CN101538311A - Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof - Google Patents
Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof Download PDFInfo
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- CN101538311A CN101538311A CN200910020656A CN200910020656A CN101538311A CN 101538311 A CN101538311 A CN 101538311A CN 200910020656 A CN200910020656 A CN 200910020656A CN 200910020656 A CN200910020656 A CN 200910020656A CN 101538311 A CN101538311 A CN 101538311A
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Abstract
The invention relates to an alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and an application thereof. The invention provides a powerful peptoid metalloprotease inhibitor which embodies outstanding selectivity between endopeptidases and exopeptidases so as to effectively treat diseases expressed by abnormal metalloprotease activity. Specifically, the invention relates to a peptoid compound with a structure of a general formula (I) and salt thereof acceptable on pharmacy. The invention also relates to a medical composition of the peptoid compound with the structure of the formula (I) and the pharmacy application thereof.
Description
Technical field
The present invention relates to a class and have inhibitors of metalloproteinase of alpha-amido acyl-ring imide peptoid skeleton 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 activity of matrix metalloproteinase (MMPs) is by the strict control of the secretion level of gene expression dose and activation of zymogen/supressor.Matrix metalloproteinase (MMPs) plays an important role in extracellular matrix degradation, tissue reconstruction process.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.et al.Clinical and Applied Immunology Reviews.2004,4 of matrix metalloproteinase (MMPs) family in Mammals, have been found at present, 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.; Etal.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 the false monospore of verdigris army, 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) participates in the degraded of substrate N terminal amino acid for depending on the metal exopeptidase of zine ion.Under the normal condition, APN is extensive low expression level in tissues such as mammiferous kidney, small intestine and central nervous system, participates in the physiological regulation of body.Studies have shown that Aminopeptidase N plays an important role in tumour generation, immunologic function adjusting and virus infection.1) APN is at the tumor cell surface high level expression.This enzyme can make the main component degraded of extracellular matrix (ECM), has destroyed the natural cover for defense of body, promotes invasion by tumor cells, growth and transfer, participates in the tumour neovascularity and generates.(Saiki，I.；et?al.Iht.J.Cancer.，1993，54，137；Sato，Y.Biol.Pharm.Bull.，2004，772，776)。2) 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 recognition capability of T cell, weakened scavenger cell and NK cell identification and kill capability simultaneously, immunity of organisms is descended tumour cell.3) APN plays an important role in upper respiratory tract infection (as: SARS) and acute enteritis as the acceptor on human corona virus HCoV-229E and Transmissible gastroenteritis virus (TGEV) surface, and its relevant (Delmas of activity with enzyme of playing a role, B., et al.Nature, 1992,357,417; Yeager, C.L.; Et al.Nature, 1992,357,420).4) APN participates in the process that the HIV virion enters host cell.Studies show that the 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 APN of high expression level 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) APN participates in the degraded of endogenous analgesic matter endorphin and enkephalin, thus cause the excessive release of P material, cause pain.6) APN degraded Angiotensin, adjusting (Mitsui, the T. of participation body blood pressure; Et al.Biol.Pharm.Bull., 2004,27,768.).
Since the nineties, develop many matrix metalloproteinases (MMPs) inhibitor, great majority are the analogue of peptide or peptide, degraded to enzyme is relatively more responsive, in addition because great majority have backbone, therefore contained rotatable singly-bound number is many, and to bad with the member's selectivity in the family, this also is most of matrix metalloproteinases (MMPs) inhibitor at the reason place that clinical stage is had one shot.Inhibitor at APN mostly is natural product in addition, the medicine 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.The inhibitors of metalloproteinase of being reported in the document is not considered the selective problems to the two (endopeptidase and exopeptidase) at present, does not therefore do deep discussion from the mechanism of action aspect.
As everyone knows, because it is little that peptide molecule generally all exists solubleness, bioavailability is low, metabolic stability is poor, very easily limited its clinical application by shortcoming such as various peptide enzyme liberating that extensively exist in the body, class peptide (Peptidomimetics, have another name called peptide analogs or peptide mimics) become novel antitumor owing to himself advantage is expected to replace polypeptide, the strategy of antiviral design and development: 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, it is difficult by the peptide enzyme liberating that class peptide and native peptides class substrate exist structural difference, biologically stable and availability height, and the long action time of compound; On the other hand, the class peptide can be simulated the native conformation of part, is complementary with the combining site of acceptor, brings into play the effect of its agonist or antagonist.In a word, class peptide layout strategy provides a valid approach for the new drug design and development, also will become antitumor, inverase hot of research and development field simultaneously.
The present invention combines MMP and APN and studies, because matrix metalloproteinase and Aminopeptidase N all belong to zine ion dependency lytic enzyme, and all participate in the degraded of extracellular matrix main component IV Collagen Type VI enzyme and the generation of tumour neovascularity, difference only is that the former is the secretor type endopeptidase, and the latter is the membranous type exopeptidase.When the design compound, introduced class peptide and conformation restriction strategy among the present invention, can improve identification and selectivity on the one hand, improved stability on the other hand lytic enzyme to target.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 in micromole's rank and embodies special selectivity the inhibition activity of MMP among the present invention, is directed to the APN screening active ingredients in addition and finds that its activity of several drug molecules all is better than the ubenimex of present unique listing.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and its production and use is provided.
The present invention is a raw material with optically pure glutamine or l-asparagine, protects amino acid whose free amine group, is converted into the cyclin imide skeleton that conformation limits by the condensing agent cyclization again by Boc on this basis, improves the selectivity to target.Under the condition of phase-transfer catalyst TBAI with ethyl bromoacetate or benzyl acetate bromide to the synthetic key intermediate of imide nitrogen atom alkylation, the dissociate amino that of the Boc group of sloughing intermediate obtains the class dipeptides or the class tripeptides of different series again with mixed anhydride method with the amino acid derivative of Boc protection.Therefore amino acid can improve the consistency of compound to tissue owing to have natural character.Sloughing benzyl ester protection obtains carboxy intermediate and sloughs the Boc protection again or carboxyl is converted into its hydroxamic acid derivs and slough the Boc protecting group again and finally obtain semicarbazide hydrochloride.Purpose all is for avidity that strengthens compound and enzyme or acceptor and metabolic stability and improves bioavailability.
The present invention designs and has synthesized the inhibitors of metalloproteinase that a class has the brand new parent nucleus.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.
Technical scheme of the present invention is as follows:
Class peptide compounds and pharmacy acceptable salt thereof with general formula I:
Wherein,
R
1Be the side chain of natural amino acid, preferred hydrogen, phenylalanine, Xie Ansuan, leucine, Isoleucine, L-Ala, tyrosine, lysine residue;
R
2Be hydrogen;
R
3Be OH, OC
2H
5Or NHOH;
N is 1 or 2;
* be that steric configuration is S or R optical purity or its raceme.
