IP Library › Granted Patent US 7,138,396

Granted Patent B2

US 7,138,396 · App. 11/045,967 · Granted Nov 21, 2006

17 β-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases

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Quick Facts

Patent No.: US 7,138,396
App. No.: 11/045,967
Granted: Nov 21, 2006
Kind: B2

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Abstract

There are disclosed compounds of the formula (I): prodrugs thereof, or pharmaceutically acceptable salts of the compounds or of said prodrugs which are useful as inhibitors of Type 3 17β-Hydroxysteroid Dehydrogenase. Also disclosed are pharmaceutical compositions containing said compounds and their use for the treatment or prevention of androgen dependent diseases.

Claims (235)

1. A method of treating androgen-dependent diseases selected from the group consisting of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenic alopecia and polycystic ovary syndrome comprising administering to a mammal in need thereof an effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof wherein,

R 1 and R 2 are the same or different and are independently selected from the group consisting of aryl, heteroaryl, arylalkyl and heteroarylalkyl, each optionally substituted with one to six groups selected from the group consisting of:

a) halogen;

b) —OCF 3 or —OCHF 2 ;

c) —CF 3 ;

d) —CN;

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 18 -heteroaryl:

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

R 4 , R 5 , R 7 and R 8 are the same or different and are independently selected from the group consisting of H, OH, OR 14 , —NR 11 R 12 , —N(R 11 )C(O)R 13 , alkyl heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 , —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 9 and R 10 are the same or different and are independently selected from the group consisting of H, F, —CF 3 , alkyl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, —NR 11 R 12 and —N(R 11 )C(O)R 13 , provided that when Z is N, then R 9 and R 10 are each not F, hydroxy, alkoxy, aryloxy, —NR 11 R 12 or

—N(R 11 )C(O)R 13 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 15 is selected from the group consisting of —NR 16 R 17 , —OR 16 , alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R 18 ; R 16 and R 17 are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R 18 , provided that when R 15 is —OR 16 , R 16 is not H;

R 18 is one to four substituents each independently selected from the group consisting of lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, alkoxy carbonyl, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl and heteroaryl; and

either X═Z═N, or X═Z═C or X is C and Z is N;

wherein the term “heteroaryl” refers to 5- to 10-membered single or benzofused aromatic ring consisting of 1 to 3 heteroatoms independently selected from the group consisting of O, S and N, provided that the rings do not possess adjacent oxygen and/or sulfur atoms, wherein said heteroaryl can be unsubstituted or substituted with one, two, or three substituents independently selected from lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino and dialkylamino; the term “heteroarylalkyl” refers to a heteroaryl group bonded through an alkyl group; the term “heterocycloalkyl” refers to a non-aromatic heterocyclic ring of 3–7 atoms containing 1–3 heteroatoms selected from N, O and S; and the term “heteroalkyl” refers to an alkyl group containing at least one heteroatom;

in combination with at least one anti-androgenic agent.

2. The method of claim 1 , wherein the anti-androgenic agent is selected from the group consisting of inhibitors of 5α-reductase type 1 and/or type 2, Flutamide, nicalutamide, bicalutamide, LHRH agonists, LHRH antagonists, inhibitors of 17α-hydroxylase/C17–20 lyase, inhibitors of 17β-Hydroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes, and combinations thereof.

3. A method of treating benign prostatic hyperplasia comprising administering to a mammal in need thereof an effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof wherein,

a) halogen;

b) —OCF 3 or —OCHF 2 ;

c) —CF 3 ;

d) —CN:

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 10 -heteroaryl:

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

R 4 , R 5 , R 7 and R 8 are the same or different and are independently selected from the group consisting of H, OH, OR 14 , —NR 11 R 12 , —N(R 11 )C(O)R 13 , alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 , —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

either X═Z═N, or X═Z═C or X is C and Z is N;

in combination with at least one agent useful in the treatment of benign prostatic hyperplasia.

4. The method of claim 3 , wherein the agent useful in the treatment or prevention of benign prostatic hyperplasia is an alpha-1 adrenergic antagonist.

5. A method of treating hair loss, comprising administering to a mammal in need thereof an effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof wherein,

a) halogen;

b) —OCF 3 or —OCHF 2 ;

c) —CF 3 ;

d) —CN;

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 18 -heteroaryl:

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 , —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 9 and R 10 are the same or different and are independently selected from the group consisting of H, F, —CF 3 , alkyl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, —NR 11 R 12 and —N(R 11 )C(O)R 3 , provided that when Z is N, then R 9 and R 10 are each not F, hydroxy, alkoxy, aryloxy, —NR 11 R 12 or —N(R 11 )C(O)R 13 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

either X═Z═N, or X═Z═C or X is C and Z is N;

in combination with at least one anti-alopecia agent.

