IP Library › Granted Patent US 7,605,152
Granted Patent B2
US 7,605,152 · App. 10/501,640 · Granted Oct 20, 2009

17-hydroxy-4-aza-androstan-3-ones as androgen receptor modulators

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Quick Facts
Patent No.
US 7,605,152
App. No.
10/501,640
Granted
Oct 20, 2009
Kind
B2
Abstract

Compounds of structural formula I as herein defined are disclosed as useful in a method for modulating the androgen receptor in a tissue selective manner in a patient in need of such modulation, as well as in a method of activating the function of the androgen receptor in a patient, and in particular the method wherein the function of the androgen receptor is blocked in the prostate of a male patient or in the uterus of a female patient and activated in bone and/or muscle tissue. These compounds are useful in the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporesis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, female sexual dysfunction, post-menopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, pancreatic cancer, renal cancer, prostate cancer, arthritis and joint repair, alone or in combination with other active agents.

Claims (89)

1. A compound of structural formula II:

or a pharmaceutically acceptable salt thereof wherein

“a” represents a single bond or a double bond;

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, fluorine, or C 1-4 alkyl when “a” represents a double bond; or two R 2 substituents are each independently hydrogen, fluorine, or C 1-4 alkyl when “a” represents a single bond;

R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl;

one of R 5 and R 6 is hydrogen and the other is arylmethyl, wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, thiazolyl, imidazolyl, benzofuranyl, and 1,3-benzodioxolyl, wherein the aryl group is unsubstituted or substituted with one to two groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl, and trifluoromethoxy.

2. A compound of structural formula II:

according to claim 1 wherein

“a” represents a single bond or a double bond;

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, fluorine, or C 1-4 alkyl when “a” represents a double bond; or two R 2 substituents are each independently hydrogen, fluorine, or C 1-4 alkyl when “a” represents a single bond;

R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl;

R 5 is hydrogen and R 6 is arylmethyl, wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, thiazolyl, imidazolyl, benzofuranyl, and1,3-benzodioxolyl, wherein the aryl group is unsubstituted or substituted with one to two groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl, and trifluoromethoxy.

3. A compound of structural formula II:

or a pharmaceutically acceptable salt thereof wherein

wherein

“a” represents a single bond or a double bond;

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, fluorine, or C 1-4 alkyl when “a” represents a double bond; or two R 2 substituents are each independently hydrogen, fluorine, or C 1-4 aikyl when “a” represents a single bond;

R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, or C 2-4 alkynyl;

R 5 and R 6 taken together are ═CHaryl, wherein aryl arylmethyl, wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, furanyl, pyrrolyl, thiazolyl, imidazolyl, benzofuranyl, and 1,3-benzodioxolyl, wherein the aryl group is unsubstituted or substituted with one to two groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl, and trifluoromethoxy.

4. A composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier.

5. A composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

6. The compound of claim 2 wherein R 1 is hydrogen or methyl and R 4 is hydrogen.

7. The compound of claim 6 wherein “a” represents a double bond.

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

9. The compound of claim 8 wherein “a” represents a double bond.

10. The compound selected from the group consisting of:

17β-hydroxy-16α-(2-trifluoromethylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(3-trifluoromethylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(4-trifluoromethylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(2-fluorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(3-fluorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(4-fluorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(3-chlorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(4-chlorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(4-trifluoromethoxybenzyl)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(3-methoxybenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-benzyl-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(2-methylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(2-naphthyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16β-(2-methylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16α-(3-methylbenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16β-(4-chlorobenzyl)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-chlorobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-fluorobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-trifluoromethylbenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-trifluoromethylbenzylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-methoxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3,4-methylenedioxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(5-methoxy-3,4-methylenedioxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3,5-difluorobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3,5-dichlorobenzylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3,4-dimethoxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(pyridin-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(pyridin-4-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(furan-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(1-methyl-imidazol-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(piperidin-4-ylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(N-t-butyloxycarbonylpiperidin-4-ylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(1,3-thiazol-2-ylmethylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(benzofuran-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(5-hydroxymethyl-furan-2-ylmethylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(1-methyl-pyrrol-2-ylmethylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(pyrrol-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-ethoxy-pyrimidin-5-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(pyrimidin-5-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-methyl-pyrimidin-5-ylmethylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-trifluoromethoxybenzylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(4-trifluoromethoxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(4-dimethylaminobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(9-methoxy-quinolin-2-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(quinoxalin-6-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(quinoxalin-7-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-hydroxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-hydroxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(4-hydroxybenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(pyridin-3-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(N-methylpiperidin-4-ylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-chloro-4-dimethylaminobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(2-amino-pyridin-3-ylmethylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-carboxymethyl-benzylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-carboxybenzylidene)4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(3-nitrobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

17β-hydroxy-16-(4-nitrobenzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one; and

17β-hydroxy-16-(benzylidene)-4-methyl-4-aza-5α-androst-1-en-3-one;

or a pharmaceutically acceptable salt thereof.

11. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

Assignments (1)
CHANGE OF NAME Recorded Jan 29, 2010
From: MERCK & CO., INC.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 023870/0001 →