Above-mentioned class peptide compounds (I) specifically comprises following compound:
(S)-ethyl 2-(3-(2-glycyl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-(the amino propionamido-of (S)-2-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((2S, 3R)-2-amino-3-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(1H-imidazol-4 yl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-4-(methylthio group) amide-based small)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(1H-indol-3-yl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(4-hydroxy phenyl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-2,6-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) piperidines-1-yl) acetic ester hydrochloride;
(S)-2-(3-(2-glycyl amido)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-(the amino propionamido-of (S)-2-)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((2S, 3R)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,6-dioxopiperidin-1-yl) acetate dihydrochloride;
2 ((S)-2,6-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) piperidines-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-(4-hydroxyl-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
(S)-2-amino-N-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) acetamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) propionamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-methylbutyryl amine hydrochlorate;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-4-methylpent amide hydrochloride;
(2S, 3R)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-methylpent amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-Phenylpropionamide hydrochloride;
(S)-2,6-diamino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-hexanamide hydrochloride;
(S)-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) tetramethyleneimine-2-carbonyl amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-(4-hydroxy phenyl) propionamide hydrochloride;
(S)-2-(3-(2-glycyl amido)-2,5-dioxy oxygen pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-(the amino propionamido-of (S)-2-)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((2S, 3R)-2-amino-4-methylpent amide group)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,5-dioxy pyrroles-1-yl) acetate dihydrochloride;
2-((S)-2,5-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-(4-tertiary butyloxycarbonyl oxygen base) Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
(S)-2-amino-N-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) acetamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) propionamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-methylbutyryl amine hydrochlorate;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-4-methylpent amide hydrochloride;
(2S, 3R)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-methylpent amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-Phenylpropionamide hydrochloride;
(S)-2,6-diamino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-hexanamide hydrochloride;
(S)-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) tetramethyleneimine-2-carbonyl amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-(4-hydroxy phenyl) propionamide hydrochloride.
The class peptide compounds intermediate of above-mentioned general formula (I) is: (S)-tertiary butyl 2,6-dioxopiperidin-3-base carbonyl acid amides; (S)-ethyl 2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-and ethyl 2-(3-amino)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-and the tertiary butyl 2,5-2,5-dioxy pyrroles-3-base carbonyl acid amides; (S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,5-dioxy pyrroles-1-yl) acetic ester.
The preparation method of above-mentioned class peptide compounds; with optically pure glutamine or l-asparagine is raw material; by Boc protection, cyclization, the synthetic key intermediate of alkylation under the condition of phase-transfer catalyst; again by obtaining the class dipeptides or the class tripeptides of different series with mixed anhydride method, slough the protection of benzyl ester and obtain carboxy intermediate and take off the Boc protection again or carboxyl is converted into its hydroxamic acid derivs and slough the Boc protecting group again and obtain semicarbazide hydrochloride with the amino acid derivative of Boc protection.
These class peptide compounds comprise matrix metalloproteinase (MMP) and 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 tissues stain ulcers or tissue ulcer's venereal disease disease, periodontopathy, epidermolysis bullosa, leukemia etc.Therefore, the invention still further relates to the pharmaceutical composition that contains (I) structural compounds.
A kind of pharmaceutical composition comprises (1) above-mentioned each class peptide compounds and (2) one or more pharmaceutically acceptable carriers or vehicle.
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises (1) above-mentioned arbitrary class peptide compounds and (2) pharmaceutically acceptable carrier, optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
In addition, the present invention comprises that also a kind of parenteral that is suitable for gives mammiferous pharmaceutical composition, comprises (1) above-mentioned arbitrary class peptide compounds and (2) pharmaceutically acceptable carrier, optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
Class peptide and conformation layout strategy have been adopted in the design that the present invention contains the compound of general formula (I) first.Class peptide and conformation restriction 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 by being different from natural peptide material, 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, it is difficult by the peptide enzyme liberating that class peptide and natural peptide matters exist structural difference, biologically stable and availability height, and the long action time of compound.
Detailed Description Of The Invention
Used definition and term
Term and definition implication used herein is as follows:
" pharmacy acceptable salt " is meant that formula (I) compound has curative effect and nontoxic salt form.It can form anion salt by arbitrary acidic-group (as carboxyl), or forms cationic salts by arbitrary basic group (as amino).A lot of such salt known in the art.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).These salt are known in the art by many formulas, comprise 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 formulas 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.
The form of all right other protected form of formula (I) class peptide compounds or derivative exists, and these forms will be apparent to those skilled in the art, and all should be contained in the scope of the present invention.
Synthetic
Target compound is synthetic through following route.
In brief; the preparation method of the class peptide compounds of above-mentioned general formula (I); the present invention is a raw material with optically pure glutamine or l-asparagine; protect amino acid whose free amine group, be converted into the cyclin imide skeleton that conformation limits by the condensing agent cyclization again by Boc on this basis, improve selectivity target.Under the condition of phase-transfer catalyst TBAI, key intermediate is synthesized in the imide nitrogen atom alkylation with ethyl bromoacetate or benzyl acetate bromide; the dissociate amino that of the Boc group of sloughing intermediate obtains the class dipeptides or the class tripeptides of different series again with mixed anhydride method with the amino acid derivative of Boc protection; therefore amino acid can improve the consistency of compound to tissue owing to have natural character.Sloughing benzyl ester protection obtains carboxy intermediate and sloughs the Boc protection again or carboxyl is converted into its hydroxamic acid derivs and slough the Boc protecting group again and finally obtain semicarbazide hydrochloride.Purpose all is for avidity that strengthens compound and enzyme or acceptor and metabolic stability and improves bioavailability.Concrete synthetic route designs in conjunction with the state of the art according to certain concrete compound that will prepare.
Be example with cyclin imide peptidyl derivative below with phenylalanine side chain, the synthetic route of this compounds of declaratives and preparation method.
Synthetic route one
Reagent: a N-hydroxyl succinyl-industry amine, dicyclohexylcarbodiimide, tetrahydrofuran (THF), 66 ℃; The b ethyl bromoacetate, tetrabutyl iodate ammonia, acetone, salt of wormwood, 56 ℃; The c trifluoroacetic acid, methylene dichloride; D Boc protects amino acid, triethylamine, tetrahydrofuran (THF), dicyclohexylcarbodiimide, 1-hydroxyl-benzo-triazole; E ethyl acetate-hydrogen chloride solution.
