CA2436983A1 - Sulfonamido ether substituted imidazoquinolines - Google Patents
Sulfonamido ether substituted imidazoquinolines Download PDFInfo
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- CA2436983A1 CA2436983A1 CA002436983A CA2436983A CA2436983A1 CA 2436983 A1 CA2436983 A1 CA 2436983A1 CA 002436983 A CA002436983 A CA 002436983A CA 2436983 A CA2436983 A CA 2436983A CA 2436983 A1 CA2436983 A1 CA 2436983A1
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Abstract
Imidazopyridine compounds that contain substituted amine functionality at th e 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokin es and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.
Description
Sulfonamido Ether Substituted Imidazoquinolines Field of the Invention This invention relates to imidazoquinoline compounds that have ether and sulfonamide or sulfamide 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 disease's.
Background of the Invention The first reliable report on the 1H imidazo[4,5-c]quinoline ring system, Backman et al., J. Or~.Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H imidazo[4,5-c]
quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J.
Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-a]quinolines.
Certain 1H 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 1H-imidazo[4,5-c] naphthyridine-4-amines, 1H-imidazo [4,5-c] pyridin-4-amines, and 1H-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.
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 an ether and sulfonamide or sulfamide containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail is fra. These compounds share the general structural formula -~- Ri Rn wherein X, RI, R2, 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 and novel intermediates useful in the synthesis of these compounds.
Background of the Invention The first reliable report on the 1H imidazo[4,5-c]quinoline ring system, Backman et al., J. Or~.Chem. 15, 1278-1284 (1950) describes the synthesis of 1-(6-methoxy-8-quinolinyl)-2-methyl-1H imidazo[4,5-c]quinoline for possible use as an antimalarial agent. Subsequently, syntheses of various substituted 1H imidazo[4,5-c]
quinolines were reported. For example, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesized the compound 1-[2-(4-piperidyl)ethyl]-1H imidazo[4,5-c]quinoline as a possible anticonvulsant and cardiovascular agent. Also, Baranov et al., Chem. Abs. 85, (1976), have reported several 2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J.
Heterocyclic Chem. 18, 1537-1540 (1981), have reported certain 2-oxoimidazo[4,5-a]quinolines.
Certain 1H 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 1H-imidazo[4,5-c] naphthyridine-4-amines, 1H-imidazo [4,5-c] pyridin-4-amines, and 1H-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.
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 an ether and sulfonamide or sulfamide containing substituent at the 1-position. The compounds are defined by Formulas (I) and (II), which are defined in more detail is fra. These compounds share the general structural formula -~- Ri Rn wherein X, RI, R2, 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 and novel intermediates useful in the synthesis of these compounds.
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), shown below.
Imidazoquinoline compounds of the invention, which have ether and sulfonamide or sulfamide functionality at the 1-position are represented by Formula (I):
NHS, N~ N
\~ Ra N
X-O- Rl (I) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of -R4-NR3-SOZ-R6-alkyl;
-R4-NR3-SOZ-R6-alkenyl;
-R4-NR3-S02-R6-aryl;
-R4-NR3-SOZ-R6-heteroaryl;
-R4-NR3-SOZ-R6-heterocyclyl;
-R4-NR3-SOZ-R~
-R4-NR3-S02-NRS-R6-alkyl;
-R4-NR3-SOZ-NRS-R6-alkenyl;
-R4-NR3-S02-NRS-R6-aryl;
-R4-NR3-SOz-NRS-R6-heteroaryl;
-R4-NR3-SOZ-NRS-R6-heterocyclyl; and -~-NR3-S02-NHS;
RZ is selected from the group consisting of -hydrogen;
Imidazoquinoline compounds of the invention, which have ether and sulfonamide or sulfamide functionality at the 1-position are represented by Formula (I):
NHS, N~ N
\~ Ra N
X-O- Rl (I) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of -R4-NR3-SOZ-R6-alkyl;
-R4-NR3-SOZ-R6-alkenyl;
-R4-NR3-S02-R6-aryl;
-R4-NR3-SOZ-R6-heteroaryl;
-R4-NR3-SOZ-R6-heterocyclyl;
-R4-NR3-SOZ-R~
-R4-NR3-S02-NRS-R6-alkyl;
-R4-NR3-SOZ-NRS-R6-alkenyl;
-R4-NR3-S02-NRS-R6-aryl;
-R4-NR3-SOz-NRS-R6-heteroaryl;
-R4-NR3-SOZ-NRS-R6-heterocyclyl; and -~-NR3-S02-NHS;
RZ is selected from the group consisting of -hydrogen;
-alkyl;
-alkenyl;
-aryh -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(Rs)2~
-CO-N~Rs)z~
-CO-C1-to alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_2-;
R3 is H, C1_io alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and R4 can join together to form a ring;
each RS is independently H, C1_lo alkyl, or C2_io alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is C~_lo alkyl; or R3 and R~ can join together to form a ring;
nisOto4;and each R present is independently selected from the group consisting of C~_Io alkyl, C~_~o alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear an ether and sulfanomide or sulfamide containing substituent at the 1-position.
Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
NHa N~
\ R2 N
I
(II) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-Ra-NRs-SO2-Rs-alkyl;
-R4-NR3-SOZ-R6-alkenyl;
-R4-NR3-SOZ R6-aryl;
-Ra-~3-S02 R6 heteroaryl;
=R4-NR3-SOZ-R6-heterocyclyl;
W-NRs-SO2-R~
-R4-NR3-SOa-NRS-Rb-alkyl;
-R4-NR3-SO~-NRS-R.6-alkenyl;
-R4-NR3-SOa-NRS-R6-aryl;
-R4-NR3-SOZ-NRS-R6-heteroaryl;
-R4-NR3-S02-NRS-R6-heterocyclyl; and -R4-NR3-SOZ-NH2i RZ is selected from the group consisting of -hydrogen;
-alkyl;
-alkenyl;
-aryh -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(Rs)2~
-CO-N~Rs)z~
-CO-C1-to alkyl;
-CO-O-C1_lo alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_2-;
R3 is H, C1_io alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and R4 can join together to form a ring;
each RS is independently H, C1_lo alkyl, or C2_io alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is C~_lo alkyl; or R3 and R~ can join together to form a ring;
nisOto4;and each R present is independently selected from the group consisting of C~_Io alkyl, C~_~o alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
The invention also includes tetrahydroimidazoquinoline compounds that bear an ether and sulfanomide or sulfamide containing substituent at the 1-position.
Such tetrahydroimidazoquinoline compounds are represented by Formula (II):
NHa N~
\ R2 N
I
(II) wherein: X is -CHRS-, -CHRS-alkyl-, or -CHRS-alkenyl-;
Rl is selected from the group consisting of:
-Ra-NRs-SO2-Rs-alkyl;
-R4-NR3-SOZ-R6-alkenyl;
-R4-NR3-SOZ R6-aryl;
-Ra-~3-S02 R6 heteroaryl;
=R4-NR3-SOZ-R6-heterocyclyl;
W-NRs-SO2-R~
-R4-NR3-SOa-NRS-Rb-alkyl;
-R4-NR3-SO~-NRS-R.6-alkenyl;
-R4-NR3-SOa-NRS-R6-aryl;
-R4-NR3-SOZ-NRS-R6-heteroaryl;
-R4-NR3-S02-NRS-R6-heterocyclyl; and -R4-NR3-SOZ-NH2i RZ 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(Rs)z -CO-N(R5)z;
-CO-C,_lo alkyl;
-CO-O-C1_io alkyl;
-Ns~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_z-;
R3 is H, C~_~o alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and RA can j oin together to form a ring;
each RS is independently H, C1_io alkyl, or C2_lo alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is C~_IO alkyl; or R3 and R~ can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_~o alkyl, C~_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Preparation of the Com ounds Compounds of the invention can be prepared according to Reaction Scheme I
where R, Rl, RZ, X and n are as defined above.
In step (1) of Reaction Scheme I a 2,4-dichloro-3-nitroquinoline of Formula X
is reacted with an amine of Formula Rl-O-X-NHz to provide a 2-chloro-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 and optionally heating. Many quinolines of Formula XI are known or can be prepared using known synthetic methods, see for example, Andre et al., U.S. Patent No.
4,988,815 and references cited therein. Many amines of Formula RI-O-X-NHZ are known;
some are commercially available and others can by prepared using known synthetic methods.
In step (2) of Reaction Scheme I a 2-chloro-3-nitroquinolin-4-amine of Formula XI
is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XII.
Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol, isopropanol or toluene.
In step (3) of Reaction Scheme I a 2-chloroquinoline-3,4-diamine of Formula XII
is reacted with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H
imidazo[4,5-c]quinoline of Formula XIII. Suitable equivalents to carboxylic acid include orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired RZ substituent in a compound of Formula XIII. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where Ra is methyl. 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.
Alternatively, step (3) can be carried out by (i) reacting the diamine of Formula XII
with an acyl halide of Formula R~C(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carned out at ambient temperature. The product can be isolated using conventional methods. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence of a base. Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
In step (4) of Reaction Scheme I a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XIII is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I.
The reaction is carried out by heating (e.g.,125-175°C) a compound of Formula XIII under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme I
CI O+ CI O
CI
N ~ N~O- (~ N ~ N-O- (~ N ~ NHZ
I /
/ CI / IVH NH
n / n / X n /
O O
X XI R~ XII
(3) NHZ CI
R E (4) N ~ N
/ N z I y R2 i / N
Rn / O Rn / X
O
I R' XIII R~
Compounds of the invention containing a sulfonamide group can be prepared according to Reaction Scheme II where R, RZ, R3, R4, X and n are as defined above, BOC
is tent-butoxycarbonyl and Ri 1 is -R6-alkyl, -Rg-aryl, -R6-heteroaryl or -R6-heterocyclyl where R6 is as defined above.
In step (1) of Reaction Scheme II the amino group of an aminoalcohol of Formula XIV is protected with a tent-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tart-butyl Bicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula XIV are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme II a protected aminoalcohol of Formula XV is converted to an iodide of Formula XVI. Iodine is added to a solution of triphenylphosphine and imidazole in dichloromethane; then a solution of a protected aminoalcohol of Formula XV in dichlorornethane is added. The reaction is carried out at ambient temperature.
In step (3) of Reaction Scheme II a 1H imidazo[4,5-a]quinolin-1-yl alcohol of Formula XVII is alkylated with an iodide of Formula XVI to provide a 1H
imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII. The alcohol of Formula XVII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide.
The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature (~I00°C).
Many compounds of Formula XVII are known, see for example, Gerster, U.S. Patent 4,689,338;
others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S.
Patent No. 5,605,899 and Gerster, U.S. Patent No. 5,175,296.
In step (4) of Reaction Scheme II a 1H imi~lazo[4,5-c]quinolin-1-yl ether of Formula XVIII is oxidized to provide a 1H imidazo[4,5-c)quinoline-SN-oxide of Formula XIX using a conventional oxidizing agent capable of forming N-oxides.
Preferably a solution of a compound of Formula XVIII in chloroform is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme II a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XIX is aminated to provide a 1H imidazo[4,5-cJquinolin-4-amine of Formula XX. Step (5) involves (i) reacting a compound of Formula XIX with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula XIX 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 (5) 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 XIX in an inert solvent such as dichloromethane or 1,2-dichloroethane with heating if necessary, adding the aminating agent to the solution, and then slowly adding the acylating agent. Optionally the reaction can be carned out in a sealed pressure vessel at an elevated temperature (85-100°).
In step (6) of Reaction Scheme II the protecting group is removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXI.
Preferably the compound of Formula XX is treated with hydrochloric acidlethanol at ambient temperature or with gentle heating.
In step (7) of Reaction Scheme II a 1H imidazo[4,5-c]quinolin-4-amine ofFormula XXI is converted to a sulfonamide of Formula XXII which is a subgenus of Formula I
using conventional synthetic methods. For example, a compound of Formula XXI
can be reacted with a sulfonyl chloride of Formula R»S(02)CI. The reaction can be carned out by adding a solution of the sulfonyl chloride in a suitable solvent such as dichloromethane or 1-methyl-2-pyrrolidinone to a solution of a compound of Formula XXI at ambient temperature. Alternatively, a compound of Formula hXI can be reacted with a sulfonic anhydride of Formula R11S(02)OS(Oz)RI1. The reaction can be run at ambient temperature in an inert solvent such as dichloromethane in the presence of a base such as pyridine or N,N-diisopropylethylamine. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
H (~) iBOC (2) BOC
HO-R4 N ~ HO-R4 N ~ I-R4 Ni XIV R3 XV R3 XVI Rs N
N W y Ra (3) / N
Rn / X
OH
NHZ ' XVII
N v N (5) ~ w N (4) ~ N
i / y R2 E N / ~~ Rz ~ N y Rz N
/ N
X
Rn / ~ Rn / X Rn .
eBOC ~ ~BOC ~ oBOC
XX R4 N ~ XIX R4 N XVIII R4 N
(6) NHZ NHZ
N N (7) N ~ N
I / N~R2 ~ I / N~Rz Rn / X , _ Rn / X
H ~ O
R4 N R4 N-S-R~~
XXI R3 XXI) R O
Compounds of the invention containing a sulfonamide group can be prepared according to Reaction Scheme III where R, R2, R3, R4, Rl, X and n are as defined above and BOC is tent-butoxycarbonyl.
In step (1) of Reaction Scheme III the amino group of an aminoalcohol of Formula XXIII is protected with a text-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula ~XIII are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme III a protected amino alcohol of Formula XXIV
is converted to a methanesulfonate of Formula XXV. A solution of a compound of Formula XXIV in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine. The reaction can be carned out at a reduced temperature (0°C). .
In step (3a) of Reaction Scheme III a methanesulfonate of Formula XXV is converted to an azide of Formula XXVI. Sodium azide is added to a solution of a compound of Formula XXV in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran. The reaction can be carried out at an elevated.temperature (80 - 100°C).
In step (3b) of Reaction Scheme III a compound of Formula XXVI is alkylated with a halide of Formula Hal-R3 to provide a compound of Formula XXVTI. In compounds where R3 is hydrogen this step is omitted. The compound of Formula XXVI
is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form the anion and then combined with the halide. The reaction can be carried out at ambient temperature.
In step (4) of Reaction Scheme III an azide of Formula XXVI or XXVII is reduced to provide an amine of Formula XXVIII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol or isopropanol.
In step (5) of Reaction Scheme III a 4-chloro-3-nitroquinoline of Formula XXIX
is reacted with an amine of Formula XXVIII to provide a 3-nitroquinoline of Formula XXX.
The reaction can be carried out by adding an amine of Formula XXVIII to a solution of a compound of Formula XXIX in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. Many quinolines of Formula XXIX are known compounds or can be prepared using known synthetic methods, see for example, U.S.
Patent 4,689,338 and references cited therein.
In step (6) of Reaction Scheme III a 3-nitroquinoline of Formula XXX is reduced to provide a 3-aminoquinoline of Formula XXXI. Preferably, the reduction is carned out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
The reaction can conveniently be carned out 6n a Parr apparatus in a suitable solvent such as toluene.
In step (7) of Reaction Scheme III a compound of Formula XXXI is reacted with a carboxylic acid or an equivalent thereof to provide a 1H imidazo[4,5-c]quinoline of Formula XVIII. Suitable equivalents to carboxylic acid include orthoesters, and l,l-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired RZ substituent in a compound of Formula XVIII. For example, triethyl orthoformate will provide a compound where RZ is hydrogen and triethyl orthovalerate will provide a compound where RZ 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 catalytic amount of pyridine hydrochloride can be included.
Alternatively, step (7) can be carried out by (i) reacting a compound of Formula XXXI with an acyl halide of Formula RzC(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of a compound of Formula XXXI in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carried out at ambient temperature or at a reduced temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence of a base. Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
Steps (8), (9), (10) and (11) are carried out in the same manner as steps (4), (5), (6) and (7) of Reaction Scheme II.
.
Reaction Scheme III
HO-X-O-R4 NHz ( ) HO-X-O-R4-~ BOC
XXIII XXIV ~~) BOC O
N3 X-O-R4 ~~ ~ -S-O-X-O-R4 ~~BOC
( H
XXVI ~(4) O XXV
N3 X_O-R4 N\ ~ HzN-X-O-R4 N\ BOC
XXVII R3 XXVIII Rs O+
N ~ N,O-I /
(5) Rn ~CI
XXIX
O
tt+
(7) N ~ NHz (g) N ~ N~O_ Rn I / NH ~ I / NH
O Rn / X
~BOC ~ ~ BOC O
...... ~ ~I R4 N ~ R4 NiBOC
Rs Rs Ra (8) O_ + NHz NHz ~N ~ N~ R (9~ N ~ N (10) N ~ N
/ N 2 I / ~ Rz ~ I ~~ Rz t N / N
n /
R O BOC R / ~ Rn / o ~ ~BOC
XIX R4 \ ~ R4 N , R
R3 R3 XX! 4 R
(11) N
~~-R
z N
i R
O
R4 N-S-R~~
NHz N
I /
n /
Compounds of the invention containing a sulfamide group can be prepared according to Reaction Scheme IV where R, RZ, R3, R4, R5, Rll, X and n are as defined above.
In step (1) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin- 4-amine of Formula XXI is reacted with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula XXXII. The reaction can be carried out by adding a solution of sulfuryl chloride in~dichloromethane to a solution of a compound of Formula XXI in dichloromethane in the presence of 1 equivalent of 4-(dimethylamino)pyridine. The reaction is preferably carried out at a reduced temperature (-78°C).
In step (2) of Reaction Scheme IV an amine of Formula HNRSRI l is reacted with the sulfamoyl chloride of Formula XXXII to provide a sulfamide of Formula XXXIII
which is a subgenus of Formula I. The reaction can be carned out by adding a solution containing 2 equivalents of the amine and 2 equivalents of triethylamine in dichloromethane to the reaction mixture from step (1). The addition is preferably carried out at a reduced temperature (-78°C). After the addition is complete the reaction mixture can be allowed to warm to ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
N ~ N S02CI2 ~ N NNRS
\ Rz ~ N
N (~) ~ / N RZ (2) R2 i Rn / X Rn / X
O O
~ [ ~ O ~R5 R4 ~ R4 N-S-CI -N-S-N
XXI R3 XXXII R3 O XXXIII R p ~Rn Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R3, R4, Rl ~, X and n are as defined above.
In step (1) of Reaction Scheme V a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXI is reduced to provide a 6,7,8,9-tetrahydro-1H irnidazo[4,5-c]quinolin-4-amine of Formula XXXIV. Preferably the reduction is tamed out by suspending or dissolving a compound of Formula XXI in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then hydrogenating. The reaction can be conveniently carried out in a Parr apparatus.
Step (2) is tamed out in the same manner as step (7) of Reaction Scheme II to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinoliri-4-amine of Formula XXXV
which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
NHz NHz NHz N N N
N~ R2 ( 1~ N / N~ Rz (~ N / N~ Rz R" / X R". X R . X
i O O.. " Q
_ I'H I
XXI ' R4 N~ R4 . N R4 N-5~~~
XXXIV XXXV I
Compounds of the invention containing a sulfarnide group can be prepared according to Reaction Scheme VI where R, Rz, R3, R4, RS, Rl~, X and n are as defined above.
In step (1) of Reaction Scheme VI a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXIV is reacted with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula ~:XXVI. The reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of a compound of Formula ~~XXIV in dichloromethane in the presence of 1 equivalent of 4-(dimethylamino)pyridine.
The reaction is preferably carried out at a reduced temperature (-78°C).
In step (2) of Reaction Scheme VI an amine of Formula HNRSRI ~ is reacted with the sulfamoyl chloride of Formula XXXVI to provide a sulfamide of Formula XX~~VII
which is a subgenus of Formula II. 'The reaction can be carried out by adding a solution containing 2 equivalents of the amine and 2 equivalents of triethylamine in dichloroinethane to the reaction mixture from step (1). The addition is preferably earned out at a reduced temperature (-7~°C). After the addition is complete the reaction mixture can be allowed to warm to ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VI
NHZ NHZ NHZ
N ~ N SOZCIZ ~ N HNRSR~~ N
I \~ RZ ~ N ~~ R ~ N \ ~ R
N (1) ~ N 2 (2) I / N~ 2 i Rn . p R° ~ R X
O O
R ~ R4 N-S-CI R N-~-N~RS
XXXIV R3 ~I R O ~Il 4 ~ O ~R»
The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I) and (II). These intermediate compounds have the structural Formula (III).
