Novel aminopyridine-derivatives

• US 20080176894A1
• Filed: 11/16/2007
• Published: 07/24/2008
• Est. Priority Date: 10/01/2003
• Status: Active Grant

• Current Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Original Assignee: Altana Pharma AG (Takeda Pharmaceutical Company Limited)
• Inventors: Fuchss, Thomas
• Granted Patent: US 7,781,453 B2
• Time in Patent Office: Days
• US Class Current: 514/303
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The compounds of Formula (I)

in which R1, R2, R3 and R4 have the meanings as given in the description are novel effective iNOS inhibitors.

Claims

1-15. -15. (canceled)

16. A method for treating an acute inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I

17. The method according to claim 16,

in which

R1 is hydrogen or 1-2C-alkyl,

R2 is hydrogen, halogen, phenyl, or R21- and/or R211-substituted phenyl, in which

R21 is 1-4C-alkyl, cyano, halogen, mono- or di-1-4C-alkylamino, trifluoromethyl, mono- or di-1-4C-alkylaminosulfonyl, hydroxyl, phenyl-1-4C-alkoxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-(R210)-piperazin-1-yl, in which

R210 is 1-4C-alkyl,

R211 is halogen,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

18. The method according to claim 16,

in which

R1 is hydrogen, methyl or ethyl,

R2 is hydrogen, iodine, bromine, phenyl, or R21- and/or R211-substituted phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino, trifluoromethyl, dimethylaminosulfonyl, hydroxyl, benzyloxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-methyl-piperazin-1-yl, in which

R211 is chlorine,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

19. The method according to claim 16,

in which

R1 is hydrogen or methyl,

R2 is bonded in the 6-position of the 3H-imidazo[4,5-b]pyridine ring, and is hydrogen, iodine, bromine, phenyl, 3-hydroxyl-phenyl, 4-(R21)-phenyl, or 3,5-di-chloro-phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino, trifluoromethyl, dimethylaminosulfonyl, benzyloxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-methyl-piperazin-1-yl, in which

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

20. The method according to claim 16,

in which

R1 is hydrogen or 1-4C-alkyl,

R2 is hydrogen, halogen, hydroxyl, nitro, amino, 1-7C-alkyl, trifluoromethyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonylamino, phenyl, R21- and/or R211-substituted phenyl, phenyl-1-4C-alkyl, phenyl-1-4C-alkyl wherein the phenyl moiety is substituted by R22, phenyl-1-4C-alkoxy, pyridyl, pyridyl substituted by R23, pyridyl-1-4C-alkyl, pyridyl-1-4C-alkyl wherein the pyridyl moiety is substituted by R24, in which

R21 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C-alkylamino, trifluoromethyl, hydroxyl, phenylsulfonylamino or phenyl-1-4C-alkoxy,

R211 is halogen or 1-4C-alkoxy,

R22 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R23 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R24 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R3 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R4 is 1-4C-alkyl,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

21. The method according to claim 16,

in which

R1 is hydrogen, methyl or ethyl,

R2 is hydrogen, iodine, bromine, phenyl, or R21-substituted phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino or trifluoromethyl,

R3 is hydrogen,

R4 is methyl,

or a salt, N-oxide or a salt of an N-oxide thereof.

22. The method according to claim 16,

in which

R1 is hydrogen or methyl,

R2 is R21-substituted phenyl, in which

R21 is aminosulphonyl, mono- or di-1-4C-alkylaminosulfonyl, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

23. The method according to claim 16, wherein the compound of formula I is of the formula Ia

24. The method according to claim 16,

in which

R1 is hydrogen,

R2 is bonded to the 6-position of the 3H-imidazo[4,5-b]pyridine ring,

R3 is hydrogen, and

R4 is methyl;

