CN100455564C - Histone de-acetylase inhibitor, preparation and application of pharmaceutical preparations of the same - Google Patents

Histone de-acetylase inhibitor, preparation and application of pharmaceutical preparations of the same Download PDF

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CN100455564C
CN100455564C CNB031468411A CN03146841A CN100455564C CN 100455564 C CN100455564 C CN 100455564C CN B031468411 A CNB031468411 A CN B031468411A CN 03146841 A CN03146841 A CN 03146841A CN 100455564 C CN100455564 C CN 100455564C
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preparation
histone
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CN1524850A (en
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鲁先治
宁志强
胡伟明
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Shenzhen Chipscreen Biosciences Co Ltd
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SHENZHEN WEIXIN BIOLOGICAL SCIENCE AND TECHNOLOGY Co Ltd
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Abstract

The present invention discloses a histone deacetylase inhibitor for treating tumors, endocrine disturbance, immune system diseases, hereditary diseases and nerve involutional diseases, a preparing method of medicinal preparations thereof and applications thereof. The structure of the histone deacetylase inhibitor is shown as general formula (I), wherein the definitions of Ar1, Ar2, Q1, Q2, Q3, J, and Z are disclosed in the specification.

Description

The preparation of NSC 630176 and medicinal preparations thereof and application
Technical field
The present invention relates to have the synthetic and clinical application aspect treatment tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders of the brand-new micromolecular compound of therapeutic action
Background technology
Abnormal gene expression plays an important role in the pathogeny of numerous disease, and these diseases comprise tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders.People's genome exists with DNA, histone and the nonhistones chromatin Structure that is packaged into, and chromatin Structure is determining a specific gene plays an important role when whether expressing.Generally speaking, spissated chromatin suppresses to transcribe, and the gene of transcriptionally active often is arranged in open chromatin.
Forming chromatinic basic repeating unit nucleosome is made of round the histone core that contains 4 kinds of histones the dna double chain.This histone core comprises a H3-H4 tetramer and two H2A-H2B dimers.Histone h1 is attached to the connection portion between nucleosome, and by it be rich in the C-terminal of positive electricity nuclear and the negative charge on the DNA chain to keep the stability of chromatin Structure.The structure of this high-sequential of nucleosome has determined that chromatin is formed and relation (the Ricky W.Johnstone of gene activation, " Histone deacetylase inhibitors:noveldrugs for the treatment of cancer ", Nature Reviews Drug Discovery 2002,1:287).The histone N-terminal can be translated the back and modify, and therefore can change STRUCTURE OF CHROMATIN and function.Wherein a kind of modification is reversible acetylize of histone afterbody lysine residue and deacetylation.The acetylation of histone level be by the acetylation of histone enzyme (Histoneacetylases, HATs) and histon deacetylase (HDAC) (Histone deacetylases, HDACs) common control.The histone N-terminal is modified except being acetylation, can also be by phosphorylation, methylate and the ADP-ribosylation.These modify influence histone electrically and function, and then change STRUCTURE OF CHROMATIN and genetic expression (Current Opinion in Oncology2001,13:477-483).
Research has in recent years disclosed being closely connected between acetylation of histone and chromatin reconstitution and gene regulating.A lot of transcriptional activator complex bodys all have intrinsic acetylation of histone enzymic activity, on the contrary, transcribe and suppress complex body and then have and recruit histon deacetylase (HDAC) (Bioassays 1998,20:615) to the activity of target gene promotor.Some specific transcriptional incitants, as nuclear receptor superfamily, cAMP effector conjugated protein (CREB), signal conduction transcriptional factors 1 (STAT-1) wait can be with various auxilliary activation sub and co-repressor selectively acting in different tissues and gene, constituted the regulated and control network of gene Selection expression.These regulated and control networks are being controlled the balance of our physical function, disturb these networks will cause disease or influence the process of disease.Therefore, regulate these transcription complex interaction between protein and provide new method (E.Korzus for treatment tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders, Transcription Factor-specific Requirements forCoactivator and Their Acetyltransferase Functions.Science 1998,279:703-707; N.J.McKenna and B.W.O ' Malley, Combinatorial Control ofGene Expression by Nuclear Receptors and Coregulators.Cell 2002,108 (4): 465-474; M.J.Pazin and J.T.Kadonaga, What ' s Up and Downwith Histone Deacetylation and Transcription? Cell 1997,89 (3): 325-328; H.Zhong, R.E.Voll and S.Ghosh, Phosphorylation of NF-B p65 byPKA Stimulates Transcriptional Activity by Promoting a Novel BivalentInteraction with the Coactivator CBP/p300.Molecular Cell 1998,1 (5): 661-671; J.S.Steffan, Histone deacetylase inhibitors arrestpolyglutamine-dependent neurodegeneration in Drosophila, Nature 2001,413:691-694; US20020115716A1, WO0056153A1).
