CN101357893A - Ethylene diamine metalloid protease inhibitor and use thereof - Google Patents
Ethylene diamine metalloid protease inhibitor and use thereof Download PDFInfo
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- CN101357893A CN101357893A CNA2008101395525A CN200810139552A CN101357893A CN 101357893 A CN101357893 A CN 101357893A CN A2008101395525 A CNA2008101395525 A CN A2008101395525A CN 200810139552 A CN200810139552 A CN 200810139552A CN 101357893 A CN101357893 A CN 101357893A
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Abstract
The invention relates to an inhibitor of ethylenediamine metalloproteinase and an application thereof. The inhibitor is a peptide compound with the structure of general formula (I), various optical isomers and salt, solvate and pro-drugs which can be accepted pharmaceutically. The invention also relates to a drug combination and the pharmaceutical application of the peptide compound with the structure of the formula (I). The invention provides a powerful inhibitor of ethylenediamine metalloproteinase and can effectively treat diseases caused by abnormal activity expression of the metalloproteinase.
Description
Technical field
The present invention relates to selectivity that a class has the quadrol skeleton suppress the metalloprotease effect the class peptide compounds preparation method, activity test and contain the composition of such peptide compounds, and the purposes of these compositions.
Background technology
1, matrix metalloproteinase (MMPs)
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 MMPs is by the strict control of the secretion level of gene expression dose and activation of zymogen/supressor, and in a lot of pathologic processes, in the growth and transfer as sacroiliitis, tissue fester, malignant tumour, MMPs has also played vital role.
28 members (Szabo, K.A.et al.Clinical andApplied Immunology Reviews.2004,4 of 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, 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 the MMPs inhibitor has become the focus in the cancer treatment drugs research.
The example of available 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.The 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 APN plays an important role in tumour generation, immunologic function adjusting and virus infection.
1) 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) 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) 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 has participated in the inflammatory reaction of T lymphocyte dependence and 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.(ShenW, 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 more than ten years, very rapid to the research and development of MMPs inhibitor, even but none listing up to now.MMPs inhibitor great majority are the analogue of peptide or peptide, degraded to enzyme is relatively more responsive, in addition because 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 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 (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 MMPs and 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 MMPs and APN, relates to the selective problems of designed class peptide compounds to both in this patent, and is expected to develop respectively the specificity selective depressant by the optimization to class peptide compounds structure.Designed class peptide compounds is directed to the APN screening active ingredients and finds that its activity of several drug molecules is faint in 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 ethylene diamine metalloid protease inhibitor and preparation method thereof is provided.
Class peptide and isostere layout strategy have been adopted in the design that the present invention contains the compound of general formula as follows (I).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 esterification under acidic conditions; the compound of gained is again through Boc or Cbz protection amido protecting; reduction; methylsulfonylization; steps such as nucleophilic substitution are synthesized key intermediate; again by with the different acyl chlorides of biologically active (as gallic acid; coffic acid; toluylic acid; forulic acid; the NSAID (non-steroidal anti-inflammatory drug) organic acid) and the amino acid derivative condensation; deprotection obtains the class dipeptides or the class tripeptides of different series then, and purpose all is for avidity that strengthens compound and enzyme or acceptor and metabolic stability.
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 with general formula I, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug.
Wherein,
R
1Be 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, C1-6 alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
R
2Be hydrogen, 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, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy;
R
3Be aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, the C1-8 carbalkoxy.
* the carbon shown in has the R configuration.
Preferably, R
1Be aryl C1-6 alkyl, aryl C2-6 thiazolinyl, heteroaryl C1-9 alkyl; R
2Be hydrogen; R
3Be aryl C1-6 alkyl, aryl C2-6 thiazolinyl, heteroaryl C1-9 alkyl, most preferably R
3It is benzyl.