Synthetic route two
Reagent: a benzyl acetate bromide, tetrabutyl iodate ammonia, acetone, salt of wormwood, 56 ℃; The b trifluoroacetic acid, methylene dichloride; C N-methylmorpholine, tetrahydrofuran (THF), isobutyl chlorocarbonate, Boc protects amino acid; The d tetrahydrobenzene, ethanol, 5% palladium/carbon, 45 ℃; E ethyl acetate-hydrogen chloride solution; The f isobutyl chlorocarbonate, triethylamine, tetrahydrofuran (THF), oxammonium hydrochloride.
Synthetic route three
Reagent: a N-hydroxy-succinamide, dicyclohexylcarbodiimide, tetrahydrofuran (THF), 66 ℃; The b benzyl acetate bromide, tetrabutyl iodate ammonia, acetone, salt of wormwood, 56 ℃; The c trifluoroacetic acid, methylene dichloride; D N-methylmorpholine, tetrahydrofuran (THF), isobutyl chlorocarbonate, Boc protects amino acid; The e tetrahydrobenzene, ethanol, 5% palladium/carbon, 45 ℃; F ethyl acetate-hydrogen chloride solution; The g isobutyl chlorocarbonate, triethylamine, tetrahydrofuran (THF), oxammonium hydrochloride.
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, can also can prepare its optically active class peptide compounds by above-mentioned route.Those skilled in the art can obtain various other isomer of cyclic imide derivative easily, and can be by conventional separation means purifying, as chirality salt or chirality chromatography column etc.
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.
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 is degraded by APN, 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.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 class peptide compounds of general formula (I) external presses down enzyme test proves that such peptide compounds is a kind of cyclin imide peptidyl metalloprotease inhibitor.
Therefore cyclic imide derivative of the present invention spatially is complementary with the MMP activities site, has shown higher inhibition activity external.
Preparation, pharmaceutical composition, dosage and taking
Cyclic imide 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 one 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.In tablet, Mars composition and the carrier with necessary compression property are with suitable mixed, with the shape and the size compression of needs.Powder and tablet preferably comprise 99% activeconstituents at the most.Suitable solid carrier comprises, for example, and calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gel, Mierocrystalline cellulose, methylcellulose gum, sodium carboxymethyl-cellulose, polyvinylpyrrolidone alkane ketone, low melt wax and ion exchange resin.
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, ylmethyl Mierocrystalline cellulose in the hydroxyl, 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.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited thereto.
The preparation of embodiment 1. ethyl 2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride (6f)
(S)-and the tertiary butyl 2,6-dioxopiperidin-3-base carbonyl acid amides (2)
The Boc-L-glutamine (41.6g, 0.17mol) and N-hydroxy-succinamide (NIISu, 19.5g 0.17mol) are dissolved among the 200ml THF, slowly drip 100ml under the cryosel bath condition and contain DCC (35.1g, THF solution 0.17mol).Dripped off in about 1 hour, and removed the ice bath stirring at room and refluxed 10 hours after 3 hours.Reaction solution is cooled to room temperature, and rotary evaporation reclaims solvent.Residue adds 50ml ethyl acetate reconcentration once.After the final residue thing added the 200ml ethyl acetate, the freezing placement of refrigerator was spent the night.With 4.0 gram diatomite filtrations, filtrate water (50ml*1) and saturated brine (50ml*1) washing, NaSO
4Dry. filter, be concentrated into dried.Again with exquisite plate crystal 35.7g, 211.5-213.8 ℃ of the yield 75%:mp (literature value 212-214 ℃) of getting of ethyl acetate-ether; IR (KBr, cm
-1): 3356,3247,1728,1695,1531; ESI-MS m/z[M+1]
+: 229.6; 1H-NMR (300MHz, DMSO-d
6): 10.76 (s, 1H), 4.27-4.18 (m, 1H), 2.77-2.65 (m, 2H), 1.95-1.87 (m, 2H), 1.39 (s, 9H).
(S)-ethyl 2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester (3)
With compound 2 (14.6g, 0.064mol), K
2CO
3(10.6g, 1.2e.q), (0.1e.q.) DL is in the 500ml anhydrous propanone for TBAI, 2.5g for tetrabutylammonium iodide.The slow down adding ethyl bromoacetate of room temperature condition (11.0ml, 1.5e.q.).Reaction solution refluxes and spends the night (about 24hs), is cooled to room temperature.Filter, concentrate yellow oil.Add the 100ml ethyl acetate, organic phase is respectively with 0.5%Na
2CO
3(10ml*3), saturated citric acid (10ml*2), saturated brine are washed till neutrality, and organic phase is filtered with anhydrous sodium sulfate drying, concentrates and gets 13 white powder 16.0g, yield 80% with ethyl acetate-ether recrystallization again; Mp134.5-136.3 ℃; ESI-MS m/z[M+1]
+315; 1H-NMR (300MHz, CDCl
3): δ 5.36 (brs, 1H), 4.59-4.41 (m, 1H), (4.57-4.43 dd, 2H, J=30.6,24.6), 4.22-4.15 (q, 2H, J=7.2), 2.96-2.88 (m, 1H), and 2.82-2.70 (m, 1H), 2.54-2.50 (m, 1H), and 1.97-1.84 (m, 1H), 1.46 (s, 9H), and 1.30-1.25 (t, 3H, J=7.2).
(S)-and ethyl 2-(3-amino)-2,6-dioxopiperidin-1-yl) acetic ester (4)
With compound 3 (2.0g 5.5mmol) is dissolved in the 22ml methylene dichloride, after treating to dissolve fully, slow Dropwise 5 .5mlTFA, about 20min adds, stirring at room 3 hours is concentrated with reaction solution, adds 20ml methylene dichloride evaporate to dryness again, repeats twice.It is standby to add the anhydrous DCM refrigerator cold-storage of 20ml; ESI-MS m/z[M+1]
+215.2.
Ethyl 2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester (5f)
7mmol Boc-L-phenylalanine is dissolved in 20mlDCM, and (8.4mmol 1.14g), stirs under the condition of ice bath to add HOBt, slow adding contains DCC, and (about 30min adds for 8.4ml, DCM solution 1.73g), remove the ice bath room temperature reaction 2-3 hour, and filtered filtrate for later use.
The DCM reserve liquid that will contain 10mmol compound 4 is controlled the pH value 7 with triethylamine (about 2 equivalents) under the condition of ice bath, slowly drips the DCM solution that 20ml contains the L-amino acid active ester of the above-mentioned Boc protection of 7mmol, and the pH of control reaction solution leads to N 7
2Protection, stirred overnight at room temperature, reacting liquid filtering is successively with 0.5%Na
2CO
3(5ml*2), 5% citric acid (5ml*2), saturated brine (5ml*2) washing, anhydrous sodium sulfate drying, column chromatographic isolation and purification, the petroleum ether-ethyl acetate gradient elution gets intermediate 5f white powder 2.95g, yield 91.3%; Mp 164.1-164.2 ℃; ESI-MS m/z[M+1]
+462.6; 1H-NMR (300MHz, CDCl
3): δ 7.33-7.18 (m, 5H), 6.85-6.83 (brd, 1H), 4.94 (brs, 1H), 4.56-4.40 (m, 4H), 4.21-4.14 (q, 2H, J=7.2), 3.12-3.10 (d, 2H, J=6.3), and 2.93-2.79 (m, 2H), 2.56-2.51 (m, 1H), and 1.94-1.67 (m, 2H), 1.45 (s, 9H), and 1.32-1.24 (t, 3H, J=7.2).
