CN101481325A - Basic amino acid metalloproteinase inhibitor and use thereof - Google Patents
Basic amino acid metalloproteinase inhibitor and use thereof Download PDFInfo
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- CN101481325A CN101481325A CNA2009100138951A CN200910013895A CN101481325A CN 101481325 A CN101481325 A CN 101481325A CN A2009100138951 A CNA2009100138951 A CN A2009100138951A CN 200910013895 A CN200910013895 A CN 200910013895A CN 101481325 A CN101481325 A CN 101481325A
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Abstract
The invention relates to a basic amino acid type metalloprotease inhibitor and the application thereof. The invention provides a strong quasi peptide metalloprotease inhibitor which can effectively cure the disease of abnormal expression of metalloprotease activity. Specifically, the invention relates to quasi peptide compounds with the structure of general formula (I), (II) or (III) and various optical isomers, pharmaceutically acceptable salts, solvates and prodrugs thereof. The invention also relates to pharmaceutical composition of quasi peptide compounds with the structure of general formula (I), (II) or (III) and drug application thereof.
Description
Technical field
The present invention relates to a kind of basic aminoacids (Methionin, ornithine, Histidine, arginine) metalloid protease inhibitor and its production and use, belong to technical field of chemistry.
Background technology
1, matrix metalloproteinase (MMPs)
Matrix metalloproteinase (MMPs) is the endopeptidase that a class relies on calcium ion and zine ion, and the regulation and control of the degraded of pair cell epimatrix, tissue reconstruction and the multiple soluble factor of iuntercellular play an important role.The activity of matrix metalloproteinase (MMPs) is by the strict control of the secretion level of gene expression dose and activation of zymogen/supressor, in a lot of pathologic processes, in the growth and transfer as sacroiliitis, tissue fester, malignant tumour, matrix metalloproteinase (MMPs) has also played vital role.
28 members (Szabo, K.A.etal.Clinical and Applied Immunology Reviews.2004,4 of matrix metalloproteinase (MMPs) family in Mammals, have been found a few days ago, 295), according to its structure, specific substrate and different cell positions are divided into different hypotypes, comprise kind of a collagenase (MMP-1,-8 ,-13 ,-18), 2 kinds of gelatinase (MMP-2,-9), 3 kinds of extracellular matrix degrading enzymes (MMP-3 ,-10,-11), 6 kinds of membranous type-matrix metalloproteinases (MMP-14 ,-15 ,-16,-17,-24 ,-25), and other are unclassified as stromlysin (MMP-7 and-26) and scavenger cell metallic elastic albumen (MMP-12) etc.Wherein gelatinase (MMP-2 and-9) has been proved to be closely related in the poor prognosis of the malignant phenotype of invasive tumor and cancer patient, and they have participated in the invasion and attack of tumour cell to basilar membrane, matrix, to penetrating of vessel wall, and the transfer of tumour cell.Recent study shows, matrix metalloproteinase (MMPs) also with the growth and the associated angiogenesis of primary tumor and secondary tumor, even the tumour birth process also played a driving role.Therefore, aiming is that the therapeutic strategy of action target spot also develops rapidly with these enzymes, and matrix metalloproteinase (MMPs) inhibitor has become the focus in the cancer treatment drugs research.
The example of available matrix metalloproteinase (MMPs) inhibitor for treating comprises: rheumatoid arthritis (Mullins, D.E.; Et al.Biochim.Biophys.Acta.1983,695,117); Osteoarthritis (Henderson, D.; Et al.Drugs of the Future, 1990,15,495); Cancer; Tumour cell shifts (Deryugina, E.I.; Et al.Cancer Metastasis Rev.2006,25,9); Multiple sclerosis (Rosenberg, G.A.et al.Ann Neurol.2001,50,431); And various tissue ulcers or tissue ulcer's venereal disease disease.As the ulcer that occurs in cornea may be because of due to the alkali burn, or because of infecting due to pseudomonas aeruginosa, Acanthamoeba, herpes simplex and the vaccinia virus.
With metal proteinase activity excessively is that other examples of the illness of feature comprise periodontopathy, epidermolysis bullosa, heating, inflammation and scleritis (Cf.Decicco, et al WO95/29892).
2, Aminopeptidase N
Aminopeptidase N (APN, CD13) be the II of gang type film in conjunction with glycoprotein, molecular weight is about 150Kd, belongs to the Gluzincins subtribe of zine ion dependency metalloprotease and Aminopeptidase M 1 family, form with homodimer is present in cytolemma, participates in the degraded of substrate N terminal amino acid.Aminopeptidase N (APN) wide expression is in kidney and IBB cell, marrow progenitor cell film, monocyte film, and central nervous system cynapse cytolemma, inoblast, endothelial cell membrane, placenta cells film surface participate in the physiological regulation of body.Studies have shown that Aminopeptidase N (APN) plays an important role in tumour generation, immunologic function adjusting and virus infection.
1) Aminopeptidase N (APN) is at the tumor cell surface high level expression.The main component of this enzyme degradable extracellular matrix (ECM) has been destroyed the natural cover for defense of body, and participates in the generation of tumour neovascularity as a novel signal transduction molecule, thereby promote tumor cell invasion and transfer (Sato Y, Biol.Pharm.Bull., 2004,27 (6): 772-776; Saiki, I.; Et al.Int.J.Cancer., 1993,54,137; Menrad A., Speicher D., Wacker J., et al.Cancer Res., 1993,53 (6): 1450-1455).2) Aminopeptidase N (APN) has also participated in the inflammatory reaction that the T lymphocyte relies on simultaneously in granulocyte and lymphocytic cell surface great expression; Can also be expressed in the antigen presenting cell surface, degraded immunologic active material (as interleukin-8); The T cell that major histocompatibility complex II type (MHC-II) the Adhesion Antigen determinant of processing of participation antigen and cell surface relies on is to antigenic identification, reduced the T cell to its antigenic recognition capability, weakened scavenger cell and NK cell identification and kill capability simultaneously, immunity of organisms is descended tumour cell.3) Aminopeptidase N (APN) is as the acceptor on human corona virus HCoV-229E and Transmissible gastroenteritis virus (TGEV) surface, in upper respiratory tract infection (as: SARS) and acute enteritis, play an important role, and its relevant (Delmas of activity with enzyme that plays a role, B., et al.Nature, 1992,357,417; Yeager, C.L; Et al.Nature, 1992,357,420).4) Aminopeptidase N (APN) has participated in the inflammatory reaction of T lymphocyte dependence and the process that the HIV virion enters host cell.Studies show that Aminopeptidase N (APN) activity is higher than the healthy volunteer far away in patient's body of infected by HIV.When HIV-1 invasion host cell, the Aminopeptidase N of high expression level (APN) can make the chemokine fMLP of HIV-1 auxiliary receptor CCR 5 desensitization by degraded, thereby reduces the natural immunity function of cell, and makes the CCR5 enhanced sensitivity, promotes that virus enters host cell.(Shen W, Li B, et al.Blood, 2000,96 (8), 2887; Shipp MA, et al.Blood, 1993,82 (4), 1052) 5) Aminopeptidase N (APN) participates in the degraded of endogenous analgesic matter endorphin and enkephalin, thus cause the excessive release of P material, cause pain.6) Aminopeptidase N (APN) degraded Angiotensin, adjusting (Mitsui, the T. of participation body blood pressure; Et al.Biol.Pharm.Bull., 2004,27,768.).
