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Title:Amino-derivatives as novel inhibitors of histone deacetylase
Abstract: This invention comprises the novel compounds of formula (I) ##STR00001## wherein n, m, t, R.sup.1, R.sup.2, L, Q, X, Y, Z and ##STR00002## have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
Inventor(s): Angibaud; Patrick Rene (Fontaine-Bellinger, FR), Van Emelen; Kristof (Sint-Niklaas, BE), Poncelet; Virginie Sophie (Le Manoir sur Seine, FR), Roux; Bruno (Saint Leeger du Bourg-Denis, FR)
Assignee: Janssen Pharmaceutica NV (Beerse, BE)
Application Number:14/538,317
Patent Claims:1. A compound of formula (I), ##STR00088## the N-oxide form, pharmaceutically acceptable addition salt, or stereo-chemically isomeric form thereof, wherein n is 1 and m is 2; t is 0 or 1 and when t is 0 then a direct bond is intended; Q is C; X is N or C; Y is N; Z is --CH.sub.2--; R.sup.1 is --C(O)NR.sup.3R.sup.4, --N(H)C(O)R.sup.7, --C(O)--C.sub.1-6alkanediylSR.sup.7, --NR.sup.8C(O)N(OH)R.sup.7, --NR.sup.8C(O)C.sub.1-6alkanediylSR.sup.7, or --NR.sup.8C(O)C.dbd.N(OH)R.sup.7 wherein R.sup.3 and R.sup.4 are each independently hydrogen, hydroxy, C.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aminoC.sub.1-6alkyl or aminoaryl; R.sup.7 is hydrogen, C.sub.1-6alkyl, C.sub.1-6alkylcarbonyl, arylC.sub.1-6alkyl, C.sub.1-6alkylpyrazinyl, pyridinone, pyrrolidinone, or methylimidazolyl; and R.sup.8 is hydrogen or C.sub.1-6alkyl; R.sup.2 is hydrogen, hydroxy, amino, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC.sub.1-6alkyl, aminocarbonylC.sub.1-6alkyl, hydroxycarbonylC.sub.1-6alkyl, hydroxyaminocarbonyl, C.sub.1-6alkyloxycarbonyl, C.sub.1-6alkylaminoC.sub.1-6alkyl, or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; -L- is a bivalent radical that is C.sub.1-6alkanediyl, carbonyl, sulfonyl, or C.sub.1-6alkanediyl substituted with phenyl; ##STR00089## is a radical selected from the group consisting of ##STR00090## ##STR00091## ##STR00092## ##STR00093## ##STR00094## wherein each s is independently 0, 1, 2, 3, 4 or 5, as allowed; each R.sup.5 and R.sup.6 is independently selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyl substituted with aryl and C.sub.3-10cycloalkyl; C.sub.1-6alkyloxy; C.sub.1-6alkyloxyC.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; cyanoC.sub.1-6alkyl; hydroxyC.sub.1-6alkyl; hydroxyC.sub.1-6alkyloxy; hydroxyC.sub.1-6alkylamino; aminoC.sub.1-6alkyloxy; di(C.sub.1-6alkyl)aminocarbonyl; di(hydroxyC.sub.1-6alkyl)amino; (aryl)(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyloxy; di(C.sub.1-6alkyl)aminoC.sub.1-6alkylamino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkylaminoC.sub.1-6alkyl; aryl sulfonyl; arylsulfonylamino; aryloxy; aryloxyC.sub.1-6alkyl; arylC.sub.2-6alkenediyl; di(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)amino(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)amino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; aminosulfonylamino(C.sub.1-6alkyl)amino; aminosulfonylamino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminosulfonylamino(C.sub.1-6alkyl)amino; di(C.sub.1-6alkyl)aminosulfonylamino(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; cyano; thiophenyl; thiophenyl substituted with di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, C.sub.1-6alkylpiperazinylC.sub.1-6alkyl, hydroxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl, hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl, di(C.sub.1-6alkyl)aminosulfonylpiperazinylC.sub.1-6alkyl, C.sub.1-6alkyloxypiperidinyl, C.sub.1-6alkyloxypiperidinylC.sub.1-6alkyl, morpholinylC.sub.1-6alkyl, hydroxyC.sub.1-6 alkyl(C.sub.1-6alkyl)aminoC.sub.1-6alkyl, or di(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkyl; furanyl; furanyl substituted with hydroxyC.sub.1-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C.sub.1-6alkyl; C.sub.1-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylC.sub.1-6alkyloxy; morpholinyl; C.sub.1-6alkylmorpholinyl; morpholinylC.sub.1-6alkyloxy; morpholinylC.sub.1-6alkyl; morpholinylC.sub.1-6alkylamino; morpholinylC.sub.1-6alkylaminoC.sub.1-6alkyl; piperazinyl; C.sub.1-6alkylpiperazinyl; C.sub.1-6alkylpiperazinylC.sub.1-6alkyloxy; piperazinylC.sub.1-6alkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl: C.sub.1-6alkylpiperazinylC.sub.1-6alkyl; C.sub.1-6alkylpiperazinylC.sub.1-6alkylamino; C.sub.1-6alkylpiperazinylC.sub.1-6alkylaminoC.sub.1-6alkyl; C.sub.1-6alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC.sub.1-6alkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC.sub.1-6alkyl; di(C.sub.1-6alkyl)aminosulfonylpiperazinyl; di(C.sub.1-6alkyl)aminosulfonylpiperazinylC.sub.1-6alkyl; hydroxyC.