Ethyl 2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride (6f)
Compound 5f (0.5g) is dissolved in 10ml 3N HCl-AcOEt, after treating to dissolve fully, stirring at room 4 hours, product 6f separates out with the form of hydrochloride, filtration, anhydrous ethyl acetate washing, dry white solid powder 0.48g, the yield 86.4% of getting; Mp 156.3-158.0 ℃; ESI-MS m/z[M+1]
+: 362.4; 1H-NMR (300MHz, DMSO-d
6): δ 9.19-9.16 (d, 1H), 8.23 (brs, 3H), and 7.35-7.27 (m, 5H), 4.87-4.79 (m, 1H), and 4.45-4.34 (dd, 2H), 4.14-4.07 (m, 3H), and 3.23-3.20 (m, 1H), 33.05-2.93 (m, 2H), and 2.82-2.74 (m, 1H), 2.04-2.01 (m, 2H), and 1.22-1.17 (t, 3H, J=7.2).
The preparation of embodiment 2.2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride (11d)
(S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester (7)
With compound 2 (18.3g, 0.086mol), K
2CO
3(14.2g, 1.2e.q), (0.1e.q.) DL is in the 300ml anhydrous propanone for TBAI, 3.1g for tetrabutylammonium iodide.The slow down adding benzyl acetate bromide of room temperature condition (30.0g, 1.5e.q.).Reaction solution refluxed 7 hours, was cooled to room temperature.Filter, concentrate yellow oil.Add the 200ml ethyl acetate, organic phase is respectively with 0.5%Na
2CO
3(20ml*2), 5% citric acid (20ml*2), saturated brine are washed till neutrality, and organic phase is filtered with anhydrous sodium sulfate drying, concentrates and gets 7 white crystals 20.8g, yield 67% with ethyl acetate-ether recrystallization again.mp?78.0-81.0℃；ESI-MS?m/z[M+1]
+：377.6；1H-NMR(300MHz，CDCl
3)：δ7.42-7.31(m，5H)，5.18-5.10(s，2H)，4.43-4.36(m，3H)，2.99-2.87(m，1H)，2.75-2.69(m，1H)，2.01-1.93(m，2H)，1.40(s，9H)。Benzyl 2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic ester (9d)
With compound 7 (2.0g 5.5mmol) is dissolved in the 22ml methylene dichloride, after treating to dissolve fully, slow Dropwise 5 .5mlTFA, about 20min adds, stirring at room 3 hours is concentrated with reaction solution, adds 20ml methylene dichloride evaporate to dryness again, repeats twice.It is standby to add the anhydrous THF refrigerator cold-storage of 20ml.
The THF solution of above-claimed cpd 8 is cooled to-20 ℃, slowly drips N-methylmorpholine (about 1.3ml), the pH value that makes solution gets solution I about 6.The 5.5mmol amino acid derivative is dissolved in the anhydrous THF of 20ml, the control solution temperature is not higher than-20 ℃, slowly add 5.5mmol (0.62ml) N-methylmorpholine, slowly add 5.5mmol (0.72ml) isobutyl chlorocarbonate (ISC) behind the 5min, the reaction that white opacity explanation preparation mixed acid anhydride occurs takes place.Reaction solution stirs 15min at-20 ℃, and the THF solution of above-mentioned pH6 is slowly dropped to the reaction solution of mixed acid anhydride, and about 20min drips off.Continuation is changed cooling fluid (ice bath) to 0 ℃, stirring reaction, TLC detection reaction process at-20 ℃ of insulation reaction 15min.
After reaction finishes,, concentrate, add the 80ml ethyl acetate, successively with 0.5%Na with the 2.0g diatomite filtration
2CO
3(20ml*2), 5% citric acid (20ml*1), saturated brine washing, anhydrous sodium sulfate drying.Filter, concentrate, dry key intermediate 9d white powder 2.49g, the yield 92.6% of getting; Mp 61.0-62.6 ℃; ESr-MS m/z[M+1]
+490.6, need not purifying and can be directly used in the next step.
2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetate (10d)
9d is dissolved in the 40ml dehydrated alcohol with 4.0mmol benzyl ester derivative, adds the 20ml tetrahydrobenzene as hydrogen donor, adds the Pd/C catalyzer of equivalent 5%, 45 ℃ of insulation reaction 1 hour, TLC monitoring reaction process.After reaction finishes with reaction solution 2.0g diatomite filtration, upper strata Pd/C catalyst recovery, filtrate is concentrated into dried, the gained residue is with the 60ml ethyl acetate, successively with 5% citric acid (10ml*2), saturated brine (10ml*1) washs, anhydrous sodium sulfate drying.Filter, concentrate the white solid powder 10d 1.46g of dehydrated alcohol recrystallization, yield 91.4%; Mp 91.2-92.0 ℃; ESI-MS m/z[M+1]
+400.4.
2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride (11d)
0.5g compound 9d is dissolved in 5ml 3N HCl-AcOEt, after treating to dissolve fully, stirring at room 4 hours, product 11d separates out with the form of hydrochloride, filter, wash white solid powder 0.32g, yield 95.2%; Mp 156.5-158.1 ℃; ESI-MS m/z[M+1]
+300.3; 1H-NMR (300MHz, DMSO-d
6): δ 9.05 (d, 1H), 8.40 (brs, 3H), 4.89-4.80 (m, 1H), 4.35-4.23 (dd, 2H, J=20.4,17.1), 3.81-3.76 (t, 1H), 3.05-2.73 (m, 2H), 2.05-1.99 (m, 2H), 1.84-1.73 (m, 1H), 1.03-0.90 (d, 6H, J=6.9).
The preparation of embodiment 3. tertiary butyls (S)-1-((S)-1-(2-(azanol base)-2-oxoethyl)-2,6-dioxopiperidin-3-amino)-4-methyl isophthalic acid-oxo pentane-2-carboxylicesters (13d)
0.2g (3.0mmol) oxammonium hydrochloride is dissolved in the 1.5ml anhydrous methanol, slowly adds the triethylamine of 0.5ml (2e.q), make amino dissociate out, precision is measured supernatant liquor, and is standby.