Since more than ten years, very rapid to the research and development of matrix metalloproteinase (MMPs) inhibitor, even but none listing up to now.Matrix metalloproteinase (MMPs) inhibitor great majority are the analogue of peptide or peptide, degraded to enzyme is relatively more responsive, in addition because matrix metalloproteinase (MMPs) shows a kind of effect characteristics of wide spectrum, except thereby ECM also other substrates of cracking such as they can be used as the enzyme that promotes growth factor expression or activates by the arrestin hydrolysis and integrate the plain tumor growth that promotes indirectly, this also is most of matrix metalloproteinases (MMPs) inhibitor at the reason place that clinical stage is had one shot.Inhibitor at Aminopeptidase N (APN) mostly is natural product in addition, the medicine ubenimex (Ubenimex) of a unique listing has the class dipeptides structure that contains beta-amino acids, be used for leukemic treatment as immunostimulant at present, but owing to be to separate to obtain from the nutrient solution of the netted streptomycete of olive (Streptomyces olivorecticuli), it is limited to originate.
Studies show that the infiltration of matrix metalloproteinase (MMPs) and Aminopeptidase N (APN) and malignant tumour and the generation of transfer and develop closely related (Sounni N.E., Janssen M., Foidart J.M., et al..Matrix Biol., 2003,22 (1), 55-61).The two is a substrate with the main component-collagen protein of extracellular matrix all, by destroying the natural cover for defense of body to tumour cell, causes the infiltration and the transfer of tumour cell.Yet the difference of the two is its degradation site difference to substrate: the former is an endopeptidase (endopeptidase), can be from degraded substrate in the middle of the peptide section; The latter is exopeptidase (ectopeptidase), is characterized in beginning the substrate of degrading by the substrate terminal amino group.The present invention combines research with matrix metalloproteinase (MMPs) and Aminopeptidase N (APN), relate to the selective problems of designed class peptide compounds in this patent, and be expected to develop respectively the specificity selective depressant by optimization to class peptide compounds structure to both.Designed class peptide compounds is directed to Aminopeptidase N (APN) screening active ingredients and finds several drug molecules it is active similar or be better than the ubenimex of present unique listing among the present invention.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of basic aminoacids (the present invention includes: Methionin, ornithine, Histidine, arginine) metalloid protease inhibitor and its production and use is provided.
Technical scheme of the present invention is:
Have general formula (I), (II) or class peptide compounds (III), with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug:
Wherein,
N is 3 or 4;
R
1Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
2Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
3Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
4Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
5Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
6Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy; Also can be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl or C1-6 alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
7Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
8Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
9Be various amino protecting groups, as nitro, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), fluorenylmethyloxycarbonyl, 2-xenyl-2-third oxygen carbonyl, phthalimide-based, p-toluenesulfonyl, trityl, formyl radical, ethanoyl, trifluoroacetyl group.
Wherein, when n=4, general formula I is the Methionin skeleton; When n=3, general formula I is the ornithine skeleton;
Specify, when n=4, R
1Be to remove aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl; the acyl group of each the seed amino acid preparation beyond the heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl; assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl; halogen, nitro, cyano group; carboxyl, halogen C1-8 alkyl, C1-8 alkoxyl group; C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy.
Above-mentioned class peptide compounds (I), (II) or (III) specifically comprise following compound:
N
6-benzoyl-N
2-benzoyl-L-Methionin,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-L-Methionin,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(3-chlorobenzene formacyl)-L-Methionin,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(2,4 dichloro benzene formyl radical)-L-Methionin,
N
6-benzoyl-N
2-(4-Methyl benzenesulfonyl base)-L-Methionin,
N
6-(3-chlorobenzene formacyl)-N
2-(3-chlorobenzene formacyl)-N
1-hydroxyl-L-lysyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(2,4 dichloro benzene formyl radical)-L-ornithine,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-L-ornithine,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-N
1-hydroxyl-L-ornithyl amine,
N
6-[(benzyloxy) carbonyl]-N
2-[(2S)-and 2-amino-3-phenyl] carbonyl }-N
1-hydroxyl-L-lysyl amine,
N
6-(4-Methyl benzenesulfonyl base)-N
2-(4-Methyl benzenesulfonyl base)-L-ornithine,
N
6-(4-Methyl benzenesulfonyl base)-N
2-(4-Methyl benzenesulfonyl base)-N
1-hydroxyl-L-ornithyl amine,
N
6-(4-chlorobenzene formacyl)-N
2-(4-chlorobenzene formacyl)-L-Methionin,
N
6-(2-chlorobenzene formacyl)-N
2-(2-chlorobenzene formacyl)-L-ornithine,
N
6-(2-chlorobenzene formacyl)-N
2-(2-chlorobenzene formacyl)-L-Methionin,
N
6-benzenesulfonyl-N
2-benzenesulfonyl-N
1-hydroxyl-L-ornithyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-benzenesulfonyl-N
1-hydroxyl-L-lysyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-benzoyl-N
1-hydroxyl-L-lysyl amine,
N
6-benzenesulfonyl-N
2-benzenesulfonyl-L-ornithine,
1-(2,4 dichloro benzene formyl radical)-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
1-benzenesulfonyl-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
1-(4-Methyl benzenesulfonyl base)-N-(4-Methyl benzenesulfonyl base)-N '-hydroxyl-L-histidyl-amine,
1-(4-nitro benzoyl)-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
(2S)-2-amino-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2,4 dichloro benzene formamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-hydrocinnamamide base-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-tolysulfonyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-benzene sulfonamido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-cinnyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-benzamide base-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-brombenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-iodobenzene formamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4-dimethoxy benzoylamino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-naphthoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(1-thenoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4,5-trimethoxy-benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-phenylacetyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-nitro-4-brombenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4-dichloro-benzoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,5-dinitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-to hydroxyl cinnyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-pyrrolidine formamido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-5-guanidine radicals valeryl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-4-methylpent amide group)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino propionamido-of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-methylbutyryl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-methylpent amide group)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-4-methylthio group amide-based small)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-Phenylpropionamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(3-indyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-glycyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-hydroxyl propionamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-maloyl group amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-sulfydryl propionamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino succinoamino of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino glutaryl amido of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(4-hydroxy phenyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-aminosuccinic acid monoamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2 aminopentanedioic acid monoamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2,6-diamino hexanoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(5-imidazolyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino propionamido-of 3-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-amino-butanamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(6-aminocaproamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide.