N
N
I
X-O-R~
(III) wherein X is -CHRs-, -CHRs-alkyl-, or-CHRs-alkenyl-;
Ri is selected from the group consisting of -R4-NR3-SOa-R6-alkyl;
-R4-NR3-SOz-R6-alkenyl;
-R4-NR3-SOa-R6-aryl;
-R4-NR3-SOZ-R~heteroaryl;
-Rø-NR3-SOZ Rb heterocyclyl;
-R4-NR3-S02-R~;
-R4-NR3-SOZ-NRs-Rg-alkyl;
-R4-NR3-S02-NRs-R.6-alkenyl;
-R4-NR3-S02-NRs-R6-aryl;
-R4-NR3-SOa-NRs-R6-heteroaryl;
-R4-NR3-SOz-NRs-Rs-heterocyclyl;and 1 S -R4-NR3-SO2-NH2;
RZ 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(Rs)a -CO-N(Rs)z;
-CO-C~_a alkyl;
-CO-O-C1_,o alkyl;
-N3~ ' -aril;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_2-;
R3 is H, C1-to alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and R4 can join to form a ring;
each RS is independently H, C1_io alkyl, or CZ_~o alkenyl;
R6 is a bond, or is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
R~ is C~_~o alkyl; or R3 and R~ can join together to form a bond;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_~o alkyl, CI_IO alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
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 adarnantyl.
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 haloaIkyl groups are chloromethyl, trifluoromethyl, and the like.
The term "aryl" as used herein includes earbocyclic 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, quinoxalinyl, benzoimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinazolinyl, purinyl, and so on. .
"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, I~ and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, 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, heteroarylaxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryIoxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, arylcarbonyloxy, arylcarbonylthio, arylcarbonylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonyIamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylarnino, 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 R~ groups include -R4-NR3-SO~,-R6-alkyl, -R4-NR3-SOZ-R6-aryl, and -R4-NR3-SOa-Rb-heteroaryl wherein the alkyl, aryl and heteroaryl groups can be unsubstituted or substituted and R4 is preferably ethylene or n-butylene.
Thiophene and quinoline are preferred heteroaryl groups Preferably no R substituents are present (i.e., n is 0). Preferred Ra 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. For substituted groups such as substituted alkyl or substituted aryl groups, preferred substituents include halogen, nitrite, methoxy, trifluoromethyl, and trifluorornethoxy. 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, polymorphs, 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 Comuositions 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 Garner.
The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antiturnor 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 wg/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 forinulations, 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-a (IFN-a) and/or tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-a, TNF-a, 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-a 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-y is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-S
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 xesponse, 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.
1 S 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-oc and/or TNF-a, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunornodulating 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; Herpes Simplex Virus Type I and Type II; molluscum contagiosum;
variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus;
influenza;
and pare-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia;
human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
candida, 2S 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 myelorna, 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-a, TNF-a, 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 pg/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.
In the examples below some of the compounds were purified using semi preparative HPLC. A Waters Fraction Lynx automated purification system was used. The semi-prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
Column: Phenomenex Luna C18(2), 10 x 50 mm, 5 micron particle size, 100A
pore; flow rate: 25 mL/min.; gradient elution from 5-65% B in 4 min., then 65 to 95 % B
in 0.1 min, then hold at 95% B for 0.4 min., where A=0.05 % trifluoroacetic acid/water and B=0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass-selective triggering.
Example 1 N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide N
N ~~0~
N
O
H
N
' ,O
O:S
Part A
A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180 mL of tetrahydrofuran (THF), under NZ, was cooled to 0°C and treated with 140 mL of 2N NaOH
solution. A solution of di-tert-butyl Bicarbonate (60.2 g, 0.276 mol) in 180 mL of THF
was then added dropwise over 1 h to the rapidly stirred solution. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 18 h.
The THF
was then removed under reduced pressure and the remaining aqueous slurry was brought to pH 3 by addition of 150 mL of 1M HZS04 solution. This was then extracted with ethyl acetate (300 mL, 100 mL) and the combined organic layers were washed with Ha0 (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give tent-butyl 2-(2-hydroxyethoxy)ethylcarbarnate as a colorless oil (47.1 g).
Part B
A rapidly stirred solution of test-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CHZC12 was cooled to 0°C under N2 and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 rnL saturated NaHC03 solution and the organic layer was separated. The organic phase was then washed with H20 (3 X 500 mL) and brine. The organic portion was dried over Na2S04 and concentrated to give 2-{2-[(tent-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Part C
A stirred solution of 2-(2-[(tart-butoxycarbonyl)amino]ethoxy]ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was ' treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90°C under NZ. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold HzO. The reaction mixture was then extracted with Et20 (3 X 300 mL). The combined organic extracts were washed with H20 (4 X 100 mL) and Brine (2 X 100 mL).
The organic portion was dried over MgS04 and concentrated to give 52.0 g of tart-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Part D
A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then ftltered through a Celite pad and concentrated to give 35.3 g of crude tart-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Part E
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL
of anhydrous CHzCl2, under NZ, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with HZO (2 X 300 mL) and brine (300 mL). The organic portion was dried over Na2S04 and concentrated to give a bright yellow solid.
Recrystallization from ethyl acetate/hexanes gave 43.6 g of tent-butyl 2- f 2-[(3-nitroquinolin-yl)amino]ethoxy}ethylcarbarnate as bright yellow crystals.
Part F
A solution of tent-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellow syrup.
Part G
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous CH2Cla was cooled to 0°C and treated with triethylarnine (4.18 rnL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mrnol) was then added dropwise over 5 min.
°The reaction was then warmed to room temperature and stirring was continued for 1 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added.
The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 inL of EtzO. The mixture was then filtered and the ftltrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL of hot MeOH and treated with activated charcoal. fine .hot solution was filtered and concentrated to give 11.1 g of tart-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow syrup. .
Part H
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After stirring 30 min, the reaction mixture was washed with 1 % NaaC03 solution (2 X 75 mL) and brine.
The organic layer was then dried over Na2S04 and concentrated to give 10.6 g of tart-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy,~ethylcarbamate as an orange foam that was used without further purification.
Part I
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy]ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60°C and treated with 10 mL of concentrated NH40H
solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHC13. The reaction mixture was then washed with H20, 1 % Na2C03 solution (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Part J
Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 1.5 h, the reaction mixture was cooled and filtered to give a gummy solid. The solid was washed EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown solid. The free base was made by dissolving the hydrochloride salt in SO mL of H20 and treating with 10%
NaOH solution. The aqueous suspension was then concentrated to dryness arid the residue was treated with CHC13. The resulting salts were removed by filtration and the filtrate was concentrated to give 3.82 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 330 (M + H)+;
'H NMR (300 MHz, DMSO-d6) 8 8.10 (d, J = 8.1 Hz, 1 H); 7.66 (d, J = 8.2 Hz, 1 H);
7.40 (m, 1 H); 7.25 (m, 1 H); 6.88 (br s, 2 H); 4.78 (t, J = 5.4 Hz, 2 H);
3.89 (t, J = 4.8 Hz, 2 H); 3.84 (t, J = 6.9 Hz, 2 H); 3 .54 (t, J = 5.4 Hz, 2 H); 3.31 (s, 3 H);
3.23 (t, J = 6.6 Hz, 2 H); 2.88 (t, J= 5.3 Hz, 2 H).
Part K
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0°C under N2. To the stirred solution were added Et3N (0.64 mL, 4.56 mmol) and methanesulfonyl chloride (176 p,L, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2 h. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL). The organic layer was separated and washed with .
Ha0 (3 X 25 mL) and brine, dried over Na2S04 and concentrated under reduced pressure to give a tan foam. The foam was dissolved in a minimum amount of MeOH and Et2O
was added and a solid percipitated from the solution. The off white solid was isolated by filtration and dried to yield 385 mg of N (2-~2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide. m.p. 114.0-117.0 °C ;
MS 408 (M + H)+; .
'H NMR (300 MHz, DMSO-d~) 8 8.05 (d, J = 7.6 Hz, 1 H); 7.61 (d, J = 8.5 Hz, 1 H);
7.42 (t, J = 8.5 Hz, 1 H); 7.24 (t, J = 7.0 Hz, 1 H); 6.99 (t, J = 4.4 Hz, 1 H); 6.51 (s, 2 H);4.76 (t, J = 5.0 Hz, 2 H); 3.88-3.81 (m, 4 H); 3.4.1 (t, J = 5.4 Hz, 2 H);
3.31 (s, 3 H);
3.23 (t, J = 6.9 Hz, 2 H); 3.04-2.99 (m, 2 H); 2,81 (s, 3 H);
'3C (75 MHz, DMSO-d6) 151.9, 145.0, 132.7, 126.7, 126.6, 121.5, 120.5, 115.1, 70.5, 70.2, 69.3, 58.5, 45.4, 42.4, 27.6.
Anal. Calcd for C~gH2sN504S~0.23 H20: %C, 52.52; %H, 6.23; %N, 17.01. Found:
%C, 52.55; %H, 6.17; %N, 16.66 Example 2 N (2- f2-[4-amino-2-(2-methoxyethyl);6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide NHZ
~ N
N ~~0~
N
O
H
N
~ ~O
O:S
Part A
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (10.0'g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtOa (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO~ was added and hydrogenation was continued for an additional 3 d.
The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of H20 then made basic (pH~l l) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5 X 75 mL) and the combined organic layers were dried over NaZS04 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,s-c]quinolin-4-amine as a tan solid.
MS 334. (M + H)+;
'.H NMR (300 MHz, CDCl3) 8 s.19 (s, 2 H); 4.49 (t, J = s.4 Hz, 2 H); 3.84 (t, J = 6.6 Hz, s 2 H); 3.71 (t, J = s.4 Hz, 2 H), 3..3 6 (t, J = 5.2 Hz, 2 H); 3.28 (s, 3 H);
3.1 s (t, J = 6.6 Hz, 2 H); 2.95 (m, 2 H); 2.82 (m, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.84 (m, 4 H), 1.47 (br s, 2 H).
Part B
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0°C under N2. To the stirred solution were added Et3N (0.84 mL, 6.00 mmol) and methanesulfonyl chloride (232 pL, 3.00 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and 1 s washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et20 and a few drops of MeOH. The resulting white powder was isolated by filtration and further purified by column chromatography (Si02, 3% MeOH/CHCl3 saturated with aqueous NH40H) to give 389 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,s-c]quinolin-1 yl]ethoxy} ethyl)methanesulfonarnide as a white powder. m.p. 151.0-1 s3.0 °C;
MS 412 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 7.00 (t, J = 5.4 Hz, 1 H); s.68 (s, 2 H); 4.44 (t, J = 5.1 Hz,2H);3.77(t,J=6.8Hz,2H);3.68(t,J=s.OHz,2H);3.39(t,J=s.8Hz,2H);
3.28 (s, 3 H); 3.11-2.99 (m, 4 H); 2.92 (m, 2 H), 2.82 (s, 3 H); 2.6s (m, 2 H); 1.75 (m, 4 2s H);
'3C (7s MHz, DMSO-d6) 1s1.3, 149.3, 146.3, 138.4, 124.9, 10S.6, 70.6, 70.s, 70.1, 44.s, 42.4, 32.7, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for CI$H29N504S: %C, s2.s4; %H, 7.10; %N, 17.02. Found: %C, s2.47;
%H, 7.22; %N, 16.83.
Example 3 N (2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide N HZ
N
N ~~0~
N
O
N
':O
O:S
Part A
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3X) under N2. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirnng overnight, the reaction was quenched with 300 mL of saturated NaHC03 solution. The reaction mixture was then treated with 200 mL of H20 and 1 L of EtaO. The organic phase was separated and washed with HzO and brine. The organic portion was then dried over MgS04 and concentrated under reduced pressure to give 41.9 g of tent-butyl 2-(2-azidoethoxy)ethyl(methyl)carbarnate as a yellow liquid.
Part B
A solution of tent-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under HZ (3 I~glcrn2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude tent-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Part C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tart-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H20 (2 X 300 mL) and brine (300 rnL).
The organic portion was dried over NaaSOa and concentrated to give a brown oil. Column chromatography (Si02, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tart-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino)ethoxy}ethyl)carbamate as a yellow solid.
Part D
A solution of tart-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.8 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy} ethyl(methyl)carbamate as an orange syrup which was carried on without further purification.
Part E
A solution of tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(rnethyl)carbamate (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH2C12 was cooled to 0°C and treated with triethylamine (2.40 mL, 17.2 mmol).
Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 3 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added.
The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. This was dissolved in 300 mL of CH~Cl2 and washed with H20 and brine.
The organic portion was dried over NaaS04 and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a yellow syrup.
Part F
A solution of test-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy} ethyl(rnethyl)carbamate~ (7.20 g, 16.8 mmol) in 200 mL of CH2C12 was treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over NaaS04 and concentrated to give 7.05 g of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate as a light brown solid.
Part G
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80°C and treated with 5 mL of concentrated solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CHZCl2. The reaction mixture was then washed with H20, 1 % Na2C03 solution (3X) and brine. The organic portion was dried over NaaS04 and concentrated to give 6.50 g of tert-butyl 2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil Part H
Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate (6.50 g, 14.7 mmol) was dissolved in 100 mL
of EtOH
and treated with 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 6 h, the reaction mixture was cooled and filtered to give a gummy solid.
The solid was washed with EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown powder. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHCl3 (5 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 3.93 g of 2-(2-methoxyethyl)-I-{2-[2-(methylamino)ethoxy]ethyl)-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 344 (M + H)+;
IH NMR (300 MHz, DMSO-d6) 8 8.07 (d, J = 7.7 Hz,~ 1 H); 7.62 (dd, J = 1.0, 8.3 Hz, 1 H); 7.42 (ddd, J = 1.0, 7.1, 8.2 Hz, 1 H); 7.22 (ddd, J = 1.1, 7.1, 8.2 Hz, 1 H); 6.49 (s, 2 H); 4.75 (t, J = 5.1 Hz, 2 H); 3.83 (t, J = 6.8 Hz, 4 H); 3.35 (t, J = 5.6 Hz, 2 H); 3.30 (s, 3 H); 3.21 (t, J = 6.9 Hz, 2 H); 2.45 (t, J = 5.6 Hz, 2 H); 2.12 (s, 3 H).
Part I
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CHzCl2 and cooled to 0°C under NZ. To the stirred solution were added Et3N (0.81 mL, 5.81 mmol) and methanesulfonyl chloride (226 ~L, 2.92 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CHZCl2 (30 mL). The organic layer was separated and washed with H20 and brine, dried over NaaS04 and concentrated under reduced pressure. Crystallization of the residue from EtOAc and CHZCl2 gave 756 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methylmethanesulfonamide as tan crystals. m.p. 145.0-146.5 °C;
MS 422 (M + H)+; ' 'H NMR (300 MHz, DMSO-d6) S 8.06 (d, J = 7.8 Hz, 1 H); 7.61 (dd, J = 0.9, 8.3 Hz, 1 H); 7.42 (t, J = 7.2 Hz, 1 H); 7.23 (ddd, J = 1Ø, 7.0, 8.0 Hz, 1 H); 6.50 (s, 2 H); 4.77 (t, J
=5.0Hz,2H);3.87(t,J=5.0Hz,2H),3.83(t,J=6.8Hz,2H);3.48(t,J=5.5Hz,2 H); 3.30 (s, 3 H); 3.22 (t, J = 6.8 Hz, 2 H); 3.13 (t, J = 5.5 Hz, 2 H); 2.77 (s, 3 H); 2.63 (s, 3 H);
t3C NMR (75 MHz, DMSO-d6) 8 153.9, 153.8, 147.0, 134.6, 128.6, 128.5, 123.4, 122.5, 117.0, 72.4, 71.2, 60.4, 51.1, 47.3, 37.3, 37.2, 29.6.
Anal. Calcd for C19Hz7N504S: %C, 54.14; %H, 6.46; %N, 16.61. Found: %C, 53.92;
%H, 6.32; %N, 16.47.
Example 4 N (2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide N ~ N~O~
N.
O
N
O;S:O
Part A
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtOa (0.5 g). The reaction mixture was shaken under Ha (3 I~g/cmz). After 4 d, an additional 0.5 g of PtOa was added and hydrogenation was continued for an additional 3 d. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL of HZO and extracted with 50 mL of CHCl3. The organic portion was removed and discarded. The aqueous portion was then made basic (pH~l2) by addition of 10%
NaOH
solution. This was then extracted with CHC13 (6 X 50 mL) and the combined organic layers were dried over Na2S04 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal.
The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with EtzO to give 3.19 g of 2-(2-methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as an off white powder.
MS 348 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 4.84 (s, 2 H); 4.48 (t, J = 5.7 Hz, 2 H); 3.84 (t, J
= 6.7 Hz, 2 H); 3.70 (t, J = 5.7 Hz, 2 H); 3.46 (t, J = 5.1 Hz, 2 H); 3.3 6 (s, 3 H);
3.14 (t, J = 6.7 Hz, 2 H); 2.96 (m, 2 H); 2.83 (m, 2 H); 2.65 (t, J= S.1 Hz, 2 H); 2.36 (s, 3 H);
1.85 (m, 4 H).
Part B
(2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CHZCIa and cooled to 0°C under Nz. To the stiired solution were added Et3N
(0.60 mL, 4.32 mmol) and methanesulfonyl chloride (167 ~L, 2.16 mmol),and the reaction was allowed to warm to room temperature over 3 h. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CH2Cl2 (30 mL).
The organic layer was separated and washed with HZO and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (Si02, 3-5%
MeOH/CHC13 saturated with aqueous NH40H) gave the product as a colorless glass. The material was then concentrated with iso-propyl alcohol to give a syrup which solidified upon standing in the freezer. The solid was dried under vacuum to give 437 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as off white crystals.
m.p. 115.3-117.8 °C ;
MS 426 (M + H)+;
H NMR (300 MHz, DMSO-d6) 8 5.65 (s, 2 H); 4.44 (t, J = 5.2 Hz, 2 H); 3.76 (t, J = 6.9 Hz,2H),3.70(t,J=5.3Hz,2H);3.47(t,J=5.5Hz,2H);3.27(s,3H);3.15(t,J=5.5 Hz, 2 H); 3.08 (t, J = 6.9 Hz, 2 H); 2.93 (m, 2 H) ; 2.78 (s, 3 H); 2.65 (s, 3 H); 2.64 (m, 2 H); 1.74 (m, 4 H);
i3C NMR (75 MHz, DMSO-d6) 8 151..2, 149.3, 146.3, 138.5, 124.9, 105.6, 70.6, 70.5, 69.2, 58.4, 49.2, 44.5, 35.4, 35.2, 32.7, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for Cl9Ha~N504S~0.40 C3H80: %C, 53.97; a%H, 7.67; %N, 15.58.
Found:
°f°C, 53.71; %H, 7.48; %N, 15.77.
Example 5 2-Butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}
1H imidazo[4,5-c]quinolin-4-amine.
S, a Under a nitrogen atmosphere, chloropropylsulfonyl chloride (0.05 ml, 0.46.mmo1) was added dropwise to a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H
imidazo[4,5-c]quinolin-4-amine (0.12 g, 0.37 mrnol) and triethylamine (0.065 ml, 0.46 mmol) in dichloromethane (5 rnl). The reaction was stirred for 20 hours followed by removal of the solvent iya vacuo. The resulting off white solid was dissolved in N,N-dimethylformamide (5mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087m1, 0.58 mmol) was added.
The reaction was stirred for 18 hours under an atmosphere of nitrogen and then quenched with water and extracted with dichloromethane (2X). The organic fractions were combined, . washed with water followed by brine, dried (NaZSO4), filtered, and concentrated ifa vacuo to provide an off white solid. Recrystallization from ethyl acetate yielded 0.068 goof 2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl)-1H imidazo[4,5-c]quinolin-4-amine as off white crystals, m.p. 152-154°C.
1H-NMR (300MHz, DMSO-d6): 8 8.06 (d, J = B.IHz, 1H), 7.62 (d, J = 7.9Hz, 1H), 7.42 (t, J = 7.6Hz, 1H), 7.23 (t, J = 7.5Hz, 1H), 6.52 (s, 2H), 4.73 (t, J =
4.99Hz, 2H), 3..86 (t, J
= S.OHz, 2H), 3.46 (t, J = 5.3Hz, 2H), 3.07 (t, J = 7.66Hz, 2H), 2.97-2.87 (m, 6H), 2.04 (quintet, J = 6.8Hz, 2H), 1.81 (quintet, J = 7.6Hz, 2H), 1.46 (sextet, J =
7.4Hz, 2H), 0.96 (t, J = 7.3Hz, 3H);
i3C-NMR (75MHz, DMSO-d6): 8 154.6, 152.9, 145.1, 133.0, 126.8, 126.6, 121.6, 120.x, 115.3, 69:2, 69.1, 47.0, 45.5, 45.0, 43.7, 29.3, 26.2, 21.9, 18.1, 13.7;
Anal calcd for CZ~Ha9N503S*0.25H20: %C, 57.84; %H, 6.82; %N, 16.06; %S, 7.35.
