EP2142190A1 - Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux - Google Patents

Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux

Info

Publication number
EP2142190A1
EP2142190A1 EP08747442A EP08747442A EP2142190A1 EP 2142190 A1 EP2142190 A1 EP 2142190A1 EP 08747442 A EP08747442 A EP 08747442A EP 08747442 A EP08747442 A EP 08747442A EP 2142190 A1 EP2142190 A1 EP 2142190A1
Authority
EP
European Patent Office
Prior art keywords
aryl
alkyl
heteroaryl
heterocycloalkyl
cycloalkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08747442A
Other languages
German (de)
English (en)
Inventor
Peter Wisdom Atadja
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=39683987&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2142190(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Publication of EP2142190A1 publication Critical patent/EP2142190A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of an HDAC inhibitor for the preparation of a medicament for the treatment of gastrointestinal cancers; a method of treating a warmblooded animal, especially a human, having gastrointestinal cancer, comprising administering to said animal a therapeutically effective amount of an HDAC inhibitor, especially a compound of formula (I), as defined herein; and to a pharmaceutical composition and a commercial package.
  • gastrointestinal cancers includes, but is not limited to, hepatocellular carcinoma and/or pancreatic cancer.
  • HDAC inhibitors histone deacetylase inhibitors
  • Reversible acetylation of histones is a major regulator of gene expression that acts by altering accessibility of transcription factors to DNA.
  • HDA histone deacetylase
  • histone acetyltrasf erase together control the level of acetylation of histones to maintain a balance. Inhibition of HDA results in the accumulation of hyperacetylated histones, which results in a variety of cellular responses.
  • HDAC inhibitors especially the compounds of formula (I), as defined herein, directly inhibit the proliferation of gastrointestinal cancer, such hepatocellular carcinoma and/or pancreatic cancer.
  • the invention relates to the use of an HDAC inhibitor for the preparation of a medicament for the treatment of gastrointestinal cancer.
  • Figure 1 illustrates that LBH589 treatment inhibits tumor growth in the HCT116 xenograft model.
  • Figure 2 illustrates co-treatment of LBH589 with 5-Fluorouracil enhances tumor growth inhibition and tumor growth delay in Colo205 colon cancer xenograft model.
  • Figure 3 illustrates the anti-proliferative and cytotoxic effects of LBH589 in 19 pancreatic cancer cell lines.
  • HDAC inhibitor compounds of particular interest for use in the inventive combination are hydroxamate compounds described by the formula (I):
  • R 1 is H; halo; or a straight-chain d-C 6 alkyl, especially methyl, ethyl or n-propyl, which methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for alkyl substituents;
  • R 2 is selected from H; Ci-C 10 alkyl, preferably Ci-C 6 alkyl, e.g., methyl, ethyl or -CH 2 CH 2 - OH; d-CgCycloalkyl; C 4 -C 9 heterocycloalkyl; C 4 -C 9 heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; -(CH 2 ) n C(O)R 6 ; -(CH 2 ) n OC(O)R 6 ; amino acyl; HON-CCOJ-CH ⁇ RO-aryl- alkyl-; and -(CH 2 ) n R 7 ;
  • R 3 and R 4 are the same or different and independently H, Ci-C 6 alkyl, acyl or acylamino, or
  • R 5 is selected from H; d-C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; acyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl; non-aromatic polyheterocycles; and mixed aryl and non-aryl polyheterocycles; n, n-,, n 2 and n 3 are the same or different and independently selected from 0-6, when n- ⁇ is 1-6, each carbon atom can be optionally and independently substituted with R 3 and/or R 4 ;
  • X and Y are the same or different and independently selected from H; halo; C r C 4 alkyl, such as CH 3 and CF 3 ; NO 2 ; C(O)Ri; OR 9 ; SR 9 ; CN; and NR 10 Rn;
  • R 6 is selected from H; C r C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; ORi 2 ; and NR 13 R 14 ;
