CN103172540A - Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof - Google Patents

Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof Download PDF

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CN103172540A
CN103172540A CN201310085903XA CN201310085903A CN103172540A CN 103172540 A CN103172540 A CN 103172540A CN 201310085903X A CN201310085903X A CN 201310085903XA CN 201310085903 A CN201310085903 A CN 201310085903A CN 103172540 A CN103172540 A CN 103172540A
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amido
oxygen
benzamide
phenyl
styroyl
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CN103172540B (en
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徐文方
张磊
张英杰
侯金宁
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Ji'nan platinum 30 Pharmaceutical Technology Co. Ltd.
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Weifang Bochuang International Biological Medical Research Institute
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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a phenylglycine histone deacetylase inhibitor as well as a preparation method and applications thereof. The invention provides a superactive histone deacetylase inhibitor, which relates to a compound with a structure shown in the general formula (I), and also relates to various optical isomers thereof, a pharmaceutically acceptable salt, a solvate and a prodrug. The invention also relates to a pharmaceutical composition containing the compound with a structure shown in the formula (I), and pharmaceutical applications thereof. According to the invention, diseases with abnormal histone deacetylase activity expression can be effectively treated.

Description

Phenylglycine class inhibitors of histone deacetylase and its preparation method and application
Technical field
The invention belongs to the pharmaceutical chemistry technical field, relate in particular to phenylglycine histone deacetylases inhibitor and its preparation method and application.
Background technology
Histon deacetylase (HDAC) (HDACs) is the lytic enzyme of a class function complexity.In nucleus, the nucleosome that the octameric histone that is being wound around by the DNA chain consists of is to consist of chromosomal structural unit, histon deacetylase (HDAC) (HDACs) can be hydrolyzed the ethanoyl on the lysine residue terminal amino group in histone (as reaction formula I), thereby cause the positive charge density of histone to increase, then the avidity that causes histone and electronegative DNA strengthens, genetic transcription is suppressed, (referring to Christian, A. H., et al. Curr. Opin. Chem. Biol., 1997,1,300; Kouzarides, T., Curr. Opin. Genet. Dev., 1999,9,40); Wolffe, A. P. Sci. Washington, 1996,272,371.In addition, the deacetylation of nucleosome histone is also assembled with chromatin, and DNA repairs with restructuring closely related, (referring to Polo, S. E., et al. Cancer Lett., 2005,220,1; Vidanes, G. M., et al. Cell, 2005,121,973).Recently, the increasing nonhistones substrate that is proved to be HDACs, as transcription factor, cytoskeletal protein, molecular chaperones etc., (referring to Glozak, M. A., et al. Gene, 2005,363,15).The function that has complexity like this just because of HDACs, its expression and active imbalance are closely related with numerous disease, comprising: cancer, neurodegenerative disease, virus infection, inflammation, leukemia, malaria and diabetes etc., wherein, cancer is the disease the most serious to human life's health threat beyond doubt.Studies show that, HDACs and tumour cell genesis are closely related, as: inhibition tumor cell differentiation and apoptosis promote tumor cell proliferation, migration and vasculogenesis, strengthen tumour cell to the resistibility of chemotherapeutics etc., (referring to Witt, O., et al. Cancer Letter., 2009,277,8).
Found in human body that at present there are 18 members in HDACs family, according to its structure, the difference of function and distribution can be divided into four classes.Wherein, I class (HDAC1,2,3 and 8), II class (IIa:HDAC4,5,7 and 9; IIb:HDAC6,10), IV class (HDAC11) belongs to zine ion dependency lytic enzyme, and III class HDACs (SIRT 1-7) is NAD +Dependent.Studies show that, closely-related with tumour is mainly zine ion dependency HDACs, and hdac inhibitor (HDACs Inhibitors, HDACi) is anticancer propagation effectively, promotes apoptosis.And it is wide that HDACi has antitumor spectra, the advantage that toxic side effect is low, and they are to solid tumor, and it is active that leukemia, lymphoma all have good inhibition.Therefore, be the focus that the shot design inhibitor has become antitumor drug research for HDACs.
The HDACi pharmacophore of report mostly comprises following three parts at present: Zinc Ions Chelated group (ZBG), hydrophobic long-chain (Linker) and protein surface cog region (Surface Recognition Domain).The Zinc Ions Chelated group can chelating HDACs the zine ion in active centre, thereby the activity of inhibitory enzyme.At present known activity is the strongest, and most widely used Zinc Ions Chelated group is hydroxamic acid group.Yet the compound that much is in clinical study does not now have good drug effect, although they have shown very excellent activity in preclinical research.And the hdac inhibitor of listing (SAHA and FK228) drug effect aspect the treatment solid tumor is very poor, and it is short that they also exist the transformation period, the difficult absorption and the relatively poor shortcoming of pharmacokinetics character.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of phenylglycine class inhibitors of histone deacetylase and its preparation method and application is provided, it is the Zinc Ions Chelated group that the present invention adopts hydroxamic acid group, the L-phenylglycine is one of indispensable amino acid of human body, be applied in the HDACi structure and can improve its lipid, promote the absorption of medicine.
Technical scheme of the present invention is as follows:
Phenylglycine histone deacetylases inhibitor with general formula I, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug,
Figure 739793DEST_PATH_IMAGE002
In general structure I:
R 1C1-12 aliphatic chain alkoxyl group, fragrant oxygen base, alkoxy aryl, heteroaryloxy, heteroaryl alkoxyl group, C1-12 aliphatic chain alkylamino radical, aromatic amino, aryl alkylamino radical, assorted aryl amine or heteroaryl alkylamino radical;
R 1Aromatic group preferably replaced by one or more following groups: hydroxamic acid base, carboxyl, methoxycarbonyl, amide group, hydrazide group, hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
R 2Hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl or general structure II;
R 2Aromatic group optional replaced by one or more following groups: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy, aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, the C1-6 alkyl, assorted alkyl, cycloalkyl;
Preferably replaced by one or more following groups: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy; The structure of general formula I I, wherein R 3The hydroxamic acid base, carboxyl, methoxycarbonyl, amide group or hydrazide group;
The structure of general formula I I:
Figure 74959DEST_PATH_IMAGE003
R wherein 3Hydroxamic acid base, carboxyl, methoxycarbonyl, amide group or hydrazide group.
