Angiogenesis inhibitors

• US 6,265,403 B1
• Filed: 01/07/2000
• Issued: 07/24/2001
• Est. Priority Date: 01/20/1999
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Tebben, Andrew J., Hungate, Randall W., Fraley, Mark E.
• Primary Examiner(s): Ford, John M.
• Assistant Examiner(s): Liu, Hong
• Application Number:
  US09/480,717
• Time in Patent Office: 564 Days
• Field of Search: 544/364, 544/124, 514/253.01, 514/235.2, 514/339, 546/277.4
• US Class Current: 514/235.2
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases and conditions such as angiogenenesis, cancer, atherosclerosis, diabetic retinopathy, and the like in mammals.

Claims

1. A compound in accordance with formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein

X—

Y═

Z is N—

CH═

CH, CH—

N═

CH, or CH—

CH═

N;

R¹ is thienyl or phenyl, said thienyl and phenyl optionally substituted with one to three substituents selected from halogen, O(C_1-6)alkyl, (C_1-6)alkyl, and OH;

R² is C_1-6 alkyl-NR⁷R⁸ or C_1-6 alkyl-heterocyclyl, wherein the heterocyclyl is piperidinyl, piperazinyl, azepinyl or morpholinyl and optionally substituted with CN, halo, or C_1-6 alkyl;

R³ is H, halogen, CN, O(C_1-6)alkyl, (C_1-6)alkyl, CO₂R, —

C_1-6 alkylene-CO₂R, or —

C_1-6 alkylene-O—

C_1-6 alkyl;

R is H or C_1-6 alkyl; and

R⁷ and R⁸ are independently H, C_1-10 alkyl, C_3-6 cycloalkyl, COR, —

C_1-6 alkylene-O—

C_1-6 alkyl, —

C_1-6 alkylene-aryl, COOR, aryl, benzyl, or NR⁷R⁸ are taken together to form a 5-7 membered heterocyclic ring optionally containing, in addition to the nitrogen atom attached to R⁷ and R⁸, one or two non-adjacent additional hetero-atoms selected from N, O, and S, and optionally substituted with CN, halo, or C_1-6 alkyl.

2. A compound according to claim 1 wherein X—

Y═

Z is CH—

N═

CH.

4. A pharmaceutical composition which is comprised of a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

3. A compound selected from the group consisting of:

1-[3-(4-methyl-piperazin-1-yl)-propyl]-3-(5-thiophen-3-yl-pyridin-3-yl)-1H-indole;

5-chloro-1-[3-(4-methyl-piperazin-1-yl)-propyl]3-(5-thiophen-3-yl-pyridin-3-yl)-1H-indole;

1-[3-(4-methyl-piperazin-1-yl)-propyl]-3-(5-thiophen-3-yl-yl-pyridin-3-yl)-1-H-indole-5-carbonitrile;

5-methoxy-1-[3-(4-methyl-piperazin-1-yl)-propyl]-3-(5-thiophen-3-yl-pyridin-3-yl)-1H-indole;

1-(3-piperidin-1-yl-propyl-3-(5-thiophen-3-yl-pyridin-3-yl)-1H-indole; and

1-(2-morpholin-4-yl-ethyl)-3-(5-thiophen-3-yl-pyridin-3-yl)-1H-indole;

or a pharmaceutically acceptable salt thereof.