IP Library › Granted Patent US 7,186,838

Granted Patent B2

US 7,186,838 · App. 10/507,239 · Granted Mar 6, 2007

Fluorinated 4-azasteroid derivatives as androgen receptor modulators

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Quick Facts

Patent No.: US 7,186,838
App. No.: 10/507,239
Granted: Mar 6, 2007
Kind: B2

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Abstract

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

Claims (203)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt or an enantiomer thereof; wherein

n is 0, 1 or 2;

a-b represents CF═CH, CHFCH 2 , or CF 2 CH 2 ;

R 1 is hydrogen, hydroxymethyl, or C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to seven fluorine atoms;

R 2 is hydrogen or C 1-4 alkyl;

R 3 is selected from

(CH 2 ) n -cycloheteroalkyl, and

(CH 2 ) n -aryl, wherein aryl is selected from

(1) phenyl,

(2) naphthyl,

(3) benzimidazolyl, or imidazopyridin

(4) benzofuranyl,

(5) benzothiophenyl,

(6) benzoxazolyl,

(7) benzothiazolyl,

(8) benzodihydrofuranyl,

(9) 1,3-benzodioxolyl,

(10) 2,3-dihydro-1,4-benzodioxinyl,

(11) indolyl,

(12) quinolyl,

(13) isoquinolyl,

(14) furanyl,

(15) thienyl,

(16) imidazolyl,

(17) oxazolyl,

(18) thiazolyl,

(19) isoxazolyl,

(20) isothiazolyl,

(21) pyrazolyl,

(22) pyrrolyl,

(23) pyridyl,

(24) pyrimidyl,

(25) pyrazinyl,

(26) thiadiazolyl,

(27) oxadiazolyl,

(28) triazolyl,

(29) tetrazolyl, and

(30) indanyl;

wherein the alkyl group or the cycloheteroalkyl group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and C 1-4 alkoxy; the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, phenyl-C 1-6 alkyl, amino-C 0-6 alkyl, C 1-6 alkylamino-C 0-6 alkyl, (C 1-6 alkyl) 2 amino-C 0-6 alkyl, phenyl-C 0-6 alkylamino-C 0-6 alkyl, (phenyl-C 0-6 alkyl)2amino-C 0-6 alkyl, C 1-6 alkylthio, phenyl-C 0-6 alkylthio, C 1-6 alkylsulfinyl, phenyl-C 0-6 alkylsulfinyl, C 1-6 alkylsulfonyl, phenyl-C 0-6 alkylsulfonyl,

C 1-6 alkoxy-C 0-6 alkyl, phenyl-C 0-6 alkoxy-C 0-6 alkyl, hydroxycarbonyl-C 0-6 alkyl, C 1-6 alkoxycarbonyl-C 0-6 alkyl, phenyl-C 0-6 alkoxycarbonyl-C 0-6 alkyl, hydroxycarbonyl-C 1-6 alkyloxy, hydroxy-C 0-6 alkyl, cyano, nitro, perfluoro-C 1-4 alkyl, perfluoro-C 1-4 alkoxy, oxo, C 1-6 alkylcarbonyloxy, phenyl-C 0-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, phenyl-C 0-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, phenyl-C 0-6 alkylsulfonylamino, C 1-6 alkoxycarbonylamino, phenyl-C 0-6 alkoxycarbonylamino, C 1-6 alkylaminocarbonylamino, phenyl-C 0-6 alkylaminocarbonylamino, (C 1-6 alkyl) 2 aminocarbonylamino, (phenyl-C 0-6 alkyl) 2 aminocarbonylamino, (C 1-6 alkyl) 2 aminocarbonyloxy, and (phenyl-C 0-6 alkyl) 2 aminocarbonyloxy; and wherein any methylene (CH 2 ) carbon atom in (CH 2 ) n is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

or R 2 and R 3 together form a 5- or 6-membered saturated ring fused with a 5- or 6-membered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O, and S.

2. The compound of claim 1 wherein R 1 is hydrogen or methyl.

3. A compound of structural formula I:

or a pharmaceutically acceptable salt or an enantiomer thereof; wherein

n is 0, 1 or 2;

a-b represents CF═CH, CHFCH 2 , or CF 2 CH 2 ;

R 1 is hydrogen, hydroxymethyl, or C 1-3 alkyl, wherein alkyl is unsubstituted or substituted with one to seven fluorine atoms;

R 2 is hydrogen or C 1-4 alkyl;

R 3 is

(CH 2 ) n -aryl, wherein aryl is selected from

(1) phenyl,

(2) naphthyl,

(3) benzimidazolyl,

(4) imidazopyridinyl

(5) benzofuranyl,

(6) benzothiophenyl,

(7) benzoxazolyl,

(8) benzothiazolyl,

(9) benzodihydrofuranyl,

(10) 1,3-benzodioxolyl,

(11) 2,3-dihydro-1,4-benzodioxinyl,

(12) indolyl,

(13) quinolyl,

(14) isoquinolyl,

(15) furanyl,

(16) thienyl,

(17) imidazolyl,

(18) oxazolyl,

(19) thiazolyl,

(20) isoxazolyl,

(21) isothiazolyl,

(22) pyrazolyl,

(23) pyrrolyl,

(24) pyridyl,

(25) pyrimidyl,

(26) pyrazinyl,

(27) thiadiazolyl,

(28) oxadiazolyl,

(29) triazolyl,

(30) tetrazolyl, and

(31) indanyl;