Found: %C, 57.90; %H, 6.79; %N, 15.92; %S, 7.55.
Examples 6 - 26 Part A
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 50 mL of CH2Clz and washed with saturated NaHC03, and brine. The organic portion was dried over NaaS04 and concetrated to give a green oil.
The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal.
The hot solution was filtered and concentrated to give 4.12 g of tart-butyl 2-[2-(2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Part B
A solution of tent-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CH2Ch, was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirnng for S
h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with HZO and brine then dried over NaaS04 and concentrated to give 3.68 g of tart-butyl 2-[2-(2-butyl-5-oxido-1H
imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(2-butyl-5-oxido-1H imidazo[4,5-a]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH4OH solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHZCIz. The reaction mixture was then washed with HZO, 1 % NaaC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 3.68 g of teYt-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Ter~t-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-a]quinolin-1-yI)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of Ha0 and reating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCIa (3 X 50 mL). The combined organic layers were dried over NaaS04 and concentrated to give 1-[2-(2-aminoethoxy)ethyl]-2-butyl-IH imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 328 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 7.95 (d, J= 8.3 Hz, 1 H); 7.83 (d, J= 8.4 Hz, I H);
7.50 (m, I H); 7.30 (m, 1 H); 5.41 (s, 2 H); 4.69 (t, J = 5.6 Hz, 2 H); 3.93 (t, J
= 5.6 Hz, 2 H);
3.39 (t, J = 5. I Hz, 2 H); 2.97 (t, J = 7.9 Hz, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.89 (m, 2 H);
~ 1.52 (m, 2 H); 1.26 (br s, 2 H); 1.01 (t, J = 7.3 Hz, 3 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) was added to a test tube containing a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine (25 mg) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 18 - 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The products were verified by accurate mass and'H NMR. The table below shows the structure of the free base and the observed accurate mass (M +
H).
Example Structure of Free Base Accurate Mass Number (obs.) NHZ
I \ N
Y\
N
420.2077 ~N
O' O~C~
NHz CH3 N \ N
\
N
7 / ~ 434.2234 N ,CHs '~\\
O~SO CH3 N \ N
I \
N
435.2196 N CHa ~N
p SO 'CH3 Example Accurate Mass Number _ Structure of Free Base - (0bs.) N \ N
N
448.2387 O
N
_\
N \ N
N
/ ~ 468.2075 H ~ \
O~S\ i O
NHz CH3 ~ N
N
11 0 474.1625 N
~ ,O
O
a Example Structure of Free Base Accurate Number Mass (obs.) NHz CH3 .
N
12 ~ 482.2214 N
~ ,O
O' \ N
/ N
O ' 13 N 486.1967 o s~o F
\ N
/
O
~
14 N ,0 493.2009 o-o \
\N
Example . Structure of Free Base Accurate Mass Number (obs.) I\
N
15 N o 493.2025 o%
N
\
N
16 ~~ ,0 498.2195 o%
roc I \ N
Y\
N
17 504.1861 ,o o, F / \
F
Example Accurate Mass Number Structure of Free Base (obs.) N
/ N
O
18 _ 518.2210 N
~ ,O
O' NHZ
N
19 , N 518.2243 ~ ,o o=
i ~ N
/ N
O
20 N 519.2158 o s~o .
Example Structure of Free Base Accurate Number Mass (obs.) NHZ
\
/ N
21 N ,0 536.1917 o-F
F
F
/
N
/
O
22 ~ -~ 544.2384 NH2 ~CHa ~ N
/
O
23 ~
,o , 546.1852 o=
o,~;o cH, Example Structure of Free Base Accurate Mass Number (obs.) NHZ ~CNa i ~ N
/
O
''~~N
24 0 ~ ,0 552.1874 F"O
F~F
' ' i.
~~ ,o o%
25 ~ ~ 615.2848 ,N
FiC N~Q i NHz CH3 Chiral N
O
26 ~N H CH3 542.2779 0' O ,°,,H
Examples 27 - 39 Part A
Using the general method of Part A of Examples 6 - 26, 4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tart-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tart-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.
Part B
Iodine (7.97 g) was added in three portions to a solution of imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1 mmol) in dichloromethane (350 mL).
After minutes a solution of the material from Part A in dichloromethane (70 mL) was added.
The reaction mixture was stirred at ambient temperature overnight. More iodine (7.97 g) was added and the reaction was stirred at ambient, temperature for 1 hr. The reaction mixture was washed with saturated sodium thiosulfate (2~) and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide an oily residue.
The residue was purified by column chromatography (silica gel eluting with 20%
ethyl acetate in hexanes) to provide 15.52 g of tart-butyl 4-(2-iodoethyl)piperidine-carboxylate as a pale yellow oil.
Part C
Under a nitrogen atmosphere, 2-(1H imidazo[4,5-c]quinolin-1-yl)butan-1-of (6.5 g, 26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g of 60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture was allowed to stir for 45 minutes by which time gas evolution had ceased. Tart-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was allowed to stir at ambient temperature for 2.5 hrs; then it was heated to 100°C and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then it was extracted with ethyl acetate (2X). The ethyl acetate extracts were washed with water (2X) and then with brine, combined, dried over sodium sulfate, ftltered and then concentrated under reduced pressure to provide a brown oil. The.oil was purified by column chromatography (silica gel eluting sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g of tent-butyl 4-{2-[2-(1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate.
Part D
Using the~general method of Examples 6 - 26 Part H, the material from Part C
was oxidized to provide tart-butyl 4-{2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as an oil.
Part E
Ammonium hydroxide solution (20 mL) was added to a solution of the material from Part D in dichloromethane (20 mL). A solution of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over a period of 5 minutes. The resulting biphasic reaction mixture was allowed to stir overnight. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a brown glass. This material was purifted by column chromatography (silica gel eluting first with 50% ethyl acetate in hexanes and then with ethyl acetate) to provide 1.0 g of tent-butyl 4-{2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as pale yellow glassy foam.
Part F
Under a nitrogen atmosphere, tart-butyl 4-{2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction .with dichloromethane (3~, the organic fractions were combined, washed with brine, dried (Na2SO4), ftltered, and the majority of the solvent was removed ifa vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
1H-NMR (300MHz, DMSO-d6) : 8 8.34 (bs, 1H), 8.19 (d, J = 8.49, 1H), 7.61 (dd;
J = 8.31, 1.13, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, SH), 0.95-0.7 (m, SH);
13C-NMR (75MHz, DMSO-d6): 8 152.8, 145.8, 140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9;
MS (CI) m/e 368.2459 (368.2450 calcd for CZIH3oNs0).
Part G
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) was added to a test tube containing a solution of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H
imidazo[4,5-c]quinolin-4-amine (25 mg) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purred by semi-preparative HPLC using the method described above. The products were verified by accurate mass and 1H
NMR. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Number Structure of Free Base Mass (obs.) NHZ
/ N
27 ~ 474 CH3 .
N~ O CHa II~
O
CHa NHZ
N
/ \
~N
/
CH3 .
N,10 iCHa -IS
N
O CHa NHz N, / \\
N
29 / ~ 488.2647 O
N, O~CH3 I/
O
Example Structure of Free Base Accurate Mass Number (obs.) NHS
/ N
30 ~ 508.2349 O
N~S
NHz / \
\
~N
31 ~ 514.1924 N~S S
NHZ
I \ N
N
O
32 ~H3 526.2241 N~S w O
F
umber Structure of Free Base ~ AccuObs.Mass NHZ
/ N
/ ~O
33 cH3 0 533.2315 N~S
O
\N
NHZ
N
N
~O
34 ~H 538.2477 N ~S~ CH
__ \~~~ O, s NHZ
N \ N
N
35 O 544.2166 O ~ ~ F
F
52, Example Structure of Free Base Accurate Mass Number (obs.) NHZ
\ \~ .
O
36 CH, 0 559.2493 N ~s N~
NHZ
N
3~ ~H ~ 586.2166 (1 ) II
N ~S ~
O ~ IS CHs O
NHZ
N
O
38 ~H 592.2144 N, ~~ _ F"F
~~(\S
p ~ ~ O F
Example Structure of Free Base Accurate Mass Number (obs.) NH=
N
I~ y 39 ~ ~° ~ 655.3173 N o ~ S N N ~ S N CH3 Examples 40 -49 Part A
A solution of teat-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy)ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 2$.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 200 mL of CHZCh and washed with saturated NaHC03, and brine. The organic portion was dried over Na2S04 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light yellow syrup.
Part B
A solution of tent-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CH2Cla was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirnng overnight, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S04 and concentrated to give 4.60 g of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH40H solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 3 h.
The reaction mixture was then cooled and treated with 100 mL of CHZCh. The reaction mixture was then washed~with HZO, 1% NazC03 solution (3X) and brine. The organic ' portion was dried over NaZS04 and concentrated to give 4.56 g of tent-butyl 2-[2-(4-amino-lH~imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Text-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56 g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (100 mL) and filtered to give the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of H20 and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCl2 (5 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to give 1.35 g of 1-[2-(2-aminoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 272 (M + H)+;
IH NMR (300 MHz, CDCl3) 8 7.98 (d, J = 8.2 Hz, 1 H); 7.88 (s, 1 H); 7.84 (d, J
= 8.4 Hz, 1 H); 7.54 (m, 1 H); 7.32 (m, 1~ H); 5.43 (s, 2 H); 4.74 (t, J = 5.2 Hz, 2 H);
3.97 (t, J = 5.2 Hz, 2 H); 3.42 (t, J = 5.1 Hz, 2 H); 2.78 (t, .I = 5.1 Hz, 2 H); 1.10 (br s, 2 H).
Part E
The compo~xnds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
1-[2-(2-Arninoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (20 mg) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test tube and then heated and sonicated to provide a solution. The sulfonyl chloride (1.1 eq.) was then added to the test tube. The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The products were verified by accurate mass and 1H NMR. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Mass Number Structure of Free Base obs.
NHZ
N
\ ' / N
O
40 392.1781 o~-NHZ
N ~ N
\
/ N
O
41 N 412.1468 o s~o ~ , NHZ
N
N
O
42 ~ 430.1348 ,o o-.
F
Number Structure of Free Base , Accuroabs,Mass NH=
/
O
43 N ,0 442.1572 o-HsC
NHZ
Ni \ N
O
44 448.1259 ,o o~
F
F
NHZ
N~ \ N
/ N
45 ~ r~ 462.1571 ,S o o Numbelr Structure of Free Base Accu obs,Mass NHZ
i j \~
N
I/
46 0 ~ ,0 480.1274 \
~F
'\F
F
NHZ
~ N
I /
O
47 ° ~ '° 488.1722 NHz N~ \ NJ
I /
°
48 ~ ~0 490.1224 o, ~~o Number Structure of Free Base Accu obs.Mass N H=
N~ \ N
/
O
49 0 ~ ,c 496.1230 F"O
F~F
Example SO
S . ' N-[10-(4-amino-2-methyl-1H imidazo[4,S-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide O
O
NH
O=S=O
~N~.
Part A
4,7-Dioxadecane-1,10-diamine (32.6 g, O.18S mole) in acetonitrile (100 mL) was chilled in an ice bath. To this was slowly added dropwise dansyl chloride (S
g, O.O18S
mole) dissolved in acetonitrile (60 mL) over a 20 min. period. Stirring in an ice bath was continued for 1.5 hr. The reaction mixture was poured into water (about 300 mL) and extracted with dichloromethane (2x 100 mL). The combined extracts were washed with water and dried to give an oil. The oil was purified by column chromatography (silica gel eluting with acetonitrile containing increasing amounts of ethanol) to provide 4.6 g of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide as a viscous oil.
'H-NMR (500 MHz, CDCl3) 1.65 (2H, quin), 1.75 (2H, quin), 2.80 (2H, t, 6.59 Hz), 2.87 (6H, s), 3.03 (2H, t, 6.1 Hz), 3.43 (2H, m), 3.47 (2H, m), 3.52 (2H, m), 3.59 (2H, t, 6.22 Hz), 7.18 (1H, d, J = 7.08 Hz)), 7.56 - 7.49 (overlapping multiplets, 2H), 8.24 (dd, 1H, J =
1.2, 7.3 Hz), 8.31 (d, 1H), 8.53 (d, 1H).
Part B
A solution of 2,4-dichloro-3-nitroquinoline (2.71 g, 0.0115 mole) in toluene (100 rnL) was cooled to 0 - 5°C in an ice bath. Triethylamine (1.5 g) was added in one portion.
A solution of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide (4.6 g, 0.01159 mole) in toluene (60 mL) was added dropwise while maintaining the temperature below 10°C. The reaction was stirred at 2 - 5°C for 4 hrs and at a room temperature of 21°C overnight (18 hours). Thin layer chromatography (dichloromethane:
ethanol) showed a trace of the amine starting material, but was mostly a bright yellow spot at the solvent front assumed to be the addition product. The toluene was removed by rotary evaporation to provide a viscous oil. The oil was purified by column chromatography (silica gel, dichloromethane/ethanol) to provide 2.4 g of N-[
10-(2-chloro-3-nitro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide.
1H-NMR (CDCl3) 1.62 (2H, quin), 2.05 (2H, quin), 2.87 (6H, s), 3.03 (2H, m), 3.47 (4H, m), 3.55 (2H, m), 3.65 (2H, m), 3.73 (2H, t, 5.37 Hz), 5.75 (1H, t, 4.39 Hz,NH), 6.91 (1H, t, 4.76 Hz, NH), 7.15 (1H, d, 7.32 Hz), 7.30 (1H, m), 7.50 (2H, overlapping t), 7.62 (1H, m), 7.82 (1H, d, 7.44 Hz), 7.88 (1H, d, 8.54 Hz), 8.22 (1H, m ), 8.29 (lH,d, 8.42), 8.52 (1'H, d, 8.06 Hz).
Part C
Material from Part B (2.2 g, 0.00357 mole) was dissolved in ethanol (150 mL).
Catalyst (about 1 g of 5% Pt/C) was added and the mixture was hydrogenated using a Parr apparatus for 30 minutes. Thin layer chromatography (ethyl acetate: hexane 1:1) showed that the reaction was complete. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to provide a sticky solid which was shown by NMR to be crude N-[ 10-(3-amino-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide. It was used without further purification.
1H-NMR (500 MHz, CDCl3) 1.60 (2H, quin), 1.90 (2H, quin), 2.87 (6H, s, NMe2), 3.00 (2H, br s), 3.45 (4H, m), 3.53 (2H, m), 3.62 (2H, t, 5.62 Hz), 3.71 (4.30 (2H, br s, NHZ ), 5.85 (1H, br s, NH), 7.11 (1H, d, J = 7.32 Hz), 7.35 (1H, m), 7.44 - 7.48 (3H, m), 7.82 (1H, d), 8.18 (1H, dd, J= 1.1, 7.2 Hz), 8.30 (1H, d, 8.66 Hz), 8.49 (1H, d, 8.54 Hz).
'3C-NMR (125 MHz) 28.48 (CH2), 30.08 (CHZ), 41.93 (CHZ), 45.27 (CH3), 45.28 (CHZ), 69.75 (CH2), 69.83 (CHZ), 70.08 (CHZ), 70.38 (CHa), 114.99 (CH), 118.84 (CH), 120.84 (CH), 123.02 (CH), 123.50 (C) , 125.67 (CH), 126.22 (CH), 128.01 (CH), 128.57 (C) 128.67 (CH), 129.22 (CH), 129.52 (C ), 129.74 (C ), 130.09 (CH), 134.72 (C), 137.17 (C), 141.82 (C), 142.03 (C), 151.75 (C).
Part D
A portion (1 g, 1.708 mmol) of the material from Part C was dissolved in tetrahydrofuran (30 mL) and then cooled in an ice-bath to about 5°C.
Freshly distilled acetyl chloride (0. 13 g, 1.78 mmol) was added with stirring. The yellow solid which immediately precipitated was isolated by filtration and washed with tetrahydrofuran.
Standing in air gave an oily solid (possibly hygroscopic). FAB (fast atom bombardment) mass spectrum suggested that this was the desired N-[10-(3-acetamido-2-chloro-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide hydrochloride together with an undetermined amount of starting material. This solid was carned on to Part E without additional puriEcation.
Part E
The crude salt from Part D was dissolved in dry methanol containing 7% ammonia (20 mL). The solution was heated at 150°C in a bomb for 6 1/2 hrs. The reaction mixture was cooled and then concentrated. The residue was combined with acetone.
Undissolved material was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (silica gel; ethanol/dichloromethane) to provide 0.45 g of a brown oil.
6'1 1H-NMR (400 MHz, CDCl3) 1.53 (2H, t, 7.08 Hz), 2.05 (2H, m), 2.45 (3H, s), 2.70 (6H, s), 2.90 (2H, t, 5.98 Hz), 3.30 (8H, br, m), 4.40 (2H, t, 6.59 Hz), 5.75 (2H, br s NHZ), 6.65 (1H, br s NHSOZ),7.00 (1H, d, 7.54 Hz), 7.14 (1H, t, 8.06 Hz), 7.30 (3H, m), 7.64 (1H, d, 8.30 Hz), 7.88 (1H, d, 8.18 Hz), 8.06 (1H, d, 7.33 Hz), 8.24 (1H, d, 8.54 Hz), 8.36 (1H, d, 8.55 Hz).
This material was then purified by high performance liquid chromatography using a Bondapak C18 12.5 nm reverse phase column (available from Waters, Milford, MA) eluting with a composite gradient of acetonitrile in water to provide the desired product.
CYTOI~INE 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 (a) (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.
Incubation The solution of test compound is added to the first well containing RPMI
complete and serial 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.
The final concentration of PBMC suspension is 1.5-2 X 106 cellslmL. 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 rpm 0200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at-30 to -70°C until analysis. The samples are analyzed for interferon-a and for tumor necrosis factor-a by ELISA.
Interferon (a) and Tumor Necrosis Factor (a) Analysis by ELISA
Interferon-a 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-a 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;
generally the highest concentration tested was 10 or 30 ~M.
Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 3 0.01 0.12 6 0.001 1 7 0.01 1 8 0.01 1 9 0.1 1 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 12 0.1 10 14 ~ 1 10 18 * 10 19 * 10 22 0.0001 10 23 0.0001 10 24 0.0001 10 0.0001 26 0.01 10 27 0.1 1 28 ' 0.1 1 37 0.1 1 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~.1VI) Number Interferon Tumor Necrosis Factor 38 * *
4$ * *
47 * , *
48 * 10 49 * 10 50 1.11 *
-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(Rs)z -CO-N(R5)z;
-CO-C,_lo alkyl;
-CO-O-C1_io alkyl;
-Ns~
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_z-;
R3 is H, C~_~o alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and RA can j oin together to form a ring;
each RS is independently H, C1_io alkyl, or C2_lo alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R~ is C~_IO alkyl; or R3 and R~ can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_~o alkyl, C~_lo alkoxy, hydroxy, halogen, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
Preparation of the Com ounds Compounds of the invention can be prepared according to Reaction Scheme I
where R, Rl, RZ, X and n are as defined above.
In step (1) of Reaction Scheme I a 2,4-dichloro-3-nitroquinoline of Formula X
is reacted with an amine of Formula Rl-O-X-NHz to provide a 2-chloro-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 and optionally heating. Many quinolines of Formula XI are known or can be prepared using known synthetic methods, see for example, Andre et al., U.S. Patent No.
4,988,815 and references cited therein. Many amines of Formula RI-O-X-NHZ are known;
some are commercially available and others can by prepared using known synthetic methods.
In step (2) of Reaction Scheme I a 2-chloro-3-nitroquinolin-4-amine of Formula XI
is reduced to provide a 2-chloroquinoline-3,4-diamine of Formula XII.
Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon. The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as ethanol, isopropanol or toluene.
In step (3) of Reaction Scheme I a 2-chloroquinoline-3,4-diamine of Formula XII
is reacted with a carboxylic acid or an equivalent thereof to provide a 4-chloro-1H
imidazo[4,5-c]quinoline of Formula XIII. Suitable equivalents to carboxylic acid include orthoesters and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired RZ substituent in a compound of Formula XIII. For example, triethyl orthoformate will provide a compound where R2 is hydrogen and triethyl orthoacetate will provide a compound where Ra is methyl. 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.
Alternatively, step (3) can be carried out by (i) reacting the diamine of Formula XII
with an acyl halide of Formula R~C(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carned out at ambient temperature. The product can be isolated using conventional methods. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence of a base. Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
In step (4) of Reaction Scheme I a 4-chloro-1H imidazo[4,5-c]quinoline of Formula XIII is aminated to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula I.
