CN102731380A

CN102731380A - 7-(N-(2-pyridyl)sulfonamide or amido)-N-hydroxy heptamide derivative, its preparation method and application thereof

Info

Publication number: CN102731380A
Application number: CN2011100933306A
Authority: CN
Inventors: 薛建; 付国良; 陈慧平; 陈春麟; 李伟; 蒋维平; 谢立成; 蔡振一; 葛啸虎
Original assignee: FANGYUAN PHARMACEUTICAL Co Ltd CHANGZHOU; Shanghai Medicilon Inc
Current assignee: FANGYUAN PHARMACEUTICAL Co Ltd CHANGZHOU; Shanghai Medicilon Inc
Priority date: 2011-04-14
Filing date: 2011-04-14
Publication date: 2012-10-17

Abstract

The invention relates to a 7-(N-(2-pyridyl)sulfonamide or amido)-N-hydroxy heptamide derivative, its preparation method and an application thereof, and provides a compound, the structure of which is as shown in the general formula (I) which is defined in the specification. The compound provided by the invention has a good activity for inhibiting HDAC and will be hopefully developed into a novel antitumor drug.

Description

7-(N-(2-pyridyl) sulfoamido or carboxamido-group)-N-hydroxyl heptamide verivate

Technical field

The invention belongs to biomedicine field, be specifically related to a kind of new inhibition of histone deacetylase family member's compound, and the preparation method of this compound and application.

Background technology

The dead number of global range internal cause tumor disease is only second to the cardiovascular and cerebrovascular diseases death toll, and significant medicine at present also is of no curative effect.Chemotherapeutics is the selection of action target for want of, is easy to cause serious toxic side effects, has greatly restricted the performance of clinical effectiveness.Therefore develop the wide spectrum low toxicity and become the focus that people pay close attention to the most with antitumor drug with target property.Eighties of last century nineties, and histone acetyltransferase (histone acetyltransferase, HAT) and histon deacetylase (HDAC) (histone deacetylase; HDAC) on molecular level, illustrated (people such as Luger, Nature, 389; 251-260,1997).Have now found that the mankind have 18 kinds of HDAC.Pennisi in 1997 and Pazin have set forth that the acetylize of Methionin epsilon-amino plays an important role on the histone in transcription (people such as Pennisi, Science, 275,155-157,1997; People such as Pazin, Cell, 89,325-328,1997).Acetylation of histone is a kind of reversible albumen covalent modification form; The acetylize of histone helps dissociating of DNA and octameric histone; Nucleosomal structure is lax, thereby various transcription factors and collaborative transcription factor can be combined with DNA binding site specificity, the transcribing of activated gene.When histone hanged down the acetylize state, nucleosomal structure was tight, made various promotion cells growths, and the genetic transcription of differentiation and apoptosis is suppressed, and is relevant with the generation of tumour.In nucleus, acetylation of histone and dna methylase inhibitor process are in running balance, and are regulated and control jointly by HATs and HDACs.HATs transfers to the ethanoyl of acetyl-CoA on the histone N-terminal certain lysine residue, and HDACs makes dna methylase inhibitor, combines closely with electronegative DNA, and chromatin is fine and close to curl, and gene transcription is suppressed.The cancer therapy drug target that the restraining effect of HDAC is considered to have development prospect.NSC 630176 (histone deacetylase inhibitors; HDACi) can promote histone or nonhistones acetylation modification; Thereby relevant proteic expression of regulating cell apoptosis and differentiation and stability; Cell death inducing and differentiation are expected to become one type of new antitumor drug.