* be that steric configuration is S or R optical purity or its raceme.
Described phenylglycine class inhibitors of histone deacetylase, preferably one of following compound:
(S)-tertiary butyl-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-amido formate ( h1);
(S)-4-chloro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h2);
(S)-2-chloro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h3);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-2- NaphthaleneMethane amide ( h4);
(S)-4-fluoro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h5);
(S)-N-hydroxyl-4-(2-(naphthyl-2-sulfoamido)-2-phenylacetyl amido)-benzamide ( h6);
(S)-4-(2-(4-(tertiary butyl)-benzene sulfonamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h7);
(S)-4-(2-benzamide base-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h8);
(S)-N-hydroxyl-4-(2-phenyl-2-(4-(trifluoromethyl)-benzene sulfonamido)-acetamido)-benzamide ( h9);
(S)-4-(2-(2,6-difluorobenzene sulfoamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h10);
(S)-4-(2-((4-chlorobenzene sulfonamide base)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h11);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-2-methoxyl group-benzamide ( h12);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-4-methoxyl group-benzamide ( h13);
(S)-N-hydroxyl-4-(2-(4-methyl-benzoylamino)-2-phenylacetyl amido)-benzamide ( h14);
(S)-3-bromo-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h15);
(S)-N-hydroxyl-4-(2-phenyl-2-(propyl group valeryl amido)-acetamido)-benzamide ( h16);
(S)-N-hydroxyl-4-(2-phenyl-2-(2-phenylacetyl amido)-acetamido)-benzamide ( h17);
(S)-N-hydroxyl-4-(2-(3-(2-methoxyl group-phenyl)-urea groups)-2-phenylacetyl amido)-benzamide ( h18);
(S)-4-(2-(3-(2,6-di-isopropyl-phenyl)-urea groups)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h19);
(S)-4-(2-(5-(dimethylin)-naphthyl-1-sulfoamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h20);
(S)-4-(3-(2-(benzamido group)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q1);
(S)-4-(3-(2-((2-fluoro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q2);
(S)-4-(3-(2-((4-fluoro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q3);
(S)-4-(3-(2-((the 4-tertiary butyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q4);
(S)-4-(3-(2-(furfuryl-2-base is amino)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q5);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((2-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q6);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-(naphthyl-1-base is amino)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q7);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((3-(trifluoromethyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q8);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((4-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q9);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-((2-methoxyl group-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q10);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-((2-hydroxyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q11);
(S)-4-(3-(2-((3-chloro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q12);
(S)-4-(3-(2-((3,5-dimethyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q13);
(S)-4-(3-(2-((3-fluoro-4-methoxyl group-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q14);
(S)-4-(3-(2-((4-fluoro-benzyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q15);
(S)-4-(3-(2-((3-bromo-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q16);
(S)-4-(3-(2-((2,6-di-isopropyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q17);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((3-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q18);
(S)-4-(3-(2-((2,4-, two chloro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q19);
The present invention also provides the application in the medicine of prevention or the treatment mammalian diseases relevant to the active unconventionality expression of histon deacetylase (HDAC) of these compounds.Described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer, neurodegenerative disease, virus infection, inflammation, leukemia, malaria and diabetes etc.
Therefore, the invention still further relates to the pharmaceutical composition that contains general formula (I) structural compounds.
In addition, the present invention also comprises a kind of oral mammiferous pharmaceutical composition that gives that is suitable for, and comprises above-mentioned general formula (I)) arbitrary compound, and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
In addition, the present invention comprises that also a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises arbitrary compound of above-mentioned general formula (I), and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
Detailed Description Of The Invention
Definition used and term
Term and definition implication used herein is as follows:
" aryl " refers to the aromatic carbocyclic group.Preferred aromatic ring contains 6-10 carbon atom.
" heteroaryl " is aromatic heterocycle, can be monocycle or bicyclic radicals.Better heteroaryl comprises, thienyl for example, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in assorted alkyl, preferably contain 2-10 atom.Assorted alkyl can be direct-connected or side chain, replacement or unsubstituted.
" cycloalkyl " is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" halogen ", or " halogen " comprises fluorine, chlorine, bromine or iodine, preferred fluorine and chlorine.
" each seed amino acid preparation acyl group " refers to group that various amino acid whose carboxyls are obtained after acidylate, preferred hydrophobic amino acid, and as glycine, L-Ala, α-amino-isovaleric acid, leucine, Isoleucine, phenylalanine, proline(Pro).
" aroyl " refers to that the aromatic carbon ring end is connected with the group of carbonyl, and preferred aromatic ring contains 6-10 carbon atom.
" 4-hetaroylpyrazol " refers to that the aromatic heterocycle end is connected with the group of carbonyl, can be monocycle or bicyclic radicals.Better heteroaryl comprises thienyl, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" cycloalkanes acyl group " refers to replace or for what replace, saturated or undersaturated annular termination is connected with the group of carbonyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" pharmacy acceptable salt " refers to that compound has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (as carboxyl), or forms cationic salts by arbitrary basic group (as amino).A lot of such salt known in the art.At the upper cationic salts that forms of any acidic-group (as carboxyl), or at the upper anion salt that forms of any basic group (as amino).It is known in the art that these salt have many, comprises salt and the organic salt (as ammonium salt) of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium) as cationic salts.Also can obtain easily anion salt by (I) that uses corresponding acid treatment alkaline form, such acid comprises mineral acid such as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid such as acetic acid, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, Acetylformic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1,2,3-, the third three acid, methylsulfonic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge provides.In addition, those of skill in the art can get certain salt according to factors such as solubleness, stability, easy preparations and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
" solvate " is the title complex that solute (as inhibitors of metalloproteinase) and solvent (as water) are combined to form.Referring to J. Honig etc., The Van Nostrand Chemist ' s Dictionary, p. 650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents (for example known to water, ethanol, acetic acid, DMF, dimethyl sulfoxide (DMSO) and this those skilled in the art or solvent that easily determine) that do not disturb inhibitors of metalloproteinase.
