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

• US 20030232837A1
• Filed: 10/15/2002
• Published: 12/18/2003
• Est. Priority Date: 10/17/2001
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Schering Corporation (Merck & Co., Inc.)
• Inventors: Paruch, Kamil, Guzi, Timothy J.
• Granted Patent: US 6,969,718 B2
• Time in Patent Office: Days
• US Class Current: 514/252.11
• 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):

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 and 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, —

R¹⁶ 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 prodrug thereof, or the pharmaceutically acceptable salt or solvate of the compound or of the prodrug selected from the group consisting of:

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

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

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

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

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

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

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

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

16. A method of treating or preventing an androgen dependent disease, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1, or the pharmaceutically acceptable salt or solvate thereof.

17. The method of claim 16, wherein the androgen dependent disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, prostatic intraepithelial neoplasia, hirsutism, acne, androgenic alopecia, polycystic ovary syndrome and combinations thereof.

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

19. A method of inhibiting 17β

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

20. A method of treating or preventing androgen-dependent diseases, comprising administering to a mammal in need thereof an effective amount of the compound of claim 1 in combination with at least one anti-androgenic agent.

21. The method of claim 20, 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.

22. A method of treating or preventing benign prostatic hyperplasia, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 in combination with at least one other agent useful for the treatment or prevention of benign prostatic hyperplasia.

23. The method of claim 22, wherein the other agent useful for the treatment or prevention of benign prostatic hyperplasia is an alpha-1 adrenergic antagonist.

24. A method of treating or preventing hair loss, comprising administering an effective amount of the compound of claim 1 in combination with at least one anti-alopecia agent.

25. The method of claim 24, wherein the anti-alopecia agent is a potassium channel agonist or a 5α

-reductase inhibitor.

26. A method of treating or preventing proliferative diseases, comprising administering concurrently or sequentially to a mammal in need of such treatment, a therapeutically effective amount of the compound of claim 1 in combination with an effective amount of at least one agent or therapy selected from the group consisting of a chemotherapeutic agent, a biological agent, surgery and radiation therapy.

27. The method of claim 26, wherein the chemotherapeutic agent is:

(a) an antineoplastic agent selected from the group consisting of Uracil mustard, Chlormethine, Cyclo-phosphamide, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Temozolomide, Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Gemcitabine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Paclitaxel (Taxol), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons, Etoposide, Teniposide 17α

-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Raloxifine, Droloxifine and Hexamethylmelamine;

or

(b) a microtubule affecting agent selected from the group consisting of allocolchicine, Halichondrin B, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel, paclitaxel derivatives, thiocolchicine, trityl cysteine, vinblastine sulfate, vincristine sulfate, epothilone A, epothilone, discodermolide estramustine, nocodazole and MAP4; and

wherein

the biological agent is selected from the group consisting of interferon-α

, interferon-β and

gene therapy; and

wherein

the proliferative disease is selected from the group consisting of lung cancer, pancreatic cancer, colon cancer, renal cancer, myeloid leukemia, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, melanoma, breast cancer, ovarian cancer, prostate cancer and combinations thereof.

28. The method of claim 27, wherein the proliferative disease is selected from the group consisting of prostate cancer, pancreatic cancer, breast cancer and ovarian cancer;

the chemotherapeutic agent is selected from the group consisting of Cyclophosphamide, 5-Fluorouracil, Temozolomide, Vincristine, Cisplatin, Carboplatin, Gemcitabine, Taxotere, paclitaxel and/or a paclitaxel derivative, and the biological agent is interferon-α

.