Hdac inhibitor (HDAC inhibitor; HDACi) as one type of PTS with research and development potentiality; Recent study shows has remarkable advantages: (1) can cause the cessation of growth cessation of tumour cell, differentiation and apoptosis (people such as Kouzarides, Genet.Dev., 9 of inducing tumor cell; 40-48,1999); (2) have the wide spectrum characteristics, kinds of tumor cells is all had positive effect (people such as Kramer, TrendsEndocrinol.Metab., 12,294-300,2001); (3) be to suppress the medicine that oncogene is transcribed into purpose, specificity to be arranged, normal cell is not caused cessation of growth cessation or apoptosis to tumour cell.This type medicine has changed the mode of action that traditional chemotherapeutics kills and wounds all quick somatoblasts, treats to the transgenation or the abnormal gene expression of tumour cell; (4) toxicity is lower, and is less to Normocellular influence, and experiment shows in the body does not even influence fetal development people such as (, Cancer Res., 61,1247-1249,2001) Nervi; (5) the vascularization process of tumor tissues be can suppress, (people such as Kwon, Int.J.Cancer, 97,290-296,2002 shifted thereby suppress tumour cell; People such as Deroanne, Oncogene, 21,427-436,2002); (6), can also possibility be provided to the prophylactic effect that plays of tumour cell for tumour high risk population's chemoprophylaxis through inhibition to histon deacetylase (HDAC).HDACi also has therapeutic action to nervous system disorders like diseases such as degeneration of carrying out property intelligence and the forfeitures of big muscle motor capacity in addition; The various kinds of cell factor there is regulating effect; Also has the potential therapeutic value to belonging to proliferative disease in addition.HDACi is with its unique antitumor action mechanism, in the research and development anti-tumor medicine, occupies critical role people such as (, Current Medicinal Chemistry, 10,1241-1253,2003) Yoshida.

HDACi (suberoylanilide hydroxamic acid (suberoylanilide hydroxamic acid is illustrated in researchs such as Finnin in 1999; SAHA) and bent ancient rhzomorph A (trichostatin A; TSA)) with the interaction mechanism of histon deacetylase (HDAC) analogue (HDLP) (people such as Finnin, Nature, 401; 188-193,1999).HDAC is one type of zine ion Ntn hydrolase, and when the catalysis histone deacetylase, zine ion forms transition state with the hydrate chelating of oxygen on the ethanoyl, the zine ion on suppressor factor and the substrate competition property ground chelating HDAC, thus bring into play its biological action.Although the HDACI constitutional features of research is varied at present; But show that through structural analysis of X ray crystalline diffraction and structure activity relationship HDACi has 3 zones: melts combine district (metal binding); Form hydrogen bond with the amino-acid residue of enzyme active sites, and and Zn ²⁺Chelating; Connect sequence (linker), occupy the throat of enzyme, the length decision melts combine district and the Zn of its chain ²⁺Bonding state; Surface cog region (surface recognition) combines with the amino-acid residue in the enzyme active sites outside, and the decision inhibitor molecules is to the identification and the combination degree of enzyme, assistant metal land and Zn ²⁺Chelating.HDACi has the cell cycle regulation ability, it can activation cycle the transcribing and reduce maturation promoting factor A and D of protein dependent kinase inhibitor P21.Nearest result of study confirms, HDACi can quicken apoptosis people such as (, Anticancer Res., 28,855-864,2008) Iacomino of tumour cell through the expression that increases death receptor TRAIL in the tumour cell.HDACi can also activate the main body immunne response and restrain generation people such as (, Curr.Opin.Pharmacol., 3,344-351,2003) Marks of tumour through polyfactorial effect.

Since first hdac inhibitor TSA is determined, found multiple structure can to HDAC produce restraining effect (WO2005/087724A, WO2005/092899A, WO2006/018657A1, WO2007/039403A, WO2007/039404).HDACi mainly comprises 6 big types: 1. fatty acid (Aliphatic Acids) comprises valproic acid (VA) and phenylbutyric acid (PA); 2. small molecules hydroxamic acid salt (hydroxamic acid); Comprise SAHA, TSA, the special (Dacinostat of darcy department; LAQ824), N-hydroxyl-3-(3-phenyl amino alkylsulfonyl phenyl) acrylic amide (Belinostat, PXD101) and the N-hydroxy-n '-3-pyridyl suberamide (pyroxamide) etc.; 3. electrophilic ketone class (electrophilic ketones) comprises TPX (Trpoxin) and AOE etc.; 4. cyclic peptide class (cyclic peptide inhibitors) comprises depsipeptide (FK228) and Apicidin.5. benzamides (benzamides) comprises MS-275 (Entinostat) and CI-1994 etc.; 6. other compounds comprise PXD101 (Belinostat) and CHAPs etc.The HDACi that structure is different is different to the active inhibition effect of dissimilar HDACs.Can suppress the activity of I type and II type HDACs like SAHA and TSA, promote histone and nonhistones acetylation modification, and FK228 mainly suppress the activity of I type HDACs, promote the acetylation modification of histone.

