CN1513839A - Benzamide kind histon deacetylase inhibiting agent having dissociation and antibred activity and its medicinal preparation - Google Patents
Benzamide kind histon deacetylase inhibiting agent having dissociation and antibred activity and its medicinal preparation Download PDFInfo
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Abstract
A phenylformylamine type histone deacetylation enzyme inhibitor with differential and anti-reproduction activity, and its application in preparing medicines for treating the diseases associated with differentiation and reproduction, such as cancer and psoriasis, are disclosed.
Description
Technical field
The present invention relates to have brand-new micromolecular compound synthetic of therapeutic action and in treatment and differentiation and the clinical application of breeding aspect the relevant disease
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 nervous system 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 nervous system disorders, Transcription Factor-specific Requirements for Coactivatorand Their Acetyltransferase Functions.Science 1998,279:703-707; N.J.McKenna and B.W.O ' Malley, Combinatorial Control of GeneExpression 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; US20020115716 Λ 1, WO0056153 Λ 1).
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 is as MS-275 (EP0847992A1, US2002/0103192A1, WO02/26696 Λ 1, WO01/70675 Λ 2, WO01/18171 Λ 2).
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.Warrcll.ct al., Thcrapcutictargeting 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 Grccncbaum 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 be used for the treatment of with differentiation with propagation relevant disorders such as cancers and the psoriasic compound with induce differentiation and antiproliferative activity 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 described compound of this class as treatment and differentiation disorders such as cancers and the psoriasic clinical application relevant with propagation.
The said compound of the present invention, its chemical structure is shown in general formula (I):
Wherein, A is phenyl ring or heterocycle, can contain 1 to 4 substituting group, its substituting group can be a halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom, the aminoalkyl of 1 to 4 carbon atom, the alkylamino of 1 to 4 carbon atom, the acyl group of 2 to 4 carbon atoms, the amido of 2 to 4 carbon atoms, the alkylthio of 1 to 4 carbon atom, the perfluoroalkyl of 1 to 4 carbon atom, the perfluoro alkoxy of 1 to 4 carbon atom, the carboxyl of 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom, phenyl or heterocyclic substituent;
B is phenyl ring or heterocycle, can contain 1 to 3 substituting group, its substituting group can be the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, alkoxy carbonyl, phenyl or the heterocyclic substituent of 1 to 4 carbon atom;
Z is the alkylene of covalent linkage, 1 to 4 carbon atom or contain-O-,-S-,-NH-,-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture;
Y for contain-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture, wherein encircle and containedly among central point (W1), the ring central point (W2) of B and the Y of A satisfy following condition: W1-W2=6.0～12.0 as the O atom of hydrogen bond receptor or the distance between the S atom (W3), W1-W3=3.0～6.0 , W2-W3=4.0～8.0 ; Distance preferable between them is: W1-W2=8.0～10.0 , W1-W3=3.0～5.0 , W2-W3=5.0～8.0 ;
R
1, R
2Be respectively hydrogen or contain the alkyl of 1 to 4 carbon atom, R
1, R
2Can also constitute a covalent linkage together;
R
3For hydrogen or contain the alkyl of 1 to 4 carbon atom;
R
4Be the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of hydrogen, halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom;
X
1, X
2, X
3, X
4One of them is the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom; All the other are respectively the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of hydrogen, halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom.
" heterocycle " of the present invention is meant the saturated or unsaturated heterocycle that contains one or more heteroatomss (nitrogen, oxygen or sulphur), as Pyrrolidine, pyrrolin, pyrazoline, piperidines, morpholine, imidazoles, pyridine etc.;
" halogen " of the present invention is fluorine, chlorine, bromine, iodine;
" alkyl of 1 to 4 carbon atom " of the present invention comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl etc.;
" alkoxyl group of 1 to 4 carbon atom " of the present invention comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy etc.;
" aminoalkyl group of 1 to 4 carbon atom " of the present invention comprises amino-ethyl, 1-aminopropyl, 1-aminopropyl etc.;
" alkyl amine group of 1 to 4 carbon atom " of the present invention comprises N-methylamino, N-ethylamino-, N-isopropylamine base etc.;
" acyl groups of 2 to 4 carbon atoms " of the present invention comprise ethanoyl, propionyl, isobutyryl etc.;
" amide group of 2 to 4 carbon atoms " of the present invention comprise acetamido, propionamido-, amide-based small, isobutyl amide etc.;
" alkylthio of 1 to 4 carbon atom " of the present invention comprises methylthio group, ethylmercapto group, rosickyite base etc.;
" perfluoroalkyl of 1 to 4 carbon atom " of the present invention comprises trifluoromethyl, pentafluoroethyl group etc.;
" perfluoro alkoxy of 1 to 4 carbon atom " of the present invention comprises trifluoromethoxy, five fluorine oxyethyl groups etc.;
" alkylene of 1 to 4 carbon atom " of the present invention comprises methylene, ethylene etc.;
" central point of ring " of the present invention is meant the pairing X of atom, the Y that constitutes ring, the mean value of Z axis values.