The reaction is carried out by heating (e.g.,125-175°C) a compound of Formula XIII under pressure in a sealed reactor in the presence of a solution of ammonia in an alkanol. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme I
CI O+ CI O
CI
N ~ N~O- (~ N ~ N-O- (~ N ~ NHZ
I /
/ CI / IVH NH
n / n / X n /
O O
X XI R~ XII
(3) NHZ CI
R E (4) N ~ N
/ N z I y R2 i / N
Rn / O Rn / X
O
I R' XIII R~
Compounds of the invention containing a sulfonamide group can be prepared according to Reaction Scheme II where R, RZ, R3, R4, X and n are as defined above, BOC
is tent-butoxycarbonyl and Ri 1 is -R6-alkyl, -Rg-aryl, -R6-heteroaryl or -R6-heterocyclyl where R6 is as defined above.
In step (1) of Reaction Scheme II the amino group of an aminoalcohol of Formula XIV is protected with a tent-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tart-butyl Bicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula XIV are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme II a protected aminoalcohol of Formula XV is converted to an iodide of Formula XVI. Iodine is added to a solution of triphenylphosphine and imidazole in dichloromethane; then a solution of a protected aminoalcohol of Formula XV in dichlorornethane is added. The reaction is carried out at ambient temperature.
In step (3) of Reaction Scheme II a 1H imidazo[4,5-a]quinolin-1-yl alcohol of Formula XVII is alkylated with an iodide of Formula XVI to provide a 1H
imidazo[4,5-c]quinolin-1-yl ether of Formula XVIII. The alcohol of Formula XVII is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form an alkoxide.
The iodide is added to the alkoxide solution at ambient temperature. After the addition is complete the reaction is stirred at an elevated temperature (~I00°C).
Many compounds of Formula XVII are known, see for example, Gerster, U.S. Patent 4,689,338;
others can readily be prepared using known synthetic routes, see for example, Gerster et al., U.S.
Patent No. 5,605,899 and Gerster, U.S. Patent No. 5,175,296.
In step (4) of Reaction Scheme II a 1H imi~lazo[4,5-c]quinolin-1-yl ether of Formula XVIII is oxidized to provide a 1H imidazo[4,5-c)quinoline-SN-oxide of Formula XIX using a conventional oxidizing agent capable of forming N-oxides.
Preferably a solution of a compound of Formula XVIII in chloroform is oxidized using 3-chloroperoxybenzoic acid at ambient temperature.
In step (5) of Reaction Scheme II a 1H imidazo[4,5-c]quinoline-SN-oxide of Formula XIX is aminated to provide a 1H imidazo[4,5-cJquinolin-4-amine of Formula XX. Step (5) involves (i) reacting a compound of Formula XIX with an acylating agent and then (ii) reacting the product with an aminating agent. Part (i) of step (5) involves reacting an N-oxide of Formula XIX 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 (5) 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 XIX in an inert solvent such as dichloromethane or 1,2-dichloroethane with heating if necessary, adding the aminating agent to the solution, and then slowly adding the acylating agent. Optionally the reaction can be carned out in a sealed pressure vessel at an elevated temperature (85-100°).
In step (6) of Reaction Scheme II the protecting group is removed by hydrolysis under acidic conditions to provide a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXI.
Preferably the compound of Formula XX is treated with hydrochloric acidlethanol at ambient temperature or with gentle heating.
In step (7) of Reaction Scheme II a 1H imidazo[4,5-c]quinolin-4-amine ofFormula XXI is converted to a sulfonamide of Formula XXII which is a subgenus of Formula I
using conventional synthetic methods. For example, a compound of Formula XXI
can be reacted with a sulfonyl chloride of Formula R»S(02)CI. The reaction can be carned out by adding a solution of the sulfonyl chloride in a suitable solvent such as dichloromethane or 1-methyl-2-pyrrolidinone to a solution of a compound of Formula XXI at ambient temperature. Alternatively, a compound of Formula hXI can be reacted with a sulfonic anhydride of Formula R11S(02)OS(Oz)RI1. The reaction can be run at ambient temperature in an inert solvent such as dichloromethane in the presence of a base such as pyridine or N,N-diisopropylethylamine. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme II
H (~) iBOC (2) BOC
HO-R4 N ~ HO-R4 N ~ I-R4 Ni XIV R3 XV R3 XVI Rs N
N W y Ra (3) / N
Rn / X
OH
NHZ ' XVII
N v N (5) ~ w N (4) ~ N
i / y R2 E N / ~~ Rz ~ N y Rz N
/ N
X
Rn / ~ Rn / X Rn .
eBOC ~ ~BOC ~ oBOC
XX R4 N ~ XIX R4 N XVIII R4 N
(6) NHZ NHZ
N N (7) N ~ N
I / N~R2 ~ I / N~Rz Rn / X , _ Rn / X
H ~ O
R4 N R4 N-S-R~~
XXI R3 XXI) R O
Compounds of the invention containing a sulfonamide group can be prepared according to Reaction Scheme III where R, R2, R3, R4, Rl, X and n are as defined above and BOC is tent-butoxycarbonyl.
In step (1) of Reaction Scheme III the amino group of an aminoalcohol of Formula XXIII is protected with a text-butoxycarbonyl group. A solution of the aminoalcohol in tetrahydrofuran is treated with di-tert-butyl dicarbonate in the presence of a base such as sodium hydroxide. Many aminoalcohols of Formula ~XIII are commercially available;
others can be prepared using known synthetic methods.
In step (2) of Reaction Scheme III a protected amino alcohol of Formula XXIV
is converted to a methanesulfonate of Formula XXV. A solution of a compound of Formula XXIV in a suitable solvent such as dichloromethane is treated with methanesulfonyl chloride in the presence of a base such as triethylamine. The reaction can be carned out at a reduced temperature (0°C). .
In step (3a) of Reaction Scheme III a methanesulfonate of Formula XXV is converted to an azide of Formula XXVI. Sodium azide is added to a solution of a compound of Formula XXV in a suitable solvent such as N,N-dimethylformamide or tetrahydrofuran. The reaction can be carried out at an elevated.temperature (80 - 100°C).
In step (3b) of Reaction Scheme III a compound of Formula XXVI is alkylated with a halide of Formula Hal-R3 to provide a compound of Formula XXVTI. In compounds where R3 is hydrogen this step is omitted. The compound of Formula XXVI
is reacted with sodium hydride in a suitable solvent such as N,N-dimethylformamide to form the anion and then combined with the halide. The reaction can be carried out at ambient temperature.
In step (4) of Reaction Scheme III an azide of Formula XXVI or XXVII is reduced to provide an amine of Formula XXVIII. Preferably, the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as palladium on carbon.
The reaction can conveniently be carried out on a Parr apparatus in a suitable solvent such as methanol or isopropanol.
In step (5) of Reaction Scheme III a 4-chloro-3-nitroquinoline of Formula XXIX
is reacted with an amine of Formula XXVIII to provide a 3-nitroquinoline of Formula XXX.
The reaction can be carried out by adding an amine of Formula XXVIII to a solution of a compound of Formula XXIX in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine. Many quinolines of Formula XXIX are known compounds or can be prepared using known synthetic methods, see for example, U.S.
Patent 4,689,338 and references cited therein.
In step (6) of Reaction Scheme III a 3-nitroquinoline of Formula XXX is reduced to provide a 3-aminoquinoline of Formula XXXI. Preferably, the reduction is carned out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon.
The reaction can conveniently be carned out 6n a Parr apparatus in a suitable solvent such as toluene.
In step (7) of Reaction Scheme III a compound of Formula XXXI is reacted with a carboxylic acid or an equivalent thereof to provide a 1H imidazo[4,5-c]quinoline of Formula XVIII. Suitable equivalents to carboxylic acid include orthoesters, and l,l-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent is selected such that it will provide the desired RZ substituent in a compound of Formula XVIII. For example, triethyl orthoformate will provide a compound where RZ is hydrogen and triethyl orthovalerate will provide a compound where RZ 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 catalytic amount of pyridine hydrochloride can be included.
Alternatively, step (7) can be carried out by (i) reacting a compound of Formula XXXI with an acyl halide of Formula RzC(O)Cl and then (ii) cyclizing. In part (i) the acyl halide is added to a solution of a compound of Formula XXXI in an inert solvent such as acetonitrile or dichloromethane. The reaction can be carried out at ambient temperature or at a reduced temperature. In part (ii) the product of part (i) is heated in an alcoholic solvent in the presence of a base. Preferably the product of part (i) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
Steps (8), (9), (10) and (11) are carried out in the same manner as steps (4), (5), (6) and (7) of Reaction Scheme II.
.
Reaction Scheme III
HO-X-O-R4 NHz ( ) HO-X-O-R4-~ BOC
XXIII XXIV ~~) BOC O
N3 X-O-R4 ~~ ~ -S-O-X-O-R4 ~~BOC
( H
XXVI ~(4) O XXV
N3 X_O-R4 N\ ~ HzN-X-O-R4 N\ BOC
XXVII R3 XXVIII Rs O+
N ~ N,O-I /
(5) Rn ~CI
XXIX
O
tt+
(7) N ~ NHz (g) N ~ N~O_ Rn I / NH ~ I / NH
O Rn / X
~BOC ~ ~ BOC O
...... ~ ~I R4 N ~ R4 NiBOC
Rs Rs Ra (8) O_ + NHz NHz ~N ~ N~ R (9~ N ~ N (10) N ~ N
/ N 2 I / ~ Rz ~ I ~~ Rz t N / N
n /
R O BOC R / ~ Rn / o ~ ~BOC
XIX R4 \ ~ R4 N , R
R3 R3 XX! 4 R
(11) N
~~-R
z N
i R
O
R4 N-S-R~~
NHz N
I /
n /
Compounds of the invention containing a sulfamide group can be prepared according to Reaction Scheme IV where R, RZ, R3, R4, R5, Rll, X and n are as defined above.
In step (1) of Reaction Scheme IV a 1H imidazo[4,5-c]quinolin- 4-amine of Formula XXI is reacted with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula XXXII. The reaction can be carried out by adding a solution of sulfuryl chloride in~dichloromethane to a solution of a compound of Formula XXI in dichloromethane in the presence of 1 equivalent of 4-(dimethylamino)pyridine. The reaction is preferably carried out at a reduced temperature (-78°C).
In step (2) of Reaction Scheme IV an amine of Formula HNRSRI l is reacted with the sulfamoyl chloride of Formula XXXII to provide a sulfamide of Formula XXXIII
which is a subgenus of Formula I. The reaction can be carned out by adding a solution containing 2 equivalents of the amine and 2 equivalents of triethylamine in dichloromethane to the reaction mixture from step (1). The addition is preferably carried out at a reduced temperature (-78°C). After the addition is complete the reaction mixture can be allowed to warm to ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme IV
N ~ N S02CI2 ~ N NNRS
\ Rz ~ N
N (~) ~ / N RZ (2) R2 i Rn / X Rn / X
O O
~ [ ~ O ~R5 R4 ~ R4 N-S-CI -N-S-N
XXI R3 XXXII R3 O XXXIII R p ~Rn Compounds of the invention can be prepared according to Reaction Scheme V
where R, R2, R3, R4, Rl ~, X and n are as defined above.
In step (1) of Reaction Scheme V a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXI is reduced to provide a 6,7,8,9-tetrahydro-1H irnidazo[4,5-c]quinolin-4-amine of Formula XXXIV. Preferably the reduction is tamed out by suspending or dissolving a compound of Formula XXI in trifluoroacetic acid, adding a catalytic amount of platinum (IV) oxide, and then hydrogenating. The reaction can be conveniently carried out in a Parr apparatus.
Step (2) is tamed out in the same manner as step (7) of Reaction Scheme II to provide a 6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinoliri-4-amine of Formula XXXV
which is a subgenus of Formula II. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme V
NHz NHz NHz N N N
N~ R2 ( 1~ N / N~ Rz (~ N / N~ Rz R" / X R". X R . X
i O O.. " Q
_ I'H I
XXI ' R4 N~ R4 . N R4 N-5~~~
XXXIV XXXV I
Compounds of the invention containing a sulfarnide group can be prepared according to Reaction Scheme VI where R, Rz, R3, R4, RS, Rl~, X and n are as defined above.
In step (1) of Reaction Scheme VI a 1H imidazo[4,5-c]quinolin-4-amine of Formula XXXIV is reacted with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula ~:XXVI. The reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of a compound of Formula ~~XXIV in dichloromethane in the presence of 1 equivalent of 4-(dimethylamino)pyridine.
The reaction is preferably carried out at a reduced temperature (-78°C).
In step (2) of Reaction Scheme VI an amine of Formula HNRSRI ~ is reacted with the sulfamoyl chloride of Formula XXXVI to provide a sulfamide of Formula XX~~VII
which is a subgenus of Formula II. 'The reaction can be carried out by adding a solution containing 2 equivalents of the amine and 2 equivalents of triethylamine in dichloroinethane to the reaction mixture from step (1). The addition is preferably earned out at a reduced temperature (-7~°C). After the addition is complete the reaction mixture can be allowed to warm to ambient temperature. The product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
Reaction Scheme VI
NHZ NHZ NHZ
N ~ N SOZCIZ ~ N HNRSR~~ N
I \~ RZ ~ N ~~ R ~ N \ ~ R
N (1) ~ N 2 (2) I / N~ 2 i Rn . p R° ~ R X
O O
R ~ R4 N-S-CI R N-~-N~RS
XXXIV R3 ~I R O ~Il 4 ~ O ~R»
The invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formulas (I) and (II). These intermediate compounds have the structural Formula (III).
N
N
I
X-O-R~
(III) wherein X is -CHRs-, -CHRs-alkyl-, or-CHRs-alkenyl-;
Ri is selected from the group consisting of -R4-NR3-SOa-R6-alkyl;
-R4-NR3-SOz-R6-alkenyl;
-R4-NR3-SOa-R6-aryl;
-R4-NR3-SOZ-R~heteroaryl;
-Rø-NR3-SOZ Rb heterocyclyl;
-R4-NR3-S02-R~;
-R4-NR3-SOZ-NRs-Rg-alkyl;
-R4-NR3-S02-NRs-R.6-alkenyl;
-R4-NR3-S02-NRs-R6-aryl;
-R4-NR3-SOa-NRs-R6-heteroaryl;
-R4-NR3-SOz-NRs-Rs-heterocyclyl;and 1 S -R4-NR3-SO2-NH2;
RZ 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(Rs)a -CO-N(Rs)z;
-CO-C~_a alkyl;
-CO-O-C1_,o alkyl;
-N3~ ' -aril;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)o_2-;
R3 is H, C1-to alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -0- groups; or R3 and R4 can join to form a ring;
each RS is independently H, C1_io alkyl, or CZ_~o alkenyl;
R6 is a bond, or is alkyl or alkenyl, which may be interrupted by one or more -O-groups;
R~ is C~_~o alkyl; or R3 and R~ can join together to form a bond;
n is 0 to 4; and each R present is independently selected from the group consisting of CI_~o alkyl, CI_IO alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
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 adarnantyl.
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 haloaIkyl groups are chloromethyl, trifluoromethyl, and the like.
The term "aryl" as used herein includes earbocyclic 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, quinoxalinyl, benzoimidazolyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, quinazolinyl, purinyl, and so on. .
"Heterocyclyl" includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, I~ and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups. Exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl, imidazolidinyl, 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, heteroarylaxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbonyl, aryloxycarbonyl, heteroaryIoxycarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, alkanoyloxy, alkanoylthio, arylcarbonyloxy, arylcarbonylthio, arylcarbonylamino, alkylaminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryldiazinyl, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkylcarbonylamino, alkenylcarbonylamino, arylcarbonylamino, arylalkylcarbonylamino, heteroarylcarbonylamino, heteroarylalkycarbonylamino, alkylsulfonylamino, alkenylsulfonyIamino, arylsulfonylamino, arylalkylsulfonylamino, heteroarylsulfonylamino, heteroarylalkylsulfonylamino, alkylaminocarbonylamino, alkenylaminocarbonylamino, arylaminocarbonylarnino, 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 R~ groups include -R4-NR3-SO~,-R6-alkyl, -R4-NR3-SOZ-R6-aryl, and -R4-NR3-SOa-Rb-heteroaryl wherein the alkyl, aryl and heteroaryl groups can be unsubstituted or substituted and R4 is preferably ethylene or n-butylene.
Thiophene and quinoline are preferred heteroaryl groups Preferably no R substituents are present (i.e., n is 0). Preferred Ra 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. For substituted groups such as substituted alkyl or substituted aryl groups, preferred substituents include halogen, nitrite, methoxy, trifluoromethyl, and trifluorornethoxy. 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, polymorphs, 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 Comuositions 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 Garner.
The term "a therapeutically effective amount" means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antiturnor 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 wg/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 forinulations, 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-a (IFN-a) and/or tumor necrosis factor-a (TNF-a) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN-a, TNF-a, 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-a 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-y is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-S
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 xesponse, 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.
1 S 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-oc and/or TNF-a, the compounds are particularly useful in the treatment of viral diseases and tumors. This immunornodulating 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; Herpes Simplex Virus Type I and Type II; molluscum contagiosum;
variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus;
influenza;
and pare-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia;
human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
candida, 2S 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 myelorna, 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-a, TNF-a, 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 pg/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.
In the examples below some of the compounds were purified using semi preparative HPLC. A Waters Fraction Lynx automated purification system was used. The semi-prep HPLC fractions were analyzed using a Micromass LC-TOFMS and the appropriate fractions were combined and centrifuge evaporated to provide the trifluoroacetate salt of the desired compound.
Column: Phenomenex Luna C18(2), 10 x 50 mm, 5 micron particle size, 100A
pore; flow rate: 25 mL/min.; gradient elution from 5-65% B in 4 min., then 65 to 95 % B
in 0.1 min, then hold at 95% B for 0.4 min., where A=0.05 % trifluoroacetic acid/water and B=0.05% trifluoroacetic acid/acetonitrile; fraction collection by mass-selective triggering.
Example 1 N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide N
N ~~0~
N
O
H
N
' ,O
O:S
Part A
A solution of 2-(2-aminoethoxy)ethanol (29.0 g, 0.276 mol) in 180 mL of tetrahydrofuran (THF), under NZ, was cooled to 0°C and treated with 140 mL of 2N NaOH
solution. A solution of di-tert-butyl Bicarbonate (60.2 g, 0.276 mol) in 180 mL of THF
was then added dropwise over 1 h to the rapidly stirred solution. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 18 h.
The THF
was then removed under reduced pressure and the remaining aqueous slurry was brought to pH 3 by addition of 150 mL of 1M HZS04 solution. This was then extracted with ethyl acetate (300 mL, 100 mL) and the combined organic layers were washed with Ha0 (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give tent-butyl 2-(2-hydroxyethoxy)ethylcarbarnate as a colorless oil (47.1 g).
Part B
A rapidly stirred solution of test-butyl 2-(2-hydroxyethoxy)ethylcarbamate (47.1 g, 0.230 mol) in 1 L of anhydrous CHZC12 was cooled to 0°C under N2 and treated with triethylamine (48.0 mL, 0.345 mol). Methanesulfonyl chloride (19.6 mL, 0.253 mol) was then added dropwise over 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred an additional 22 h. The reaction was quenched by addition of 500 rnL saturated NaHC03 solution and the organic layer was separated. The organic phase was then washed with H20 (3 X 500 mL) and brine. The organic portion was dried over Na2S04 and concentrated to give 2-{2-[(tent-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate as a brown oil (63.5 g).
Part C
A stirred solution of 2-(2-[(tart-butoxycarbonyl)amino]ethoxy]ethyl methanesulfonate (63.5 g, 0.224 mol) in 400 mL of N,N-dimethylformamide (DMF) was ' treated with NaN3 (16.1 g, 0.247 mol) and the reaction mixture was heated to 90°C under NZ. After 5 h, the solution was cooled to room temperature and treated with 500 mL of cold HzO. The reaction mixture was then extracted with Et20 (3 X 300 mL). The combined organic extracts were washed with H20 (4 X 100 mL) and Brine (2 X 100 mL).
The organic portion was dried over MgS04 and concentrated to give 52.0 g of tart-butyl 2-(2-azidoethoxy)ethylcarbamate as a light brown oil.
Part D
A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (47.0 g, 0.204 mol) in MeOH was treated with 4 g of 10% Pd on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then ftltered through a Celite pad and concentrated to give 35.3 g of crude tart-butyl 2-(2-aminoethoxy)ethylcarbamate as a colorless liquid that was used without further purification.