Existing multiple at present HDACi gets into clinical experimental stage, and the vivo and vitro test shows that all a lot of HDACi have the strong antitumous effect of low toxicity; Multiple HDACi such as FK228, SAHA, TSA, VPA and MS-275 etc. have got into blood system malignant tumour and clinical I of solid tumor and II phase experimental stage, and these medicines not only use separately and can show antitumor action, and the also associating other drug that has (like vitamin A acid etc.) plays synergy; And can also strengthen the susceptibility of tumour cell to chemicotherapy; Make part tumor drug resistance phenomenon significantly improve (Glaser, Biochem Pharmacol, 74; 659-671,2007).The medicine Vorinostat (vorinostat) of first HDACi of U.S. FDA approved in 2006 is as antitumor drug, and produces listing by the Merck company of the U.S..The medicine of China's approval at present mainly contains VPA and TSA etc.(people such as Alma, Molecular Cancer, 4 such as Alma; The I phase of 22,2005) carrying out sodium valproate in treating 12 routine cervical cancer patients tests, and detects tumour deacetylation enzyme activity after oral 5 days; Find that it has descended 80%, the degree of acetylation of H3 and H4 raises, and toxic side effect is little; Do not influence patient's daily life, have very high clinical meaning.(people such as Fadi, Clin Cancer Res, 14 such as Fadi; 6296-6301; 2008) the I phase is giving 5-azacytidine and valproic acid drug combination to the 55 routine patients that mammary cancer, lung cancer, tumor of head and neck and cervical cancer etc. are arranged in testing, and 6 months persons of stable disease average out to account for 25%.Detected histone methylated and degree of acetylation at the 1st day of administration and the 10th day, find obviously to raise than the 1st day acetylation of histone level in the 10th day.Overcome in the II clinical trial phase of various chemotherapeutics tolerances at Magnesium Valproate associating methylation inhibitor Prparat 5968; Tumour patients such as 15 routine cervical cancers, ovarian cancer, mammary cancer and the lung cancer of reception test give Magnesium Valproate 40mg/kg 3 times/day and Prparat 5968 slow releasing tablet respectively 1 week before chemotherapy.The result shows that wherein 12 examples (4 routine partial reactions and 8 routine stable disease) have clinical meaning, reaches 80%; Toxic side effect is little and mainly show blood system, and all patients all can tolerate; With Hela cell control group relatively, all patients' deacetylation enzyme level all descend in various degree people such as (, Ann Oncol, 18,1529-1538,2007) Candelaria.What these tests were studied emphatically is drug safety, clinical effectiveness and apoptosis, and genetic expression changes, and the contact between the karyomit(e) degree of acetylation is to illustrate the concrete mechanism of action of medicine separately of HDACi class, for clinical III phase experimental study is offered help.

From to the recognizing apparent genetic further investigation of apparent genetic phenomenon, the validity of tumour epigenetic treatment has obtained sufficient confirmation in external and experimentation on animals.But because the cause of disease of tumour and pathogenesis are complicated; And at present to the deficiency of the mechanism understanding of the relation of epigenetic modification and tumour and epigenetic modification regulatory gene; And acetylation of histone and deacetylation modification are important mode in the tumour epigenetics; Therefore strengthen that various HDACi are reached associating separately and take place with tumour, the research of development dependency will help the epigenetic mechanism of promoting mutual understanding, and then instruct the development of tumor treatment and new drug.Undoubtedly, along with further investigation, provide novel HDACi to have broad application prospects to the HDACi anticancer mechanism.

Summary of the invention

The present invention further studies the verivate of small molecules hydroxamic acid salt HDACi, at this a kind of hdac inhibitor of novel structure is provided.

In one aspect of the invention, a kind of compound with structure shown in the consummate formula (I) is provided, below is called formula (I) compound:

Wherein, A is carbonyl or sulfuryl,

R is alkyl, aryl, substituted aryl or azepine aryl.

