WO2002046194A2 - Imidazopyridines substituees - Google Patents

Imidazopyridines substituees Download PDF

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Publication number
WO2002046194A2
WO2002046194A2 PCT/US2001/046915 US0146915W WO0246194A2 WO 2002046194 A2 WO2002046194 A2 WO 2002046194A2 US 0146915 W US0146915 W US 0146915W WO 0246194 A2 WO0246194 A2 WO 0246194A2
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Prior art keywords
alkyl
aryl
compound
alkenyl
heteroaryl
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PCT/US2001/046915
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English (en)
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WO2002046194A3 (fr
Inventor
Kyle J. Lindstrom
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3M Innovative Properties Company
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Priority to UA2003042937A priority Critical patent/UA74593C2/uk
Priority to AU2002239547A priority patent/AU2002239547B2/en
Priority to MXPA03005013A priority patent/MXPA03005013A/es
Priority to PL01365739A priority patent/PL365739A1/xx
Priority to BR0116034-6A priority patent/BR0116034A/pt
Priority to KR10-2003-7007533A priority patent/KR20030070048A/ko
Priority to SK714-2003A priority patent/SK7142003A3/sk
Priority to IL15588501A priority patent/IL155885A0/xx
Priority to AU3954702A priority patent/AU3954702A/xx
Priority to HU0600592A priority patent/HUP0600592A2/hu
Application filed by 3M Innovative Properties Company filed Critical 3M Innovative Properties Company
Priority to EP01987315A priority patent/EP1343783A2/fr
Priority to JP2002547931A priority patent/JP2004525868A/ja
Priority to NZ526085A priority patent/NZ526085A/xx
Priority to CA002431040A priority patent/CA2431040A1/fr
Priority to EEP200300273A priority patent/EE200300273A/xx
Publication of WO2002046194A2 publication Critical patent/WO2002046194A2/fr
Publication of WO2002046194A3 publication Critical patent/WO2002046194A3/fr
Priority to NO20032453A priority patent/NO20032453L/no
Priority to HR20030465A priority patent/HRP20030465A2/hr
Priority to HK04106187A priority patent/HK1063466A1/xx

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to imidazopyridine compounds that have substituted amine functionality at the 1 -position, and to pharmaceutical compositions containing such compounds.
  • a further aspect of this invention relates to the use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals, and in the treatment of diseases, including viral and neoplastic diseases.
  • the compounds of Formula (I) 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) to the animal.
  • the invention provides methods of synthesizing the compounds of the invention and intermediates useful in the synthesis of these compounds.
  • X is alkylene or alkenylene
  • Y is -CO-, -CS-, or -S0 2 -;
  • Z is a bond, -0-, -S-, or -NR 5 -;
  • Ri is aryl, heteroaryl, heterocyclyl, C ⁇ _ 20 alkyl or C 2 I 2 0 alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of: -alkyl;
  • R. 2 is selected from the group consisting of:
  • R 3 and R are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each R 5 is independently H or C ⁇ -10 alkyl; or a pharmaceutically acceptable salt thereof.
  • step (1) of Reaction Scheme I a 3-nitropyridine-2,4-disulfonate of Formula X is reacted with an amine of Formula R ⁇ -Z-Y-N(R 5 )-X-NH2 to provide a 3-nitro-4- aminopyridine-2-sulfonate of Formula XI. Due to the presence of two sulfonate groups that could in principle be displaced, the reaction may provide a mixture of products that can be readily separated using conventional techmques such as column chromatography.
  • the reaction is preferably carried out by adding the amine to a solution of a compound of Formula X in a suitable solvent such as dichloromethane in the presence of a tertiary amine such as triethylamine.
  • the reaction can be run at a reduced temperature (0°C) in order to decrease the amount of undesired 2-aminated and 2,4-diaminated side products.
  • 3-Nitropyridine-2,4-disulfonates are known and can be readily prepared using known synthetic methods, see for example, Lindstom et al., U.S. Patent No. -5,446, 153 and the references cited therein.
  • step (2) of Reaction Scheme I a 3-nitro-4-aminopyridine-2-sulfonate of Formula XI is reacted with dibenzylamine to provide a 2-dibenzylamino-3-nitropyridin-4-amine of Formula XII.
  • the reaction is carried out by combining a compound of Formula XI, dibenzylamine, and a tertiary amine such as triethylamine in an inert solvent such as benzene, toluene or xylene and heating the resulting mixture.