  • R 7 is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 and NR 12 SO 2 R 6 ;
  • R 8 is selected from H; OR 15 ; NR 13 R 14 ; C r C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
  • R 9 is selected from C r C 4 alkyl, e.g., CH 3 and CF 3 ; C(O)-alkyl, e.g., C(O)CH 3 ; and C(O)CF 3 ;
  • R 10 and R 11 are the same or different and independently selected from H, C r C 4 alkyl and -C(O)-alkyl;
  • R 12 is selected from H; C r C 6 alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl;
  • R 13 and R 14 are the same or different and independently selected from H; CrC ⁇ alkyl; C 4 -C 9 cycloalkyl; C 4 -C 9 heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl, or
  • R 13 and R 14 together with the nitrogen to which they are bound, are C 4 -
  • R 15 is selected from H, C r C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZRi 2 ;
  • R 16 is selected from C r C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, poly heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;
  • R 17 is selected from C r C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR 13 R 14 ; m is an integer selected from 0-6; and Z is selected from O; NR 13 ; S; and S(O), or a pharmaceutically acceptable salt thereof.
  • Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
  • Alkyl substituents include straight- and branched-CrC 6 alkyl, unless otherwise noted.
  • suitable straight- and branched-CrC ⁇ alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, f-butyl and the like.
  • the alkyl substituents include both unsubstituted alkyl groups and alkyl groups that are substituted by one or more suitable substituents, including unsaturation, i.e., there are one or more double or triple C-C bonds; acyl; cycloalkyl; halo; oxyalkyl; alkylamino; aminoalkyl; acylamino; and OR 15 , e.g., alkoxy.
  • Preferred substituents for alkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
  • Cycloalkyl substituents include C 3 -C 9 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified.
  • cycloalkyl substituents include both unsubstituted cycloalkyl groups and cycloalkyl groups that are substituted by one or more suitable substituents, including d-Cealkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR 15 , such as alkoxy.
  • Preferred substituents for cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
  • alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as, without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
  • Heterocycloalkyl substituents include 3- to 9-membered aliphatic rings, such as 4- to 7-membered aliphatic rings, containing from 1-3 heteroatoms selected from nitrogen, sulfur, oxygen.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane and 1 ,4-oxathiapane.
  • the rings are unsubstituted or substituted on the carbon atoms by one or more suitable substituents, including Ci-C 6 alkyl; C 4 -C 9 cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR 15 , e.g., alkoxy.
  • suitable substituents including Ci-C 6 alkyl; C 4 -C 9 cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR 15 , e.g., alkoxy.
  • nitrogen heteroatoms are unsubstituted or substituted by H, C 1 -C 4 alkyl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl; aminoacyl; alkylsulfonyl; and arylsulfonyl.
  • Cycloalkylalkyl substituents include compounds of the formula -(CH 2 ) n5 -cycloalkyl, wherein n5 is a number from 1-6.
  • Suitable alkylcycloalkyl substituents include cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and the like. Such substituents are unsubstituted or substituted in the alkyl portion or in the cycloalkyl portion by a suitable substituent, including those listed above for alkyl and cycloalkyl.
  • Aryl substituents include unsubstituted phenyl and phenyl substituted by one or more suitable substituents including d-C 6 alkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; O(CO)alkyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; aminosulfonyl; arylsulfonyl and OR 15 , such as alkoxy.
  • Preferred substituents include including CrC 6 alkyl; cycloalkyl, e.g., cyclopropylmethyl; alkoxy; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl and aminosulfonyl.
