PHENYLANALINE AMIDE DERIVATIVES USEFUL FOR TREATING INSULIN-RELATED DISEASES AND CONDITIONS

• US 20120115811A1
• Filed: 02/12/2010
• Published: 05/10/2012
• Est. Priority Date: 02/13/2009
• Status: Active Grant

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Du, Xiaohui, Fu, Zice, Houze, Jonathan B., Jiao, Xian Yun, Kim, Yong-Jae, Li, Leping, Liu, Jinqian, Medina, Julio C., Shen, Wang, Yu, Ming, Lizarzaburu, Mike Elias, Turcotte, Simon
• Granted Patent: US 8,785,468 B2
• Time in Patent Office: Days
• US Class Current: 514/61
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• 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

Provided herein are compounds of formula I: wherein A, B, X, R¹, R² and subscript n are as defined in the following disclosure. Compositions comprising the compounds are also provided, as well as methods for their use, for example, in treatment of type 2 diabetes and type 2 diabetes-related conditions.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein A is selected from the group consisting of furanyl, imidazolyl, isoxazolyl, oxazolyl, phenyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl, each of which is optionally substituted.

3. The compound of claim 1, wherein A is monosubstituted, disubstituted or trisubstituted, each substituent being independently selected from the group consisting of amino, carboxy, halo, hydroxy, heterocyclyl, monosubstituted amino, optionally substituted (C₁-C₅)alkyl, optionally substituted (C₁-C₅)alkylamino, optionally substituted (C₁-C₅)alkoxy and optionally substituted halo(C₁-C₅)alkyl.

4. The compound of claim 1, wherein B is s selected from the group consisting of furanyl, imidazolyl, isoxazolyl, oxazolyl, phenyl, piperidinyl, piperazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl and triazolyl, each of which is optionally substituted.

5. The compound of claim 4, wherein B is monosubstituted or disubstituted, each substituent being independently selected from the group consisting of —

CN, —

C(O)R′

, —

CO₂R′

, —

C(O)NR′

R″

, -halo, —

NO₂, ═

NR′

, —

NR′

C(NH₂)═

NR″

, —

NR′

-C(O)NR″

R′

″

, —

NR′

C(O)R″

, —

NR′

C(O)OR″

, —

NR′

R″

, —

NR′

S(O)₂R″

, ═

O, —

OC(O)NR′

R″

, —

OC(O)R′

, —

OR′

, —

R′

, ═

S, —

S(O)R′

, —

S(O)₂R′

, —

S(O)₂NR′

R″ and

—

SR′

, wherein R′

, R″ and

R′

″

each independently refer to hydrogen, alkyl, amidoalkyl, aminoalkyl, aryl, carboxyalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaryl, heterocyclyl (optionally substituted with ═

O, ═

S, methyl, methoxy or —

NHCH₃), heterocyclylalkyl (optionally substituted with ═

O, ═

S, methyl, methoxy or —

NHCH₃) or hydroxyalkyl.

6. The compound of claim 4, wherein X is -L-Z and wherein L is a divalent radical selected from the group consisting of —

CH₂—

, —

CH(CH₃)—

, —

C(CH₃)₂—

, —

CH(CH₂CH₃)— and

7. The compound of claim 6, wherein Z is selected from the group consisting of cyclopropyl, tetrahydropyranyl, tetrahydrofuranyl, pyridinyl, thiazolyl, pyrimidinyl, imidazolyl, triazolyl, pyrazolyl, oxazolyl, tetrazolyl, pyrazinyl and isooxazolyl, each of which is optionally mono- or di-substituted with a substituent independently selected from the group consisting of acyl, amino, carboxy, carboxyalkyl, halo, hydroxy, hydroxyalkyl, monosubstituted amino, optionally substituted (C₁-C₅)alkyl, optionally substituted (C₁-C₅)alkoxy, optionally substituted halo(C₁-C₅)alkyl and oxo.

8. The compound of claim 6, wherein Z is —

COOH.

9. The compound of claim 1, wherein X is hydrogen.

10. The compound of claim 1, wherein R² is H or methyl.

11. The compound of claim 1, wherein the compound has formula IV:

12. The compound of claim 1, wherein the compound has formula V:

13. The compound of claim 1, wherein the compound has formula VI:

14. The compound of claim 1, wherein the compound has formula VII:

15. The compound of claim 1, wherein the compound has formula VIII:

16. The compound of claim 15, wherein A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyrazol-3-yl, optionally substituted pyrazol-4-yl, optionally substituted pyridine-4-yl and optionally substituted thiazol-5-yl.

17. The compound of claim 15, wherein Z is selected from the group consisting of pyridin-2-yl, thiazol-2-yl, thiazol-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, imidazol-2-yl, imidazol-4-yl, 1,2,3-triazol-4-yl, pyrazol-3-yl, tetrazol-5-yl, pyrazin-2-yl, 1,2,4-triazol-3-yl and isooxazol-3-yl, each of which is optionally substituted.

18. The compound of claim 17, wherein R¹ is fluoro and subscript n is 0 or 1.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 1.

20. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 15.

21. A compound according to claim 1 for use in a therapy.

22. A compound according to claim 1 for use in treating type 2 diabetes, diabetic ketoacidosis, hyperglycemia, diabetic neuropathy, obesity, metabolic syndrome, inflammation, asthma, psoriasis, arthritis, rheumatoid arthritis or inflammatory bowel disease.

23. Use of a compound according to claim 1 for the manufacture of a medicament for the treatment of type 2 diabetes, diabetic ketoacidosis, hyperglycemia, diabetic neuropathy, obesity, metabolic syndrome, inflammation, asthma, psoriasis, arthritis, rheumatoid arthritis and/or inflammatory bowel disease.

24. A method for treating a disease or condition, or symptom thereof, wherein the disease or condition is selected from the group consisting of type 2 diabetes, diabetic ketoacidosis, hyperglycemia, diabetic neuropathy, obesity, metabolic syndrome, inflammation, asthma, psoriasis, arthritis, rheumatoid arthritis, inflammatory bowel disease, cancer and neurologic disorder, the method comprising administering to a subject having the disease or condition a therapeutically effective amount of a compound according to claim 1.

25. The method of claim 24, wherein the disease or condition is selected from the group consisting of type 2 diabetes, diabetic ketoacidosis, hyperglycemia and diabetic neuropathy.

26. The method of claim 24, wherein the subject is a human.

27. The method of claim 24, wherein the compound is administered orally, parenterally or topically.

28. The method of claim 24, wherein the compound is administered in combination with a second therapeutic agent useful for treating type 2 diabetes, diabetic ketoacidosis, hyperglycemia, diabetic neuropathy, or a symptom thereof.

29. The method of claim 28, wherein the second therapeutic agent is sulfonylurea, metformin, acarbose, nateglinide, pioglitazone or rosiglitazone.

30. A method for modulating insulin concentration in plasma in a subject, comprising administering an amount of a compound according to claim 1 to the subject to modulate insulin concentration in plasma.

31. A method comprising administering an amount of a compound of claim 1 to a subject wherein the amount of the compound is effective to

a) reduce food intake;

b) lower plasma glucagon;

c) reduce gastric motility or delay gastric emptying;

or

d) stimulate insulin release in the subject.