Small organic molecule regulators of cell proliferation

• US 6,683,192 B2
• Filed: 09/26/2001
• Issued: 01/27/2004
• Est. Priority Date: 03/30/2000
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Porter, Jeffrey, Rubin, Lee, Price, Stephen, Guicherit, Oivin M., Boyd, Edward Andrew, Stibbard, John Harry Alexander, Baxter, Anthony David
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): JIANG, SHAOJIA A
• Application Number:
  US09/964,276
• Publication Number:
  US 20020198236A1
• Time in Patent Office: 853 Days
• Field of Search: 549/32, 546/281.1, 546/211, 546/269.7, 546/272.7, 514/443, 514/277, 514/252.01, 514/256
• US Class Current: 549/32
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07D 333/70 : attached in position 2
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

A compound represented in general formula (X) and (XI):

Claims

1. compound represented in general formula (X):

wherein, as valence and stability permit,

Ar represents a substituted or unsubstituted aryl or heteroaryl ring;

X is selected from —

C(═

O)—

, —

C(═

S)—

, —

S(O₂)—

, —

S(O)—

, and a methylene group optionally substituted with 1-2 lower alkyls;

Y is absent for each occurrence;

Z is absent or represents a substituted or unsubstituted aryl, carbocyclyl, heterocyclyl, or heteroaryl ring, or a lower alkyl, nitro, cyano, or halogen substituent;

R represents, independently for each occurrence, H or substituted or unsubstituted lower alkyl;

Cy′

represents a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl;

M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two M taken together represent substituted or unsubstituted ethene or ethyne, wherein some or all occurrences of M in M_j form all or part of a cyclic structure;

j represents an integer from 2 to 7;

i represents 0 for all occurrences except in the sequence N—

M_i—

Y—

Ar, where i represents 1;

and k represents 0.

2. The compound of claim 1, wherein M_j includes a cycloalkyl ring having 5-7 ring atoms.

3. The compound of claim 2, wherein NR₂ represents NHMe.

4. The compound of claim 1, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

5. The compound of claim 4, wherein the amine is a methylamino group.

6. The compound of claim 1, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

7. The compound of claim 6, wherein the benzo ring is a 1,4-difluorobenzene ring.

8. A compound represented in general formula (XI):

wherein, as valence and stability permit,

Ar represents a substituted or unsubstituted aryl or heteroaryl ring;

X is selected from —

C(═

O)—

, —

C(═

S)—

, —

S(O₂)—

, —

S(O)—

, and a methylene group optionally substituted with 1-2 lower alkyls;

Y is absent for each occurrence;

Z is absent or represents a substituted or unsubstituted aryl, carbocyclyl, heterocyclyl, or heteroaryl ring, or a lower alkyl, nitro, cyano, or halogen substituent;

R represents, independently for each occurrence, H or substituted or unsubstituted lower alkyl;

Cy′

represents a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl;

M represents, independently for each occurrence, a substituted or unsubstituted methylene group, or two adjacent M taken together represent substituted or unsubstituted ethene or ethyne;

Cy represents a substituted or unsubstituted aryl, heterocyclyl, heteroaryl, or cycloalkyl, including polycyclic groups;

i represents 0 for all occurrences except in the sequence N—

M_i—

Y—

Ar, where i represents 1; and

k represents 0.

9. The compound of claim 8, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

10. The compound of claim 9, wherein the amine is a methylamino group.

11. The compound of claim 8, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

12. The compound of claim 11, wherein the benzo ring is a 1,4-difluorobenzene ring.

13. The compound of claim 8, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

14. The compound of claim 13, wherein Cy represents a substituted or unsubstituted cycloalkyl group.

15. The compound of claim 13, wherein NR₂ represents a secondary amine.

16. The compound of claim 13, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

17. The compound of claim 16, wherein each R independently represents H or a lower alkyl.

18. The compound of claim 15, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

19. The compound of claim 18, wherein each R independently represents H or a lower alkyl.

20. The compound of claim 13, wherein Cy represents a substituted or unsubstituted cycloalkyl group.

21. The compound of claim 20, wherein NR₂ represents a secondary amine.

22. The compound of claim 20, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

23. The compound of claim 21, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

24. The compound of claim 21, wherein each R independently represents H or a lower alkyl.

25. The compound of claim 22, wherein each R independently represents H or a lower alkyl.

26. The compound of claim 22, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

27. The compound of claim 8, wherein NR₂ represents a secondary amine.

28. The compound of claim 27, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

29. The compound of claim 27, wherein each R independently represents H or a lower alkyl.

30. The compound of claim 28, wherein Cy represents a substituted or unsubstituted cycloalkyl group.