  • Suitable aryl groups include C 1 -C 4 alkylphenyl, d ⁇ alkoxyphenyl, trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl, dimethylaminophenyl, aminopropylphenyl, carbethoxyphenyl, methanesulfonylphenyl and tolylsulfonylphenyl.
  • Aromatic polycycles include naphthyl, and naphthyl substituted by one or more suitable substituents including Ci-C 6 alkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl; aminosulfonyl and OR 15 , such as alkoxy.
  • suitable substituents including Ci-C 6 alkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl; aminosulfonyl and OR 15 ,
  • Heteroaryl substituents include compounds with a 5- to 7-membered aromatic ring containing one or more heteroatoms, e.g., from 1-4 heteroatoms, selected from N, O and S.
  • Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine and the like.
  • heteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl, the alkyl substituents identified above, and another heteroaryl substituent.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R 13 ; especially useful N substituents include H, Ci-C 4 alkyl, acyl, aminoacyl and sulfonyl.
  • Arylalkyl substituents include groups of the formula -(CH 2 ) n5 -aryl, -(CH 2 ) n5-1 -(CH-aryl)- (CH 2 ) n5 -aryl or -(CH 2 ) n5 -iCH(aryl)(aryl), wherein aryl and n5 are defined above.
  • Such arylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl, tolyl-3-propyl, 2- phenylpropyl, diphenylmethyl, 2-diphenylethyl, 5,5-dimethyl-3-phenylpentyl and the like.
  • Arylalkyl substituents are unsubstituted or substituted in the alkyl moiety or the aryl moiety or both as described above for alkyl and aryl substituents.
  • Heteroarylalkyl substituents include groups of the formula -(CH 2 ) n5 -heteroaryl, wherein heteroaryl and n5 are defined above and the bridging group is linked to a carbon or a nitrogen of the heteroaryl portion, such as 2-, 3- or 4-pyridylmethyl, imidazolylmethyl, quinolylethyl and pyrrolylbutyl. Heteroaryl substituents are unsubstituted or substituted as discussed above for heteroaryl and alkyl substituents.
  • Amino acyl substituents include groups of the formula -C(O)-(CH 2 ) n -C(H)(NR 13 R 14 )- (CH 2 ) n -R 5 , wherein n, R 13 , R 14 and R 5 are described above.
  • Suitable aminoacyl substituents include natural and non-natural amino acids, such as glycinyl, D-tryptophanyl, L-lysinyl, D- or L-homoserinyl, 4-aminobutryic acyl and ⁇ -3-amin-4-hexenoyl.
  • Non-aromatic polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and each ring can contain zero, one or more double and/or triple bonds.
  • Suitable examples of non-aromatic polycycles include decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo-[/]-azulene. Such substituents are unsubstituted or substituted as described above for cycloalkyl groups.
  • Mixed aryl and non-aryl polycycle substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered and at least one ring is aromatic.
  • Suitable examples of mixed aryl and non-aryl polycycles include methylenedioxyphenyl, b/s-methylenedioxyphenyl, 1 ,2,3,4-tetrahydronaphthalene, dibenzosuberane, dihdydroanthracene and 9H-fluorene.
  • substituents are unsubstituted or substituted by nitro or as described above for cycloalkyl groups.
  • Polyheteroaryl substituents include bicyclic and tricyclic fused ring systems where each ring can independently be 5- or 6-membered and contain one or more heteroatom, e.g., 1 , 2, 3 or 4 heteroatoms, chosen from O, N or S such that the fused ring system is aromatic.
  • Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline and the like.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R 13 , especially useful N substituents include H, Ci-C 4 alkyl, acyl, aminoacyl and sulfonyl.
  • Non-aromatic polyheterocyclic substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom, e.g., 1 , 2, 3 or 4 heteroatoms, chosen from O, N or S and contain zero or one or more C-C double or triple bonds.
