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

• US 6,969,718 B2
• Filed: 10/15/2002
• Issued: 11/29/2005
• Est. Priority Date: 10/17/2001
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Paruch, Kamil, Guzi, Timothy J.
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): Tucker, Zachary C.
• Application Number:
  US10/271,358
• Publication Number:
  US 20030232837A1
• Time in Patent Office: 1,141 Days
• Field of Search: 514/253.01, 514/253.02, 544/360
• US Class Current: 514/253.01
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

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

1. A compound of the formula (I):

or a pharmaceutically acceptable salt of the compound wherein,

R¹ is selected from the group consisting of aryl, heteroaryl, arylalkyl, heteroarylalkyl and diphenylalkyl, each optionally substituted with one to six groups selected from the group consisting of;

a) halogen;

b) —

OCF₃ or —

OCHF₂;

c) —

CF₃;

d) —

CN;

e) alkyl or R¹⁸-alkyl;

f) heteroalkyl or R¹⁸-heteroalkyl;

g) aryl or R¹⁸-aryl;

h) heteroaryl or R¹⁸-heteroaryl;

i) arylalkyl or R¹⁸-arylalkyl;

j) heteroarylalkyl or R¹⁸-heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —

SO₂-alkyl;

o) —

NR¹¹R¹²;

p) —

N(R¹¹)C(O)R¹³,

q) methylenedioxy;

r) difluoramethylenedioxy;

s) trifluoroalkoxy;

t) —

SCH₃ or —

SCF₃; and

u) —

SO₂CF₃ or —

NHSO₂CF₃;

R² and R³ are each independently selected from the group consisting of H, —

OH, alkoxy, alkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, trifluoroalkyl, heteroalkyl, arylalkyl, heteroarylalkyl, arylalkoxy, heteroarylalkoxy, —

(CH₂)_n—

NR¹¹R¹² and —

(CH₂)_n—

SR¹¹, provided that when X is N, then R² and R³ are each not —

OH, alkoxy, arylalkoxy or heteroarylalkoxy;

R⁴, R⁵, R⁷ and R⁸ are each independently selected from the group consisting of H, —

OR¹⁴, —

NR¹¹R¹², —

N(R¹¹)C(O)R¹³, alkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,

provided that when Z and/or X is N, then R⁴, R⁵, R⁷ and R⁸ are each not —

OR¹⁴, —

NR¹¹R¹² or —

N(R¹¹)C(O)R¹³;

R⁶ is selected from the group consisting of —

C(O)R¹⁵ and —

SO₂R¹⁵;

R⁹ and R¹⁰ are each independently selected from the group consisting of H, F, —

CF₃, —

CHF₂, alkyl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocyoloalkyl, hydroxy, alkoxy, aryloxy, —

NR¹¹R¹² and —

N(R¹¹)C(O)R¹³, provided that when Z is N, then R⁹ and R¹⁰ are each not F, hydroxy, alkoxy, aryloxy, —

NR¹¹R¹² or —

N(R¹¹)C(O)R¹³;

R¹¹ is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹² is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹³ is selected from the group consisting of alkyl, alkoxy and aryloxy;

R¹⁴ is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹⁵ is selected from the group consisting of —

NR¹⁶R¹⁷, —

OR¹⁶, alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl and heteroarylalkyl, each optionally substituted with R¹⁸;

R¹⁶ and R¹⁷ are each independently selected from the group consisting of alkyl, aryl, arylalkyl, heteroalkyl and heteroaryl, each optionally substituted with R¹⁸, and H, provided that when R¹⁵ is —

OR¹⁶, R¹⁶ is not H;

R¹⁸ is one to four substituents each independently selected from the group consisting of lower alkyl, halo, cyano, nitro, haloalkyl, hydroxy, alkoxy, carboxy, carboxyalkyl, carboxamide, mercapto, amino, alkylamino, dialkylamino, sulfonyl, sulfonamido, aryl and heteroaryl;

X is N;

Z is C;

and

n is 1-4,

wherein the term “

heteroaryl”

refers to 5- or 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 “

heterocyoloalkyl”

refers to a non-aromatic, heterocyclic ring of 3-7 atoms containing 1-3 heteroatoms selected from N, O and S; and

the term “

heterocycloalkylalkyl”

refers to a heterocycloalkyl group bonded through an alkyl group.