For instance, cells whose development and differentiation are subjected to the regulation and control that gene program is expressed, and this is the regulation and control on the chromatin Structure level.Heritable variation or sudden change cause constitutive activation oncogene such as RAS, perhaps make the suppressor gene inactivation such as the p53 of tumour, all will influence to comprise a series of minutes subprocess of transcribing.In addition; some cause the heritable variation of acetylation of histone enzyme and the unusual effect of deacetylase; as their target gene is misplaced; or make acetylation of histone enzyme functionally inactive; or overexpression histon deacetylase (HDAC) etc. all can be broken the process of cell normal development and differentiation; cause the generation and the development (Current Opinion Genet.Development 1999,9:40-48 and 175-184) of tumour.Some human tumors produce relevant with the imbalance of deacetylation enzymic activity with the acetylation of histone enzyme; one of them example is in people's acute myelocytic leukemia patient; common to 15 and No. 17 chromosomal dystopys, the ectopic result can produce the fusion rotein of a kind of RAR of comprising α, PML and three kinds of protein moleculars of PLZF.This unusual fusion rotein can combine with the cis-acting elements of RAR; and by recruiting the histon deacetylase (HDAC) that high-affinity is arranged with powerful combination of SMRT co-repressor; make the target gene expression of RAR be subjected to lasting inhibition; and (Oncogene 2001,20:7204-7215) to have lost reaction to retinoic acid.Retinoic acid acceptor (RAR) is a kind of dependence part activated transcription factor, and it has important effect to the differentiation of marrow.The heterodimer that RAR and RXR constitute can be incorporated on the retinoic acid response element of target gene promoter region.When being deficient in vitamin A acid, RAR/RXR can recruit SIN/HDAC by co-repressor NCOR and SMRT and suppress to transcribe; And after adding part, HDAC is released, and RAR/RXR can have the active cofactor combination of HAT and activated transcription with TIF2, CBP etc. immediately.Therefore, activate or the differentiation that suppresses to contain the gene pairs medullary cell of retinoic acid response element plays a very important role.And the inhibitor that adds HDAC can make acute myeloid leukemia cell recover retinoic acid is induced the ability of differentiation, hints that unusual dna methylase inhibitor is a key factor of leukemia pathogenic process.
Existing report shows, can suppress the expression of some cancer suppressor genes when the histon deacetylase (HDAC) overexpression, as p53.P53 is a crucial regulation and control person of cell proliferation, it signal can be passed to control the cell cycle gene, and when ambient pressure exists cell death inducing.The realization of p53 function is that mainly it can be directly combines and activated transcription with special dna sequence dna, if undergo mutation and make functionally inactive in its DNA land, then regular meeting causes cancer.Evidence suggests that CBP/p300 can raise p53 (W.Gu and R.G.Roeder by making histone and p53 acetylize; Activation of p53 Sequence-Specific DNA Bindingby Acetylation of the p53 C-Terminal Domain.Cell 1997,90 (4): 595-606.).On the contrary; the intravital HDAC-1 of Mammals, HDAC-2 and HDAC-3 can reduce p53 (L.-J.Juan by making histone and p53 deacetylation; et al.; Histone Deacetylases Specifically Down-regulate p53-dependent GeneActivation.The Journal of Biological Chemistry 2000,275 (27): 20436-20443).
