Fused tricyclic compounds as inhibitors of 17beta-hydroxysteroid dehydrogenase 3

• US 20050250753A1
• Filed: 02/25/2005
• Published: 11/10/2005
• Est. Priority Date: 03/01/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Vite, Gregory D., Gavai, Ashvinikumar V., Norris, Derek J., Fink, Brian E., Han, Wen-Ching, Tokarski, John S., Xiao, Hai-Yun, Misra, Raj N.
• Granted Patent: US 7,417,040 B2
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 225/02 not condensed with other rings
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 491/04 Ortho-condensed systems

Abstract

Fused tricyclic compounds, methods of using such compounds in the treatment of hormone sensitive diseases such as prostate cancer, and pharmaceutical compositions containing such compounds.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein:

X₁═

X₂ is —

CR₁═

CR₃—

, —

CR₁R₂—

CR₃R₄—

, —

C(═

O)—

CR₃R₄—

, —

S—

CR₃R₄—

, —

S(═

O)—

CR₃R₄—

, —

S(═

O)₂—

CR₃R₄—

, —

O—

CR₃R₄—

, —

CR₁R₂—

S—

, —

CR₁R₂—

S(═

O)—

, —

CR₁R₂—

S(═

O)₂—

, —

CR₁R₂—

C(═

O)—

, or —

CR₁R₂—

O—

;

R₂, R₄, R₆ and R₁₀ are each independently hydrogen, halogen, cyano, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_e, S(═

O)₂OR_e, NR_bR_c, NR_bS(═

O)₂R_e, S(═

O)₂NR_bR_c, C(═

O)OR_e, C(═

O)R_a, C(═

O)NR_bR_c, OC(═

O)R_a, OC(═

O)NR_bR_c, NR_bC(═

O)OR_e, NR_dC(═

O)NR_bR_c, NR_dS(═

O)₂NR_bR_c, or NR_bC(═

O)R_a,

wherein;

R₂ and R₄ together may optionally form a 3-7 membered carbocyclic ring or 3-7 membered heterocyclic ring;

R₁ and R₃ are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_e, C(═

O)OR_c, C(═

O)R_a, NR_bR_c, NR_bC(═

O)R_a, C(═

O)NR_bR_c, OC(═

O)R_a, or OC(═

O)NR_bR_c, wherein R₁ and R₃ together may optionally form a 3-7 membered optionally substituted carbocyclic ring or 3-7 membered optionally substituted heterocyclic ring;

R₉ is H, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, or NR_bR_c;

m is 1-4; and

n is 1-4;

provided that;

at least one of R₆ and R₁₀ is not H; and

when X₁═

X₂ is —

S—

CR₃R₄—

, each R₁₀ is H, and m=1, R₆ at the C-3 position is not H, methyl, halogen, OMe, CF₃, or SCF₃.

3. The compound of claim 1, wherein:

X₁═

X₂ is —

CR₁═

CR₃—

, —

CR₁R₂—

CR₃R₄—

, —

C(═

O)—

CR₃R₄—

, —

S—

CR₃R₄—

, —

S(═

O)—

CR₃R₄—

, —

O—

CR₃R₄—

, —

CR₁R₂—

S—

, —

CR₁R₂—

S(═

O)—

, CR₁R₂—

C(═

O)—

, or —

CR₁R₂—

O—

;

R₆ and R₁₀ are each independently hydrogen, halogen, cyano, nitro, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_a, S(═

O)₂R_c, S(═

O)₂OR_e, NR_bR_c, NR_bS(═

O)₂R_e, S(═

O)₂NR_bR_c, C(═

O)OR_e, C(═

O)R_a, C(═

O)NR_bR_c, OC(═

O)R_a, OC(═

O)NR_bR_c, NR_bC(═

O)OR_e, NR_dC(═

O)NR_bR_c, NR_dS(═

O)₂NR_bR_c, or NR_bC(═

O)R_a;