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

25. The method according to claim 16, wherein the compound is selected from the group consisting of:

a. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-3H-imidazo[4,5-b]pyridine,

b. (R,S)-2-[3-(2-Amino-4-methylpyridin-6-yl)prop-2-yl]-3H-imidazo[4,5-b]pyridine,

c. (R,S)-2-[4-(2-Amino-4-methylpyridin-6-yl)but-2-yl]-3H-imidazo[4,5-b]pyridine,

d. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine,

e. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-phenyl-3H-imidazo[4,5-b]pyridine,

f. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-cyano-phenyl)-3H-imidazo[4,5-b]pyridine,

g. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-p-tolyl-3H-imidazo[4,5-b]pyridine,

h. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine,

i. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridine,

j. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-chloro-phenyl)-3H-imidazo[4,5-b]pyridine,

k. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-iodo-phenyl)-3H-imidazo[4,5-b]pyridine,

l. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-trifluoromethyl-phenyl)-3H-imidazo[4,5-b]pyridine,

m. 6-{2-[6-(3-Benzyloxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

n. 6-{2-[6-(3,5-Dichloro-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

o. 6-{2-[6-(4-Benzyloxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

p. 3-{2-[2-(6-Amino-4-methyl-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-phenol,

q. 6-(2-{6-[4-(Azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4-methyl-pyridin-2-ylamine,

r. 4-Methyl-6-(2-{6-[4-(pyrrolidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

s. 4-Methyl-6-(2-{6-[4-(piperidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

t. 4-{2-[2-(6-Amino-4-methyl-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,N-dimethyl-benzenesulfonamide,

u. 4-Methyl-6-(2-{6-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

v. 2-[2-(2-Amino-4-methoxypyridin-6-yl)ethyl]-3H-imidazo[4,5-b]pyridine

and the pharmaceutically acceptable salts, N-oxides and salts of the N-oxides thereof.

26. A method for treating a chronic inflammatory disease of peripheral organs and the central nervous system (CNS) in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I

27. The method according to claim 26,

in which

R1 is hydrogen or 1-2C-alkyl,

R2 is hydrogen, halogen, phenyl, or R21- and/or R211-substituted phenyl, in which

R21 is 1-4C-alkyl, cyano, halogen, mono- or di-1-4C-alkylamino, trifluoromethyl, mono- or di-1-4C-alkylaminosulfonyl, hydroxyl, phenyl-1-4C-alkoxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-(R210)-piperazin-1-yl, in which

R210 is 1-4C-alkyl,

R211 is halogen,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

28. The method according to claim 26,

in which

R1 is hydrogen, methyl or ethyl,

R2 is hydrogen, iodine, bromine, phenyl, or R21- and/or R211-substituted phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino, trifluoromethyl, dimethylaminosulfonyl, hydroxyl, benzyloxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-methyl-piperazin-1-yl, in which

R211 is chlorine,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

29. The method according to claim 26,

in which

R1 is hydrogen or methyl,

R2 is bonded in the 6-position of the 3H-imidazo[4,5-b]pyridine ring, and is hydrogen, iodine, bromine, phenyl, 3-hydroxyl-phenyl, 4-(R21)-phenyl, or 3,5-di-chloro-phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino, trifluoromethyl, dimethylaminosulfonyl, benzyloxy, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-methyl-piperazin-1-yl, in which

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

30. The method according to claim 26,

in which

R1 is hydrogen or 1-4C-alkyl,

R2 is hydrogen, halogen, hydroxyl, nitro, amino, 1-7C-alkyl, trifluoromethyl, 3-7C-cycloalkyl, 3-7C-cycloalkyl-1-4C-alkyl, 1-4C-alkoxy, completely or predominantly fluorine-substituted 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkoxycarbonyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonylamino, phenyl, R21- and/or R211-substituted phenyl, phenyl-1-4C-alkyl, phenyl-1-4C-alkyl wherein the phenyl moiety is substituted by R22, phenyl-1-4C-alkoxy, pyridyl, pyridyl substituted by R23, pyridyl-1-4C-alkyl, pyridyl-1-4C-alkyl wherein the pyridyl moiety is substituted by R24, in which

