Claims for Patent: 8,277,807

Summary for Patent: 8,277,807

Title:	Pharmaceutical combinations
Abstract:	The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): ##STR00001## or salts, tautomers, solvates and N-oxides thereof; wherein R.sup.1 is hydroxy or hydrogen; R.sup.2 is hydroxy; methoxy or hydrogen; provided that at least one of R.sup.1 and R.sup.2 is hydroxy; R.sup.3 is selected from hydrogen; halogen; cyano; optionally substituted C.sub.1-5 hydrocarbyl and optionally substituted C.sub.1-5 hydrocarbyloxy; R.sup.4 is selected from hydrogen; a group --(O).sub.n--R.sup.7 where n is 0 or 1 and R.sup.7 is an optionally substituted acyclic C.sub.1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C.sub.1-5 hydrocarbyl-amino; or R.sup.3 and R.sup.4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR.sup.5R.sup.6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 inhibitors.
Inventor(s):	Gallagher; Neil James (Basel, CH), Lyons; John Francis (Cambridge, GB), Thompson; Neil Thomas (Cambridge, GB), Yule; Stephen Murray (Cambridge, GB), Murray; Christopher William (Cambridge, GB)
Assignee:	Astex Therapeutics Limited (Cambridge, GB)
Application Number:	12/445,141
Patent Claims:	1. A combination comprising one or more ancillary compound(s) and a compound of the formula (VI): ##STR00323## or a salt, solvate, tautomer or N-oxide thereof; wherein the bicyclic group: ##STR00324## is selected from the structures Cl, C5 and C6: ##STR00325## wherein n is 0, 1, 2 or 3; R.sup.1 is hydroxy or hydrogen; R.sup.2a is hydroxy or methoxy provided that at least one of R.sup.1 and R.sup.2a is hydroxy; R.sup.3 is selected from cyano; C.sub.1-5 hydrocarbyl and C.sub.1-5 hydrocarbyloxy; wherein the C.sub.1-5 hydrocarbyl and C.sub.1-5 hydrocarbyloxy moieties are each optionally substituted by one or more substituents selected from hydroxy, halogen, C.sub.1-2 alkoxy, amino, mono- and di-C.sub.1-2 alkylamino, and aryl and heteroaryl groups of 5 to 12 ring members; R.sup.4a is selected from hydrogen, fluorine, chlorine and methoxy; R.sup.8 is selected from hydrogen and fluorine; and R.sup.10 is selected from: halogen; hydroxy; trifluoromethyl; cyano; nitro; carboxy; amino; mono- or di-C.sub.1-4 hydrocarbylamino; carbocyclic and heterocyclic groups having from 3 to 12 ring members; and a group R.sup.a--R.sup.b; wherein: R.sup.a is a bond, O, CO, X.sup.1C(X.sup.2), C(X.sup.2)X.sup.1, X.sup.1C(X.sup.2)X.sup.1, S, SO, SO.sub.2, NR.sup.c, SO.sub.2NR.sup.c or NR.sup.cSO.sub.2; and R.sup.b is selected from hydrogen; carbocyclic and heterocyclic groups having from 3 to 12 ring members; and C.sub.1-12 hydrocarbyl optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-8 non-aromatic hydrocarbylamino, and carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C.sub.1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO.sub.2, NR.sup.c, X.sup.1C(X.sup.2), C(X.sup.2)X.sup.1 or X.sup.1C(X.sup.2)X.sup.1; R.sup.c is selected from R.sup.b, hydrogen and C.sub.1-4 hydrocarbyl; and X.sup.1 is O, S or NR.sup.c and X.sup.2 is .dbd.O, .dbd.S or .dbd.NR.sup.c, wherein the one or more ancillary compound(s) is selected from the group consisting of: I. corticosteroids, antiandrogens, antiestrogens, aromatase inhibitors and GNRAs; II. interferons and interleukins; III. tretinoin, alitretinoin and bexarotene; IV. rituximab, tositumomab and gemtuzumab ozogamicin; alemtuzumab, alemtuzumab, and bevacizumab; V. camptothecin compounds; VI. 5-fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine, raltitrexed, pemetrexed and methotrexate; VII. vinca alkaloids; VIII. taxanes; IX. epothilones; X. platinum compounds; XI. anthracycline derivatives, mitoxantrone and podophyllotoxin derivatives; XII. aziridines, nitrogen mustards, nitrosurea alkylating agents and bisalkanesulfonates; XIII. CDK inhibitors; XIV. COX-2 inhibitors; XV. trichostatin A, suberoylanilide hydroxamic