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:
R
6-B-COOH
(III)
Wherein, A, Z, Y, B, R
1, R
2Ditto described; R
5Be-C (=Q) OH (Q is O or S atom) or contain-NH
2Structure; Work as R
5For-C (=Q) during OH (Q is O or S atom), R
6For containing-NH
2Structure; Work as R
5For containing-NH
2Structure the time, R
6Be-C (=Q) OH (Q is O or S atom).
(b) general formula (IV) compound and logical formula V compound are carried out condensation reaction and obtain target compound (I):
Wherein, R
3, R
4, X
1, X
2, X
3And X
4Ditto described.
Above-mentioned condensation reaction (a) and (b) be catalyzer with the peptide condensing agent, as the dicyclohexyl carbimide, N, N-phosphinylidyne diimidazole etc.
Above-mentioned condensation reaction (a) and temperature of reaction (b) are 0～80 ℃, and the reaction times is 4～72 hours.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 differentiation of inducing and antiproliferative activity, can be used for the treatment of disorders such as cancers and the psoriasis relevant with propagation with differentiation, especially leukemia and solid tumor is had excellent curative effect.
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.
The invention has the advantages that, described compound and medicinal preparations thereof cause for the therapeutic gene abnormal expression as: tumour, endocrine regulation, disease of immune system, inherited disease and nervous system disorders have better curative effect.
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.
Embodiment 1
4-[N-(3-pyridine acryl) aminomethyl] benzoic preparation
In reaction flask, add 0.33 gram (2.01mmol) 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 0.30 gram (2.01mmol) 3-pyridyloxy acrylic acid, stirring at room reaction 3 hours, drip 2 milliliters (2.00mmol) then and be dissolved with the benzoic 1N sodium hydroxide solution of 0.30 gram (2.00mmol) 4-aminomethyl, room temperature continued stirring reaction 8 hours.With the reaction mixture vacuum concentration, in residue, add 2 milliliters of saturated nacl aqueous solutions, and regulate pH value to 5 with concentrated hydrochloric acid.With solid filtering, frozen water washing, dry 0.46 gram (82%) target compound that gets of separating out.HRMS (C
16H
14N
2O
3) calculated value (%): 282.2988; Measured value (%): 282.2990.Ultimate analysis (C
16H
14N
2O
3) calculated value (%): C, 68.07%; H, 5.00%; N, 9.92%; Measured value (%): C, 68.21%; H, 5.03%; N, 9.90%.
Embodiment 2
N-(2-amino-5-fluorophenyl)-4-[N-(3-pyridine acryl) aminomethyl]
The preparation of benzamide
In reaction flask, add 0.29 gram (1.78mmol) N, N-phosphinylidyne diimidazole, 0.50 gram (1.78mmol) 4-[N-(3-pyridine acryl) amino methyl] phenylformic acid and 15 milliliters of tetrahydrofuran (THF)s, 45 ℃ of stirring reactions 1 hour.After the reaction mixture cooling, join another and contain 10 milliliters of tetrahydrofuran (THF)s, 0.28 gram (2.22mmol) 4-fluoro-1, in the reaction flask of 2-phenylenediamine and 0.20 gram (1.78mmol) trifluoroacetic acid, stirring at room reaction 24 hours.With solid filtering, tetrahydrofuran (THF) washing, dry 0.40 gram (57%) target compound that gets of separating out.