R₂ and R₄ are each independently hydrogen, cyano, nitor, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_c, NR_bR_c, NR_bS(═

O)₂R_e, S(═

O)₂NR_bR_c, C(═

O)OR_e, C(═

O)R_a, C(═

O)NR_bR_c, OC(═

O)R_a, OC(═

O)NR_bR_c, NR_bC(═

O)OR_e, NR_dC(═

O)NR_bR_c, NR_dS(═

O)₂NR_bR_c, or NR_bC(═

O)R_a, wherein R₂ and R₄ together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring;

R₁ and R₃ are each independently hydrogen, cyano, nitro, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_e, C(═

O)OR_e, C(═

O)R_a, NR_bR_c, NR_bC(═

O)R_a, C(═

O)NR_bR_c, OC(═

O)R_a, or OC(═

O)NR_bR_c, wherein R₁ and R₃ together may optionally form a 3-6 membered optionally substituted carbocyclic ring or 3-6 membered optionally substituted heterocyclic ring;

R₉ is H, C₁-C₄ alkyl or substituted C₁-C₄ alkyl, cycloalkyl or substituted cycloalkyl, or NR_bR_c;

m is 1-4; and

n is 1-4;

provided that;

at least one of R₆ and R₁₀ is not H; and

when X₁═

X₂ is —

S—

CR₃R₄—

, each R₁₀ is H, and m=1, R₆ at the C-3 position is not H, methyl, halogen, OMe, CF₃, or SCF₃.

4. The compound of claim 1 having the following structure Ia,

5. The compound of claim 1 having the following structure Ib,

6. The compound of claim 5, wherein R₉ is H, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, or NH₂, or

7. The compound of claim 6, wherein R₇ and R₈ are each independently hydrogen, halogen, cyano, nitro, SMe, S(═

O)₂Me, or OMe, and wherein at least one of R₇ and R₈ is not hydrogen.

8. The compound of claim 7, wherein Y is —

C(═

O)—

.

9. The compound of claim 8, wherein X₁═

X₂ is —

CH═

CH—

, —

CH₂—

CH₂—

, or

10. The compound of claim 9, wherein R₉ is methyl;

R₁₀ and R₁₁ are each independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_c, S(═

O)₂R_e, NR_bR_c, NR_bS(═

O)₂R_e, C(═

O)OR_e, C(═

O)R_e, C(═

O)NR_bR_c, OC(═

O)R_a, NR_bC(═

O)OR_e, or NR_bC(═

O)R_a.

11. The compound of claim 1 having the following structure Ib,

12. The compound of claim 11, wherein R₉ is H, methyl, CF₃, ethyl, isopropyl, cyclopropyl, NH₂, or

13. The compound of claim 12, wherein R₇ and R₈ are each independently hydrogen, halogen, cyano, nitro, SMe, S(═

O)₂Me, or OMe, and wherein at least one of R₇ and R₈ is not hydrogen.

14. The compound of claim 13, wherein Y is —

C(═

O)—

, and wherein R₃ and R₄ are each independently H.

15. The compound of claim 14, wherein R₉ is methyl;

R₁₀ and R₁₁ are each independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_e, NR_bR_c, NR_bS(═

O)₂R_e, C(═

O)OR_e, C(═

O)R_e, C(═

O)NR_bR_c, OC(═

O)R_a, NR_bC(═

O)OR_e, or NR_bC(═

O)R_a, and wherein R_a, R_b, R_c, R_d and R_e are as described above.

16. The compound of claim 1 having the following structure Ib,

17. The compound of claim 16, wherein R₉ is H, methyl, CF₃, ethyl, isopropyl, cyclopropyl, NH₂, or

18. The compound of claim 17, wherein R₇ and R₈ are each independently hydrogen, halogen, cyano, nitro, SMe, S(═

O)₂Me, or OMe, and wherein at least one of R₇ and R₈ is not hydrogen.