Above-mentioned experiment shows that the improper transcripting suppressioning action that is mediated by HDACs can change STRUCTURE OF CHROMATIN, disturbs normal cytodifferentiation, causes the generation of tumour and other proliferative disease.Therefore, the activity of inhibition HDAC may be the effective ways of treatment tumour and other proliferative disease.
Had been found that the inhibitor of several histone deacetylases, comprised (1) short chain fatty acid, as butyric acid and benzenebutanoic acid; (2) organic hydroxamic acid is as suberoylanilidehydroxamic acid (SAHA) and trichostatin A (TSA); (3) contain 2-amino-8-oxygen-9, the cyclic tetrapeptide of 10-epoxy decanoyl is as trapoxin and HC-toxon; (4) do not contain 2-amino-8-oxygen-9, the cyclic tetrapeptide of 10-epoxy decanoyl is as Apicidin and FK228; (5) benzamide compound, as MS-275 (EP0847992A1, US2002/0103192A1, WO02/26696A1, WO01/70675A2, WO01/18171A2).
Butyric acid is as a kind of inhibitor of cell proliferation and the inductor of cytodifferentiation; its activity mainly comes from inhibition (the A.Nudelman and A.Rephaeli to histon deacetylase (HDAC); Novel Mutual Prodrug of Retinoic and Butyric Acids with EnhancedAnticancer Activity.J.Med.Chem.2000,43 (15): 2962-2966.).Benzenebutanoic acid can be used for treating separately diseases such as thalassemia, tokoplasmosis, malaria, also can with retinoic acid combination therapy acute myelocytic leukemia (R.P.Warrell.et al., Therapeutictargeting of transcription in acute promyelocytic leukemia by use of aninhibitor of histone deacetylase.J.Natl.Cancer Inst.1998,90 (21): 1621-1625.).Valproic acid is an anticonvulsant drug, also be found to be (the C.J.Phiel et al. that works by direct inhibition of histone deacetylase, Histone Deacetylase Is aDirect Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen.The Journal of Biological Chemistry 2001,276 (39): 36734-36741; EP1170008A1).
Some benzamide compounds just have the NSC 630176 activity under lower micromolar concentrations.Wherein the lead compound MS-275 of Mitsui Chemicals company development is that first is proved to be the NSC 630176 that has oral antitumour activity in animal body, and there is not severe side effect (A.Saito et al., A syntheticinhibitor of histone deacetylase, MS-27-275, with marked in vivoantitumor activity against human tumors.Proceedings of the NationalAcademy of Sciences of the United States of America 1999,96 (8): 4592-4597; EP 0847992 A1).At present, MS-275 just carries out leukemic clinical study in the Greenebaum of University of Maryland Cancer center, carry out clinical study (E.B.Levit, Clinical Trials in Leukemiafocus on New Treatment Approaches.2001 Release-University ofMaryland Medical News 2001 Maryland of solid tumor simultaneously in American National cancer research institute Http:// www.umm.edu/news/ Releases/karp.html, A Phase I Study of an Oral Histone DeacetylaseInhibitor, MS-275, in Refractory Solid Tumors and Lymphomas.2001, National Cancer Institute).Yet the compound that better performance is arranged that some are new still awaits exploitation, so that can obtain the medicine that stronger HDAC suppresses active and lower side effect.
Technology contents
One of the object of the invention is to disclose the compound with treatment tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders aspect of a class based on the histon deacetylase (HDAC) design;
Two of the object of the invention is to disclose the preparation method of the described compound of this class;
Three of the object of the invention is to disclose the clinical application of the described compound of this class as treatment tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders.