1H?MR(300MHz，DMSO-d
6)：δppm：4.49(2H，d)，4.84(2H，br.s)，6.60(1H，t)，6.80(2H，m)，6.96(1H，t)，7.18(1H，d)，7.42(2H，d)，7.52(1H，d)，7.95(2H，d)，8.02(1H，d)，8.56(1H，d)，8.72(1H，br.t)，8.78(1H，s)，9.60(1H，br.s。IR?(KBr)cm
-1：3310，1655，1631，1524，130，750。HRMS (C
22H
19N
4O
2F) calculated value (%): 390.4170; Measured value (%): 390.4172.Ultimate analysis (C
22H
19N
4O
2F) calculated value (%): C, 67.68%; H, 4.40%; N, 14.35; Measured value (%): C, 67.52%; H, 4.38%; N, 14.42%.
Embodiment 3
The benzoic preparation of 4-(N-cinnamamide methyl)
In reaction flask, add 0.33 gram (2.01mmol) 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 0.30 gram (2.01mmol) 3-pyridyloxy acrylic acid, stirring at room reaction 3 hours, drip 2 milliliters (2.00mmol) then and be dissolved with the benzoic 1N sodium hydroxide solution of 0.30 gram (2.00mmol) 4-aminomethyl, room temperature continued stirring reaction 8 hours.With the reaction mixture vacuum concentration, in residue, add 2 milliliters of saturated nacl aqueous solutions, and regulate pH value to 7 with concentrated hydrochloric acid.With solid filtering, frozen water washing, dry 0.51 gram (91%) target compound that gets of separating out.HRMS (C
17H
15NO
3) calculated value (%): 281.3242; Measured value (%): 281.3240.Ultimate analysis (C
17H
15NO
3) calculated value (%): C, 72.58%; H, 5.38%; N, 4.98%; Measured value (%): C, 72.42%; H, 5.37%; N, 4.87%.
Embodiment 4
N-(2-amino-5-fluorophenyl)-4-(N-cinnamamide methyl)
The preparation of benzamide
In reaction flask, add 0.29 gram (1.78mmol) N, N-phosphinylidyne diimidazole, 0.50 gram (1.78mmol) 4-(N-cinnamamide methyl) phenylformic acid and 15 milliliters of tetrahydrofuran (THF)s, 45 ℃ of stirring reactions 1 hour.After the reaction mixture cooling, join another and contain 10 milliliters of tetrahydrofuran (THF)s, 0.28 gram (2.22mmol) 4-fluoro-1, in the reaction flask of 2-phenylenediamine and 0.20 gram (1.78mmol) trifluoroacetic acid, stirring at room reaction 16 hours.With solid filtering, tetrahydrofuran (THF) washing, dry 0.45 gram (64%) target compound that gets of separating out.
1H?NMR(300MHz，DMSO-d
6)：δppm：4.42(2H，d)，4.92(2H，br.s)，6.62(1H，t)，6.78(2H，m)，7.01(1H，t)，7.32(5H，m)，7.54(5H，m)，8.76(1H，br.t)，9.58(1H，br.s)。IR(KBr)cm
-1：3306，1618，1517，1308，745。HRMS (C
23H
20N
3O
2F) calculated value (%): 389.4292; Measured value (%): 389.4294.Ultimate analysis (C
23H
20N
3O
2F) calculated value (%): C, 70.94%; H, 5.18%; N, 10.79; Measured value (%): C, 70.72%; H, 5.18%; N, 10.88%.
Embodiment 5
Compound N-(2-amino-5-fluorophenyl)-4-[N-(3-pyridine acryl) aminomethyl] benzamide (CS02100055), N-(2-aminophenyl)-4-[N-(4-fluorophenyl acryl) aminomethyl] benzamide (CS02100019) and N-(2-aminophenyl)-4-[N-(3-pyridine methoxycarbonyl) aminomethyl] benzamide (MS275, histon deacetylase (HDAC) vitro inhibition activity EP0847992)
HDAC colorimetric analysis test kit is adopted in experiment, and (BIOMOL Rcscarch Laboratorics, 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.