acid, JNJ-16241199, LAQ-824, MGCD-0103, PXD-101; XVI. selective immunoresponse modulators; XVII. temozolomide, decitabine, 5-azacitidine, pseudoisocytidine and 5-fluoro-2'-deoxycytidine; XVIII. bortezimib and bleomycin; XIX. aurora inhibitors; XX. herbimycin, geldanamycin, 17-AAG, 17-DMAG, CNF-2024, and IPI-504; XXI. checkpoint targeting agents; XXII. DNA repair inhibitors; XXIII. inhibitors of G-protein coupled receptor inhibitors; XXIV. trastuzumab, cetuximab, panitumumab, tipifamib, gefitinib, erlotinib, bevacizumab, sunitinib, imatinib mesylate, sorafenib dasatinib, lapatinib, nilotinib, vandetanib, vatalinib and CHIR-258 and XXV. anti-emetic agents, agents that prevent or decrease the duration of chemotherapy associated neutropenia and prevent complications that arise from reduced levels of red blood cells or white blood cells, agents that inhibit bone resorption, bisphosphonate agents, agents that suppress inflammatory responses, agents that reduce blood levels of growth hormone and IGF-I in acromegaly patients, antidotes to drugs that decrease levels of folic acid, and agents for the treatment of oedema and thromoembolic episodes. 2. A combination according to claim 1 wherein R.sup.1 and R.sup.2a are both hydroxy. 3. A combination according to claim 1 wherein R.sup.3 is selected from isopropyl and tert-butyl. 4. A combination according to claim 1 wherein R.sup.4a is hydrogen and R.sup.8 is hydrogen. 5. A combination according to claim 1 wherein the compound of the formula (VI) is a compound of the formula (VIIa): ##STR00326## wherein R.sup.3 is selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl and C.sub.3-4 cycloalkyl groups; R.sup.4a is selected from hydrogen, fluorine, chlorine and methoxy; R.sup.8 is hydrogen or fluorine; n is 0, 1 2 or 3; R.sup.10 is selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members; a group R.sup.a--R.sup.b wherein R.sup.a is a bond, O, CO, X.sup.1C(X.sup.2), C(X.sup.2)X.sup.1, X.sup.1C(X.sup.2)X.sup.1, S, SO, SO.sub.2, NR.sup.c, SO.sub.2NR.sup.c or NR.sup.cSO.sub.2; and R.sup.b is selected from hydrogen, carbocyclic and heterocyclic groups having from 3 to 12 ring members, and a C.sub.1-12 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-8 non-aromatic hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C.sub.1-12 hydrocarbyl group may optionally be replaced by O, S, SO, SO.sub.2, NR.sup.c, X.sup.1C(X.sup.2), C(X.sup.2)X.sup.1, or X.sup.1C(X.sup.2)X.sup.1; R.sup.c is selected from R.sup.b, hydrogen and C.sub.1-4 hydrocarbyl; and X.sup.1 is O, S or NR.sup.c and X.sup.2 is .dbd.O, .dbd.S or .dbd.NR.sup.c. 6. A combination according to claim 5 wherein the compound of the formula (VIIa) is a compound of formula (VIIb): ##STR00327## wherein R.sup.3 is selected from C.sub.1-5 alkyl, C.sub.2-5 alkenyl and C.sub.3-4 cycloalkyl groups; R.sup.4a is selected from hydrogen, fluorine, chlorine and methoxy; R.sup.8 is hydrogen or fluorine; n is 0, 1 2 or 3; and R.sup.10cc is selected from: halogen; CO.sub.2R.sup.14 wherein R.sup.14 is hydrogen or C.sub.1-6 alkyl; C.sub.1-4 alkyl optionally substituted by hydroxy or C.sub.1-2 alkoxy; C.sub.1-4 alkoxy optionally substituted by hydroxy or C.sub.1-2 alkoxy; or a group [sol], CH.sub.2[sol], C(O)[sol], OCH.sub.2CH.sub.2[sol] or OCH.sub.2CH.sub.2CH.sub.2[sol] where [sol] is selected from the following groups ##STR00328## wherein X.sup.4 is NH or O, m is 0 or 1, n is 1, 2 or 3, R.sup.11 is hydrogen, COR.sup.12, C(O)OR.sup.12 or R.sup.12; R.sup.12 is C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, aryl, aryl-C.sub.1-6 alkyl or CH.sub.2R.sup.15; and R.sup.15 is selected from hydrogen, C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, hydroxy-C.sub.1-6 alkyl, piperidine, N--C.sub.1-6 alkylpiperazine, piperazine, morpholine, COR.sup.13 or C(O)OR.sup.13; and R.sup.13 is C.sub.1-6 alkyl. 