In a preferred embodiment, A is a sulfuryl; R is aryl or substituted aryl; Preferred chlorine substituted-phenyl, fluorine substituted-phenyl, ethanoyl substituted-phenyl, acetamido substituted-phenyl, xenyl, alkyl-substituted phenyl, methoxyl group substituted-phenyl, fluoro methoxyl group substituted-phenyl, nitro substituted-phenyl or naphthyl, preferred especially following compound:

7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-ethanoyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(2,4-two chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(3-xenyl) sulfoamido)-N-hydroxyl heptamide;

7-(4-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(2-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-acetamido-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-three fluoro methoxyl group-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(3-nitro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(1-naphthyl) sulfoamido)-N-hydroxyl heptamide;

7-(4-butyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(2-naphthyl) sulfoamido)-N-hydroxyl heptamide;

7-(3,4-dimethoxy-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-sec.-propyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide; With

7-(3-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide.

In another preferred embodiment, A is a carbonyl, and R is alkyl, substituted-phenyl or azepine aryl, preferred especially following compound:

7-(4-fluoro-N-(2-pyridyl) benzoylamino)-N-hydroxyl heptamide;

7-(N-(2-pyridyl) acetamido)-N-hydroxyl heptamide; With

7-(N-(2-pyridyl) nicotinoyl amido)-N-hydroxyl heptamide.

" alkyl " according to the invention preferably contains 1～6 saturated group of carbon atom, and more preferably 1～4 saturated group of carbon atom comprises methyl, ethyl, cyclopropyl, propyl group, sec.-propyl, butyl, isobutyl-, sec.-butyl." aryl " refers to monocycle, two ring or trinucleated carbocyclic ring aromatic groups, and comprises and contain two groups through the direct-connected monocycle carbocyclic ring of covalent linkage aromatic nucleus; The example of this group has phenyl, xenyl and naphthyl." substituted aryl " is meant that the aromatic nucleus of above-mentioned aryl has substituting group." heteroaryl " refers to contain the heteroatomic monocyclic, bicyclic or tricyclic aromatic group of one or more S of being selected from, N or O, and comprises the group that contains through direct two these type of monocycles that link to each other of covalent linkage or this type of monocycle and a monocyclic aryl ring; The example of this group has thienyl, benzothienyl, furyl, benzofuryl, pyrryl, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazole base, pyrazolyl 、 oxazolyl, benzoxazolyl 、 isoxazolyl, benzoisoxazole base, isothiazolyl, triazolyl, benzotriazole base, thiadiazolyl group 、 oxadiazole base, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, indyl or indazolyl.

In another aspect of this invention, a kind of method for preparing above-claimed cpd is provided, comprises:

Step a: formula (II) amine compound and formula (III) halogenated compound react in the presence of alkali and obtain formula (IV) compound,

Step b: the formula of step a gained (IV) compound and formula V compound react in the presence of alkali and obtain formula (VI) compound,

and

Step c: the formula of step b gained (VI) compound obtains formula (I) compound with the oxammonium hydrochloride reaction in the presence of alkali,

Wherein, A, R as above define, and X is a chlorine or bromine.

In step a, the alkali that adopts can be yellow soda ash, salt of wormwood, sodium hydrogencarbonate, saleratus, and temperature of reaction can be 100～130 ℃, and the reaction times is 4～6 hours.

In step b, the alkali that is adopted can be triethylamine, pyridine or N, the N-diisopropylethylamine, and temperature of reaction is 40～60 ℃, the reaction times is 20～30 hours.

In step c, the alkali that is adopted is Pottasium Hydroxide or sodium hydroxide, and temperature of reaction is 20～30 ℃, and the reaction times is 20～30 hours.

In still another aspect of the invention, a kind of pharmacy acceptable salt or its hydrate are provided, by The compounds of this invention and mineral acid with the acid salt that forms of organic acid or with mineral alkali with or the organic basic base addition salt or the quaternary ammonium salt that become.Wherein, said mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; Said organic acid is selected from acetate, oxalic acid, Hydrocerol A, phenylformic acid, Whitfield's ointment, toxilic acid, LAURIC ACID 99 MIN, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, methylsulfonic acid, dextrocamphoric acid, lactic acid, nicotinic acid, styracin, tosic acid, Phenylsulfonic acid, L-glutamic acid and racemic melic acid; Said mineral alkali comprises the oxyhydroxide of basic metal, alkali-metal oxyhydroxide, earth alkali metal; Said organic bases is selected from triethylamine, N-methyl D-glycosamine, choline three (methylol) amino-methane, L-l-arginine, L-Methionin, N-ethylpiperidine and dibenzyl amine.