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl; C.sub.1-6alkyloxypiperidinyl; C.sub.1-6alkyloxypiperidinylC.sub.1-6alkyl; piperidinylaminoC.sub.1-6alkylamino; piperidinylaminoC.sub.1-6alkylaminoC.sub.1-6alkyl; (C.sub.1-6alkylpiperidinyl)(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkylamin- o; (C.sub.1-6alkylpiperidinyl)(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkylam- inoC.sub.1-6alkyl; hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkyloxyC.sub.1-6alkylpiperazinylC.sub.1-6alkyl; (hydroxyC.sub.1-6alkyl)(C.sub.1-6alkyl)amino; (hydroxyC.sub.1-6alkyl)(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; hydroxyC.sub.1-6alkylaminoC.sub.1-6alkyl; di(hydroxyC.sub.1-6alkyl)aminoC.sub.1-6alkyl; pyrrolidinylC.sub.1-6alkyl; pyrrolidinylC.sub.1-6alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from the group consisting of C.sub.1-6alkyl and trihaloC.sub.1-6alkyl; pyridinyl; pyridinyl substituted with C.sub.1-6alkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC.sub.1-6alkyl; quinolinyl; indolyl; phenyl; phenyl substituted with one, two, or three substituents independently selected from the group consisting of halo, amino, nitro, C.sub.1-6alkyl, C.sub.1-6alkyloxy, hydroxyC.sub.1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC.sub.1-4alkyloxy, C.sub.1-4alkylsulfonyl, C.sub.1-4alkyloxyC.sub.1-4alkyloxy, C.sub.1-4alkyloxycarbonyl, aminoC.sub.1-4alkyloxy, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyloxy, di(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminocarbonyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkylaminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)amino(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)amino(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, aminosulfonylamino(C.sub.1-4alkyl)amino, aminosulfonylamino(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminosulfonylamino(C.sub.1-4alkyl)amino, di(C.sub.1-4alkyl)aminosulfonylamino(C.sub.1-4alkyl)aminoC.sub.1-6alkyl, cyano, piperidinylC.sub.1-4alkyloxy, pyrrolidinylC.sub.1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminosulfonylpiperazinyl, di(C.sub.1-4alkyl)aminosulfonylpiperazinylC.sub.1-4alkyl, hydroxyC.sub.1-4alkylpiperazinyl, hydroxyC.sub.1-4alkylpiperazinylC.sub.1-4alkyl, C.sub.1-4alkyloxypiperidinyl, C.sub.1-4alkyloxypiperidinylC.sub.1-4alkyl, hydroxyC.sub.1-4alkyloxyC.sub.1-4alkylpiperazinyl, hydroxyC.sub.1-4alkyloxyC.sub.1-4alkylpiperazinylC.sub.1-4alkyl, (hydroxyC.sub.1-4alkyl)(C.sub.1-4alkyl)amino, (hydroxyC.sub.1-4alkyl)(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, di(hydroxyC.sub.1-4alkyl)amino, di(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkyl, furanyl, furanyl substituted with --CH.dbd.CH--CH.dbd.CH--, pyrrolidinylC.sub.1-4alkyl, pyrrolidinylC.sub.1-4alkyloxy, morpholinyl, morpholinylC.sub.1-4alkyloxy, morpholinylC.sub.1-4alkyl, morpholinylC.sub.1-4alkylamino, morpholinylC.sub.1-4alkylaminoC.sub.1-4alkyl, piperazinyl, C.sub.1-4alkylpiperazinyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkyloxy, piperazinylC.sub.1-4alkyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkyl, C.sub.1-4alkylpiperazinylC.sub.1-4alkylamino, C.sub.1-4alkylpiperazinylC.sub.1-4alkylaminoC.sub.1-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC.sub.1-4alkyl, piperidinylaminoC.sub.1-4alkylamino, piperidinylaminoC.sub.1-4alkylaminoC.sub.1-4alkyl, (C.sub.1-4alkylpiperidinyl)(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkylamin- o, (C.sub.1-4alkylpiperidinyl)(hydroxyC.sub.1-4alkyl)aminoC.sub.1-4alkylam- inoC.sub.1-4alkyl, pyridinylC.sub.1-4alkyloxy, hydroxyC.sub.1-4alkylamino, hydroxyC.sub.1-4alkylaminoC.sub.1-4alkyl, di(C.sub.1-4alkyl)aminoC.sub.1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC.sub.1-4alkyloxy, and thiophenylC.sub.1-4alkylamino; each R.sup.5 and R.sup.6 can be placed on the nitrogen in replacement of the hydrogen; wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl.