Above-mentioned class peptide compounds (I) specifically comprises following compound:
(2S)-2, the 6-diamino-N-[(2R)-and 2-amino-3-hydrocinnamyl] hexanamide,
(2S)-2-amino-4-methylthio group-N-[(2R)-2-amino-3-hydrocinnamyl] butyramide,
4-amino-N-[(2R)-2-amino-3-hydrocinnamyl] butyramide,
6-amino-N-[(2R)-2-amino-3-hydrocinnamyl] hexanamide,
(2S)-2-amino-3-hydroxy-n-[(2R)-and 2-amino-3-hydrocinnamyl] propionic acid amide,
N-[(2R)-2-amino-3-hydrocinnamyl]-the 3-hydrocinnamamide,
(2S)-2, the 5-diamino-N-[(2R)-and 2-amino-3-hydrocinnamyl] valeramide,
2-amino-N-[(2R)-2-amino-3-hydrocinnamyl] ethanamide,
(2S)-2-amino-4-methyl-N-[(2R)-2-amino-3-hydrocinnamyl]-3-hydroxyl-L-prolineamide,
(2S)-2-amino-N-[(2R)-2-amino-3-hydrocinnamyl]-the 3-hydrocinnamamide,
(2S)-2-amino-4-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] valeramide,
(2S)-2-amino-3-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] valeramide,
N-[(2R)-2-amino-3-hydrocinnamyl]-L-tetramethyleneimine acid amides,
(3S)-3-amino-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
(2S)-2-amino-3-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
N-[(2R)-2-amino-3-hydrocinnamyl]-L-histidyl-amine,
N-[(2R)-2-amino-3-hydrocinnamyl]-4-methyl-benzsulfamide,
(2S)-2-amino-3-sulfydryl-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-phenylallene acid amides,
N-[(2R)-and 2-amino-3-hydrocinnamyl]-3,4,5-trimethoxy-benzamide,
N-[(2R)-2-amino-3-hydrocinnamyl]-the 2-phenylacetamide,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3, the 4-dimethoxy) phenylallene acid amides,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3-methoxyl group-4-hydroxyl) phenylallene acid amides,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3, the 4-dihydroxyl) phenylallene acid amides,
N-[(2R)-2-amino-3-hydrocinnamyl]-4-nitro-benzamide,
N-[(2R)-and 2-amino-3-hydrocinnamyl]-3,5-dinitrobenzene-benzamide,
4-{N-[(2R)-and 2-amino-3-hydrocinnamyl] formamido-} methyl benzoate,
The class peptide compounds intermediate for preparing above-mentioned general formula (I) is: (2R)-and 2-tertiary butyloxycarbonyl amide group-3-phenyl-propylamine, or 2-tertiary butyloxycarbonyl amido-N-[(2R)-and 2-tertiary butyloxycarbonyl amido-3-hydrocinnamyl] ethanamide.
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 the pharmaceutical composition that contains (I) structural compounds.
A kind of pharmaceutical composition comprises each class peptide compounds and (2) one or more pharmaceutically acceptable carriers or vehicle of (1) claim 1-3.
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises the arbitrary class peptide compounds of (1) claim 1-3 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 the arbitrary class peptide compounds of (1) claim 1-3 and (2) pharmaceutically acceptable carrier, optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
Detailed Description Of The Invention
Used definition and term
Term and definition implication used herein is as follows:
" 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.
" halogen ", or " halogen " comprises fluorine, chlorine, bromine or iodine, preferred fluorine and chlorine.
" 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.
" heteroaryl " is aromatic heterocycle, 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.
" 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 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 Van Nostrand 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.
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.
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.
Synthetic
Target compound is synthetic through following route.
In brief, be raw material with optics amino acid, here we to select the D-phenylalanine for use be example, in succession through esterification, the Boc protection, reduction, methylsulfonylization is with the S of sodium azide
N2 substitution reactions are reduced in protonic solvent through magnesium, again through the polypeptide condensation, slough protecting group and obtain target compound.
