 2008-09-23 3M Innovative Properties Company Immunostimulatory compositions and methods of stimulating an immune response
EP2269632A2 (en) 2002-08-15 2011-01-05 3M Innovative Properties Co. Immunostimulatory compositions and methods of stimulating an immune response
US7112677B2 (en) 2002-09-26 2006-09-26 3M Innovative Properties Company 1H-imidazo dimers
US6818650B2 (en) 2002-09-26 2004-11-16 3M Innovative Properties Company 1H-imidazo dimers
US10105426B2 (en) 2002-12-30 2018-10-23 Trustees Of Dartmouth College Immunostimulatory combinations
EP2572715A1 (en) 2002-12-30 2013-03-27 3M Innovative Properties Company Immunostimulatory Combinations
EP2572714A1 (en) 2002-12-30 2013-03-27 3M Innovative Properties Company Immunostimulatory Combinations
US8110582B2 (en) 2003-03-04 2012-02-07 3M Innovative Properties Company Prophylactic treatment of UV-induced epidermal neoplasia
US8426457B2 (en) 2003-03-13 2013-04-23 Medicis Pharmaceutical Corporation Methods of improving skin quality
US7696159B2 (en) 2003-03-25 2010-04-13 Graceway Pharmaceuticals, Llc Treatment for basal cell carcinoma
US8835394B2 (en) 2003-03-25 2014-09-16 Medicis Pharmaceutical Corporation Treatment for basal cell carcinoma
US7923560B2 (en) 2003-04-10 2011-04-12 3M Innovative Properties Company Delivery of immune response modifier compounds
EP1653959A2 (en) * 2003-08-14 2006-05-10 3M Innovative Properties Company Lipid-modified immune response modifiers
JP2007521317A (en) * 2003-08-14 2007-08-02 スリーエム イノベイティブ プロパティズ カンパニー Lipid-modified immune response modifier
EP1653959A4 (en) * 2003-08-14 2009-04-08 3M Innovative Properties Co Lipid-modified immune response modifiers
US8871782B2 (en) 2003-10-03 2014-10-28 3M Innovative Properties Company Alkoxy substituted imidazoquinolines
JP2012006976A (en) * 2003-11-25 2012-01-12 Three M Innovative Properties Co Substituted imidazo ring system and method
JP2007512370A (en) * 2003-11-25 2007-05-17 スリーエム イノベイティブ プロパティズ カンパニー Substituted imidazo ring systems and methods
US8691837B2 (en) 2003-11-25 2014-04-08 3M Innovative Properties Company Substituted imidazo ring systems 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
US10722573B2 (en) 2009-03-25 2020-07-28 The Board Of Regents, The University Of Texas System Compositions for stimulation of mammalian innate immune resistance to pathogens
WO2010111485A1 (en) 2009-03-25 2010-09-30 The Board Of Regents Of The University Of Texas System Compositions for stimulation of mammalian innate immune resistance to pathogens
US9441005B2 (en) 2011-05-18 2016-09-13 University Of Kansas Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds
US8728486B2 (en) 2011-05-18 2014-05-20 University Of Kansas Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds
WO2013013055A1 (en) 2011-07-21 2013-01-24 Rubigo Therapeutics, Inc. System for drug delivery and monitoring
US10660971B2 (en) 2012-07-18 2020-05-26 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
US10548988B2 (en) 2012-07-18 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds for targeted immunotherapy
EP3632458A1 (en) 2013-07-26 2020-04-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of bacterial infections
EP4056594A1 (en) 2014-01-10 2022-09-14 Birdie Biopharmaceuticals Inc. Compounds and compositions for immunotherapy
WO2015103987A1 (en) 2014-01-10 2015-07-16 Shanghai Birdie Biotech, Inc. Compounds and compositions for treating her2 positive tumors
US11786604B2 (en) 2014-01-10 2023-10-17 Birdie Biopharmaceuticals, Inc. Compounds and compositions for treating HER2 positive tumors
US10328158B2 (en) 2014-01-10 2019-06-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US11633495B2 (en) 2014-01-10 2023-04-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US10548985B2 (en) 2014-01-10 2020-02-04 Birdie Biopharmaceuticals, Inc. Compounds and compositions for treating EGFR expressing tumors
WO2015103989A1 (en) 2014-01-10 2015-07-16 Shanghai Birdie Biotech, Inc. Compounds and compositions for immunotherapy
WO2015103990A1 (en) 2014-01-10 2015-07-16 Shanghai Birdie Biotech, Inc. Compounds and compositions for treating egfr expressing tumors
US11633494B2 (en) 2014-01-10 2023-04-25 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
US10780180B2 (en) 2014-01-10 2020-09-22 Birdie Biopharmaceuticals, Inc. Compounds and compositions for immunotherapy
WO2016004876A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Anti-pd-l1 combinations for treating tumors
EP4001311A1 (en) 2014-07-09 2022-05-25 Birdie Biopharmaceuticals Inc. Anti-pd-l1 combinations for treating tumors
WO2016004875A1 (en) 2014-07-09 2016-01-14 Shanghai Birdie Biotech, Inc. Combination therapy compositions and methods for treating cancers
US11279761B2 (en) 2014-07-09 2022-03-22 Birdie Biopharmaceuticals, Inc. Anti-PD-L1 combinations for treating tumors
US11130812B2 (en) 2014-09-01 2021-09-28 Birdie Biopharmaceuticals, Inc. Anti PD-L1 conjugates for treating tumors
EP4148069A1 (en) 2014-09-01 2023-03-15 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
EP3763742A1 (en) 2014-09-01 2021-01-13 Birdie Biopharmaceuticals Inc. Anti-pd-l1 conjugates for treating tumors
US10286065B2 (en) 2014-09-19 2019-05-14 Board Of Regents, The University Of Texas System Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds
US11136397B2 (en) 2016-01-07 2021-10-05 Birdie Pharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
US11220552B2 (en) 2016-01-07 2022-01-11 Birdie Biopharmaceuticals, Inc. Anti-CD20 combinations for treating tumors
US11702476B2 (en) 2016-01-07 2023-07-18 Birdie Biopharmaceuticals, Inc. Anti-EGFR combinations for treating tumors
US11046781B2 (en) 2016-01-07 2021-06-29 Birdie Biopharmaceuticals, Inc. Anti-HER2 combinations for treating tumors
WO2018087699A2 (en) 2016-11-09 2018-05-17 The Board Of Regents Of The University Of Texas System Methods and compositions for adaptive immune modulation
US11826422B2 (en) 2016-11-09 2023-11-28 Board Of Regents, The University Of Texas System Methods and compositions for adaptive immune modulation
US11053240B2 (en) 2017-04-27 2021-07-06 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
US11834448B2 (en) 2017-04-27 2023-12-05 Birdie Biopharmaceuticals, Inc. 2-amino-quinoline derivatives
US11517567B2 (en) 2017-06-23 2022-12-06 Birdie Biopharmaceuticals, Inc. Pharmaceutical compositions
WO2021116420A1 (en) 2019-12-13 2021-06-17 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of tlr7 and/or tlr8 agonists for the treatment of leptospirosis

