4-Azasteroids for treatment of hyperandrogenic conditions
View Patent ↗Compounds of structural Formula (I) and pharmacologically acceptable salts and esters thereof possess 5α-reductase inhibitory activity. These compounds inhibit 5α-reductase type 1 and type 2. The compounds of structural Formula I are useful in the systemic, including oral, and parenteral, including topical, treatment and prevention of hyperandrogenic conditions including prostatic carcinoma, benign prostatic hyperplasia, acne vulgaris, seborrhea, androgenic alopecia (also called androgenetic alopecia) which includes male- and female-pattern baldness, female hirsutism, and prostatitis. A class of compounds of the present invention are also potent antiandrogens. The present invention also relates to novel compositions containing such compounds, methods of their use and methods of their manufacture.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt or ester thereof, wherein:
R 1 is selected from methyl and ethyl;
R 2 is selected from:
(a) H, and
(b) C 1-6 alkyl;
R 3 is heteroaryl, either unsubstituted or substituted with one to three substituents independently selected from:
(1) halo (F, Cl, Br, I),
(2) C 1-2 alkyl;
(3) trifluoromethyl,
(4) nitro,
(5) hydroxy,
(6) cyano,
(7) amino,
(8) C 1-2 alkyloxy,
(9) phenyl, and
(10) heteroaryl; and
R 4 selected from:
(a) C 1-4 alkyl,
(b) phenyl, and
(c) heteroaryl.
2. The compound according to claim 1 wherein R 1 is methyl.
3. The compound according to claim 2 wherein R 2 is selected from
(a) H, and
(b) methyl.
4. The compound according to claim 3 wherein heteroaryl is selected from:
(a) pyridyl,
(b) pyrazinyl,
(c) pyrazolyl, and
(d) thiazolyl;
either unsubstituted or substituted with one to three substituents independently selected from:
(1) halo,
(2) C 1-2 alkyl,
(3) trifluoromethyl,
(4) nitro,
(5) hydroxy,
(6) cyano,
(7) amino, and
(8) C 1-2 alkyloxy.
5. The compound according to claim 3 selected from:
(a) N-(4-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(b) N-(3-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(c) N-(pyrazinyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(d) N-(3-pyrazoyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(e) N-(2-thiazolyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide.
6. A method of treating prostatic cancer in a human being in need of such treatment, comprising administering a therapeutically effective amount of the compound according to claim 1 .
7. A method of treating prostatic cancer in a human being in need of such treatment, comprising administering a therapeutically effective amount of the compound according to claim 5 .
8. A method of inhibiting 5α-reductase type 1, 5α-reductase type 2 and the human androgen receptor in a human in need of such inhibition by administering 0.01 to 1,000 mg per day of a compound according to claim 1 .
9. The method according to claim 8 of inhibiting 5α-reductase type 1, 5α-reductase type 2 and the human androgen receptor in a human in need of such inhibition by administering 0.001 mg/kg to 7 mg/kg per day of a compound selected from:
(a) N-(4-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(b) N-(3-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(c) N-(pyrazinyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(d) N-(3-pyrazoyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(e) N-(2-thiazolyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide.
10. A method of inhibiting 5α-reductase type 1, 5α-reductase type 2 and the human androgen receptor in a human in need of such inhibition by administering 0.01 to 1,000 mg per day of a compound selected from:
(a) N-(4-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(b) N-(3-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-18β-carboxamide,
(c) N-(pyrazinyl)-3-oxo-4methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(d) N-(3-pyrazoyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide, and
(e) N-(2-thiazolyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide.
11. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. The composition according to claim 11 adapted for oral administration.
13. The composition according to claim 11 wherein the compound is selected from:
(a) N-(4-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(b) N-(3-pyridyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(c) N-(pyrazinyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide,
(d) N-(3-pyrazoyl)-3-oxo-4-methyl-4-aza-5α-androst-1-ene-17β-carboxamide, and
(e) N-(2-thiazolyl)-3-oxo-4-aza-4-methyl-5α-androst-1-ene-17β-carboxamide.
14. N-( 2 - trifluoromethyl - phenyl )- 3 - oxo - 4 - aza - 4 - methyl - 5 α - androst - 1 - ene - 17 β - carboxamide.
15. A composition comprising N-( 2 - trifluoromethyl - phenyl )- 3 - oxo - 4 - aza - 4 - methyl - 5 α - androst - 1 - ene - 17 β - carboxamide and a pharmaceutically acceptable carrier.