EP2142190A1 - Use of hdac inhibitors for the treatment of gastrointestinal cancers - Google Patents

Use of hdac inhibitors for the treatment of gastrointestinal cancers

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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
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EP
European Patent Office
Prior art keywords
aryl
alkyl
heteroaryl
heterocycloalkyl
cycloalkyl
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EP08747442A
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German (de)
French (fr)
Inventor
Peter Wisdom Atadja
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Novartis AG
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Novartis AG
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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.

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Abstract

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 warm-blooded 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.

Description

USE OF HDAC INHIBITORS FOR THE TREATMENT OF GASTROINTESTINAL CANCERS
Field of the Invention
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.
Background of the Invention
Patients suffering from gastrointestinal cancers have low overall survival rates. The standard treatment of chemotherapy is not always effective. Therefore, there is a need to develop novel treatment methods.
Summary of the Invention
The term "gastrointestinal cancers", as used herein, includes, but is not limited to, hepatocellular carcinoma and/or pancreatic cancer.
The compounds of formula (I), as defined herein, are histone deacetylase inhibitors (HDAC inhibitors). Reversible acetylation of histones is a major regulator of gene expression that acts by altering accessibility of transcription factors to DNA. In normal cells, histone deacetylase (HDA) and 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.
Surprisingly, it was now found that 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.
Hence, the invention relates to the use of an HDAC inhibitor for the preparation of a medicament for the treatment of gastrointestinal cancer. Detailed Description of the Drawings
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.
Detailed Description of the Invention
HDAC Inhibitor Compounds
HDAC inhibitor compounds of particular interest for use in the inventive combination are hydroxamate compounds described by the formula (I):
wherein
R1 is H; halo; or a straight-chain d-C6alkyl, 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;
R2 is selected from H; Ci-C10alkyl, preferably Ci-C6alkyl, e.g., methyl, ethyl or -CH2CH2- OH; d-CgCycloalkyl; C4-C9heterocycloalkyl; C4-C9heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; -(CH2)nC(O)R6; -(CH2)nOC(O)R6; amino acyl; HON-CCOJ-CH^RO-aryl- alkyl-; and -(CH2)nR7;
R3 and R4 are the same or different and independently H, Ci-C6alkyl, acyl or acylamino, or
R3 and R4, together with the carbon to which they are bound, represent C=O, C=S or C=NR8, or R2, together with the nitrogen to which it is bound, and R3, together with the carbon to which it is bound, can form a C4-C9heterocycloalkyl, a heteroaryl, a polyheteroaryl, a non-aromatic polyheterocycle, or a mixed aryl and non-aryl polyheterocycle ring;
R5 is selected from H; d-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; 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-,, n2 and n3 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 R3 and/or R4;
X and Y are the same or different and independently selected from H; halo; CrC4alkyl, such as CH3 and CF3; NO2; C(O)Ri; OR9; SR9; CN; and NR10Rn;
R6 is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; ORi2; and NR13R14;
R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14 and NR12SO2R6;
R8 is selected from H; OR15; NR13R14; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R9 is selected from CrC4alkyl, e.g., CH3 and CF3; C(O)-alkyl, e.g., C(O)CH3; and C(O)CF3;
R10 and R11 are the same or different and independently selected from H, CrC4alkyl and -C(O)-alkyl;
R12 is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl;
C4-C9heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R13 and R14 are the same or different and independently selected from H; CrCβalkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl, or
R13 and R14, together with the nitrogen to which they are bound, are C4-
Cgheterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R15 is selected from H, CrC6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZRi2; R16 is selected from CrC6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, poly heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R17 is selected from CrC6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, aromatic polycycles, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0-6; and Z is selected from O; NR13; S; and S(O), or a pharmaceutically acceptable salt thereof.
As appropriate, "unsubstituted" means that there is no substituent or that the only substituents are hydrogen.
Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or chloro.
Alkyl substituents include straight- and branched-CrC6alkyl, unless otherwise noted. Examples of suitable straight- and branched-CrCβalkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, f-butyl and the like. Unless otherwise noted, 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 OR15, e.g., alkoxy. Preferred substituents for alkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
Cycloalkyl substituents include C3-C9cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. Unless otherwise noted, 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 OR15, such as alkoxy. Preferred substituents for cycloalkyl groups include halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.
The above discussion of 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. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane and 1 ,4-oxathiapane. Unless otherwise noted, the rings are unsubstituted or substituted on the carbon atoms by one or more suitable substituents, including Ci-C6alkyl; C4-C9cycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; halo; amino; alkyl amino and OR15, e.g., alkoxy. Unless otherwise noted, nitrogen heteroatoms are unsubstituted or substituted by H, C1-C4alkyl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; acyl; aminoacyl; alkylsulfonyl; and arylsulfonyl.
Cycloalkylalkyl substituents include compounds of the formula -(CH2)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-C6alkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; O(CO)alkyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; aminosulfonyl; arylsulfonyl and OR15, such as alkoxy. Preferred substituents include including CrC6alkyl; cycloalkyl, e.g., cyclopropylmethyl; alkoxy; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl and aminosulfonyl. Examples of suitable aryl groups include C1-C4alkylphenyl, 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-C6alkyl; alkylcycloalkyl, e.g., cyclopropylmethyl; oxyalkyl; halo; nitro; amino; alkylamino; aminoalkyl; alkyl ketones; nitrile; carboxyalkyl; alkylsulfonyl; arylsulfonyl; aminosulfonyl and OR15, such as alkoxy.
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. Unless otherwise noted, 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 R13; especially useful N substituents include H, Ci-C4alkyl, acyl, aminoacyl and sulfonyl.
Arylalkyl substituents include groups of the formula -(CH2)n5-aryl, -(CH2)n5-1-(CH-aryl)- (CH2)n5-aryl or -(CH2)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 -(CH2)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)-(CH2)n-C(H)(NR13R14)- (CH2)n-R5, wherein n, R13, R14 and R5 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. Such 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. Unless otherwise noted, polyheteroaryl substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents, including alkyl, the alkyl substituents identified above and a substituent of the formula -O-(CH2CH=CH(CH3)(CH2))i-3H. Nitrogen atoms are unsubstituted or substituted, e.g., by R13, especially useful N substituents include H, Ci-C4alkyl, 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. Suitable examples of non-aromatic polyheterocycles include hexitol, c/s-perhydro-cyclohepta[ύ]pyridinyl, decahydro-benzo[/][1 ,4]oxazepinyl, 2,8-dioxabicyclo[3.3.0]octane, hexahydro-thieno[3,2-ύ]thiophene, perhydropyrrolo[3,2- ύ]pyrrole, perhydronaphthyridine, perhydro-1H-dicyclopenta[ύ,e]pyran. Unless otherwise noted, 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 R13, especially useful N substituents include H, d-C4alkyl, 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[ύ,e][1 ,4]diazepine, 1 ,2-dihydropyrrolo[3,4-j!)][1 ,5]benzodiazepine, 1 ,5-dihydro- pyrido[2,3-ύ][1 ,4]diazepin-4-one, 1 ,2,3,4,6,11-hexahydro-benzo[ύ]pyrido[2,3-e][1 ,4]diazepin- 5-one. Unless otherwise noted, mixed aryl and non-aryl polyheterocyclic substituents are unsubstituted or substituted on a carbon atom by one or more suitable substituents including -N-OH, =N-OH, alkyl and the alkyl substituents identified above. Nitrogen atoms are unsubstituted or substituted, e.g., by R13; especially useful N substituents include H, C1-C4alkyl, acyl, aminoacyl and sulfonyl. Amino substituents include primary, secondary and tertiary amines and in salt form, quaternary amines. Examples of 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)NR13R14, where W is R16, H or cycloalkylalkyl.
Acylamino substituents include substituents of the formula -N(R12)C(O)-W, -N(R12)C(O)-O-W and -N(R12)C(O)-NHOH and R12 and W are defined above.
The R2 substituent HON-C(O)-CH=C(R1 )-aryl-alkyl- is a group of the formula:
Preferences for each of the substituents include the following: R1 is H, halo or a straight-chain d-C4alkyl;
R2 is selected from H, CrC6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(O)R6, amino acyl and -(CH2)nR7;
R3 and R4 are the same or different and independently selected from H and Ci-C6alkyl, or
R3 and R4, together with the carbon to which they are bound, represent C=O, C=S or C=NR8;
R5 is selected from H, C^Cealkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, a aromatic polycycle, a non-aromatic polycycle, a mixed aryl and non-aryl polycycle, polyheteroaryl, a non-aromatic polyheterocycle, and a mixed aryl and non-aryl polyheterocycle; n, n-i, n2 and n3 are the same or different and independently selected from 0-6, when 1I1 is 1-6, each carbon atom is unsubstituted or independently substituted with R3 and/or R4; X and Y are the same or different and independently selected from H, halo, Ci-C4alkyl, CF3, NO2, C(O)Ri, OR9, SR9, CN and NR10Rn;
R6 is selected from H, Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12 and NR13R14;
R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14 and NR12SO2R6;
R8 is selected from H, OR15, NR13R14, Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R9 is selected from d-C4alkyl and C(O)-alkyl;
R10 and R11 are the same or different and independently selected from H, CrC4alkyl and -C(O)-alkyl;
R12 is selected from H, Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl;
R13 and R14 are the same or different and independently selected from H, Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and amino acyl;
R15 is selected from H, Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R16 is selected from Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12;
R17 is selected from Ci-Cβalkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and NR13R14; m is an integer selected from 0-6; and Z is selected from O, NR13, S and S(O); or a pharmaceutically acceptable salt thereof.
Useful compounds of the formula (I), include those wherein each of R1, X, Y, R3 and R4 is H, including those wherein one of n2 and n3 is O and the other is 1 , especially those wherein R2 is H or -CH2-CH2-OH.
One suitable genus of hydroxamate compounds are those of formula (Ia): wherein n4 is 0-3;
R2 is selected from H, Ci-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(O)R6, amino acyl and -(CH2)nR7; and
R5 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.
Another suitable genus of hydroxamate compounds are those of formula (Ia):
wherein n4 is 0-3;
R2 is selected from H, Ci-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(O)R6, amino acyl and -(CH2)nR7;
R5 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-C1- C4alkylphenyl, such as p-methoxyphenyl, and p-Ci-C4alkylphenyl; 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^alkylphenyl, such as p-methyl, m,m-diethylphenyl; or a pharmaceutically acceptable salt thereof.
Another interesting genus is the compounds of formula (Ib): wherein
R2 is selected from H; CrC6alkyl; C4-C6cycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; (CH2)2-4OR2i, where R2i is H, methyl, ethyl, propyl and /-propyl; 11 and
R5 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.
Another interesting genus of hydroxamate compounds are the compounds of formula (Ic):
wherein the ring containing Z1 is aromatic or non-aromatic, which non-aromatic rings are saturated or unsaturated,
Z1 is O, S or N-R20;
R18 is H; halo; CrC6alkyl (methyl, ethyl, f-butyl); C3-C7cycloalkyl; aryl, e.g., unsubstituted phenyl or phenyl substituted by 4-OCH3 or 4-CF3; or heteroaryl, such as 2-furanyl, 2-thiophenyl or 2-, 3- or 4-pyridyl;
R20 is H; d-Cβalkyl; 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; A1 is 1 , 2 or 3 substituents which are independently H; -OR19; halo; alkylamino; aminoalkyl; halo; or heteroarylalkyl, e.g., pyridylmethyl; Rig is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl and -(CH2CH=CH(CH3)(CH2))1-3H;
R2 is selected from H, CrC6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, -(CH2)nC(O)R6, amino acyl and -(CH2)nR7; 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 R2 is H, or -(CH2)pCH2OH, wherein p is 1-3, especially those wherein R1 is H; such as those wherein R1 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 Z1 is N-R20. Among these compounds R2 is preferably H or -CH2- CH2-OH and the sum of q and r is preferably 1.
Another interesting genus of hydroxamate compounds are the compounds of formula (Id):
wherein
Z1 is O, S or N-R20;
R18 is H; halo; d-Cβalkyl (methyl, ethyl, f-butyl); C3-C7cycloalkyl; aryl, e.g., unsubstituted phenyl or phenyl substituted by 4-OCH3 or 4-CF3; or heteroaryl;
R20 is H; CrC6alkyl, CrC6alkyl-C3-C9cycloalkyl, 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); A1 is 1 , 2 or 3 substituents which are independently H, C1-C6SlKyI, -OR19 or halo;
R19 is selected from H; C1-C6SlKyI; C4-C9cycloalKyl; C4-C9heterocycloalKyl; 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 R2 is H or -(CH2)PCH2OH, wherein p is 1-3, especially those wherein R1 is H; such as those wherein R1 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. Among these compounds R2 is preferably H or -CH2-CH2-OH and the sum of q and r is preferably 1.
The present invention further relates to compounds of the formula (Ie):
or a pharmaceutically acceptable salt thereof. The variable substituents are as defined above.
Especially useful compounds of formula (Ie), are those wherein R18 is H, fluoro, chloro, bromo, a C1-C4BlKyI group, a substituted C1-C4BlKyI group, a C3-C7cycloalKyl group, unsubstituted phenyl, phenyl substituted in the para position, or a heteroaryl, e.g., pyridyl, ring.
Another group of useful compounds of formula (Ie), are those wherein R2 is H or -(CH2)pCH2OH, wherein p is 1-3, especially those wherein R1 is H; such as those wherein R1 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. Among these compounds R2 is preferably H or -CH2-CH2-OH and the sum of q and r is preferably 1. Among these compounds p is preferably 1 and R3 and R4 are preferably H. Another group of useful compounds of formula (Ie), are those wherein R18 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; R2 is H or -(CH2)pCH2OH, wherein p is 1-3; especially those wherein R1 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. Among these compounds R2 is preferably H or -CH2-CH2-OH and the sum of q and r is preferably 1.
Those compounds of formula (Ie), wherein R20 is H or d-Cβalkyl, especially H, are important members of each of the subgenuses of compounds of formula (Ie) described above.
Λ/-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, Λ/-hydroxy-3-[4-[[[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide and Λ/-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]- 2£-2-propenamide or a pharmaceutically acceptable salt thereof, are important compounds of formula (Ie).
The present invention further relates to the compounds of the formula (If):
or a pharmaceutically acceptable salt thereof. The variable substituents are as defined above.
Useful compounds of formula (If), are include those wherein R2 is H or -(CH2)pCH2OH, wherein p is 1-3, especially those wherein R1 is H; such as those wherein R1 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. Among these compounds R2 is preferably H or -CH2-CH2-OH and the sum of q and r is preferably 1.
Λ/-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. Examples of 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. Examples of ammonium salts are ammonium salt and tetramethylammonium salt. Examples of organic amine addition salts are salts with morpholine and piperidine. Examples of amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine. Sulfonate salts include mesylate, tosylate and benzene sulfonic acid salts.
Additional HDAI compounds within the scope of formula (I), and their synthesis, are disclosed in WO 02/22577. Two preferred compounds within the scope of WO 02/22577 are:
Λ/-hydroxy-3-[4-[(2-hydroxyethyl){2-(1/-/-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof; and
Λ/-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof. 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 IC50 value between 50 and 2500 nM, more preferably between 250 and 2000 nM, and most preferably between 500 and 1250 nM.
Furthermore, 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.
The term "treatment", as used herein, 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.
The person skilled in the pertinent art is fully enabled to select relevant test models to prove the hereinbefore and hereinafter mentioned beneficial effects on gastrointestinal cancer, of a compound inhibiting the HDAC activity. The pharmacological activity of 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. Examples
Example 1
Monolayer Growth Inhibition Assay
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. Cells were suspended in complete media at densities of between 103 and 104 cell/ml, respectively, and added per well. The appropriate medium (200 μl) was then added. Twenty-four hours later, 10 μl of MTS solution , were added to one plates to determine the activity at the time of compound addition (T0). This plate was incubated at 370C for 4 hours and the optical density was measured on a Molecular Devices Thermomax at 490 nm using the Softmax program. The T0 plate served as a reference for initial activity at the beginning of the experiment.
Compound addition began 24 hours after seeding, the same time as the T0 determination. Serial dilutions at 4-fold 2-fold, 1-fold, 0.5-fold, 0.25-fold and 0.125-fold of previously determined IC50 values of each compound were made in a 96-deep well plate with the highest concentrations on the edge of the plate. Each of the six dilutions were added in triplicate and complete medium was added to the empty outer rows without cells. The compounds were added to the plates singly or in combination with Compound III (LBH589). The plates were incubated at 370C for 72 hours from seeding. The MTS solution was added (as for the T0 plate) and read four hours later. In order to analyze the data, the average value of media alone (background) was subtracted from each experimental well and the triplicate values were averaged for each compound dilution. The following formulas were used to calculate percent growth.
If X > T0, % Growth = 100 x ((X-T0)/(GC -T0)) If X < T0, % Growth = 100 x (X-To)/To)
T0 = average value of T0 minus background GC = average value of untreated cells (in triplicate) minus background
X = average value of compound treated cells (in triplicate) minus background
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 IC50S and LD50s , employing the user-defined spline function in Microsoft Excel.
The Anti-proliferation and cytotoxic effects of LBH589 in a large panel of 36 colon cancer cell lines are described in the attached Table:
Colon cancer cell lines were treated with DMSO vehicle control or varying concentrations of LBH589 for 3 days. Cell proliferation was measured on the day of cell plating and on the third day post-treatment. IC50 and LD50 values were calculated as described above. LBH589 exhibits potent anti-proliferative effect on all 36 colon cancer cell lines examined, as demonstrated by the low nanomolar concentrations of IC50 values. LBH589 also exhibits potent cytotoxic effect in the great majority of the colon cancer cell lines tested with LD50 < 1 μM (n=31).
Example 2
Female athymic nude mice were implanted subcutaneously with HCT116 colon cancer cells. When tumors reached a medan tumor volume of 120 mm3, 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.
Example 3
Female athymic nude mice were implanted subcutaneously with Colo205 colon cancer cells. When tumors reached a medan tumor volume of 220 mm3, 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. For tumor growth inhibition (Figure 2A), 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. For tumor growth delay (Figure 2B), compound activity was measured as the change in median calculated time to the study end point (TTE), which was predefined as tumor volume of 1000 mm3. Median TTE for vehicle, LBH, 5-FU, and combined treatment was 39.5 days, 32.9 days, 44.5 days, and 57.1 days respectively. Treatment with LBH589 or 5-FU single agent led to tumor growth inhibition (TGI) and tumor growth delay (TGD). More importantly, the combined treatment significantly enhanced both TGI and TGD. Figure 2 illustrates the results. Example 4
Pancreatic cancer cell lines were treated with DMSO vehicle control or varying concentrations of LBH589 for 3 days. Cell proliferation was measured on the day of cell plating and on the third day post-treatment. IC50 and LD50 values were calculated as described above. LBH589 exhibits potent antiproliferative effect on all 12 pancreatic cancer cell lines examined, as demonstrated by the low nanomolar concentrations of IC50 values. LBH589 also exhibits strong cytotoxic effect in the majority of the pancreatic cancer cell lines tested with LD50 < 1 μM (n=10).
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 μM. The results are described in Figure 3.

Claims

What is Claimed:
1. The use of an HDAC inhibitor for the preparation of a medicament for the treatment of gastrointestinal cancer.
2. Use according to Claim 1 , wherein the HDAC inhibitor is a compound of the formula (I):
wherein
R1 is H; halo; or a straight-chain Ci-C6alkyl, 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;
R2 is selected from H; CrC10alkyl, preferably d-Cβalkyl, e.g., methyl, ethyl or -CH2CH2- OH; C4-C9cycloalkyl; C4-C9heterocycloalkyl; C4-C9heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; -(CH2)nC(O)R6; -(CH2)nOC(O)R6; amino acyl; HON-C(O)-CH=C(R1)-aryl-alkyl-; and -(CH2)nR7;
R3 and R4 are the same or different and, independently, H; Ci-C6alkyl; acyl; or acylamino; or
R3 and R4, together with the carbon to which they are bound, represent C=O, C=S or C=NR8; or
R2, together with the nitrogen to which it is bound, and R3, together with the carbon to which it is bound, can form a C4-C9heterocycloalkyl; a heteroaryl; a polyheteroaryl; a non-aromatic polyheterocycle; or a mixed aryl and non-aryl polyheterocycle ring;
R5 is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; 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, rπ, n2 and n3 are the same or different and independently selected from 0-6, when is 1-6, each carbon atom can be optionally and independently substituted with R3 and/or R4;
X and Y are the same or different and independently selected from H; halo; Ci-C4alkyl, such as CH3 and CF3; NO2; C(O)Ri; OR9; SR9; CN; and NR10Rn;
R6 is selected from H; Ci-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR12; and NR13R14;
R7 is selected from OR15; SR15; S(O)R16; SO2R17; NR13R14; and NR12SO2R6;
R8 is selected from H; OR15; NR13R14; d-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R9 is selected from Ci-C4alkyl, e.g., CH3 and CF3; C(O)-alkyl, e.g., C(O)CH3; and C(O)CF3;
R10 and R11 are the same or different and independently selected from H; C1-C4alkyl; and -C(O)-alkyl;
R12 is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl;
C4-C9heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R13 and R14 are the same or different and independently selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl; or
R13 and R14, together with the nitrogen to which they are bound, are
C4-C9heterocycloalkyl; heteroaryl; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle;
R15 is selected from H; Ci-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12;
R16 is selected from C^Cealkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12;
R17 is selected from C^Cealkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; aromatic polycycles; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR13R14; m is an integer selected from 0-6; and Z is selected from O; NR13; S; and S(O), pharmaceutically acceptable salt thereof.
3. Use according to Claim 2, wherein the compound of formula (I) is Λ/-hydroxy-3-[4-[[[2- (2-methyl-1 H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2£-2-propenamide having the formula (III):
or a pharmaceutically acceptable salt thereof.
4. Use according to any one of Claims 1 to 3, wherein the gastrointestinal cancer is hepatocellular carcinoma or pancreatic cancer.
5. Use according to any one of Claims 1 to 3, wherein the warm-blooded animal is a human.
6. A method of treating gastrointestinal cancer comprising administering a therapeutically effective amount of an HDAC inhibitor to a warm-blooded animal in need thereof.
7. A method according to Claim 6, comprising administering a therapeutically effective amount of a compound of formula (I):
wherein
R1 is H; halo; or a straight-chain d-C6alkyl, 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;
R2 is selected from H; CrC10alkyl, preferably CrC6alkyl, e.g., methyl, ethyl Or -CH2CH2- OH; C4-C9cycloalkyl; C4-C9heterocycloalkyl; C4-C9heterocycloalkylalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; -(CH2)nC(O)R6; -(CH2)nOC(O)R6; amino acyl; HON-C(O)-CH=C(R1)-aryl-alkyl-; and -(CH2)nR7;
R3 and R4 are the same or different and, independently, H; CτC6alkyl; acyl; or acylamino; or
R3 and R4, together with the carbon to which they are bound, represent C=O, C=S or C=NR8; or
R2, together with the nitrogen to which it is bound, and R3, together with the carbon to which it is bound, can form a C4-C9heterocycloalkyl; a heteroaryl; a polyheteroaryl; a non-aromatic polyheterocycle; or a mixed aryl and non-aryl polyheterocycle ring;
R5 is selected from H; CrC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; 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^ n2 and n3 are the same or different and independently selected from 0-6, when n-i is 1-6, each carbon atom can be optionally and independently substituted with R3 and/or R4;
X and Y are the same or different and independently selected from H; halo; CτC4alkyl, such as CH3 and CF3; NO2; C(O)R1; OR9; SR9; CN; and NR10Rn;
R6 is selected from H; CτC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; cycloalkylalkyl, e.g., cyclopropylmethyl; aryl; heteroaryl; arylalkyl, e.g., benzyl and 2-phenylethenyl; heteroarylalkyl, e.g., pyridylmethyl; OR12; and NR13R14;
R7 is selected from OR15; SR15; S(O)R16; SO2R17; NR13R14; and NR12SO2R6;
R8 is selected from H; OR15; NR13R14; d-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl;
R9 is selected from Ci-C4alkyl, e.g., CH3 and CF3; C(O)-alkyl, e.g., C(O)CH3; and C(O)CF3;
R10 and R11 are the same or different and independently selected from H; CτC4alkyl; and -C(O)-alkyl;
R12 is selected from H; CτC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl;
C4-C9heterocycloalkylalkyl; aryl; mixed aryl and non-aryl polycycle; heteroaryl; arylalkyl, e.g., benzyl; and heteroarylalkyl, e.g., pyridylmethyl; Ri3 and Ri4 are the same or different and independently selected from H; CτC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl, e.g., benzyl; heteroarylalkyl, e.g., pyridylmethyl; amino acyl; or
Ri3 and R14, together with the nitrogen to which they are bound, are
C4-C9heterocycloalkyl; heteroaryl; polyheteroaryl; non-aromatic polyheterocycle; or mixed aryl and non-aryl polyheterocycle;
Ri5 is selected from H; CτC6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12;
Ri6 is selected from Ci-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; heteroaryl; polyheteroaryl; arylalkyl; heteroarylalkyl; and (CH2)mZR12;
R17 is selected from Ci-C6alkyl; C4-C9cycloalkyl; C4-C9heterocycloalkyl; aryl; aromatic polycycles; heteroaryl; arylalkyl; heteroarylalkyl; polyheteroaryl and NR13R14; m is an integer selected from 0-6; and Z is selected from O; NR13; S; and S(O), or a pharmaceutically acceptable salt thereof to a warm-blooded animal in need thereof.
8. The method according to claim 6, wherein the compound of formula (I) is Λ/-hydroxy- 3-[4-[[[2-(2-methyl-1 H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2£-2-propenamide having the formula (III):
or a pharmaceutically acceptable salt thereof.
9. The method according to claim 6, wherein the gastrointestinal cancer is hepatocellular carcinoma or pancreatic cancer.
10. The method according to claim 6, wherein the warm-blooded animal is a human.
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TW200908964A (en) 2009-03-01
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CN101674825A (en) 2010-03-17
CL2008001269A1 (en) 2008-12-19
MA31356B1 (en) 2010-05-03
KR20100016171A (en) 2010-02-12
CA2683554A1 (en) 2008-11-13
IL201318A0 (en) 2010-05-31
RU2009144842A (en) 2011-06-10
ZA200906739B (en) 2010-06-30
TN2009000427A1 (en) 2011-03-31
MX2009011692A (en) 2009-11-10
WO2008137630A1 (en) 2008-11-13
BRPI0811112A2 (en) 2014-12-23

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