Table 1.MS275, CS02100055 and CS02100019 are to the vitro inhibition of histon deacetylase (HDAC)
| Compound | Inhibition percentage under the different concns | IC 50(μM) | |||
| ????1μM??????????????5μM????????????????10μM?????????????50μM | |||||
| ?MS-275 | ????14.7 | ????19.1 | ????64.1 | ????82.3 | ??8.4 |
| ?CS02100055 | ????17.5 | ????37.3 | ????62.1 | ????78.4 | ??7.2 |
| ?CS02100019 | ????11.3 | ????24.9 | ????28.4 | ????29.8 | ??＞50.0 |
Embodiment 6
Compound N-(2-amino-5-fluorophenyl)-4-[N-(3-pyridine acryl) aminomethyl] benzamide (CS02100055), N-(2-aminophenyl)-4-[N-(4-fluorophenyl acryl) aminomethyl] benzamide (CS02100019) and N-(2-aminophenyl) 4-[N-(3-pyridine methoxycarbonyl) aminomethyl] (MS275, EP0847992) the cancer cells growth in vitro suppresses active to benzamide
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 2.MS-275, CS2100055 and CS02100019 are to the growth-inhibiting effect of cancer cell
| Compound | The GI of different tumour cells 50(μM) * | ||||||||
| ??U2OS | ??HeLa | ??DU-145 | ??SMMC-7721 | ??HepG2 | ?293 | ??MCF-7 | ??231 | ??H292 | |
| ??MS-275 | ????1.0 | ????25 | ????13 | ????20 | ????3.2 | ??16 | ????6.3 | ??5.0 | ??16 |
| ?CS02100055 | ????2.0 | ????40 | ????25 | ????16 | ????4.0 | ??50 | ????5.0 | ??7.9 | ??50 |
| ?CS02100019 | ????2.5 | ????50 | ????50 | ????50 | ????3.2 | ??25 | ????5.0 | ??7.9 | ??50 |
| Compound | The GI of different tumour cells 50(μM) * | ||||||||
| ??LNCaP | ??SK-N-SII | ??PANC-I | ??SK-OV-3 | ?SGC-7901 | ??Raji | ?IIL-60 | ?28SC | ?Jurkat | |
| ?Ms-275 | ????2.5 | ????50 | ????5.0 | ????50 | ????50 | ??6.3 | ????0.32 | ??4.0 | ??1.6 |
| ?CS02100055 | ????4.0 | ????50 | ????6.3 | ????50 | ????50 | ??4.0 | ????0.4 | ??5.8 | ??1.5 |
| ?CS02100019 | ????10 | ????50 | ????5.0 | ????50 | ????50 | ??2.0 | ????0.5 | ??2.0 | ??1.0 |
| ?CS02100019 | ????10 | ????50 | ????5.0 | ????50 | ????50 | ??2.0 | ????0.5 | ??2.0 | ??1.0 |
*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
Embodiment 7
Compound N-(2-amino-5-fluorophenyl)-4-[N-(3-pyridine acryl) aminomethyl] benzamide (CS02100055), N-(2-aminophenyl)-4-[N-(3-pyridine methoxycarbonyl) aminomethyl] benzamide (MS275, EP0847992) and Trichostatin A (TSA) nuclear hormone receptor transcriptional activation
The transcriptional activation experiment of nuclear receptor is to finish with the reporter gene system.Concrete operations are as follows: in the day before yesterday of transfection with the U2OS cell inoculation to 96 orifice plates, the density when making transfection is 50-80%.With the cDNA expression vector transfectional cell of FuGene6 transfection reagent (Roche) with following each nuclear receptor, be respectively glucocorticoid receptor (GR), superoxide propagation activated receptor γ (PPAR γ), estrogen receptor alpha (ER α) and erss (ER β), go back the corresponding luciferase reporter gene plasmid of cotransfection and confidential reference items plasmid β-gal simultaneously.Wherein GR and PPAR γ also cotransfection retinoids X acceptor (RXR).Added all cpds and solvent control (DMSO) after the transfection in 24 hours.Drug effect lysing cell and carry out the detection of uciferase activity after 24 hours, the activity of also measuring beta-galactosidase enzymes simultaneously is to proofread and correct transfection efficiency.Experimental result as shown in Figure 1.
Among Fig. 1 Trichostatin A, MS-275 and CS2100055 to the transcriptional activation of nuclear receptor [part of every kind of nuclear receptor of LD representative, CS55 represents CS2100055, ordinate zou represents to induce relatively multiple.In all experiments, compound concentration is as follows: TSA0.2 μ M, MS-275 μ M, CS551 μ M.Dexamethasone (0.1 μ M), rosiglitazone (10 μ M) and estradiol (0.01 μ M) are respectively as the part of GR, PPAR γ and ER.