Preparing above-mentioned general formula (I), (II) or class peptide compounds intermediate (III) is: N
6-[(benzyloxy) carbonyl]-L-Methionin, N
6-[(benzyloxy) carbonyl]-L-ornithine, N-[(tert.-butoxy) carbonyl]-L-Histidine benzyl ester or (2S)-2-amino-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide.
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises above-mentioned general formula (I), (II) or (III) class peptide compounds and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
In addition, the present invention comprises that also a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises above-mentioned general formula (I), (II) or (III) class peptide compounds and pharmaceutically acceptable carrier, optional one or more pharmaceutically acceptable vehicle that comprises.
These class peptide compounds comprise matrix metalloproteinase or Aminopeptidase N at prevention or treatment and metalloprotease, the application of the medicine of the mammalian diseases that active unconventionality expression is relevant.Described and the related mammalian disease metal proteinase activity unconventionality expression comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer's venereal disease disease, periodontopathy, epidermolysis bullosa, leukemia etc.Therefore, the invention still further relates to and contain (I), (II) or (III) pharmaceutical composition of structural compounds.
Detailed Description Of The Invention
Used definition and term
Term and definition implication used herein is as follows:
" aroyl " is meant that the aromatic carbon ring end is connected with the group of carbonyl.Preferred aromatic ring contains 6-10 carbon atom.
" halogen ", or " halogen " comprises fluorine, chlorine, bromine or iodine, preferred fluorine and chlorine.
" acyl group of each seed amino acid preparation ": be meant the group that various amino acid whose carboxyls are obtained after acidylate, preferred neutral a-amino acid is as phenylalanine, tyrosine, leucine.
" cycloalkanes acyl group " is replacement or unsubstituted, and saturated or undersaturated annular termination is connected with the group of carbonyl, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" 4-hetaroylpyrazol " is the group that the aromatic heterocycle end is connected with carbonyl, can be monocycle or bicyclic radicals.Preferable heteroaryl comprises, thienyl for example, furyl, pyrryl, pyridyl, pyrazinyl, thiazolyl, pyrimidyl, quinolyl and tetrazole base, benzothiazolyl, benzofuryl, indyl etc.
" assorted alkyl " refers to saturated or unsaturated, carbon atoms and at least one heteroatomic chain, and wherein any one heteroatoms is non-conterminous.Contain 2-15 atom (carbon atom) in the assorted alkyl, preferably contain 2-10 atom.Assorted alkyl can be direct-connected or side chain, replacement or unsubstituted.
" aryl " is meant the aromatic carbocyclic group.Preferred aromatic ring contains 6-10 carbon atom.
" cycloalkyl " is replacement or unsubstituted, saturated or undersaturated cyclic group, and it contains carbon atom and/or one or more heteroatoms.This ring can be monocycle or condensed ring, the ring system of bridged ring or volution.Monocycle has 3-9 atom usually, preferably has 4-7 atom, and many rings contain 7-17 atom, preferably contain 7-13 atom.
" pharmacy acceptable salt " be meant formula (I), (II) or (III) compound have curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (as carboxyl), or forms cationic salts by arbitrary basic group (as amino).A lot of such salt known in the art.Go up the cationic salts that forms at any acidic-group (as carboxyl), or go up the anion salt that forms at any basic group (as amino).It is known in the art that these salt have many, comprises the salt and the organic salt (as ammonium salt) of basic metal (as sodium and potassium) and alkaline-earth metal (as magnesium and calcium) as cationic salts.Also can obtain anion salt easily by (I) that uses corresponding acid treatment alkaline form, such acid comprises mineral acid such as sulfuric acid, nitric acid, phosphoric acid etc.; Or organic acid such as acetate, propionic acid, oxyacetic acid, 2 hydroxy propanoic acid, 2-oxo propionic acid, oxalic acid, propanedioic acid, succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid, tartrate, 2-hydroxyl-1,2,3-the third three acid, methylsulfonic acid, ethyl sulfonic acid, benzene methanesulfonic acid, 4-toluene sulfonic acide, cyclohexyl-sulfinic acid, 2 hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid etc.These salt are that those of skill in the art know, and those skilled in the art can prepare any salt that this area knowledge is provided.In addition, those of skill in the art can get certain salt according to solubleness, stability, easy preparation etc. and give up another kind of salt.The mensuration of these salt and optimization are in those of skill in the art's experience scope.
" solvate " is the title complex that solute (as inhibitors of metalloproteinase) and solvent (as water) are combined to form.Referring to J.Honig etc., The VanNostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents of not disturbing inhibitors of metalloproteinase (solvent known to for example water, ethanol, acetate, the N, dinethylformamide, dimethyl sulfoxide (DMSO) and this those skilled in the art or that determine easily).
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. have defined the form of The compounds of this invention or all possible steric isomer of its physiological derivative.Unless indication is arranged in addition, the chemical name of The compounds of this invention comprises the mixture of all possible stereochemical form, affiliated mixture comprises all diastereomers and the enantiomorph of basic structure molecule, and the single isomeric forms of the The compounds of this invention of substantially pure, promptly wherein contain and be lower than 10%, preferably be lower than 5%, particularly be lower than 2%, most preferably be lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in the scope of the present invention.
Formula (I), (II) or (III) the class peptide compounds can also other protected form or the form of derivative exist, these forms will be apparent to those skilled in the art, and all should be contained in the scope of the present invention.