The said compound of the present invention, its chemical structure is shown in general formula (I):
Figure C0314684100121
Wherein, Ar 1Be aryl or heterocyclic aryl, can contain one or more substituting groups, its substituting group can be halogen, amino, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, aminoalkyl group, alkylamino, acyl group, amido, alkylthio, perfluoroalkyl, perfluoro alkoxy, carboxyl, phenyl or heterocyclic substituent;
Ar 2Be arylene or heterocycle arylene, can contain one or more substituting groups, its substituting group can be halogen, amino, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, aminoalkyl group, alkylamino, acyl group, amido, alkylthio, perfluoroalkyl, perfluoro alkoxy, carboxyl, phenyl or heterocyclic substituent;
Q 1, Q 2, Q 3Be respectively covalent linkage or C 1-7Alkylene, this alkylene can be linear or cyclic, can be saturated or undersaturated, can contain one or more substituting groups, its substituting group can be halogen, amino, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, aminoalkyl group, alkylamino, acyl group, amido, alkylthio, perfluoroalkyl, perfluoro alkoxy, carboxyl, phenyl or heterocyclic substituent;
J is one of following array structure:
Figure C0314684100131
Wherein, R 1Be H, alkyl, aralkyl, heterocycle aralkyl, heterocyclic substituent, aryl or heterocyclic aryl;
Z is-OH or 2-aminocyclohexyl.
One of the disorders such as cancers that treatment of the present invention and differentiation are relevant with propagation and preferred method of psoriasic compound shown in general formula (1), Ar wherein 1Be heterocyclic aryl;
Ar 2Be arylene;
Q 1, Q 2, Q 3Be respectively covalent linkage or C 1-2Alkylene;
J is one of following array structure:
Figure C0314684100132
Wherein, R 1Be H or alkyl;
Z is-OH or 2-aminocyclohexyl.
The disorders such as cancers that treatment of the present invention and differentiation are relevant with propagation and the preferred method of psoriasic compound two shown in general formula (1), Ar wherein 1Be pyridine;
Ar 2Be phenyl ring;
Q 1, Q 2, Q 3Be respectively covalent linkage or C 1-2Alkylene;
J is one of following array structure:
Figure C0314684100141
Wherein, R 1Be H;
Z is-OH or 2-aminocyclohexyl.
" halogen " of the present invention is fluorine, chlorine, bromine, iodine;
" alkyl " of the present invention comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl etc.;
" alkoxyl group " of the present invention comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy etc.;
" aminoalkyl group " of the present invention comprises amino-ethyl, 1-aminopropyl, 1-aminopropyl etc.;
" alkyl amine group " of the present invention comprises N-methylamino, N-ethylamino-, N-isopropylamine base etc.;
" acyl group " of the present invention comprises ethanoyl, propionyl, isobutyryl etc.;
" amide group " of the present invention comprises acetamido, propionamido-, amide-based small, isobutyl amide etc.;
" alkylthio " of the present invention comprises methylthio group, ethylmercapto group, rosickyite base etc.;
" perfluoroalkyl " of the present invention comprises trifluoromethyl, pentafluoroethyl group etc.;
" perfluoro alkoxy " of the present invention comprises trifluoromethoxy, five fluorine oxyethyl groups etc.;
" C of the present invention 1-7Alkylene ", comprise-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH=CH-,-CH=CH-CH=CH-etc.
" aralkyl " of the present invention comprises benzyl, styroyl, 3-phenyl propyl, 1-menaphthyl etc.;
" heterocycle aralkyl " of the present invention comprises furfuryl, 3-furylmethyl, 2-picolyl etc.;
" heterocycle " of the present invention is meant the saturated or unsaturated heterocycle that contains one or more heteroatomss (nitrogen, oxygen or sulphur), comprises Pyrrolidine, pyrrolin, pyrazoline, piperidines, morpholine, imidazoles, pyridine etc.;
" aryl " of the present invention comprises containing substituting group or not containing substituent aromatic ring that substituting group can be halogen, amino, hydroxyl, alkyl or alkoxyl group, as phenyl, naphthyl etc.;
" heterocyclic aryl " of the present invention, be meant five members containing one or more heteroatomss (O, S or N atom), six Yuans monocycles or nine members, ten Yuans Bicyclic substituting groups, as furans, thiophenol, pyrroles, imidazoles, triazole, pyridine, pyrazine, pyrimidine, quinoline, indoles, benzoglyoxaline etc.;
The synthetic method of the said compound of the present invention is as follows:
(a) general formula (II) compound and general formula (III) compound are carried out condensation reaction and obtain general formula (IV) compound:
Ar 1-Q 1-R 2
(II)
Wherein, Ar 1, Ar 2, Q 1, Q 2, Q 3, J is ditto described; R 2For-OH or-NH 2Work as R 2During for-OH, R 3For-NH 2Work as R 2-NH 2The time, R 3For-OH.