Synthetic route:
Reagent: (a) methyl alcohol, hydrochloric acid; (b) dimethyl dicarbonate butyl ester, methylene dichloride, triethylamine, 0 ℃; (c) Lithium Aluminium Hydride, ether; (d) methylsulfonyl chloride, tetrahydrofuran (THF), 0 ℃; (e) sodium azide, the inferior maple of diformazan; (f) magnesium, methyl alcohol; (g) dimethyl dicarbonate butyl ester, methylene dichloride, triethylamine, 0 ℃; (h) isobutyl chlorocarbonate, N-methylmorpholine, tetrahydrofuran (THF) ,-15 ℃; (i) the saturated ethyl acetate of hydrogenchloride; (j) oxalyl chloride, methylene dichloride, 0 ℃; (k) triethylamine, tetrahydrofuran (THF), 0 ℃.
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.For example raw material D-phenylalanine is replaced with its optical isomer (L configuration).Those skilled in the art can obtain various other isomer of ethylene diamine 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 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.
The class peptide compounds of general formula (I) external presses down enzyme test proves that such peptide compounds is a kind of ethylenediamines peptide inhibitors of metalloproteinase
Therefore ethylene diamine derivative of the present invention spatially is complementary with the MMP activities site, has shown higher inhibition activity external.And it can be metabolized to active fragments in vivo, and as coffic acid, cinnamic acid derivative still has anti-tumor activity, has therefore also shown higher anti-tumor activity in vivo
Preparation, pharmaceutical composition, dosage and taking
Ethylene diamine 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.
Description of drawings
Fig. 1 and Fig. 2 are that compound 15n docks result schematic diagram with the active region of APN.
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) (2R)-phenylalanine methyl ester hydrochloride (2).In the 250ml three-necked bottle, (20g 0.121mol) is suspended in the 150ml anhydrous methanol phenylalanine, feeds exsiccant HCl gas to solution becomes and clarifies, and continues logical HCl gas, till the solution becomes muddiness.Reaction solution is rotated evaporate to dryness get white solid.Evaporate to dryness again behind the dissolve with methanol, triplicate is to eliminate HCl gas.Behind a spot of dissolve with methanol, add anhydrous diethyl ether, separate out a large amount of white precipitates, the refrigerator standing over night.Filtration drying is weighed, and gets 22.7g crystalloid solid.Productive rate 86.90%, mp 158-160.5 ℃.
2) (2R)-2-tertiary butyloxycarbonyl amide group-methyl phenylpropionate (3).(10.8g 0.02mol) is suspended in the 200ml anhydrous methylene chloride, adds 16.3ml triethylamine (0.12mol) and dimethyl dicarbonate butyl ester ((Boc) under the condition of ice bath with phenylalanine methyl ester hydrochloride
2O, 9.6g, 0.04mol), stirring at room 12 hours.The TLC monitoring is not to there being the raw material point, and stopped reaction is used the 1M phosphate aqueous solution successively, after the saturated sodium bicarbonate aqueous solution washing, dewaters with anhydrous sodium sulphate, filters, and with chlorine liquid rotation evaporate to dryness, gets the colorless oil product.
3) (2R)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propyl alcohol (4).(2.8g 0.01mol) is dissolved in the anhydrous diethyl ether, under condition of ice bath, adds LiAlH in batches with compound 3
4(0.76g 0.02mol), kept room temperature reaction 8 hours.(concentrated hydrochloric acid: cancellation reaction water 1: 1), reaction 10min filters, and removes adhesive residue, and filtrate is rotated evaporate to dryness, obtains white solid to add hydrochloric acid soln in reaction solution.Productive rate 78.68%, mp:92-93 ℃.
