Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition

• US 20070004677A1
• Filed: 06/26/2006
• Published: 01/04/2007
• Est. Priority Date: 06/27/2005
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sutton, James, Ruel, Rejean, Lawrence, R., Chao, Hannguang
• Granted Patent: US 7,816,382 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention provides novel urea mimics and analogues of Formula (I):
or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, W, and R⁶ are as defined herein. These compounds are selective inhibitors of the human P2Y₁ receptor which can be used as medicaments.

Claims

1. A compound of Formula (I):

2. A compound according to claim 1, wherein:

ring A is substituted with 0-4 R¹ and selected from;

and ring B is

substituted with 0-3 R⁷.

3. A compound according to claim 2, wherein:

W is —

NHCO—

, —

NHCO₂—

, —

NHCO₂CH₂—

, —

NHCON(Me)-, —

NHCOCH₂NH—

, —

NHCOCH(Me)-, NHCOCH₂CH₂—

, —

NHCOCH₂CONH—

, —

NHCH₂—

, —

NHCH₂CH₂CH₂—

, —

NHSO₂—

, —

NHSO₂CH₂—

, —

NHCONHNHCO—

, —

CH₂CONH—

,

4. A compound according to claim 3, wherein:

R¹ is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF₃, OCF₃, CN, NO₂, —

(CH₂)_r—

OR^c, —

(CH₂)_r—

NR¹²R¹³, —

(CH₂)_r—

CO₂R^c, —

(CH₂)_r—

C(O)NR¹²R¹³, C_1-4 alkyl substituted with 0-2 R^a, C_2-4 alkenyl substituted with 0-2 R^a, C₂₄ alkynyl substituted with 0-2 R^a, —

(CH₂)_r-phenyl substituted with 0-3 R^b, or —

(CH₂)_r-5- to 10-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^b;

alternatively, two R¹s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising;

carbon atoms and 0-2 additional heteroatoms selected from N, NH, O, and S(O)_p.

5. A compound according to claim 4, wherein:

R¹ is, independently at each occurrence, Me, Pr, i-Pr, Bu, t-Bu, F, Cl, Br, OMe, CF₃, OCF₃, N(Me)₂, —

CH₂N(Me)₂, —

CH₂N(Et)₂, NO₂, —

OCOMe, Ph, OPh, —

CH₂OBn, 4-F-Ph, 2-OMe-Ph, or 2-Me-thiazol-4-yl;

alternatively, two R¹s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising;

carbon atoms and 0-2 additional heteroatoms selected from N, NH, O, and S(O)_p.

6. A compound according to claim 5, wherein:

ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 3-OCF₃-Ph, 4-OCF₃-Ph, 4-N(Me)₂-Ph, 2-CH₂N(Me)₂-Ph, 4-CH₂N(Et)₂-Ph, 3-NO₂-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH₂OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF₃)-Ph, 1-naphthyl, 2-naphthyl,

7. A compound according to claim 6, wherein:

R⁶ is 2-t-Bu-Ph, or 3-t-Bu-Ph.

8. A compound according to claim 1, wherein:

ring A is Ph, 2-Me-Ph, 3-Me-Ph, 4-Me-Ph, 3-Pr-Ph, 4-Pr-Ph, 4-Bu-Ph, 4-t-Bu-Ph, 2-Cl-Ph, 3-Cl-Ph, 4-Cl-Ph, 3-Br-Ph, 4-Br-Ph, 2-OMe-Ph, 3-OMe-Ph, 3-CF₃-Ph, 4-CF₃-Ph, 3-OCF₃-Ph, 4-OCF₃-Ph, 4-N(Me)₂-Ph, 2-CH₂N(Me)₂-Ph, 4-CH₂N(Et)₂-Ph, 3-NO₂-Ph, 2-OCOMe-Ph, 3-Ph-Ph, 4-Ph-Ph, 3-OPh-Ph, 4-CH₂OBn-Ph, 3-(2-OMe-Ph)-OPh, 4-(4-F-Ph)-Ph, 2,4-diCl-Ph, 3,4-diCl-Ph, 3,5-diCl-Ph, 3,5-di(OMe)-Ph, 3,5-di(CF₃)-Ph, 1-naphthyl, 2-naphthyl,

ring B is selected from;

W is —

NHCO—

, —

NHCO₂—

, —

NHCO₂CH₂—

, —

NHCON(Me)-, —

NHCOCH₂NH—

, —

NHCOCH(Me)-, NHCOCH₂CH₂—

, —

NHCOCH₂CONH—

, —

NHCH₂—

, —

NHCH₂CH₂CH₂—

, —

NHSO₂—

, —

NHSO₂CH₂—

, —

NHCONHNHCO—

, —

CH₂CONH—

,

R⁶ is 2-t-Bu-Ph, or 3-t-Bu-Ph.

9. A compound according to claim 1, wherein the compound is selected from the exemplified examples of the present invention or a stereoisomer or pharmaceutically acceptable salt, or solvate form thereof.

10. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

11. A method for treating a thromboembolic disorder, comprising:

administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

12. A method according to any one of claims 11, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.

13. A method according to claim 11, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.