In one side more of the present invention, a kind of pharmaceutical composition is provided, The compounds of this invention and pharmaceutical diluents, drug excipient and/or pharmaceutical carrier.The formulation of said pharmaceutical composition is tablet, capsule, pulvis, granule, lozenge, gelifying agent or injection.

In also one side of the present invention, the application of compound of the present invention in the preparation antitumor drug is provided.

It is active that compound of the present invention has good inhibition HDAC.Therefore, novel cpd provided by the present invention is expected to be developed to the targeted drug into the treatment tumour.

Embodiment

Embodiment below in conjunction with concrete further specifies the present invention, notices that following embodiment only is exemplary and unrestricted the present invention.

(1) preparation of formula (I) compound:

Wherein, A is carbonyl or sulfuryl; R is alkyl, aryl, substituted aryl or azepine aryl; X is bromine or chlorine.

In step a; Reactant formula (II) amine compound and formula (III) halogenated compound direct reaction and need not solvent; (III) halogenated compound can be excessive a little, for example the mol ratio of formula (II) amine compound and formula (III) halogenated compound can be 1: 1～1: 1.1, preferred 1: 1.05.Can adopt and (III) alkali of halogenated compound equimolar amount, the alkali that adopts includes but not limited to, yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus, preferably yellow soda ash or salt of wormwood.Step a temperature of reaction can be 100～130 ℃, and the reaction times can be 4～6 hours.After reaction finished, separation and purification obtained general formula (IV) compound.

In step b, formula (IV) compound and the formula V compound of step a gained is dissolved in suitable solvent, suitable solvent includes but not limited to methylene dichloride (DCM), N, dinethylformamide (DMF) or THF (THF) etc.The mol ratio of formula (IV) compound and formula V compound is 1: 1.2～1: 1.8, preferred 1: 1.5.Add the alkali with the formula V compound, the alkali that is adopted can be triethylamine, pyridine or N, N-diisopropylethylamine, reacting by heating.Usually step b reacts under reflux state, and promptly temperature of reaction is generally 40～60 ℃, and the reaction times can be 20～30 hours.After reaction finished, separation and purification obtained general formula (VI) compound.

In step c, add alkali at the solution that is dissolved with oxammonium hydrochloride, stirring reaction is about 30 minutes, and solvent for use can be methyl alcohol or ethanol etc., and used alkali can be Pottasium Hydroxide or sodium hydroxide, but used alkali oxammonium hydrochloride is for waiting mole.Add formula (VI) compound and the extra alkali of step b gained then, reacted under the room temperature 20～30 hours, the room temperature here is interpreted as 20～30 ℃.The extra alkali that adds also can be Pottasium Hydroxide or sodium hydroxide, and its molar weight with respect to formula (VI) compound is excessive for slightly, for example 1.1～1.5 equivalents.The mol ratio of formula (VI) compound and oxammonium hydrochloride can be 1: 10～and 1: 20, preferred: 1: 14～1: 18.After reaction finished, separation and purification obtained general formula (I) compound.

The method that the monitoring of the reaction end of above-mentioned reaction can adopt those skilled in the art to use always, for example TLC.The separation method that adopted those skilled in the art of the separation and purification of intermediate product and end product use always, for example, extraction, column chromatography, recrystallization etc.The spectroscopic analysis means that Tong Guo this area of formula (I) compound is used always are definite, for example ¹HNMR, MS etc.

Preparation with particular compound further specifies the present invention below.Use abbreviation as giving a definition at following embodiment or other parts of this paper:

Among the embodiment, compound ¹H-NMR is interior mark by Bruke AM-400 type nmr determination with TMS, and chemical shift is represented with δ (ppm); Mass spectrum is measured with Finnign-MAT212 type mass spectrograph.

The column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces (thin-layer chromatography H type), HSGF 254 types that thin layer chromatography board is produced for Yantai Zhifu experiment chemical plant.

Embodiment 1:7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide

Step a: in the 50ml flask, with the 2-EL-970 (7.67g, 81.6mmol) be dissolved in 7-chloro-N-methoxyl group heptamide (18.192g, 81.6mmol) in, add then salt of wormwood (11.26g, 81.6mmol).Be warming up to 120 ℃ of reactions 4 hours subsequently.Question response finishes to be cooled to room temperature, in reaction solution, adds dissolve with methanol, filters, and revolves and does filtrating, isolates white solid intermediate product 7-(N-(2-pyridyl) amido)-N-methoxyl group heptamide (3.558g), yield: 18.5% through silica gel column chromatography.