4) (2R)-2-tertiary butyloxycarbonyl amide group-3-phenyl-methylsulfonic acid propyl ester (5).(2.5g 0.01mol) is dissolved in the anhydrous tetrahydro furan, and ice bath is cooled to 0 ℃ with compound 4, the adding triethylamine (2.08ml, 0.015mol), the slow dropping contains methylsulfonyl chloride (1.7g under the condition of ice bath, 0.01mol) tetrahydrofuran solution, about 0.5h drips off. and remove ice bath, room temperature reaction 5h is in reaction solution impouring cold water, white solid is separated out, filtration drying gets 2.85g, productive rate 86.63%.mp：105-108℃。
5) tertiary butyl (2-azido-methyl-1-styroyl) carbamate (6).With compound (10g 0.030mol) is dissolved in DMF, control in warm 55-60 ℃, add in batches sodiumazide (3.96g, 0.060mol), isothermal reaction, TLC monitoring reaction process.After reaction finishes, in reaction solution impouring 300ml cold water, be positioned over the refrigerator internal cooling and leave standstill, separate out a large amount of yellow solids, filtration drying gets the 6.51g crude product, column chromatographic isolation and purification (eluent: petroleum ether-ethyl acetate 10: 1), obtain the pure product of 5.24g, productive rate 63.52%.mp：112-114℃。
6) (2R)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propylamine (7).(4g 0.015mol) is dissolved in the anhydrous methanol, and ice bath is cooled to 0 ℃, and add magnesium rod (1.08g 0.045mol), reacts through about 0.5h, and temperature rise in the reaction solution has a large amount of gases to produce TLC monitoring reaction process in batches with compound 6.After reaction finishes, the reaction solution steaming is removed, residue adds the cold water dilution, and transfers its pH value to 9-10.Use ether extraction, saturated common salt water washing organic phase, anhydrous sodium sulfate drying filters, and steaming desolventizes, and gets the 2.13g white solid, productive rate 56.35%.mp：71-74℃。ESI-MS m/z：251.1(M+H)；
1H-NMR(MeOD)δppm 1.41(s，9H)，2.59-2.65(J
1＝6，J
2＝12，dd，1H)，2.71-2.81(m，3H)，3.79(m，1H)，7.18-7.32(m，5H)。
7) preparation of tert-butoxy carbonyl glycine (9).Be equipped with respectively in both sides and add the 0.1mol glycine in the 500ml three-necked bottle of two constant pressure funnels, stirring rake, after 110ml sodium hydroxide solution (1N) dissolving, ice bath is cooled to zero degree.Slowly add 50ml and contain carbonic acid di-t-butyl ester ((Boc)
2O, 21.8g, THF solution 0.11mol).Control pH between 8 ~ 9 with the 1N sodium hydroxide solution simultaneously.Dropwised in about 1 hour, and stirred 1 hour under the condition of ice bath.Remove ice bath, stirring at room 18 hours.Control pH 8 ~ 9 with 1N NaOH in the whole process.After reaction finishes reaction solution is concentrated to steam except that THF, residual solution is with petroleum ether extraction (100ml * 3), and water is used 1N KHSO again
4(or KHSO
4Solid) be adjusted to pH2 ~ 3, again with ethyl acetate extraction (150ml * 10), organic phase was with anhydrous sodium sulfate drying 12 hours.Filter, concentrate promptly.mp：87-88℃。
8) 2-tertiary butyloxycarbonyl amido-N-[(2R)-2-tertiary butyloxycarbonyl amido-3-hydrocinnamyl] ethanamide (10a).Under-15 ℃, (1.54g is 0.088mol) with N-methylmorpholine (1.05ml for tert-butoxy carbonyl glycine, 0.096mol) be dissolved among the THF (15ml) agitation and dropping isobutyl chlorocarbonate (1.23ml, THF 0.096mol) (10ml) solution, behind the reaction 0.5h, drip compound 7 (2g, THF solution 0.08mol), continue reaction 1h, remove cryostat, room temperature reaction 5h, filter, remove solvent under reduced pressure, residue is dissolved in ethyl acetate, use 5%NaHCO successively
3The aqueous solution, 10% aqueous citric acid solution, saturated common salt water washing organic phase, anhydrous sodium sulfate drying filters, and uses re-crystallizing in ethyl acetate, obtains the 2.45g white solid.Productive rate 73.84%.mp＝103-105℃.ESI-MS m/z：408.3(M+H)；
1H-NMR(DMSO)δppm 1.22(s，9H)，1.38(s，9H)，2.58-2.61(m，1H)，2.67-2.74(J
1＝5.4，J
2＝13.8，dd，1H)，3.01-3.07(m，1H)，3.16-3.19(m，1H)，3.50-3.56(m，2H)，3.66-3.68(m，1H)7.17-7.27(m，5H)。
9) 2-amino-N-[(2R)-2-amino-3-hydrocinnamyl] acetamide hydrochloride (11a).With compound 10 (1.0g 0.0024mol) is dissolved in the saturated ethyl acetate of hydrochloric acid (15ml), TLC monitoring reaction process, behind the room temperature reaction 5h, the adularescent solid is separated out, filtration washing obtains the 0.38g white solid, productive rate 78.35%.mp＝195.5-197.8℃。ESI-MS m/z：208.3(M+H)；
1H-NMR(D
2O)δppm 2.81-2.89(J
1＝6，J
2＝15，dd，1H)，2.94-3.01(J
1＝6，J
2＝15，dd，1H)，3.38-3.48(J
1＝4.5，J
2＝15，dd，1H)，3.49-3.56(J
1＝4.5，J
2＝15，dd，1H)，3.62-3.73(m，1H)，3.80(s，2H)，7.23-7.37(m，5H)。
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.