  • step (3) of Reaction Scheme I the nitro group of a 2-dibenzylamino-3- nitropyridin-4-amine of Formula XII is reduced to an amino group.
  • the reduction is preferably carried out using NiB 2 which is generated in situ from sodium borohydride and nickel chloride hydrate in methanol.
  • the reaction is preferably carried out at ambient temperature.
  • a 2-dibenzylaminopyridine-3,4-diamine of Formula XIII is reacted with a carboxylic acid or an equivalent thereof to provide a 4- dibenzylamino-lH-imidazo[4,5-c]pyridine of Formula XV.
  • 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 R2 substituent in a compound of Formula XV. For example, triethyl orthoformate will provide a compound where R 2 is hydrogen and triethyl orthoacetate will provide a compound where R 2 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.
  • a catlayst such as pyridine hydrochloride can be included.
  • a compound of Formula XV can be prepared in two steps by (a) reacting a diamine of Formula XIII with an acyl halide of formula R 2 C(O)Cl or R 2 C(O)Br to provide a compound of Formula XTV and then (b) cyclizing.
  • step (4a) the acyl halide is added to a solution of the diamine in an inert solvent such as acetonitrile, pyridine or dichloromethane. The reaction can be carried out at ambient temperature.
  • step (4b) the product of step (4a) is heated in an alcoholic solvent in the presence of a base.
  • step (4a) is refluxed in ethanol in the presence of an excess of triethylamine or heated with methanolic ammonia.
  • step (4b) can be carried out by heating the product of step (4a) in pyridine. If step (4a) was carried out in pyridine, step (4b) can be carried out by heating the reaction mixture after analysis indicates that step (4a) is complete.
  • a 4-dibenzylamino-lH-imidazo[4,5-c]pyridine of Formula XV is hydrogenolyzed to provide the 4-amino-lH-imidazo[4,5-c]pyridine of Formula I.
  • the compound of Formula XV is heated in formic acid in the presence of palladium hydroxide on carbon.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme II the amine protecting groups of a 1H- imidazo[4,5-c]pyridine of Formula XVI are removed to provide a lH-imidazo[4,5- cjpyridine of Formula ⁇ .
  • a solution of a compound of Formula XVI in a suitable solvent such as dichloromethane is treated with tiiflic acid at ambient temperature.
  • Compounds of Formula XVI can be prepared using the synthetic method described in Reaction Scheme I.
  • step (1) a 2,4-disulfonate of Formula X is reacted with an amine of formula BOC-NR5-X-N ⁇ 2. Steps 2-4 are then carried out as described above to provide a compound of Formula XVI which is a subgenus of Formula XV.
  • step (2a) of Reaction Scheme II a lH-imidazo[4,5-c]pyridine of Formula II is reacted with an acid chloride of formula R ⁇ -C(0)Cl or an acid anhydride of formula Ri- C(O)OC(0)-R ⁇ to provide a lH-imidazo[4,5-c]pyridin-l-yl amide of Formula XVII which is a subgenus of Formula I.
  • the reaction is preferably carried out by adding the acid chloride or acid anhydride to a solution of a compound of Formula II in a suitable solvent such as dichloromethane or acetonitrile in the presence of a base such as triethylamine.
  • the reaction can be run at a reduced temperature (0°C) or at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • the reaction is preferably carried out by adding the isocyanate or isothiocyanate to a solution of a compound of Formula II in a suitable solvent such as dichloromethane at a reduced temperature (0°C).
  • a suitable solvent such as dichloromethane
  • step (2c) of Reaction Scheme II a lH-imidazo[4,5-c]pyridine of Formula II is reacted with a sulfonyl chloride of formula R S(0) 2 Cl or a sulfonic anhydride of formula R ⁇ -S(O) 2 ⁇ S(O) 2 -R ⁇ to provide a lH-imidazo[4,5-c]pyridin-l-yl sulfonamide of Formula
  • the reaction is preferably carried out by adding the sulfonyl chloride or sulfonic anhydride to a solution of a compound of Formula II in a suitable solvent such as dichloromethane in the presence of a base such as triethylamine.