2. A compound of formula (I), ##STR00095## the N-oxide form, pharmaceutically acceptable addition salt, or stereo-chemically isomeric form thereof, wherein n is 1; m is 2; t is 0; Q is C; X is N or C; Y is N; Z is --CH.sub.2--; R.sup.1 is --C(O)NR.sup.3R.sup.4, --C(O)--C.sub.1-6alkanediylSR.sup.7, --NR.sup.8C(O)N(OH)R.sup.7, --NR.sup.8C(O)C.sub.1-6alkanediylSR.sup.7, or --NR.sup.8C(O)C.dbd.N(OH)R.sup.7 wherein R.sup.3 and R.sup.4 are each independently selected from the group consisting of hydrogen, hydroxy, hydroxyC.sub.1-6alkyl, and aminoC.sub.1-6alkyl; R.sup.2 is hydrogen, hydroxy, amino, hydroxyC.sub.1-6alkyl, C.sub.1-6alkyl, C.sub.1-6alkyloxy, arylC.sub.1-6alkyl, aminocarbonyl, aminoC.sub.1-6alkyl, C.sub.1-6alkylaminoC.sub.1-6alkyl, or di(C.sub.1-6alkyl)aminoC.sub.1-6alkyl; -L- is a bivalent radical selected from the group consisting of C.sub.1-6alkanediyl, carbonyl and sulfonyl; ##STR00096## is a radical selected from the group consisting of ##STR00097## ##STR00098## ##STR00099## ##STR00100## ##STR00101## s is 0, 1, 2, 3 or 4, as allowed; R.sup.5 is selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; hydroxyC.sub.1-6alkyl; aryloxy; di(C.sub.1-6alkyl)amino; cyano; thiophenyl; furanyl; furanyl substituted with hydroxyC.sub.1-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C.sub.1-6alkyl; C.sub.1-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; morpholinyl; C.sub.1-6alkylmorpholinyl; piperazinyl; C.sub.1-6alkylpiperazinyl; hydroxyC.sub.1-6alkylpiperazinyl; C.sub.1-6 alkyloxypiperidinyl; pyrazolyl; pyrazolyl substituted with one or two substituents selected from the group consisting of C.sub.1-6alkyl and trihaloC.sub.1-6alkyl; pyridinyl; pyridinyl substituted with C.sub.1-6alkyloxy, aryloxy, or aryl; pyrimidinyl; quinolinyl; indolyl; phenyl; and phenyl substituted with one or two substituents independently selected from the group consisting of halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, and trifluoromethyl; and R.sup.6 is selected from the group consisting of hydrogen; halo; hydroxy; amino; nitro; trihaloC.sub.1-6alkyl; trihaloC.sub.1-6alkyloxy; C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylcarbonyl; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylsulfonyl; hydroxyC.sub.1-6alkyl; aryloxy; di(C.sub.1-6alkyl)amino; cyano; pyridinyl; phenyl; and phenyl substituted with one or two substituents independently selected from the group consisting of halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, and trifluoromethyl; wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl.