Step b: be dissolved with 7-(N-(2-pyridyl) amido)-N-methoxyl group heptamide (3.558g, 15.08mmol) (4.8g is in 75ml dichloromethane solution 22.62mmol) with the 3-chlorobenzene sulfonyl chloride; Add N; The N-diisopropylethylamine (2.92g, 22.62mmol), reflux 24 hours.Reaction finishes to be cooled to room temperature, revolves dry reaction liquid, isolates oily intermediate product 7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-methoxyl group heptamide (4.4g) through silica gel column chromatography.Yield: 71%.

Step c: (13.7g, (11.71g 198.54mmol), at room temperature stirred 30 minutes, filtered to add Pottasium Hydroxide in 200ml methanol solution 198.54mmol) to being dissolved with oxammonium hydrochloride.(4.4g, 10.73mmol) (823.05mg 13.95mmol) joins in the filtrating with other 1.3 times of normal Pottasium Hydroxide with 7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-methoxyl group heptamide.Continued at room temperature stirring reaction 24 hours.After reaction finishes, in reaction system, add entry, with the hydrochloric acid neutralization reaction solution of 2mol/L to pH=7.Add ethyl acetate extraction, extraction liquid is used the saturated common salt water washing, and anhydrous sodium sulfate drying revolves dried.Silica gel column chromatography is isolated 7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide (4.18g), yield: 94.6%. ¹H-NMR (400MHz, CDCl ₃): δ 8.59 (s, 1H), 8.35 (d, J=4.4Hz, 1H), 7.76 (t, J=8.0Hz, 1H); 7.57-7.51 (m, 3H), 7.45 (d, J=7.6Hz, 1H), 7.38 (t, J=8.0Hz, 1H); 7.21 (t, J=6.4Hz, 1H), 3.74 (t, J=6.8Hz, 2H), 2.12 (t, J=6.8Hz; 2H), and 1.62-1.56 (m, 2H), 1.46-1.40 (m, 2H), 1.36-1.26 (m, 4H) .MS: theoretical value: [C ₁₈H ₂₂ClN ₃O ₄S] ⁺(m/z): 411.90, test value: 412.1.

Adopt similar method to prepare following embodiment 2～20 compounds (seeing table 1):

Table 1:

Adopt this area salifying method commonly used with the compound of above-mentioned preparation with pharmaceutically can acid, alkali form acid salt, base addition salt, quaternary ammonium salt.Mineral acid can be selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid; Organic acid can be selected from acetate, oxalic acid, Hydrocerol A, phenylformic acid, Whitfield's ointment, toxilic acid, LAURIC ACID 99 MIN, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, methylsulfonic acid, dextrocamphoric acid, lactic acid, nicotinic acid, styracin, tosic acid, Phenylsulfonic acid, L-glutamic acid and racemic melic acid; Mineral alkali can be selected from the oxyhydroxide of basic metal, alkali-metal oxyhydroxide, earth alkali metal; Organic bases can be selected from triethylamine, N-methyl D-glycosamine, choline three (methylol) amino-methane, L-l-arginine, L-Methionin, N-ethylpiperidine and dibenzyl amine.

(2) preparation of drug combination of the present invention:

