Synthesis of selective androgen receptor modulators
View Patent ↗The present invention relates to a synthetic process for the preparation of a novel class of androgen receptor targeting agents (ARTA) which demonstrate androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor. The agents define a new subclass of compounds which are selective androgen receptor modulators (SARM) which are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of chronic muscular wasting; e) decreasing the incidence of, halting or causing a regression of prostate cancer; f) oral androgen relacement and/or other clinical therpauetic and/or diagnostic areas. The process of the present invention is suitable for large-scale preparation, since all of the steps give rise to highly pure compounds, thus avoiding complicated purification procedures which ultimately lower the yield. Thus the present invention provides methods for the synthesis of non-steroidal agonist compounds, that can be used for industrial large-scale synthesis, and that provide highly pure products in high yield.
1. A process for preparing a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:
wherein
X is O,
T is OH, OR, NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
Q is halogen, CN NHCOCH 3 or NHCOCF 3 ,
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 . CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
said process comprising the step of coupling an amide of formula II:
wherein Z, Y R 1 and T are as defined above and L is a leaving group,
with a compound of formula III:
wherein Q and X are as defined above.
2. The process according to claim 1 , wherein T is OH.
3. The process according to claim 1 , wherein R 1 is CH 3 .
4. The process according to claim 1 , wherein Z is NO 2 .
5. The process according to claim 1 , wherein Z is CN.
6. The process according to claim 1 , wherein Y is CF 3 .
7. The process according to claim 1 , wherein Q is NHCOCH 3 .
8. The process according to claim 1 , wherein Q is F.
9. The process according to claim 1 , wherein Q is in the para position.
10. The process according to claim 1 , wherein Z is in the para position.
11. The process according to claim 1 , wherein Y is in the meta position.
12. The process according to claim 1 , wherein said SARM compound is represented by the structure of formula IV:
13. The process according to claim 1 , wherein said SARM compound is represented by the structure of formula V:
14. The process according to claim 1 , wherein said SARM compound is represented by the structure of formula VI:
15. The process according to claim 1 , wherein said coupling step is carried out in the presence of a base.
16. The process according to claim 1 , wherein the leaving group L is Br.
17. The process according to claim 1 , wherein the amide of formula II is prepared by
i) preparing a carboxylic acid of formula VIII by ring opening of a cyclic compound of formula IX
wherein L, R 1 and T are as defined above, and T 1 is O or NH; and
ii) reacting an amine of formula VII:
wherein Z and Y are as defined above, with the carboxylic acid of formula VIII in the presence of a coupling reagent, to produce the amide of formula II.
18. The process according to claim 17 , wherein step (a) is carried out in the presence of HBr.
19. The process according to claim 1 , further comprising the step of converting said selective androgen receptor modulator (SARM) compound to its, isomer, pharmaceutically acceptable salt, pharmaceutical product, N-oxide, hydrate or any combination thereof.
20. A process for preparing a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:
wherein
X is O,
T is OH, OR, NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
Q is halogen, CN NHCOCH 3 ; or NHCOCF 3
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
said process comprising the steps of:
a) preparing a carboxylic acid of formula VIII by ring opening of a cyclic compound of formula IX
wherein L, R 1 and T are as defined above, and T 1 is O or NH;
b) reacting an amine of formula VII:
wherein Z and Y are as defined above, with the carboxylic acid of formula VIII in the presence of a coupling reagent, to produce an amide of formula II
c) coupling the amide of formula II with a compound of formula III:
wherein Q and X are as defined above.
21. The process according to claim 20 , wherein T is OH.
22. The process according to claim 20 , wherein R 1 is CH 3 .
23. The process according to claim 20 , wherein Z is NO 2 .
24. The process according to claim 20 , wherein Z is CN.
25. The process according to claim 20 , wherein Y is CF 3 .
26. The process according to claim 20 , wherein Q is NHCOCH 3 .
27. The process according to claim 20 , wherein Q is F.
28. The process according to claim 20 , wherein Q is in dthe para position.
29. The process according to claim 20 , wherein Z is in the para position.
30. The process according to claim 20 , wherein Y is in the meta position.
31. The process according to claim 20 , wherein said SARM compound is represented by the structure of formula IV:
32. The process according to claim 20 , wherein said SARM compound is represented by the structure of formula V:
33. The process according to claim 20 , wherein said SARM compound is represented by the structure of formula VI:
34. The process according to claim 20 , wherein step (b) is carried out in the presence of a base.
35. The process according to claim 20 , wherein the leaving group L is Br.
36. The process according to claim 20 , wherein step (a) is carried out in the presence of HBr.
37. The process according to claim 20 , further comprising the step of converting said selective androgen receptor modulator (SARM) compound to its, isomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof.
38. A process for preparing a selective androgen receptor modulator (SARM) compound having in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor, said compound represented by the structure of formula I:
wherein
X is O,
T is OH, OR, NHCOCH 3 , or NHCOR;
Z is NO 2 , CN, COOH, COR, NHCOR or CONHR;
Y is CF 3 , F, I, Br, Cl, CN, CR 3 or SnR 3 ;
Q is halogen, CN NHCOCH 3 or NHCOCF 3
R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and
R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
said process comprising the steps of:
a) preparing a carboxylic acid of formula VIII by ring opening of a cyclic compound of formula IX in the presence of HBr
wherein L, R 1 and T are as defined above, and T 1 is O or NH;
b) reacting an amine of formula VII:
wherein Z and Y are as defined above, with the carboxylic acid of formula VIII in the presence of a coupling reagent, to produce an amide of formula II
c) coupling the amide of formula II with a compound of formula III:
wherein Q and X are as defined above.
39. The process according to claim 38 , wherein T is OH.
40. The process according to claim 38 , wherein R 1 is CH 3 .
41. The process according to claim 38 , wherein Z is NO 2 .
42. The process according to claim 38 , wherein Z is CN.
43. The process according to claim 38 , wherein Y is CF 3 .
44. The process according to claim 38 , wherein Q is NHCOCH 3 .
45. The process according to claim 38 , wherein Q is F.
46. The process according to claim 38 , wherein Q is in the para position.
47. The process according to claim 38 , wherein Z is in the para position.
48. The process according to claim 38 , wherein Y is in the meta position.
49. The process according to claim 38 , wherein said SARM compound is represented by the structure of formula IV:
50. The process according to claim 38 , wherein said SARM compound is represented by the structure of formula V:
51. The process according to claim 38 , wherein said SARM compound is represented by the structure of formula VI:
52. The process according to claim 38 , wherein step (b) is carried out in the presence of a base.
53. The process according to claim 38 , wherein the leaving group L is Br.
54. The process according to claim 38 , further comprising the step of converting said selective androgen receptor modulator (SARM) compound to its, isomer, pharmaceutically acceptable salt, N-oxide, hydrate or any combination thereof.