3. The compound as claimed in claim 1, wherein R.sup.1 is --C(O)NH(OH); R.sup.2 is hydrogen; -L- is a bivalent radical that is carbonyl, sulfonyl, or C.sub.1-6alkanediyl substituted with phenyl; ##STR00102## is a radical that is (a-1), (a-20), or (a-43); s is 0 or 1; and each R.sup.5 is hydrogen or phenyl.

4. The compound as claimed in claim 1, wherein R.sup.1 is --C(O)NH(OH); R.sup.2 is hydrogen; -L- is a bivalent radical that is carbonyl or sulfonyl; ##STR00103## is a radical that is (a-1) or (a-20); each s is independently 0 or 1; and each R.sup.5 is independently selected from the group consisting of hydrogen and phenyl.

5. The compound according to claim 1 that is ##STR00104##

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.

7. A process of preparing a pharmaceutical composition as claimed in claim 6 comprising intimately mixing the pharmaceutically acceptable carrier and the compound.

8. A process for preparing a compound as claimed in claim 1, comprising reacting an intermediate of formula (II) ##STR00105## with an appropriate acid, yielding a hydroxamic acid of formula (I-a) ##STR00106##

9. The method of claim 8 wherein the acid is trifluoroacetic acid.

10. A method of detecting or identifying a histone deactylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim 1 and a HDAC.

11. A composition comprising a compound of claim 1 and an additional anti-cancer agent that is cisplatin, carboplatin, oxalyplatin, paclitaxel, docetaxel, irinotecan, topotecan, etoposide, teniposide, vinblastine, vincristine, vinorelbine, 5-fluorouracil, gemcitabine, capecitabine, cyclophosphamide, chlorambucil, carmustine, lomustine, daunorubicin, doxorubicin, idarubicin, mitoxantrone, trastuzumab, tamoxifen, toremifene, droloxifene, faslodex, raloxifene, exemestane, anastrozole, letrazole, vorozole, vitamin D, accutane, azacytidine, flavoperidol, imatinib mesylate, gefitinib, butyrate, 4-phenylbutyrate or valproic acid, suberoylanilide hydroxamic acid (SAHA), biaryl hydroxamate A-161906, bicyclic aryl-N-hydroxycarboxamides, pyroxamide, CG-1521, PXD-101, sulfonamide hydroxamic acid, LAQ-824, trichostatin A (TSA), oxamflatin, scriptaid, m-carboxy cinnamic acid bishydroxamic acid, trapoxin-hydroxamic acid analogue, trapoxin, apidicin, depsipeptide, MS-275, CI-994, or depudecin.

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Inventors Patent Expiration Status Orphan Source
Genentech
HERCEPTIN
trastuzumab
VIAL; INTRAVENOUS1037920011998-09-25► Subscribe Janssen Pharmaceutica NV (Beerse, BE) Angibaud; Patrick Rene (Fontaine-Bellinger, FR), Van Emelen; Kristof (Sint-Niklaas, BE), Poncelet; Virginie Sophie (Le Manoir sur Seine, FR), Roux; Bruno (Saint Leeger du Bourg-Denis, FR) ► SubscribeRXOrphansearch
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International Patent Family for Patent: ► Subscribe

Country Document Number Publication Date
South Africa200407232Oct 06, 2005
South Africa200407233Oct 06, 2005
South Africa200407234Oct 06, 2005
South Africa200407235Oct 04, 2005
South Africa200407236Oct 06, 2005
South Africa200407237Sep 28, 2005
World Intellectual Property Organization (WIPO)03075929Sep 18, 2003
World Intellectual Property Organization (WIPO)03076395Sep 18, 2003
World Intellectual Property Organization (WIPO)03076400Sep 18, 2003
World Intellectual Property Organization (WIPO)03076401Sep 18, 2003
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