  • a suitable solvent such as dichloromethane
  • the reaction can be run at a reduced temperature (0°C) or at ambient temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • step (1) of Reaction Scheme III a lH-imidazo[4,5-e]pyridine of Formula ⁇ is reacted with a sulfamoyl chloride of formula R ⁇ -N(R 5 )S(O) 2 Cl to provide a 1H- imidazo[4,5-c]pyridin-l-yl sulfamide of Formula XXI which is a subgenus of Formula I.
  • the sulfamoyl chloride is added to a solution of the compound of Formula II in a suitable solvent such as 1,2-dichloroethane in the presence of a base such as triethylamine.
  • the reaction can be run at an elevated temperature.
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • a sulfamide of Formula XXI can be prepared in two steps by (a) reacting a lH-imidazo[4,5-c]pyridine of Formula II with sulfuryl chloride to generate in situ a sulfamoyl chloride of Formula XX and then (b) reacting the sulfamoyl choride with an amine of formula R ⁇ -N(R 5 ) ⁇ .
  • step (la) the reaction can be carried out by adding a solution of sulfuryl chloride in dichloromethane to a solution of a compound of Formula II in the presence of 1 equivalent of 4-(dimethylamino)pyridine.
  • the reaction is preferably carried out at a reduced temperature (-78°C).
  • step (lb) a solution containing 2 equivalents of R ⁇ -N(R 5 )H and 2 equivalents of triethylamine in dichloromethane is added to the reaction mixture from step (la).
  • the reaction is preferably carried out at a reduced temperature (-78°C).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • Step (1) of Reaction Scheme IV a 2,4-dihydroxy-3-nitropyridine of Formula XXII is chlorinated using conventional chlorinating agents to provide a 2,4-dichloro-3- nitropyridine of Formula XXIII.
  • a compound of Formula XXII is combined with phosphorous oxychloride and heated.
  • Many 2,4-dihydroxy-3-nitropyridines of Formula XXII are known and others can be readily prepared using known synthetic methods, see for example, Lindstom et al., U.S.
  • step (2) of Reaction Scheme TV a 2,4-dichloro-3-nitropyridine of Formula XXIII is reacted with an amine of formula BOC-NR 5 -X-NH 2 to provide a 2-chloro-3- nitropyridine of Formula XXTV.
  • the reaction is preferably carried out by adding the amine to a solution of a compound of Formula XXIII in a suitable solvent such as N,N- dimethylformamide in the presence of a tertiary amine such as triethylamine.
  • step (3) of Reaction Scheme IV a 2-chloro-3-nitropyridine of Formula XXIV is reacted with phenol to provide a 3-nitro-2-phenoxypyridine of Formula XXV.
  • Phenol is reacted with sodium hydride in a suitable solvent such as diglyme to form the phenoxide.
  • the phenoxide is then reacted at an elevated temperature with a compound of Formula XXIV.
  • step (4) of Reaction Scheme IV a 3-nit ⁇ o-2-phenoxypyridine of Formula XXV is reduced to provide a 3-amino-2-phenoxypyridine of Formula XXVI.
  • the reduction is carried out using a conventional heterogeneous hydrogenation catalyst such as platinum on carbon or palladium on carbon.
  • step (5) of Reaction Scheme IV a 3-amino-2-phenoxypyridine of Formula XXVI is reacted with a carboxylic acid or an equivalent thereof to provide a 4-phenoxy-lH- imidazo[4,5-c]quinoline of Formula .
  • 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 R 2 substituent in a compound of Formula IV.
  • triethyl orthoformate will provide a compound where R2 is hydrogen and trimethyl orthovalerate will provide a compound where R 2 is butyl.
  • the reaction can be run in the absence of solvent or in an inert solvent such as toluene.
  • the reaction is run with sufficient heating to drive off any alcohol or water formed as a byproduct of the reaction.
  • a catalyst such as pyridine hydrochloride can be included.
  • step (5) can be carried out by (i) reacting a compound of Formula XXVI with an acyl halide of formula R2C(O)Cl or R 2 C(O)Br and then (ii) cyclizing.
  • the acyl halide is added to a solution of a compound of Formula XXV in an inert solvent such as acetonitrile, pyridine or dichloromethane.
  • the reaction can be carried out at ambient temperature.
  • the product of part (i) is heated in pyridine.
  • step (6) of Reaction Scheme IV the BOC group is removed from a compound of Formula TV to provide 4-phenoxy-lH-imidazo[4,5-c]quinoline of Formula V.