This condensation reaction is with N, and N-phosphinylidyne diimidazole (CDI) is a catalyzer, and earlier with N, N-phosphinylidyne diimidazole and general formula (II) compound reacts and makes active intermediate, and then reacts with general formula (III) compound and to make general formula (IV) compound;
(b) general formula (IV) compound and logical formula V compound are carried out condensation reaction and obtain target compound (I):
H 2N-Z
(V)
Wherein, Z is ditto described.
This condensation reaction is catalyzer with the Vinyl chloroformate, Vinyl chloroformate and general formula (IV) compound is reacted to make active intermediate earlier, and then reacts with logical formula V compound and to make general formula (I) compound.
Above-mentioned condensation reaction (a) and temperature of reaction (b) are-10～80 ℃, and the reaction times is 1～72 hour.The reaction solvent for use is a common solvent, as benzene, toluene, tetrahydrofuran (THF), dioxane, methylene dichloride, chloroform, N, dinethylformamide etc.In case of necessity, alkali such as sodium hydroxide, triethylamine, pyridine etc. be can add, or sour example hydrochloric acid, acetic acid, trifluoroacetic acid etc. added.
The described compound of general formula (I) can adopt common separation method to carry out purifying, as extraction, recrystallization, column chromatography etc.
Compound of the present invention has the curative effect for the treatment of tumour, endocrine regulation, disease of immune system, inherited disease and neurodegenerative disorders aspect.
The said compound of the present invention, can make common medicinal preparations, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, can add common carrier materials such as spices, sweeting agent, liquid or solid filler or thinner and (see " pharmaceutical excipient handbook, American Pharmaceutical Association, in October, 1986).Said preparation contains 1～70% effective constituent usually, and preferable content is 5～50%, and all the other components are carrier filler, thinner or solvent.
The said compound of the present invention can carry out administration to Mammals (comprising the people) by oral or injection system clinically, wherein especially with oral way the best.Dosage is 0.0001～200mg/kg body weight every day.Optimal dose is decided on individuality, and dosage is less when beginning usually, increases consumption then gradually.
Further illustrate content of the present invention below in conjunction with example, but protection scope of the present invention is not limited only to these examples.Per-cent of the present invention all is weight percentage except that indicating especially.
Specific implementation method embodiment 1
4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] benzoic preparation
Figure C0314684100171
In reaction flask, add 0.81 gram (5.0mmol) N, N-phosphinylidyne diimidazole and 10 milliliters of tetrahydrofuran (THF)s, be cooled to 0 ℃, drip 10 milliliters of tetrahydrofuran solutions that are dissolved with 0.63 gram (5.0mmol) 4-fluorophenyl methanol, stirring at room reaction 3 hours, the Dropwise 5 milliliter is dissolved with the benzoic 1M sodium hydroxide solution of 0.76 gram (5.0mmol) 4-aminomethyl then, and room temperature continued stirring reaction 5 hours.With the reaction mixture vacuum concentration, in residue, add 5 milliliters of saturated nacl aqueous solutions, and regulate pH value to 7 with concentrated hydrochloric acid.With solid filtering, frozen water washing, dry 1.19 gram (78.8%) target compounds that get of separating out.