Part E
A stirred solution of 4-chloro-3-nitroquinoline (31.4 g, 0.151 mol) in 500 mL
of anhydrous CHzCl2, under NZ, was treated with triethylamine (43 mL, 0.308 mol) and tert-butyl 2-(2-aminoethoxy)ethylcarbamate (0.151 mol). After stirring overnight, the reaction mixture was washed with HZO (2 X 300 mL) and brine (300 mL). The organic portion was dried over Na2S04 and concentrated to give a bright yellow solid.
Recrystallization from ethyl acetate/hexanes gave 43.6 g of tent-butyl 2- f 2-[(3-nitroquinolin-yl)amino]ethoxy}ethylcarbarnate as bright yellow crystals.
Part F
A solution of tent-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellow syrup.
Part G
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous CH2Cla was cooled to 0°C and treated with triethylarnine (4.18 rnL, 30.0 mmol).
Methoxypropionyl chloride (3.30 mL, 30.3 mrnol) was then added dropwise over 5 min.
°The reaction was then warmed to room temperature and stirring was continued for 1 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added.
The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 inL of EtzO. The mixture was then filtered and the ftltrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL of hot MeOH and treated with activated charcoal. fine .hot solution was filtered and concentrated to give 11.1 g of tart-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow syrup. .
Part H
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.22 g, 24.7 mmol) in 250 mL of CHCl3 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 9.12 g, 40.8 mmol). After stirring 30 min, the reaction mixture was washed with 1 % NaaC03 solution (2 X 75 mL) and brine.
The organic layer was then dried over Na2S04 and concentrated to give 10.6 g of tart-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy,~ethylcarbamate as an orange foam that was used without further purification.
Part I
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy]ethylcarbamate (10.6 g, 24.6 mmol) in 100 mL of 1,2-dichloroethane was heated to 60°C and treated with 10 mL of concentrated NH40H
solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was treated with an additional 1 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHC13. The reaction mixture was then washed with H20, 1 % Na2C03 solution (2X) and brine. The organic portion was dried over NaZS04 and concentrated to give 10.6 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a brown foam.
Part J
Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (10.6 g, 24.6 mmol) was treated with 75 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 1.5 h, the reaction mixture was cooled and filtered to give a gummy solid. The solid was washed EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown solid. The free base was made by dissolving the hydrochloride salt in SO mL of H20 and treating with 10%
NaOH solution. The aqueous suspension was then concentrated to dryness arid the residue was treated with CHC13. The resulting salts were removed by filtration and the filtrate was concentrated to give 3.82 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 330 (M + H)+;
'H NMR (300 MHz, DMSO-d6) 8 8.10 (d, J = 8.1 Hz, 1 H); 7.66 (d, J = 8.2 Hz, 1 H);
7.40 (m, 1 H); 7.25 (m, 1 H); 6.88 (br s, 2 H); 4.78 (t, J = 5.4 Hz, 2 H);
3.89 (t, J = 4.8 Hz, 2 H); 3.84 (t, J = 6.9 Hz, 2 H); 3 .54 (t, J = 5.4 Hz, 2 H); 3.31 (s, 3 H);
3.23 (t, J = 6.6 Hz, 2 H); 2.88 (t, J= 5.3 Hz, 2 H).
Part K
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0°C under N2. To the stirred solution were added Et3N (0.64 mL, 4.56 mmol) and methanesulfonyl chloride (176 p,L, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2 h. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL). The organic layer was separated and washed with .
Ha0 (3 X 25 mL) and brine, dried over Na2S04 and concentrated under reduced pressure to give a tan foam. The foam was dissolved in a minimum amount of MeOH and Et2O
was added and a solid percipitated from the solution. The off white solid was isolated by filtration and dried to yield 385 mg of N (2-~2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide. m.p. 114.0-117.0 °C ;
MS 408 (M + H)+; .
'H NMR (300 MHz, DMSO-d~) 8 8.05 (d, J = 7.6 Hz, 1 H); 7.61 (d, J = 8.5 Hz, 1 H);
7.42 (t, J = 8.5 Hz, 1 H); 7.24 (t, J = 7.0 Hz, 1 H); 6.99 (t, J = 4.4 Hz, 1 H); 6.51 (s, 2 H);4.76 (t, J = 5.0 Hz, 2 H); 3.88-3.81 (m, 4 H); 3.4.1 (t, J = 5.4 Hz, 2 H);
3.31 (s, 3 H);
3.23 (t, J = 6.9 Hz, 2 H); 3.04-2.99 (m, 2 H); 2,81 (s, 3 H);
'3C (75 MHz, DMSO-d6) 151.9, 145.0, 132.7, 126.7, 126.6, 121.5, 120.5, 115.1, 70.5, 70.2, 69.3, 58.5, 45.4, 42.4, 27.6.
Anal. Calcd for C~gH2sN504S~0.23 H20: %C, 52.52; %H, 6.23; %N, 17.01. Found:
%C, 52.55; %H, 6.17; %N, 16.66 Example 2 N (2- f2-[4-amino-2-(2-methoxyethyl);6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide NHZ
~ N
N ~~0~
N
O
H
N
~ ~O
O:S
Part A
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-4-amine (10.0'g, 27.3 mmol) was dissolved in 50 mL of trifluoroacetic acid and treated with PtOa (1.0 g). The reaction mixture was shaken under H2 (3 Kg/cm2). After 4 d, an additional 0.5 g of PtO~ was added and hydrogenation was continued for an additional 3 d.
The reaction was then filtered through Celite and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 200 mL of H20 then made basic (pH~l l) by addition of 10% NaOH solution. This was then extracted with CHCl3 (5 X 75 mL) and the combined organic layers were dried over NaZS04 and concentrated to give 5.17 g of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,s-c]quinolin-4-amine as a tan solid.
MS 334. (M + H)+;
'.H NMR (300 MHz, CDCl3) 8 s.19 (s, 2 H); 4.49 (t, J = s.4 Hz, 2 H); 3.84 (t, J = 6.6 Hz, s 2 H); 3.71 (t, J = s.4 Hz, 2 H), 3..3 6 (t, J = 5.2 Hz, 2 H); 3.28 (s, 3 H);
3.1 s (t, J = 6.6 Hz, 2 H); 2.95 (m, 2 H); 2.82 (m, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.84 (m, 4 H), 1.47 (br s, 2 H).
Part B
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CHZC12 and cooled to 0°C under N2. To the stirred solution were added Et3N (0.84 mL, 6.00 mmol) and methanesulfonyl chloride (232 pL, 3.00 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and 1 s washed with H20 and brine, dried over Na2S04 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et20 and a few drops of MeOH. The resulting white powder was isolated by filtration and further purified by column chromatography (Si02, 3% MeOH/CHCl3 saturated with aqueous NH40H) to give 389 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,s-c]quinolin-1 yl]ethoxy} ethyl)methanesulfonarnide as a white powder. m.p. 151.0-1 s3.0 °C;
MS 412 (M + H)+;
1H NMR (300 MHz, DMSO-d6) 8 7.00 (t, J = 5.4 Hz, 1 H); s.68 (s, 2 H); 4.44 (t, J = 5.1 Hz,2H);3.77(t,J=6.8Hz,2H);3.68(t,J=s.OHz,2H);3.39(t,J=s.8Hz,2H);
3.28 (s, 3 H); 3.11-2.99 (m, 4 H); 2.92 (m, 2 H), 2.82 (s, 3 H); 2.6s (m, 2 H); 1.75 (m, 4 2s H);
'3C (7s MHz, DMSO-d6) 1s1.3, 149.3, 146.3, 138.4, 124.9, 10S.6, 70.6, 70.s, 70.1, 44.s, 42.4, 32.7, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for CI$H29N504S: %C, s2.s4; %H, 7.10; %N, 17.02. Found: %C, s2.47;
%H, 7.22; %N, 16.83.
Example 3 N (2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide N HZ
N
N ~~0~
N
O
N
':O
O:S
Part A
Sodium hydride (60% oil dispersion, 9.1 g, 228 mmol) was placed in a round bottom flask and washed with hexanes (3X) under N2. The dried sodium hydride was treated with 800 mL of anhydrous THF. A solution of tent-butyl 2-(2-azidoethoxy)ethylcarbamate (41.9 g, 182 mmol) in 200 mL of THF was then added to the stirred sodium hydride solution over 40 min. After addition was complete, the reaction was stirred an additional 20 min followed by addition of methyl iodide (13.6 mL, 218 mmol). After stirnng overnight, the reaction was quenched with 300 mL of saturated NaHC03 solution. The reaction mixture was then treated with 200 mL of H20 and 1 L of EtaO. The organic phase was separated and washed with HzO and brine. The organic portion was then dried over MgS04 and concentrated under reduced pressure to give 41.9 g of tent-butyl 2-(2-azidoethoxy)ethyl(methyl)carbarnate as a yellow liquid.
Part B
A solution of tent-butyl 2-(2-azidoethoxy)ethyl(methyl)carbamate (41.9 g, 170 mmol) in 600 mL of MeOH was treated with 2.5 g of 10% Pd on carbon and shaken under HZ (3 I~glcrn2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 37.2 g of crude tent-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate as a light yellow liquid.
Part C
A stirred solution of 4-chloro-3-nitroquinoline (32.3 g, 155 mmol) in 400 mL
of anhydrous CHZC12, under N2, was treated with triethylamine (43.1 mL, 310 mmol) and tart-butyl 2-(2-aminoethoxy)ethyl(methyl)carbamate (37.2 g, 171 mmol). After stirring overnight, the reaction mixture was washed with H20 (2 X 300 mL) and brine (300 rnL).
The organic portion was dried over NaaSOa and concentrated to give a brown oil. Column chromatography (Si02, 33% ethyl acetate/hexanes-67% ethyl acetate/hexanes) gave 46.7 g of tart-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino)ethoxy}ethyl)carbamate as a yellow solid.
Part D
A solution of tart-butyl methyl(2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethyl)carbamate (6.56 g, 16.8 mmol) in 75 mL of toluene was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.8 g of crude tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy} ethyl(methyl)carbamate as an orange syrup which was carried on without further purification.
Part E
A solution of tent-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethyl(rnethyl)carbamate (6.05 g, 16.8 mmol) in 200 mL of anhydrous CH2C12 was cooled to 0°C and treated with triethylamine (2.40 mL, 17.2 mmol).
Methoxypropionyl chloride (1.72 mL, 17.2 mmol) was then added dropwise over 5 min.
The reaction was then warmed to room temperature and stirring was continued for 3 h.
The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 200 mL of EtOH and 7.2 mL of triethylamine was added.
The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et20. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. This was dissolved in 300 mL of CH~Cl2 and washed with H20 and brine.
The organic portion was dried over NaaS04 and concentrated under reduced pressure to give a brown oil. The oil was dissolved in 100 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 7.20 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a yellow syrup.
Part F
A solution of test-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy} ethyl(rnethyl)carbamate~ (7.20 g, 16.8 mmol) in 200 mL of CH2C12 was treated with MCPBA (77%, 4.32 g, 19.3 mmol). After stirring 6 h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over NaaS04 and concentrated to give 7.05 g of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate as a light brown solid.
Part G
A solution of tent-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80°C and treated with 5 mL of concentrated solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CHZCl2. The reaction mixture was then washed with H20, 1 % Na2C03 solution (3X) and brine. The organic portion was dried over NaaS04 and concentrated to give 6.50 g of tert-butyl 2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil Part H
Tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy)ethyl(methyl)carbamate (6.50 g, 14.7 mmol) was dissolved in 100 mL
of EtOH
and treated with 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 6 h, the reaction mixture was cooled and filtered to give a gummy solid.
The solid was washed with EtOH and Et20 and dried under vacuum to give the hydrochloride salt as a light brown powder. The free base was made by dissolving the hydrochloride salt in 50 mL of HZO and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHCl3 (5 X 50 mL). The combined organic layers were dried over NaZS04 and concentrated to give 3.93 g of 2-(2-methoxyethyl)-I-{2-[2-(methylamino)ethoxy]ethyl)-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 344 (M + H)+;
IH NMR (300 MHz, DMSO-d6) 8 8.07 (d, J = 7.7 Hz,~ 1 H); 7.62 (dd, J = 1.0, 8.3 Hz, 1 H); 7.42 (ddd, J = 1.0, 7.1, 8.2 Hz, 1 H); 7.22 (ddd, J = 1.1, 7.1, 8.2 Hz, 1 H); 6.49 (s, 2 H); 4.75 (t, J = 5.1 Hz, 2 H); 3.83 (t, J = 6.8 Hz, 4 H); 3.35 (t, J = 5.6 Hz, 2 H); 3.30 (s, 3 H); 3.21 (t, J = 6.9 Hz, 2 H); 2.45 (t, J = 5.6 Hz, 2 H); 2.12 (s, 3 H).
Part I
2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (1.00 g, 2.92 mmol) was dissolved in 30 mL of anhydrous CHzCl2 and cooled to 0°C under NZ. To the stirred solution were added Et3N (0.81 mL, 5.81 mmol) and methanesulfonyl chloride (226 ~L, 2.92 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CHZCl2 (30 mL). The organic layer was separated and washed with H20 and brine, dried over NaaS04 and concentrated under reduced pressure. Crystallization of the residue from EtOAc and CHZCl2 gave 756 mg of N (2- f 2-[4-amino-2-(2-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methylmethanesulfonamide as tan crystals. m.p. 145.0-146.5 °C;
MS 422 (M + H)+; ' 'H NMR (300 MHz, DMSO-d6) S 8.06 (d, J = 7.8 Hz, 1 H); 7.61 (dd, J = 0.9, 8.3 Hz, 1 H); 7.42 (t, J = 7.2 Hz, 1 H); 7.23 (ddd, J = 1Ø, 7.0, 8.0 Hz, 1 H); 6.50 (s, 2 H); 4.77 (t, J
=5.0Hz,2H);3.87(t,J=5.0Hz,2H),3.83(t,J=6.8Hz,2H);3.48(t,J=5.5Hz,2 H); 3.30 (s, 3 H); 3.22 (t, J = 6.8 Hz, 2 H); 3.13 (t, J = 5.5 Hz, 2 H); 2.77 (s, 3 H); 2.63 (s, 3 H);
t3C NMR (75 MHz, DMSO-d6) 8 153.9, 153.8, 147.0, 134.6, 128.6, 128.5, 123.4, 122.5, 117.0, 72.4, 71.2, 60.4, 51.1, 47.3, 37.3, 37.2, 29.6.
Anal. Calcd for C19Hz7N504S: %C, 54.14; %H, 6.46; %N, 16.61. Found: %C, 53.92;
%H, 6.32; %N, 16.47.
Example 4 N (2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide N ~ N~O~
N.
O
N
O;S:O
Part A
2-(2-Methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-1H imidazo[4,5-c]quinolin-4-amine (4.22 g, 12.3 mmol) was dissolved in 25 mL of trifluoroacetic acid and treated with PtOa (0.5 g). The reaction mixture was shaken under Ha (3 I~g/cmz). After 4 d, an additional 0.5 g of PtOa was added and hydrogenation was continued for an additional 3 d. The reaction mixture was then filtered through Celite and concentrated under reduced pressure to give a yellow oil. The yellow oil was dissolved in 50 mL of HZO and extracted with 50 mL of CHCl3. The organic portion was removed and discarded. The aqueous portion was then made basic (pH~l2) by addition of 10%
NaOH
solution. This was then extracted with CHC13 (6 X 50 mL) and the combined organic layers were dried over Na2S04 and concentrated to a brown oil. The brown oil was dissolved in 100 mL of hot MeOH and treated with 1 g of activated charcoal.
The hot solution was filtered through Celite and concentrated to dryness. The resulting gummy solid was concentrated several times with EtzO to give 3.19 g of 2-(2-methoxyethyl)-1- f 2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-4-amine as an off white powder.
MS 348 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 4.84 (s, 2 H); 4.48 (t, J = 5.7 Hz, 2 H); 3.84 (t, J
= 6.7 Hz, 2 H); 3.70 (t, J = 5.7 Hz, 2 H); 3.46 (t, J = 5.1 Hz, 2 H); 3.3 6 (s, 3 H);
3.14 (t, J = 6.7 Hz, 2 H); 2.96 (m, 2 H); 2.83 (m, 2 H); 2.65 (t, J= S.1 Hz, 2 H); 2.36 (s, 3 H);
1.85 (m, 4 H).
Part B
(2-(2-Methoxyethyl)-1-{2-[2-(methylamino)ethoxy]ethyl}-6,7,8,9-tetrahydro-1H
imidazo[4,5-c]quinolin-4-amine (750 mg, 2.16 mmol) was dissolved in 30 mL of anhydrous CHZCIa and cooled to 0°C under Nz. To the stiired solution were added Et3N
(0.60 mL, 4.32 mmol) and methanesulfonyl chloride (167 ~L, 2.16 mmol),and the reaction was allowed to warm to room temperature over 3 h. The reaction mixture was then quenched by addition of saturated NaHC03 solution (30 mL) and CH2Cl2 (30 mL).
The organic layer was separated and washed with HZO and brine, dried over Na2S04 and concentrated under reduced pressure. Purification by column chromatography (Si02, 3-5%
MeOH/CHC13 saturated with aqueous NH40H) gave the product as a colorless glass. The material was then concentrated with iso-propyl alcohol to give a syrup which solidified upon standing in the freezer. The solid was dried under vacuum to give 437 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide as off white crystals.
m.p. 115.3-117.8 °C ;
MS 426 (M + H)+;
H NMR (300 MHz, DMSO-d6) 8 5.65 (s, 2 H); 4.44 (t, J = 5.2 Hz, 2 H); 3.76 (t, J = 6.9 Hz,2H),3.70(t,J=5.3Hz,2H);3.47(t,J=5.5Hz,2H);3.27(s,3H);3.15(t,J=5.5 Hz, 2 H); 3.08 (t, J = 6.9 Hz, 2 H); 2.93 (m, 2 H) ; 2.78 (s, 3 H); 2.65 (s, 3 H); 2.64 (m, 2 H); 1.74 (m, 4 H);
i3C NMR (75 MHz, DMSO-d6) 8 151..2, 149.3, 146.3, 138.5, 124.9, 105.6, 70.6, 70.5, 69.2, 58.4, 49.2, 44.5, 35.4, 35.2, 32.7, 27.6, 23.8, 23.1, 23Ø
Anal. Calcd for Cl9Ha~N504S~0.40 C3H80: %C, 53.97; a%H, 7.67; %N, 15.58.
Found:
°f°C, 53.71; %H, 7.48; %N, 15.77.
Example 5 2-Butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}
1H imidazo[4,5-c]quinolin-4-amine.
S, a Under a nitrogen atmosphere, chloropropylsulfonyl chloride (0.05 ml, 0.46.mmo1) was added dropwise to a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H
imidazo[4,5-c]quinolin-4-amine (0.12 g, 0.37 mrnol) and triethylamine (0.065 ml, 0.46 mmol) in dichloromethane (5 rnl). The reaction was stirred for 20 hours followed by removal of the solvent iya vacuo. The resulting off white solid was dissolved in N,N-dimethylformamide (5mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087m1, 0.58 mmol) was added.
The reaction was stirred for 18 hours under an atmosphere of nitrogen and then quenched with water and extracted with dichloromethane (2X). The organic fractions were combined, . washed with water followed by brine, dried (NaZSO4), filtered, and concentrated ifa vacuo to provide an off white solid. Recrystallization from ethyl acetate yielded 0.068 goof 2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl)-1H imidazo[4,5-c]quinolin-4-amine as off white crystals, m.p. 152-154°C.
1H-NMR (300MHz, DMSO-d6): 8 8.06 (d, J = B.IHz, 1H), 7.62 (d, J = 7.9Hz, 1H), 7.42 (t, J = 7.6Hz, 1H), 7.23 (t, J = 7.5Hz, 1H), 6.52 (s, 2H), 4.73 (t, J =
4.99Hz, 2H), 3..86 (t, J
= S.OHz, 2H), 3.46 (t, J = 5.3Hz, 2H), 3.07 (t, J = 7.66Hz, 2H), 2.97-2.87 (m, 6H), 2.04 (quintet, J = 6.8Hz, 2H), 1.81 (quintet, J = 7.6Hz, 2H), 1.46 (sextet, J =
7.4Hz, 2H), 0.96 (t, J = 7.3Hz, 3H);
i3C-NMR (75MHz, DMSO-d6): 8 154.6, 152.9, 145.1, 133.0, 126.8, 126.6, 121.6, 120.x, 115.3, 69:2, 69.1, 47.0, 45.5, 45.0, 43.7, 29.3, 26.2, 21.9, 18.1, 13.7;
Anal calcd for CZ~Ha9N503S*0.25H20: %C, 57.84; %H, 6.82; %N, 16.06; %S, 7.35.
