Granted Patent B2

US 9,359,285 · App. 14/519,053 · Granted Jun 7, 2016

Abstract

Claims (64)

1. A method for treating a patient having a condition susceptible to treatment with an androgen receptor modulator, comprising administering to the patient an effective amount of a compound of Formula II:

wherein:

R 1 is NO 2 or CN;

R 2 is selected from among F, Cl, Br, I, SR A , NO 2 and CF 3 ;

R 3 and R 4 are each independently selected from hydrogen, F, Cl, OR A , an optionally substituted C 1 -C 4 alkyl, and CF 3 ;

R 5 is hydrogen;

R 10 is hydrogen;

R 6a and R 7a are each independently hydrogen or an optionally substituted C 1 -C 6 alkyl;

R 9 is selected from an optionally substituted C 1 -C 8 alkyl, an optionally substituted C 1 -C 8 heteroalkyl, CH(R D )OR A , CH(R D )NR A R B and COR A ;

R 12 and R 13 are each independently selected from hydrogen, F, Cl, OR A and (CH 2 ) m R C ;

R A and R B are hydrogen;

R C is selected from an optionally substituted aryl and an optionally substituted heteroaryl that is optionally with a substituent selected from F, Cl, Br, I, CN, OR A , NO 2 , NR A R B , SR A , SOR A , SO 2 R A , an optionally substituted C 1 -C 4 alkyl, CF 3 , and an optionally substituted C 1 -C 4 heteroalkyl;

R D is hydrogen or CF 3 ;

Z is CR A R B ;

n is 0; and

m is 1 or 2,

or a pharmaceutically acceptable salt thereof,

wherein the condition is selected from the group consisting of acne, male-pattern baldness, cancer cachexia, hirsutism, hypogonadism, osteoporosis, impotence, breast cancer, prostate cancer and prostatic hyperplasia.

2. The method according to claim 1 , wherein the patient has cancer cachexia.

3. The method according to claim 1 , wherein the patient has acne.

4. The method of claim 1 , wherein the compound is selected from:

(2R)—N-(4-nitro-3-trifluoromethylphenyl)-2-(hydroxymethyl)pyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

(2R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-(1-(R)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine;

cis-2,5-Dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

trans-2,5-dimethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

4-Benzyl-2-hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidine;

2-Fluoro-4-(2-hydroxymethyl-pyrrolidin-1-yl)-benzonitrile;

5-Hydroxymethyl-1-(4-nitro-3-trifluoromethylphenyl)-pyrrolidin-3-ol;

2-(Aminomethyl)-1-(4-Nitro-3-trifluoromethylphenyl)-pyrrolidine;

(R)—N-(4-nitro-3-trifluoromethylphenyl)-2-hydroxymethylpyrrolidine;

(R)—N-(3-Trifluoromethyl-4-nitrophenyl)-2-formylpyrrolidine;

N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(S)-hydroxy-2,2,2-trifluoroethyl)pyrrolidine; and

N-(3-Trifluoromethyl-4-nitrophenyl)-2-(R)-(1-(R)-hydroxy-2,2,2-trifluoro-ethyl)pyrrolidine;

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 , wherein the compound of Formula (II) is a compound of Formula (IIB), or pharmaceutically acceptable salts thereof:

wherein:

R 1 is NO 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 are each hydrogen;

R 6a and R 7a are each independently selected from hydrogen and an optionally substituted C 1 -C 6 alkyl;

R 9 is COR A , CH(R D )OR A , and CH(R D )NR A R B ;

R 10 is hydrogen; and

R 12 and R 13 are each independently selected from hydrogen, F, Cl, OR A , and (CH 2 ) m R C .

6. The method of claim 1 , wherein:

R 1 is NO 2 or CN;

R 2 is CF 3 ;

R 3 , R 4 , and R 5 are each hydrogen;

R 6a is hydrogen;

R 7a is hydrogen or methyl;

R 9 is selected from formyl, hydroxymethyl and 1-hydroxy-2,2,2-trifluoroethyl;

R 10 is hydrogen;

R 12 is hydrogen; and

R 13 is, F, OH and benzyl.

7. The method of claim 1 , wherein the compound of Formula (II) has formula

or pharmaceutically acceptable salts thereof.

8. The method of claim 1 , wherein the compound of Formula (II) has Formula

or pharmaceutically acceptable salts thereof.

9. The method according to claim 1 , wherein the patient has hypogonadism.

10. The method according to claim 1 , wherein the patient has osteoporosis.

11. The method according to claim 1 , wherein the patient has male pattern baldness.

12. The method according to claim 1 , wherein the patient has breast cancer.

13. The method according to claim 1 , wherein the patient has prostate cancer.

Assignments (11)