  • a solution of a compound of Formula IV in a suitable solvent such as dichloromethane is treated with trifluoroacetic acid or hydrochloric acid at a reduced temperature.
  • step (7) of Reaction Scheme IV a 4-phenoxy-lH-imidazo[4,5-e]quinoline of Formula V is converted to a 4-phenoxy-lH-imidazo[4,5-c]quinolin-l-yl sulfonamide of Formula VI using the method of step (2c) of Reaction Scheme II.
  • step (8) of Reaction Scheme IV 4-phenoxy-lH-imidazo[4,5-c]quinolin-l-yl sulfonamide of Formula VI is aminated to provide a 4-amino-lH-imidazo[4,5-c]quinolin- 1-yl sulfonamide of Formula XIX which is a subgenus of Formula I.
  • the reaction can be carried out by combining a compound of Formula VI with ammonium acetate in a sealed tube and heating ( ⁇ 150°C).
  • the product or a pharmaceutically acceptable salt thereof can be isolated using conventional methods.
  • the invention also provides novel compounds useful as intermediates in the synthesis of the compounds of Formula I. These intermediates have structural Formulas (II) - (VI) described in more detail below.
  • One class of intermediate compounds has Formula (II):
  • X is alkylene or alkenylene
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl;
  • R 3 and R-i are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each Rs is independently H or Cj.io alkyl; or a pharmaceutically acceptable salt thereof.
  • Q is NO 2 or NH 2 ;
  • X is alkylene or alkenylene
  • R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each R5 is independently H or C MO alkyl; or a pharmaceutically acceptable salt thereof.
  • Another class of intermediates has the Formula (TV):
  • X is alkylene or alkenylene
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl;
  • R 3 and R 4 are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each R 5 is independently H or C ⁇ - ⁇ 0 alkyl; or a pharmaceutically acceptable salt thereof.
  • X is alkylene or alkenylene
  • R 2 is selected from the group consisting of: -hydrogen; -alkyl; -alkenyl; -alkyl-O-alkyl; -alkyl-S-alkyl; -alkyl-O-aryl; -alkyl-S-aryl;
  • R 3 and R are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each R5 is independently H or CM O alkyl; or a pharmaceutically acceptable salt thereof.
  • Another class of intermediates has the Formula (VI):
  • X is alkylene or alkenylene
  • Ri is aryl, heteroaryl, heterocyclyl, C 1 - 2 0 alkyl or C 2 - 20 alkenyl, each of which may be unsubstituted or substituted by one or more substituents independently selected from the group consisting of: -alkyl;
  • R ⁇ is selected from the group consisting of:
  • R3 and j are independently selected from the group consisting of alkyl, alkenyl, halogen, alkoxy, amino, alkylamino, dialkylamino and alkylthio; and each R5 is independently H or C ⁇ - 10 alkyl; or a pharmaceutically acceptable salt thereof.
  • alkyl As used herein, the terms "alkyl”, “alkenyl” and the prefix “alk-” are inclusive of both straight chain and branched chain groups and of cyclic groups, i.e. cycloalkyl and cycloalkenyl. Unless otherwise specified, these groups contain from 1 to 20 carbon atoms, with alkenyl groups containing from 2 to 20 carbon atoms. Preferred groups have a total of up to 10 carbon atoms. Cyclic groups can be monocyclic or polycyclic and preferably have from 3 to 10 ring carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and adamantyl.
  • haloalkyl is inclusive of groups that are substituted by one or more halogen atoms, including perfluorinated groups. This is also true of groups that include the prefix "halo-”. Examples of suitable haloalkyl groups are chloromethyl, trifluoromethyl, and the like.
  • aryl as used herein includes carbocyclic aromatic rings or ring systems. Examples of aryl groups include phenyl, naphthyl, biphenyl, fluorenyl and indenyl.
  • heteroaryl includes aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl.
  • quinolinyl isoquinolinyl, indolyl, isoindolyl, triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl, pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl, naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl, and so on.
  • Heterocyclyl includes non-aromatic rings or ring systems that contain at least one ring hetero atom (e.g., O, S, N) and includes all of the fully saturated and partially unsaturated derivatives of the above mentioned heteroaryl groups.
  • exemplary heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, mo ⁇ holinyl, thiomo ⁇ holinyl, piperidinyl, piperazinyl, thiazolidinyl, isothiazolidinyl, and imidazolidinyl.
