Process for the preparation of 1,2-dihydroquinolines

• US 6,001,846 A
• Filed: 02/17/1998
• Issued: 12/14/1999
• Est. Priority Date: 02/17/1998
• Status: Expired due to Fees

• Current Assignee: Ligand Pharmaceuticals, Inc.
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Edwards, James P., Carreira, Erick M., Jones, Todd K., Riggenberg, Josef D.
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US09/024,986
• Time in Patent Office: 665 Days
• Field of Search: 514/285, 546/62, 546/77, 546/78
• US Class Current: 514/285
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

A method for preparing 1,2-dihydroquinolines that is more flexible than the Skraup reaction is provided. The method comprises treating an ortho-alkenyl aniline with a ketone in the presence of a Lewis acid. Novel intermediates and products of this method useful as steroid receptor modulators, as well as pharmaceutical compositions and methods of use thereof are also claimed.

Claims

1. A process for the preparation of a 1,2-dihydroquinoline of structural formula 12, ##STR12## wherein R^1-6 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, F, Cl, Br, I, CN, CF₃, CF₂ CF₃, CO₂ R⁷ (where R⁷ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR⁷ R⁸ (where R⁸ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where, alternatively, R⁷ and R⁸ combine to form a four- to seven-membered ring), OR⁹ (where R⁹ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl), NR⁷ R⁹, SR⁹, SOR⁹, or SO₂ R⁹ ;

R^16-17 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) or Cl;

or where R¹⁶ and R¹⁷ taken together form a saturated or unsaturated five- to seven-membered, optionally substituted ring;

and R^18-19 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁸ and R¹⁹ taken together form a three- to eight-membered, optionally substituted ring;

that comprises the steps of;

a) treating a compound of structural formula 5 ##STR13## with a halogenating agent to form a compound of structural formula 8, ##STR14## wherein X represents chloro, bromo, or iodo;

b) treating the ortho-haloaniline 8 with a metallated olefin in the presence of a catalyst or catalysts to form a compound of structural formula 10; and

##STR15## c) treating the ortho-alkenylaniline cross-coupling product 10 with a ketone in the presence of a catalyst to form a compound of structural formula 12.

2. The process of claim 1 wherein the halogenating agent of step (a) is a brominating agent or an iodinating agent.

3. The process of claim 1 wherein the metallated olefin of step (b) is an alkenyl borane or an alkenyl stannane.

4. The process of claim 1 wherein the catalyst or catalysts of step (b) are palladium catalysts.

5. The process of claim 1 wherein the ortho-alkenylaniline cross-coupling product 10 is either the E or Z isomer, or a mixture of both.

6. The process of claim 1 wherein the compound of structural formula 10 is treated with any ketone in the presence of a protic or Lewis acid to form the 1,2-dihydroquinoline 12.

7. A process for the preparation of a 1,2-dihydroquinoline of structural formula 12, ##STR16## wherein R^1-6 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, F, Cl, Br, I, CN, CF₃, CF₂ CF₃, CO₂ R⁷ (where R⁷ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR⁷ R⁸ (where R⁸ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where, alternatively, R⁷ and R⁸ combine to form a four- to seven-membered ring), OR⁹ (where R⁹ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl or substituted aryl, heteroaryl or substituted heteroaryl), NR⁷ R⁹, SR⁹, SOR⁹, or SO₂ R⁹ ;

R^16-17 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) or Cl;

or where R¹⁶ and R¹⁷ taken together form a five- to seven-membered, optionally substituted ring;

and R^18-19 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁸ and R¹⁹ taken together form a saturated or unsaturated three- to eight-membered, optionally substituted ring;

that comprises the steps of;

a) treating a compound of structural formula 5 ##STR17## with a halogenating agent to form a compound of structural formula 8, ##STR18## wherein X represents chloro, bromo, or iodo;

b) protecting the nitrogen of the ortho-haloaniline 8 derived to yield a compound of structural formula 13, ##STR19## wherein P represents SiR¹⁰ R¹¹ R¹² (where R^10-12 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl);

COR¹³ (where R¹³ represents CF₃, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, aryl or substituted aryl);

CO₂ R¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl);

CONR¹⁴ R¹⁵ (where R¹⁵ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁴ and R¹⁵ taken together form a five- to seven-membered ring);

benzyl or substituted benzyl;

or allyl or substituted allyl; and

c) treating the N-protected ortho-haloaniline 13 with a metallated olefin in the presence of a catalyst or catalysts to yield an intermediate that is subsequently deprotected to form a compound of structural formula 10; and

##STR20## d) treating the ortho-alkenylaniline cross-coupling product 10 with a ketone in the presence of a catalyst to form a compound of structural formula 12.