Aforesaid substituting group self also can be replaced by one or more substituting groups.Such substituting group is included in C.Hansch and A.Leo, those substituting groups of listing among the Substituent Constants for Correlation Analysis in Chemistry and Biology (1979).Preferred substituted comprises, alkyl for example, thiazolinyl, alkoxyl group, hydroxyl, the oxygen base, nitro, amino, aminoalkyl group (as aminomethyl etc.), cyano group, halogen, carboxyl, carbonylic alkoxy (as carbonyl oxyethyl group etc.), sulfenyl, aryl, cycloalkyl, heteroaryl, Heterocyclylalkyl (as piperidyl, morpholinyl, pyrryl etc.), imino-, hydroxyalkyl, aryloxy, arylalkyl, and combination.
The preparation method of described compound, reactions steps and reaction formula are as follows:
With optics amino acid is raw material, and through esterification protection carboxyl, selective protection one bit amino through polypeptide condensation linking group, is sloughed protecting group in succession, again through polypeptide condensation linking group, methyl esters is being obtained target compound through respective reaction.
Synthetic route:
Above-mentioned R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9Such as claim 1 definition;
Reagent in the above-mentioned reaction formula: (a) ventilation breather, 1mol/L hydrochloric acid, water, 80-90 ℃ of (b) sodium bicarbonate, benzyloxy dicarbonyl chloride, 0 ℃ of (c) saturated oxalic acid tetraacethyl solution, 25 ℃ of (d) methyl alcohol, hydrogenchloride, 25 ℃ (e) as used be various above-mentioned carboxylic acids, methylene dichloride, triethylamine, 4-Dimethylamino pyridine, the 1-hydroxy benzo triazole, 1,1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride ,-5 ℃; As used be the corresponding acyl chlorides of various above-mentioned carboxylic acids, methylene dichloride, triethylamine ,-15 ℃; As the R6 haloalkane, sodium hydrogen, acetonitrile ,-15 ℃ of (f) palladium carbon, hydrogen (g) preparation carboxylic acid: 2mol/L sodium hydroxide, 1mol/L hydrochloric acid, 25 ℃; Preparation hydroxamic acid: azanol potassium, anhydrous methanol, 25 ℃; The preparation hydrazides: 80% hydrazine hydrate, 5 hours (h) bromobenzyls that reflux, salt of wormwood, acetone, the saturated ethyl acetate (j) of 5 hours (i) hydrogenchloride of refluxing is as R
9It is nitro: nitrosonitric acid, oleum, 0 ℃.
The concrete operations step of described compound will be described in detail in an embodiment.
Those skilled in the art can change to improve yield above-mentioned steps; they can determine the synthetic route according to the ABC of this area; as the selective reaction thing, solvent and temperature, thus can improve yield with the generation of avoiding side reaction by using various GPF (General Protection False bases.These conventional guard methods can be referring to for example T.Greene, Protecting Groups in OrganicSynthesis.
Obviously, above-mentioned route is that stereoselectivity is synthetic, also can prepare its optically active class peptide compounds by above-mentioned route.For example raw material L-Methionin, L-ornithine, L-Histidine, L-arginine are replaced with its optical isomer (D configuration).Those skilled in the art can obtain various other isomer of Methionin, ornithine, Histidine, arginine analog derivative easily, and can be by conventional separation means purifying, as chirality salt or chirality chromatography column etc.
Matrix metalloproteinase (MMPs) suppresses active test description in Vijaykumar, M.B. etc., and Matrix Biol.2000 is in 19,26.Succinyl gelatin has proved can be by gelatinase (comprising MMP-2 ,-9) hydrolysis, and the height of the free amine group concentration that peptide bond hydrolysis produces is proportionate with the enzymic activity size.Free amine group in the succinyl oxide protection gelatin, the uncle's ammonia and 2,4 that exposes after the hydrolysis, 6-trinitro-benzene-sulfonic acid (TNBS) reaction solution is determined amino content by the optical density that detects the 450nm place, thereby determines the activity of gelatinase.
Aminopeptidase N (APN) suppresses active test description in Lejczak, and .Biochemistry such as B are in 1989,28,3549.Substrate L-leucyl-p-N-methyl-p-nitroaniline be created in the p-N-methyl-p-nitroaniline that 405nm has absorption, and the size of the concentration of p-N-methyl-p-nitroaniline and enzymic activity is proportionate by Aminopeptidase N (APN) degraded.Determine the content of p-N-methyl-p-nitroaniline by the optical density that detects the 405nm place, thereby determine the activity of aminopeptidase, reflect that indirectly inhibitor suppresses the size of degree to enzymic activity.
The MTT detection method is used in the test of the cytoactive of compound, the HL-60 cell suspension inoculation is in 96 orifice plates), add the substratum that contains the different concns compound in every hole, after hatching, with MTT dyeing, after continuing to hatch, on microplate reader, measure the absorbancy OD value in every hole at the 570nm place, calculate inhibitory rate of cell growth, thereby determine the activity of compound.
General formula (I), (II) or class peptide compounds (III) external presses down enzyme test proves that such peptide compounds is a kind of Methionin, ornithine, Histidine, arginine class peptide inhibitors of metalloproteinase.
Therefore Methionin of the present invention, ornithine, Histidine, arginine derivative spatially are complementary with the MMP activities site, have shown higher inhibition activity external.
The pharmaceutical composition that contains The compounds of this invention:
Part derivative of the present invention can free form or is existed with salt form.Pharmacy acceptable salt of the known chemical compound lot type of those skilled in the art and preparation method thereof.Pharmacy acceptable salt comprises conventional avirulent salt, comprises such compound alkali and quaternary ammonium salt inorganic or that organic acid forms.
Compound of the present invention can form hydrate or solvate.The one skilled in the art known with compound formed hydrate or form the method for solvate when in solution, concentrating during with the water freeze-drying with appropriate organic solvent.
The present invention comprises the medicine that contains the therapeutic dose The compounds of this invention and the pharmaceutical composition of one or more pharmaceutically acceptable carriers and/or vehicle.Carrier comprises as salt solution, buffer saline, and glucose, water, glycerine, ethanol and their binding substances are hereinafter discussed in more detail.If desired, said composition can also comprise wetting agent or emulsifying agent in a small amount, or the pH buffer reagent.Said composition can be liquid, suspension, emulsion, tablet, pill, capsule, extended release preparation or powder.Said composition can be mixed with suppository with traditional tamanori and carrier such as triglyceride.Oral preparations can comprise the mannitol of standard vector such as medicine grade, lactose, starch, Magnesium Stearate, soluble saccharin, Mierocrystalline cellulose and magnesiumcarbonate or the like.Preparation and deciding optionally, preparation can design mixing, granulation and compression or solvent components.In another approach, said composition can be mixed with nano particle.
The pharmaceutical carrier that uses can for, for example, solid or liquid.