  • the aryl, heteroaryl, and heterocyclyl groups can be unsubstituted or substituted by one or more substituents independently selected from the group consisting of alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy, haloalkylthio, halogen, nitro, hydroxy, mercapto, cyano, carboxy, formyl, aryl, aryloxy, arylthio, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroarylalkoxy, heteroarylalkylthio, amino, alkylamino, dialkylamino, heterocyclyl, heterocycloalkyl, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl, arylcarbonyl, heteroarylcarbon
  • preferred Y groups are - CO - and -S0 2 -; Z is preferably a bond or - NR 5 -; and Rj is preferably C1-4 alkyl, aryl, or substituted aryl.
  • Preferred R 2 groups include alkyl groups having 1 to 4 carbon atoms (i.e., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl), methoxyethyl, ethoxymethyl, and cyclopropylmethyl.
  • R 3 and R 4 are preferably methyl.
  • One or more of these preferred substitutents, 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 such as diastereomers and enantiomers, salts, solvates, polymo ⁇ hs, and the like.
  • the invention specifically includes each of the compound's enantiomers as well as racemic mixtures of the enantiomers.
  • compositions of the invention contain a therapeutically effective amount of a compound of the invention as described above in combination with a pharmaceutically acceptable carrier.
  • a therapeutically effective amount means an amount of the compound sufficient to induce a therapeutic effect, such as cytokine induction, antitumor activity, and/or antiviral activity.
  • a therapeutic effect such as cytokine induction, antitumor activity, and/or antiviral activity.
  • the exact amount of active compound used in a pharmaceutical composition of the invention will vary according to factors known to those of skill in the art, such as the physical and chemical nature of the compound, the nature of the carrier, and the intended dosing regimen, it is anticipated that the compositions of the invention will contain sufficient active ingredient to provide a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg, of the compound to the subject.
  • Any of the conventional dosage forms may be used, such as tablets, lozenges, parenteral formulations, syrups, creams, ointments, aerosol formulations, transdermal patches, transmucosal patches and the like.
  • the compounds of the invention can be administered as the single therapeutic agent in the treatment regimen, or the compounds of the invention may be administered in combination with one another or with other active agents, including additional immune response modifiers, antivirals, antibiotics, etc.
  • the compounds of the invention have been shown to induce the production of certain cytokines in experiments performed according to the tests set forth below. These results indicate that the compounds are useful as immune response modifiers that can modulate the immune response in a number of different ways, rendering them useful in the treatment of a variety of disorders.
  • Cytokines whose production may be induced by the administration of compounds according to the invention generally include interferon- (IFN- ) and/or tumor necrosis factor- ⁇ (TNF- ⁇ ) as well as certain interleukins (IL). Cytokines whose biosynthesis may be induced by compounds of the invention include IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12, and a variety of other cytokines. Among other effects, these and other cytokines can inhibit virus production and tumor cell growth, making the compounds useful in the treatment of viral diseases and tumors. Accordingly, the invention provides a method of inducing cytokine biosynthesis in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • Certain compounds of the invention have been found to preferentially induce the expression of IFN- ⁇ in a population of hematopoietic cells such as PBMCs (peripheral blood mononuclear cells) containing pDC2 cells (precursor dendritic cell-type 2) without concomitant production of significant levels of inflammatory cytokines.
  • PBMCs peripheral blood mononuclear cells
  • pDC2 cells precursor dendritic cell-type 2
  • the compounds of the invention affect other aspects of the innate immune response. For example, natural killer cell activity may be stimulated, an effect that may be due to cytokine induction.
  • the compounds may also activate macrophages, which in turn stimulates secretion of nitric oxide and the production of additional cytokines. Further, the compounds may cause proliferation and differentiation of B-lymphocytes. Compounds of the invention also have an effect on the acquired immune response.
  • T helper type 1 (Thl) cytokine IFN- ⁇ is induced indirectly and the production of the T helper type 2 (Th2) cytokines IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.
  • Th2 T helper type 2
  • IL-4, IL-5 and IL-13 are inhibited upon administration of the compounds.
  • This activity means that the compounds are useful in the treatment of diseases where upregulation of the Th 1 response and/or downregulation of the Th2 response is desired.