  • non-aromatic polyheterocycles include hexitol, c/s-perhydro-cyclohepta[ ⁇ ]pyridinyl, decahydro-benzo[/][1 ,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2- ⁇ ]thiophene, perhydropyrrolo[3,2- ⁇ ]pyrrole, perhydronaphthyridine, perhydro-1H-dicyclopenta[ ⁇ ,e]pyran.
  • non-aromatic polyheterocyclic substituents are unsubstituted or substituted on a carbon atom by one or more substituents, including alkyl and the alkyl substituents identified above.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R 13 , especially useful N substituents include H, d-C 4 alkyl, acyl, aminoacyl and sulfonyl.
  • Mixed aryl and non-aryl polyheterocycles substituents include bicyclic and tricyclic fused ring systems where each ring can be 4- to 9-membered, contain one or more heteroatom chosen from O, N or S, and at least one of the rings must be aromatic.
  • Suitable examples of mixed aryl and non-aryl polyheterocycles include 2,3-dihydroindole, 1 ,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenz[j!),e][1 ,4]diazepine, 5H-dibenzo[ ⁇ ,e][1 ,4]diazepine, 1 ,2-dihydropyrrolo[3,4-j!][1 ,5]benzodiazepine, 1 ,5-dihydro- pyrido[2,3- ⁇ ][1 ,4]diazepin-4-one, 1 ,2,3,4,6,11-hexahydro-benzo[ ⁇ ]pyrido[2,3-e][1 ,4]diazepin- 5-one.
  • Nitrogen atoms are unsubstituted or substituted, e.g., by R 13 ; especially useful N substituents include H, C 1 -C 4 alkyl, acyl, aminoacyl and sulfonyl.
  • Amino substituents include primary, secondary and tertiary amines and in salt form, quaternary amines.
  • amino substituents include mono- and di-alkylamino, mono- and di-aryl amino, mono- and di-arylalkyl amino, aryl-arylalkylamino, alkyl-arylamino, alkyl-arylalkylamino and the like.
  • Sulfonyl substituents include alkylsulfonyl and arylsulfonyl, e.g., methane sulfonyl, benzene sulfonyl, tosyl and the like.
  • Acyl substituents include groups of formula -C(O)-W, -OC(O)-W, -C(O)-O-W or -C(O)NR 13 R 14 , where W is R 16 , H or cycloalkylalkyl.
  • Acylamino substituents include substituents of the formula -N(R 12 )C(O)-W, -N(R 12 )C(O)-O-W and -N(R 12 )C(O)-NHOH and R 12 and W are defined above.
  • R 1 is H, halo or a straight-chain d-C 4 alkyl
  • R 2 is selected from H, C r C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH 2 ) n C(O)R 6 , amino acyl and -(CH 2 ) n R 7 ;
  • R 3 and R 4 are the same or different and independently selected from H and Ci-C 6 alkyl, or
  • R 6 is selected from H, Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR 12 and NR 13 R 14 ;
  • R 7 is selected from OR 15 , SR 15 , S(O)R 16 , SO 2 R 17 , NR 13 R 14 and NR 12 SO 2 R 6 ;
  • R 8 is selected from H, OR 15 , NR 13 R 14 , Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
  • R 9 is selected from d-C 4 alkyl and C(O)-alkyl
  • R 10 and R 11 are the same or different and independently selected from H, C r C 4 alkyl and -C(O)-alkyl;
  • R 12 is selected from H, Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
  • R 13 and R 14 are the same or different and independently selected from H, Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and amino acyl;
  • R 15 is selected from H, Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;
  • R 16 is selected from Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH 2 ) m ZR 12 ;
  • R 17 is selected from Ci-C ⁇ alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and NR 13 R 14 ; m is an integer selected from 0-6; and Z is selected from O, NR 13 , S and S(O); or a pharmaceutically acceptable salt thereof.
  • Useful compounds of the formula (I), include those wherein each of R 1 , X, Y, R 3 and R 4 is H, including those wherein one of n 2 and n 3 is O and the other is 1 , especially those wherein R 2 is H or -CH 2 -CH 2 -OH.
  • hydroxamate compounds are those of formula (Ia): wherein n 4 is 0-3;
  • R 2 is selected from H, Ci-C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH 2 ) n C(O)R 6 , amino acyl and -(CH 2 ) n R 7 ; and
  • R 5 is heteroaryl; heteroarylalkyl, e.g., pyridylmethyl; aromatic polycycles; non-aromatic polycycles; mixed aryl and non-aryl polycycles; polyheteroaryl or mixed aryl; and non-aryl polyheterocycles; or a pharmaceutically acceptable salt thereof.