Found: %C, 57.90; %H, 6.79; %N, 15.92; %S, 7.55.
Examples 6 - 26 Part A
A solution of tart-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (3.46 g, 10.0 mmol) in 50 mL of toluene was treated with triethylorthovalerate (2.5 mL, 14.5 mmol) and the reaction mixture was heated to reflux. A 25 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 4 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 50 mL of CH2Clz and washed with saturated NaHC03, and brine. The organic portion was dried over NaaS04 and concetrated to give a green oil.
The green oil was dissolved in 50 mL of hot MeOH and treated with activated charcoal.
The hot solution was filtered and concentrated to give 4.12 g of tart-butyl 2-[2-(2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a yellow oil.
Part B
A solution of tent-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CH2Ch, was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirnng for S
h, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with HZO and brine then dried over NaaS04 and concentrated to give 3.68 g of tart-butyl 2-[2-(2-butyl-5-oxido-1H
imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(2-butyl-5-oxido-1H imidazo[4,5-a]quinolin-1-yl)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) in 100 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH4OH solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (1.87 g, 9.81 mmol) over a 10 min period. The reaction mixture was then sealed in a pressure vessel and heating was continued for 2 h. The reaction mixture was then cooled and treated with 100 mL of CHZCIz. The reaction mixture was then washed with HZO, 1 % NaaC03 solution (3X) and brine. The organic portion was dried over Na2S04 and concentrated to give 3.68 g of teYt-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Ter~t-butyl 2-[2-(4-amino-2-butyl-1H imidazo[4,5-a]quinolin-1-yI)ethoxy]ethylcarbamate (3.68 g, 8.60 mmol) was suspended in 20 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (50 mL) and filtered to give 2.90 g of the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of Ha0 and reating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCIa (3 X 50 mL). The combined organic layers were dried over NaaS04 and concentrated to give 1-[2-(2-aminoethoxy)ethyl]-2-butyl-IH imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 328 (M + H)+;
'H NMR (300 MHz, CDCl3) 8 7.95 (d, J= 8.3 Hz, 1 H); 7.83 (d, J= 8.4 Hz, I H);
7.50 (m, I H); 7.30 (m, 1 H); 5.41 (s, 2 H); 4.69 (t, J = 5.6 Hz, 2 H); 3.93 (t, J
= 5.6 Hz, 2 H);
3.39 (t, J = 5. I Hz, 2 H); 2.97 (t, J = 7.9 Hz, 2 H); 2.76 (t, J = 5.1 Hz, 2 H); 1.89 (m, 2 H);
~ 1.52 (m, 2 H); 1.26 (br s, 2 H); 1.01 (t, J = 7.3 Hz, 3 H).
Part E
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) was added to a test tube containing a solution of 1-[2-(2-aminoethoxy)ethyl]-2-butyl-1H imidazo[4,5-c]quinolin-4-amine (25 mg) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 18 - 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The products were verified by accurate mass and'H NMR. The table below shows the structure of the free base and the observed accurate mass (M +
H).
Example Structure of Free Base Accurate Mass Number (obs.) NHZ
I \ N
Y\
N
420.2077 ~N
O' O~C~
NHz CH3 N \ N
\
N
7 / ~ 434.2234 N ,CHs '~\\
O~SO CH3 N \ N
I \
N
435.2196 N CHa ~N
p SO 'CH3 Example Accurate Mass Number _ Structure of Free Base - (0bs.) N \ N
N
448.2387 O
N
_\
N \ N
N
/ ~ 468.2075 H ~ \
O~S\ i O
NHz CH3 ~ N
N
11 0 474.1625 N
~ ,O
O
a Example Structure of Free Base Accurate Number Mass (obs.) NHz CH3 .
N
12 ~ 482.2214 N
~ ,O
O' \ N
/ N
O ' 13 N 486.1967 o s~o F
\ N
/
O
~
14 N ,0 493.2009 o-o \
\N
Example . Structure of Free Base Accurate Mass Number (obs.) I\
N
15 N o 493.2025 o%
N
\
N
16 ~~ ,0 498.2195 o%
roc I \ N
Y\
N
17 504.1861 ,o o, F / \
F
Example Accurate Mass Number Structure of Free Base (obs.) N
/ N
O
18 _ 518.2210 N
~ ,O
O' NHZ
N
19 , N 518.2243 ~ ,o o=
i ~ N
/ N
O
20 N 519.2158 o s~o .
Example Structure of Free Base Accurate Number Mass (obs.) NHZ
\
/ N
21 N ,0 536.1917 o-F
F
F
/
N
/
O
22 ~ -~ 544.2384 NH2 ~CHa ~ N
/
O
23 ~
,o , 546.1852 o=
o,~;o cH, Example Structure of Free Base Accurate Mass Number (obs.) NHZ ~CNa i ~ N
/
O
''~~N
24 0 ~ ,0 552.1874 F"O
F~F
' ' i.
~~ ,o o%
25 ~ ~ 615.2848 ,N
FiC N~Q i NHz CH3 Chiral N
O
26 ~N H CH3 542.2779 0' O ,°,,H
Examples 27 - 39 Part A
Using the general method of Part A of Examples 6 - 26, 4-piperidineethanol (10 g, 77.4 mmol) was reacted with di-tart-butyl dicarbonate (17.7 g, 81.3 mmol) to provide 13.1 g of tart-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate as a clear oil.
Part B
Iodine (7.97 g) was added in three portions to a solution of imidazole (3.89 g, 57.1 mmol) and triphenylphosphine (14.98 g, 57.1 mmol) in dichloromethane (350 mL).
After minutes a solution of the material from Part A in dichloromethane (70 mL) was added.
The reaction mixture was stirred at ambient temperature overnight. More iodine (7.97 g) was added and the reaction was stirred at ambient, temperature for 1 hr. The reaction mixture was washed with saturated sodium thiosulfate (2~) and brine, dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide an oily residue.
The residue was purified by column chromatography (silica gel eluting with 20%
ethyl acetate in hexanes) to provide 15.52 g of tart-butyl 4-(2-iodoethyl)piperidine-carboxylate as a pale yellow oil.
Part C
Under a nitrogen atmosphere, 2-(1H imidazo[4,5-c]quinolin-1-yl)butan-1-of (6.5 g, 26.9 mmol) was added in three portions to a suspension of sodium hydride (1.4 g of 60%, 35.0 mmol) in anhydrous N,N-dimethylformamide. The reaction mixture was allowed to stir for 45 minutes by which time gas evolution had ceased. Tart-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (10.05 g, 29.6 mmol) was added dropwise over a period of 15 minutes. The reaction mixture was allowed to stir at ambient temperature for 2.5 hrs; then it was heated to 100°C and stirred overnight. Analysis by HPLC showed that the reaction was about 35% complete. Saturated ammonium chloride solution was added, the resulting mixture was allowed to stir for 20 minutes and then it was extracted with ethyl acetate (2X). The ethyl acetate extracts were washed with water (2X) and then with brine, combined, dried over sodium sulfate, ftltered and then concentrated under reduced pressure to provide a brown oil. The.oil was purified by column chromatography (silica gel eluting sequentially with 30% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and ethyl acetate) to provide 2.2 g of tent-butyl 4-{2-[2-(1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate.
Part D
Using the~general method of Examples 6 - 26 Part H, the material from Part C
was oxidized to provide tart-butyl 4-{2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as an oil.
Part E
Ammonium hydroxide solution (20 mL) was added to a solution of the material from Part D in dichloromethane (20 mL). A solution of tosyl chloride (0.99 g, 5.2 mmol) in dichloromethane (10 mL) was added over a period of 5 minutes. The resulting biphasic reaction mixture was allowed to stir overnight. The reaction mixture was diluted with chloroform and saturated sodium bicarbonate solution. The layers were separated. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a brown glass. This material was purifted by column chromatography (silica gel eluting first with 50% ethyl acetate in hexanes and then with ethyl acetate) to provide 1.0 g of tent-butyl 4-{2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate as pale yellow glassy foam.
Part F
Under a nitrogen atmosphere, tart-butyl 4-{2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)butoxy]ethyl}piperidine-1-carboxylate (1.00 g, 2.1 mmol) and ethanolic hydrochloric acid (10 ml, 20 mmol) were combined and the solution was stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the resulting tan solid was dissolved in water. Saturated aqueous sodium carbonate was added until the pH reached 10. After extraction .with dichloromethane (3~, the organic fractions were combined, washed with brine, dried (Na2SO4), ftltered, and the majority of the solvent was removed ifa vacuo. Hexane was added to form a precipitate. Vacuum filtration yielded 0.5 g of 1-{1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
1H-NMR (300MHz, DMSO-d6) : 8 8.34 (bs, 1H), 8.19 (d, J = 8.49, 1H), 7.61 (dd;
J = 8.31, 1.13, 1H), 7.45-7.39 (m, 1H), 7.25-7.19 (m, 1H), 6.55 (s, 2H), 5.25-5.15 (m, 1H), 4.00-3.80 (m, 2H), 3.5-3.3 (m, 2H), 2.8-2.64 (m, 2H), 2.22-2.11 (m, 2H), 2.09-1.99 (m, 2H), 1.8-1.63 (bs, 1H), 1.37-1.0 (m, SH), 0.95-0.7 (m, SH);
13C-NMR (75MHz, DMSO-d6): 8 152.8, 145.8, 140.6, 133.0, 127.8, 127.0, 126.9, 121.3, 121.0, 115.5, 71.8, 68.1, 58.4, 46.1, 36.3, 33.1, 32.7, 24.5, 9.9;
MS (CI) m/e 368.2459 (368.2450 calcd for CZIH3oNs0).
Part G
The compounds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
The sulfonyl chloride or the sulfamoyl chloride (1.1 eq.) was added to a test tube containing a solution of 1- f 1-[(2-piperidin-4-ylethoxy)methyl]propyl}-1H
imidazo[4,5-c]quinolin-4-amine (25 mg) in dichloromethane (5 mL). The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purred by semi-preparative HPLC using the method described above. The products were verified by accurate mass and 1H
NMR. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Number Structure of Free Base Mass (obs.) NHZ
/ N
27 ~ 474 CH3 .
N~ O CHa II~
O
CHa NHZ
N
/ \
~N
/
CH3 .
N,10 iCHa -IS
N
O CHa NHz N, / \\
N
29 / ~ 488.2647 O
N, O~CH3 I/
O
Example Structure of Free Base Accurate Mass Number (obs.) NHS
/ N
30 ~ 508.2349 O
N~S
NHz / \
\
~N
31 ~ 514.1924 N~S S
NHZ
I \ N
N
O
32 ~H3 526.2241 N~S w O
F
umber Structure of Free Base ~ AccuObs.Mass NHZ
/ N
/ ~O
33 cH3 0 533.2315 N~S
O
\N
NHZ
N
N
~O
34 ~H 538.2477 N ~S~ CH
__ \~~~ O, s NHZ
N \ N
N
35 O 544.2166 O ~ ~ F
F
52, Example Structure of Free Base Accurate Mass Number (obs.) NHZ
\ \~ .
O
36 CH, 0 559.2493 N ~s N~
NHZ
N
3~ ~H ~ 586.2166 (1 ) II
N ~S ~
O ~ IS CHs O
NHZ
N
O
38 ~H 592.2144 N, ~~ _ F"F
~~(\S
p ~ ~ O F
Example Structure of Free Base Accurate Mass Number (obs.) NH=
N
I~ y 39 ~ ~° ~ 655.3173 N o ~ S N N ~ S N CH3 Examples 40 -49 Part A
A solution of teat-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy)ethylcarbamate (6.92 g, 20.0 mmol) in 100 mL of toluene was treated with triethylorthoformate (4.65 mL, 2$.0 mmol) and the reaction mixture was heated to reflux. A 100 mg portion of pyridinium hydrochloride was then added and refluxing was continued for 2 h. The reaction was then concentrated to dryness under reduced pressure.
The residue was dissolved in 200 mL of CHZCh and washed with saturated NaHC03, and brine. The organic portion was dried over Na2S04 and concentrated to give a green oil. The green oil was dissolved in 200 mL of hot MeOH and treated with 10 g of activated charcoal. The hot solution was filtered and concentrated to give 5.25 g of tert-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light yellow syrup.
Part B
A solution of tent-butyl 2-[2-(1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (5.25 g, 14.7 mmol) in 200 mL of CH2Cla was treated with MCPBA (77%, 3.63 g, 16.3 mmol). After stirnng overnight, the reaction mixture was treated with saturated NaHC03 solution and the layers were separated. The organic portion was washed with H20 and brine then dried over Na2S04 and concentrated to give 4.60 g of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part C
A solution of tent-butyl 2-[2-(5-oxido-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80 °C and treated with 10 mL of concentrated NH40H solution.
To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH40H solution and then sealed in a pressure vessel and heating was continued for 3 h.
The reaction mixture was then cooled and treated with 100 mL of CHZCh. The reaction mixture was then washed~with HZO, 1% NazC03 solution (3X) and brine. The organic ' portion was dried over NaZS04 and concentrated to give 4.56 g of tent-butyl 2-[2-(4-amino-lH~imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Part D
Text-butyl 2-[2-(4-amino-1H imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.56 g, 12.3 mmol) was dissolved in 100 mL of EtOH and treated with 30 mL of 2M HCl in EtOH and the mixture was heated to reflux with stirring. After 3 h, the reaction mixture was concentrated to give a solid. The solid was triturated with hot EtOH (100 mL) and filtered to give the product as the hydrochloride salt. The free base was made by dissolving the hydrochloride salt in 50 mL of H20 and treating with 5 mL of concentrated NH40H. The aqueous suspension was extracted with CHZCl2 (5 X 50 mL). The combined organic layers were dried over Na2S04 and concentrated to give 1.35 g of 1-[2-(2-aminoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine as a tan powder.
MS 272 (M + H)+;
IH NMR (300 MHz, CDCl3) 8 7.98 (d, J = 8.2 Hz, 1 H); 7.88 (s, 1 H); 7.84 (d, J
= 8.4 Hz, 1 H); 7.54 (m, 1 H); 7.32 (m, 1~ H); 5.43 (s, 2 H); 4.74 (t, J = 5.2 Hz, 2 H);
3.97 (t, J = 5.2 Hz, 2 H); 3.42 (t, J = 5.1 Hz, 2 H); 2.78 (t, .I = 5.1 Hz, 2 H); 1.10 (br s, 2 H).
Part E
The compo~xnds in the table below were prepared according to the synthetic method of step (7) of Reaction Scheme II above using the following general method.
1-[2-(2-Arninoethoxy)ethyl]-1H imidazo[4,5-c]quinolin-4-amine (20 mg) and 1-methyl-2-pyrrolidinone (5 mL) were combined in a test tube and then heated and sonicated to provide a solution. The sulfonyl chloride (1.1 eq.) was then added to the test tube. The test tube was capped and then placed on a shaker at ambient temperature for 20 hr. The solvent was removed by vacuum centrifugation. The residue was purified by semi-preparative HPLC using the method described above. The products were verified by accurate mass and 1H NMR. The table below shows the structure of the free base and the observed accurate mass (M + H).
Example Accurate Mass Number Structure of Free Base obs.
NHZ
N
\ ' / N
O
40 392.1781 o~-NHZ
N ~ N
\
/ N
O
41 N 412.1468 o s~o ~ , NHZ
N
N
O
42 ~ 430.1348 ,o o-.
F
Number Structure of Free Base , Accuroabs,Mass NH=
/
O
43 N ,0 442.1572 o-HsC
NHZ
Ni \ N
O
44 448.1259 ,o o~
F
F
NHZ
N~ \ N
/ N
45 ~ r~ 462.1571 ,S o o Numbelr Structure of Free Base Accu obs,Mass NHZ
i j \~
N
I/
46 0 ~ ,0 480.1274 \
~F
'\F
F
NHZ
~ N
I /
O
47 ° ~ '° 488.1722 NHz N~ \ NJ
I /
°
48 ~ ~0 490.1224 o, ~~o Number Structure of Free Base Accu obs.Mass N H=
N~ \ N
/
O
49 0 ~ ,c 496.1230 F"O
F~F
Example SO
S . ' N-[10-(4-amino-2-methyl-1H imidazo[4,S-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide O
O
NH
O=S=O
~N~.
Part A
4,7-Dioxadecane-1,10-diamine (32.6 g, O.18S mole) in acetonitrile (100 mL) was chilled in an ice bath. To this was slowly added dropwise dansyl chloride (S
g, O.O18S
mole) dissolved in acetonitrile (60 mL) over a 20 min. period. Stirring in an ice bath was continued for 1.5 hr. The reaction mixture was poured into water (about 300 mL) and extracted with dichloromethane (2x 100 mL). The combined extracts were washed with water and dried to give an oil. The oil was purified by column chromatography (silica gel eluting with acetonitrile containing increasing amounts of ethanol) to provide 4.6 g of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide as a viscous oil.
'H-NMR (500 MHz, CDCl3) 1.65 (2H, quin), 1.75 (2H, quin), 2.80 (2H, t, 6.59 Hz), 2.87 (6H, s), 3.03 (2H, t, 6.1 Hz), 3.43 (2H, m), 3.47 (2H, m), 3.52 (2H, m), 3.59 (2H, t, 6.22 Hz), 7.18 (1H, d, J = 7.08 Hz)), 7.56 - 7.49 (overlapping multiplets, 2H), 8.24 (dd, 1H, J =
1.2, 7.3 Hz), 8.31 (d, 1H), 8.53 (d, 1H).
Part B
A solution of 2,4-dichloro-3-nitroquinoline (2.71 g, 0.0115 mole) in toluene (100 rnL) was cooled to 0 - 5°C in an ice bath. Triethylamine (1.5 g) was added in one portion.
A solution of N-(10-amino-4,7-dioxadecyl)-5-dimethylaminonaphthalene-1-sulfonamide (4.6 g, 0.01159 mole) in toluene (60 mL) was added dropwise while maintaining the temperature below 10°C. The reaction was stirred at 2 - 5°C for 4 hrs and at a room temperature of 21°C overnight (18 hours). Thin layer chromatography (dichloromethane:
ethanol) showed a trace of the amine starting material, but was mostly a bright yellow spot at the solvent front assumed to be the addition product. The toluene was removed by rotary evaporation to provide a viscous oil. The oil was purified by column chromatography (silica gel, dichloromethane/ethanol) to provide 2.4 g of N-[
10-(2-chloro-3-nitro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide.
1H-NMR (CDCl3) 1.62 (2H, quin), 2.05 (2H, quin), 2.87 (6H, s), 3.03 (2H, m), 3.47 (4H, m), 3.55 (2H, m), 3.65 (2H, m), 3.73 (2H, t, 5.37 Hz), 5.75 (1H, t, 4.39 Hz,NH), 6.91 (1H, t, 4.76 Hz, NH), 7.15 (1H, d, 7.32 Hz), 7.30 (1H, m), 7.50 (2H, overlapping t), 7.62 (1H, m), 7.82 (1H, d, 7.44 Hz), 7.88 (1H, d, 8.54 Hz), 8.22 (1H, m ), 8.29 (lH,d, 8.42), 8.52 (1'H, d, 8.06 Hz).
Part C
Material from Part B (2.2 g, 0.00357 mole) was dissolved in ethanol (150 mL).
Catalyst (about 1 g of 5% Pt/C) was added and the mixture was hydrogenated using a Parr apparatus for 30 minutes. Thin layer chromatography (ethyl acetate: hexane 1:1) showed that the reaction was complete. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to provide a sticky solid which was shown by NMR to be crude N-[ 10-(3-amino-2-chloro-4-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide. It was used without further purification.
1H-NMR (500 MHz, CDCl3) 1.60 (2H, quin), 1.90 (2H, quin), 2.87 (6H, s, NMe2), 3.00 (2H, br s), 3.45 (4H, m), 3.53 (2H, m), 3.62 (2H, t, 5.62 Hz), 3.71 (4.30 (2H, br s, NHZ ), 5.85 (1H, br s, NH), 7.11 (1H, d, J = 7.32 Hz), 7.35 (1H, m), 7.44 - 7.48 (3H, m), 7.82 (1H, d), 8.18 (1H, dd, J= 1.1, 7.2 Hz), 8.30 (1H, d, 8.66 Hz), 8.49 (1H, d, 8.54 Hz).
'3C-NMR (125 MHz) 28.48 (CH2), 30.08 (CHZ), 41.93 (CHZ), 45.27 (CH3), 45.28 (CHZ), 69.75 (CH2), 69.83 (CHZ), 70.08 (CHZ), 70.38 (CHa), 114.99 (CH), 118.84 (CH), 120.84 (CH), 123.02 (CH), 123.50 (C) , 125.67 (CH), 126.22 (CH), 128.01 (CH), 128.57 (C) 128.67 (CH), 129.22 (CH), 129.52 (C ), 129.74 (C ), 130.09 (CH), 134.72 (C), 137.17 (C), 141.82 (C), 142.03 (C), 151.75 (C).