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. have defined the form of the compounds of this invention or all possible steric isomer of its physiological derivative.Unless indication is separately arranged, the chemical name of the compounds of this invention comprises the mixture of all possible stereochemical form, affiliated mixture comprises all diastereomers and the enantiomorph of basic structure molecule, and the single isomeric forms of the compounds of this invention of substantially pure, namely wherein contain lower than 10%, preferably lower than 5%, particularly lower than 2%, most preferably lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in scope of the present invention.
The form of all right other the protected form of general formula (I) compound or derivative exists, and these forms will be apparent to those skilled in the art, and all should be contained in scope of the present invention.
Substituting group as above self also can be replaced by one or more substituting groups.Such substituting group is included in C. Hansch and A. Leo, those substituting groups of listing in Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituting group comprises, alkyl for example, thiazolinyl, alkoxyl group, hydroxyl, the oxygen base, nitro, amino, aminoalkyl group (as aminomethyl etc.), cyano group, halogen, carboxyl, carbonylic alkoxy (as carbonyl oxyethyl group etc.), sulfenyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl (as piperidyl, morpholinyl, pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combination.
The preparation method of described compound, reactions steps and reaction formula are as follows:
The preparation method comprises the steps:
Synthetic route 1: take optically pure L-phenylglycine as raw material, through the amido protection, the polypeptide condensation connects the methyl p-aminobenzoate hydrochloride in succession; the amido deprotection; the polypeptide condensation connects the R group, with azanol potassium nucleophilic reaction, makes at last hydroximic acid and obtains end product.Reaction formula is as follows:
Synthetic route 1:
Wherein, the acyl group of R, aroyl, 4-hetaroylpyrazol; aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl; the cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl; aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen; nitro, cyano group, halogen C1-8 alkyl; C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy.
Reagent in said synthesis route 1 reaction formula: (1) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (2) Acetyl Chloride 98Min., methyl alcohol; (3) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (4) the saturated ethyl acetate solution of hydrogenchloride; (5) various acyl chlorides, triethylamine, tetrahydrofuran (THF); (6) azanol potassium, anhydrous methanol.
Prepare the intermediate of described phenylglycine class inhibitors of histone deacetylase, this intermediate is:
Route 1:((S)-2-((tertbutyloxycarbonyl)-amido)-2-toluylic acid, methyl-4-amino-methyl benzoate hydrochloride, (S)-methyl-4-(2-((tertbutyloxycarbonyl)-amido)-2-phenylethylamine base)-methyl benzoate, (S)-methyl-4-(2-phenylethylamine base)-methyl benzoate.
The structural formula of the target compound of synthetic route 1 is as follows:
Figure 446477DEST_PATH_IMAGE005
Figure 475613DEST_PATH_IMAGE006
Figure 778418DEST_PATH_IMAGE007
Figure 260215DEST_PATH_IMAGE008
Figure 142721DEST_PATH_IMAGE009
Synthetic route 2: take L-phenylglycine and para-amino benzoic acid as raw material, the L-phenylglycine is through the protection amido, and the polypeptide condensation connects the R group, and amido takes off the Boc protection and obtains intermediate j1-j19.Para-amino benzoic acid is through the protection amido, and the polypeptide condensation connects 6-amidcaproic acid methyl ester hydrochloride, and amido takes off the Boc protection, and the triphosgene cationoid reaction obtains intermediate p.Intermediate j1-j19 and intermediate p nucleophilic reaction obtain intermediate q1-q19, and q1-q19 and azanol potassium nucleophilic reaction are made hydroximic acid at last.Reaction formula is as follows:
Synthetic route 2:
Figure 26363DEST_PATH_IMAGE010
Wherein, R is aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl, cycloalkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy.
Reagent in said synthesis route 2 reaction formula: (7) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (8) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (9) the saturated ethyl acetate solution of hydrogenchloride; (10) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (11) Acetyl Chloride 98Min., methyl alcohol; (12) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (13) the saturated ethyl acetate solution of hydrogenchloride; (14) triphosgene, dioxane, j1-j19, triethylamine, methylene dichloride; (15) azanol potassium, anhydrous methanol.
Prepare the intermediate of described phenylglycine class inhibitors of histone deacetylase, this intermediate is:
Route 2:4-(tertbutyloxycarbonyl-amido)-phenylformic acid, methyl-6-amido-methyl caproate hydrochloride, methyl-6-(4-(tertbutyloxycarbonyl-amido)-benzoylamino)-methyl caproate, methyl-6-(4-amido-benzoylamino)-methyl caproate hydrochloride.
The structural formula of the target compound of synthetic route 2 is as follows:
Figure 500070DEST_PATH_IMAGE011
Figure 469163DEST_PATH_IMAGE012
Figure 931192DEST_PATH_IMAGE013
Figure 934920DEST_PATH_IMAGE014
Those skilled in the art can change to improve yield to above-mentioned steps; they can determine synthetic route according to the ABC of this area; as the selective reaction thing, solvent and temperature, thus can improve yield with the generation of avoiding side reaction by using various GPF (General Protection False bases.These conventional guard methods can be referring to for example T. Greene, Protecting Groups in Organic Synthesis..