Also Published As

Publication number Publication date
NZ526087A (en) 2004-11-26
HRP20030462A2 (en) 2004-04-30
JP2004529078A (en) 2004-09-24
US6683088B2 (en) 2004-01-27
WO2002046191A2 (en) 2002-06-13
PT1341791E (en) 2005-09-30
CZ20031560A3 (en) 2004-05-12
JP2004532810A (en) 2004-10-28
HUP0600600A2 (en) 2006-11-28
ZA200305272B (en) 2005-01-26
NO20032473L (en) 2003-05-30
CZ20031563A3 (en) 2004-02-18
CN1253452C (en) 2006-04-26
ZA200305274B (en) 2004-10-18
US7612083B2 (en) 2009-11-03
CA2436980C (en) 2011-03-29
CZ20031591A3 (en) 2003-11-12
RU2003116059A (en) 2005-02-10
MXPA03004975A (en) 2003-09-05
ZA200305275B (en) 2004-10-08
CA2436984A1 (en) 2002-06-13
US20020193396A1 (en) 2002-12-19
ATE319711T1 (en) 2006-03-15
AU3951702A (en) 2002-06-18
BR0116047A (en) 2003-09-30
MXPA03004973A (en) 2004-01-29
KR20040023576A (en) 2004-03-18
SK6842003A3 (en) 2003-12-02
NO326159B1 (en) 2008-10-13
UA74852C2 (en) 2006-02-15
RU2003116123A (en) 2004-11-20
PL365883A1 (en) 2005-01-10
DE60111076D1 (en) 2005-06-30
EP1341792A2 (en) 2003-09-10
EP1341790B1 (en) 2007-02-14
NO20032473D0 (en) 2003-05-30
CN1297554C (en) 2007-01-31
CN1479738A (en) 2004-03-03
US20040077678A1 (en) 2004-04-22
US6656938B2 (en) 2003-12-02
IL155884A0 (en) 2003-12-23
RU2302418C2 (en) 2007-07-10
NO20032596L (en) 2003-06-06
CA2436983A1 (en) 2002-06-13
CN1479739A (en) 2004-03-03
HUP0600605A2 (en) 2006-11-28
AU3953002A (en) 2002-06-18
CZ20031592A3 (en) 2004-01-14
ES2242782T3 (en) 2005-11-16
HRP20030467A2 (en) 2004-04-30
ZA200305273B (en) 2004-10-08
DE60117859T2 (en) 2006-11-23
EP1341791A2 (en) 2003-09-10
CN1247575C (en) 2006-03-29
CZ303462B6 (en) 2012-09-26
NZ526088A (en) 2004-12-24
PL365907A1 (en) 2005-01-10
US20050148619A1 (en) 2005-07-07
CY1106569T1 (en) 2012-01-25
HRP20030463A2 (en) 2004-04-30
DE60111076T2 (en) 2006-05-04
KR20040047733A (en) 2004-06-05
WO2002046190A2 (en) 2002-06-13
AR035664A1 (en) 2004-06-23
US20030158192A1 (en) 2003-08-21
US7132429B2 (en) 2006-11-07
CY1105586T1 (en) 2010-07-28
CN1511155A (en) 2004-07-07
EE200300271A (en) 2003-10-15
EP1341789A2 (en) 2003-09-10
SI1341790T1 (en) 2007-06-30
SK287264B6 (en) 2010-04-07
JP2010031040A (en) 2010-02-12
WO2002046190A3 (en) 2003-07-17
CA2431151A1 (en) 2002-06-13
NZ526106A (en) 2004-11-26
US7049439B2 (en) 2006-05-23
MXPA03004974A (en) 2003-09-05
JP2004521092A (en) 2004-07-15
CZ20031562A3 (en) 2004-03-17
BR0116470A (en) 2005-08-16
AU2002239530B2 (en) 2006-09-28
PL365995A1 (en) 2005-01-24
US6670372B2 (en) 2003-12-30
DE60117859D1 (en) 2006-05-04
EP1339715A2 (en) 2003-09-03
IL155904A0 (en) 2003-12-23
UA75622C2 (en) 2006-05-15
HK1069166A1 (en) 2005-05-13
IL156043A0 (en) 2003-12-23
HUP0600338A2 (en) 2006-08-28
HRP20030467B1 (en) 2009-04-30
SK7102003A3 (en) 2003-10-07
CN1537111A (en) 2004-10-13
IL156044A0 (en) 2003-12-23
BR0116464A (en) 2006-02-21
HK1064383A1 (en) 2005-01-28
KR20030070050A (en) 2003-08-27
AR035665A1 (en) 2004-06-23
NO20032452L (en) 2003-07-16
US20050234088A1 (en) 2005-10-20
SK287732B6 (en) 2011-07-06
HUP0400710A2 (en) 2004-06-28