Embodiment 2
N-(2-aminocyclohexyl)-4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] preparation of benzamide (HYM0513)
Figure C0314684100181
In reaction flask, add 0.21 gram (0.70mmol) 4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] phenylformic acid and 4 adding milliliter tetrahydrofuran (THF)s, be cooled to 0 ℃, add 0.21 gram (2.10mmol) triethylamine and 0.12 gram (1.10mmol) Vinyl chloroformate, continue reaction 30min in 0 ℃.Remove by filter the solid of generation, filtrate is changed in another reaction flask, add 0.32 gram (2.80mmol) cyclohexanediamine, room temperature reaction 10 hours, vacuum concentration gets crude product, chromatographic separation (developping agent: chloroform: methyl alcohol=8: 1) get 0.15 gram (53.7%) target compound, m.p.178-180 ℃.IR(KBr)cm -1：3328，2926，1691，1629，1540，1266，1140。 1HNMR(300MHz，DMSO-d 6)：δppm：1.12-1.24(m，6H)，1.66(m，2H)，1.86(m，2H)，2.61(m，1H)，3.47(m，1H)，4.24(d，2H)，5.03(s，3H)，7.18(t，2H)，7.30(d，2H)，7.41(t，2H)，7.75(d，1H)，7.80(d，2H)，8.04(m，1H)。HRMS (C 22H 26FN 3O 3) calculated value (%): 399.4629; Measured value (%): 399.4627.
Embodiment 3
N-hydroxyl-4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] preparation of benzamide (HYM0512)
Figure C0314684100191
In reaction flask, add 0.21 gram (0.70mmol) 4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] phenylformic acid and 4 adding milliliter tetrahydrofuran (THF)s, be cooled to 0 ℃, add 0.21 gram (2.10mmol) triethylamine and 0.12 gram (1.1mmol) Vinyl chloroformate, continue reaction 30min in 0 ℃, remove by filter the solid of generation, collect filtrate for later use.In another reaction flask, add 0.21 gram (3.0mmol) oxammonium hydrochloride, 0.17 gram (3.0mmol) potassium hydroxide and 5 ml methanol, stirring at normal temperature reaction 30min, drip above-mentioned filtrate, stirring at normal temperature reaction 20 hours, vacuum concentration gets crude product, chromatographic separation (developping agent: chloroform: methyl alcohol=4: 1) get 0.12 gram (53.9%) target compound.IR(KBr)cm -1：3331，2914，1632，1629，1518，1263。 1HNMR(300MHz，DMSO-d 6)：δppm：4.24(d，2H)，5.03(s，3H)，7.18(t，2H)，7.30(d，2H)，7.41(t，2H)，7.75(d，1H)，7.80(d，2H)，8.68(s，1H)，10.34(s，1H)。HRMS (C 16H 15FN 2O 4) calculated value (%): 318.3023; Measured value (%): 318.3020.
Embodiment 4
4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] benzoic preparation
Figure C0314684100192
In reaction flask, add 0.81 gram (5.0mmol) N, N-phosphinylidyne diimidazole and 10 milliliters of tetrahydrofuran (THF)s, be cooled to 0 ℃, drip 10 milliliters of tetrahydrofuran solutions that are dissolved with 0.54 gram (5.0mmol) 3-4-hydroxymethylpiperidine, stirring at room reaction 3 hours, the Dropwise 5 milliliter is dissolved with the benzoic 1M sodium hydroxide solution of 0.76 gram (5.0mmol) 4-aminomethyl then, and room temperature continued stirring reaction 5 hours.With the reaction mixture vacuum concentration, in residue, add 5 milliliters of saturated nacl aqueous solutions, and regulate pH value to 7 with concentrated hydrochloric acid.With solid filtering, frozen water washing, dry 1.20 gram (83.9%) target compounds that get of separating out.
Embodiment 5
N-(2-aminocyclohexyl)-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] preparation of benzamide (HYM0504)
Figure C0314684100201
In reaction flask, add 0.20 gram (0.70mmol) 4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] phenylformic acid and 4 adding milliliter tetrahydrofuran (THF)s, be cooled to 0 ℃, add 0.21 gram (2.10mmol) triethylamine and 0.12 gram (1.10mmol) Vinyl chloroformate, continue reaction 30min in 0 ℃.Remove by filter the solid of generation, filtrate is changed in another reaction flask, add 0.32 gram (2.80mmol) cyclohexanediamine, room temperature reaction 10 hours, vacuum concentration gets crude product, chromatographic separation (developping agent: chloroform: methyl alcohol=8: 1) get 0.12 gram (44.9%) target compound, m.p.159-160 ℃.IR(KBr)cm -1：3303，2933，1694，1595，1549，1421，1227，1137。 1H?NMR(300MHz，DMSO-d 6)：δppm：1.25(m，4H)，1.69(m，2H)，1.90(m，2H)，2.92(m，1H)，4.22(m，2H)，5.09(s，3H)，7.00(s，1H)，7.27(d，1H)，7.39(s，1H)，7.62(s，1H)，7.77(s，1H)，7.86(m，3H)，8.55(m，1H)。HRMS (C 21H 26N 4O 3) calculated value (%): 382.4602; Measured value (%): 382.4603.
