CN1524850A - 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 PDFInfo
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- CN1524850A CN1524850A CNA031468411A CN03146841A CN1524850A CN 1524850 A CN1524850 A CN 1524850A CN A031468411 A CNA031468411 A CN A031468411A CN 03146841 A CN03146841 A CN 03146841A CN 1524850 A CN1524850 A CN 1524850A
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- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940127237 mood stabilizer Drugs 0.000 description 1
- 239000004050 mood stabilizer Substances 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000012622 synthetic inhibitor Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100000462 teratogen Toxicity 0.000 description 1
- 239000003439 teratogenic agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 108010060597 trapoxin A Proteins 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Abstract
The invention discloses a histone deacetylase inhibitor for treating tumor, parasecretion, immunity system diseases, hereditary diseases and nerve diseases, the preparing process and use of its medicinal preparation, its structure is illustrated by the general formula (I) disclosed in the specification.
Description
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 p5 3 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 0847992A1).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):
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:
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:
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:
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
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]
The preparation of benzamide (HYM0513)
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。
1H?NMR(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]
The preparation of benzamide (HYM0512)
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。
1H?NMR(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
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 (5.0mmo1) 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]
The preparation of benzamide (HYM0504)
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]
The preparation of benzamide (HYM0505)
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)
Table 2. compound is to the growth-inhibiting effect of tumour cell
| Compound | The GI of different tumour cells 50(μM) * | ||||||||
| ??U2OS | ????HeLa | ??DU-145 | ??SMMC-7721 | ??HepG2 | ??293 | ??MCF-7 | ????231 | ??H292 | |
| ?HYM0504 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????50 | ????50 | ????50 |
| ?HYM0505 | ????5 | ????25 | ????50 | ????5 | ????16 | ??20 | ????25 | ????20 | ????40 |
| ?HYM0512 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????50 | ????50 | ????50 |
| ?HYM0513 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????50 | ????50 | ????50 |
| Compound | The GI of different tumour cells 50(μM) * | ||||||||
| ??LNCaP | ?SK-N-SH | ??PANC-1 | ??SK-OV-3 | ???SGC-7901 | ?Raji | ???HL-60 | ???28SC | ?Jurkat | |
| ?HYM0504 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????50 | ????50 | ????50 |
| ?HYM0505 | ????32 | ????50 | ????50 | ????50 | ????50 | ??2.5 | ????0.63 | ????2.5 | ????3.2 |
| ?HYM0512 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????20 | ????50 | ????50 |
| ?HYM0513 | ????50 | ????50 | ????50 | ????50 | ????50 | ??50 | ????50 | ????50 | ????50 |
*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 (11)
1. a NSC 630176 is characterized in that, the general structure of the steric isomer of this compound, enantiomer, diastereomer, hydrate and salt thereof is as follows:
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 its substituting group of one or more substituting groups 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:
Wherein, R
1Be H, alkyl, aralkyl, heterocycle aralkyl, heterocyclic substituent, aryl or heterocyclic aryl;
Z is-OH or 2-aminocyclohexyl.
2. compound as claimed in claim 1 is characterized in that, one of preferred method of described compound is:
Ar
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:
Wherein, R
1Be H or alkyl;
Z is-OH or 2-aminocyclohexyl.
3. compound as claimed in claim 1 is characterized in that, two of the preferred method of described compound is:
Ar
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:
Wherein, R
1Be H;
Z is-OH or 2-aminocyclohexyl.
4. the preparation method of compound as claimed in claim 1 is characterized in that, the steric isomer of described compound, enantiomer, diastereomer, hydrate and salt thereof can be prepared by following two steps reaction:
(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.
(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.
5. preparation process as claimed in claim 4, it is characterized in that, reaction (a) is with N, N-phosphinylidyne diimidazole (CDI) is a catalyzer, 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.
6. preparation process as claimed in claim 4, it is characterized in that, reaction (b) 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.
7. synthetic method as claimed in claim 4 is characterized in that, the temperature of reaction of reaction (a) and reaction (b) is-10～80 ℃, and the reaction times is 1～72 hour.
8. the preparation method of NSC 630176 medicinal preparations is characterized in that, its medicinal preparations is made up of active ingredient histon deacetylase (HDAC) salt and pharmaceutical carrier auxiliary material or thinner.
9. medicinal preparations as claimed in claim 8 is characterized in that, described effective dose is that per kilogram of body weight medication every day is between 0.0001～200mg.
10. medicinal preparations as claimed in claim 8 is characterized in that, its application method can be per os, intranasal, through skin, through modes such as lung, intramuscular injection or intravenous injections.
11. compound as claimed in claim 1, it is characterized in that, the medicinal preparations of this compound can share with tumor chemical therapy medicine or methyltransferase inhibitors commonly used, is used for the treatment of cell breeding disease, can add one or more pharmaceutical carrier auxiliary material or thinners.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009067856A1 (en) * | 2007-10-26 | 2009-06-04 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Histone deacetylase inhibitor, composition and use thereof |
| CN101397295B (en) * | 2008-11-12 | 2012-04-25 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
| CN102936215A (en) * | 2012-11-09 | 2013-02-20 | 怀化学院 | Synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide |
| CN102020638B (en) * | 2009-09-16 | 2013-05-08 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| WO2016206138A1 (en) * | 2015-06-23 | 2016-12-29 | 清安医药科技武汉有限公司 | Histone deacetylase inhibitor and preparation method and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6174905B1 (en) * | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
| JP2001081031A (en) * | 1999-08-30 | 2001-03-27 | Schering Ag | Benzamide derivative-containing preparation having improved solubility and oral adsorption |
| PE20020354A1 (en) * | 2000-09-01 | 2002-06-12 | Novartis Ag | HYDROXAMATE COMPOUNDS AS HISTONE-DESACETILASE (HDA) INHIBITORS |
-
2003
- 2003-09-12 CN CNB031468411A patent/CN100455564C/en not_active Expired - Lifetime
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| WO2009067856A1 (en) * | 2007-10-26 | 2009-06-04 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Histone deacetylase inhibitor, composition and use thereof |
| CN101827811B (en) * | 2007-10-26 | 2013-12-04 | 浙江海正药业股份有限公司 | Histone deacetylase inhibitor, preparation and use thereof |
| CN101397295B (en) * | 2008-11-12 | 2012-04-25 | 深圳微芯生物科技有限责任公司 | 2-dihydroindolemanone derivates as histone deacetylase inhibitor, preparation method and use thereof |
| CN102020638B (en) * | 2009-09-16 | 2013-05-08 | 深圳微芯生物科技有限责任公司 | 2-indolinone derivative with protein kinase inhibition activity and histone deacetylase inhibition activity and preparation method and application thereof |
| CN102936215A (en) * | 2012-11-09 | 2013-02-20 | 怀化学院 | Synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide |
| CN102936215B (en) * | 2012-11-09 | 2013-12-25 | 怀化学院 | Synthesizing method for 2-sulfydryl-N-(6-(3-arylurea) hexyl) amide |
| WO2016206138A1 (en) * | 2015-06-23 | 2016-12-29 | 清安医药科技武汉有限公司 | Histone deacetylase inhibitor and preparation method and use thereof |
| CN106317175A (en) * | 2015-06-23 | 2017-01-11 | 清安医药科技武汉有限公司 | Histone deacetylase inhibitor and preparation method and application thereof |
| CN106317175B (en) * | 2015-06-23 | 2020-01-31 | 杨思遥 | Histone deacetylase inhibitor and preparation method and application thereof |
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