Synergistic methods and compositions for treating cancer

• US 6,537,988 B2
• Filed: 03/26/2001
• Issued: 03/25/2003
• Est. Priority Date: 03/27/2000
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Lee, Francis Y.
• Primary Examiner(s): KRASS, FREDERICK F
• Application Number:
  US09/817,456
• Publication Number:
  US 20020002162A1
• Time in Patent Office: 729 Days
• Field of Search: 514/221, 514/449, 514/922, 514/2, 514/8
• US Class Current: 514/221
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 41/00 Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention provides a synergistic method for the treatment of cancer which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of: (1) at least agent selected from the group consisting of cytotoxic agents and cytostatic agents, and (2) a compound of formula I

or a pharmaceutically acceptable salt thereof. The present invention further provides a pharmaceutical composition for the synergistic treatment of cancer which comprises at least one agent selected from the group consisting of antiproliferative cytotoxic agents and antiproliferative cytostatic agents, a compound of formula I, and a pharmaceutically acceptable carrier.

Claims

1. A method for the treatment of cancer which comprises administering to a mammalian specie in need thereof a synergistically, therapeutically effective amount of (1) at least one agent selected from the group consisting of anti-proliferative cytotoxic agents and cytostatic agents and (2) a compound of formula I

or a pharmaceutically acceptable salt thereof wherein

R₁ is Cl, Br, CN, optionally substituted phenyl, or optionally substituted 2-,3- or 4-pyridyl;

R₂ is optionally substituted lower alkyl, or optionally substituted aralkyl;

R₃ and R₅ are each independently optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted heterocyclo;

R₄ is hydrogen or lower alkyl;

Z₁ is CO, SO₂, CO₂ or SO₂N(R₅)—

; and

n is 1 or 2;

provided that the cytotoxic agent and/or cytostatic agent is administered simultaneously with or prior to the formula I compound.

2. The method according to claim 1 wherein the cytotoxic agent is administered prior to the formula I compound.

3. The method according to claim 1 wherein the cytotoxic agent comprises radiation therapy.

4. The method according to claim 1, wherein the cytostatic agent is administered prior to the formula I compound.

5. The method according to claim 1 for the synergistic treatment of cancerous solid tumors.

6. The method according to claim 1 wherein the cytotoxic agent is selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, and a platinum coordination complex.

7. The method according to claim 1 wherein the cytotoxic agent is selected from the group consisting of an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

8. The method according to claim 1 wherein the cytotoxic agent is selected from the group consisting of paclitaxel, docetaxel, 7-O-methylthiomethyl-paclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3′

-tert-butyl-3′

-N-tert-butyloxycarbonyl-4-deacetyl-3′

-dephenyl-3′

-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, a pyridobenzoindole, an interferon and an interleukin.

9. The method according to claim 1 wherein the cytotoxic agent is selected from the group consisting of a taxane and an epothilone.

10. The method according to claim 1 wherein the cytotoxic agent is selected from the group consisting of paclitaxel, docetaxel, 7-O-methylthiomethyl-paclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3′

-tert-butyl-3′

-N-tert-butyloxycarbonyl-4-deacetyl-3′

-dephenyl-3′

-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione and [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

11. The method according to claim 1 wherein

R₁ is Br, or CN;

R₂ is optionally substituted benzyl;

R₃ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted 2-thienyl, or optionally substituted 1-piperidinyl;

R₄ is hydrogen, or methyl;

Z₁ is CO, SO₂, or SO₂N(R₅)—

;

R₅ is optionally substituted lower alkyl or optionally substituted phenyl; and

n is 1.

12. The method according to claim 1 wherein

R₁ is CN;

R₂ is optionally substituted benzyl;

R₃ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted 2-thienyl, or optionally substituted 1-piperidinyl;

R₄ is hydrogen, or methyl;

Z is CO, or SO₂; and

n is 1.

13. The method according to claim 1 wherein

R₁ is CN;

R₂ is benzyl;

R₃ is n-propyl, n-butyl, 3-methoxypropyl, 2-thienyl, 5-bromo-2-thienyl, phenyl, 4-methoxyphenyl, or 1-piperidinyl;

R₄ is hydrogen;

Z is SO₂; and

n is 1.

14. The method according to claim 1 wherein the formula I compound is selected from the group consisting of

(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-(1-oxobutyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-4-[(5-bromo-2-thienyl)sulfonyl]-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-yl methyl)-3-(phenyl methyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-yl methyl)-4-[(4-methoxyphenyl)sulfonyl]-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(propylsulfonyl)-1H-1,4-benzodiazepine;

(R)-4-(butylsulfonyl)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(1-piperidinylsulfonyl)-1H-1,4-benzodiazepine;

(R)-4-(3-methoxypropylsulfonyl)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine; and

pharmaceutically acceptable salts thereof.

