Claims for Patent: 8,541,461

Summary for Patent: 8,541,461

Title:	Pharmaceutical combinations comprising pyrazole derivatives as protein kinase modulators
Abstract:	The invention provides a combination comprising an ancillary compound (e.g. one, two or more ancillary compounds) and a compound of the formula (I) having protein kinase B inhibiting activity: wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R.sup.1 and NR.sup.2R.sup.3 and a maximum chain length of 4 atoms extending between E and NR.sup.2R.sup.3, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom .alpha. with respect to the NR.sup.2R.sup.3 group and provided that the oxo group when present is located at a carbon atom .alpha. with respect to the NR.sup.2R.sup.3 group; E is a monocyclic or bicyclic carbocyclic or heterocyclic group; R.sup.1 is an aryl or heteroaryl group; and R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in the claims. Also provided are patient packs, pharmaceutical kits and packs and compositions containing the combinations, methods for preparing the combinations and their use in combination therapy as anticancer agents. ##STR00001##
Inventor(s):	Thompson; Neil Thomas (Cambridge, GB), Boyle; Robert George (Cambridge, GB), Collins; Ian (Redhill, GB), Garrett; Michelle Dawn (Walton-on-Thames, GB), Lyons; John Francis (Cambridge, GB), Thompson; Kyla Merriom (Cambridge, GB)
Assignee:	Astex Therapeutics Limited (Cambridge, GB) The Institute of Cancer Research Royal Cancer Hospital (London, GB) Cancer Research Technology Limited (London, GB)
Application Number:	11/993,823
Patent Claims:	1. A combination comprising an ancillary compound and a compound of the formula (I): ##STR00277## or a salt, solvate, tautomer or N-oxide thereof; wherein A is a saturated hydrocarbon linker group containing from 1 to 7 carbon atoms, the linker group having a maximum chain length of 5 atoms extending between R.sup.1 and NR.sup.2R.sup.3 and a maximum chain length of 4 atoms extending between E and NR.sup.2R.sup.3, wherein one of the carbon atoms in the linker group may optionally be replaced by an oxygen or nitrogen atom; and wherein the carbon atoms of the linker group A may optionally bear one or more substituents selected from oxo, fluorine and hydroxy, provided that the hydroxy group when present is not located at a carbon atom .alpha. with respect to the NR.sup.2R.sup.3 group and provided that the oxo group when present is located at a carbon atom .alpha. with respect to the NR.sup.2R.sup.3 group; E is phenyl or pyridine wherein E is unsubstituted or has up to 4 substituents R.sup.8 selected from hydroxy, chlorine, bromine, trifluoromethyl, cyano, C.sub.1-4 hydrocarbyloxy optionally substituted by C.sub.1-2 alkoxy or hydroxy, and C.sub.1-4 hydrocarbyl optionally substituted by C.sub.1-2 alkoxy or hydroxy; R.sup.1 is phenyl or pyridine which is unsubstituted or bears one or more substituents selected from hydroxy; C.sub.1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; CONH.sub.2; nitro; C.sub.1-4 hydrocarbyloxy and C.sub.1-4 hydrocarbyl each optionally substituted by C.sub.1-2 alkoxy, carboxy or hydroxy; C.sub.1-4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C.sub.1-4 alkyl; phenyl-C.sub.1-4 alkoxy; heteroaryl-C.sub.1-4 alkyl; heteroaryl-C.sub.1-4 alkoxy and phenoxy, wherein the heteroaryl, heteroaryloxy, phenyl, phenyl-C.sub.1-4 alkyl, phenyl-C.sub.1-4 alkoxy, heteroaryl-C.sub.1-4 alkyl, heteroaryl-C.sub.1-4 alkoxy and phenoxy groups are each optionally substituted with 1, 2 or 3 substituents selected from C.sub.1-2 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, CONH.sub.2, C.sub.1-2 hydrocarbyloxy and C.sub.1-2 hydrocarbyl each optionally substituted by methoxy or hydroxy; R.sup.2 and R.sup.3 are independently selected from hydrogen, C.sub.1-4 hydrocarbyl and C.sub.1-4 acyl wherein the hydrocarbyl and acyl moieties are optionally substituted by one or more substituents selected from fluorine, hydroxy, amino, methylamino, dimethylamino and methoxy; or R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached form a cyclic group selected from an imidazole group and a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR.sup.2R.sup.3 and the carbon atom of linker group A to which it is attached together form a cyano group; R.sup.4 is selected from hydrogen, halogen, C.sub.1-5 saturated hydrocarbyl, C.sub.1-5 