8. The process of claim 7 wherein the halogenating agent of step (a) is a brominating agent or an iodinating agent.

9. The process of claim 7 wherein the nitrogen atom of the ortho-haloaniline is protected in step (b) as an N-trimethylsilyl analogue or as an N-trifluoracetyl analogue.

10. The process of claim 7 wherein the metallated olefin of step (c) is an alkenyl borane or an alkenyl stannane.

11. The process of claim 7 wherein the catalyst or catalysts of step (c) are palladium catalysts.

12. The process of claim 7 wherein the ortho-alkenylaniline cross-coupling product 10 is either the E or Z isomer, or a mixture of both.

13. The process of claim 7 wherein the compound of structural formula 10 is treated with any ketone in the presence of a protic or Lewis acid to form the 1,2-dihydroquinoline 12.

14. A compound having the formula:

##STR21## wherein R^1-6 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, F, Cl, Br, I, CN, CF₃, CF₂ CF₃, CO₂ R⁷ (where R⁷ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR⁷ R⁸ (where R⁸ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where, alternatively, R⁷ and R⁸ combine to form a four- to seven-membered ring), OR⁹ (where R⁹ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), NR⁷ R⁹, SR⁹, SOR⁹, or SO₂ R⁹ ;

R¹⁶ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) or Cl;

R¹⁷ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ or Cl;

or where R¹⁶ and R¹⁷ taken together form a saturated or unsaturated five- to seven-membered, optionally substituted ring;

and R^18-19 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁸ and R¹⁹ taken together form a three- to eight-membered, optionally substituted ring.

15. A compound of claim 14 wherein each of R¹⁶, 18, 19 differs from the other two substitutents (R¹⁶ ≠

R¹⁸ ≠

R¹⁹ ≠

R¹⁶).

16. A compound of claim 14 wherein each of R^16-19 differs from the other three substituents (R¹⁶ ≠

R¹⁷ ≠

R¹⁸ ≠

R¹⁹ ;

R¹⁸ ≠

R¹⁶ ≠

R¹⁹ ≠

R¹⁷).

17. A compound of claim 14 wherein R¹⁶ and R¹⁷ are identical (R¹⁶ =R¹⁷).

18. A compound of claim 14 wherein R¹⁷ and R¹⁸ are identical (R¹⁷ =R¹⁸).

19. A compound of claim 14 wherein R¹⁷ and R¹⁹ are identical (R¹⁷ =R¹⁹).

20. A compound of claim 14 wherein R¹⁸ and R¹⁹ are identical (R¹⁸ =R¹⁹), except that R¹⁸ and R¹⁹ cannot represent CH₃ (R¹⁸, 19 ≠

CH₃).

21. A compound of claim 14 wherein R¹⁶ and R¹⁸ are identical (R¹⁶ =R¹⁸), except that R¹⁶, R¹⁸ and R¹⁹ cannot represent CH₃ (R¹⁶, 18, 19 ≠

CH₃).

22. A compound of claim 14 wherein R¹⁶ and R¹⁹ are identical (R¹⁶ =R¹⁹), except that R¹⁶, R¹⁸ and R¹⁹ cannot represent CH₃ (R¹⁶, 18 ,19 ≠

CH₃).

23. A compound of claim 14 wherein R^16-18 are identical (R¹⁶ =R¹⁷ =R¹⁸).

24. A compound of claim 14 wherein R¹⁶, 17, 19 are identical (R¹⁶ =R¹⁷ =R¹⁹).

25. A compound of claim 14 wherein R^17-19 are identical (R¹⁷ =R¹⁸ =R¹⁹).

26. A compound of claim 14 wherein R¹⁶, 18, 19 are identical (R¹⁶ =R¹⁸ =R¹⁹), except that R¹⁶, 18, 19 cannot represent CH₃ (R¹⁶, 18, 19 ≠

CH₃).

27. A compound of claim 14 wherein R^16-19 are identical (R¹⁶ =R¹⁷ =R¹⁸ =R¹⁹).

28. A compound of claim 14 that is a steroid receptor modulator.

29. A compound of claim 14 that is a progesterone receptor agonist.

30. A compound of claim 14 that is a progesterone receptor partial agonist.

31. A compound of claim 14 that is a progesterone receptor antagonist.

32. A method of affecting progesterone receptor activity comprising the in vivo administration of a compound of claim 14.

33. A method of modulating the activity of the progesterone receptor comprising administering to a patient an effective amount of a compound of claim 14.

34. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 14, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A pharmaceutical composition of claim 34, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.