2.0mmol carboxylic acid derivative 10d is dissolved in the anhydrous THF of 20ml, the control solution temperature is not higher than-20 ℃, slowly add 4.0mmol (0.57ml) triethylamine, slowly add 2.02mmol (0.28ml) isobutyl chlorocarbonate (ISC) behind the 5min, the reaction that white opacity explanation preparation mixed acid anhydride occurs takes place.Reaction solution stirs 15min at-20 ℃, and the methanol solution that will contain azanol slowly drops to the reaction solution of mixed acid anhydride, and about 20min drips off.Continuation is changed cooling fluid (ice bath) to 0 ℃, stirring reaction, TLC detection reaction process at-20 ℃ of insulation reaction 15min.Diatomite filtration after reaction finishes concentrates, and adds the 30ml ethyl acetate, successively uses 0.05%NaHCO
3(5ml*2), 5% citric acid (5ml*1), the saturated brine washing is to neutrality, anhydrous sodium sulfate drying.With the ethyl acetate solution filtering and concentrating, obtain 12d off-white color pressed powder 0.78g, yield 94.1%; ESI-MS m/z[M+1]
+415.4.
Above-claimed cpd 12d is dissolved in 5ml 3N HCl-AcOEt, and after treating to dissolve fully, stirring at room 2-3 hour, product 13d separated out with the form of hydrochloride, filter, wash white solid powder 0.42g, yield 79.8%; Mp 176.3-176.9 ℃; ESI-MS m/z[M+1]
+315.3; 1H-NMR (300MHz, DMSO-d
6): δ 8.89 (brs, 1H), 8.25 (brs, 3H), 4.90-4.85 (brs, 1H), 4.66-4.59 (m, 1H), 4.57-4.25 (dd, 2H), 3.98-3.75 (m, 1H), 3.06-2.96 (m, 1H), 2.81-2.66 (m, 1H), 2.01-1.98 (s, 2H), 1.82-1.74 (m, 1H), 1.68-1.55 (m, 2H), 0.95-0.80 (d, 6H).
The preparation of embodiment 4.2-((S)-3 ((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride (11f)
Preparation method with 9d-11d among the embodiment 2 makes 9f-11f respectively.
Benzyl 2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester (9f):
White powder 2.54g, yield 88.2%, mp 139.4-140.4 ℃; ESI-MS m/z[M+1]
+524.6; 1H-NMR (300MHz, CDCl3): δ 7.39-7.18 (s, 10H), 6.80 (s, 1H), and 5.19-5.15 (s, 2H), 4.93 (m, 1H), and 4.62-4.46 (m, 3H), 3.11-3.09 (d, 2H, J=6.0), 2.93-2.72 (m, 2H), 2.50 (m, 1H), 1.87-1.72 (m, 1H), 1.41 (s, 9H)).
2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetate (10f):
White powder 1.28g, yield 73.8%; Mp 89.2-91.5 ℃; ESI-MS m/z[M+1]
+434.5; 1H-NMR (300MHz, CDCl3): δ 7.30-7.17 (m, 5H), 5.27-5.25 (s, 1H), 4.67-4.41 (m, 4H), 3.07-2.74 (m, 4H), 2.39-2.32 (m, 1H), 1.90-1.88 (m, 1H), 1.36 (s, 9H).
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride (11f):
White powder 0.32g, yield 93.8%; Mp 135.6-138.2 ℃; ESI-MS m/z[M+1]
+334.3; 1H-NMR (300MHz, DMSO-d6): δ 9.15 (s, 1H), 8.24 (brs, 3H), and 7.35-7.28 (s, 5H), 4.87-4.78 (m, 1H), 4.37-4.25 (dd, 2H, J=19.2,16.8), 4.07-3.99 (m, 1H), 3.24-3.19 (m, 1H), and 3.04-2.92 (m, 2H), 2.79-2.72 (m, 1H), and 2.01-1.99 (m, 2H).
Embodiment 5. (the S)-2-amino-N-(preparation of (S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-Phenylpropionamide hydrochloride (13f)
With 12d among the embodiment 2, the preparation method of 13d makes 12f respectively, 13f.
The tertiary butyl (S)-1-((S)-1-(2-(azanol base)-2-oxoethyl)-2,6-dioxopiperidin-3-amino)-1-oxo-3-phenyl-propane-2-carboxylicesters (12f):
White powder 0.80g, yield 89.2%; Mp 101.1-102.6 ℃; ESI-MS m/z[M+1]
+449.3; 1H-NMR (300MHz, CDCl3): δ 10.25 (brs, 1H), 7.80 (s, 1H), 7.26-7.19 (s, 5H), 5.44 (s, 1H), 4.65-4.35 (m, 4H), 3.12-2.75 (m, 4H), 2.05 (m, 2H), 1.32 (s, 9H).
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-Phenylpropionamide hydrochloride (13f):
White powder 0.49g, yield 84.9%; Mp 171.1-172.6 ℃; ESI-MS m/z[M+1]
+349.4; 1H-NMR (300MHz, DMSO-d
6): δ 10.62 (s, 1H), 8.86 (s, 1H), 8.24 (s, 1H), 7.38-7.26 (s, 5H), 4.88-4.80 (m, 1H), 4.23-4.10 (dd, 2H, J=20.7,15.6), 3.24-3.18 (m, 1H), and 3.05-2.87 (m, 2H), 2.73-2.71 (m, 1H), 2.01-1.98 (s, 2H).
The preparation of embodiment 6.2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride (20f)
(S)-and the tertiary butyl 2,5-2,5-dioxy pyrroles-3-base carbonyl acid amides (15)
Compound 14 (23.2g, 0.1mol) and N-hydroxy-succinamide (NHSu, 13.8g 0.12mol) are dissolved among the 400ml THF, slowly drip 100ml under the cryosel bath condition and contain DCC (35.1g, THF solution 0.17mol).Dripped off in about 1 hour, and removed the ice bath stirring at room and refluxed 10 hours after 3 hours.Reaction solution is cooled to room temperature, and rotary evaporation reclaims solvent.Residue adds 50ml ethyl acetate reconcentration once.After the final residue thing added the 200ml ethyl acetate, the freezing placement of refrigerator was spent the night.With 4.0 gram diatomite filtrations, filtrate water (50ml*1) and saturated brine (50ml*1) washing, NaSO
4Dry. filter, be concentrated into dried.Again with exquisite 15 plate crystal 18.3g, 168.2-168.7 ℃ of the yield 85%:mp of getting of ethyl acetate-ether; ESI-MS m/z[M+1]
+215.3; 1H-NMR (300MHz, CDCl3): δ 11.19 (s, 1H), 7.46-7.43 (d, 1H, J=8.7), 4.33-4.25 (m, 1H), 2.89-2.80 (dd, 2H, J=17.7,9.3), 1.95-1.87 (m, 2H), 1.39 (s, 9H).