saturated hydrocarbyloxy, cyano, and CF.sub.3; and R.sup.5 is selected from hydrogen, halogen, C.sub.1-5 saturated hydrocarbyl, C.sub.1-5 saturated hydrocarbyloxy, cyano, CONH.sub.2, CONHR.sup.9, CF.sub.3, NH.sub.2, NHCOR.sup.9 or NHCONHR.sup.9; R.sup.9 is a group R.sup.9a or (CH.sub.2)R.sup.9a, wherein R.sup.9a is a monocyclic or bicyclic group which may be carbocyclic or heterocyclic; the carbocyclic group or heterocyclic group R.sup.9a being optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-4 hydrocarbylamino; 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, heterocyclic groups having from 3 to 12 ring members, and a C.sub.1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C.sub.1-8 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 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; and wherein (I) the ancillary compound is selected from: (a) the group consisting of trastuzumab, cetuximab, erlotinib, gefitinib, bevacizumab, imatinib and sorafinib; (b) an ancillary PKB inhibitor; (c) a CDK inhibitor; (d) a COX-2 inhibitor; (e) a HDAC inhibitor; (f) temozolomide; (g) bortezimib; and (h) a combination of two or more of (a) to (g); or (II) the ancillary compound is a cytotoxic compound selected from: (a) camptothecin compounds; (b) the group consisting of 5-fluorouracil, fludarabine, gemcitabine, capecitabine, cytarabine, ralitrexed, pemetrexed and methotrexate; (c) vinca alkaloids; (d) taxanes; (e) epothilones; (f) platinum compounds; (g) the group consisting of an anthracycline derivative, mitoxantrone and a podophyllotoxin derivative; (h) the group consisting of nitrogen mustard compound, a nitrosurea, cyclophosphamide, Busulfan and mitomycin C; and (i) a combination of two or more of (a) to (h); or (III) the ancillary compound is selected from: (a) the group consisting of alemtuzumab, anti-CD20, CD22, CD33, or CD52, rituximab/rituxamab, tositumomab, gemtuzumab ozogamicin and bevacizumab; and (b) a combination of two or more of (a); or (IV) the ancillary compound is selected from: (a) the group consisting of antiandrogens, antiestrogens, aromatase inhibitors, and GNRAs; (b) the group consisting of interferons and interleukins; (c) the group consisting of tretinoin, alitretinoin, and bexarotene; and (d) a combination of two or more of (a) to (c). 2. A combination according to claim 1 comprising an ancillary compound and a compound of the formula (Ia): ##STR00278## or a salt, solvate, tautomer or N-oxide thereof; wherein R.sup.2 and R.sup.3 are independently selected from hydrogen, C.sub.1-4 hydrocarbyl and C.sub.1-4 acyl; or R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or one of R.sup.2 and R.sup.3 together with the nitrogen atom to which they are attached and one or more atoms from the linker group A form a saturated monocyclic heterocyclic group having 4-7 ring members and optionally containing a second heteroatom ring member selected from O and N; or NR.sup.2R.sup.3 and the carbon atom of linker group A to which it is attached together form a cyano group; R.sup.4 is selected from hydrogen, halogen, C.sub.1-5 saturated hydrocarbyl, cyano and CF.sub.3; and R.sup.5 is selected from hydrogen, halogen, C.sub.1-5 saturated hydrocarbyl, cyano, CONH.sub.2, CONHR.sup.9, CF.sub.3, NH.sub.2, NHCOR.sup.9 or NHCONHR.sup.9; and R.sup.9 is phenyl or benzyl each optionally substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-4 hydrocarbylamino; 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, heterocyclic groups having from 3 to 12 ring members, and a C.sub.1-8 hydrocarbyl group optionally substituted by one or more substituents selected from hydroxy, oxo, halogen, cyano, nitro, carboxy, amino, mono- or di-C.sub.1-4 hydrocarbylamino, carbocyclic and heterocyclic groups having from 3 to 12 ring members and wherein one or more carbon atoms of the C.sub.1-8 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. 3. A combination according to claim 1 wherein the portion R.sup.1-A-NR.sup.2R.sup.3 is represented by the formula R.sup.1-(G).sub.k-(CH.sub.2).sub.m--W--O.sub.b--(CH.sub.2).sub.n--(CR.sup- .6R.sup.7).sub.p--NR.sup.2R.sup.3 wherein G is NH, NMe or O; W is attached to the group E and is selected from (CH.sub.2).sub.j--CR.sup.20, (CH.sub.2).sub.j--N and (NH).sub.j--CH; b is 0 or 1, j is 0 or 1, k is 0 or l, m is 0 or 1, n is 0, 1, 2, or 3 and p is 0 or 1; the sum of b and k is 0 or 1; the sum of j, k, m, n and p does not exceed 4; R.sup.6 and R.sup.7 are the same or different and are selected from methyl and ethyl, or CR.sup.6R.sup.7 forms a cyclopropyl group; and R.sup.20 is selected from hydrogen, methyl, hydroxy and fluorine. 