The typical solid carrier comprises lactose, terra alba, sucrose, talcum, gel, agar, pectin, gum arabic, Magnesium Stearate, stearic acid or the like.Solid carrier can comprise that one or more may be simultaneously as sweetener, lubricant, solubilizing agent, suspension agent, filler, glidant, compression aid, the material of tackiness agent or tablet-disintegrating agent; It can also be an encapsulating material.In powder, carrier is pulverizing solid, and it mixes with pulverizing activeconstituents.Activeconstituents and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs in tablet.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
Exemplary of liquid carriers comprises syrup, peanut oil, and sweet oil, water, or the like.Liquid vehicle is used to prepare solution, suspension, emulsion, syrup, the composition of tincture and sealing.Activeconstituents can dissolve or be suspended in pharmaceutically acceptable liquid vehicle such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or fat.Liquid vehicle can comprise other suitable medicated premix such as solubilizing agent, emulsifying agent, and buffer reagent, sanitas, sweetener, sweetener, suspension agent, thickening material, pigment, viscosity modifier is stablized shape or osmotic pressure-conditioning agent.The suitable example that is used for the liquid vehicle of oral and administered parenterally comprises that water (partly comprises as above-mentioned additive, derivatived cellulose for example, the preferably carboxymethyl cellulose sodium salt solution), alcohol (comprises monohydroxy-alcohol and polyvalent alcohol, and oils (for example fractionated coconut oil and peanut oil) ethylene glycol for example) and their derivative.The carrier that is used for administered parenterally can also be grease such as ethyl oleate and sec.-propyl myristate.Aseptic liquid vehicle is used for the aseptic fluid composition of administered parenterally.The liquid vehicle that is used for pressurized compositions can be halohydrocarbon or other pharmaceutically acceptable propelling agents.Sterile solution or aaerosol solution composition of liquid medicine can be used for, for example, and intravenously, intramuscular, intraperitoneal or subcutaneous injection.But single pushes or injection gradually during injection, goes into 30 minutes the interior perfusion of passages through which vital energy circulates.This compound can also be with the form oral administration of liquid or solids composition.
Carrier or vehicle can comprise time lag material known in the art, as glyceryl monostearate or distearin, also can comprise wax, ethyl cellulose, Vltra tears, methyl methacrylate or the like.When preparation is used for when oral, generally acknowledge PHOSALPG-50 (phospholipid and 1, the 2-propylene glycol is concentrated, A.Nattermann ﹠amp; Cie.GmbH) 0.01% tween 80 in is used for the preparation of the acceptable oral preparation of other compounds, can be adapted to the preparation of all cpds of the present invention.
Can use medicament forms miscellaneous when giving The compounds of this invention.If the use solid carrier, preparation can be tablet, is placed into powder or piller form or lozenge or lozenge form in the hard capsule.The amount of solid carrier changes to a great extent, but preferably from about 25mg to about 1.0g.If the use liquid vehicle, preparation can be syrup, emulsion, soft capsule, aseptic injectable solution or suspension in the liquid suspension of ampoule or bottle or non-water.
In order to obtain stable water miscible formulation, compound or its pharmacy acceptable salt can be dissolved in the organic or inorganic aqueous acid, 0.3M succsinic acid or citric acid solution.Optionally, the tart derivative can be dissolved in suitable basic solution.If can not get soluble form, compound can be dissolved in suitable cosolvent or their combination.The example of suitable cosolvent like this includes but are not limited to, and concentration range is from the ethanol of 0-60% cumulative volume, propylene glycol, Liquid Macrogol, polysorbate 80, glycerine, polyoxyethylene fatty acid ester, Fatty Alcohol(C12-C14 and C12-C18) or glycerine hydroxy fatty acid ester or the like.
Various release systems are known and can be used for the administration of compound or other various preparations, and these preparations comprise tablet, capsule, and injectable solution, the capsule in the liposome, particulate, microcapsule, or the like.The method of introducing includes, but are not limited to skin, intracutaneous, intramuscular, endoperitoneal, intravenous, subcutaneous, nasal cavity, lung, peridural, eyes and (preferred usually) oral route.Compound can be by administration easily any or that other is suitable, for example by injecting or bolus injection, by epithelium or the mucous membrane circuit (for example, oral mucosa, rectum and intestinal mucosa, or the like) absorb or the support by carrying medicament and can be in other biological promoting agent administration together.Can whole body or topical.Be used for nose, when the treatment of segmental bronchus or lung disease or prevention, preferred route of administration is oral, nasal administration or segmental bronchus smoke substance or atomizer.
The present invention contains as the design of above-mentioned general formula (I), (II) or compound (III) and has adopted class peptide and isostere layout strategy.Class peptide and isostere strategy have been widely used in design and development field antiviral, antitumor drug, its structure is made of the structure that is similar to peptide natural or alpha-non-natural amino acid, but overall conformation is different from natural peptide material again, on the one hand, the class peptide has the intrinsic activity of substrate, can improve selectivity and usefulness simultaneously by the active centre activity of coming inhibitory enzyme of identification enzyme to target site; In addition, class peptide and natural peptide matters exist structural difference and are difficult for by the peptide enzyme liberating, and biologically stable and availability are improved, and the long action time of compound.
Particularly; the present invention is a raw material with optical purity amino acid; by the selective protection mono amino, through condensation, deprotection, the synthetic key intermediate of step such as condensation, esterification again, purpose all is for avidity that strengthens compound and enzyme or acceptor and metabolic stability.
The present invention designs the inhibitors of metalloproteinase that synthetic one class has the brand new parent nucleus, and but in vitro tests shows its acellular cytotoxic activity but embodies remarkable vitro enzymic activity, is expected to become the anticancer drug candidate of a class non-cytotoxicity class.
Description of drawings
Fig. 1 is a compound N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-N
1-hydroxyl-L-ornithyl amine (wq09) dock with the active region of Aminopeptidase N (APN) result by Sybyl7.0 with the 3-D display synoptic diagram.
Fig. 2 is a compound N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-N
1-hydroxyl-L-ornithyl amine (wq09) docks the result with the active region of Aminopeptidase N (APN) and shows synoptic diagram by Ligplot with two dimension.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited thereto.