(S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,5-dioxy pyrroles-1-yl) acetic ester (16)
With compound 15 (18.3g, 0.086mol), K
2CO
3(14.2g, 1.2e.q), (0.1e.q.) DL is in the 300ml anhydrous propanone for TBAI, 3.1g for tetrabutylammonium iodide.The slow down adding benzyl acetate bromide of room temperature condition (30.0g, 1.5e.q.).Reaction solution refluxed 7 hours, was cooled to room temperature.Filter, concentrate yellow oil.Add the 200ml ethyl acetate, organic phase is respectively with 0.5%Na
2CO
3(20ml*2), 5% citric acid (20ml*2), saturated brine are washed till neutrality, and organic phase is filtered with anhydrous sodium sulfate drying, concentrates and gets 16 white crystals 20.8g with ethyl acetate-ether recrystallization again, 107.0-112.0 ℃ of yield 67%:mp; ESI-MS m/z[M+1]
+363.5; 1H-NMR (300MHz, CDCl3): δ 7.58 (brs, 1H), 7.38 (s, 5H), 5.17 (s, 2H), 4.47 (m, 1H), 4.285 (m, 2H), 3.06-3.03 (m, 1H), 2.64-2.58 (m, 1H), 1.38 (s, 9H).
Benzyl 2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic ester (18f):
With compound 16 (2.0g 5.5mmol) is dissolved in the 22ml methylene dichloride, after treating to dissolve fully, slow Dropwise 5 .5mlTFA, about 20min adds, stirring at room 3 hours is concentrated with reaction solution, adds 20ml methylene dichloride evaporate to dryness again, repeats twice.It is standby to add the anhydrous THF refrigerator cold-storage of 20ml.
THF solution with above-mentioned 17 is cooled to-20 ℃, slowly drips N-methylmorpholine (about 1.3ml), and the pH value that makes solution gets solution I about 6.The 5.5mmol amino acid derivative is dissolved in the anhydrous THF of 20ml, the control solution temperature is not higher than-20 ℃, slowly add 5.5mmol (0.62ml) N-methylmorpholine, slowly add 5.5mmol (0.72ml) isobutyl chlorocarbonate (ISC) behind the 5min, the reaction that white opacity explanation preparation mixed acid anhydride occurs takes place.Reaction solution stirs 15min at-20 ℃, and the THF solution of above-mentioned pH6 is slowly dropped to the reaction solution of mixed acid anhydride, and about 20min drips off.Continuation is changed cooling fluid (ice bath) to 0 ℃, stirring reaction, TLC detection reaction process at-20 ℃ of insulation reaction 15min.
After reaction finishes,, concentrate, add the 80ml ethyl acetate, successively with 0.5%Na with the 2.0g diatomite filtration
2CO
3(10ml*2), 5% citric acid (10ml*1), saturated brine is washed till the center, anhydrous sodium sulfate drying.Filter, concentrate key intermediate 18f colorless oil 3.24g, yield 90.8%; ESI-MS m/z[M+1]+510.6,1H-NMR (300MHz, CDCl3): δ 7.39-7.17 (m, 10H), 6.97-6.94 (d, 1H), 5.16 (s, 2H), 5.06-5.04 (m, 1H), 4.39-4.33 (m, 4H), 3.10-3.01 (m, 3H), 2.75-2.67 (m, 1H), 1.39 (s, 9H).
2-((S)-3-((S)-2-(tertiary butyloxycarbonyl amide group)-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetate (19f)
18f is dissolved in the 40ml dehydrated alcohol with 4.0mmol benzyl ester derivative, adds the 20ml tetrahydrobenzene as hydrogen donor, adds the Pd/C catalyzer of equivalent 5%, and 45 ℃ are incubated 1 hour, TLC monitoring reaction process.After reaction finishes with reaction solution 4.0g diatomite filtration, upper strata Pd/C catalyst recovery, filtrate is concentrated into dried, the gained residue is with the 60ml ethyl acetate, successively with 5% citric acid (10ml*2), saturated brine (10ml*1) washs, anhydrous sodium sulfate drying.Filtering and concentrating, the Dry Sack pressed powder 1.86g of dehydrated alcohol recrystallization, yield 86.9%; Mp 93.1-94.8 ℃; ESI-MS m/z[M+1]
+420.4;
1H-NMR (300MHz, CDCl3): δ 7.61 (s, 1H), 7.21-7.06 (s, 5H), 5.52 (m, 1H), 4.59-4.50 (m, 1H), 4.33-4.18 (dd, 2H, J=29.1,17.4), 3.17-2.62 (m, 4H), 1.91-1.51 (m, 2H), 1.34 (d, 9H).
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride (20f)
0.3-0.5g carboxylic compound 19 is dissolved in 5ml 3N HCl-AcOEt, and after treating to dissolve fully, stirring at room 2-3 hour, product 20f separated out with the form of hydrochloride, filter, wash white solid powder 0.31g, yield 91.4%:mp167.9-169.1 ℃; ESI-MS m/z [M+1]
+320.3;
1H-NMR (300MHz, DMSO-d6): δ 9.49-9.46 (d, 1H, J=7.2,8.60 (brs, 3H), and 7.36-7.25 (s, 5H), 4.75-4.68 (dd, 1H, J=13.5,8.7), 4.18-4.03 (dd, 2H, J=27.6,17.4), 3.99 (m, 1H), 3.11-3.09 (d, 2H, J=6.0), 3.08-2.99 (dd, 1H, J=17.7,9.0), (2.53-2.45 dd, 1H, J=17.7,5.4).
Embodiment 7. (the S)-2-amino-N-(preparation of (S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-Phenylpropionamide hydrochloride (22f)
The 0.2g oxammonium hydrochloride is suspended in the 1.5ml anhydrous methanol, slowly adds the 0.5ml triethylamine, make amino dissociate out, solution for standby.
2.0mmol carboxylic acid derivative 19f is dissolved in the anhydrous THF of 20ml, the control solution temperature is not higher than-20 ℃, slowly add the 2e.q triethylamine, slowly add the 1.01e.q isobutyl chlorocarbonate behind the 5min, the reaction that white opacity explanation preparation mixed acid anhydride occurs takes place.Reaction solution stirs 15min at-20 ℃, and the above-mentioned methanol solution that contains azanol is slowly dropped to the reaction solution of mixed acid anhydride, and about 20min drips off.Continuation is changed cooling fluid (ice bath) to 0 ℃, stirring reaction, TLC detection reaction process at-20 ℃ of insulation reaction 15min.Concentrate after reaction finishes, add the 30ml ethyl acetate, successively use 0.05%NaHCO3,5% citric acid, saturated brine washing, anhydrous sodium sulfate drying.With the ethyl acetate solution filtering and concentrating, obtain the off-white color pressed powder and need not purifying and be directly used in bottom reaction.
