Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives

• US 7,112,603 B2
• Filed: 02/10/2004
• Issued: 09/26/2006
• Est. Priority Date: 05/24/2000
• Status: Expired due to Fees

• Current Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Agouron Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Gao, Ping, Koenig, Marcel, Moon, Malcolm Wilson, Morozowich, Walter
• Primary Examiner(s): Saeed, Kamal A.
• Application Number:
  US10/774,415
• Publication Number:
  US 20050107340A1
• Time in Patent Office: 959 Days
• Field of Search: 514/418, 548/467, 548/468, 548/486
• US Class Current: 514/418
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07F 9/5728 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom

Abstract

The present invention is directed to prodrugs of certain 3-(pyrrol-2-yl-methylidene)-2-indolinone derivatives that modulate the activity of protein kinases (“PKs”). Pharmaceutical compositions comprising these compounds, methods of treating diseases related to abnormal PK activity utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

Claims

1. A compound of the formula (I):

2. The compound of claim 1, wherein R⁸ and R¹⁰ are each independently methyl.

3. The compound of claim 1, wherein R^2′

is hydrogen, acyl or —

P(O)(OR)(OR′

) and R⁷ is hydrogen;

R³ is hydrogen or lower unsubstituted alkyl;

R⁴ is selected from the group consisting of hydrogen, halogen, aryl and S-sulfonamido;

R⁵ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, and heteroaryl; and

R⁶ is hydrogen.

4. The compound of claim 3, wherein R³ is hydrogen or methyl.

5. The compound of claim 3, wherein R⁴ is hydrogen, chloro, fluoro, bromo or phenyl.

6. The compound of claim 5, wherein R⁴ is hydrogen or fluoro.

7. The compound of claim 3, wherein R⁵ is hydrogen, methyl, ethyl, methoxy, phenyl or pyridyl.

8. The compound of claim 7, wherein R⁵ is hydrogen.

9. The compound of claim 1, wherein R^2′

is hydrogen.

10. The compound of claim 1, wherein R^2′

is —

P(O)(OR)(OR′

).

11. The compound of claim 1, wherein R^2′

is acyl.

48. A pharmaceutical composition comprising a compound of any one of claims 1, 12, 15, 31 or 39 and a pharmaceutically acceptable carrier.

52. A method of synthesizing a compound of formula I comprising:

(a) reacting a compound of the formula V;

12. A compound of the formula (II):

13. The compound of claim 12, wherein R⁹ is (2-diethylaminoethyl)-aminocarbonyl, (2-ethylaminoethyl)aminocarbonyl, 2-(pyrrolidin-1-ylethyl)-aminocarbonyl, 3-(morpholin-4-yl)propyl-aminocarbonyl, or 3-(morpholin-4-yl)-2-hydroxypropylaminocarbonyl.

14. The compound of claim 13, wherein R⁹ is (2-diethylaminoethyl)aminocarbonyl, or (2-ethylaminoethyl)-aminocarbonyl.

15. A compound of the formula II:

16. The compound of claim 15, wherein R^3′

and R^4′

are lower alkyl optionally substituted with hydroxyl.

17. The compound of claim 15, wherein R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, 2-(S)-hydroxymethylpyrrolidin-1-yl, 2-(S)-carboxy-pyrrolidin-1-yl, piperazin-1-yl, or a 4-methylpiperazin-1-yl group.

18. The compound of claim 17, wherein R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl group.

19. The compound of claim 15, wherein R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyrro-1-yl, pyridin-1-yl, oxazol-3-yl, isoxazol-2-yl, pyrazin-1-yl, pyradizin-1-yl, quinolin-1-yl, or a imidazol-1-yl heteroaryl ring.

20. The compound of claim 19, wherein R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyridin-1-yl ring.

21. The compound of claim 15, wherein R³ is hydrogen or methyl.

22. The compound of claim 15, wherein R⁴ is hydrogen, chloro, fluoro, bromo or phenyl.

23. The compound of claim 22, wherein R⁴ is hydrogen or fluoro.

24. The compound of claim 15, wherein R⁵ is hydrogen, methyl, ethyl, methoxy, phenyl or pyridyl.

25. The compound of claim 24, wherein R⁵ is hydrogen.

26. The compound of claim 15, wherein:

R^1′

, R³, R⁵, R⁶, and R⁷ are hydrogen;

R⁴ is halo;

R⁸ and R¹⁰ are unsubstituted lower alkyl;

R⁹ is —

C(═

O)NHR¹³ wherein R¹³ is lower alkyl substituted with amino or heteroalicyclic and optionally substituted with hydroxyl; and

R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl, 2-(S)-hydroxymethylpyrrolidin-1-yl, 2-(S)-carboxypyrrolidin-1-yl, piperazin-1-yl, or a 4-methylpiperazin-1-yl group.