Obviously, above-mentioned route is that stereoselectivity is synthetic, also can prepare its optically active class peptide compounds by above-mentioned route.For example raw material L-phenylglycine is replaced with its optical isomer (D configuration).Those skilled in the art can obtain various other isomer easily, and can be by conventional separation means purifying, as chirality salt or chirality chromatography column etc.
High homology due to each hypotype catalytic center of zine ion dependency histon deacetylase (HDAC) (HDACs); the Hela cell extract that we select to contain histon deacetylase (HDAC) (comprises HDAC1; HDAC2, HDAC3 and HDAC8) carry out the enzymic activity test.HDACs active fluoro analytical procedure (two-step approach) can fast, conveniently detect HDACs active, simple to operate, highly sensitive.The first step contains the Methionin HDACs fluorogenic substrate (Boc-Lys(acetyl)-AMC) of an acetylize side chain, and the Hela cell extract sample incubation with containing histon deacetylase (HDAC) makes the substrate deacetylate, activates substrate.Second step, use pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm), thereby calculate inhibiting rate according to the fluorescence intensity of inhibitor group and control group, and ask and calculate the IC50 value.The enzymic activity test philosophy is seen reaction formula II.
Thiazolyl blue detection method (mtt assay) is used in the test of the cytoactive of compound, human tissue cell's lymphoma cell strain (U937), human erythroleukemia cell's strain (K562), the cell suspension of people's acute leukemia cells strain (HL60) is inoculated in respectively 96 orifice plates, add the substratum that contains the different concns compound in every hole, after hatching, dye with MTT, after continuing to hatch, measure the absorbancy (OD value) in every holes at 570 nm places on microplate reader, calculate inhibitory rate of cell growth, thus the activity of deterministic compound.
The compound of general formula (I) external presses down enzyme test proves that this compounds is effective phenylglycine derivatives histone deacetylases inhibitor.
Phenylglycine derivatives of the present invention spatially is complementary with the avtive spot of histon deacetylase (HDAC), has therefore shown that external higher inhibition is active.
Figure 48370DEST_PATH_IMAGE015
Reaction formula II
In reaction formula II, Histone deacetylase is histon deacetylase (HDAC), and Trypsin is trypsinase, and 4-amino-7-methylcoumarin is 4-amino-7-methylcoumarin.
The pharmaceutical composition that contains the compounds of this invention
Part derivative of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt inorganic or that organic acid forms.
Compound of the present invention can form hydrate or solvate.The one skilled in the art is known to compound formed hydrate or form the method for solvate when concentrated with suitable organic solvent in solution during freeze-drying together with water.
The present invention comprises the medicine that contains the therapeutic dose the compounds of this invention, and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, and glucose, water, glycerine, ethanol and their binding substances are hereinafter discussed in more detail.If necessary, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate etc.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can be solid or liquid.
Typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid etc.Solid carrier can comprise that one or more may be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents mixes with suitable ratio with the carrier with necessary compression property in tablet, with shape and the size compression of needs.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
Typical liquid vehicle comprises syrup, peanut oil, sweet oil, water etc.Liquid vehicle is for the preparation of solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, mixture both or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-conditioning agent.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, and oils (for example fractionated coconut oil and peanut oil) ethylene glycol for example) and their derivative.The carrier that is used for administered parenterally can also be grease such as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.During injection, but single pushes or injects gradually, enters the interior perfusion of passages through which vital energy circulates of 30 minutes.This compound can also be with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate etc.When preparation is used for when oral, (phosphatide (phospholipid) is concentrated with 1,2-PD, A. Nattermann ﹠amp to generally acknowledge PHOSALPG-50; Cie. 0.01% tween 80 GmbH) is used for the preparation of the acceptable oral preparations of other compounds, can be adapted to the preparation of the various compounds of the present invention.
Can use medicament forms miscellaneous when giving the compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension in the liquid suspension of ampoule or bottle or non-water.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, acid derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester etc.
Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in liposome, particulate, microcapsule, etc.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (usually preferred) oral route.Compound can be by administration easily any or that other is suitable, for example by injecting or bolus injection, by epithelium or the mucous membrane circuit (for example, oral mucosa, rectum and intestinal mucosa, etc.) absorb or the support by carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
Compound in the present invention H8, q4, q6, q15, q18Inhibition activity to histone deacetylase 8 hypotype (HDAC8) is better than positive control drug, has good DEVELOPMENT PROSPECT, and can be used as the lead compound of finding new and effective NSC 630176.In addition, compound H8, q4, q6Demonstrate the activity that is better than positive control Vorinostat (SAHA) in the test of extracorporeal anti-tumor cell proliferation, have good DEVELOPMENT PROSPECT.
Description of drawings
Fig. 1 be compound (S)-N-hydroxyl-4-(2-(3-(2-methoxyl group-phenyl)-urea groups)-2-phenylacetyl amido)-benzamide ( H18,Ball-and-stick model) and (S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((3-(trifluoromethyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( Q8,Bar-shaped model) with the active region of histon deacetylase (HDAC) 2 hypotypes dock result by Sybyl7.3 with the 3-D display schematic diagram.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited to this.
Synthesizing of embodiment 1. the compounds of this invention
With ( h2) and ( q1) be example:
1) (S)-2-((tertbutyloxycarbonyl)-amido)-2-toluylic acid b
L-phenylglycine (15.1 g, 100 mmol) is dissolved in the mixing solutions (methyl alcohol: water=9:1), add triethylamine (15.1 g of 300 mL methanol-waters, 150 mmol), after ice bath 30 minutes, add dimethyl dicarbonate butyl ester (32.7 g, 150 mmol).After room temperature reaction 8 hours, steam except the solvent in reaction solution, and be acidified to pH4-5 with the citric acid solution of 1 mol/L, then use ethyl acetate extraction three times, after merging, organic phase uses the saturated common salt water washing, anhydrous magnesium sulfate drying, solvent evaporated gets crude product, and (ethyl acetate: normal hexane=1:8) recrystallization gets the 17.2g white solid to crude product through the mixed solvent of ethyl acetate normal hexane.Productive rate: 91.56%, ESI-MS m/z: 252.3[M+H +].