Above-claimed cpd 21f is dissolved in 5ml 3N HCl-AcOEt, and after treating to dissolve fully, stirring at room 2-3 hour, product 22f separated out with the form of hydrochloride, filter, wash white solid powder 0.34g, 91.7%; Mp 155.8-157.2 ℃; ESI-MSm/z [M+1]
+335.3;
1H-NMR (300MHz, DMSO-d6): δ 10.70 (s, 1H), 9.46 (brs, 1H), 9.28-9.25 (d, 1H), 8.24 (brs, 3H), 7.06-7.04 (d, 2H, J=8.4), 6.73-6.70 (d, 2H, J=8.4), 4.82 (m, 1H), 4.48 (m, 1H), 4.31-4.22 (m, 2H), 3.15-3.09 (m, 1H), 2.95-2.88 (m, 2H), 2.77-2.62 (m, 1H).
Embodiment 8 target compounds suppress gelatinase activity test (In vitro)
Test principle and detailed step are referring to CN 1528745A pyrrolidinyl metalloprotease inhibitor and preparation method thereof.
Experimental result sees Table one, table two.
Embodiment 9 target compounds suppress the activity test (In vitro) of Aminopeptidase N
Test principle and detailed step are referring to CN1974554A pyrrolidinyl metalloprotease inhibitor and preparation method thereof.
Experimental result sees Table, table two.
Experimental result shows: all compounds all show the stronger external enzymic activity that presses down, except that compound 6 and 20 series, the majority of compounds of every other series has has all met or exceeded the activity level of positive control drug ubenimex to HL60 cell inhibiting level.Wherein compound 11a, 11b, 11e, 13d, 13e, 13f and 22d are to the level that enzyme selectivity has has also all met or exceeded the positive control drug ubenimex that presses down of APN and MMP-2.
Table one, compound 6,11, the 13 external enzyme test results that press down
Numerical value is the mean value of three experiments in a table, " ± " back numeric representation standard deviation.
Table two, compound 20 and the 22 external enzyme test results that press down
Numerical value is the mean value of three experiments in a table, " ± " back numeric representation standard deviation.
Embodiment 10 target compounds suppress tumor cell proliferation test (In vitro)
(1) test principle:
Antitumor drug can be in various degree the growth of inhibition tumour cell, thereby reach antineoplastic purpose, do in vitro tests with tumor cell line, by the mtt assay anti-tumor activity of detection compound fast.
Thiazolyl blue, be called for short MTT, but permeate through cell membranes enters in the cell, succinodehydrogenase in the viable cell plastosome can make exogenous MTT be reduced to insoluble bluish voilet crystallization Formazan and be deposited in the cell, dimethyl sulfoxide (DMSO) can be dissolved this crystallisate, measure its absorbance value with enzyme-linked immunosorbent assay instrument, can reflect cell quantity indirectly.The amount that the MTT crystallisate forms is directly proportional with viable count, and is irrelevant with dead cell.Variation by simultaneous test group and control group absorbance value can compound of reaction anti-tumor activity.
(2) test materials:
Clone: HL-60, ES-2, A549 are with the RPMI-1640 substratum that contains 10% foetal calf serum, at 5%CO
2The CO of concentration
2Cultivate in the incubator.
Articles for use: disposable filter, 96 orifice plates
MTT solution: take by weighing 250mg MTT, put into small beaker, add 50ml PBS lucifuge and fully dissolve.Millipore filter degerming with 0.22um.
The configuration of test-compound solution:
Accurately take by weighing each compound, with the substratum dissolving, filtration sterilization is standby.
Testing sequence:
1, collecting cell is abandoned old substratum, with new substratum re-suspended cell.
2, cell counting, the HL-60 cell is adjusted cell to 2 * 10 with substratum
5/ ml; ES-2, A549 cell are adjusted cell to 1 * 10
5/ ml.
3, pass in 50 μ l cell to 96 orifice plates, 96 orifice plates are put into incubator.
4, behind the cultivation 4h, add the compound of 50 μ l different concns tonsures, 3 multiple holes of each tonsure, control group adds 50 μ l substratum.
5, behind the cultivation 48h, in 96 orifice plates, add MTT solution, 10 μ l/ holes.
6, behind the cultivation 4h, the centrifugal substratum supernatant of abandoning adds 100 μ l DMSO in 96 orifice plates, and fully after the dissolving, microplate reader detects the absorbance of 570nm, 630nm wavelength for referencial use.
Data processing:
Calculate inhibiting rate according to absorbance with following formula:
Be X-coordinate with the inhibiting rate then, concentration is ordinate zou, utilizes semi-logarithmic coordinate paper to obtain the half-inhibition concentration IC50 value of each compound.
(3) test-results: table three
* numerical value is the mean value of three experiments in the table, " ± " back numeric representation standard deviation
Experimental result shows: compound 13d, 13f and 22f have reached the same activity level of positive control drug ubenimex to the inhibition activity of HL60, ES-2 and three kinds of tumor cell lines of A549.
Embodiment 11 target compounds suppress lotus liver cancer H22 mouse blood road and shift test (in vivo test)
Concrete grammar and operation steps are seen CN 1528745A pyrrolidinyl metalloprotease inhibitor and preparation method thereof.
Food grade Xylo-Mucine (CMC-Na)
Table four, in vivo test result
*Expression p＜0.05,
*Expression p＜0.01,
* *Expression p＜0.001
Adopt SPSS15.0 software during data processing, earlier each group data is carried out homogeneity test of variance (Test ofHomogeneity of Variances), adopt One-Way ANOVA method to carry out variance analysis again, adopt LSD and SNK to compare in twos respectively.
When data processing adopted One-Way ANOVA method comparative group differences, each organized body weight and blank group there are no significant difference (p＜0.05); Each organizes the heavy and blank group of lung there are no significant difference (p＜0.05); There is utmost point significant difference (p＜0.01) in the tubercle number average.Compare with the blank group, the heavy there was no significant difference explanation of body weight and lung institute synthetic class inhibitor peptides toxic side effect is less; The tubercle number obviously reduces explanation institute synthetic class inhibitor peptides and has shown inhibition metastases activity in the fabulous body.
Claims (8)
1. the class peptide compounds and the pharmacy acceptable salt thereof that have general formula I:
Wherein,
R
1Be the side chain of natural amino acid, preferred hydrogen, phenylalanine, Xie Ansuan, leucine, Isoleucine, L-Ala, tyrosine or lysine residue;
R
2Be hydrogen;
R
3Be OH, OC
2H
5Or NHOH;
N is 1 or 2;
*Be that steric configuration is S or R optical purity or its raceme.