Synthesizing of embodiment 1. The compounds of this invention
1. with N
6-(2,4 dichloro benzene formyl radical)-N
2-benzenesulfonyl-N
1-hydroxyl-L-lysyl amine is example:
1) N
6The preparation of-[(benzyloxy) carbonyl]-L-Methionin (1)
2.92g Methionin, 2.25g ventilation breather are dissolved in the 50ml 1mol/L hydrochloric acid, 80-90 ℃ was stirred 2 hours, filtered.After the cooling, transfer pH value to 8～9 with sodium bicarbonate, stand-by.4.2g benzyloxy dicarbonyl chloride is dissolved in the 30ml acetone, splashes in the above-mentioned solution under the cryosel bath condition, stirred 12 hours, filter.Filter cake is suspended in the saturated oxalic acid tetraacethyl of the 50ml solution, stirs 24 hours, filters, and repeats 2 times, and last gained filtration cakes torrefaction gets white powder 4.3g, productive rate 76%.
2) N
6The preparation of-[(benzyloxy) carbonyl]-L-lysine methyl ester hydrochloride (2)
In 250 milliliters the three-necked bottle, add 40 gram N
6-[(benzyloxy) carbonyl]-L-Methionin adds 120 milliliters anhydrous methanol again, stirs and makes its suspendible.Ice bath, logical HCl gas, the deicing of dropping back was bathed in 30 minutes, continued logical HCl gas 5-6 hour, and concentrating under reduced pressure adds a small amount of anhydrous diethyl ether crystallization, the anhydrous diethyl ether washing, drying gets white solid 38.7 grams, productive rate 82%, fusing point 118-120 ℃.
3) N
6-[(benzyloxy) carbonyl]-N
2The preparation of-benzenesulfonyl-L-lysine methyl ester (3)
Compound (2) 3.3 gram places 50 milliliters of anhydrous methylene chlorides, stirs, and slowly drips 1.5 milliliters of anhydrous triethylamines, drip finish after, continue to stir 30 minutes.After slowly splash into 1 times of equivalent benzene sulfonyl chloride again, TLC detects.
Reaction is finished, and removes solvent under reduced pressure, adds 100 milliliters of ethyl acetate, uses 1N hydrochloric acid, saturated aqueous common salt, saturated sodium bicarbonate, saturated common salt water washing successively.Organic phase is spent the night with anhydrous sodium sulfate drying, and silicagel column separates (sherwood oil: ethyl acetate=4:1), get white solid 3.7 grams, productive rate 86%.
4) N
6-amino-N
2The preparation of-benzenesulfonyl-L-lysine methyl ester (4)
Press mass ratio 20:1,1.0g compound (3) and 0.5g palladium carbon are suspended in the 20ml anhydrous methanol, sealing feeds hydrogen, stirs 24 hours, filters, and solvent is divided exactly in decompression, and drying gets transparent oily matter, productive rate 96%.
5) N
6-(2,4 dichloro benzene formyl radical)-N
2The preparation of-benzenesulfonyl-L-lysine methyl ester (5)
Compound (4) 3.0 gram places 50 milliliters of anhydrous methylene chlorides, stirs, and slowly drips 1.5 milliliters of anhydrous triethylamines, drip finish after, continue to stir 30 minutes.After slowly splash into 1 times of equivalent 2,4 dichlorobenzyl chloride again, TLC detects.
Reaction is finished, and removes solvent under reduced pressure, adds 100 milliliters of ethyl acetate, uses 1N hydrochloric acid, saturated aqueous common salt, saturated sodium bicarbonate, saturated common salt water washing successively.Organic phase is spent the night with anhydrous sodium sulfate drying, and silicagel column separates (sherwood oil: ethyl acetate=4:1), get white solid 3.6 grams, productive rate 78%.
6) NH
2The preparation of OK
The saturated absolute methanol solution of 14mL KOH is added drop-wise in the absolute methanol solution that 24mL contains 4.67g (67mmol) oxammonium hydrochloride, and temperature is lower than 40 ℃ in the control, dropwise, and the cooling reaction solution, filtering white KCl precipitation, the airtight preservation of gained filtrate is standby.
7) N
6-(2,4 dichloro benzene formyl radical)-N
2-benzenesulfonyl-N
1The preparation of-hydroxyl L-lysyl amine
Compound (5) 1.6 grams add above-mentioned 16 milliliters of NH
2The absolute methanol solution of OK stirs room temperature reaction, TLC detection reaction process.Reaction is finished, and glacial acetic acid transfers pH value near neutral.Remove methyl alcohol under reduced pressure, add 50 milliliters of ethyl acetate, saturated common salt water washing 3 times.Anhydrous sodium sulfate drying, (methylene dichloride: methyl alcohol=20:1) separate gets white solid 0.3 gram, productive rate 19% to silicagel column.mp＝144-146℃。ESI-MS?m/z：474.2(M+H)：
1H-NMR(DMSO-d6，δ?ppm)：1.052-1.508(m，6H)，3.017-3.167(m，2H)，3.348-3.567(m，1H)，7.393-7.794(m，8H)，8.026-8.054(d，J＝8.4Hz，1H)，8.407(t，J＝11.1Hz，1H)，8.851(s，1H)，10.621(s，1H)。
Embodiment 2 target compounds suppress gelatinase activity test (In vitro)
Test principle and detailed test procedure are referring to CN 1528745A pyrrolidinyl metalloprotease inhibitor and preparation method thereof, and experimental result sees Table 1.
Embodiment 3 target compounds suppress the activity test (In vitro) of Aminopeptidase N
Test principle and detailed test procedure are referring to CN 1974554A cyclin imide peptidyl metalloprotease inhibitor and application thereof, and experimental result sees Table 1.
The external enzyme test result that presses down of table 1.
aNumerical value is the mean value of three tests in the table, the numeric representation standard deviation after " ± ".
Last table test data shows that compound wq09, wq16,6a, 12p all are better than the positive control drug ubenimex to the inhibition activity of Aminopeptidase N, have the excellent development prospect.
Embodiment 4 target compounds suppress the activity test (In vitro) of cell proliferation
1.[material] the HL-60 cell strain, the blue MTT of tetramethyl-azo azoles, 10% foetal calf serum, 96 orifice plates
2.[method]
Cell cultures people's acute myeloblastic leukemia cell HL60 is introduced by Chinese Academy of Sciences's Shanghai cell.Adopt conventional the cultivation.All use the logarithmic phase cell during experiment.