Methyl-4-amino-methyl benzoate hydrochloride d
Compound c(13.7 g, 100 mmol) are dissolved in 100 mL methyl alcohol, drip the 23.6g Acetyl Chloride 98Min. under condition of ice bath.Finish, after 7540 oC refluxed 4 hours, steam except methyl alcohol and remaining Acetyl Chloride 98Min., get white crystals with the ether recrystallization dProductive rate: 86%, ESI-MS m/z: 152.2[M+H +].
Methyl-4-(2-((tertbutyloxycarbonyl)-amido)-2-phenylethylamine base)-methyl benzoate e
Compound b(12.6 g, 50 mmol) are dissolved in 200 mL tetrahydrofuran (THF)s, add triethylamine (5.5 g, 55 mmol), add O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid (TBTU) (18 g, 55 mmol).After room temperature reaction 20 minutes, add compound d (9.4 g, 50 mmol), then add triethylamine (5.0 g, 50 mmol).After room temperature reaction 6 hours, steam except the tetrahydrofuran (THF) in reaction solution, use the acetic acid ethyl dissolution product, use respectively the citric acid solution of 1 mol/L, saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous magnesium sulfate drying, solvent evaporated gets crude product, and crude product gets the 15.36 shallow white solids of g through re-crystallizing in ethyl acetate eProductive rate: 80%, ESI-MS m/z: 385.4[M+H +].
Methyl-4-(2-phenylethylamine base)-methyl benzoate f
Compound eAfter (3.8 g, 10 mmol) are dissolved in 5 mL anhydrous ethyl acetates, add wherein the 10 saturated ethyl acetate solutions of mL hydrogenchloride.Adularescent Precipitation gradually in reaction process will precipitate filtering after 3 hours, fully wash with ether, after drying 1.98 g white powders fProductive rate: 62%, ESI-MS m/z: 285.2[M+H +].
Methyl-4-(2-(4-chloro-benzamide)-2-phenylethylamine base)-methyl benzoate g2
Compound f(1.0 g, 3.1 mmol) are dissolved in 50 mL tetrahydrofuran (THF)s, add triethylamine (0.67 g, 6.2 mmol), add 2-chloro-benzoyl chloride (0.6 g, 3.4 mmol).After room temperature reaction 6 hours, steam except the tetrahydrofuran (THF) in reaction solution, use the acetic acid ethyl dissolution product, use respectively the citric acid solution of 1 mol/L, saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous magnesium sulfate drying, solvent evaporated gets crude product, and crude product gets 0.92 g white solid through re-crystallizing in ethyl acetate g2Productive rate: 72%, ESI-MS m/z: 423.3[M+H +].
Chloro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide h2
Azanol potassium (NH 2OK) preparation of solution: the saturated absolute methanol solution of 14 mL potassium hydroxide is added drop-wise in the absolute methanol solution that 24 mL contain 4.67 g (67 mmol) oxammonium hydrochloride, in controlling, temperature is lower than 40 oC, dropwise, cooling reaction solution, filtering white Repone K precipitation, gained filtrate is airtight to be saved backup.
Compound g2After (0.88 g, 2.0 mmol) are dissolved in 10 mL anhydrous methanols, add wherein the 3.5 above-mentioned azanol potassium of mL (NH 2OK) solution.0.5 after hour, steam except methyl alcohol, the hydrochloric acid soln of 2 mol/L is acidified to pH3-4, then use ethyl acetate extraction, use the saturated common salt water washing after the combined ethyl acetate layer, through anhydrous magnesium sulfate drying, solvent evaporated gets crude product, and crude product gets 0.45 g white powder through re-crystallizing in ethyl acetate h2Productive rate: 51%, 1H NMR (600 MHz, (CD 3) 2SO) δ 11.10 (s, 1H), 10.58 (s, 1H), 9.15 (d, J=7.8 Hz), 8.93 (s, 1H), 7.98-7.97 (m, 2H), 7.72 (d, J=8.4 Hz), 7.67 (d, J=9.0 Hz), 7.58 (d J=7.2 Hz, 2H), 7.56-7.54 (m, 2H), 7.42-7.35 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 5.84 (d, J=7.8 Hz, 1H).
7) (S)-tertiary butyl-(2-benzyl amino-2-oxygen-1-styroyl)-amino-manthanoate i1
Compound i1Synthetic method with eConsistent.Difference is: take benzylamine as raw material, and products obtained therefrom (S)-tertiary butyl-(2-benzyl amino-2-oxygen-1-styroyl)-amino-manthanoate i1, productive rate: 65%, ESI-MS m/z: 369.4[M+H +].
Amido-N-benzyl-2-phenylacetamide j1
Compound j1Synthetic method with fConsistent.Products obtained therefrom (S)-2-amido-N-benzyl-2-phenylacetamide j1, productive rate: 75%, ESI-MS m/z: 269.3[M+H +].
Tertbutyloxycarbonyl-amido)-phenylformic acid k
Compound kSynthetic method with bConsistent.Difference is: take para-amino benzoic acid as raw material, and products obtained therefrom 4-(tertbutyloxycarbonyl-amido)-phenylformic acid para-amino benzoic acid k, productive rate: 68%, ESI-MS m/z: 238.3[M+H +].
Methyl-6-amido-methyl caproate hydrochloride m
Compound mSynthetic method with dConsistent.Difference is: take 6-amido-caproic acid as raw material, and products obtained therefrom methyl-6-amido-methyl caproate hydrochloride m, productive rate: 68%, ESI-MS m/z: 145.3[M+H +].