7. A combination according to claim 1 wherein the compound of formula (VI) is: (3-tert-butyl-4-hydroxy-phenyl)-(2,3-dihydro-indol-1-yl)-methano- ne; (1,3-dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-isopropyl-phenyl)-methano- ne; (3-tert-butyl-4-hydroxy-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone; (1,3-dihydro-isoindol-2-yl)-(4-hydroxy-3-isopropyl-phenyl)-methanone; (1,3-dihydro-isoindol-2-yl)-(5-ethyl-2,4-dihydroxy-phenyl)-methanone; (5-cyclopropyl-2,4-dihydroxy-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanon- e; (5-sec-butyl-2,4-dihydroxy-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanon- e; (5-chloro-1,3-dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-isopropyl-phenyl)- -methanone; [5-(3-amino-propoxy)-1,3-dihydro-isoindol-2-yl]-(2,4-dihydroxy-5-isopropy- l-phenyl)methanone; (1,3-Dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-trifluoromethyl-phenyl)-meth- anone; (2,4-Dihydroxy-5-isopropyl-phenyl)-{4-[2-(2-methoxy-ethoxy)-ethoxy]- -1,3-dihydroisoindol-2-yl}methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[4-(2-dimethylamino-ethoxy)-1,3-dihydr- o-isoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihy- droisoindol-2-yl]methanone; (3-sec-Butyl-4-hydroxy-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone; (5-tert-Butyl-2,4-dihydroxy-phenyl)-(1,3-dihydro-isoindol-2-yl)-methanone- ; (1,3-Dihydro-isoindol-2-yl)-(2-hydroxy-5-isopropyl-4-methoxy-phenyl)-met- hanone; (4,7-difluoro-1,3-dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-isopropy- l-phenyl)-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-fluoro-1,3-dihydro-isoindol-2-yl)-m- ethanone; (1,3-dihydro-isoindol-2-yl)-(3-fluoro-2,4-dihydroxy-5-isopropyl-- phenyl)-methanone; (1,3-dihydro-isoindol-2-yl)-(2-fluoro-4,6-dihydroxy-3-isopropyl-phenyl)-m- ethanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(4-fluoro-1,3-dihydro-isoindo- l-2-yl)-methanone hydrochloride; (5-chloro-6-methoxy-1,3-dihydro-iso-indol-2-yl)-(2,4-dihydroxy-5-isopropy- l-phenyl)methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-methoxy-ethoxy)-1,3-dihydro-isoi- ndol-2-yl]methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(3-morpholin-4-yl-propoxy)-1,3-dihy- droisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-dimethylamino-ethoxy)-1,3-dihydr- o-isoindol-2-yl]-methanone; (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-isopropyl-phenyl)-me- thanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-methoxy-1,3-dihydro-isoindo- l-2-yl)-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-morpholin-4-yl-1,3-dihydro-isoindol- -2-yl)-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihyd- ro-isoindol-2-yl]-methanone; 2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxyl- ic acid methyl ester; 2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindole-5-carboxyl- ic acid; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-morpholin-4-ylmethyl-1,3-di- hydro-isoindol-2-yl)methanone; {3-[2-(2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yloxy- ]-propyl}carbamic acid tert-butyl ester; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-methyl-1,3-dihydro-isoindol-2-yl)-m- ethanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-isopropylamino-ethoxy)-- 1,3-dihydro-isoindol-2-yl]-methanone; N-{2-[2,4-dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-yloxy]- -ethyl}-2-morpholin-4-yl-acetamide; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-hydroxy-1-methyl-piperidin-4-yl)- -1,3-dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-{5-[4-(4-methyl-piperazin-1-yl)-piperi- din-1-yl]-1,3-dihydro-isoindol-2-yl}-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-piperazin-1-yl-phenyl)-1,3-dihyd- ro-isoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(1-dimethylamino-2-hydroxy-ethyl)-1- ,3-dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-dimethylamino-1-hydroxy-ethyl)-1- ,3-dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(piperazine-1-carbonyl)-1,3-dihydro- -isoindol-2-yl]-methanone