The cell growth detects (mtt assay) HL-60 cell suspension and is adjusted to 1 * 10
5/ ml is inoculated in 96 orifice plates (50 μ l/ hole), 10
4Individual cells/well.Behind the bed board 4h, add the substratum that 50ul contains the different concns compound in every hole, 800,600,400,200,100ug/ml make that the compound final concentration is respectively in the hole:, each concentration is established three multiple holes, do blank when not adding the hole reading of cell, add the hole that cell do not add compound and make the compound blank well, ubenimex is made the compound positive control.In 37 ℃, 5% CO
2In hatch 48h, every hole adds the MTT staining fluid of 10 μ l 0.5%, after continuing to hatch 4h, 2500rpm, centrifugal 30min throws plate then and abandons substratum in the hole, adds DMSO, 100ul/ hole.Measure the absorbancy OD value in every hole on the microplate reader in the 570nm place, inhibitory rate of cell growth is calculated as follows:
Table 2 cell proliferation experiment result
| Compound | IC 50(mM) | Compound | IC 50(mM) | Compound | IC 50(mM) | Compound | IC 50(mM) |
| Ubenimex | 1.65 | 9b | 0.0029 | 12h | 1.24 | wq09 | 2.48 |
| 6b | 2.67 | 12c | 0.36 | 12o | 1.79 | wq10 | 8.91 |
| 6c | 0.08 | 12d | 1.09 | 12p | 1.74 | wq16 | 4.20 |
| 9a | 0.0098 | 12e | 0.92 | 12r | 0.94 | wq17 | 8.37 |
Last table test data shows, the performance of most compounds in cell proliferation experiment all near or be better than the positive control drug ubenimex, have the excellent development prospect.
The structure activity study of embodiment 5 target compounds
Application software Sybyl7.0 docks target compound with the active region of Aminopeptidase N (APN), accompanying drawing 1 has been showed the butt joint result who has better active compound wq09 in this series.
As shown in Figure 1, the configuration of compound wq09 and the configuration of ubenimex and the active region of Aminopeptidase N (APN) certain similarity is arranged when combining, wq09 can occupy the hydrophobicity pocket of Aminopeptidase N (APN) well, simultaneously the zine ion that carbonyl in the structure and amino can chelating Aminopeptidase N (APN) active regions.Fig. 2 is the two-dirnentional structure synoptic diagram that docks with Aminopeptidase N (APN) with Ligplot mimic wq09, and we can obtain from figure, the Gly of wq09 and Aminopeptidase N (APN) catalytic center
261, Ala
262, Ser
826, Lys
864Can form intermolecular hydrogen bonding, go back and Met
260, Tyr
376, Arg
825Has the hydrophobicity effect.Thereby these constitutional featuress carry out the structure activity study rational expectation for us and design has the active APN inhibitor of better inhibition foundation is provided.
Claims (10)
1. the compound of general formula I, II or III:
Wherein,
N is 3 or 4;
R
1Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
2Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
3Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
4Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
5Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
6Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy; Also can be aryl, heteroaryl, aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl or C1-6 alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
7Be hydrogen, the acyl group of each seed amino acid preparation, aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl, heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl, assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, carboxyl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy;
R
8Be the hydroxamic acid base, carboxyl, methoxycarbonyl or hydrazide group;
R
9Be various amino protecting groups, as nitro, tertbutyloxycarbonyl, carbobenzoxy-(Cbz), fluorenylmethyloxycarbonyl, 2-xenyl-2-third oxygen carbonyl, phthalimide-based, p-toluenesulfonyl, trityl, formyl radical, ethanoyl, trifluoroacetyl group
Wherein, when n=4, general formula I is the Methionin skeleton; When n=3, general formula I is the ornithine skeleton;
Specify, when n=4, R
1Be to remove aroyl, 4-hetaroylpyrazol, aryl C1-6 alkyloyl; the acyl group of each the seed amino acid preparation beyond the heteroaryl C1-9 alkyloyl, C1-6 alkyloyl, arylsulfonyl; assorted alkylsulfonyl, aryl C1-6 alkane alkylsulfonyl or heteroaryl C1-9 alkane alkylsulfonyl, optional by one or more following groups replacements: hydroxyl; halogen, nitro, cyano group; carboxyl, halogen C1-8 alkyl, C1-8 alkoxyl group; C1-6 alkyl-carbonyl, C1-8 carbalkoxy or aryl C1-8 carbalkoxy.
2. compound as claimed in claim 1 is characterized in that: among formula I, II or the III
*Shown carbon has the S configuration.
3. compound as claimed in claim 1 or 2 is characterized in that: R
1, R
3, R
4, R
6Be aryl C1-6 alkyloyl, preferred para-orientation benzoyl group, the preferred electron withdrawing group of substituting group; R
1, R
3, R
4, R
6Be aryl C1-6 alkane alkylsulfonyl, preferred para-orientation benzenesulfonyl, the preferred electron withdrawing group of substituting group; R
1, R
3, R
4, R
6Be the acyl group of each seed amino acid preparation, preferred phenylalanine, tyrosine.
4. compound as claimed in claim 1 or 2 is characterized in that: R
2, R
5Be the hydroxamic acid base, carboxyl, methoxycarbonyl, hydrazide group, preferred hydroxamic acid base.
5. compound as claimed in claim 1 or 2 is characterized in that: R
9It is nitro.