6. The method of claim 4 wherein the anti-alopecia agent is a potassium channel agonist or a 5α-reductase inhibitor.

7. A method of treating androgen-dependent diseases selected from the group consisting of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenic alopecia and polycystic ovary syndrome comprising administering to a mammal in need of such treatment an effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

a) halogen;

b) —OCF 3 or —OCHF 2 ;

c) —CF 3 ;

d) —CN;

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 18 -heteroaryl;

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 , —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 15 is selected from the group consisting of —NR 1 R 7 , —OR 16 , alkyl cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R 18 ; R 16 and R 17 are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R 18 , provided that when R 15 is —OR 16 , R 16 is not H;

X and Z are the same or different and are independently selected from the group consisting of C and N,

in combination with at least one anti-androgenic agent.

8. The method of claim 7 , wherein the anti-androgenic agent is selected from the group consisting of inhibitors of 5α-reductase type 1 and/or type 2, Flutamide, nicalutamide, bicalutamide, LHRH agonists, LHRH antagonists, inhibitors of 17α-hydroxylase/C17–20 lyase, inhibitors of 17β-Hydroxysteroid dehydrogenase/17β-oxidoreductase isoenzymes, and combinations thereof.

9. A method of treating benign prostatic hyperplasia comprising administering to a mammal in need thereof an effective amount of a compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

a) halogen;

b) —OCF 3 or OCHF 2 ;

c) —CF 3 ;

d) —CN;

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 18 -heteroaryl;

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

R 4 , R 5 , R 7 and R 8 are the same or different and are independently selected from the group consisting of H, OH, OR 14 , —NR 11 R 12 , —N(R 11 )C(O)R 13 alkyl heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 , —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 15 is selected from the group consisting of —NR 16 R 7 —OR 16 , alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R 18 ; R 16 and R 17 are the same or different and are independently selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R 18 , provided that when R 15 is —OR 16 , R 16 is not H;

X and Z are the same or different and are independently selected from the group consisting of C and N,

in combination with at least one agent useful in the treatment of benign prostatic hyperplasia.

10. The method of claim 9 , wherein the agent useful in the treatment or prevention of benign prostatic hyperplasia is an alpha-1 adrenergic antagonist.

11. A method of treating hair loss, comprising administering to a mammal an effective amount of a compound according to formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

a) halogen;

b) —OCF 3 or —OCHF 2 ;

c) —CF 3 ;

d) —CN;

e) alkyl or R 18 -alkyl;

f) heteroalkyl or R 18 -heteroalkyl;

g) aryl or R 18 -aryl;

h) heteroaryl or R 18 -heteroaryl;

i) arylalkyl or R 18 -arylakyl;

j) heteroarylalkyl or R 18 -heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —SO 2 -alkyl;

o) —NR 11 R 12 ;

p) —N(R 11 )C(O)R 13 ,

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —SCH 3 or —SCF 3 ; and

u) —SO 2 CF 3 or —NHSO 2 CF 3 ;

R 3 is H, —OH, alkoxy or alkyl, provided that when X is N, R 3 is not —OH or alkoxy;

R 4 , R 5 , R 7 and R 8 are the same or different and are independently selected from the group consisting of H, OH, OR 4 , —NR 11 R 12 , —N(R 11 )C(O)R 13 , alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R 4 , R 5 , R 7 and R 8 are not OH, OR 14 —NR 11 R 12 , or —N(R 11 )C(O)R 13 ;

R 6 is selected from the group consisting of —C(O)R 15 and —SO 2 R 15 ;

R 11 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R 12 is selected from the group consisting of H, alkyl, aryl and heteroaryl:

R 13 is selected from the group consisting of alkyl, alkoxy and aryloxy;

R 14 is selected from the group consisting of H, alkyl, aryl and heteroaryl;

X and Z are the same or different and are independently selected from the group consisting of C and N,

in combination with at least one anti-alopecia agent.

12. The method of claim 11 wherein the anti-alopecia agent is a potassium channel agonist or a 5α-reductase inhibitor.

Assignments (1)

CHANGE OF NAME Recorded Aug 30, 2012

From: SCHERING CORPORATION

To: MERCK SHARP & DOHME CORP.

Reel/Frame 028884/0151 →