  • the compounds are expected to be useful in the treatment of atopic diseases, e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • atopic diseases e.g., atopic dermatitis, asthma, allergy, allergic rhinitis; systemic lupus erythematosis; as a vaccine adjuvant for cell mediated immunity; and possibly as a treatment for recurrent fungal diseases and chlamydia.
  • the immune response modifying effects of the compounds make them useful in the treatment of a wide variety of conditions. Because of their ability to induce the production of cytokines such as IFN- ⁇ and/or TNF- ⁇ , the compounds are particularly useful in the treatment of viral diseases and tumors.
  • This immunomodulating activity suggests that compounds of the invention are useful in treating diseases such as, but not limited to, viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; He ⁇ es Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; HIV; CMV; VZV; rhinovirus; adenovirus; coronavirus; influenza; and para-influenza; intraepithelial neoplasias such as cervical intraepithelial neoplasia; human papillomavirus (HPV) and associated neoplasias; fungal diseases, e.g.
  • viral diseases including genital warts; common warts; plantar warts; Hepatitis B; Hepatitis C; He ⁇ es Simplex Virus Type I and Type II; molluscum contagiosum; variola, particularly variola major; HIV;
  • Candida aspergillus, and cryptococcal meningitis
  • neoplastic diseases e.g., basal cell carcinoma, haiiy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g., basal cell carcinoma, haiiy cell leukemia, Kaposi's sarcoma, renal cell carcinoma, squamous cell carcinoma, myelogenous leukemia, multiple myeloma, melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and other cancers
  • parasitic diseases e.g.
  • Additional diseases or conditions that can be treated using the compounds of the invention include actinic keratosis; eczema; eosinophilia; essential thrombocyfhaemia; 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.
  • the compounds could enhance or stimulate the healing of wounds, including chronic wounds.
  • the compounds may be useful for treating the opportunistic infections and tumors that occur after suppression of cell mediated immunity in, for example, transplant patients, cancer patients and HIV patients.
  • An amount of a compound effective to induce cytokine biosynthesis is an amount sufficient to cause one or more cell types, such as monocytes, macrophages, dendritic cells and B-cells to produce an amount of one or more cytokines such as, for example, IFN- ⁇ , TNF- ⁇ , IL-1, IL-6, IL-10 and IL-12 that is increased over the background level of such cytokines.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • the invention also provides a method of treating a viral infection in an animal and a method of treating a neoplastic disease in an animal comprising administering an effective amount of a compound or composition of the invention to the animal.
  • An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality as compared to untreated control animals.
  • the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • An amount of a compound effective to treat a neoplastic condition is an amount that will cause a reduction in tumor size or in the number of tumor foci. Again, the precise amount will vary according to factors known in the art but is expected to be a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 ⁇ g/kg to about 5 mg/kg.
  • Valeryl chloride (3 mL, 24.7 mmol) was added to a solution of the material from Part C in acetonitrile (200 mL). The reaction mixture was stirred at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was combined with ethanol and triethylamine (5 g, 49 mmol.). The reaction mixture was heated at reflux overnight and then concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane and water. The dichloromethane layer was separated and then loaded onto a silica gel column. The column was eluted with 9:90:1 ethyl acetate:dichloromethane: methanol. The fractions containing product were combined and then concentrated under reduced pressure to provide 6.5 g of tert-butyl 4-
  • Triflic acid (16g, 107 mmol) was added to a solution of the material from Part D
  • the aqueous layer contained an insoluble oil that was extracted with dichloromethane.
  • the organic layer was combined with magnesium sulfate, stirred for 5 minutes and filtered.
  • the filtrate was concentrated under reduced pressure to provide a solid which was recrystallized from toluene to provide lg of l-(4-aminobutyl)-2-butyl-6J-dimethyl-lH-imidazo[4,5- c]pyridin-4-amine.
  • Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of l-(4-aminobutyl)-2- butyl-6J-dimethyl-lH-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL).
  • the reaction mixture was cooled in an ice bath.
  • Benzoyl chloride (0.07 mL, 0.5 mmol) was added and the reaction mixture was removed from the ice bath.
  • the reaction mixture was washed twice with water and then concentrated under reduced pressure.
  • the resulting residue was purified by flash chromatography eluting with 10% methanol in dichloromethane to provide an oily brown material.
  • Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of l-(4-aminobutyl)-2- butyl-6J-dimethyl-lH-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (160 mL). The reaction mixture was cooled in an ice bath. Methanesulfonic anhydride (90 mg, 0.5 mmol) was added and the reaction mixture was removed from the ice bath. The reaction mixture was stirred for 35 minutes. The reaction mixture was washed three times with water, concentrated under reduced pressure, and triturated with a minimum volume of methyl acetate.
  • Triethylamine (0.07 mL, 0.5 mmol) was added to a solution of l-(4-aminobutyl)-2- butyl-6J-dimethyl-lH-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL).
  • the reaction mixture was cooled in an ice bath.
  • 4- Fluorobenzenesulfonyl chloride 113 mg, 0.5 mmol was added and the reaction mixture was removed from the ice bath.
  • the reaction mixture was stirred at ambient temperature for 48 hours.
  • the reaction mixture was washed with water (2 X 150 mL) and then concentrated under reduced pressure.
  • Phenylisocyanate (0.056 mL, 0.5 mmol) was added to a chilled solution of of 1 -(4- aminobutyl)-2-butyl-6J-dimethyl-lH-imidazo[4,5-c]pyridin-4-amine (150 mg, 0.5 mmol) in dichloromethane (150 mL). The ice bath was removed. A white precipitate formed after 5 minutes. The reaction mixture was allowed to stir for 30 minutes and then it was concentrated under reduced pressure to provide an off-white crystalline solid.
  • Triethylamine (0.031 mL, 0.23 mmol) was added to a solution of l-(4- aminobutyl)-2-butyl-6J-dimethyl-lH-imidazo[4,5-c]pyridin-4-amine (67 mg, 0.23 mmol) in dichloromethane (45 mL). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol) was added. The reaction mixture was removed from the ice bath. The reaction mixture was allowed to stir at ambient temperature for ⁇ 113 hours. Analysis by ⁇ PLC indicated that the reaction was not complete. The dichloromethane was removed under reduced pressure.
  • 1,2- Dichloroethane 50 mL was added and the reaction mixture was heated to 60°C. After 3 hours, more dimethylsulfamoyl chloride (2.5 ⁇ L) was added and heating was continued. After 22 hours the reaction temperature was raised to reflux and the reaction mixture was refluxed for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure.
  • Part E A mixture of the material from Part D, triethyl orthoacetate (3.59 mL, 19.58 mmol), anhydrous toluene (75 mL) and pyridine hydrochloride (0J5 g) was heated at reflux for 1 hour and then concentrated under reduced pressure to provide a brown oil.
  • the reaction mixture was concentrated under reduced pressure to provide a brown oil.
  • the reaction was judged to be complete in 10 minutes.
  • the reaction mixture was concentrated under reduced pressure to provide a brown oil.
  • the oil was dissolved in dichloromethane and was washed with 5% aqueous sodium hydroxide. The aqueous layer was separated and then extracted with dichloromethane. The organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide a brown solid.
  • N-[4-(2 ,6J-trimethyl-4-phenoxy- 1 H-imidazo [4, 5 -cjpyridin- 1 - yl)butyl]methanesulfonamide (4.20 g, 10.4 mmol) and ammonium acetate (42 g) were combined and then heated in a sealed tube at 150°C for 36 hrs.
  • the reaction mixture was allowed to cool and then it was dissolved in chloroform.
  • the solution was extracted with 10 % aqueous sodium hydroxide solution.
  • the aqueous layer was separated and then extracted multiple times with chloroform.
  • the organic layers were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide a yellow oil.
  • Triethylamine (3.3 mL, 23.7 mmol) was added to a chilled (0°C) mixture of tert- butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient tempera tureand stirred for 2 hours.
  • the reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-( ⁇ 3-[(ethoxyacetyl)amino]-5,6-dimethyl-2- phenoxypyridin-4-yl ⁇ amino)butylcarbamate as a brown oil.
  • the oil was combined with pyridine (130 mL) and heated at reflux overnight.
  • the reaction mixture was concentrated under reduced pressure to provide a brown oil.
  • the oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.
  • N- ⁇ 4-[2-(ethoxymethyi)-6J- dimethyl-4-phenoxy- 1 H-imidazo[4,5-c]pyridin- 1 -yljbutyl ⁇ methanesulfonamide 5.86 g, 13.1 mmol
  • reaction was quenched with 10% aqueous sodium carbonate.
  • the phases were separated and the aqueous fraction was extracted with dichloromethane.