2. compound as claimed in claim 1 is characterized in that it being following compound:
(S)-ethyl 2-(3-(2-glycyl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-(the amino propionamido-of (S)-2-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((2S, 3R)-2-amino-3-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(1H-imidazol-4 yl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-4-(methylthio group) amide-based small)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(1H-indol-3-yl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2-amino-3-(4-hydroxy phenyl)-propionamido-)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,6-dioxopiperidin-1-yl) acetic ester hydrochloride;
Ethyl 2-((S)-2,6-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) piperidines-1-yl) acetic ester hydrochloride;
(S)-2-(3-(2-glycyl amido)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-(the amino propionamido-of (S)-2-)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((2S, 3R)-2-amino-4-methylpent amide group)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,6-dioxopiperidin-1-yl) acetate dihydrochloride;
2-((S)-2,6-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) piperidines-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-(4-hydroxyl-Phenylpropionamide base)-2,6-dioxopiperidin-1-yl) acetic acid hydrochloride;
(S)-2-amino-N-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) acetamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) propionamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-methylbutyryl amine hydrochlorate;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-4-methylpent amide hydrochloride;
(2S, 3R)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-methylpent amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-Phenylpropionamide hydrochloride;
(S)-2,6-diamino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-hexanamide hydrochloride;
(S)-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl) tetramethyleneimine-2-carbonyl amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,6-dioxopiperidin-3-yl)-3-(4-hydroxy phenyl) propionamide hydrochloride;
(S)-2-(3-(2-glycyl amido)-2,5-dioxy oxygen pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-(the amino propionamido-of (S)-2-)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-methylbutyryl amido)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-(the amino 4-methylpent of (S)-2-amide group)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((2S, 3R)-2-amino-4-methylpent amide group)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2,6-diamino hexanoyl amido)-2,5-dioxy pyrroles-1-yl) acetate dihydrochloride;
2-((S)-2,5-dioxy-3-((S)-tetramethyleneimine-2-carbonyl amide group) pyrroles-1-yl) acetic acid hydrochloride;
2-((S)-3-((S)-2-amino-3-(4-tertiary butyloxycarbonyl oxygen base) Phenylpropionamide base)-2,5-dioxy pyrroles-1-yl) acetic acid hydrochloride;
(S)-2-amino-N-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) acetamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) propionamide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-methylbutyryl amine hydrochlorate;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-4-methylpent amide hydrochloride;
(2S, 3R)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-methylpent amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-Phenylpropionamide hydrochloride;
(S)-2,6-diamino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-hexanamide hydrochloride;
(S)-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl) tetramethyleneimine-2-carbonyl amide hydrochloride;
(S)-2-amino-N-((S)-(1-(2-(azanol base)-2-oxygen ethyl)-2,5-dioxy pyrroles-3-yl)-3-(4-hydroxy phenyl) propionamide hydrochloride.
3. the intermediate of the described class peptide compounds of preparation claim 1 is characterized in that, is (S)-tertiary butyl 2,6-dioxopiperidin-3-base carbonyl acid amides; (S)-ethyl 2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-and ethyl 2-(3-amino)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,6-dioxopiperidin-1-yl) acetic ester; (S)-and the tertiary butyl 2,5-2,5-dioxy pyrroles-3-base carbonyl acid amides; (S)-benzyl-2-(3-(tertiary butyloxycarbonyl amide group)-2,5-dioxy pyrroles-1-yl) acetic ester.
4. the preparation method of the described class peptide compounds of claim 1; it is characterized in that; with optically pure glutamine or l-asparagine is raw material; by Boc protection, cyclization, the synthetic key intermediate of alkylation under the condition of phase-transfer catalyst; again by obtaining the class dipeptides or the class tripeptides of different series with mixed anhydride method, slough the protection of benzyl ester and obtain carboxy intermediate and take off the Boc protection again or carboxyl is converted into its hydroxamic acid derivs and slough the Boc protecting group again and obtain semicarbazide hydrochloride with the amino acid derivative of Boc protection.
5. claim 1 or 2 class peptide compounds are used to prevent or the application of the medicine of the mammalian diseases that treatment is relevant with the active unconventionality expression of Aminopeptidase N with matrix metalloproteinase MMP in preparation, described related mammalian disease with matrix metalloproteinase MMP and the active unconventionality expression of Aminopeptidase N comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer's venereal disease disease, periodontopathy, epidermolysis bullosa, leukemia.
6. pharmaceutical composition comprises class peptide compounds and (2) one or more pharmaceutically acceptable carriers or the vehicle of (1) claim 1 or 2.
7. one kind is suitable for the mammiferous pharmaceutical composition of orally give, comprises class peptide compounds and (2) pharmaceutically acceptable carrier of (1) claim 1 or 2, optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
8. one kind is suitable for parenteral and gives mammiferous pharmaceutical composition, comprises class peptide compounds and (2) pharmaceutically acceptable carrier of (1) claim 1 or 2, optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
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|---|---|---|---|
| CN2009100206569A CN101538311B (en) | 2009-04-16 | 2009-04-16 | Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof |
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|---|---|---|---|
| CN2009100206569A CN101538311B (en) | 2009-04-16 | 2009-04-16 | Alpha-amido acyl-ring imide peptoid metalloprotease inhibitor and application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103848778A (en) * | 2014-03-28 | 2014-06-11 | 潍坊高新生物园发展有限公司 | Aminopeptidase N inhibitor and preparation method and application thereof |
| CN112079762A (en) * | 2020-09-22 | 2020-12-15 | 陕西科技大学 | Surfactant with self-demulsification capability and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1528745A (en) * | 2003-10-21 | 2004-09-15 | 山东大学 | Pyrrolidine matrix metall oprotease inhibitor and preparing method thereof |
| CN100560568C (en) * | 2006-12-12 | 2009-11-18 | 山东大学 | Cyclin imide peptidyl metalloprotease inhibitor and application thereof |
-
2009
- 2009-04-16 CN CN2009100206569A patent/CN101538311B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103848778A (en) * | 2014-03-28 | 2014-06-11 | 潍坊高新生物园发展有限公司 | Aminopeptidase N inhibitor and preparation method and application thereof |
| CN103848778B (en) * | 2014-03-28 | 2016-01-06 | 潍坊高新生物园发展有限公司 | A kind of aminopeptidase N inhibitor and preparation method thereof and application |
| CN112079762A (en) * | 2020-09-22 | 2020-12-15 | 陕西科技大学 | Surfactant with self-demulsification capability and preparation method and application thereof |
| CN112079762B (en) * | 2020-09-22 | 2021-11-05 | 陕西科技大学 | Surfactant with self-demulsification capability and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
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| CN101538311B (en) | 2012-10-31 |
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