19. The compound of claim 18, wherein Y is —

C(═

O)—

, and wherein R₁, R₂, R₃ and R₄ are each independently hydrogen.

20. The compound of claim 19, wherein X₁═

X₂ is —

O—

CH₂—

, or —

CH₂—

O—

;

R₉ is methyl; and

R₁₀ and R₁₁ are each independently hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, heterocycle or substituted heterocycle, aryl or substituted aryl, OR_a, SR_a, S(═

O)R_e, S(═

O)₂R_e, NR_bR_c, NR_bS(═

O)₂R_e, C(═

O)OR_e, C(═

O)R_e, C(═

O)NR_bR_c, OC(═

O)R_a, NR_bC(═

O)OR_e, or NR_bC(═

O)R_a.

21. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically-acceptable carrier or diluent.

22. A pharmaceutical composition of claim 21, further comprising at least one other anti-cancer agent or cytotoxic agent.

23. The pharmaceutical composition of claim 22, wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine, paclitaxel, docetaxel, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols, proteasome inhibitors including bortezomib and biological response modifiers, androgen receptor antagonists, LH/RH antagonists, taxane analogues, and estrogen receptor antagonists.

24. A method of inhibiting the activity of 17β

-hydroxysteroid dehydrogenase type 3 enzyme which comprises administering to a mammalian species in need thereof an effective amount of at least one compound according to claim 1.

25. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound according to claim 1, wherein said condition or disorder is selected from the group consisting of proliferate diseases, cancers, benign prostate hypertrophia, benign prostatic hyperplasia, adenomas and neoplasies of the prostate, benign or malignant tumor cells containing the androgen receptor, brain cancer, skin cancer, bladder cancer, lymphatic cancer, liver cancer, kidney cancer, pancreatic cancer, prostate cancer, hirsutism, acne, precocious puberty, angiogenic conditions or disorders, hyperpilosity, inflammation, immune modulation, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppressing spermatogenesis, male and female sexual dysfunction, libido, cachexia, anorexia, inhibition of muscular atrophy in ambulatory patients, androgen supplementation for age related decreased testosterone levels in men, cancers expressing the estrogen receptor, breast cancer, ovarian cancer, uterine cancer, endometrial cancer, hot flushes, vaginal dryness, menopause, amennoreahea, dysmennoreahea, contraception, pregnancy termination, cancers containing the progesterone receptor, cyclesynchrony, meniginoma, fibroids, labor induction, autoimmune diseases, Alzheimer'"'"'s disease, psychotic disorders, drug dependence, non-insulin dependent Diabetes Mellitus, dopamine receptor mediated disorders, heart disease, congestive heart failure, disregulation of cholesterol homeostasis, and attenuating the metabolism of a pharmaceutical agent.

26. The method of claim 25, wherein said condition or disorder is prostate cancer, polycystic ovary syndrome or hirsutism.

27. The method of claim 25, further comprising administering to a mammalian species in need thereof, a therapeutically effective amount of at least one other anti-cancer or cytotoxic agent in combination with at least one compound according to claim 1.

28. The method of claim 27, wherein said anti-cancer or cytotoxic agent is selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, megestrol acetate, anastrozole, letrozole, borazole, exemestane, flutamide, nilutamide, bicalutamide, cyproterone acetate, gosereline acetate, leuprolide, finasteride, metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, growth factor antibodies, growth factor receptor antibodies, bevacizumab, cetuximab, tyrosine kinase inhibitors, serine/threonine kinase inhibitors, methotrexate, 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, cisplatin, carboplatin, nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa, vincristine, vinorelbine, vinblastine, vinflunine, paclitaxel, docetaxel, taxane analogues, epothilone analogs, discodermolide analogs, eleutherobin analogs, etoposide, teniposide, amsacrine, topotecan, flavopyridols, proteasome inhibitors, androgen receptor antagonists, LH/RH antagonists, and estrogen receptor antagonists.