  • n 4 is 0-3;
  • R 2 is selected from H, Ci-C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH 2 ) n C(O)R 6 , amino acyl and -(CH 2 ) n R 7 ;
  • R 5 is aryl; arylalkyl; aromatic polycycles; non-aromatic polycycles and mixed aryl; and non-aryl polycycles, especially aryl, such as p-fluorophenyl, p-chlorophenyl, P-O-C 1 - C 4 alkylphenyl, such as p-methoxyphenyl, and p-Ci-C 4 alkylphenyl; and arylalkyl, such as benzyl, ortho-, meta- or para-f luorobenzyl, ortho-, meta- or para-chlorobenzyl, ortho-, meta- or para-mono, di- or tri-O-CrC ⁇ alkylbenzyl, such as ortho-, meta- or para-methoxy benzyl, m,p-diethoxybenzyl, o,m,p-triimethoxybenzyl and ortho-, meta- or para-mono, di- or tri-Cr
  • R 2 is selected from H; CrC 6 alkyl; C 4 -C 6 cycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; (CH 2 ) 2 - 4 OR 2 i, where R 2 i is H, methyl, ethyl, propyl and /-propyl; 1 1 and
  • R 5 is unsubstituted 1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl, or substituted 1H-indol- 3-yl, such as 5-fluoro-1H-indol-3-yl or 5-methoxy-1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl; or a pharmaceutically acceptable salt thereof.
  • ring containing Z 1 is aromatic or non-aromatic, which non-aromatic rings are saturated or unsaturated,
  • Z 1 is O, S or N-R 20 ;
  • R 18 is H; halo; C r C 6 alkyl (methyl, ethyl, f-butyl); C 3 -C 7 cycloalkyl; aryl, e.g., unsubstituted phenyl or phenyl substituted by 4-OCH 3 or 4-CF 3 ; or heteroaryl, such as 2-furanyl, 2-thiophenyl or 2-, 3- or 4-pyridyl;
  • R 20 is H; d-C ⁇ alkyl; e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl, e.g., acetyl, propionyl and benzoyl; or sulfonyl, e.g., methanesulfonyl, ethanesulfonyl, benzenesulfonyl and toluenesulfonyl;
  • a 1 is 1 , 2 or 3 substituents which are independently H; -OR 19 ; halo; alkylamino; aminoalkyl; halo; or heteroarylalkyl, e.g., pyridylmethyl; Rig is selected from H; C r C 6 alkyl; C 4 -C 9 cycloalkyl
  • R 2 is selected from H, C r C 6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH 2 ) n C(O)R 6 , amino acyl and -(CH 2 ) n R 7 ;
  • v is O, 1 or 2;
  • p is 0-3; and q is 1-5 and r is 0; or q is 0 and r is 1-5; or a pharmaceutically acceptable salt thereof.
  • the other variable substituents are as defined above.
  • Especially useful compounds of formula (Ic), are those wherein R 2 is H, or -(CH 2 )pCH 2 OH, wherein p is 1-3, especially those wherein R 1 is H; such as those wherein R 1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3, especially those wherein Z 1 is N-R 20 .
  • R 2 is preferably H or -CH 2 - CH 2 -OH and the sum of q and r is preferably 1.
  • Z 1 is O, S or N-R 20 ;
  • R 18 is H; halo; d-C ⁇ alkyl (methyl, ethyl, f-butyl); C 3 -C 7 cycloalkyl; aryl, e.g., unsubstituted phenyl or phenyl substituted by 4-OCH 3 or 4-CF 3 ; or heteroaryl;
  • R 20 is H; CrC 6 alkyl, CrC 6 alkyl-C 3 -C 9 cycloalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl, e.g., acetyl, propionyl and benzoyl; or sulfonyl, e.g., methanesulfonyl, ethanesulfonyl, benzenesulfonyl, toluenesulfonyl);
  • a 1 is 1 , 2 or 3 substituents which are independently H, C 1 -C 6 SlKyI, -OR 19 or halo;
  • R 19 is selected from H; C 1 -C 6 SlKyI; C 4 -C 9 cycloalKyl; C 4 -C 9 heterocycloalKyl; aryl; heteroaryl; arylalKyl, e.g., benzyl; and heteroarylalKyl, e.g., pyridylmethyl; p is 0-3; and q is 1-5 and r is 0; or q is 0 and r is 1-5; or a pharmaceutically acceptable salt thereof.
  • the other variable substituents are as defined above.
  • Especially useful compounds of formula (Id), are those wherein R 2 is H or -(CH 2 ) P CH 2 OH, wherein p is 1-3, especially those wherein R 1 is H; such as those wherein R 1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.
  • R 2 is preferably H or -CH 2 -CH 2 -OH and the sum of q and r is preferably 1.
  • the present invention further relates to compounds of the formula (Ie):
  • variable substituents are as defined above.