Methyl-6-(4-(tertbutyloxycarbonyl-amido)-benzoylamino)-methyl caproate n
Compound k(4.74 g, 20 mmol) are dissolved in 100 mL tetrahydrofuran (THF)s, add triethylamine (2.2 g, 22 mmol), add O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid (TBTU) (7.2 g, 22 mmol).After room temperature reaction 20 minutes, add compound m (3.63 g, 20 mmol), then add triethylamine (2.0 g, 20 mmol).After room temperature reaction 6 hours, steam except the tetrahydrofuran (THF) in reaction solution, use the acetic acid ethyl dissolution product, use respectively the citric acid solution of 1 mol/L, saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous magnesium sulfate drying, solvent evaporated gets crude product, and crude product gets the 4.37 shallow white solids of g through re-crystallizing in ethyl acetate nProductive rate: 60%, ESI-MS m/z: 365.4[M+H +].
Methyl-6-(4-amido-benzoylamino)-methyl caproate hydrochloride o
Compound oSynthetic method with fConsistent.Products obtained therefrom methyl-6-(4-amido-benzoylamino)-methyl caproate hydrochloride o, productive rate: 56%, ESI-MS m/z: 265.3[M+H +].
Methyl-6-(4-(3-(2-benzyl amino-2-oxygen-1-styroyl)-urea groups)-benzoylamino)-methyl caproate p1
Triphosgene (0.75 g, 2.5 mmol) is dissolved in 50 mL dioxane, and ice bath drips 10mL o(1.5 g, 5 mmol )Dioxane solution, finish, after 110 oC refluxed 6 hours, evaporate to dryness dioxane, products therefrom were directly used in next step reaction.
The previous step product is dissolved in the 50mL methylene dichloride, adds triethylamine (0.75 g, 7.5 mmol), adds j1(1.8 g, 7.5 mmol), room temperature reaction steamed except methylene dichloride after 4 hours.Use the acetic acid ethyl dissolution product, use respectively the citric acid solution of 1 mol/L, saturated sodium bicarbonate solution, saturated aqueous common salt respectively wash 3 times, anhydrous magnesium sulfate drying, and solvent evaporated gets crude product, and crude product gets the 1.46 shallow white solids of g through re-crystallizing in ethyl acetate p1Productive rate: 55%, ESI-MS m/z: 559.6[M+H +].
Benzamido group)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide q1
Compound q1Synthetic method with h1Consistent.Difference is: with p1Be raw material, (S)-4-(3-(2-(benzamido group)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide q1, productive rate: 43%, 1H NMR (600 MHz, (CD 3) 2SO) δ 10.35 (s, 1H), 9.21 (s, 1H), 8.95 (d, J=5.4 Hz, 1H), 8.65 (d, J=1.2 Hz, 1H), 8.25 (t, J=5.4 Hz, 1H), 7.73 (d, J=9 Hz, 2H), 7.46 (d, J=7.2 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.38-7.36 (m, 2H), 7.31 (d, J=7.2 Hz, 1H), 7.28 (s, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.24-7.21 (m, 2H), 7.15 (d, J=7.8 Hz, 2H), 5.41 (d, J=7.8 Hz, 1H), 4.29 (d, J=6 Hz, 2H), 3.20 (d, J=6 Hz, 2H), 1.65 (t, J=7.2 Hz, 2H), 1.52 (t, J=7.8 Hz, 2H), 1.49-1.47 (m, 2H), 1.31-1.24 (m, 2H).
Embodiment 2 target compound inhibition of histone deacetylase activity tests (In vitro)
Histon deacetylase (HDAC) (HDACs) active fluoro analytical procedure is mainly in two steps: the first step; the Methionin HDACs fluorogenic substrate (Boc-Lys(acetyl)-AMC) that contains an acetylize side chain; (comprise HDAC1 with the Hela cell extract sample that contains histon deacetylase (HDAC); HDAC2; HDAC3 and HDAC8) hatch; make the substrate deacetylate, activate substrate.Second step, use pancreatin hydrolysis Boc-Lys-AMC, produce this fluorophor of AMC (being chromophoric group), measure fluorescence intensity in emission wavelength/excitation wavelength (390nm/460nm), thereby calculate inhibiting rate according to the fluorescence intensity of inhibitor group and control group, and ask and calculate IC 50Value.The enzymic activity test philosophy is seen patent specification part associated viscera.Experimental result sees Table 1.
  
The external enzyme test result that presses down of table 1. compound (I)
Figure 201310085903X100002DEST_PATH_IMAGE001
The SAHA commodity are called Zolinza, and general Vorinostat by name is the NSC 630176 of U.S. food Drug Administration (FDA) in approval listing in 2006.
Above-mentioned test result shows, the tyrosine derivative compounds all shows the stronger inhibition of histon deacetylase (HDAC) active, wherein compound H8, q4, q6, q15, q18Inhibition activity to histon deacetylase (HDAC) is better than positive control drug Vorinostat (SAHA), has good DEVELOPMENT PROSPECT, and can be used as the lead compound of finding new and effective NSC 630176.
Embodiment 3 target compounds suppress the activity test (In vitro) of cell proliferation
Choose enzymic activity compound preferably H8, q4, q6Carry out the activity test of vitro inhibition cancer cell multiplication, the results are shown in Table 2.
The term explanation:
U937: human tissue cell's lymphoma cell strain.
K562: human erythroleukemia cell's strain.
HL60: people's acute leukemia cells strain.
SAHA: commodity are called Zolinza, and general Vorinostat by name is the NSC 630176 of U.S. food Drug Administration (FDA) in approval listing in 2006.
DMSO: dimethyl sulfoxide (DMSO).
IC 50: half-inhibition concentration.
1.[material] U937, K562, HL60 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates
2.[method]
Cell culturesU937, K562, three kinds of tumor cell lines of HL60 all adopt cellar culture.All use the logarithmic phase cell during experiment.