Claims (21)
1. one kind has the differentiation and the benzamide histone deacetylase enzyme inhibitors of antiproliferative activity, it is characterized in that the general structure of the steric isomer of this compound, enantiomer, diastereomer, hydrate and salt thereof is as follows:
Wherein, A is phenyl ring or heterocycle, can contain 1 to 4 substituting group, its substituting group can be a halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom, the aminoalkyl of 1 to 4 carbon atom, the alkylamino of 1 to 4 carbon atom, the acyl group of 2 to 4 carbon atoms, the amido of 2 to 4 carbon atoms, the alkylthio of 1 to 4 carbon atom, the perfluoroalkyl of 1 to 4 carbon atom, the perfluoro alkoxy of 1 to 4 carbon atom, the carboxyl of 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom, phenyl or heterocyclic substituent;
B is phenyl ring or heterocycle, can contain 1 to 3 substituting group, its substituting group can be the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, alkoxy carbonyl, phenyl or the heterocyclic substituent of 1 to 4 carbon atom;
Z is the alkylene of covalent linkage, 1 to 4 carbon atom or contain-O-,-S-,-NH-,-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture;
Y for contain-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture, wherein encircle and containedly among central point (W1), the ring central point (W2) of B and the Y of A satisfy following condition: W1-W2=6.0～12.0 as the O atom of hydrogen bond receptor or the distance between the S atom (W3), W1-W3=3.0～6.0 , W2-W3=4.0～8.0 ; Distance preferable between them is: W1-W2=8.0～10.0 , W1-W3=3.0～5.0 , W2-W3=5.0～8.0 ;
R
1, R
2Be respectively hydrogen or contain the alkyl of 1 to 4 carbon atom, R
1, R
2Can also constitute a covalent linkage together;
R
3For hydrogen or contain the alkyl of 1 to 4 carbon atom;
R
4Be the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of hydrogen, halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom;
X
1, X
2, X
3, X
4One of them is the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom; All the other are respectively the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of hydrogen, halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom.
2, the benzamide histone deacetylase enzyme inhibitors with differentiation and antiproliferative activity according to claim 1; it is characterized in that the general structure of the steric isomer of described compound intermediate, enantiomer, diastereomer, hydrate and salt thereof is as follows:
Wherein, A is phenyl ring or heterocycle, can contain 1 to 4 substituting group, its substituting group can be a halogen, amino, hydroxyl, nitro, cyano group, the alkyl of 1 to 4 carbon atom, the alkoxyl group of 1 to 4 carbon atom, the aminoalkyl of 1 to 4 carbon atom, the alkylamino of 1 to 4 carbon atom, the acyl group of 2 to 4 carbon atoms, the amido of 2 to 4 carbon atoms, the alkylthio of 1 to 4 carbon atom, the perfluoroalkyl of 1 to 4 carbon atom, the perfluoro alkoxy of 1 to 4 carbon atom, the carboxyl of 1 to 4 carbon atom, the alkoxy carbonyl of 1 to 4 carbon atom, phenyl or heterocyclic substituent;
B is phenyl ring or heterocycle, can contain 1 to 3 substituting group, its substituting group can be the carboxyl of the perfluoro alkoxy of the perfluoroalkyl of the alkylthio of the amido of the acyl group of the alkylamino of the aminoalkyl of the alkoxyl group of the alkyl of halogen, amino, hydroxyl, nitro, cyano group, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 2 to 4 carbon atoms, 2 to 4 carbon atoms, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, 1 to 4 carbon atom, alkoxy carbonyl, phenyl or the heterocyclic substituent of 1 to 4 carbon atom;
Z is the alkylene of covalent linkage, 1 to 4 carbon atom or contain-O-,-S-,-NH-,-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture;
Y for contain-CO-,-CS-,-SO-,-SO
2-linear structure, ring texture or linear structure and the combination of ring texture, wherein encircle and containedly among central point (W1), the ring central point (W2) of B and the Y of A satisfy following condition: W1-W2=6.0～12.0 as the O atom of hydrogen bond receptor or the distance between the S atom (W3), W1-W3=3.0～6.0 , W2-W3=4.0～8.0 ; Distance preferable between them is: W1-W2=8.0～10.0 , W1-W3=3.0～5.0 , W2-W3=5.0～8.0 ;
R
1, R
2Be respectively hydrogen or contain the alkyl of 1 to 4 carbon atom, R
1, R
2Can also constitute a covalent linkage together;
3. one kind has the differentiation and the benzamide histone deacetylase enzyme inhibitors of antiproliferative activity, it is characterized in that: the steric isomer of described compound, enantiomer, diastereomer, hydrate and salt thereof react by following two steps and are prepared:
(a) general formula (II) compound and general formula (III) compound are carried out condensation reaction and obtain general formula (IV) compound:
R
6-B-COOH
(III)
Wherein, A, Z, Y, B, R
1, R
2According to claim 1; R
5Be-C (=Q) OH (Q is O or S atom) or contain-NH
2Structure; Work as R
5For-C (=Q) during OH (Q is O or S atom), R
6For containing-NH
2Structure; Work as R
5For containing-NH
2Structure the time, R
6Be-C (=Q) OH (Q is O or S atom).