The compounds of this invention can add suitable drug thinner, drug excipient and/or pharmaceutical carrier and form pharmaceutical composition.The compound that the present invention relates to can be made into the formulation through any any administration consistent with its pharmacokinetic properties; And process any pharmaceutically acceptable form of medication, as in blood dosing, oral administration, the intestines, non-enteron aisle and oral administration or the like.Optional formulation is tablet, capsule, pulvis, granule, lozenge, gelifying agent or injection.The form of the compsn of Orally-administrable can be tablet, capsule, powder, particle, lozenge, liquid or gel product such as oral, part or sterile parenteral solutions or suspension-s.Tablet for oral administration or capsule can adopt unit dosage, and can contain conventional excipients, like tackiness agent, like syrup, gum arabic, gelatin, Sorbitol Powder, yellow glue advanced in years or Vinylpyrrolidone polymer; Filler is like lactose, sucrose, W-Gum, calcium phosphate, Sorbitol Powder or glycocoll; Lubricant is like Magnesium Stearate, talcum, polyoxyethylene glycol or silicon-dioxide; Disintegrating agent is like yam starch; Wetting agent such as Sodium Lauryl Sulphate BP/USP.Can be according to the method for knowing in the conventional pharmacy practice with tablet coating.The form of oral liquid can be, for example, and water-based or oily suspensions, solution, emulsion, syrup or can be rendered as water before use or drying prods that other suitable carrier is rebuild.This liquid preparation can contain conventional additive, like suspension agent, and for example Sorbitol Powder, syrup, tame myolin, glucose syrup, gelatin, hydrogenation edible-fat; Emulsifying agent, for example Yelkin TTS, sorbitan monooleate or gum arabic; Non-aqueous carrier (can comprise edible oil), for example Prunus amygdalus oil, fractionated coconut oil, oily ester such as glycerine, Ucar 35 or ethanol; Sanitas, for example methyl paraben or propylben or Sorbic Acid, the words that need also can contain conventional seasonings or tinting material.And various injection form of medication, freeze-drying, powder pin, injection, transfusion, the administration of little stamen micropin epidermis or the like.

For parenterai administration, particularly injection solution or suspensoid, the especially active compound aqueous solution in gathering the hydroxyl-oxethyl Viscotrol C is suitable.

As carrier system, also can use the surfactivity auxiliary agent, such as salt or animal or plant phosphatide and its mixture of bile acide, and liposome or its composition.

The concrete dosage level that is used for any particular patient will depend on and various factors, comprising the seriousness of activity, age, body weight, state of health, sex, diet, administration number of times, route of administration, excretion rate, the drug regimen of the particular compound that adopts and the specified disease of receiving treatment.Optimal dose level and administration frequency will be confirmed by clinical trial.

(3) biological activity test of The compounds of this invention:

Use available from the HDAC fluorescence activity assay kit of BPS and measure the active ability of compound inhibition of histone deacetylase.In brief, when existing or not having suppressor factor, the substrate (Fluorogenic, acetylated peptide substrate) of fluorophore tagged is hatched with the HDAC enzyme.Thereby the deacetylated substrate that makes of substrate is to the responsive fluorescence that produces of Methionin photographic developer.Final fluorophore can be read plate appearance or photofluorometer analysis through fluorescence.Therefore, substrate hatched with the HDAC enzyme cause signal to strengthen, and when having hdac inhibitor signal weakening.

The per-cent of the contrast that data representation records when not having suppressor factor, all samples is wanted the subtracting background signal, following no:

% activity=[(Si-B)/(S0-B)] * 100

Wherein, there is substrate in Si, and the signal when enzyme and suppressor factor, S0 are to have substrate, the signal when enzyme and suppressor factor are dissolved in carrier wherein, and B is the background signal that records when not having enzyme.

Confirm IC ₅₀Adopt Graphpad Prism software during value, the result of 10 data points is fitted to S shape dose response curve equation with variable slope (the active logarithm with compound concentration of %), confirm IC through nonlinear regression analysis then ₅₀Value.

IC ₅₀The result is included into one of 3 scopes, defines as follows:

Scope A:IC ₅₀Less than 100nM

Scope B:IC ₅₀From 101nM to 1000nM

Scope C:IC ₅₀Greater than 1001nM

Following table 2 has been listed the result of this paper part embodiment compound.

Table 2:

Embodiment	Inhibition to HDAC is active
		1	B
2	B
		4	A
5	A
		11	C
15	B

6 embodiment compounds listing in the last table 2 all have certain restraining effect to the HDAC enzymic activity, wherein compound 4 and 5 couples of HDAC enzymic activity 503nhibiting concentration IC ₅₀Less than 100nM, with positive compound SAHA (to the IC of HDAC ₅₀Value is 26.44nM) very approaching, demonstrate strongly inhibited effect to the HDAC enzymic activity.

The compounds of this invention can be united use with many known pharmaceutically active substances.For example, The compounds of this invention can with drug combinations such as transcription regulaton factor (like the assorted nitrogen-2 ' of 5--Deoxyribose cytidine, vitamin A acid, mRNA transcription inhibitor flavopiridol), apoptosis receptors ligand (like Zorubicin, vincristine(VCR), VP, Docetaxel), chemotherapeutics (like antimetabolite gemcitabine, all-trans-retinoic acid) and SU11752, radioactive rays.