Growth of Cells detects (mtt assay)HCT116, SKOV3, the HL60 cell suspension all is adjusted to 1 * 10 5/ ml is inoculated in respectively 96 orifice plates (50 μ l/ hole), 5000 cells/well.After bed board 4h, add 50ul to contain the substratum of different concns compound in every hole, 1000,200,40,8,1.6,0.32ug/ml make that in the hole, the compound final concentration is respectively:, each concentration is established three multiple holes, do blank when not adding the hole reading of cell, add the hole that cell do not add compound and make the compound blank well, SAHA makes the compound positive control.In 37 ℃, hatch 48 h in 5% carbonic acid gas, every hole adds the MTT staining fluid of 10 μ l 0.5%, after continuing to hatch 4 h, 2500 rpm, then centrifugal 30min abandons substratum in plate hole, adds dimethyl sulfoxide (DMSO), the 200ul/ hole.On microplate reader, in the absorbancy OD value in the 570 every holes of mensuration, nm place, inhibitory rate of cell growth is calculated as follows:
Figure 260225DEST_PATH_IMAGE017
aIn table, numerical value is the mean value of three tests, the numeric representation standard deviation after " ± ".
Upper table test data shows, compound h8, q4With q6Demonstrate the activity that is better than positive control SAHA in the test of extracorporeal anti-tumor cell proliferation, have good DEVELOPMENT PROSPECT.

Claims (10)

1. phenylglycine class inhibitors of histone deacetylase, have the structure of general formula I,
With and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug,
Figure 156312DEST_PATH_IMAGE001
In general structure I:
R 1C1-12 aliphatic chain alkoxyl group, fragrant oxygen base, alkoxy aryl, heteroaryloxy, heteroaryl alkoxyl group, C1-12 aliphatic chain alkylamino radical, aromatic amino, aryl alkylamino radical, assorted aryl amine or heteroaryl alkylamino radical;
R 2Acyl group, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl, heteroaryl C1-9 alkane alkylsulfonyl or the general structure II of hydrogen, each seed amino acid preparation;
The structure of general formula I I:
Figure 210855DEST_PATH_IMAGE002
R wherein 3Hydroxamic acid base, carboxyl, methoxycarbonyl, amide group or hydrazide group,
* be that steric configuration is S or R optical purity or its raceme.
2. phenylglycine class inhibitors of histone deacetylase as claimed in claim 1, is characterized in that: described R 1In aromatic group preferably replaced by one or more following groups: hydroxamic acid base, carboxyl, methoxycarbonyl, amide group, hydrazide group, hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy.
3. phenylglycine class inhibitors of histone deacetylase as claimed in claim 1, is characterized in that: described R 2In aromatic group optional replaced by one or more following groups: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy, aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl or cycloalkyl.
4. phenylglycine class inhibitors of histone deacetylase as claimed in claim 3, is characterized in that: described R 2Preferably replaced by one or more following groups: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy.
5. Phenylglycine class inhibitors of histone deacetylase as claimed in claim 1 is characterized in that: be one of following compound:
(S)-tertiary butyl-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-amido formate ( h1);
(S)-4-chloro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h2);
(S)-2-chloro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h3);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-2-naphthoamide ( h4);
(S)-4-fluoro-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h5);
(S)-N-hydroxyl-4-(2-(naphthyl-2-sulfoamido)-2-phenylacetyl amido)-benzamide ( h6);
(S)-4-(2-(4-(tertiary butyl)-benzene sulfonamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h7);
(S)-4-(2-benzamide base-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h8);
(S)-N-hydroxyl-4-(2-phenyl-2-(4-(trifluoromethyl)-benzene sulfonamido)-acetamido)-benzamide ( h9);
(S)-4-(2-(2,6-difluorobenzene sulfoamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h10);
(S)-4-(2-((4-chlorobenzene sulfonamide base)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h11);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-2-methoxyl group-benzamide ( h12);
(S)-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-4-methoxyl group-benzamide ( h13);
(S)-N-hydroxyl-4-(2-(4-methyl-benzoylamino)-2-phenylacetyl amido)-benzamide ( h14);
(S)-3-bromo-N-(2-((4-(azanol base)-phenyl)-amido)-2-oxygen-1-styroyl)-benzamide ( h15);
(S)-N-hydroxyl-4-(2-phenyl-2-(propyl group valeryl amido)-acetamido)-benzamide ( h16);
(S)-N-hydroxyl-4-(2-phenyl-2-(2-phenylacetyl amido)-acetamido)-benzamide ( h17);
(S)-N-hydroxyl-4-(2-(3-(2-methoxyl group-phenyl)-urea groups)-2-phenylacetyl amido)-benzamide ( h18);
(S)-4-(2-(3-(2,6-di-isopropyl-phenyl)-urea groups)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h19);
(S)-4-(2-(5-(dimethylin)-naphthyl-1-sulfoamido)-2-phenylacetyl amido)-N-hydroxyl-benzamide ( h20);
(S)-4-(3-(2-(benzamido group)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q1);
(S)-4-(3-(2-((2-fluoro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q2);
(S)-4-(3-(2-((4-fluoro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q3);
(S)-4-(3-(2-((the 4-tertiary butyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q4);
(S)-4-(3-(2-(furfuryl-2-base is amino)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q5);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((2-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q6);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-(naphthyl-1-base is amino)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q7);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((3-(trifluoromethyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q8);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((4-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q9);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-((2-methoxyl group-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q10);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-((2-hydroxyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-benzamide ( q11);
(S)-4-(3-(2-((3-chloro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q12);
(S)-4-(3-(2-((3,5-dimethyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q13);
(S)-4-(3-(2-((3-fluoro-4-methoxyl group-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q14);
(S)-4-(3-(2-((4-fluoro-benzyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q15);
(S)-4-(3-(2-((3-bromo-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q16);
(S)-4-(3-(2-((2,6-di-isopropyl-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q17);
(S)-N-(6-(azanol base)-6-oxygen-hexyl)-4-(3-(2-oxygen-1-phenyl-2-((3-(methyl)-phenyl)-amido)-ethyl)-urea groups)-benzamide ( q18);
(S)-4-(3-(2-((2,4-, two chloro-phenyl)-amido)-2-oxygen-1-styroyl)-urea groups)-N-(6-(azanol base)-6-oxygen-hexyl)-benzamide ( q19).