R21 is cyano, halogen, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, aminocarbonyl, mono- or di-1-4C-alkylaminocarbonyl, 1-4C-alkylcarbonylamino, 1-4C-alkoxycarbonyl, aminosulfonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C-alkylamino, trifluoromethyl, hydroxyl, phenylsulfonylamino or phenyl-1-4C-alkoxy,

R211 is halogen or 1-4C-alkoxy,

R22 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R23 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R24 is halogen, 1-4C-alkyl or 1-4C-alkoxy,

R3 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,

R4 is 1-4C-alkyl,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

31. The method according to claim 26,

in which

R1 is hydrogen, methyl or ethyl,

R2 is hydrogen, iodine, bromine, phenyl, or R21-substituted phenyl, in which

R21 is methyl, cyano, chlorine, fluorine, dimethylamino or trifluoromethyl,

R3 is hydrogen,

R4 is methyl,

or a salt, N-oxide or a salt of an N-oxide thereof.

32. The method according to claim 26,

in which

R1 is hydrogen or methyl,

R2 is R21-substituted phenyl, in which

R21 is aminosulphonyl, mono- or di-1-4C-alkylaminosulfonyl, or —

S(O)₂-Het, in which

Het is azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, or 4N-(1-4C-alkyl)-piperazin-1-yl,

R3 is hydrogen,

R4 is methyl, or methoxy,

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

33. The method according to claim 26, wherein the compound of formula I is of the formula Ia

34. The method according to claim 26,

in which

R1 is hydrogen,

R2 is bonded to the 6-position of the 3H-imidazo[4,5-b]pyridine ring,

R3 is hydrogen, and

R4 is methyl;

or a pharmaceutically acceptable salt, N-oxide or salt of an N-oxide thereof.

35. The method according to claim 26, wherein the compound is selected from the group consisting of:

a. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-3H-imidazo[4,5-b]pyridine,

b. (R,S)-2-[3-(2-Amino-4-methylpyridin-6-yl)prop-2-yl]-3H-imidazo[4,5-b]pyridine,

c. (R,S)-2-[4-(2-Amino-4-methylpyridin-6-yl)but-2-yl]-3H-imidazo[4,5-b]pyridine,

d. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-bromo-3H-imidazo[4,5-b]pyridine,

e. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-phenyl-3H-imidazo[4,5-b]pyridine,

f. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-cyano-phenyl)-3H-imidazo[4,5-b]pyridine,

g. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-p-tolyl-3H-imidazo[4,5-b]pyridine,

h. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-fluoro-phenyl)-3H-imidazo[4,5-b]pyridine,

i. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-dimethylamino-phenyl)-3H-imidazo[4,5-b]pyridine,

j. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-chloro-phenyl)-3H-imidazo[4,5-b]pyridine,

k. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-iodo-phenyl)-3H-imidazo[4,5-b]pyridine,

l. 2-[2-(2-Amino-4-methylpyridin-6-yl)ethyl]-6-(4-trifluoromethyl-phenyl)-3H-imidazo[4,5-b]pyridine,

m. 6-{2-[6-(3-Benzyloxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

n. 6-{2-[6-(3,5-Dichloro-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

o. 6-{2-[6-(4-Benzyloxy-phenyl)-3H-imidazo[4,5-b]pyridin-2-yl]-ethyl}-4-methyl-pyridin-2-ylamine,

p. 3-{2-[2-(6-Amino-4-methyl-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-phenol,

q. 6-(2-{6-[4-(Azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-4-methyl-pyridin-2-ylamine,

r. 4-Methyl-6-(2-{6-[4-(pyrrolidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

s. 4-Methyl-6-(2-{6-[4-(piperidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

t. 4-{2-[2-(6-Amino-4-methyl-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridin-6-yl}-N,N-dimethyl-benzenesulfonamide,

u. 4-Methyl-6-(2-{6-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-pyridin-2-ylamine,

v. 2-[2-(2-Amino-4-methoxypyridin-6-yl)ethyl]-3H-imidazo[4,5-b]pyridine

and the pharmaceutically acceptable salts, N-oxides and salts of the N-oxides thereof.