hydrochloride; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3- -dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihy- droisoindol-2-yl]methanone; [5-(2-amino-ethoxy)-1,3-dihydro-isoindol-2-yl]-(2,4-dihydroxy-5-isopropyl- -phenyl)methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-- methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-{5-[4-(2-hydroxy-ethyl)-pipe- razin-1-yl]-1,3dihydro-isoindol-2-yl}-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-morpholin-4-yl-piperidin-1-yl)-1- ,3-dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(1-methyl-piperidin-4-ylamino)-1,3-- dihydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-isopropyl-piperazin-1-yl)-1,3-di- hydroisoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-piperazin-1-yl-1,3-dihydro-isoindol- -2-yl)methanone; 4-[2-(2,4-Dihydroxy-5-isopropyl-benzoyl)-2,3-dihydro-1H-isoindol-5-ylamin- o]piperidine-1-carboxylic acid tert-butyl ester; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(piperidin-4-ylamino)-1,3-dihydro-i- soindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[4-(4-methyl-piperazin-1-yl)-1,3-dihyd- ro-isoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[4-(piperidin-4-ylamino)-1,3-dihydro-i- soindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-dimethylaminomethyl-1,3-dihydro-iso- indol-2-yl)methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazine-1-carbonyl)-1,- 3-dihydro-isoindol-2-yl]-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-{5-[2-(2,2-dimethyl-propylamino)-ethox- y]-1,3-dihydro-isoindol-2-yl}-methanone; [5-(2-cyclopentylamino-ethoxy)-1,3-dihydro-isoindol-2-yl]-(2,4-dihydroxy-- 5-isopropylphenyl)-methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-(5-piperidin-1-ylmethyl-1,3-dihydro-is- oindol-2-yl)methanone; (2,4-Dihydroxy-5-isopropyl-phenyl)-[5-(4-hydroxypiperidin-4-yl)-1,3-dihyd- ro-isoindol-2-yl]-methanone; (5-chloro-6-hydroxy-1,3-dihydro-isoindol-2-yl)-(2,4-dihydroxy-5-isopropyl- -phenyl)methanone; (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-yl)-1,3-dihyd- ro-isoindol-2-yl]-methanone; or (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(2-dimethylamino-ethoxy)-7-methyl-1- ,3-dihydroisoindol-2-yl]-methanone; or salts, solvates, N-oxides and tautomers thereof. 8. A combination according to claim 1 wherein the ancillary compound and compound of formula (VI) are: (a) physically associated; or (b) in admixture; or (c) chemically or physicochemically linked; or (d) chemically or physicochemically co-packaged; or (e) unmixed but co-packaged or co-presented. 9. The combination according to claim 1 wherein the compound of formula (VI) is the L-lactate salt of (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3- -dihydro-isoindol-2-yl]-methanone. 10. A pharmaceutical composition comprising a combination according to claim 1 and a pharmaceutically acceptable carrier. 11. A method for: the inhibition or treatment of a disease state or condition mediated by Hsp90, which method comprises administering to a subject in need thereof a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or alleviating or reducing the incidence of a disease state or condition mediated by Hsp90, which method comprises administering to a subject in need thereof a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or inhibiting Hsp90, which method comprises contacting the Hsp90 with an Hsp90-inhibiting combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 12. A method for: treating a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to a subject in need thereof a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in an amount to inhibit abnormal cell growth; or alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to the mammal a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 in an amount to inhibit abnormal cell growth; or