EP1341791B1 (en) 2005-05-25
CZ20031561A3 (en) 2004-04-14
SK7132003A3 (en) 2003-10-07
TWI222972B (en) 2004-11-01
DE60126645D1 (en) 2007-03-29
RU2315049C2 (en) 2008-01-20
DE60126645T2 (en) 2007-11-22
ZA200305270B (en) 2004-08-26
SK7122003A3 (en) 2003-11-04
AR035667A1 (en) 2004-06-23
EP1343784B1 (en) 2006-03-08
ATE296301T1 (en) 2005-06-15
NO20032596D0 (en) 2003-06-06
RU2003116063A (en) 2004-12-10
AU2002232482B2 (en) 2006-10-19
CA2436980A1 (en) 2002-06-13
BR0116026A (en) 2004-12-21
AU3951602A (en) 2002-06-18
NO20032452D0 (en) 2003-05-28
AU2002239516B2 (en) 2006-11-09
NZ526086A (en) 2005-11-25
HK1066005A1 (en) 2005-03-11
RU2308456C2 (en) 2007-10-20
US6953804B2 (en) 2005-10-11
US20030212091A1 (en) 2003-11-13
AU3249702A (en) 2002-06-18
KR20030070049A (en) 2003-08-27
HRP20030466A2 (en) 2004-06-30
EP1341790A2 (en) 2003-09-10
PL207340B1 (en) 2010-12-31
EE200300274A (en) 2003-10-15
ES2260323T3 (en) 2006-11-01
IL155903A0 (en) 2003-12-23
ATE353895T1 (en) 2007-03-15
AU2002230618B2 (en) 2006-11-02
WO2002046192A3 (en) 2003-02-13
WO2002046193A2 (en) 2002-06-13
CN1894244A (en) 2007-01-10
DK1341791T3 (en) 2005-09-19
WO2002046191A3 (en) 2003-03-13
PL361948A1 (en) 2004-10-18
SK7152003A3 (en) 2003-09-11
TW584633B (en) 2004-04-21
JP2004523498A (en) 2004-08-05
WO2002046189A3 (en) 2003-03-20
EE200300270A (en) 2003-10-15
MXPA03004972A (en) 2004-01-29
EP1343784A2 (en) 2003-09-17
AU2002232497B2 (en) 2006-11-02
PL392462A1 (en) 2010-11-22
HRP20030461A2 (en) 2004-06-30
NO20032595L (en) 2003-06-06
DK1341790T3 (en) 2007-06-04
EE200300272A (en) 2003-10-15
RU2003116649A (en) 2005-02-10
HUP0400704A2 (en) 2004-06-28
JP2004515500A (en) 2004-05-27
AU2002239517B2 (en) 2006-11-02
NO20032449L (en) 2003-05-28
NO20032451D0 (en) 2003-05-28
AR035669A1 (en) 2004-06-23
WO2002046188A3 (en) 2003-03-13
WO2002046188A2 (en) 2002-06-13
KR20040028691A (en) 2004-04-03
AU3061802A (en) 2002-06-18
BR0116032A (en) 2006-02-21
CN1252070C (en) 2006-04-19
NZ526105A (en) 2004-11-26
HUP0700062A2 (en) 2007-05-02
AU3248202A (en) 2002-06-18
AR035668A1 (en) 2004-06-23
CN1487939A (en) 2004-04-07
CZ295848B6 (en) 2005-11-16
NO20032449D0 (en) 2003-05-28
KR20040028690A (en) 2004-04-03
RU2351598C2 (en) 2009-04-10
PL366330A1 (en) 2005-01-24
TWI293300B (en) 2008-02-11
EE200300268A (en) 2003-10-15
HRP20030464A2 (en) 2004-06-30
WO2002046189A2 (en) 2002-06-13
EE200300275A (en) 2003-10-15
NO20032595D0 (en) 2003-06-06
PT1341790E (en) 2007-05-31
ZA200305271B (en) 2004-10-08
CA2436846C (en) 2010-11-16
CA2430844A1 (en) 2002-06-13
NZ526089A (en) 2004-11-26
AR035666A1 (en) 2004-06-23
JP4437189B2 (en) 2010-03-24
JP2004515501A (en) 2004-05-27
US20040092545A1 (en) 2004-05-13
BR0116052A (en) 2006-02-21
ES2281456T3 (en) 2007-10-01
SK7112003A3 (en) 2003-12-02
PL366115A1 (en) 2005-01-24
US20040106640A1 (en) 2004-06-03
IL155950A0 (en) 2003-12-23
DK1343784T3 (en) 2006-07-10
NO20032451L (en) 2003-07-16
MXPA03005012A (en) 2003-09-05
MXPA03005011A (en) 2003-09-05
WO2002046193A3 (en) 2003-02-27
CA2436846A1 (en) 2002-06-13