Claims

1. formula (I) compound is characterized in that,

Wherein, A is carbonyl or sulfuryl,

R is alkyl, aryl, substituted aryl or azepine aryl.

2. compound according to claim 1 is characterized in that, A is a sulfuryl, and R is aryl or substituted aryl.

3. compound according to claim 2; It is characterized in that R is chlorine substituted-phenyl, fluorine substituted-phenyl, ethanoyl substituted-phenyl, acetamido substituted-phenyl, xenyl, alkyl-substituted phenyl, methoxyl group substituted-phenyl, fluoro methoxyl group substituted-phenyl, nitro substituted-phenyl or naphthyl.

4. compound according to claim 3 is characterized in that, said compound is:

7-(3-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-ethanoyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(2,4-two chloro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(3-xenyl) sulfoamido)-N-hydroxyl heptamide;

7-(4-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(2-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-acetamido-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(3-nitro-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(1-naphthyl) sulfoamido)-N-hydroxyl heptamide;

7-(4-butyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(N-(2-pyridyl)-(2-naphthyl) sulfoamido)-N-hydroxyl heptamide;

7-(3,4-dimethoxy-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide;

7-(4-sec.-propyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide; Or

7-(3-methyl-N-(2-pyridyl) benzene sulfonamido)-N-hydroxyl heptamide.

5. compound according to claim 1 is characterized in that, A is a carbonyl, and R is C _1～3Alkyl, substituted-phenyl or azepine aryl.

6. compound according to claim 5 is characterized in that, said compound is:

7-(4-fluoro-N-(2-pyridyl) benzoylamino)-N-hydroxyl heptamide;

7-(N-(2-pyridyl) acetamido)-N-hydroxyl heptamide; Or

7-(N-(2-pyridyl) nicotinoyl amido)-N-hydroxyl heptamide.

7. a method for preparing the said compound of claim 1 is characterized in that, comprising:

and

Wherein, X is a chlorine or bromine.

8. method according to claim 7 is characterized in that, in step a, the alkali that adopts is yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus, and temperature of reaction is 100～130 ℃, and the reaction times is 4～6 hours.

9. method according to claim 7 is characterized in that, in step b, the alkali that is adopted is triethylamine, pyridine or N, the N-diisopropylethylamine, and temperature of reaction is 40～60 ℃, the reaction times is 20～30 hours.

10. method according to claim 7 is characterized in that, in step c, the alkali that is adopted is Pottasium Hydroxide or sodium hydroxide, and temperature of reaction is 20～30 ℃, and the reaction times is 20～30 hours.

11. a pharmacy acceptable salt or its hydrate; It is characterized in that, said pharmacy acceptable salt be according to each described compound in the claim 1～6 and mineral acid with the acid salt that forms of organic acid or with mineral alkali with or the organic basic base addition salt or the quaternary ammonium salt that become.

12. pharmacy acceptable salt according to claim 11 or its hydrate, said mineral acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid.

13. pharmacy acceptable salt according to claim 11 or its hydrate, said organic acid is selected from acetate, oxalic acid, Hydrocerol A, phenylformic acid, Whitfield's ointment, toxilic acid, LAURIC ACID 99 MIN, oxysuccinic acid, fumaric acid, succsinic acid, tartrate, methylsulfonic acid, dextrocamphoric acid, lactic acid, nicotinic acid, styracin, tosic acid, Phenylsulfonic acid, L-glutamic acid and racemic melic acid.

14. pharmacy acceptable salt according to claim 11 or its hydrate, said mineral alkali comprise the oxyhydroxide of basic metal, alkali-metal oxyhydroxide, earth alkali metal.

15. pharmacy acceptable salt according to claim 11 or its hydrate, said organic bases are selected from triethylamine, N-methyl D-glycosamine, choline three (methylol) amino-methane, L-l-arginine, L-Methionin, N-ethylpiperidine and dibenzyl amine.

16. a pharmaceutical composition is characterized in that, comprises according to each described compound and pharmaceutical diluents, drug excipient and/or pharmaceutical carrier in the claim 1～6.

17. pharmaceutical composition according to claim 16 is characterized in that, the formulation of said pharmaceutical composition is tablet, capsule, pulvis, granule, lozenge, gelifying agent or injection.

18. according to the application of each described compound in the claim 1～6 in the preparation anti-tumor drug.