(b) general formula (IV) compound and logical formula V compound are carried out condensation reaction and obtain target compound (I):
Wherein, R
3, R
4, X
1, X
2, X
3And X
4According to claim 1.
4. preparation process as claimed in claim 3 is characterized in that, condensation reaction (a) and (b) be catalyzer with the peptide condensing agent.
5. peptide condensing agent as claimed in claim 4 can be the dicyclohexyl carbimide, N, N-phosphinylidyne diimidazole.
6. preparation method as claimed in claim 3 is characterized in that, condensation reaction (a) and temperature of reaction (b) are 0～80 ℃, and the reaction times is 4～72 hours.
7. have the benzamide histone deacetylase enzyme medicinal preparations of cytodifferentiation and antiproliferative activity, it is characterized in that, its preparation is made up of the derivative of active ingredient benzamide or its salt and pharmaceutical carrier auxiliary material or thinner.
8. medicinal preparations as claimed in claim 7 is characterized in that, described preparation is used for the treatment of the disease relevant with propagation with cytodifferentiation, comprises psoriasis, leukemia, solid tumor.
9. medicinal preparations as claimed in claim 7 is characterized in that the content of its contained active principle is between 0.0001～200mg.
10. medicinal preparations as claimed in claim 7 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. as claimed in claim 8 being used for the treatment of and the medicinal preparations of cytodifferentiation, it is characterized in that described effective dose is per kilogram of body weight medication every day 0.0001～200mg with the propagation relative disease.
12. 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.
13. the medicinal preparations that is used to activate nuclear receptor of compound as claimed in claim 1 is characterized in that, its preparation is made up of the derivative of active ingredient benzamide or its salt and pharmaceutical carrier auxiliary material or thinner.
14. medicinal preparations as claimed in claim 13 is characterized in that, the content of its contained active principle is between 0.0001～200mg.
15. medicinal preparations as claimed in claim 13 is characterized in that, its application method can be per os, intranasal, through skin, through modes such as lung, intramuscular injection or intravenous injections.
16. compound as claimed in claim 1 is characterized in that, can treat the disease that is lowly caused by the nuclear receptor regulation and control under its effective dose.
17. compound as claimed in claim 1 is characterized in that, can treat under its effective dose because the active caused disease that descends of nuclear receptor.
18. the disease that receptor modulators as claimed in claim 16 lowly causes is characterized in that, described disease comprises the disease relevant with internal secretion, immunity/inflammatory disease, genetic diseases, neurological deterioration disease etc.
19. the active caused disease that descends of nuclear receptor as claimed in claim 17 is characterized in that described disease comprises the disease relevant with internal secretion, immunity/inflammatory disease, genetic diseases, neurodegenerative disorders etc.
20. the method for the disease that treatment as claimed in claim 16 is lowly caused by nuclear receptor regulation and control is characterized in that, described compound medicinal preparations, and its effective dose is per kilogram of body weight medication every day 0.0001～200mg.
21. as claimed in claim 17 being used for the treatment of because the method for the active caused disease that descends of nuclear receptor is characterized in that described compound medicinal preparations effective dose is per kilogram of body weight medication every day 0.0001～200mg.
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| CN 03139760 CN1284772C (en) | 2003-07-04 | 2003-07-04 | Benzamide kind histon deacetylase inhibiting agent having dissociation and antibred activity and its medicinal preparation |
| TW093135522A TW200524869A (en) | 2003-07-04 | 2004-11-19 | Benzamide kind histon deacetylase inhibiting agent having dissociation and antibred activity and its medicinal preparation |
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Also Published As
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| TWI370815B (en) | 2012-08-21 |
| CN1284772C (en) | 2006-11-15 |
| TW200524869A (en) | 2005-08-01 |
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