6-PHENYL-1H-IMIDAZO[4,5-c]PYRIDINE-4-CARBONITRILE DERIVATIVES

• US 20090099172A1
• Filed: 07/15/2008
• Published: 04/16/2009
• Est. Priority Date: 07/16/2007
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme BV (Merck & Co., Inc.)
• Original Assignee: N. V. Organon
• Inventors: Rankovic, Zoran, Jones, Philip Stephen, Fradera, Xavier, Bennett, David Jonathan, Cai, Jiaqiang
• Granted Patent: US 7,932,251 B2
• Time in Patent Office: Days
• US Class Current: 514/234.2
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives having the general Formula I

• • to pharmaceutical compositions comprising the same as well as to the use of these derivatives for the preparation of a medicament for the treatment of cathepsin S related diseases such as atherosclerosis, obesity, inflammation and immune disorders, such as rheumatoid arthritis, psoriasis, cancer, and chronic pain, such as neuropathic pain.

Claims

1. A 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative having the general Formula I

2. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 wherein R₁ is H.

3. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 2, wherein R₃ is CF₃ and R₄ is H.

4. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 3, wherein X is O and n is 1 or 2 or 3.

5. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 4, wherein Y is NR₅R₆.

6. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 4, wherein Y is Z and wherein Z is pyridyl.

7. The 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 which is selected from

6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(3-pyrrolidin-1-ylpropoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-[4-(3-N,N-diethylamino-propoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile,

1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethylpiperazin-1-yl-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(3,3-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(cis-3,5-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-(4-(3-[4-(N-methylaminocarbonyl)-piperidin-1-yl]-propoxy}-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(2-ethyl-imidazol-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-[1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[2-(cis-3,5-dimethyl-piperazin-1-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(pyridin-2-yl-methoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethyl-piperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile,

1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazin-1-yl)-propoxy]-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;

6-(4-(2-(1-ethylpiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate; and

1-methyl-6-[4-(6-methyl-pyridin-2-ylmethoxy)-3-trifluoromethyl-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a 6-phenyl-1H-imidazo[4,5-c]-pyridine-4-carbonitrile derivative of claim 1, or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable auxilliaries.

9. The pharmaceutical composition of claim 8, wherein the 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative is selected from the group consisting of

6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(3-pyrrolidin-1-ylpropoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-[4-(3-N,N-diethylamino-propoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethylpiperazin-1-yl)-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(3,3-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(cis-3,5-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)-propoxy}-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-(4-[3-(4-ethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-(4-{3-[4-(N-methylaminocarbonyl)-piperidin-1-yl]-propoxy}-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(2-ethyl-imidazol-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[2-(cis-3,5-dimethyl-piperazin-1-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-triaza-spiro[4,5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(pyridin-2-yl-methoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethyl-piperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazin-1-yl)-propoxy]-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;

6-(4-(2-(1-ethylpiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate; and

1-methyl-6-[4-(6-methyl-pyridin-2-ylmethoxy)-3-trifluoromethyl-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

or a pharmaceutically acceptable salt thereof.

10. A method for the treatment of a disorder selected from the group consisting of osteoporosis, atherosclerosis, inflammation, immune disorders and chronic pain, the method comprising administering an effective amount of a 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative of claim 1 or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the immune disorder is selected from the group consisting of rheumatoid arthritis and psoriasis.

12. The method of claim 10, wherein the chronic pain is neuropathic pain.

13. The method of claim 10, wherein the 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivative is selected from the group consisting of

6-[4-(3-dimethylaminopropoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-(3-pyrrolidin-1-ylpropoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-[4-(3-N,N-diethylamino-propoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[3-(trifluoromethyl)-4-(3-(3,3,4-trimethylpiperazin-1-yl)-propoxy)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(3,3-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(cis-3,5-dimethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[3-(4-methylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethylpiperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-(4-{3-[4-(N-methylaminocarbonyl)-piperidin-1-yl]-propoxy}-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(2-ethyl-imidazol-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[2-(cis-3,5-dimethyl-piperazin-1-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{4-[2-(8-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]dec-3-yl)-ethoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-[4-pyridin-2-yl-methoxy)-3-(trifluoromethyl)-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

6-{4-[3-(4-ethyl-piperazin-1-yl)-propoxy]-3-(trifluoromethyl)-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

1-methyl-6-{3-(trifluoromethyl)-4-[(3-(S)-isopropylpiperazin-1-yl)-propoxy]-phenyl}-1H-imidazo[4,5-c]pyridine-4-carbonitrile hydrochloride;

6-(4-(2-(1-ethylpiperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile 2,2,2-trifluoroacetate; and

1-methyl-6-[4-(6-methyl-pyridin-2-ylmethoxy)-3-trifluoromethyl-phenyl]-1H-imidazo[4,5-c]pyridine-4-carbonitrile;

or a pharmaceutically acceptable salt thereof.