wherein the alkyl group or the cycloheteroalkyl group is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, and C 1-4 alkoxy; the aryl group as defined in items (1) to (30) is unsubstituted or substituted with one to three groups independently selected from halogen, phenyl, C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, phenyl-C 1-6 alkyl, amino-C 0-6 alkyl, C 1-6 alkylamino-C 0-6 alkyl, (C 1-6 alkyl) 2 amino-C 0-6 alkyl, phenyl-C 0-6 alkylamino-C 0-6 alkyl, (phenyl-C 0-6 alkyl) 2 amino-C 0-6 alkyl, C 1-6 alkylthio, phenyl-C 0-6 alkylthio, C 1-6 alkylsulfinyl, phenyl-C 0-6 alkylsulfinyl, C 1-6 alkylsulfonyl, phenyl-C 0-6 alkylsulfonyl,

C 1-6 alkoxy-C 1-6 alkyl, phenyl-C 0-6 alkoxy-C 0-6 alkyl, hydroxycarbonyl-C 0-6 alkyl, C 1-6 alkoxycarbonyl-C 0-6 alkyl, phenyl-C 0-6 alkoxycarbonyl-C 0-6 alkyl, hydroxycarbonyl-C 1-6 alkyloxy, hydroxy-C 0-6 alkyl, cyano, nitro, perfluoro-C 1-4 alkyl, perfluoro-C 1-4 alkoxy, oxo, C 1-6 alkylcarbonyloxy, phenyl-C 0-6 alkylcarbonyloxy, C 1-6 alkylcarbonylamino, phenyl-C 0-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, phenyl-C 0-6 alkylsulfonylamino, C 1-6 alkoxycarbonylamino, phenyl-C 0-6 alkoxycarbonylamino, C 1-6 alkylaminocarbonylamino, phenyl-C 0-6 alkylaminocarbonylamino, (C 1-6 alkyl) 2 aminocarbonylamino, (phenyl-C 0-6 alkyl) 2 aminocarbonylamino, (C 1-6 alkyl) 2 aminocarbonyloxy, and (phenyl-C 0-6 alkyl) 2 aminocarbonyloxy; and wherein any methylene (CH 2 ) carbon atom in (CH 2 ) n is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) group are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

or R 2 and R 3 together form a 5- or 6-membered saturated ring fused with a 5- or 6-membered aromatic ring system having 0, 1, or 2 heteroatoms selected from the N, O, and S.

4. The compound of claim 3 , wherein R 1 is hydrogen or methyl.

5. The compound of claim 1 wherein a-b represents CF═CH.

6. The compound of claim 1 wherein a-b represents CHFCH 2 .

7. The compound of claim 1 wherein R 2 is hydrogen and R 3 is (CH 2 ) n -aryl.

8. The compound of claim 7 wherein n is 0 or 1.

9. The compound of claim 1 wherein R 1 is methyl, a-b represents CF═CH, R 2 is hydrogen, and R 3 is (CH 2 ) n -aryl.

10. The compound of claim 9 wherein n is 0 or 1.

11. The compound of claim 1 wherein R 1 is methyl, a-b represents CHFCH 2 , R 2 is hydrogen, and R 3 is (CH 2 ) n -aryl.

12. The compound of claim 11 wherein n is 0 or 1.

13. The compound of claim 1 wherein R 1 is methyl, a-b represents CF═CH, R 2 is hydrogen, and R 3 is (CH 2 ) n -cycloheteroalkyl.

14. The compound of claim 13 , wherein n is 0 or 1.

15. The compound of claim 1 wherein R 1 is methyl, a-b represents CHFCH 2 , R 2 is hydrogen, and R 3 is (CH 2 ) n -cycloheteroalkyl.

16. The compound of claim 15 , wherein n is 0 or 1.

17. The compound of claim 2 chosen from:

N-(2-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(3-fluorophenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-chlorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(4-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(3-methoxyphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(3-methylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(3-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(4-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(4-chloro-2-fluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2,4-difluorophenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(α-methylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(phenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(4-chloro-2-trifluoromethylphenyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(5-methylpyridin-2-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(thiophen-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(thiophen-3-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-trifluoromethylphenylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(benzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(1-methylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(1-methyl-5-trifluoromethylbenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(5-chlorobenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(5-methoxybenzimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(benzthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(thiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(4-methylthiazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(thiazol-4-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(1-methylimidazol-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(tetrahydro-2H-pyran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(tetrahydro-2H-pyran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2,3-dihydro-1,4-benzodioxin-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2,3-dihydro-1,4-benzodioxin-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(tetrahydrofuran-2(S)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(tetrahydrofuran-2(R)-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(3H-imidazo[4,5-b]pyridin-2-ylmethyl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-carboxamide;

N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(2-trifluoromethylphenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(3-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(4-methoxyphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(2-trifluoromethylphenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(2-chlorophenyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(2-fluorophenylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(benzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(1-methylbenzimidazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(thiazol-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

N-(furan-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide; and

N-(thiophen-2-ylmethyl)-2α-fluoro-4-methyl-3-oxo-4-aza-5α-androstan-17β-carboxamide;

pharmaceutically acceptable salts and enantiomers thereof.

18. The compound of claim 17 chosen from: