KR20100016171A - Use of hdac inhibitors for the treatment of gastrointestinal cancers - Google Patents

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 HAD inhibitors for the treatment of gastrointestinal cancer {USE OF HDAC INHIBITORS FOR THE TREATMENT OF GASTROINTESTINAL CANCERS}

The present invention provides the use of an HDAC inhibitor for the manufacture of a medicament for the treatment of gastrointestinal cancer; A method of treating a warm blooded animal suffering from gastrointestinal cancer, in particular a human, a warm blooded animal suffering from gastrointestinal cancer comprising administering a therapeutically effective amount of an HDAC inhibitor, in particular a compound of formula (I) as defined herein; And pharmaceutical compositions and commercial packages.

Patients with gastrointestinal cancer have low overall survival. Standard treatment of chemotherapy is not always effective. Therefore, the development of new treatment methods is needed.

Summary of the Invention

The term “gastrointestinal cancer” as used herein includes, but is not limited to, hepatocellular carcinoma and / or pancreatic cancer.

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 transcription factor access to DNA. In normal cells, histone deacetylase (HDA) and histone acetyltransferase together control the acetylation levels of histones to be balanced. Inhibition of HDA accumulates hyperacetylated histones, resulting in a variety of cellular responses.

Surprisingly, it has now been found that HDAC inhibitors, in particular compounds of formula (I) as defined herein, directly inhibit the proliferation of gastrointestinal cancers such as hepatocellular carcinoma and / or pancreatic cancer.

Accordingly, the present invention relates to the use of HDAC inhibitors for the manufacture of a medicament for the treatment of gastrointestinal cancer.

1 illustrates that LBH589 treatment inhibits tumor growth in an HCT116 xenograft model.

2 illustrates that co-treatment of LBH589 with 5-fluorouracil enhances tumor growth inhibition and tumor growth delay in Colo205 colon cancer xenograft model.

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 combinations of the invention are the HDAC inhibitor compounds which are the hydroxyxamate compounds represented by the formula (I) or pharmaceutically acceptable salts thereof.

Where

R ₁ is H, halo or straight chain C ₁ -C ₆ alkyl, in particular methyl, ethyl or n-propyl, wherein the methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for the alkyl substituents Without;

R ₂ is H, C ₁ -C ₁₀ alkyl, preferably C ₁ -C ₆ alkyl (eg methyl, ethyl or —CH ₂ CH ₂ —OH), C ₄ -C ₉ cycloalkyl, C _4- C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg For example, pyridylmethyl),-(CH ₂ ) _n C (O) R ₆ ,-(CH ₂ ) _n OC (O) R ₆ , amino acyl, HON-C (O) -CH = C (R ₁ ) -Aryl-alkyl- and-(CH ₂ ) _n R ₇ ;

R ₃ and R ₄ are the same or different and are independently H, C ₁ -C ₆ alkyl, acyl or acylamino, or

R ₃ and R ₄ together with the carbon to which they are attached represent C═O, C═S or C═NR ₈ ; or

R ₂ together with the nitrogen to which it is attached, and R ₃ together with the carbon to which it is attached, C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or aryl and non-aryl polyhetero Can form a cycle of mixed rings;

R ₅ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (eg, benzyl), heteroarylalkyl ( For example, pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryls, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles Is selected from;

n, n ₁ , n ₂ and n ₃ are the same or different and are independently selected from 0 to 6, and when n ₁ is 1 to 6 each carbon atom is independently selected from R ₃ and / or R ₄ Can be substituted;

X and Y are the same or different and are from H, halo, C ₁ -C ₄ alkyl such as CH ₃ and CF ₃ , NO ₂ , C (O) R ₁ , OR ₉ , SR ₉ , CN and NR ₁₀ R ₁₁ Independently selected;

R ₆ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl ( For example benzyl and 2-phenylethenyl), heteroarylalkyl (eg, pyridylmethyl), 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 H, OR ₁₅ , NR ₁₃ R ₁₄ , C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ) And heteroarylalkyl (eg pyridylmethyl);

R ₉ is selected from C ₁ -C ₄ alkyl, for example CH ₃ and CF ₃ , C (O) -alkyl, for example C (O) CH ₃ , and C (O) CF ₃ ;

R ₁₀ and R ₁₁ are the same or different and are independently selected from H, C ₁ -C ₄ alkyl and —C (O) -alkyl;

R ₁₂ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycles , Heteroaryl, arylalkyl (eg benzyl) and heteroarylalkyl (eg pyridylmethyl);

R ₁₃ and R ₁₄ are the same or different and are H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ), Heteroarylalkyl (eg, pyridylmethyl), amino acyl, or

R ₁₃ and R ₁₄ together with the nitrogen to which they are attached form a non-aryl polyheterocycle with C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl;

R ₁₅ is selected from H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Become;

R ₁₆ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Is selected from;

R ₁₇ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR ₁₃ R Selected from ₁₄ ;

m is an integer selected from 0 to 6;

Z is selected from O, NR ₁₃ , S and S (O).

Suitably, "unsubstituted" means that no substituent is present or the only substituent is hydrogen.

Halo substituents are selected from fluoro, chloro, bromo and iodo, preferably fluoro or chloro.

Unless stated otherwise, alkyl substituents include straight and branched C ₁ -C ₆ alkyl. Examples of suitable straight and branched C ₁ -C ₆ alkyl substituents are methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl and the like. Unless stated otherwise, alkyl substituents include unsubstituted alkyl groups and one or more suitable substituents (including acyl, cycloalkyl, halo, oxyalkyl, alkylamino, including unsaturated (ie, one or more double or triple CC bonds are present), Aminoalkyl, acylamino, and both alkyl groups substituted by OR ₁₅ , such as alkoxy). Preferred substituents for the alkyl group are halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

Unless otherwise specified, cycloalkyl substituents include C ₃ -C ₉ cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Unless stated otherwise, cycloalkyl substituents include one or more suitable cycloalkyl groups and one or more suitable groups including C ₁ -C ₆ alkyl, halo, hydroxy, aminoalkyl, oxyalkyl, alkylamino and OR ₁₅ (eg alkoxy) And both cycloalkyl groups substituted by substituents. Preferred substituents for cycloalkyl groups are halo, hydroxy, alkoxy, oxyalkyl, alkylamino and aminoalkyl.

The above discussion of alkyl and cycloalkyl substituents also applies to the alkyl portion of other substituents, including alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.

Heterocycloalkyl substituents include 3- to 9-membered aliphatic rings containing 1 to 3 heteroatoms selected from nitrogen, sulfur, oxygen, such as 4- to 7-membered aliphatic rings. Examples of suitable heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazil, tetrahydropyranyl, morpholino, 1,3-diazapan, 1,4-dia Keyboard, 1,4-oxazapan and 1,4-oxathiapan. Unless stated otherwise, the rings are C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg pyridylmethyl) on carbon atoms , Unsubstituted or substituted by one or more suitable substituents, including halo, amino, alkyl amino, and OR ₁₅ (eg, alkoxy). Unless stated otherwise, nitrogen heteroatoms are H, C ₁ -C ₄ alkyl, arylalkyl (eg benzyl), heteroarylalkyl (eg pyridylmethyl), acyl, aminoacyl, alkylsulfonyl and arylsulfonyl Substituted or unsubstituted by

Cycloalkylalkyl substituents include compounds of the _formula- (CH ₂ ) n ₅ -cycloalkyl, where n 5 is a number from 1 to 6. Suitable alkylcycloalkyl substituents include cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl and the like. Such substituents are unsubstituted or substituted in the alkyl moiety or the cycloalkyl moiety by suitable substituents including those listed above for alkyl and cycloalkyl.

Aryl substituents include unsubstituted phenyl and C ₁ -C ₆ alkyl, cycloalkylalkyl (eg cyclopropylmethyl), O (CO) alkyl, oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl Phenyl substituted by one or more suitable substituents including ketones, nitriles, carboxyalkyl, alkylsulfonyl, aminosulfonyl, arylsulfonyl and OR ₁₅ (eg alkoxy). Preferred substituents include C ₁ -C ₆ alkyl, cycloalkyl (eg cyclopropylmethyl), alkoxy, oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketone, nitrile, carboxyalkyl, alkylsulfonyl, Arylsulfonyl and aminosulfonyl. Examples of suitable aryl groups include C ₁ -C ₄ alkylphenyl, C ₁ -C ₄ alkoxyphenyl, trifluoromethylphenyl, methoxyphenyl, hydroxyethylphenyl, dimethylaminophenyl, aminopropylphenyl, carbethoxyphenyl, Methanesulfonylphenyl and tolylsulfonylphenyl.

Aromatic polycyclos include naphthyl, and C ₁ -C ₆ alkyl, alkylcycloalkyl (eg cyclopropylmethyl), oxyalkyl, halo, nitro, amino, alkylamino, aminoalkyl, alkyl ketones, nitrile, carboxyalkyl, alkyl Naphthyl substituted by one or more suitable substituents, including sulfonyl, arylsulfonyl, aminosulfonyl, and OR ₁₅ (eg, alkoxy).

Heteroaryl substituents include compounds having 5- to 7-membered aromatic rings containing one or more heteroatoms (eg, 1 to 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 stated otherwise, heteroaryl substituents are unsubstituted or substituted on the carbon atom by one or more suitable substituents including alkyl, said alkyl substituents, and another heteroaryl substituent. Nitrogen atoms are, for example, unsubstituted or substituted by R ₁₃ , and particularly useful N substituents are H, C ₁ -C ₄ alkyl, acyl, aminoacyl and sulfonyl.

Arylalkyl substituents include _:-( CH ₂ ) _n5 -aryl,-(CH ₂ ) _n5-1- (CH-aryl)-(CH ₂ ) _n5 -aryl _or- (CH ₂ ) _n5-1 -CH (aryl (Aryl) wherein aryl and n5 are as defined above. Examples of the arylalkyl substituents include benzyl, 2-phenylethyl, 1-phenylethyl, tolyl-3-propyl, 2-phenylpropyl, diphenylmethyl, 2-diphenylethyl, 5,5-dimethyl-3-phenylpentyl, and the like. There is this. The arylalkyl substituent is unsubstituted or substituted in the alkyl moiety or the aryl moiety, or both, as described above for the alkyl and aryl substituents.

Heteroarylalkyl substituents include groups of the _formula- (CH ₂ ) n ₅ -heteroaryl, wherein heteroaryl and n 5 are as defined above and the bridging group is linked to the carbon or nitrogen of the heteroaryl moiety, for example 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 the formulas -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 Is as described above). Suitable aminoacyl substituents include natural and non-natural amino acids such as glycinyl, D-tryptophanyl, L-ricinyl, D- or L-homoselinyl, 4-aminobutyric acid acyl and ± -3- Amine-4-hexenoyl.

Non-aromatic polycycle substituents include bicyclic and tricyclic fused ring systems in which each ring may be 4- to 9-membered and may contain zero or one or more double and / or triple bonds. . Suitable examples of non-aromatic polycycles are decalin, octahydroindene, perhydrobenzocycloheptene and perhydrobenzo- [f] -azulene. The 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 in which each ring may be 4- to 9-membered and at least one ring is aromatic. Suitable examples of mixed aryl and non-aryl polycycles include methylenedioxyphenyl, bis-methylenedioxyphenyl, 1,2,3,4-tetrahydronaphthalene, dibenzosuberan, dihydroanthracene, 9H-fluorene There is this. The substituents are unsubstituted or substituted by nitro or as described above for cycloalkyl groups.

As polyheteroaryl substituents, each ring may be independently 5- or 6-membered, and one or more heteroatoms selected from O, N or S such that the fused ring system is aromatic (e.g., 1, 2, 3 or 4 Fused ring systems of bicyclic and tricyclic, which may contain heteroatoms). Suitable examples of polyheteroaryl ring systems include quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine, furopyridine, indole, benzofuran, benzothiofuran, benzindole, benzoxazole, pyrroloquinoline and the like. Unless stated otherwise, polyheteroaryl substituents include one or more alkyl on carbon atoms, one or more alkyl substituents, and substituents of the formula -O- (CH ₂ CH = CH (CH ₃ ) (CH ₂ )) _1-3 H Unsubstituted or substituted by a suitable substituent. The nitrogen atom is unsubstituted or substituted, for example by R ₁₃ , and particularly useful N substituents are H, C ₁ -C ₄ alkyl, acyl, aminoacyl and sulfonyl.

As non-aromatic polyheterocyclic substituents, each ring may be 4- to 9-membered and contains one or more heteroatoms (eg, 1, 2, 3 or 4 heteroatoms) selected from O, N or S And bicyclic and tricyclic fused ring systems that may contain 0 or one or more CC double or triple bonds. Suitable examples of non-aromatic polyheterocycles include hexitol, cis-perhydro-cyclohepta [b] pyridinyl, decahydro-benzo [f] [1,4] oxazepineyl, 2,8-dioxabicyclo [3.3.0] octane, hexahydro-thieno [3,2-b] thiophene, perhydropyrrolo [3,2-b] pyrrole, perhydronaphthyridine, perhydro-1H-dicyclopenta [b , e] piran. Unless stated otherwise, non-aromatic polyheterocyclic substituents are unsubstituted or substituted by one or more substituents including alkyl and the above alkyl substituents on a carbon atom. The nitrogen atom is unsubstituted or substituted, for example by R ₁₃ , and particularly useful N substituents are H, C ₁ -C ₄ alkyl, acyl, aminoacyl and sulfonyl.

As mixed aryl and non-aryl polyheterocycle substituents, each ring may be 4- to 9-membered, contain one or more heteroatoms selected from O, N, or S, and one or more rings must be aromatic Bicyclic and tricyclic fused ring systems are included. Suitable examples of mixed aryl and non-aryl polyheterocycles include 2,3-dihydroindole, 1,2,3,4-tetrahydroquinoline, 5,11-dihydro-10H-dibenz [b, e] [1,4] diazepine, 5H-dibenzo [b, e] [1,4] diazepine, 1,2-dihydropyrrolo [3,4-b] [1,5] benzodiazepine, 1,5 -Dihydro-pyrido [2,3-b] [1,4] diazepin-4-one, 1,2,3,4,6,11-hexahydro-benzo [b] pyrido [2,3 -e] [1,4] diazepin-5-ones. Unless stated otherwise, mixed aryl and non-aryl polyheterocyclic substituents are unsubstituted or substituted on the carbon atom by one or more suitable substituents including -N-OH, = N-OH, alkyl, and the above alkyl substituents. Do not. The nitrogen atom is unsubstituted or substituted, for example by R ₁₃ , and particularly useful N substituents are H, C ₁ -C ₄ alkyl, acyl, aminoacyl and sulfonyl.

Amino substituents include primary, secondary and tertiary amines, and quaternary amines in salt form. 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, for example methane sulfonyl, benzene sulfonyl, tosyl and the like.

Acyl substituents include the formulas -C (O) -W, -OC (O) -W, -C (O) -OW or -C (O) NR ₁₃ R ₁₄ , wherein W is R ₁₆ , H or cycloalkyl Alkyl).

Acylamino substituents include the formulas -N (R ₁₂ ) C (O) -W, -N (R ₁₂ ) C (O) -OW and -N (R ₁₂ ) C (O) -NHOH (R ₁₂ and W Substituents as defined above).

HON-C (O) -CH = C (R ₁ ) -aryl-alkyl-, which is a R ₂ substituent, is a group of the formula:

For each substituent,

R ₁ is H, halo or straight chain C ₁ -C ₄ alkyl;

R ₂ is H, C ₁ -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 are independently selected from H and C ₁ -C ₆ alkyl, or

R ₃ and R ₄ together with the carbon to which they are attached represent C═O, C═S or C═NR ₈ ;

R ₅ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, aromatic polycycle, non-aromatic polycycle , Mixed aryl and non-aryl polycycles, polyheteroaryls, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles;

n, n ₁ , n ₂ and n ₃ are the same or different and are independently selected from 0 to 6 and when n ₁ is 1 to 6 each carbon atom is independently substituted with R ₃ and / or R ₄ Is not substituted or substituted;

X and Y are the same or different and are independently selected from H, halo, C ₁ -C ₄ alkyl, CF ₃ , NO ₂ , C (O) R ₁ , OR ₉ , SR ₉ , CN and NR ₁₀ R ₁₁ ;

R ₆ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR ₁₂ and NR ₁₃ Selected from 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 ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl Become;

R ₉ is selected from C ₁ -C ₄ alkyl and C (O) -alkyl;

R ₁₀ and R ₁₁ are the same or different and are independently selected from H, C ₁ -C ₄ alkyl and —C (O) -alkyl;

R ₁₂ is selected from H, C ₁ -C ₆ 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 are H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and amino Independently selected from acyl;

R ₁₅ is selected from H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Become;

R ₁₆ is selected from C ₁ -C ₆ 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 C ₁ -C ₆ 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;

Preference is given to compounds in which Z is selected from O, NR ₁₃ , S, S (O) or a pharmaceutically acceptable salt thereof.

Useful compounds of formula (I) include those in which one of n ₂ and n ₃ is 0 and the other is 1, in particular R ₁ , X, Y, R, including R ₂ being H or —CH ₂ —CH ₂ —OH Included are compounds wherein ₃ and R ₄ are each H.

One suitable class of hydroxamate compounds is a compound of formula la or a pharmaceutically acceptable salt thereof.

Where

n ₄ is 0 to 3;

R ₂ is H, C ₁ -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 heteroaryl, heteroarylalkyl (eg, pyridylmethyl), aromatic polycycle, non-aromatic polycycle, mixed aryl and non-aryl polycycle, polyheteroaryl, or mixed aryl and non-aryl Polyheterocycle.

Another suitable class of hydroxysamate compounds is a compound of formula la or a pharmaceutically acceptable salt thereof.

<Formula Ia>

Where

n ₄ is 0 to 3;

R ₂ is H, C ₁ -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, in particular aryl, for example p-fluorophenyl, p-chlorophenyl, pOC ₁ -C ₄ alkylphenyls such as p-methoxyphenyl, and pC ₁ -C ₄ alkylphenyls, and arylalkyls such as benzyl, ortho-, meta- or para-fluorobenzyl, ortho-, meta- or para -Chlorobenzyl, ortho-, meta- or para-mono-, di- or tri-OC ₁ -C ₄ alkylbenzyl, such as ortho-, meta- or para-methoxybenzyl, m, p-diethoxybenzyl, o , m, p-trimethoxybenzyl, and ortho-, meta- or para-mono-, di- or tri-C ₁ -C ₄ alkylphenyls such as p-methyl, m, m-diethylphenyl.

Another class of interest is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof.

Where

R ₂ ′ is H, C ₁ -C ₆ alkyl, C ₄ -C ₆ cycloalkyl, cycloalkylalkyl (eg cyclopropylmethyl), (CH ₂ ) _2-4 OR ₂₁ , wherein R ₂₁ is H, methyl , Ethyl, propyl, and i-propyl;

R ₅ ″ is unsubstituted 1H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl, or substituted 1H-indol-3-yl, for example 5-fluoro-1H-indole -3-yl or 5-methoxy-1 H-indol-3-yl, benzofuran-3-yl or quinolin-3-yl.

Another class of hydroxyxamate compounds of interest is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof.

Where

The ring containing Z ₁ is aromatic or non-aromatic, said non-aromatic ring being saturated or unsaturated;

Z ₁ is O, S or NR ₂₀ ;

R ₁₈ is H, halo, C ₁ -C ₆ alkyl (methyl, ethyl, t-butyl), C ₃ -C ₇ cycloalkyl, aryl (eg unsubstituted phenyl, or 4-OCH ₃ or 4-CF ₃ Phenyl substituted by, or heteroaryl (eg, 2-furanyl, 2-thiophenyl, or 2-, 3- or 4-pyridyl);

R ₂₀ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-C ₃ -C ₉ cycloalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (Eg, pyridylmethyl), acyl (eg acetyl, propionyl and benzoyl) or sulfonyl (eg methanesulfonyl, ethanesulfonyl, benzenesulfonyl and toluenesulfonyl);

A ₁ is independently 1, 2 or 3 substituents that are H, C ₁ -C ₆ alkyl, —OR ₁₉ , halo, alkylamino, aminoalkyl, halo or heteroarylalkyl (eg, pyridylmethyl);

R ₁₉ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg pyridyl Methyl) and — (CH ₂ CH═CH (CH ₃ ) (CH ₂ )) _1-3 H;

R ₂ is H, C ₁ -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 0, 1 or 2;

p is 0 to 3;

q is 1 to 5 and r is 0; or

q is 0 and r is 1-5.

Other variable substituents are as defined above.

Particularly useful compounds of formula (Ic) are compounds in which R ₂ is H or — (CH ₂ ) _p CH ₂ OH where p is 1 to 3, in particular compounds in which R ₁ is H, for example R ₁ is H And X and Y are each H, q is 1 to 3 and r is 0, or a compound wherein q is 0 and r is 1 to 3, in particular Z ₁ is NR ₂₀ . Among these compounds, R ₂ is preferably H or —CH ₂ —CH ₂ —OH, and it is preferable that the sum of q and r is 1.

Another class of hydroxyxamate compounds of interest is the compound of formula (Id) or a pharmaceutically acceptable salt thereof.

Where

Z ₁ is O, S or NR ₂₀ ;

R ₁₈ is H, halo, C ₁ -C ₆ alkyl (methyl, ethyl, t-butyl), C ₃ -C ₇ cycloalkyl, aryl (eg unsubstituted phenyl, or 4-OCH ₃ or 4-CF ₃ Phenyl substituted by) or heteroaryl;

R ₂₀ is H, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl-C ₃ -C ₉ cycloalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (Eg, pyridylmethyl), acyl (eg, acetyl, propionyl and benzoyl) or sulfonyl (eg, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, toluenesulfonyl);

A ₁ is independently 1, 2 or 3 substituents that are H, C ₁ -C ₆ alkyl, —OR ₁₉ or halo;

R ₁₉ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl) and heteroarylalkyl (eg pyridyl Methyl);

p is 0 to 3;

q is 1 to 5 and r is 0; or

q is 0 and r is 1-5.

Other variable substituents are as defined above.

Particularly useful compounds of formula Id are compounds in which R ₂ is H or — (CH ₂ ) _p CH ₂ OH where p is 1 to 3, in particular compounds in which R ₁ is H, for example R ₁ is H And X and Y are each H, q is 1 to 3 and r is 0, or q is 0 and r is 1 to 3. Among these compounds, R ₂ is preferably H or —CH ₂ —CH ₂ —OH, and it is preferable that the sum of q and r is 1.

In addition, the present invention relates to a compound of formula (Ie) or a pharmaceutically acceptable salt thereof.

Wherein the variable substituents are as defined above.

Particularly useful compounds of formula (Ie) are those wherein R ₁₈ is H, fluoro, chloro, bromo, C ₁ -C ₄ alkyl group, substituted C ₁ -C ₄ alkyl group, C ₃ -C ₇ cycloalkyl group, unsubstituted phenyl, para Phenyl substituted at the —position, or a heteroaryl (eg, pyridyl) ring.

Another group of compounds of formula (Ie) that are useful are compounds in which R ₂ is H or — (CH ₂ ) _p CH ₂ OH where p is 1 to 3, in particular compounds in which R ₁ is H, for example R ₁ Is H, X and Y are each H, q is 1-3 and r is 0, or q is 0 and r is 1-3. Among these compounds, R ₂ is preferably H or —CH ₂ —CH ₂ —OH, and it is preferable that the sum of q and r is 1. Among these compounds, p is preferably 1, and R ₃ and R ₄ are preferably H.

Another group of compounds of formula (Ie) that are useful are those wherein R ₁₈ is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl , 2-thiophenyl, or 2-, 3- or 4-pyridyl, wherein 2-furanyl, 2-thiophenyl, and 2-, 3- or 4-pyridyl substituents are described above for heteroaryl rings As substituted or unsubstituted), and R ₂ is H or-(CH ₂ ) _p CH ₂ OH, wherein p is 1 to 3, in particular R ₁ is H, and X and Y are each H, q is 1-3 and r is 0, or q is 0 and r is 1-3. Among these compounds, R ₂ is preferably H or —CH ₂ —CH ₂ —OH, and it is preferable that the sum of q and r is 1.

Compounds of formula (Ie) in which R ₂₀ is H or C ₁ -C ₆ alkyl (in particular H) are important members of each of the subclasses of compounds of formula (Ie) described above.

N-hydroxy-3- [4-[[(2-hydroxyethyl) [2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E-2-propenamide, N -Hydroxy-3- [4-[[[2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E-2-propenamide and N-hydroxy-3- [4 -[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propenamide or a pharmaceutically acceptable salt thereof is important to be.

In addition, the present invention relates to a compound of formula If or a pharmaceutically acceptable salt thereof.

Wherein the variable substituents are as defined above.

Useful compounds of formula If are compounds in which R ₂ is H or — (CH ₂ ) _p CH ₂ OH where p is 1 to 3, in particular compounds in which R ₁ is H, for example R ₁ is H, X and Y are each H, q is 1-3 and r is 0, or q is 0 and r is 1-3. Among these compounds, R ₂ is preferably H or —CH ₂ —CH ₂ —OH, and it is preferable that the sum of q and r is 1.

N-hydroxy-3- [4-[[[2- (benzofur-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propenamide or a pharmaceutically acceptable salt thereof is important Compound of formula If.

The compounds described above are generally used in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, where appropriate, pharmaceutically acceptable base addition salts and acid addition salts, such as metal salts such as alkali metal and alkaline earth metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts and sulfo Nate salts are included. Acid addition salts include inorganic acid addition salts (such as hydrochloride, sulfates and phosphates) and organic acid addition salts (such as alkyl sulfonates, arylsulfonates, acetates, maleates, fumarates, tartrates, citrate and lactates). ) Is included. Examples of metal salts are alkali metal salts (eg lithium salts, sodium salts and potassium salts), alkaline earth metal salts (eg magnesium salts and calcium salts), aluminum salts and zinc salts. Examples of ammonium salts are ammonium salts and tetramethylammonium salts. 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.

Further HDAI compounds within the scope of formula (I) and methods for their synthesis are disclosed in WO 02/22577. Two preferred compounds within the scope of WO 02/22577 are

N-hydroxy-3- [4-[(2-hydroxyethyl) {2- (1H-indol-3-yl) ethyl] -amino] methyl] phenyl] -2E-2-pro Phenamide or a pharmaceutically acceptable salt thereof; And

N-hydroxy-3- [4-[[[2- (2-methyl-1 H-indol-3-yl) -ethyl] -amino] methyl] phenyl] -2E-2-propene Amides or pharmaceutically acceptable salts thereof

to be.

In particular, the present invention relates to the use of HDAC inhibitors for the manufacture of a medicament for the treatment of gastrointestinal cancer.

The HDAC inhibitors used in the present invention exhibit IC ₅₀ values in the assays described above, preferably from 50 to 2500 nM, more preferably from 250 to 2000 nM, most preferably from 500 to 1250 nM.

In addition, the present invention relates to the administration of a therapeutically effective amount of an HDAC inhibitor to a warm-blooded animal, in particular a human, in need of treatment of gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer, preferably to a warm-blooded animal in need thereof. A method of treating gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer, comprising administering a therapeutically effective amount of a compound of formula (I) as defined above, or a salt of said compound having at least one salt-forming group.

As used herein, the term “treatment” encompasses the treatment of a patient who has a gastrointestinal cancer or delays the progression of the disease in a patient who is in the pre-stage of gastrointestinal cancer.

The present invention relates to the treatment of gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer, comprising administering to a warm-blooded animal in need of treatment for gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer, a therapeutically effective amount of an HDAC inhibitor for gastrointestinal cancer, in particular hepatocellular carcinoma or pancreatic cancer. Provide a method of treatment.

Those skilled in the art can sufficiently select appropriate test models to demonstrate the beneficial effects of compounds that inhibit the HDAC activity mentioned above and below on gastrointestinal cancer. The pharmacological activity of the compounds that inhibit HDAC activity can be demonstrated, for example, by suitable clinical studies or the examples described below.

The present invention also provides the use of a compound of formula (I) as defined herein, and the use of the combination of the invention for the manufacture of a medicament for the treatment of lymphocytic disease.

Example 1

Monolayer Growth Inhibition Analysis

MTT is a colorimetric assay that measures the rate of cell proliferation. 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 enzyme Reducing equivalents such as, NADH and NADPH were generated. The resulting intracellular purple formazan could be solubilized and quantified by spectrophotometric means. The signal produced was directly proportional to the cell number. To describe the MTT assay in detail, experiments were carried out using 6- or 9-point drug titers in multi-well tissue culture dishes, leaving the external rows empty. The cells were suspended in complete medium at a density of 10 ³ to 10 ⁴ cells / mL each and added per well. Then appropriate medium (200 μl) was added. After 24 hours, 10 μl of MTS solution was added to one plate to measure activity at compound addition time (T ₀ ). The plate was incubated at 37 ° C. for 4 hours and the optical density was measured at Molecular Devices Thermomax at 490 nm using the Softmax program. The T ₀ plate served as a reference for initial activity at the start of the experiment.

Compound addition started 24 hours after seeding and at the same time T ₀ was measured. Serial dilutions of 4, 2, 1, 0.5, 0.25, and 0.125 times IC ₅₀ values of each compound measured in advance were transferred to a 96-deep well plate. The edges were prepared at the highest concentrations. Six dilutions were added in triplicate each and complete medium was added to empty external rows without cells. Compounds were added to the plates alone or in combination with compound III (LBH589). Plates were incubated at 37 ° C. for 72 hours after seeding. MTS solution was added (as in T ₀ plate) and read after 4 hours. To analyze the data, the mean value of medium alone (background) was subtracted from each experimental well and the triple value was averaged for each compound dilution. The following formula was used to calculate the growth rate (%).

T ₀ = T ₀ -average value of the background

GC = untreated cells (triple)-mean value of background

X = compound treated cells (triple)-mean value of background

IC ₅₀ , the concentration of LBH589 necessary to inhibit cell growth by 50%, and LD50, the concentration required to reduce cell number (killed cells) to 50% of the original inoculum, were measured. "% Growth" was plotted against compound concentration and used to calculate IC ₅₀ and LD50 using a user-defined spline function in Microsoft Excel.

The anti-proliferative and cytotoxic effects of LBH589 in 36 different panels of colon cancer cell lines are listed in Table 1 below.

Colon cancer cell lines were treated with DMSO vehicle control, or various concentrations of LBH589 for 3 days. Cell proliferation was measured on the day of cell plating and 3 days after treatment. IC50 and LD50 values were calculated as described above. As evidenced by the low nanomolarity IC50 values, LBH589 showed potent anti-proliferative effects in all 36 colon cancer cell lines tested. In addition, LBH589 showed potent cytotoxic effects in the majority of colon cancer cell lines tested (LD50 <1 μM, n = 31).

Example 2

HCT116 colon cancer cells were implanted subcutaneously in female athymic nude mice. When the median tumor volume reached 120 mm ³ , mice were randomized into groups of eight mice. Mice were treated intravenously (iv) five times per week for 5 weeks with 5, 10 or 20 mg / kg of LBH589, or once weekly for 3 weeks with 75 mg / kg of 5-fluorouracil. Animals were measured weekly with calipers. Compound activity was measured as% change (% T / C) of tumor volume of treated animals relative to control animals. Percent degeneration was measured as the percent change in final tumor volume at the end of the study relative to the starting tumor volume. LBH589 treatment at 5 or 10 mg / kg inhibited HCT116 tumor growth with 17% and 6%% T / C, respectively. Treatment with 20 mg / kg of LBH589 resulted in 8% tumor degeneration. The results are shown in FIG.

Example 3

Colo205 colon cancer cells were implanted subcutaneously in female athymic nude mice. When the median tumor volume reached 220 mm ³ , mice were randomized into groups of 10 mice. Mice are treated intravenously every Monday, Wednesday, and Friday for 30 weeks with 30 mg / kg of LBH589, or once weekly for 3 weeks with 75 mg / kg of 5-fluorouracil, or both formulations The combinations were treated. For tumor growth inhibition (FIG. 2A), compound activity was measured as% change (% T / C) of tumor volume of treated animals relative to control animals. Percent degeneration was measured as the percent change in final tumor volume at the end of the study relative to the starting tumor volume. For tumor growth delay (FIG. 2B), compound activity was measured as the change in median time (TTE) calculated at study termination time point (predetermined to tumor volume of 1000 mm ³ ). Median TTE values for vehicle, LBH, 5-FU, and combination treatment were 39.5 days, 32.9 days, 44.5 days, and 57.1 days, respectively. Treatment with LBH589 or 5-FU single agents resulted in tumor growth inhibition (TGI) and tumor growth delay (TGD). More importantly, the combination treatment significantly enhanced both TGI and TGD. The results are explained in FIG.

Example 4

Pancreatic cancer cell lines were treated with DMSO vehicle control, or various concentrations of LBH589 for 3 days. Cell proliferation was measured on the day of cell plating and 3 days after treatment. IC50 and LD50 values were calculated as described above. As evidenced by low nanomolarity IC50 values, LBH589 showed potent anti-proliferative effects in all 12 pancreatic cancer cell lines tested. In addition, LBH589 showed potent cytotoxic effects in the majority of pancreatic cancer cell lines tested (LD50 <1 μM, n = 10).

The anti-proliferative and cytotoxic effects of LBH589 in 12 panels of pancreatic cancer cell lines are described in Table 2 below.

Nineteen panels of pancreatic cancer cell lines were independently assessed by cell proliferation assays. Cells were treated for 6 days with DMSO vehicle control, or various concentrations of LBH589. Consistent with the results shown in Table 2, LBH589 exhibited low nanomolarity IC50 values, demonstrating potent anti-proliferative effects in all 19 pancreatic cancer cell lines. In addition, LBH589 showed potent cytotoxic effects in 18 of 19 pancreatic cancer cell lines (LD 50 <1 μM). The results are shown in FIG.

Claims (10)

Use of an HDAC inhibitor for the manufacture of a medicament for the treatment of gastrointestinal cancer. The use according to claim 1, wherein the HDAC inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I>

Where R ₁ is H, halo or straight chain C ₁ -C ₆ alkyl, in particular methyl, ethyl or n-propyl, wherein the methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for the alkyl substituents Without; R ₂ is H, C ₁ -C ₁₀ alkyl, preferably C ₁ -C ₆ alkyl (eg methyl, ethyl or —CH ₂ CH ₂ —OH), C ₄ -C ₉ cycloalkyl, C _4- C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg For example, pyridylmethyl),-(CH ₂ ) _n C (O) R ₆ ,-(CH ₂ ) _n OC (O) R ₆ , amino acyl, HON-C (O) -CH = C (R ₁ ) -Aryl-alkyl- and-(CH ₂ ) _n R ₇ ; R ₃ and R ₄ are the same or different and are independently H, C ₁ -C ₆ alkyl, acyl or acylamino, or R ₃ and R ₄ together with the carbon to which they are attached represent C═O, C═S or C═NR ₈ ; or R ₂ together with the nitrogen to which it is attached, and R ₃ together with the carbon to which it is attached, C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or aryl and non-aryl polyhetero Can form a cycle of mixed rings; R ₅ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (eg, benzyl), heteroarylalkyl ( For example, pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryls, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles Is selected from; n, n ₁ , n ₂ and n ₃ are the same or different and are independently selected from 0 to 6, and when n ₁ is 1 to 6 each carbon atom is independently selected from R ₃ and / or R ₄ Can be substituted; X and Y are the same or different and are from H, halo, C ₁ -C ₄ alkyl such as CH ₃ and CF ₃ , NO ₂ , C (O) R ₁ , OR ₉ , SR ₉ , CN and NR ₁₀ R ₁₁ Independently selected; R ₆ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl ( For example benzyl and 2-phenylethenyl), heteroarylalkyl (eg, pyridylmethyl), 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 H, OR ₁₅ , NR ₁₃ R ₁₄ , C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ) And heteroarylalkyl (eg pyridylmethyl); R ₉ is selected from C ₁ -C ₄ alkyl, for example CH ₃ and CF ₃ , C (O) -alkyl, for example C (O) CH ₃ , and C (O) CF ₃ ; R ₁₀ and R ₁₁ are the same or different and are independently selected from H, C ₁ -C ₄ alkyl and —C (O) -alkyl; R ₁₂ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycles , Heteroaryl, arylalkyl (eg benzyl) and heteroarylalkyl (eg pyridylmethyl); R ₁₃ and R ₁₄ are the same or different and are H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ), Heteroarylalkyl (eg, pyridylmethyl), amino acyl, or R ₁₃ and R ₁₄ together with the nitrogen to which they are attached form a non-aryl polyheterocycle with C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl; R ₁₅ is selected from H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Become; R ₁₆ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Is selected from; R ₁₇ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR ₁₃ R Selected from ₁₄ ; m is an integer selected from 0 to 6; Z is selected from O, NR ₁₃ , S and S (O). 3. A compound according to claim 2 wherein the compound of formula (I) is N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] Methyl] phenyl] -2E-2-propenamide or a pharmaceutically acceptable salt thereof. <Formula III>

Use according to any one of claims 1 to 3, wherein the gastrointestinal cancer is hepatocellular carcinoma or pancreatic cancer. The use according to any one of claims 1 to 3, wherein the warm-blooded animal is a human. A method of treating gastrointestinal cancer, comprising administering a therapeutically effective amount of an HDAC inhibitor to a warm blooded animal in need thereof. The method of claim 6 comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a warm blooded animal in need thereof. <Formula I>

Where R ₁ is H, halo or straight chain C ₁ -C ₆ alkyl, in particular methyl, ethyl or n-propyl, wherein the methyl, ethyl and n-propyl substituents are unsubstituted or substituted by one or more substituents described below for the alkyl substituents Without; R ₂ is H, C ₁ -C ₁₀ alkyl, preferably C ₁ -C ₆ alkyl (eg methyl, ethyl or —CH ₂ CH ₂ —OH), C ₄ -C ₉ cycloalkyl, C _4- C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl (eg benzyl), heteroarylalkyl (eg For example, pyridylmethyl),-(CH ₂ ) _n C (O) R ₆ ,-(CH ₂ ) _n OC (O) R ₆ , amino acyl, HON-C (O) -CH = C (R ₁ ) -Aryl-alkyl- and-(CH ₂ ) _n R ₇ ; R ₃ and R ₄ are the same or different and are independently H, C ₁ -C ₆ alkyl, acyl or acylamino, or R ₃ and R ₄ together with the carbon to which they are attached represent C═O, C═S or C═NR ₈ ; or R ₂ together with the nitrogen to which it is attached, and R ₃ together with the carbon to which it is attached, C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or aryl and non-aryl polyhetero Can form a cycle of mixed rings; R ₅ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, acyl, aryl, heteroaryl, arylalkyl (eg, benzyl), heteroarylalkyl ( For example, pyridylmethyl), aromatic polycycles, non-aromatic polycycles, mixed aryl and non-aryl polycycles, polyheteroaryls, non-aromatic polyheterocycles, and mixed aryl and non-aryl polyheterocycles Is selected from; n, n ₁ , n ₂ and n ₃ are the same or different and are independently selected from 0 to 6, and when n ₁ is 1 to 6 each carbon atom is independently selected from R ₃ and / or R ₄ Can be substituted; X and Y are the same or different and are from H, halo, C ₁ -C ₄ alkyl such as CH ₃ and CF ₃ , NO ₂ , C (O) R ₁ , OR ₉ , SR ₉ , CN and NR ₁₀ R ₁₁ Independently selected; R ₆ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, cycloalkylalkyl (eg cyclopropylmethyl), aryl, heteroaryl, arylalkyl ( For example benzyl and 2-phenylethenyl), heteroarylalkyl (eg, pyridylmethyl), 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 H, OR ₁₅ , NR ₁₃ R ₁₄ , C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ) And heteroarylalkyl (eg pyridylmethyl); R ₉ is selected from C ₁ -C ₄ alkyl, for example CH ₃ and CF ₃ , C (O) -alkyl, for example C (O) CH ₃ , and C (O) CF ₃ ; R ₁₀ and R ₁₁ are the same or different and are independently selected from H, C ₁ -C ₄ alkyl and —C (O) -alkyl; R ₁₂ is H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, C ₄ -C ₉ heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycles , Heteroaryl, arylalkyl (eg benzyl) and heteroarylalkyl (eg pyridylmethyl); R ₁₃ and R ₁₄ are the same or different and are H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl (eg benzyl ), Heteroarylalkyl (eg, pyridylmethyl), amino acyl, or R ₁₃ and R ₁₄ together with the nitrogen to which they are attached form a non-aryl polyheterocycle with C ₄ -C ₉ heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl; R ₁₅ is selected from H, C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Become; R ₁₆ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH ₂ ) _m ZR ₁₂ Is selected from; R ₁₇ is C ₁ -C ₆ alkyl, C ₄ -C ₉ cycloalkyl, C ₄ -C ₉ heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR ₁₃ R Selected from ₁₄ ; m is an integer selected from 0 to 6; Z is selected from O, NR ₁₃ , S and S (O). 7. A compound according to claim 6, wherein the compound of formula I is N-hydroxy-3- [4-[[[2- (2-methyl-1H-indol-3-yl) -ethyl] -amino] Methyl] phenyl] -2E-2-propenamide or a pharmaceutically acceptable salt thereof. <Formula III>

The method of claim 6, wherein the gastrointestinal cancer is hepatocellular carcinoma or pancreatic cancer. The method of claim 6, wherein the warm-blooded animal is a human.

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