  • Especially useful compounds of formula (Ie), are those wherein R 18 is H, fluoro, chloro, bromo, a C 1 -C 4 BlKyI group, a substituted C 1 -C 4 BlKyI group, a C 3 -C 7 cycloalKyl group, unsubstituted phenyl, phenyl substituted in the para position, or a heteroaryl, e.g., pyridyl, ring.
  • R 2 is H or -(CH 2 ) p CH 2 OH, wherein p is 1-3, especially those wherein R 1 is H; such as those wherein R 1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.
  • R 2 is preferably H or -CH 2 -CH 2 -OH and the sum of q and r is preferably 1.
  • p is preferably 1 and R 3 and R 4 are preferably H.
  • R 18 is H, methyl, ethyl, f-butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl, 2-thiophenyl, or 2-, 3- or 4-pyridyl wherein the 2-furanyl, 2-thiophenyl and 2-, 3- or 4-pyridyl substituents are unsubstituted or substituted as described above for heteroaryl rings;
  • R 2 is H or -(CH 2 )pCH 2 OH, wherein p is 1-3; especially those wherein R 1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.
  • R 2 is preferably H or -CH 2 -CH 2 -OH and the sum of q and r is preferably 1.
  • the present invention further relates to the compounds of the formula (If):
  • variable substituents are as defined above.
  • Useful compounds of formula (If), are include those wherein R 2 is H or -(CH 2 )pCH 2 OH, wherein p is 1-3, especially those wherein R 1 is H; such as those wherein R 1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.
  • R 2 is preferably H or -CH 2 -CH 2 -OH and the sum of q and r is preferably 1.
  • ⁇ /-hydroxy-3-[4-[[[2-(benzofur-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof is an important compound of formula (If).
  • the compounds described above are often used in the form of a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include, when appropriate, pharmaceutically acceptable base addition salts and acid addition salts, e.g., metal salts, such as alkali and alkaline earth metal salts, ammonium salts, organic amine addition salts and amino acid addition salts and sulfonate salts.
  • Acid addition salts include inorganic acid addition salts, such as hydrochloride, sulfate and phosphate; and organic acid addition salts, such as alkyl sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate.
  • metal salts are alkali metal salts, such as lithium salt, sodium salt and potassium salt; alkaline earth metal salts, such as magnesium salt and calcium salt, aluminum salt and zinc salt.
  • ammonium salts are ammonium salt and tetramethylammonium salt.
  • organic amine addition salts are salts with morpholine and piperidine.
  • amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine.
  • Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.
  • the present invention pertains in particular to the use of HDAC inhibitors for the preparation of a medicament for the treatment of gastrointestinal cancer.
  • An HDAC inhibitor as used for the present invention displays in the assay described above preferably an IC 50 value between 50 and 2500 nM, more preferably between 250 and 2000 nM, and most preferably between 500 and 1250 nM.
  • the invention relates to a method of treating gastrointestinal cancer, especially hepatocellular carcinoma or pancreatic cancer, comprising administering a therapeutically effective amount of an HDAC inhibitor to a warm-blooded animal, in particular a human, in need thereof, preferably a therapeutically effective amount of a compound of formula (I), as defined above, or the salt of such compound having at least one salt-forming group, to a warm-blooded animal, preferably a human, in need thereof.
  • a therapeutically effective amount of an HDAC inhibitor to a warm-blooded animal, in particular a human, in need thereof, preferably a therapeutically effective amount of a compound of formula (I), as defined above, or the salt of such compound having at least one salt-forming group, to a warm-blooded animal, preferably a human, in need thereof.
  • treatment comprises the treatment of patients having gastrointestinal cancer or being in a pre-stage of said cancer which effects the delay of progression of the disease in said patients.
  • the present invention provides a method of treating gastrointestinal cancer, especially hepatocellular carcinoma or pancreatic cancer, comprising administering an HDAC inhibitor in an amount which is therapeutically effective against gastrointestinal cancer, especially hepatocellular carcinoma or pancreatic cancer, to a warm-blooded animal in need thereof.
  • a compound inhibiting the HDAC activity may, e.g., be demonstrated in a suitable clinical study or by means of the Examples described below.
  • the present invention also provides the use of a compound of formula (I), as defined herein, and the use of a COMBINATION OF THE INVENTION for the preparation of a medicament for the treatment of lymphoproliferative diseases.
  • the MTT is a colorimetric assay to determine the cell proliferation rate.
  • the yellow tetrazolium MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) is reduced by metabolically active cells, in part by the action of dehydrogenase enzymes, to generate reducing equivalents such as NADH and NADPH.
  • the resulting intracellular purple formazan can be solubilized and quantified by spectrophotometric means.
  • the signals produced is directly proportional to the cell numbers. Describing the MTT assay in detail, experiments were done using six-point or 9 point drug titrations in multi-well tissue culture dishes, with outer rows left empty.
  • IC50 the concentration of LBH589 required to inhibit cell growth by 50% and LD50s the concentration required to reduce cell number (kill cells) to 50% the original innoculum were determined.
  • the "% Growth" was plotted against compound concentration and used to calculate IC 50 S and LD50s , employing the user-defined spline function in Microsoft Excel.
  • mice Female athymic nude mice were implanted subcutaneously with HCT116 colon cancer cells. When tumors reached a medan tumor volume of 120 mm 3 , mice were randomized into groups of 8 mice. Mice were treated with LBH589 at 5, 10 or 20 mg/kg intravenously (iv) 5 times a week for 3 weeks or 75 mg/kg of 5-Fluorouracil intravenously once a week for 3 weeks. Animals were calipered weekly. Compound activity was determined as the percent change in tumor volume of treated animals over control animals (%T/C). The percentage of regression was determined as the percent change in the final tumor volume at the end of the study over the starting tumor volume. Treatment with LBH589 at 5 or 10 mg/kg inhibited HCT116 tumor growth with %T/C of 17% and 6% respectively. Treatment with LBH589 at 20 mg/kg resulted in tumor regression of 8%. The results are described in Figure 1.
  • mice Female athymic nude mice were implanted subcutaneously with Colo205 colon cancer cells. When tumors reached a medan tumor volume of 220 mm 3 , mice were randomized into groups of 10 mice. Mice were treated with LBH589 at 30 mg/kg intravenously on Monday, Wednesday, Friday per week for 3 weeks, 75 mg/kg of 5-Fluorouracil intraperitoneal ⁇ once a week for 3 weeks, or combination of the two agents.
  • compound activity was measured as the percent change in tumor volume of treated animals over control animals (%T/C). The percentage of regression was determined as the percent change in the final tumor volume at the end of the study over the starting tumor volume.
  • TTE median calculated time to the study end point
  • TGI tumor growth inhibition
  • TGD tumor growth delay
  • Table 2 describes the anti-proliferative and cytotoxic effects of LBH589 in a panel of 12 pancreatic cancer cell lines.
  • a panel of 19 pancreatic cancer cell lines was independently assessed in cell proliferation assays.
  • Cells were treated with DMSO vehicle control or varying concentrations of LBH589 for 6 days. Consistent with results presented in Table 2, LBH589 exhibits potent antiproliferative effect on all 19 pancreatic cancer cell lines, showing low nanomolar concentrations of IC50 values. LBH589 also exhibits potent cytotoxic effect in 18 of the 19 pancreatic cancer cell lines, with LD50 ⁇ 1 ⁇ M. The results are described in Figure 3.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