4. A combination according to claim 3 wherein k is 0, m is 0 or 1, n is 0, 1, 2 or 3 and p is 0. 5. A combination according to claim 1 wherein E is selected from 1,4-phenylene, 1,3-phenylene, 2,5-pyridylene and 2,4-pyridylene, each of which is unsubstituted or substituted by up to 4 substituents R.sup.8 as defined in claim 1. 6. A combination according to claim 1 wherein the compound of formula (I) is a compound of the formula (II): ##STR00279## or a salt, solvate, tautomer or N-oxide thereof; wherein the group A is attached to the meta or para position of the benzene ring and q is 0-4. 7. A combination according to claim 6 wherein the compound of formula (II) is a compound having the formula (III): ##STR00280## or a salt, solvate, tautomer or N-oxide thereof; where A' is the residue of the group A. 8. A combination according to claim 1 wherein the compound of formula (I) is a compound having the formula (IV): ##STR00281## or a salt, solvate, tautomer or N-oxide thereof; wherein z is 0, 1 or 2, R.sup.20 is selected from hydrogen, methyl, hydroxy and fluorine, provided that when z is 0, R.sup.20 is other than hydroxy. 9. A combination according to claim 1 wherein the compound of formula (I) is a compound having the formula (V): ##STR00282## or a salt, solvate, tautomer or N-oxide thereof. 10. A combination according to claim 1 wherein R.sup.1 is selected from phenyl, which is unsubstituted or bears one or more substituents selected from hydroxy; C.sub.1-4 acyloxy; fluorine; chlorine; bromine; trifluoromethyl; cyano; CONH.sub.2; nitro; C.sub.1-4 hydrocarbyloxy and C.sub.1-4 hydrocarbyl each optionally substituted by C.sub.1-2 alkoxy, carboxy or hydroxy; C.sub.1-4 acylamino; benzoylamino; pyrrolidinocarbonyl; piperidinocarbonyl; morpholinocarbonyl; piperazinocarbonyl; five and six membered heteroaryl and heteroaryloxy groups containing one or two heteroatoms selected from N, O and S; phenyl; phenyl-C.sub.1-4 alkyl; phenyl-C.sub.1-4 alkoxy; heteroaryl-C.sub.1-4 alkyl; heteroaryl-C.sub.1-4 alkoxy and phenoxy, wherein the heteroaryl, heteroaryloxy, phenyl, phenyl-C.sub.1-4 alkyl, phenyl-C.sub.1-4 alkoxy, heteroaryl-C.sub.1-4 alkyl, heteroaryl-C.sub.1-4 alkoxy and phenoxy groups are each optionally substituted with 1, 2 or 3 substituents selected from C.sub.1-2 acyloxy, fluorine, chlorine, bromine, trifluoromethyl, cyano, CONH.sub.2, C.sub.1-2 hydrocarbyloxy and C.sub.1-2 hydrocarbyl each optionally substituted by methoxy or hydroxy. 11. A combination according to claim 10 wherein R.sup.1 is a mono-chlorophenyl or dichlorophenyl group. 12. A combination according to claim 1 wherein R.sup.4 is selected from hydrogen and methyl and R.sup.5 is selected from hydrogen, methyl and cyano. 13. A combination according to claim 1 wherein R.sup.2 and R.sup.3 are independently selected from hydrogen, C.sub.1-4 hydrocarbyl and C.sub.1-4 acyl. 14. A combination according to claim 13 wherein R.sup.2 and R.sup.3 are independently selected from hydrogen and methyl. 15. A combination according to claim 14 wherein R.sup.2 and R.sup.3 are both hydrogen. 16. A combination according to claim 1 wherein the compound of the formula (I) is selected from the group consisting of: 2-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propionitrile; 2-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-2-phenyl-ethylamine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 2-[3-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-1-phenyl-ethylamine; 3-phenyl-2-[3-(1H-pyrazol-4-yl)-phenyl]-propylamine; 3-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; {3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; {3-(3,4-difluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-am- ine; {3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-am- ine; 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide; 3-(4-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 