6. the preparation method of claim 1,2,3,4 or 5 described phenylglycine class inhibitors of histone deacetylase, is characterized in that: comprise the steps:
Synthetic route 1: take optically pure L-phenylglycine as raw material, through the amido protection, the polypeptide condensation connects the methyl p-aminobenzoate hydrochloride in succession; the amido deprotection, the polypeptide condensation connects the R group, with azanol potassium nucleophilic reaction; make at last hydroximic acid and obtain end product, reaction formula is as follows:
Synthetic route 1:
Figure 640700DEST_PATH_IMAGE003
Wherein, the acyl group of R, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, cycloalkanes acyl group, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
Reagent in said synthesis route 1 reaction formula: (1) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (2) Acetyl Chloride 98Min., methyl alcohol; (3) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (4) the saturated ethyl acetate solution of hydrogenchloride; (5) various acyl chlorides, triethylamine, tetrahydrofuran (THF); (6) azanol potassium, anhydrous methanol;
Prepare the intermediate of described phenylglycine class inhibitors of histone deacetylase, this intermediate is:
Route 1:((S)-2-((tertbutyloxycarbonyl)-amido)-2-toluylic acid, methyl-4-amino-methyl benzoate hydrochloride, (S)-methyl-4-(2-((tertbutyloxycarbonyl)-amido)-2-phenylethylamine base)-methyl benzoate, (S)-methyl-4-(2-phenylethylamine base)-methyl benzoate.
7. the preparation method of the described phenylglycine class of claim 1 or 2 inhibitors of histone deacetylase, is characterized in that: comprise the steps:
Synthetic route 2: take L-phenylglycine and para-amino benzoic acid as raw material, the L-phenylglycine is through the protection amido, and the polypeptide condensation connects the R group, and amido takes off the Boc protection and obtains intermediate j1-j19; Para-amino benzoic acid is through the protection amido, and the polypeptide condensation connects 6-amidcaproic acid methyl ester hydrochloride, and amido takes off the Boc protection, and the triphosgene cationoid reaction obtains intermediate p; Intermediate j1-j19 and intermediate p nucleophilic reaction obtain intermediate q1-q19, and q1-q19 and azanol potassium nucleophilic reaction are made hydroximic acid at last; Reaction formula is as follows:
Synthetic route 2:
Figure 413484DEST_PATH_IMAGE004
Wherein, R is aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, C1-6 alkyl, assorted alkyl or cycloalkyl;
Optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
Reagent in said synthesis route 2 reaction formula: (7) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (8) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (9) the saturated ethyl acetate solution of hydrogenchloride; (10) dimethyl dicarbonate butyl ester, 1mol/L sodium hydroxide solution, tetrahydrofuran (THF); (11) Acetyl Chloride 98Min., methyl alcohol; (12) O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid, triethylamine, tetrahydrofuran (THF); (13) the saturated ethyl acetate solution of hydrogenchloride; (14) triphosgene, dioxane, j1-j19, triethylamine, methylene dichloride; (15) azanol potassium, anhydrous methanol;
Prepare the intermediate of described phenylglycine class inhibitors of histone deacetylase, this intermediate is:
Route 2:4-(tertbutyloxycarbonyl-amido)-phenylformic acid, methyl-6-amido-methyl caproate hydrochloride, methyl-6-(4-(tertbutyloxycarbonyl-amido)-benzoylamino)-methyl caproate, methyl-6-(4-amido-benzoylamino)-methyl caproate hydrochloride.
8. claim 1,2,3, the application of 4 or 5 described phenylglycine class inhibitors of histone deacetylase in the medicine for preparing prevention or the treatment mammalian diseases relevant to the active unconventionality expression of histon deacetylase (HDAC); described related mammalian disease with the active unconventionality expression of histon deacetylase (HDAC) comprises: cancer; neurodegenerative disease; virus infection; inflammation; leukemia, malaria and diabetes.
9. one kind is suitable for the oral mammiferous pharmaceutical composition that gives, and comprises claim 1,2,3,4 or 5 described phenylglycine class inhibitors of histone deacetylase and one or more pharmaceutically acceptable carriers or vehicle.
10. one kind is suitable for parenteral and gives mammiferous pharmaceutical composition, comprises claim 1,2,3,4 or 5 described phenylglycine class inhibitors of histone deacetylase and one or more pharmaceutically acceptable carriers or vehicle.
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JP2019522674A (en) * 2016-07-18 2019-08-15 イタルファルマコ ソシエタ ペル アチオニＩｔａｌｆａｒｍａｃｏ Ｓｏｃｉｅｔａ Ｐｅｒ Ａｚｉｏｎｉ Benzo-N-hydroxyamide compounds having antitumor activity
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CN105481736A (en) * 2015-12-28 2016-04-13 山东大学 Phenylglycine-containing cinnamamide histone deacetylase inhibitor, and preparation method and application thereof
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CN112218857A (en) * 2018-02-16 2021-01-12 星座制药公司 P300/CBP HAT inhibitors and methods of use thereof
CN112218857B (en) * 2018-02-16 2023-11-21 星座制药公司 P300/CBP HAT inhibitors and methods of use thereof
CN115141123A (en) * 2022-05-20 2022-10-04 沈阳药科大学 Compound, preparation method thereof and application thereof in preparation of histone deacetylase and epoxide hydrolase dual inhibitor

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