27. The compound of claim 26, wherein R⁹ is (2-diethylaminoethyl)-aminocarbonyl, (2-ethylaminoethyl)-aminocarbonyl, 2-(pyrrolidin-1-ylethyl)aminocarbonyl, 3-(morpholin-4-yl)propyl-aminocarbonyl, 3-(morpholin-4-yl)-2-hydroxypropylaminocarbonyl, particularly (2-diethylaminoethyl)aminocarbonyl, or (2-ethylaminoethyl)-aminocarbonyl.

28. The compound of claim 27, wherein R⁹ is (2-diethylaminoethyl)aminocarbonyl, or (2-ethylaminoethyl)-aminocarbonyl.

29. The compound of claim 27, wherein R^3′

and R^4′

together with the nitrogen atom to which they are attached form a pyrrolidin-1-yl group.

30. The compound of claim 15, which is (3Z)-3-{[3,5-dimethyl-4-(2-diethylaminoethylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one;

(3Z)-3-{[3,5-dimethyl-4-(2-ethylaminoethylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one;

or (3Z)-3-{[3,5-dimethyl-4-(3-morpholin-4-yl-2-hydroxypropylaminocarbonyl)-1H-pyrrol-2-yl]-methylidene}-1-(1-pyrrolidinylmethyl)-1,3-dihydro-2H-indol-2-one.

49. A pharmaceutical composition comprising a compound of claim 30 and a pharmaceutically acceptable carrier.

50. The pharmaceutical composition of claim 49, wherein said composition is administered orally.

31. A compound of the formula III:

32. The compound of claim 31, wherein R⁹ is 2-(dimethylaminoethyl) aminocarbonyl, 2-(diethylaminoethyl)aminocarbonyl, 2-(pyrrolidin-1-ylethyl)aminocarbonyl, or 2-(morpholin-4-ylethyl)aminocarbonyl.

33. The compound of claim 31, wherein

R³ is hydrogen or lower unsubstituted alkyl;

R⁴ is selected from the group consisting of hydrogen, halogen, aryl and S-sulfonamido;

R⁵ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, and heteroaryl; and

R⁶ and R⁷ are hydrogen.

34. The compound of claim 31, wherein R³is hydrogen or methyl.

35. The compound of claim 31, wherein R⁴ is hydrogen, chloro, fluoro, bromo or phenyl.

36. The compound of claim 35, wherein R⁴ is hydrogen or fluoro.

37. The compound of claim 31, wherein R⁵ is hydrogen, methyl, ethyl, methoxy, phenyl or pyridyl.

38. The compound of claim 37, wherein R⁵ is hydrogen.

53. A method of synthesizing a compound of formula III comprising:

(a) reacting a compound of the formula V;

39. A compound of the formula IV:

40. The compound of claim 39, wherein R⁹ is 2-(dimethylaminoethyl) aminocarbonyl, 2-(diethylaminoethyl)aminocarbonyl, 2-(pyrrolidin-1-ylethyl)aminocarbonyl, or 2-(morpholin-4-ylethyl)aminocarbonyl.

41. The compound of claim 39, wherein

R³ is hydrogen or lower unsubstituted alkyl;

R⁴ is selected from the group consisting of hydrogen, halogen, aryl and S-sulfonamido;

R⁵ is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, aryl, and heteroaryl; and

R⁶ and R⁷ are hydrogen.

42. The compound of claim 39, wherein R³ is hydrogen or methyl.

43. The compound of claim 39, wherein R⁴ is hydrogen, chloro, fluoro, bromo or phenyl.

44. The compound of claim 42, wherein R⁴ is hydrogen or fluoro.

45. The compound of claim 39, wherein R⁵ is hydrogen, methyl, ethyl, methoxy, phenyl or pyridyl.

46. The compound of claim 45, wherein R⁵ is hydrogen.

47. The compound of claim 39, wherein R^a and R^b are hydrogen.

54. A method of synthesizing a compound of formula IV comprising:

(a) reacting a compound of the formula V;

51. The pharmaceutical composition of 49, wherein said composition is administered parenterally.