2. The compound of claim 1 wherein,

R¹ is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

a) halogen;

b) —

OCF₃;

c) —

CF₃;

d) —

CN;

e) (C1-C20)alkyl or R¹⁸—

(C1-C20)alkyl;

f) heteroalkyl or R¹⁸-heteroalkyl;

g) aryl or R¹⁸-aryl;

h) heteroaryl or R¹⁸-heteroaryl;

i) arylalkyl or R¹⁸-arylalkyl;

j) heteroarylalkyl or R¹⁸-heteroarylalkyl;

k) hydroxy;

l) alkoxy;

m) aryloxy;

n) —

SO₂-alkyl;

o) —

NR¹¹R¹²;

p) —

N(R¹¹)C(O)R¹³;

q) methylenedioxy;

r) difluoromethylenedioxy;

s) trifluoroalkoxy;

t) —

SCH₃; and

u) —

SO₂CF₃;

R⁴, R⁵, R⁷ and R⁸ are each independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —

OR¹⁴, —

NR¹¹R¹²,

R¹¹ is selected from the group consisting of H alkyl;

Z is C; and

n is 1-3.

3. The compound of claim 1, wherein:

R¹ is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of;

a) halogen;

b) —

OCF₃;

c) —

CF₃;

e) (C1-C6)alkyl or R¹⁸—

(C1-C6)alkyl;

f) heteroalkyl or R¹⁸-heteroalkyl;

g) aryl or R¹⁸-aryl;

i) arylalkyl or R¹⁸-arylalkyl;

j) heteroarylalkyl or R¹⁸-heteroarylalkyl; and

l) alkoxy; and

s) trifluoroalkoxy;

R⁴, R⁵, R⁷ and R⁸ are each independently selected from the group consisting of H, —

OR¹⁴, —

NR¹¹R¹², alkyl, aryl, cycloalkyl, arylalkyl, heteroalkyl, heteroarylalkyl, heterocycloalkyl,

R¹¹ is selected from the group consisting of H and alkyl;

Z is C; and

n is 1-3.

4. The compound of claim 1 wherein:

R¹ is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of;

a) halogen;

b) —

OCF₃;

c) —

CF₃;

e) (C1-C6)alkyl or R¹⁸—

(C1-C6)alkyl;

l) alkoxy; and

s) trifluoroalkoxy;

R² and R³ are each independently selected from the group consisting of H, alkyl, and heteroalkyl;

R⁴, R⁵, R⁷ and R⁸ are each independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, cycloalkyl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, —

OR¹⁴, —

NR¹¹R¹²,

R¹¹ is selected from the group consisting of H and alkyl; and

Z is C.

5. The compound of claim 1 wherein,

R¹ is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one to six groups selected from the group consisting of:

a) halogen;

b) —

OCF₃;

c) —

CF₃;

l) alkoxy; and

s) trifluoroalkoxy;

R² is alkyl;

R³ is H;

R⁴ and R⁵ are each independently selected from the group consisting of H, (C1-C6)alkyl, heteroalkyl and

R⁷ is selected from the group consisting of H, alkyl, —

OR¹⁴ and —

NR¹¹R¹²;

R⁸ is selected from the group consisting of H, alkyl, aryl and heteroaryl;

R¹¹ is selected from the group consisting of H and alkyl; and

Z is C.

6. The compound of claim 1 wherein,

R¹ is selected from the group consisting of phenyl and pyridyl, each optionally substituted with one to six groups selected from the group consisting of:

a) Br;

F or Cl;

b) —

OCF₃;

c) —

CF₃;

l) methoxy, ethoxy or cyclopropylmethoxy; and

s) —

OCH₂CF₃;

R² is selected from the group consisting of methyl, ethyl, propyl, cyclopropylmethyl and t-butyl;

R³ is H;

R⁴ and R⁵ are each independently selected from the group consisting of H, methyl, ethyl, isopropyl and t-butyl;

R⁷ is selected from the group consisting of H, —

OR¹⁴ and alkyl;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹⁴ are each independently selected from the group consisting of H and alkyl;

R¹³ is alkyl;

R¹⁵ is selected from the group consisting of —

NR¹⁶R¹⁷, —

OR¹⁸ and alkyl;

R¹⁶ and R¹⁷ are each independently selected from the group consisting of H and alkyl; and

Z is C.

7. The compound of claim 1, or the pharmaceutically acceptable salt of the compound selected from the group consisting of:

8. The compound according to claim 1, or the pharmaceutically acceptable salt of the compound selected from the group consisting of:

9. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

10. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

11. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

12. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

13. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

14. The compound according to claim 8, or the pharmaceutically acceptable salt of the compound which is:

15. A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier therefor.

16. A method of inhibiting Type 3 17β

-hydroxysteroid dehydrogenases and thereby treating an androgen dependent disease wherein the androgen dependent disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenic alopecia, and polycystic ovary syndrome which method comprises administering to patient a therapeutically effective amount of the compound of claim 1, or the pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein the androgen dependent disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia and prostatic intraepithelial neoplasia.

18. A method of inhibiting Type 3 17β

-hydroxysteroid dehydrogenases, which comprises administering to a patient a therapeutically effective amount of the compound of claim 1, or the pharmaceutically acceptable salt thereof.