Part D
A portion (1 g, 1.708 mmol) of the material from Part C was dissolved in tetrahydrofuran (30 mL) and then cooled in an ice-bath to about 5°C.
Freshly distilled acetyl chloride (0. 13 g, 1.78 mmol) was added with stirring. The yellow solid which immediately precipitated was isolated by filtration and washed with tetrahydrofuran.
Standing in air gave an oily solid (possibly hygroscopic). FAB (fast atom bombardment) mass spectrum suggested that this was the desired N-[10-(3-acetamido-2-chloro-quinolinyl)amino-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide hydrochloride together with an undetermined amount of starting material. This solid was carned on to Part E without additional puriEcation.
Part E
The crude salt from Part D was dissolved in dry methanol containing 7% ammonia (20 mL). The solution was heated at 150°C in a bomb for 6 1/2 hrs. The reaction mixture was cooled and then concentrated. The residue was combined with acetone.
Undissolved material was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (silica gel; ethanol/dichloromethane) to provide 0.45 g of a brown oil.
6'1 1H-NMR (400 MHz, CDCl3) 1.53 (2H, t, 7.08 Hz), 2.05 (2H, m), 2.45 (3H, s), 2.70 (6H, s), 2.90 (2H, t, 5.98 Hz), 3.30 (8H, br, m), 4.40 (2H, t, 6.59 Hz), 5.75 (2H, br s NHZ), 6.65 (1H, br s NHSOZ),7.00 (1H, d, 7.54 Hz), 7.14 (1H, t, 8.06 Hz), 7.30 (3H, m), 7.64 (1H, d, 8.30 Hz), 7.88 (1H, d, 8.18 Hz), 8.06 (1H, d, 7.33 Hz), 8.24 (1H, d, 8.54 Hz), 8.36 (1H, d, 8.55 Hz).
This material was then purified by high performance liquid chromatography using a Bondapak C18 12.5 nm reverse phase column (available from Waters, Milford, MA) eluting with a composite gradient of acetonitrile in water to provide the desired product.
CYTOI~INE 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 (a) (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.
Incubation The solution of test compound is added to the first well containing RPMI
complete and serial 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.
The final concentration of PBMC suspension is 1.5-2 X 106 cellslmL. 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 rpm 0200 x g) at 4°C. The cell-free culture supernatant is removed with a sterile polypropylene pipet and transferred to sterile polypropylene tubes. Samples are maintained at-30 to -70°C until analysis. The samples are analyzed for interferon-a and for tumor necrosis factor-a by ELISA.
Interferon (a) and Tumor Necrosis Factor (a) Analysis by ELISA
Interferon-a 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-a 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;
generally the highest concentration tested was 10 or 30 ~M.
Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 3 0.01 0.12 6 0.001 1 7 0.01 1 8 0.01 1 9 0.1 1 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~M) Number Interferon Tumor Necrosis Factor 12 0.1 10 14 ~ 1 10 18 * 10 19 * 10 22 0.0001 10 23 0.0001 10 24 0.0001 10 0.0001 26 0.01 10 27 0.1 1 28 ' 0.1 1 37 0.1 1 Cytokine Induction in Human Cells Example Lowest Effective Concentration (~.1VI) Number Interferon Tumor Necrosis Factor 38 * *
4$ * *
47 * , *
48 * 10 49 * 10 50 1.11 *
Claims (24)
1. A compound of the formula (I):
wherein: X is -CHR5-, -CHR5-alkyl-, or -CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4-NR3-SO2-R6-alkyl;
-R4-NR3-SO2-R6-alkenyl;
-R4-NR3-SO2-R6-aryl;
-R4-NR3-SO2-R6-heteroaryl;
-R4-NR3-SO2-R6-heterocyclyl;
-R4-NR3-SO2-R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2-;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R3 and R4 can join together to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein: X is -CHR5-, -CHR5-alkyl-, or -CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4-NR3-SO2-R6-alkyl;
-R4-NR3-SO2-R6-alkenyl;
-R4-NR3-SO2-R6-aryl;
-R4-NR3-SO2-R6-heteroaryl;
-R4-NR3-SO2-R6-heterocyclyl;
-R4-NR3-SO2-R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2-;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R3 and R4 can join together to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
2. A compound or salt of claim 1 wherein X is --CH(alkyl)(alkyl)- , wherein the alkyl groups can be the same or different.
3. A compound or salt of claim 1 wherein X is -CH2-CH2-.
4. A compound or salt of claim 1 wherein X is -CH(C2H5)(CH2)-.
5. A compound or salt of claim 1 wherein R2 is H.
6. A compound or salt of claim 1 wherein R2 is alkyl.
7. A compound or salt of claim 1 wherein R2 is -alkyl-O-alkyl.
8. A compound or salt of claim 1 wherein R3 and R4 join to form a heterocyclic ring.
9. A compound or salt of claim 1 wherein R1 is -R4 NR3-SO2-R6-aryl.
10. A compound selected from the group consisting of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy} ethyl)methanesulfonamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;
N-(2-{2-[4-amino-2-(2.-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methylmethanesulfonamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide;
2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine; and N-[10-(4-amino-2-methyl-1H imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide;
or a pharmaceutically acceptable salt thereof.
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;
N-(2-{2-[4-amino-2-(2.-methoxyethyl)-1H imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N
methylmethanesulfonamide;
N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N methylmethanesulfonamide;
2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine; and N-[10-(4-amino-2-methyl-1H imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide;
or a pharmaceutically acceptable salt thereof.
11. A compound of the formula (II) wherein: X is -CHR5-, -CHR5-alkyl-, or -CHR5-alkenyl-;
R1 is selected from the group consisting of;
-R4-NR3-SO2-R6-alkyl;
-R4-NR3-SO2-R6-alkenyl;
-R4-NR3-SO2-R6-aryl;
-R4 NR3-SO2-R6-heteroaryl;
-R4-NR3-SO2-R6 heterocyclyl;
-R4-NR3-SO2-R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R3 and R4 can join together to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
R1 is selected from the group consisting of;
-R4-NR3-SO2-R6-alkyl;
-R4-NR3-SO2-R6-alkenyl;
-R4-NR3-SO2-R6-aryl;
-R4 NR3-SO2-R6-heteroaryl;
-R4-NR3-SO2-R6 heterocyclyl;
-R4-NR3-SO2-R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more -O- groups; or R3 and R4 can join together to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, alkyl, or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1_lo alkyl, C1-10 alkoxy, hydroxy, halogen, and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
12. A compound or salt of claim 11 wherein R2 is H or alkyl.
13. A compound or salt of claim 11 wherein R2 is ~alkyl~O~alkyl.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 1 and a pharmaceutically acceptable carrier.
15. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
16. The method of claim 15 wherein the cytokine is IFN-.alpha..
17. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
18. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 1 to the animal.
19. A compound of the formula (III):
wherein X is ~CHR5-, -CHR5-alkyl-, or -CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR3~SO2~R6~alkyl;
-R4~NR3~SO2~R6~alkenyl;
-R4~NR3~SO2~R6~aryl;
-R4~NR3~SO2~R6~heteroaryl;
-R4~NR3~SO2~R6~heterocyclyl;
-R4~NR3~SO2~R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2-;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more ~O~ groups; or R4 and R3 can join to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, or is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
wherein X is ~CHR5-, -CHR5-alkyl-, or -CHR5-alkenyl-;
R1 is selected from the group consisting of:
-R4~NR3~SO2~R6~alkyl;
-R4~NR3~SO2~R6~alkenyl;
-R4~NR3~SO2~R6~aryl;
-R4~NR3~SO2~R6~heteroaryl;
-R4~NR3~SO2~R6~heterocyclyl;
-R4~NR3~SO2~R7;
-R4-NR3-SO2-NR5-R6-alkyl;
-R4-NR3-SO2-NR5-R6-alkenyl;
-R4-NR3-SO2-NR5-R6-aryl;
-R4-NR3-SO2-NR5-R6-heteroaryl;
-R4-NR3-SO2-NR5-R6-heterocyclyl; and -R4-NR3-SO2-NH2;
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(R5)2;
-CO-N(R5)2;
-CO-C1-10 alkyl;
-CO-O-C1-10 alkyl;
-N3;
-aryl;
-heteroaryl;
-heterocyclyl;
-CO-aryl; and -CO-heteroaryl;
Y is -O- or -S(O)0-2-;
R3 is H, C1-10 alkyl, or arylalkyl;
each R4 is independently alkyl or alkenyl, which may be interrupted by one or more ~O~ groups; or R4 and R3 can join to form a ring;
each R5 is independently H, C1-10 alkyl, or C2-10 alkenyl;
R6 is a bond, or is alkyl or alkenyl, which may be interrupted by one or more -O- groups;
R7 is C1-10 alkyl; or R3 and R7 can join together to form a ring;
n is 0 to 4; and each R present is independently selected from the group consisting of C1-10 alkyl, C1-10 alkoxy, hydroxy, halogen and trifluoromethyl;
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of claim 11 and a pharmaceutically acceptable carrier.
21. A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 11 to the animal.
22. The method of claim 21 wherein the cytokine is IFN-.alpha..
23. A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 11 to the animal.
24. A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of claim 11 to the animal.
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US25421800P | 2000-12-08 | 2000-12-08 | |
US60/254,218 | 2000-12-08 | ||
PCT/US2001/046582 WO2002046190A2 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
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Family
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CA002430844A Withdrawn CA2430844A1 (en) | 2000-12-08 | 2001-12-06 | Aryl ether substituted imidazoquinolines |
CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
CA002431151A Withdrawn CA2431151A1 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
CA002436984A Abandoned CA2436984A1 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
CA002436983A Abandoned CA2436983A1 (en) | 2000-12-08 | 2001-12-06 | Sulfonamido ether substituted imidazoquinolines |
CA2436846A Expired - Fee Related CA2436846C (en) | 2000-12-08 | 2001-12-06 | Thioether substituted imidazoquinolines |
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CA2436980A Expired - Fee Related CA2436980C (en) | 2000-12-08 | 2001-12-06 | Amido ether substituted imidazoquinolines |
CA002431151A Withdrawn CA2431151A1 (en) | 2000-12-08 | 2001-12-06 | Heterocyclic ether substituted imidazoquinolines |
CA002436984A Abandoned CA2436984A1 (en) | 2000-12-08 | 2001-12-06 | Urea substituted imidazoquinoline ethers |
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Families Citing this family (206)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5741908A (en) | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
UA67760C2 (en) * | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Imidazonaphthyridines and use thereof to induce the biosynthesis of cytokines |
US6331539B1 (en) * | 1999-06-10 | 2001-12-18 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
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 |
US6916925B1 (en) | 1999-11-05 | 2005-07-12 | 3M Innovative Properties Co. | Dye labeled imidazoquinoline compounds |
JP3436512B2 (en) * | 1999-12-28 | 2003-08-11 | 株式会社デンソー | Accelerator device |
US6545017B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
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 |
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 |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
US6660747B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6667312B2 (en) * | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6664265B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6664264B2 (en) | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6525064B1 (en) | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
US7226928B2 (en) * | 2001-06-15 | 2007-06-05 | 3M Innovative Properties Company | Methods for the treatment of periodontal disease |
EP1450804B9 (en) * | 2001-11-29 | 2009-04-01 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
WO2004080430A2 (en) * | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Methods of improving skin quality |
CA2365732A1 (en) | 2001-12-20 | 2003-06-20 | Ibm Canada Limited-Ibm Canada Limitee | Testing measurements |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
IL147953A (en) | 2002-02-01 | 2008-04-13 | Meir Bialer | Derivatives and pharmaceutical compositions of n-hydroxymethyl tetramethylcyclopropyl- |
EP1478327B1 (en) * | 2002-02-22 | 2015-04-29 | Meda AB | Method of reducing and treating uvb-induced immunosuppression |
GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
AU2003237386A1 (en) * | 2002-06-07 | 2003-12-22 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
AU2003281340B2 (en) | 2002-07-02 | 2009-04-09 | Southern Research Institute | Inhibitors of FtsZ and uses thereof |
ATE488246T1 (en) | 2002-08-15 | 2010-12-15 | 3M Innovative Properties Co | IMMUNO-STIMULATORY COMPOSITIONS AND METHODS FOR STIMULATING AN IMMUNE RESPONSE |
JP2006503068A (en) | 2002-09-26 | 2006-01-26 | スリーエム イノベイティブ プロパティズ カンパニー | 1H-Imidazo dimer |
AU2003301052A1 (en) | 2002-12-20 | 2004-07-22 | 3M Innovative Properties Company | Aryl / hetaryl substituted imidazoquinolines |
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WO2004071459A2 (en) | 2003-02-13 | 2004-08-26 | 3M Innovative Properties Company | Methods and compositions related to irm compounds and toll-like receptor 8 |
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AU2004218349A1 (en) | 2003-03-04 | 2004-09-16 | 3M Innovative Properties Company | Prophylactic treatment of UV-induced epidermal neoplasia |
AU2004220534A1 (en) * | 2003-03-07 | 2004-09-23 | 3M Innovative Properties Company | 1-amino 1H-imidazoquinolines |
US7163947B2 (en) * | 2003-03-07 | 2007-01-16 | 3M Innovative Properties Company | 1-Amino 1H-imidazoquinolines |
JP2006523212A (en) * | 2003-03-13 | 2006-10-12 | スリーエム イノベイティブ プロパティズ カンパニー | Diagnosis method of skin lesion |
JP2006520245A (en) | 2003-03-13 | 2006-09-07 | スリーエム イノベイティブ プロパティズ カンパニー | How to remove a tattoo |
US20040192585A1 (en) | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
US20040265351A1 (en) * | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
CA2521682A1 (en) * | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
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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 |
JP2007501252A (en) * | 2003-08-05 | 2007-01-25 | スリーエム イノベイティブ プロパティズ カンパニー | Formulation containing immune response modifier |
AR045260A1 (en) * | 2003-08-12 | 2005-10-19 | 3M Innovative Properties Co | COMPOUNDS CONTAINING IMIDAZO-OXIMA REPLACED |
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WO2005020912A2 (en) * | 2003-08-25 | 2005-03-10 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
WO2005018574A2 (en) * | 2003-08-25 | 2005-03-03 | 3M Innovative Properties Company | Immunostimulatory combinations and treatments |
AR045529A1 (en) | 2003-08-27 | 2005-11-02 | 3M Innovative Properties Co | IMIDAZOQUINOLINAS REPLACED WITH ARILOXI OR ARILALQUILENOXI GROUPS |
US20060216333A1 (en) * | 2003-09-02 | 2006-09-28 | Miller Richard L | Methods related to the treatment of mucosal associated conditions |
US20050054665A1 (en) * | 2003-09-05 | 2005-03-10 | 3M Innovative Properties Company | Treatment for CD5+ B cell lymphoma |
JP2007505629A (en) * | 2003-09-17 | 2007-03-15 | スリーエム イノベイティブ プロパティズ カンパニー | Selective regulation of TLR gene expression |
US20090075980A1 (en) * | 2003-10-03 | 2009-03-19 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and Analogs Thereof |
SG149829A1 (en) | 2003-10-03 | 2009-02-27 | 3M Innovative Properties Co | Pyrazolopyridines and analogs thereof |
US7544697B2 (en) * | 2003-10-03 | 2009-06-09 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridines and analogs thereof |
CN1897948A (en) * | 2003-10-03 | 2007-01-17 | 3M创新有限公司 | Alkoxy substituted imidazoquinolines |
WO2005041891A2 (en) * | 2003-10-31 | 2005-05-12 | 3M Innovative Properties Company | Neutrophil activation by immune response modifier compounds |
US8598192B2 (en) | 2003-11-14 | 2013-12-03 | 3M Innovative Properties Company | Hydroxylamine substituted imidazoquinolines |
EP1685129A4 (en) * | 2003-11-14 | 2008-10-22 | 3M Innovative Properties Co | Oxime substituted imidazo ring compounds |
PL1687305T3 (en) * | 2003-11-21 | 2008-12-31 | Novartis Ag | 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 |
JP4891088B2 (en) | 2003-11-25 | 2012-03-07 | 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 |
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 |
CN1914203A (en) * | 2003-12-04 | 2007-02-14 | 3M创新有限公司 | Sulfone substituted imidazo ring ethers |
US7888349B2 (en) * | 2003-12-29 | 2011-02-15 | 3M Innovative Properties Company | Piperazine, [1,4]Diazepane, [1,4]Diazocane, and [1,5]Diazocane fused imidazo ring compounds |
JP2007517035A (en) * | 2003-12-29 | 2007-06-28 | スリーエム イノベイティブ プロパティズ カンパニー | Arylalkenyl and arylalkynyl substituted imidazoquinolines |
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 |
US20050158325A1 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Immunomodulatory combinations |
JP4991520B2 (en) * | 2004-03-15 | 2012-08-01 | スリーエム イノベイティブ プロパティズ カンパニー | Immune response modulator formulation and method |
EP1730143A2 (en) | 2004-03-24 | 2006-12-13 | 3M Innovative Properties Company | Amide substituted imidazopyridines, imidazoquinolines, and imidazonaphthyridines |
EP1735010A4 (en) * | 2004-04-09 | 2008-08-27 | 3M Innovative Properties Co | 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 |
WO2006009826A1 (en) | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Aryloxy and arylalkyleneoxy substituted thiazoloquinolines and thiazolonaphthyridines |
WO2006065280A2 (en) | 2004-06-18 | 2006-06-22 | 3M Innovative Properties Company | Isoxazole, dihydroisoxazole, and oxadiazole substituted imidazo ring compounds and methods |
WO2006038923A2 (en) | 2004-06-18 | 2006-04-13 | 3M Innovative Properties Company | Aryl substituted imidazonaphthyridines |
EP1765348B1 (en) * | 2004-06-18 | 2016-08-03 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
US8541438B2 (en) | 2004-06-18 | 2013-09-24 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
WO2006009832A1 (en) * | 2004-06-18 | 2006-01-26 | 3M Innovative Properties Company | Substituted imidazo ring systems and methods |
AU2005282726B2 (en) * | 2004-09-02 | 2011-06-02 | 3M Innovative Properties Company | 1-alkoxy 1H-imidazo ring systems and methods |
WO2006029115A2 (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 |
WO2006029223A2 (en) * | 2004-09-08 | 2006-03-16 | Children's Medical Center Corporation | Method for stimulating the immune response of newborns |
WO2006031878A2 (en) * | 2004-09-14 | 2006-03-23 | Novartis Vaccines And Diagnostics Inc. | Imidazoquinoline compounds |
EP1804583A4 (en) * | 2004-10-08 | 2009-05-20 | 3M Innovative Properties Co | 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 |
EP1831226B1 (en) * | 2004-12-30 | 2012-08-08 | 3M Innovative Properties Company | Chiral tetracyclic compounds inducing interferon biosynthesis |
US8034938B2 (en) | 2004-12-30 | 2011-10-11 | 3M Innovative Properties Company | Substituted chiral fused [1,2]imidazo[4,5-c] ring compounds |
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 |
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 |
CA2594253C (en) | 2004-12-30 | 2015-08-11 | 3M Innovative Properties Company | Treatment for cutaneous metastases |
WO2006084251A2 (en) | 2005-02-04 | 2006-08-10 | Coley Pharmaceutical Group, Inc. | Aqueous gel formulations containing immune reponse modifiers |