Similar Documents

Publication Publication Date Title
CA2436846C (en) Thioether substituted imidazoquinolines
US6664264B2 (en) Thioether substituted imidazoquinolines
US6667312B2 (en) Thioether substituted imidazoquinolines
AU2002239530A1 (en) Thioether substituted imidazoquinolines
US6660747B2 (en) Amido ether substituted imidazoquinolines
US20020107262A1 (en) Substituted imidazopyridines
AU2002232497A1 (en) Urea substituted imidazoquinoline ethers
EP1541572A1 (en) Thioether substituted imidazoquinolines
AU2002315009B2 (en) Thioether substituted imidazoquinolines

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ CZ DE DE DK DK DM DZ EC EE EE ES FI 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 NO NZ PH PL PT RO RU SD SE SG SI SK SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE 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: 155904

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 526087

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2436846

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/004975

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: PV2003-1560

Country of ref document: CZ

Ref document number: 1020037007534

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: P20030467A

Country of ref document: HR

Ref document number: 7102003

Country of ref document: SK

Ref document number: 2002547929

Country of ref document: JP

Ref document number: 01820161X

Country of ref document: CN

Ref document number: 2002239530

Country of ref document: AU

ENP Entry into the national phase

Ref country code: RU

Ref document number: RU A

WWE Wipo information: entry into national phase

Ref document number: 2003/05274

Country of ref document: ZA

Ref document number: 2001987297

Country of ref document: EP

Ref document number: 200305274

Country of ref document: ZA

WWP Wipo information: published in national office

Ref document number: 1020037007534

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1-2003-500496

Country of ref document: PH

WWP Wipo information: published in national office

Ref document number: 2001987297

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2003-1560

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 526087

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 526087

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2001987297

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: PV2003-1560

Country of ref document: CZ