Embodiment 6
N-hydroxyl-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] preparation of benzamide (HYM0505)
Figure C0314684100211
In reaction flask, add 0.20 gram (0.70mmol) 4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] phenylformic acid and 4 adding milliliter tetrahydrofuran (THF)s, be cooled to 0 ℃, add 0.21 gram (2.10mmol) triethylamine and 0.12 gram (1.1mmol) Vinyl chloroformate, continue reaction 30min in 0 ℃, remove by filter the solid of generation, collect filtrate for later use.In another reaction flask, add 0.21 gram (3.0mmol) oxammonium hydrochloride, 0.17 gram (3.0mmol) potassium hydroxide and 5 ml methanol, stirring at normal temperature reaction 30min, drip above-mentioned filtrate, stirring at normal temperature reaction 20 hours, vacuum concentration gets crude product, chromatographic separation (developping agent: chloroform: methyl alcohol=4: 1) get 0.10 gram (47.5%) target compound.IR(KBr)cm -1：3308，2911，1682，1583，1549，1229。 1H?NMR(300MHz，DMSO-d 6)：δppm：4.22(m，2H)，5.09(s，3H)，7.00(s，1H)，7.27(d，1H)，7.39(s，1H)，7.62(s，1H)，7.77(s，1H)，7.86(m，3H)，8.72(s，1H)、10.40(s，1H)。HRMS (C 15H 15N 3O 4) calculated value (%): 301.2996; Measured value (%): 301.2998.
Embodiment 7
Compound N-(2-aminocyclohexyl)-4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] benzamide (HYM0513), N-hydroxyl-4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] benzamide (HYM0512), N-(2-aminocyclohexyl)-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] benzamide (HYM0504) and N-hydroxyl-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] benzamide (HYM0505) is to the inhibition of histon deacetylase (HDAC) external activity
HDAC colorimetric analysis test kit is adopted in experiment, and (BIOMOL Research Laboratories, PA USA) finishes.All operations all carries out according to laboratory manual.At first tested compound is added in 96 orifice plates by different concns; mix and add the substrate of histon deacetylase (HDAC) then with the nuclear extract of HeLa cell; place for 37 ℃ and use color development stopping liquid termination reaction after 10 minutes, on microplate reader, read the result subsequently with the 405nm wavelength.The calculating of inhibiting rate is carried out with reference to specification sheets.Experimental result sees Table 1 (non-activity during NA:10 μ M).
Embodiment 8
Compound N-(2-aminocyclohexyl)-4-N-(4-fluorobenzene methoxycarbonyl) aminomethyl] benzamide (HYM0513), N-hydroxyl-4-[N-(4-fluorobenzene methoxycarbonyl) aminomethyl] benzamide (HYM0512), N-(2-aminocyclohexyl)-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] benzamide (HYM0504) and N-hydroxyl-4-[N-(pyridine-3-methoxycarbonyl) aminomethyl] benzamide (HYM0505) suppresses active to the cancer cells growth in vitro
Measure growth inhibition ratio with the MTS method.Inoculation 5000 in every hole of cell to be measured (the cell inoculation amount differences of the different speeds of growth) in 96 orifice plates.Cultivate the testing compound that adds different concns after 24 hours, continue cultivation and add 20 μ lMTS detection substrate (Promega) in every hole after 48 hours, incubate to bathe after 2 hours for 37 ℃ and on microplate reader, read the result with the 490nm wavelength.Amount of viable cell calculates with experimental group/control group * 100% relatively.The compound concentration of cell growth inhibition 50% is designated as GI 50All compounds all are dissolved among the DMSO, and carry out 1: 1000 dilution when dosing, make final concentration≤0.1% of DMSO.Each tests all independent triplicate, and experimental result sees Table 2.