WO2007120121A2 (en) | 2005-02-09 | 2007-10-25 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted thiazolo[4,5-c] ring compounds and methods |
ES2475728T3 (en) | 2005-02-09 | 2014-07-11 | 3M Innovative Properties Company | Thiazoloquinolines and alkoxy substituted thiazolonaphthyridines |
WO2006086634A2 (en) | 2005-02-11 | 2006-08-17 | Coley Pharmaceutical Group, Inc. | Oxime and hydroxylamine substituted imidazo[4,5-c] ring compounds and methods |
CA2597446A1 (en) | 2005-02-11 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Substituted imidazoquinolines and imidazonaphthyridines |
CN101203529A (en) | 2005-02-18 | 2008-06-18 | 诺华疫苗和诊断公司 | Proteins and nucleic acids from meningitis/sepsis-associated escherichia coli |
ES2595363T3 (en) | 2005-02-18 | 2016-12-29 | J. Craig Venter Institute, Inc. | Sepsis associated with meningitis proteins and nucleic acids / Escherichia coli |
US8343993B2 (en) | 2005-02-23 | 2013-01-01 | 3M Innovative Properties Company | Hydroxyalkyl substituted imidazonaphthyridines |
CA2598437A1 (en) * | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Method of preferentially inducing the biosynthesis of interferon |
AU2006216798A1 (en) | 2005-02-23 | 2006-08-31 | Coley Pharmaceutical Group, Inc. | Hydroxyalkyl substituted imidazoquinoline compounds and methods |
EP1851224A2 (en) | 2005-02-23 | 2007-11-07 | 3M Innovative Properties Company | Hydroxyalkyl substituted imidazoquinolines |
JP2008533148A (en) | 2005-03-14 | 2008-08-21 | スリーエム イノベイティブ プロパティズ カンパニー | Treatment method for 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 |
CA2602683A1 (en) | 2005-04-01 | 2006-10-12 | Coley Pharmaceutical Group, Inc. | Pyrazolopyridine-1,4-diamines and analogs thereof |
US20080193474A1 (en) * | 2005-04-25 | 2008-08-14 | Griesgraber George W | Immunostimulatory Compositions |
CA2615626A1 (en) | 2005-07-18 | 2007-01-25 | Novartis Ag | Small animal model for hcv replication |
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 |
JP2009507856A (en) | 2005-09-09 | 2009-02-26 | コーリー ファーマシューティカル グループ,インコーポレイテッド | Amide and carbamate derivatives of N- {2- [4-amino-2- (ethoxymethyl) -1H-imidazo [4,5-c] quinolin-1-yl] -1,1-dimethylethyl} methanesulfonamide and Method |
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 |
AU2006310163B2 (en) | 2005-11-04 | 2011-09-15 | Seqirus UK Limited | Influenza vaccine with reduced amount of oil-in-water emulsion as adjuvant |
PT2368572T (en) | 2005-11-04 | 2020-06-16 | Seqirus Uk Ltd | Adjuvanted vaccines with non-virion antigens prepared from influenza viruses grown in cell culture |
EP1948173B1 (en) | 2005-11-04 | 2013-07-17 | 3M Innovative Properties Company | Hydroxy and alkoxy substituted 1h-imidazoquinolines and methods |
US8697087B2 (en) | 2005-11-04 | 2014-04-15 | Novartis Ag | Influenza vaccines including combinations of particulate adjuvants and immunopotentiators |
EP2377551A3 (en) | 2005-11-04 | 2013-04-24 | Novartis Vaccines and Diagnostics S.r.l. | Adjuvanted influenza vaccines including cytokine-inducing agents |
ES2619160T7 (en) | 2006-01-27 | 2020-07-29 | Seqirus Uk Ltd | Flu vaccines containing hemagglutinin and matrix proteins |
US8951528B2 (en) | 2006-02-22 | 2015-02-10 | 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 |
ES2536426T3 (en) | 2006-03-23 | 2015-05-25 | Novartis Ag | Imidazoquinoxaline compounds as immunomodulators |
EP2010530A2 (en) * | 2006-03-23 | 2009-01-07 | Novartis AG | Methods for the preparation of imidazole-containing compounds |
ES2388556T3 (en) * | 2006-03-23 | 2012-10-16 | Novartis Ag | Immunopotentiating compounds |
JP2009534303A (en) | 2006-03-24 | 2009-09-24 | 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 ゲーエムベーハー アンド カンパニー カーゲー | Preserving influenza vaccines that are not refrigerated |
SG173336A1 (en) | 2006-03-31 | 2011-08-29 | Novartis Ag | Combined mucosal and parenteral immunization against hiv |
DK2054431T3 (en) | 2006-06-09 | 2012-01-02 | Novartis Ag | Conformers of bacterial adhesins |
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 |
EP2064230A2 (en) | 2006-08-16 | 2009-06-03 | Novartis AG | Immunogens from uropathogenic escherichia coli |
WO2008030511A2 (en) | 2006-09-06 | 2008-03-13 | Coley Pharmaceuticial Group, Inc. | Substituted 3,4,6,7-tetrahydro-5h, 1,2a,4a,8-tetraazacyclopenta[cd]phenalenes |
CA3016948A1 (en) | 2006-09-11 | 2008-03-20 | Seqirus UK Limited | Making influenza virus vaccines without using eggs |
EA200900784A1 (en) | 2006-12-06 | 2009-12-30 | Новартис Аг | VACCINES INCLUDING ANTIGENS FROM FOUR STRAINS OF THE 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 |
PL2185191T3 (en) | 2007-06-27 | 2013-02-28 | 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 |
AU2008347400B2 (en) * | 2008-01-15 | 2014-12-11 | Meda Ab | Treatment of colon diseases or prevention of colorectal carcinoma with imidazoquinoline derivatives |
NZ588191A (en) | 2008-03-03 | 2012-06-29 | Irm Llc | Compounds and compositions as tlr activity modulators |
EP2889042A3 (en) | 2008-03-18 | 2015-10-14 | Novartis AG | Improvements in preparation of influenza virus vaccine antigens |
EP3549602A1 (en) | 2009-03-06 | 2019-10-09 | GlaxoSmithKline Biologicals S.A. | Chlamydia antigens |
MX2011010050A (en) | 2009-03-25 | 2011-12-14 | Univ Texas | Compositions for stimulation of mammalian innate immune resistance to pathogens. |
EP2510947B1 (en) | 2009-04-14 | 2016-02-10 | GlaxoSmithKline Biologicals SA | Compositions for immunising against Staphylococcus aureus |
CN102548577A (en) | 2009-04-27 | 2012-07-04 | 诺华有限公司 | Adjuvanted vaccines for protecting against influenza |
AU2013203591B2 (en) * | 2009-05-01 | 2017-01-19 | University Court Of The University Of Dundee | Treatment or prophylaxis of proliferative conditions |
GB0907551D0 (en) * | 2009-05-01 | 2009-06-10 | Univ Dundee | Treatment or prophylaxis of proliferative conditions |
CN105214080A (en) | 2009-07-15 | 2016-01-06 | 诺华股份有限公司 | RSV F protein compositions and its manufacture method |
PL2464658T3 (en) | 2009-07-16 | 2015-03-31 | Novartis Ag | Detoxified escherichia coli immunogens |
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 |
RS55819B1 (en) | 2010-08-17 | 2017-08-31 | 3M Innovative Properties Co | Lipidated immune response modifier compound compositions, formulations, and methods |
EP2651937B8 (en) | 2010-12-16 | 2016-07-13 | Sumitomo Dainippon Pharma Co., Ltd. | Imidazo[4,5-c]quinolin-1-yl derivative useful in therapy |
EP2667892B1 (en) | 2011-01-26 | 2019-03-27 | GlaxoSmithKline Biologicals SA | Rsv immunization regimen |
PT3275892T (en) | 2011-05-13 | 2020-04-08 | Glaxosmithkline Biologicals Sa | Pre-fusion rsv f antigens |
US8728486B2 (en) | 2011-05-18 | 2014-05-20 | University Of Kansas | Toll-like receptor-7 and -8 modulatory 1H imidazoquinoline derived compounds |
CA2838158C (en) | 2011-06-03 | 2019-07-16 | 3M Innovative Properties Company | Heterobifunctional linkers with polyethylene glycol segments and immune response modifier conjugates made therefrom |
BR112013031039B1 (en) | 2011-06-03 | 2020-04-28 | 3M Innovative Properties Co | hydrazine compounds 1h-imidazoquinoline-4-amines, conjugates made from these compounds, composition and pharmaceutical composition comprising said compounds and conjugates, uses thereof and method of manufacturing the conjugate |
US20130023736A1 (en) | 2011-07-21 | 2013-01-24 | Stanley Dale Harpstead | Systems for drug delivery and monitoring |
CA2854934A1 (en) | 2011-11-07 | 2013-05-16 | Novartis Ag | Carrier molecule comprising a spr0096 and a spr2021 antigen |
WO2013108272A2 (en) | 2012-01-20 | 2013-07-25 | International Centre For Genetic Engineering And Biotechnology | Blood stage malaria vaccine |
CN103566377A (en) | 2012-07-18 | 2014-02-12 | 上海博笛生物科技有限公司 | Targeted immunotherapy for cancer |
LT2941233T (en) | 2013-01-07 | 2020-10-26 | The Trustees Of The University Of Pennsylvania | Compositions and methods for treating cutaneous t cell lymphoma |
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 |
EP3065741B1 (en) | 2013-11-05 | 2021-09-22 | 3M Innovative Properties Company | Sesame oil based injection formulations |
EP2870974A1 (en) | 2013-11-08 | 2015-05-13 | Novartis AG | Salmonella conjugate vaccines |
JP2017503803A (en) | 2014-01-10 | 2017-02-02 | シャンハイ バーディー バイオテック インコーポレイテッド | Compounds and compositions for treating EGFR expressing tumors |
KR20160132109A (en) | 2014-03-26 | 2016-11-16 | 글락소스미스클라인 바이오로지칼즈 에스.에이. | Mutant staphylococcal antigens |
CN105233291A (en) | 2014-07-09 | 2016-01-13 | 博笛生物科技有限公司 | Combined therapy composition and combined therapy method for treating cancers |
CN105440135A (en) | 2014-09-01 | 2016-03-30 | 博笛生物科技有限公司 | Anti-PD-L1 conjugate for treating tumors |
WO2016004876A1 (en) | 2014-07-09 | 2016-01-14 | Shanghai Birdie Biotech, Inc. | Anti-pd-l1 combinations for treating tumors |
CN105461767B (en) * | 2014-08-07 | 2019-03-12 | 富力 | A kind of chemical synthesis process of forsythin |
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 |
RU2722149C1 (en) * | 2015-09-14 | 2020-05-27 | Пфайзер Инк. | New derivatives of imidazo [4,5-c] quinolines and imidazo [4,5-c] [1,5] naphthyridines as lrrk2 inhibitors |
JP2018531318A (en) * | 2015-09-29 | 2018-10-25 | ザ・ユニバーシティ・オブ・シカゴThe University Of Chicago | Polymer conjugate vaccine |
WO2017059280A1 (en) | 2015-10-02 | 2017-04-06 | The University Of North Carolina At Chapel Hill | Novel pan-tam inhibitors and mer/axl dual inhibitors |
CN106943598A (en) | 2016-01-07 | 2017-07-14 | 博笛生物科技(北京)有限公司 | Anti- HER2 for treating tumour is combined |
CN115554406A (en) | 2016-01-07 | 2023-01-03 | 博笛生物科技有限公司 | anti-CD 20 combinations for the treatment of tumors |
CN115252792A (en) | 2016-01-07 | 2022-11-01 | 博笛生物科技有限公司 | anti-EGFR combinations for the treatment of tumors |
CN110234401B (en) | 2016-11-09 | 2024-03-01 | 德克萨斯大学系统董事会 | Methods and compositions for adaptive immunomodulation |
CN108794467A (en) | 2017-04-27 | 2018-11-13 | 博笛生物科技有限公司 | 2- amino-quinoline derivatives |
JP7080501B2 (en) | 2017-06-23 | 2022-06-06 | バーディー バイオファーマシューティカルズ インコーポレイテッド | Pharmaceutical composition |
EP3728255B1 (en) | 2017-12-20 | 2022-01-26 | 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 |
SG11202007518RA (en) | 2018-02-28 | 2020-09-29 | Pfizer | Il-15 variants and uses thereof |
US11370788B2 (en) * | 2018-02-28 | 2022-06-28 | 3M Innovative Properties Company | Substituted imidazo[4,5-c]quinoline compounds with an N-1 branched group |
WO2019224716A2 (en) | 2018-05-23 | 2019-11-28 | Pfizer Inc. | Antibodies specific for gucy2c and uses thereof |
KR102602329B1 (en) | 2018-05-23 | 2023-11-16 | 화이자 인코포레이티드 | Antibodies specific for CD3 and their uses |
CA3101277A1 (en) * | 2018-05-24 | 2019-11-28 | 3M Innovative Properties Company | N-1 branched cycloalkyl substituted imidazo[4,5-c]quinoline compounds, compositions, and methods |
US20210213010A1 (en) * | 2018-07-24 | 2021-07-15 | 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 |
WO2020128893A1 (en) | 2018-12-21 | 2020-06-25 | Pfizer Inc. | Combination treatments of cancer comprising a tlr agonist |
EP3921322A4 (en) * | 2019-02-07 | 2022-07-20 | Canwell Biotech Limited | Phosphorus imidazoquinoline amine derivatives, pharmaceutical compositions and therapeutic methods thereof |
KR20210136014A (en) | 2019-02-12 | 2021-11-16 | 암브룩스, 인코포레이티드 | Compositions, methods and uses thereof containing antibody-TLR agonist conjugates |
CN114599360A (en) * | 2019-10-29 | 2022-06-07 | 骏达贸易有限公司 | 4-amino-imidazoquinoline compounds and uses thereof |
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 |
AU2020410410A1 (en) | 2019-12-17 | 2022-06-09 | Pfizer Inc. | Antibodies specific for CD47, PD-L1, and uses thereof |
CN116323668A (en) | 2020-07-17 | 2023-06-23 | 辉瑞公司 | Therapeutic antibodies and uses thereof |
CA3190606A1 (en) | 2020-08-20 | 2022-02-24 | Ambrx, Inc. | Antibody-tlr agonist conjugates, methods and uses thereof |
Family Cites Families (98)
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 |
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 |
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 |
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 |
WO1992006093A1 (en) * | 1990-10-05 | 1992-04-16 | Minnesota Mining And Manufacturing Company | Process for the preparation of imidazo[4,5-c]quinolin-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 |
SG46492A1 (en) * | 1991-03-01 | 1998-02-20 | Minnesota Mining & Mfg | 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 |
US5648516A (en) | 1994-07-20 | 1997-07-15 | Minnesota Mining And Manufacturing Company | Fused cycloalkylimidazopyridines |
ATE195735T1 (en) | 1993-07-15 | 2000-09-15 | Minnesota Mining & Mfg | IMIDAZO (4,5-C)PYRIDINE-4-AMINE |
US5352784A (en) * | 1993-07-15 | 1994-10-04 | 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 |
US5693811A (en) * | 1996-06-21 | 1997-12-02 | Minnesota Mining And Manufacturing Company | Process for preparing tetrahdroimidazoquinolinamines |
US5741908A (en) * | 1996-06-21 | 1998-04-21 | Minnesota Mining And Manufacturing Company | Process for reparing imidazoquinolinamines |
US5759109A (en) * | 1996-09-09 | 1998-06-02 | Martini; Byron Rocco | Simulated golf ball instructional device |
EP0938315B9 (en) * | 1996-10-25 | 2008-02-20 | 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 |
US6069149A (en) * | 1997-01-09 | 2000-05-30 | Terumo Kabushiki Kaisha | 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 |
CA2361936C (en) * | 1999-01-08 | 2009-06-16 | 3M Innovative Properties Company | Formulations comprising imiquimod or other immune response modifiers for treating mucosal conditions |
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 |
US6756382B2 (en) | 1999-06-10 | 2004-06-29 | 3M Innovative Properties Company | Amide substituted imidazoquinolines |
US6541485B1 (en) | 1999-06-10 | 2003-04-01 | 3M Innovative Properties Company | Urea substituted imidazoquinolines |
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 |
US6573273B1 (en) * | 1999-06-10 | 2003-06-03 | 3M Innovative Properties Company | Urea 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 |
US6677348B2 (en) | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Aryl ether substituted imidazoquinolines |
US6664265B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
US6660735B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Urea substituted imidazoquinoline ethers |
US6545017B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Urea substituted imidazopyridines |
US6677347B2 (en) * | 2000-12-08 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamido ether substituted imidazoquinolines |
US6545016B1 (en) * | 2000-12-08 | 2003-04-08 | 3M Innovative Properties Company | Amide substituted imidazopyridines |
US6664260B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Heterocyclic ether substituted imidazoquinolines |
US6664264B2 (en) * | 2000-12-08 | 2003-12-16 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
US6667312B2 (en) * | 2000-12-08 | 2003-12-23 | 3M Innovative Properties Company | Thioether substituted imidazoquinolines |
CA2430206A1 (en) | 2000-12-08 | 2002-06-13 | 3M Innovative Properties Company | Screening method for identifying compounds that selectively induce interferon alpha |
UA74852C2 (en) | 2000-12-08 | 2006-02-15 | 3M Innovative Properties Co | Urea-substituted imidazoquinoline ethers |
US6525064B1 (en) * | 2000-12-08 | 2003-02-25 | 3M Innovative Properties Company | Sulfonamido substituted imidazopyridines |
UA74593C2 (en) | 2000-12-08 | 2006-01-16 | 3M Innovative Properties Co | Substituted imidazopyridines |
US6660747B2 (en) * | 2000-12-08 | 2003-12-09 | 3M Innovative Properties Company | Amido ether substituted imidazoquinolines |
EP1401437A1 (en) | 2001-06-15 | 2004-03-31 | 3M Innovative Properties Company | Immune response modifiers for the treatment of periodontal disease |
CA2458876A1 (en) | 2001-08-30 | 2003-03-13 | 3M Innovative Properties Company | Methods of maturing plasmacytoid dendritic cells using immune response modifier molecules |
US20030139364A1 (en) | 2001-10-12 | 2003-07-24 | University Of Iowa Research Foundation | Methods and products for enhancing immune responses using imidazoquinoline compounds |
US20040014779A1 (en) | 2001-11-16 | 2004-01-22 | 3M Innovative Properties Company | Methods and compositions related to IRM compounds and toll-like recptor pathways |
WO2004080430A2 (en) | 2003-03-13 | 2004-09-23 | 3M Innovative Properties Company | Methods of improving skin quality |
EP1450804B9 (en) | 2001-11-29 | 2009-04-01 | 3M Innovative Properties Company | Pharmaceutical formulations comprising an immune response modifier |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
EP1478327B1 (en) | 2002-02-22 | 2015-04-29 | Meda AB | Method of reducing and treating uvb-induced immunosuppression |
GB0211649D0 (en) | 2002-05-21 | 2002-07-03 | Novartis Ag | Organic compounds |
EP1511746A2 (en) | 2002-05-29 | 2005-03-09 | 3M Innovative Properties Company | Process for imidazo[4,5-c]pyridin-4-amines |
AU2003237386A1 (en) | 2002-06-07 | 2003-12-22 | 3M Innovative Properties Company | Ether substituted imidazopyridines |
ATE488246T1 (en) | 2002-08-15 | 2010-12-15 | 3M Innovative Properties Co | IMMUNO-STIMULATORY COMPOSITIONS AND METHODS FOR STIMULATING AN IMMUNE RESPONSE |
JP2006503068A (en) | 2002-09-26 | 2006-01-26 | スリーエム イノベイティブ プロパティズ カンパニー | 1H-Imidazo dimer |
WO2004053057A2 (en) | 2002-12-11 | 2004-06-24 | 3M Innovative Properties Company | Gene expression systems and recombinant cell lines |
WO2004053452A2 (en) | 2002-12-11 | 2004-06-24 | 3M Innovative Properties Company | Assays relating to toll-like receptor activity |
AU2003301052A1 (en) * | 2002-12-20 | 2004-07-22 | 3M Innovative Properties Company | Aryl / hetaryl substituted imidazoquinolines |
EP2572715A1 (en) | 2002-12-30 | 2013-03-27 | 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 |
EP1599726A4 (en) | 2003-02-27 | 2009-07-22 | 3M Innovative Properties Co | Selective modulation of tlr-mediated biological activity |
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JP2006523212A (en) | 2003-03-13 | 2006-10-12 | スリーエム イノベイティブ プロパティズ カンパニー | Diagnosis method of skin lesion |
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JP2006523452A (en) | 2003-03-25 | 2006-10-19 | スリーエム イノベイティブ プロパティズ カンパニー | Selective activation of cellular activity mediated through a common Toll-like receptor |
US20040192585A1 (en) | 2003-03-25 | 2004-09-30 | 3M Innovative Properties Company | Treatment for basal cell carcinoma |
CA2521682A1 (en) | 2003-04-10 | 2004-12-16 | 3M Innovative Properties Company | Delivery of immune response modifier compounds using metal-containing particulate support materials |
EA200600540A1 (en) | 2003-09-05 | 2006-08-25 | Анадис Фармасьютикалз, Инк. | INTRODUCTION OF TLR7 LIGANDS AND THEIR TREATMENTS FOR THE TREATMENT OF HEPATITIS C VIRUS INFECTION |
-
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- 2001-12-10 AR ARP010105726A patent/AR035664A1/en active IP Right Grant
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2003
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- 2003-10-29 US US10/696,476 patent/US20040092545A1/en not_active Abandoned
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2004
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2005
- 2005-01-25 HK HK05100647A patent/HK1069166A1/en not_active IP Right Cessation
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2007
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2009
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