36. A pharmaceutical composition of claim 34, wherein the compound is administered to a patient as a dosage unit from about 1 μ

g/kg of body weight to about 500 mg/kg of body weight.

37. A pharmaceutical composition of claim 34, wherein the compound is administered to a patient as a dosage unit from about 10 μ

g/kg of body weight to about 250 mg/kg of body weight.

38. A pharmaceutical composition of claim 34, wherein the compound is administered to a patient as a dosage unit from about 20 μ

g/kg of body weight to about 100 mg/kg of body weight.

39. A pharmaceutical composition of claim 34, wherein the composition is effective in:

hormone replacement therapy;

modulating fertility;

pregnancy maintenance;

treating dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas, and treating hormone dependent cancers such as cancers of the breast, ovaries, and endometrium.

40. A pharmaceutical composition that modulates progesterone receptor activity comprising an effective amount of a progesterone receptor modulating compound of the formula:

##STR22## wherein R^1-6 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, F, Cl, Br, I, CN, CF₃, CF₂ CF₃, CO₂ R⁷ (where R⁷ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR⁷ R⁸ (where R⁸ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where, alternatively, R⁷ and R⁸ combine to form a four- to seven-membered ring), OR⁹ (where R⁹ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), NR⁷ R⁹, SR⁹, SOR⁹, or SO₂ R⁹ ;

R¹⁶ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) or Cl;

R¹⁷ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ or Cl;

or where R¹⁶ and R¹⁷ taken together form a saturated or unsaturated five- to seven-membered, optionally substituted ring;

and R^18-19 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁸ and R¹⁹ taken together form a three- to eight-membered, optionally substituted ring;

or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

41. A pharmaceutical composition of claim 40 comprising an agonistically effective amount of the progesterone receptor modulating compound.

42. A pharmaceutical composition of claim 40 comprising an partially agonistically effective amount of the progesterone receptor modulating compound.

43. A pharmaceutical composition of claim 40 comprising an antagonistically effective amount of the progesterone receptor modulating compound.

44. A pharmaceutical composition of claim 40, wherein the composition is formulated for oral, topical, intravenous, suppository or parental administration.

45. A pharmaceutical composition of claim 40, wherein the compound is administered to a patient as a dosage unit at from about 1 μ

g/kg of body weight to about 500 mg/kg of body weight.

46. A pharmaceutical composition of claim 40, wherein the compound is administered to a patient as a dosage unit at from about 10 μ

g/kg of body weight to about 250 mg/kg of body weight.

47. A pharmaceutical composition of claim 40, wherein the compound is administered to a patient as a dosage unit at from about 20 μ

g/kg of body weight to about 100 mg/kg of body weight.

48. A pharmaceutical composition of claim 40, wherein the composition is effective in:

hormone replacement therapy;

modulating fertility;

pregnancy maintenance;

treating dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyomas, and treating hormone dependent cancers such as cancers of the breast, ovaries, and endometrium.

49. A method of treating a patient requiring progesterone receptor therapy comprising administering to a patient an effective amount of a progesterone receptor modulating compound having the formula:

##STR23## wherein R^1-6 independently represent H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, F, Cl, Br, I, CN, CF₃, CF₂ CF₃, CO₂ R⁷ (where R⁷ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), CONR⁷ R⁸ (where R⁸ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where, alternatively, R⁷ and R⁸ combine to form a four- to seven-membered ring), OR⁹ (where R⁹ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl), NR⁷ R⁹, SR⁹, SOR⁹, or SO₂ R⁹ ;

R¹⁶ represents H, C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ (where R¹⁴ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) or Cl;

R¹⁷ represents C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OR¹⁴ or Cl;

or where R¹⁶ and R¹⁷ taken together form a saturated or unsaturated five- to seven-membered, optionally substituted ring;

and R^18-19 independently represent C₁ -C₆ alkyl, substituted C₁ -C₆ alkyl, allyl, substituted allyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;

or where R¹⁸ and R¹⁹ taken together form a three- to eight-membered, optionally substituted ring.

50. A method of treating a patient according to claim 49, wherein the progesterone receptor modulating compound is a progestone receptor agonist.

51. A method of treating a patient according to claim 49, wherein the progesterone receptor modulating compound is a progestone receptor partial agonist.

52. A method of treating a patient according to claim 49, wherein the progesterone receptor modulating compound is a progestone receptor antagonist.

53. A method of treating a patient according to claim 49, wherein the progesterone receptor modulating compound is effective in:

hormone replacement therapy;

modulating fertility;

pregnancy maintenance;

treating dysfunctional uterine bleeding, dysmenorrhea, endometriosis, leiomyornas, and treating hormone dependent cancers such as cancers of the breast, ovaries, and endometrium.