Table 1.Compound is to the vitro inhibition of histon deacetylase (HDAC)
Figure C0314684100231
Table 2. compound is to the growth-inhibiting effect of tumour cell
Figure C0314684100241
*The cell source:
U2OS: human osteosarcoma cell HeLa: human cervical carcinoma cell
DU-145: Human Prostate Cancer Cells SGC-7901: gastric carcinoma cells
SMMC-7721: human liver cancer cell HepG2: human liver cancer cell
293: HEKC MCF-7: human breast cancer cell
MDA-MB-231: human breast cancer cell H292: human lung carcinoma cell
LNCaP: Human Prostate Cancer Cells SK-N-SH: human neuroblastoma
PANC-1: human pancreatic cancer cell SK-OV-3: Proliferation of Human Ovarian Cell
28SC: people's mononuclear macrophage Raji: people Burkitt lymphoma
HL-60: human myeloid leukemia cell Jurkat: human T lymphocyte's leukemia

Claims (8)

1. compound or its salt with following general formula (I):
Figure C031468410002C1
Wherein, Ar 1Be pyridine ring or phenyl ring, unsubstituted or substituting group is arranged on the ring, substituting group is halogen, alkyl, alkoxyl group or trifluoromethyl;
Ar 2Be phenyl ring;
Q 1For-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2-;
Q 2For-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2-;
Q 3Be covalent linkage;
J is
R 1Be H or alkyl;
Z is hydroxyl or 2-aminocyclohexyl.
2. according to the compound of claim 1, wherein:
Ar 1Be phenyl ring;
Ar 2Be phenyl ring;
Q 1For-CH 2-;
Q 2For-CH 2-;
Q 3Be covalent linkage;
J is
Figure C031468410003C1
R 1Be H;
Z is hydroxyl or 2-aminocyclohexyl.
3. according to the compound of claim 1 or 2, wherein:
Ar 1Be pyridine ring;
Ar 2Be phenyl ring;
Q 1For-CH 2-;
Q 2For-CH 2-;
Q 3Be covalent linkage;
J is
Figure C031468410003C2
R 1Be H;
Z is hydroxyl or 2-aminocyclohexyl.
4. the preparation method of the compound of general formula (I), this method comprises the steps:
(a) general formula (II) compound and general formula (III) compound are carried out condensation reaction and obtain general formula (IV) compound:
Ar 1-Q 1-R 2
(II)
Wherein, Ar 1, Ar 2, Q 1, Q 2, Q 3, J is identical with the described definition of claim 1; R 2For-OH; R 3For-NH 2
(b) general formula (IV) compound and logical formula V compound are carried out condensation reaction and obtain general formula (I) compound:
H 2N-Z
(V)
Wherein, Z is identical with the described definition of claim 1.
5. according to the preparation method of claim 4, wherein, reactions steps (a) is with N, N-phosphinylidyne diimidazole is a catalyzer, make N earlier, N-phosphinylidyne diimidazole and general formula (II) compound reacts and makes active intermediate, and then reacts with general formula (III) compound and to make general formula (IV) compound.
6. according to the preparation method of claim 4, wherein, reactions steps (b) is catalyzer with the Vinyl chloroformate, Vinyl chloroformate and general formula (IV) compound is reacted make active intermediate, and then react with logical formula V compound and to make general formula (I) compound.
7. according to the preparation method of claim 4, wherein, the temperature of reaction of described reactions steps (a) and reactions steps (b) is-10～80 ℃, and the reaction times is 1～72 hour.
8. a NSC 630176 medicinal preparations is characterized in that, said preparation is made up of the compound of the described general formula of claim 1 (I) and pharmaceutical carrier auxiliary material or thinner.
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