  • the organic fractions were combined, washed with water followed by brine, dried (Na ⁇ SO, ⁇ ), decanted and evaporated to yield a yellow oil.
  • cytokine induction An in vitro human blood cell system is used to assess cytokine induction. Activity is based on the measurement of interferon ( ⁇ ) and tumor necrosis factor ( ⁇ ) (IFN and TNF, respectively) secreted into culture media as described by Testerman et. al. In “Cytokine Induction by the Immunomodulators Imiquimod and S-27609", Journal of Leukocyte Biology, 58, 365-372 (September, 1995).
  • ⁇ interferon
  • ⁇ tumor necrosis factor
  • PBMCs Peripheral blood mononuclear cells
  • Histopaque®-1077 The PBMCs are washed twice with Hank's Balanced Salts Solution and then are suspended at 3-4 x 10 6 cells/mL in RPMI complete.
  • the PBMC suspension is added to 48 well flat bottom sterile tissue culture plates (Costar, Cambridge, MA or Becton Dickinson Labware, Lincoln Park, NJ) containing an equal volume of RPMI complete media containing test compound.
  • the compounds are solubilized in dimethyl sul oxide (DMSO).
  • DMSO concentration should not exceed a final concentration of 1% for addition to the culture wells.
  • the compounds are generally tested at concentrations ranging from 0.12 to 30 ⁇ M.
  • test compound is added at 60 ⁇ M to the first well containing RPMI complete and serial 3 fold dilutions are made in the wells.
  • the PBMC suspension is then added to the wells in an equal volume, bringing the test compound concentrations to the desired range (0.12 to 30 ⁇ M).
  • the final concentration of PBMC suspension is 1.5-2 X 10 6 cells/mL.
  • the plates are covered with sterile plastic lids, mixed gently and then incubated for 18 to 24 hours at 37°C in a 5% carbon dioxide atmosphere.
  • Interferon ( ⁇ ) concentration is determined by ELISA using a Human Multi-Species kit from PBL Biomedical Laboratories, New Brunswick, NJ. Results are expressed in pg/mL.
  • Tumor necrosis factor ( ⁇ ) 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.

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Abstract

L'invention concerne des composés d'imidazopyridine renfermant une fonctionnalité amine substituée en position 1. Ces composés sont utiles comme modificateurs de la réponse immune. Les composés et compositions selon l'invention peuvent induire la biosynthèse de différentes cytokines et sont utiles dans le traitement d'une palette de pathologies, notamment des maladies virales et néoplastiques.
PCT/US2001/046915 2000-12-08 2001-12-06 Imidazopyridines substituees WO2002046194A2 (fr)

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UA2003042937A UA74593C2 (en) 2000-12-08 2001-06-12 Substituted imidazopyridines
CA002431040A CA2431040A1 (fr) 2000-12-08 2001-12-06 Imidazopyridines substituees
PL01365739A PL365739A1 (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
BR0116034-6A BR0116034A (pt) 2000-12-08 2001-12-06 Imidazopiridinas substituìdas
KR10-2003-7007533A KR20030070048A (ko) 2000-12-08 2001-12-06 치환 이미다조피리딘
SK714-2003A SK7142003A3 (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
IL15588501A IL155885A0 (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
EP01987315A EP1343783A2 (fr) 2000-12-08 2001-12-06 Imidazopyridines substituees
HU0600592A HUP0600592A2 (en) 2000-12-08 2001-12-06 Substituted imidazopyridines, pharmaceutical compositions containing them and intermediates
AU2002239547A AU2002239547B2 (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
AU3954702A AU3954702A (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
JP2002547931A JP2004525868A (ja) 2000-12-08 2001-12-06 置換イミダゾピリジン類
NZ526085A NZ526085A (en) 2000-12-08 2001-12-06 Substituted imidazopyridines
MXPA03005013A MXPA03005013A (es) 2000-12-08 2001-12-06 Imidazopiridinas sustituidas.
EEP200300273A EE200300273A (et) 2000-12-08 2001-12-06 Asendatud imidasopüridiinid
NO20032453A NO20032453L (no) 2000-12-08 2003-05-28 Substituerte imidazopyridiner
HR20030465A HRP20030465A2 (en) 2000-12-08 2003-06-06 Substituted imidazopyridines
HK04106187A HK1063466A1 (en) 2000-12-08 2004-08-18 Substituted imidazopyridines

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