La présente invention concerne l'utilisation d'un inhibiteur de la HDAC pour préparer un médicament destiné au traitement des cancers gastro-intestinaux. L'invention concerne également un procédé de traitement d'un animal à sang chaud, en particulier un être humain, ayant un cancer gastro-intestinal, ledit procédé comprenant l'administration audit animal d'une quantité thérapeutiquement efficace d'un inhibiteur de la HDAC, en particulier un composé de formule (I) tel que défini ici. L'invention concerne en outre une composition pharmaceutique et un emballage commercial.
EP08747442A 2007-05-04 2008-05-02 Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux Withdrawn EP2142190A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US91599607P 2007-05-04 2007-05-04
PCT/US2008/062341 WO2008137630A1 (fr) 2007-05-04 2008-05-02 Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux

Publications (1)

Publication Number Publication Date
EP2142190A1 true EP2142190A1 (fr) 2010-01-13

Family

ID=39683987

Family Applications (1)

Application Number Title Priority Date Filing Date
EP08747442A Withdrawn EP2142190A1 (fr) 2007-05-04 2008-05-02 Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux

Country Status (16)

Country Link
EP (1) EP2142190A1 (fr)
JP (1) JP2010526149A (fr)
KR (1) KR20100016171A (fr)
CN (1) CN101674825A (fr)
AU (1) AU2008247603A1 (fr)
BR (1) BRPI0811112A2 (fr)
CA (1) CA2683554A1 (fr)
CL (1) CL2008001269A1 (fr)
IL (1) IL201318A0 (fr)
MA (1) MA31356B1 (fr)
MX (1) MX2009011692A (fr)
RU (1) RU2009144842A (fr)
TN (1) TN2009000427A1 (fr)
TW (1) TW200908964A (fr)
WO (1) WO2008137630A1 (fr)
ZA (1) ZA200906739B (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20020354A1 (es) * 2000-09-01 2002-06-12 Novartis Ag Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda)
US20070167499A1 (en) * 2003-10-27 2007-07-19 A*Bio Pte Ltd. Biaryl linked hydroxamates: preparation and pharmaceutical applications
MXPA06004735A (es) * 2003-10-27 2006-12-14 S Bio Pte Ltd Hidroxamatos conectados a acilurea y a sulfonilurea.
WO2006075165A1 (fr) * 2005-01-13 2006-07-20 Btg International Limited Combinaison de virus oncolytiques a des inhibiteurs d'angiogenese

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2008137630A1 *

Also Published As

Publication number Publication date
WO2008137630A1 (fr) 2008-11-13
AU2008247603A1 (en) 2008-11-13
RU2009144842A (ru) 2011-06-10
JP2010526149A (ja) 2010-07-29
IL201318A0 (en) 2010-05-31
BRPI0811112A2 (pt) 2014-12-23
MX2009011692A (es) 2009-11-10
TW200908964A (en) 2009-03-01
ZA200906739B (en) 2010-06-30
KR20100016171A (ko) 2010-02-12
TN2009000427A1 (en) 2011-03-31
MA31356B1 (fr) 2010-05-03
CN101674825A (zh) 2010-03-17
CA2683554A1 (fr) 2008-11-13
CL2008001269A1 (es) 2008-12-19

Similar Documents

Publication Publication Date Title
AU2007328281B2 (en) Combination of an HDAC inhibitor and an antimetabolite
US20100137398A1 (en) Use of hdac inhibitors for the treatment of gastrointestinal cancers
JP5876435B2 (ja) 骨髄腫の処置のためのｈｄａｃ阻害剤の使用
WO2008137630A1 (fr) Utilisation d'inhibiteurs de la hdac pour le traitement des cancers gastro-intestinaux
WO2008150782A1 (fr) Utilisation d'inhibiteurs de hdac pour le traitement de la destruction osseuse
AU2008204928B2 (en) Formulations of deacetylase inhibitors
WO2008141114A1 (fr) Utilisation d'inhibiteurs hdac pour le traitement du mélanome
WO2008002634A1 (fr) Utilisation d'inhibiteurs de la hdac pour le traitement des lymphomes
AU2006306240A1 (en) Combination of histone deacetylase inhibitors and radiation

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20091204

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1140142

Country of ref document: HK

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20121201

REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1140142

Country of ref document: HK