4-(4-chloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-chloro-phenyl)-1-methyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-phenyl-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-[4-(3,5-dimethyl-1H-pyrazol-4-yl)-phenyl]-4-phenyl-piperidine; dimethyl-{3-[4-(1H-pyrazol-4-yl)-phenyl]-3-pyridin-2-yl-propyl}-amine; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine (R); {2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-am- ine (S); 4-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-morph- oline; 4-{4-[1-(4-chloro-phenyl)-2-pyrrolidin-1-yl-ethyl]-phenyl}-1H-pyraz- ole; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-isopropyl-a- mine; dimethyl-{2-phenyl-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-amine; {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-dimethyl-amine; {2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (R); 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine (S); 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide; 1-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-piperazine; 1-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-piperidine; 4-{4-[2-azetidin-1-yl-1-(4-chloro-phenyl)-ethyl]-phenyl}-1H-pyrazole; 1-phenyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 2-(4-chloro-phenyl)-N-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide; N-methyl-2,2-bis-[4-(1H-pyrazol-4-yl)-phenyl]-acetamide; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-ethyl-amine; 4-{4-[1-(4-chloro-phenyl)-2-imidazol-1-yl-ethyl]-phenyl}-1H-pyrazole; methyl-{2-(4-phenoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; {2-(4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; methyl-{2-[4-(pyrazin-2-yloxy)-phenyl]-2-[4-(1H-pyrazol-4-yl)-phenyl]-eth- yl}-amine; methyl-{2-phenoxy-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-amine; 2-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methoxy}-ethylamine; 4-{4-[1-(4-chloro-phenyl)-3-pyrrolidin-1-yl-propyl]-phenyl}-1H-pyrazole; 4-{4-[3-azetidin-1-yl-1-(4-chloro-phenyl)-propyl]-phenyl}-1H-pyrazole; methyl-{3-naphthalen-2-yl-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-amine; {3-(4-fluoro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 4-{4-[4-(4-chloro-phenyl)-piperidin-4-yl]-phenyl}-1H-pyrazole-3-carbonitr- ile; 3-(4-phenoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; 1-methyl-4-{phenyl-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-[1,4]diazepane; {3-(3-chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine- ; methyl-{2-phenyl-2-[6-(1-pyrazol-4-yl)-pyridin-3-yl]-ethyl}-amine; 4-{4-[1-(4-chloro-phenyl)-3-imidazol-1-yl-propyl]-phenyl}-1H-pyrazole; 4-[4-(3-imidazol-1-yl-1-phenoxy-propyl)-phenyl]-1H-pyrazole; 4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenol; 1-{(4-chloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; {2-(4-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; {2-(3-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-methyl-amine; 4-[4-(2-methoxy-ethoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine- ; 4-[4-(3-methoxy-propoxy)-phenyl]-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidi- ne; 3-(3,4-dichloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propionamide; 2-(4-{2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-phenoxy)-isonic- otinamide; {2-(4-chloro-phenoxy)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-met- hyl-amine; 3-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino- }-propan-1-ol; 2-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino}-ethanol; 3-{2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethylamino}-propan-1- -ol; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-ethyl}-cyclopropyl- methyl-amine; methyl-[2-[4-(1H-pyrazol-4-yl)-phenyl]-2-(4-pyridin-3-yl-phenyl)-ethyl]-a- mine; 4-{3-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-propyl}-phenol; 3-(4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 4-(4-chloro-phenyl)-4-[4-(3-methyl-1H-pyrazol-4-yl)-phenyl]-piperidine; 2-(4-chloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-morpholine; (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid; 4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-benzonitrile; {2-(4-chloro-phenyl)-2-[4-(1-pyrazol-4-yl)-phenyl]-propyl}-methyl-amine; 1-(4-chloro-phenyl)-2-methylamino-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 4-(3,4-dichloro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(3-chloro-4-methoxy-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-(4-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 