the inhibition or treatment of a proliferative disorders selected from a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin; a hematopoieitic tumour of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumor of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma which method comprises administering to a subject in need thereof a combination as defined in any one of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or alleviating or reducing the incidence of a proliferative disorders selected from a carcinoma of the bladder, breast, colon, kidney, epidermis, liver, lung, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, gastrointestinal system, or skin; a hematopoietic tumor of lymphoid lineage; a hematopoietic tumor of myeloid lineage; thyroid follicular cancer; a tumour of mesenchymal origin; a tumor of the central or peripheral nervous system; melanoma; semmoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoacanthoma; thyroid follicular cancer; or Kaposi's sarcoma which method comprises administering to a subject in need thereof a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or the treatment of a cancer which method comprises administering to a subject in need thereof a combination as defined in anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, which method is characterized by the absence of drug resistance. 13. A method of modulating a cellular process by inhibiting the activity of Hsp90 using a combination according to anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 14. A method: for the inhibition or treatment of a viral infection, which method comprises administering to a subject in need thereof a combination according to anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; or for blocking or inhibiting viral replication in a host organism, which method comprises administering to the host organism a combination according to anyone of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. 15. A method for: the inhibition or treatment of a disease state or condition mediated by Hsp90 which method comprises administering to the subject a compound of the formula (VI) according to claim 1, (VIIa) according to claim 5 or (VIIb) according to claim 6 in a subject which is undergoing treatment with one or more ancillary compounds; or the inhibition or treatment of a disease state or condition comprising or arising from abnormal cell growth in a mammal which method comprises administering to the subject a compound of the formula (VI) according to claim 1, (VIIa) according to claim 5 or (VIIb) according to claim 6 in a subject which is undergoing treatment with one or more ancillary compounds; or treating a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to the mammal a compound of the formula (VI) according to claim 1, (VIIa) according to claim 5 or (VIIb) according to claim 6 in an amount effective in inhibiting abnormal cell growth, wherein the mammal is undergoing treatment with one or more ancillary compounds; or alleviating or reducing the incidence of a disease or condition comprising or arising from abnormal cell growth in a mammal, which method comprises administering to the mammal a compound of the formula (VI) according to claim 1, (VIIa) according to claim 5 or (VIIb) according to claim 6 in an amount effective in inhibiting abnormal cell growth, wherein the mammal is undergoing treatment with one or more ancillary compounds. 16. A method for (i) sensitizing malignant cells to one or more ancillary compounds; (ii) alleviating or reducing the incidence of resistance to one or more ancillary compounds; (iii) reversing resistance to the one or more ancillary compounds of claim 1; (iv) potentiating the activity of the one or more ancillary compounds of claim 1; (v) delaying or inhibiting the onset of resistance to the one or more ancillary compounds of claim 1, which method comprises administering to a subject undergoing treatment with said ancillary compound a compound of the formula (VI) according to claim 1, (VIIa) according to claim 5 or (VIIb) according to claim 6. 