15. The method according to claim 14 wherein the pharmaceutically acceptable salt is selected from the group consisting of the hydrochloride salt, the methanesulfonic acid salt and the trifluoroacetic acid salt.

16. The method according to claim 10 wherein the formula I compound is (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

17. The method according to claim 1 wherein the cytotoxic agent is paclitaxel and the formula I compound is (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1 wherein the cytotoxic agent is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione and the formula I compound is

(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-yl methyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1 H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1 wherein the mammalian specie is a human.

20. The method according to claim 1 wherein the cytostatic agent is selected from the group consisting of surgical castration, chemical castration, tamoxifen, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline, 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazoline, hormone, steroids, steroid synthetic analogs, 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex, antiangiogenics, matrix metalloproteinase inhibitors, VEGF inhibitors, ZD6474, SU6668, anti-Her2 antibodies, EGFR inhibitors, EKB-569, Imclone antibody C225, src inhibitors, bicalutamide, epidermal growth factor inhibitors, Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, P13 inhibitors, PDGF inhibitors, combretastatins, MET kinase inhibitors, MAP kinase inhibitors, inhibitors of non-receptor and receptor tyrosine kinases, inhibitors of integrin signaling, and inhibitors of insulin-like growth factor receptors.

21. The method according to claim 1, wherein the cytostatic agent is selected from the group consisting of bicalutamide, tamoxifen, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline, Her-1 inhibitors, and trastuzumab.

22. A pharmaceutical composition for the synergistic treatment of cancer which comprises one or both of a cytostatic agent and a cytotoxic agent, and also comprises a compound of formula I as described in claim 1, and a pharmaceutically acceptable carrier.

23. The composition according to claim 22 for the synergistic treatment of cancerous solid tumors.

24. The composition according to claim 22 wherein the cytotoxic agent is one or more antineoplastic agents selected from the group consisting of a microtubule-stabilizing agent, a microtubule-disruptor agent, an alkylating agent, an anti-metabolite, epidophyllotoxin, an antineoplastic enzyme, a topoisomerase inhibitor, procarbazine, mitoxantrone, and a platinum coordination complex.

25. The composition according to claim 22 wherein the cytotoxic agent is one or more antineoplastic agents selected from the group consisting of an anthracycline drug, a vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a taxane, an epothilone, discodermolide, a pteridine drug, a diynene, an aromatase inhibitor and a podophyllotoxin.

26. The composition according to claim 22 wherein the cytotoxic agent is one or more antineoplastic agents selected from the group consisting of paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3′

-tert-butyl-3′

-N-tert-butyloxycarbonyl-4-deacetyl-3′

-dephenyl-3′

-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo-[14.1.0]heptadecane-5,9-dione, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, dichloro-methotrexate, mitomycin C, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, vindesine, leurosine, estramustine, cisplatin, carboplatin, cyclophosphamide, bleomycin, ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide, a pyridobenzoindole, an interferon and an interleukin.

27. The composition according to claim 22 wherein the cytotoxic agent is one or more cytotoxic agents selected from the group consisting of a taxane and an epothilone.

28. The composition according to claim 22 wherein the cytotoxic agent is one or more antineoplastic agents selected from the group consisting of paclitaxel, docetaxel, 7-O-methylthiomethylpaclitaxel, 4-desacetyl-4-methylcarbonatepaclitaxel, 3′

-tert-butyl-3′

-N-tert-butyloxycarbonyl-4-deacetyl-3′

-dephenyl-3′

-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel, C-4 methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C, epothilone D, desoxyepothilone A, desoxyepothilone B, [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione and [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.

29. The composition according to claim 22, wherein the cytostatic agent is selected from the group consisting of surgical castration, chemical castration, tamoxifen, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline, 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazoline, hormones, steroids, steroid synthetic analogs, 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone, Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Zoladex, antiangiogenics, matrix metalloproteinase inhibitors, VEGF inhibitors, ZD6474, SU6668, anti-Her2 antibodies, EGFR inhibitors, EKB-569, Imclone antibody C225, src inhibitors, bicalutamide, epidermal growth factor inhibitors, Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, P13 inhibitors, PDGF inhibitors, combretastatins, MET kinase inhibitors, MAP kinase inhibitors, inhibitors of non-receptor and receptor tyrosine kinases, inhibitors of integrin signaling, and inhibitors of insulin-like growth factor receptors.

30. The composition according to claim 22, wherein the cytostatic agent is selected from the group consisting of bicalutamide, tamoxifen, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline, Her-1 inhibitors, and trastuzumab.