4-[4-(1H-pyrazol-4-yl)-phenyl]-1,2,3,4,5,6-hexahydro-[4,4']bipyridinyl; 3-(3-chloro-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propylamine; 2-methylamino-1-(4-nitro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol; 2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 2-(4-chloro-phenyl)-2-fluoro-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 3-(3,4-dichloro-phenyl)-3-[6-(1H-pyrazol-4-yl)-pyridin-3-yl]-propylamine; 2-(4-chloro-3-fluoro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; 4-(2-chloro-3-fluoro-phenyl)-4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidine; 1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; 2-(3,4-dichloro-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethylamine; {2-(3-chloro-4-methoxy-phenyl)-2-[4-(1H-pyrazol-4-yl)-phenyl]-ethyl}-meth- yl-amine; 4-{4-[2-azetidin-1-yl-1-(4-chloro-phenoxy)-ethyl]-phenyl}-1H-pyr- azole; 3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propyl- amine; {3-(3-chloro-4-methoxy-phenyl)-3-[4-(1H-pyrazol-4-yl)-phenyl]-propy- l}-methyl-amine; 1-{(3,4-dichloro-phenyl)-[4-(1H-pyrazol-4-yl)-phenyl]-methyl}-piperazine; and C-(4-chloro-phenyl)-C-[4-(1H-pyrazol-4-yl)-phenyl]-methylamine; and salts, solvates, tautomers and N-oxides thereof. 17. A combination according to claim 1 in the form of a pharmaceutical pack, kit or patient pack. 18. A combination according to claim 1 wherein the ancillary compound comprises: an antiandrogen, antiestrogen, aromatase inhibitor, or GNRA selected from tamoxifen, fulvestrant, raloxifene, toremifene, droloxifene, letrozole, anastrozole, exemestane, bicalutamide, luprolide, megestrol/megestrel acetate, vorozole, aminoglutethimide, bexarotene, goserelin, leuprolide/leuporelin, triptorelin, buserelin, abarelix, goserelin acetate and leuprolide acetate; an ancillary PKB inhibitor selected from SF1126, rapamycin analogues, KRX-0401, API-2/TCN, RX-0201, enzastaurin HCl, SR-13668, PX-316, Perifosine, and NL-71-101; a CDK inhibitor selected from seliciclib, alvocidib, 7-hydroxy-staurosporine, JNJ-7706621, BMS-387032, PHA533533, PD332991, ZK-304709, and AZD-5438; COX-2 inhibitor celecoxib; a HDAC inhibitor selected from TSA, SAHA, JNJ-16241199, LAQ-824, MGCD-0103, PXD-101, JNJ-16241199, LAQ-824, MGCD-0103, PXD-101, chlamydocin, and A-173; a camptothecin compound selected from irinotecan and topotecan; a vinca alkaloid selected from vinblastine, vincristine, vinorelbine, vindesine, and vinvesir; a taxane selected from paclitaxel and docetaxel; an epothilone selected from epothilone A, epothilone B, ixabepilone, patupilone, BMS-310705, BMS-247550, KOS-862 and ZK-EPO; or a platinum compound selected from chloro(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, tetraplatin, cisplatin, carboplatin and oxaliplatin. 19. A combination according to claim 1 containing two or more ancillary compounds. 20. A combination according to claim 19 wherein at least one of the two ancillary compounds and compound of formula (I), or a salt, solvate, tautomer or N-oxide thereof, are physically associated. 21. A combination according to claim 19 wherein at least one of the two ancillary compounds and compound of formula (I), or a salt, solvate, tautomer or N-oxide thereof, are non-physically associated. 22. A combination according to claim 1 wherein the compound of formula (I) is 2-amino-1-(4-chloro-phenyl)-1-[4-(1H-pyrazol-4-yl)-phenyl]-ethanol- , or a salt, solvate, tautomer or N-oxide thereof. 23. A combination according to claim 22 wherein the compound of formula (I) is in the form of a salt. 24. A combination according to claim 22 wherein the compound of formula (I) is in the form of a di-hydrochloride salt. 25. A combination according to claim 1 wherein the ancillary compound and compound of formula (I), or a salt, solvate, tautomer or N-oxide thereof, are physically associated. 26. A combination according to claim 1 wherein the ancillary compound and compound of formula (I), or a salt, solvate, tautomer or N-oxide thereof, are non-physically associated.

Details for Patent 8,541,461

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2039-02-26
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	05/07/2001		2039-02-26
Genzyme Corporation	LEMTRADA	alemtuzumab	Injection	103948	11/14/2014		2039-02-26
Genzyme Corporation	CAMPATH	alemtuzumab	Injection	103948	10/12/2004		2039-02-26