17. The combination of claim 1, wherein the ancillary compound is selected from the group consisting of: I. tamoxifen; toremifene; raloxifene; medroxyprogesterone; megestrol/megestrel; aminoglutethimide; letrozole; anastrozole; exemestane; goserelin; leuprolide; abarelix; fluoxymestrone; diethylstilbestrol; ketoconazole; fulvestrant; flutamide; bicalutimide; nilutamide; cyproterone and buserelin, II. interferon .alpha.-2b, interferon .alpha.-2a, Proleukin.RTM. IL-2, Picibanil, Romurtide, Sizofuran, Virulizin and Thymosin alpha 1; III. tretinoin, alitretinoin and bexarotene; IV. rituximab, tositumomab and gemtuzumab ozogamicin; alemtuzumab, alemtuzumab, and bevacizumab; V. irinotecan and topotecan; VI. 5-fluorouracil, capecitabine, gemcitabine, cytarabine, fludarabine, raltitrexed, pemetrexed and methotrexate; VII. vindesine, vinvesir, vinblastine, vincristine and vinorelbine; VIII. paclitaxel, docetaxel; IX. ixabepilone, patupilone, BMS-247550 and desoxyeopthilone; X. cisplatin, carboplatin and oxaliplatinchloro(diethylenediamino)-platinum (II) chloride; dichloro(ethylenediamino)-platinum (II); spiroplatin; iproplatin; diamino(2-ethylmalonato)platinum (II); (1,2-diaminocyclohexane)malonatoplatinum (II); (4-carboxyphthalo)-(1,2-diaminocyclohexane)platinum (II); (1,2-diaminocyclohexane)(isocitrato)platinum (II); (1,2-diaminocyclohexane)-cis-(pyruvato)platinum (II); onnaplatin; and tetraplatin; XI. anthracycline derivatives, mitoxantrone and podophyllotoxin derivatives; XII. cyclophosphamide, ifosfamide/ifosphamide, chlorambucil, carmustine and lomustine, mitomycin, busulfan, estramustine, mechlorethamine, melphalan, bischloroethylnitrosurea, cyclohexylchloroethylnitrosurea, methylcyclohexylchloroethylnitrosurea, nimustine, procarbazine, dacarbazine, temozolimide and thiotepa; XIII. seliciclib, alvocidib, 7-hydroxy-staurosporine, PHA533533 and PD332991; XIV. celecoxib, arcoxia and lumiracoxib; XV. trichostatin A, suberoylanilide hydroxamic acid, PXD-101; XVI. lenalidomide and thalidomide; XVII. temozolomide, decitabine, 5-azacitidine, pseudoisocytidine and 5-fluoro-2'-deoxycytidine; XVIII. bortezimib and bleomycin; XIX. PHA-739358; XX. IPI-504; XXI. bendamustine, BSI-201 and AG-014699; XXII. atrasentan; XXIII. trastuzumab, cetuximab, panitumumab, tipifarnib, gefitinib, erlotinib, bevacizumab, sunitinib, imatinib mesylate, sorafenib dasatinib, lapatinib, nilotinib, vandetanib, vatalinib and CHIR-258 and XXIV. erythropoietin, granulocyte macrophage-colony stimulating factor, granulocyte colony stimulating factor, zoledronate, pamidronate, ibandronate, dexamethazone, prednisone, prednisolone, octreotide acetate, leucovorin, folinic acid and megestrol acetate. 18. The combination of claim 1, wherein the ancillary compound is selected from the group consisting of: Paclitaxel Cisplatin Dacarbazine Erlotinib Imatinib Sunitinib Nilotinib Trastuzumab Bortezomib Gemcitabine Cytarabine Decitabine Docetaxel 5-fluorouracil lapatinib letrozole and tamoxifen. 19. The combination of claim 18, wherein the ancillary compound is selected from the group consisting of Paclitaxel Cisplatin Dacarbazine Erlotinib Imatinib Sunitinib and Nilotinib. 20. The combination according to claim 1 wherein the compound of formula (VI) is (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmet- hyl)-1,3-dihydro-isoindol-2-yl]-methanone.

Details for Patent 8,277,807

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2026-10-12
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2026-10-12
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2026-10-12
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2026-10-12
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2026-10-12