6. compound as claimed in claim 1 is characterized in that it being one of following compound:
N
6-benzoyl-N
2-benzoyl-L-Methionin,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-L-Methionin,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(3-chlorobenzene formacyl)-L-Methionin,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(2,4 dichloro benzene formyl radical)-L-Methionin,
N
6-benzoyl-N
2-(4-Methyl benzenesulfonyl base)-L-Methionin,
N
6-(3-chlorobenzene formacyl)-N
2-(3-chlorobenzene formacyl)-N
1-hydroxyl-L-lysyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-(2,4 dichloro benzene formyl radical)-L-ornithine,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-L-ornithine,
N
6-(4-nitro benzoyl)-N
2-(4-nitro benzoyl)-N
1-hydroxyl-L-ornithyl amine,
N
6-[(benzyloxy) carbonyl]-N
2-[(2S)-and 2-amino-3-phenyl] carbonyl }-N
1-hydroxyl-L-lysyl amine,
N
6-(4-Methyl benzenesulfonyl base)-N
2-(4-Methyl benzenesulfonyl base)-L-ornithine,
N
6-(4-Methyl benzenesulfonyl base)-N
2-(4-Methyl benzenesulfonyl base)-N
1-hydroxyl-L-ornithyl amine,
N
6-(4-chlorobenzene formacyl)-N
2-(4-chlorobenzene formacyl)-L-Methionin,
N
6-(2-chlorobenzene formacyl)-N
2-(2-chlorobenzene formacyl)-L-ornithine,
N
6-(2-chlorobenzene formacyl)-N
2-(2-chlorobenzene formacyl)-L-Methionin,
N
6-benzenesulfonyl-N
2-benzenesulfonyl-N
1-hydroxyl-L-ornithyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-benzenesulfonyl-N
1-hydroxyl-L-lysyl amine,
N
6-(2,4 dichloro benzene formyl radical)-N
2-benzoyl-N
1-hydroxyl-L-lysyl amine,
N
6-benzenesulfonyl-N
2-benzenesulfonyl-L-ornithine,
1-(2,4 dichloro benzene formyl radical)-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
1-benzenesulfonyl-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
1-(4-Methyl benzenesulfonyl base)-N-(4-Methyl benzenesulfonyl base)-N '-hydroxyl-L-histidyl-amine,
1-(4-nitro benzoyl)-N-benzenesulfonyl-N '-hydroxyl-L-histidyl-amine,
(2S)-2-amino-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2,4 dichloro benzene formamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-hydrocinnamamide base-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-tolysulfonyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-benzene sulfonamido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-cinnyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-benzamide base-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-brombenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-iodobenzene formamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4-dimethoxy benzoylamino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-naphthoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(1-thenoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-chloro-benzoyl amino)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4,5-trimethoxy-benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-phenylacetyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-methoxy benzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-nitro-4-brombenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,4-dichloro-benzoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(3,5-dinitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-to hydroxyl cinnyl amido-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-nitrobenzamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-toluyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-pyrrolidine formamido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-5-guanidine radicals valeryl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-4-methylpent amide group)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino propionamido-of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-methylbutyryl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-methylpent amide group)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-4-methylthio group amide-based small)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-Phenylpropionamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(3-indyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-glycyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-hydroxyl propionamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-maloyl group amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-amino-3-sulfydryl propionamido-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino succinoamino of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino glutaryl amido of 2-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(4-hydroxy phenyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2-aminosuccinic acid monoamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2 aminopentanedioic acid monoamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(2,6-diamino hexanoyl amido)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-[2-amino-3-(5-imidazolyl) propionamido-]-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(the amino propionamido-of 3-)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide,
(2S)-2-(4-amino-butanamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide or
(2S)-2-(6-aminocaproamide base)-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide.
7. the intermediate of preparation claim 1 or 2 described compounds is characterized in that: N
6-[(benzyloxy) carbonyl]-L-Methionin, N
6-[(benzyloxy) carbonyl]-L-ornithine, N-[(tert.-butoxy) carbonyl]-L-Histidine benzyl ester or (2S)-2-amino-N-hydroxyl-5-(3-nitro guanidine radicals) valeramide.
8. the preparation method of the described compound of claim 1 is characterized in that with optics amino acid be raw material, and selecting L-Methionin for use is example, and in succession through esterification, selective protection 6-bit amino connects R through the polypeptide condensation
1Group is sloughed protecting group, connects R through the polypeptide condensation
3Group is sloughed ester group through respective reaction at last and is obtained target compound; Reaction formula is as follows:
Above-mentioned R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9Such as claim 1 definition;
Reagent in the above-mentioned reaction formula: (a) ventilation breather, 1mol/L hydrochloric acid, water, 80-90 ℃ of (b) sodium bicarbonate, benzyloxy dicarbonyl chloride, 0 ℃ of (c) saturated oxalic acid tetraacethyl solution, 25 ℃ of (d) methyl alcohol, hydrogenchloride, 25 ℃ (e) as used be various above-mentioned carboxylic acids, methylene dichloride, triethylamine, 4-Dimethylamino pyridine, the 1-hydroxy benzo triazole, 1,1-ethyl-3-(3-dimethylamine propyl) carbodiimide hydrochloride ,-5 ℃; As used be the corresponding acyl chlorides of various above-mentioned carboxylic acids, methylene dichloride, triethylamine ,-15 ℃; As R
6Use haloalkane, sodium hydrogen, acetonitrile ,-15 ℃ of (f) palladium carbon, hydrogen (g) preparation carboxylic acid: 2mol/L sodium hydroxide, 1mol/L hydrochloric acid, 25 ℃; Preparation hydroxamic acid: azanol potassium, anhydrous methanol, 25 ℃; The preparation hydrazides: 80% hydrazine hydrate, 5 hours (h) bromobenzyls that reflux, salt of wormwood, acetone, the saturated ethyl acetate (j) of 5 hours (i) hydrogenchloride of refluxing is as R
9It is nitro: nitrosonitric acid, oleum, 0 ℃.
9. each compound of claim 1-6 comprises matrix metalloproteinase or Aminopeptidase N at preparation prevention or treatment and metalloprotease, the application in the medicine of the mammalian diseases that active unconventionality expression is relevant; Described and the related mammalian disease metal proteinase activity unconventionality expression comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer venereal disease disease, periodontopathy, epidermolysis bullosa and leukemia.
10. pharmaceutical composition comprises each compound and one or more pharmaceutically acceptable carriers or vehicle of claim 1-6.
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| WO2013026942A1 (en) | 2011-08-25 | 2013-02-28 | The Provost, Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin | Tubulin binding agents |
| CN103893813A (en) * | 2012-12-28 | 2014-07-02 | 财团法人工业技术研究院 | Polymer composition and polymer material |
| CN109020846A (en) * | 2018-07-25 | 2018-12-18 | 山东大学 | O- replaces tyrosine Bcl-2 protein inhibitor and preparation method and application |
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2009
- 2009-01-21 CN CN2009100138951A patent/CN101481325B/en not_active Expired - Fee Related
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101811976A (en) * | 2010-04-07 | 2010-08-25 | 北京欧凯纳斯科技有限公司 | Preparation method of N omega-methyl-lysine |
| CN101811976B (en) * | 2010-04-07 | 2013-01-30 | 北京欧凯纳斯科技有限公司 | Preparation method of N omega-methyl-lysine |
| WO2013026942A1 (en) | 2011-08-25 | 2013-02-28 | The Provost, Fellows, Foundation Scholars, And The Other Members Of Board, Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth, Near Dublin | Tubulin binding agents |
| CN103893813A (en) * | 2012-12-28 | 2014-07-02 | 财团法人工业技术研究院 | Polymer composition and polymer material |
| CN109020846A (en) * | 2018-07-25 | 2018-12-18 | 山东大学 | O- replaces tyrosine Bcl-2 protein inhibitor and preparation method and application |
| CN109020846B (en) * | 2018-07-25 | 2020-12-29 | 山东大学 | O-substituted tyrosine Bcl-2 protein inhibitor, preparation method and application thereof |
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