31. The composition according to claim 22 wherein

R₁ is Br, or CN;

R₂ is optionally substituted benzyl;

R₃ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted 2-thienyl, or optionally substituted 1-piperidinyl;

R₄ is hydrogen, or methyl;

Z₁ is CO, SO₂, or SO₂N(R₅)—

;

R₅ is optionally substituted lower alkyl, or optionally substituted phenyl; and

n is 1.

32. The composition according to claim 22 wherein

R₁ is CN;

R₂ is optionally substituted benzyl;

R₃ is optionally substituted lower alkyl, optionally substituted phenyl, optionally substituted 2-thienyl, or optionally substituted 1-piperidinyl;

R₄ is hydrogen, or methyl;

Z is CO, or SO₂; and

n is 1.

33. The composition according to claim 22 wherein

R₁ is CN;

R₂ is benzyl;

R₃ is n-propyl, n-butyl, 3-methoxypropyl, 2-thienyl, 5-bromo-2-thienyl, phenyl, 4-methoxyphenyl, or 1-piperidinyl;

R₄is hydrogen;

Z is SO₂; and

n is 1.

34. The composition according to claim 22 wherein the formula I compound is selected from the group consisting of

(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)4-(1-oxobutyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-4-[(5-bromo-2-thienyl)sulfonyl]-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-4-[(4-methoxyphenyl)sulfonyl]-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(phenylsulfonyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(propylsulfonyl)-1H-1,4-benzodiazepine;

(R)-4-(butylsulfonyl)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-1H-1,4-benzodiazepine;

(R)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(1-piperidinylsulfonyl)-1H-1,4-benzodiazepine;

(R)-4-(3-methoxypropylsulfonyl)-7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-yl methyl)-3-(phenyl methyl)-1H-1,4-benzodiazepine; and

pharmaceutically acceptable salts thereof.

35. The composition according to claim 34 wherein the pharmaceutically acceptable salt is selected from the group consisting of the hydrochloride salt, the methanesulfonic acid salt and the trifluoroacetic acid salt.

36. The composition according to claim 34 wherein the formula I compound is (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

37. The composition according to claim 22 wherein the cytotoxic agent is paclitaxel and the formula I compound is (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

38. The composition according to claim 22 wherein the cytotoxic agent is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione and the formula I compound is

(R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-yl methyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

39. The method according to claim 1 wherein the cancer is a cancer of the prostate, the breast, a non-small cell lung cancer, a metastatic bladder cancer, a colorectal cancer, or a pancreatic cancer.

40. The composition according to claim 22 wherein the cytotoxic agent is one or more cytotoxic agents chosen from the group consisting of paclitaxel, cis-platin, carboplatin, gemcytabine, CPT-11, leucovorin, tegafur, uracil, 5-fluorouracil, 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazoline, and 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline).

41. The method according to claim 1 wherein said at least one cytotoxic agent is paclitaxel which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

42. The method according to claim 1 wherein said at least one cytotoxic agent is [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17-oxabicyclo[14.1.0]heptadecane-5,9-dione which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

43. The method according to claim 1 wherein said at least one cytotoxic agent is CPT-11 which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

44. The method according to claim 1 wherein said at least one cytotoxic agent is gemcitabine or a pharmaceutically acceptable salt thereof which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

45. The method according to claim 1 wherein said at least one cytostatic agent is 4-(3-bromophenylamino)-6,7-bis(methoxy)quinazoline which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenyl methyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

46. The method according to claim 1 wherein said at least one cytostatic agent is trastuzumab which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

47. The method according to claim 1 wherein said at least one cytostatic agent is 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4-morpholinyl)propoxy)quinazoline which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

48. The method according to claim 1 wherein said at least one cytostatic agent is tamoxifen which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

49. The method according to claim 1 wherein said at least one cytostatic agent is castration which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

50. The method according to claim 1 wherein said at least one cytotoxic agent is N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide or a pharmaceutically acceptable salt thereof which is administered prior to the administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof.

51. The method according to claim 1 wherein said at least one cytotoxic agent is paclitaxel and is administered during about a three hour infusion at about 135 mg/m2 followed by a one hour infusion of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof at about 50 mg/m2, both paclitaxel and (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof being administered at about three week intervals as needed.

52. The method according to claim 1 wherein said at least one cytotoxic agent is paclitaxel and is administered during about a one hour infusion at about 80 mg/m2 followed by about a one hour infusion of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof at about 80 mg/m2, both paclitaxel and (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof being administered at about weekly intervals as needed.

53. The method as claimed in claim 1 wherein two cytotoxic agents are administered, said cytotoxic agents being paclitaxel which is infused for about 3 hours at about 135 mg/m2 followed by about a twenty minute infusion of carboplatin at AUC equal to about 6, paclitaxel and carboplatin being administered at about three week intervals, said method further comprising about weekly administration of (R)-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine-7-carbonitrile or a pharmaceutically acceptable salt thereof at about 80 mg/m2.