Numerical value is the mean value of three tests in the table, the numeric representation standard deviation after " ± ".
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 HL 60 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, bestatin makes 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) |
| Ubenimex | 1.65 | ||
| 11h | 2.29 | 11n | 1.09 |
| 11i | 3.2 | 15n | 0.63 |
The structure activity study of embodiment 5 target compounds
Application software Sybyl7.0 docks target compound with the active region of APN, accompanying drawing 1 has been showed the butt joint result who has best active compound 15n in this series.
As shown in Figure 1, the configuration of compound 15n has certain similarity when combining in the active region with APN with the configuration of ubenimex (dark structure among the left figure), 15n can occupy the hydrophobicity pocket A of APN well, C, C ', simultaneously carbonyl in the structure and amino zine ion that can chelating APN active region.Fig. 2 is the two-dirnentional structure synoptic diagram that docks with APN with Ligplot mimic 15n, and we can obtain from figure, the amino acid conserved sequence (HEXXHX of 15n and APN catalytic center
18E) three amino acid His
297, Glu
298, His
301Formed hydrophobic bond respectively; 15n and Tyr in addition
381Also formed stronger hydrophobic interaction.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, with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug:
Wherein,
R
1Be 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, the C1-6 alkyl, the non-steroidal anti-inflammatory drugs organic acid, the N end is protected or is not protected natural or the alpha-non-natural amino acid derivative, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, C1-8 carbalkoxy, aryl C1-8 carbalkoxy;
R
2Be hydrogen, 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, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy;
R
3Be aryl C1-6 alkyl, heteroaryl C1-9 alkyl, aryl C2-6 thiazolinyl, heteroaryl C2-6 thiazolinyl, aryl C2-6 alkynyl, heteroaryl C2-6 alkynyl, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, the C1-6 alkyl-carbonyl, the C1-8 carbalkoxy.
2. compound as claimed in claim 1 is characterized in that: the carbon among the formula I shown in the * has the R configuration.
3. compound as claimed in claim 1 or 2 is characterized in that: R
3Be aryl C1-6 alkyl, aryl C2-6 thiazolinyl, heteroaryl C1-9 alkyl, wherein preferred benzyl.
4. compound as claimed in claim 1 or 2 is characterized in that: R
1Be aryl C1-6 alkyl, aryl C2-6 thiazolinyl, heteroaryl C1-9 alkyl.
5. compound as claimed in claim 1 or 2 is characterized in that: R
2Be hydrogen.
6. compound as claimed in claim 1 is characterized in that it being one of following compound:
2-amino-N-[(2R)-2-amino-3-hydrocinnamyl] ethanamide,
(2S)-2-amino-N-[(2R)-2-amino-3-hydrocinnamyl]-the 3-hydrocinnamamide,
(2S)-2-amino-4-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] valeramide,
(2S)-2-amino-3-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] valeramide,
N-[(2R)-2-amino-3-hydrocinnamyl]-L-tetramethyleneimine acid amides,
(3S)-3-amino-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
(2S)-2-amino-3-methyl-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
(2S)-2-amino-4-methyl-N-[(2R)-2-amino-3-hydrocinnamyl]-3-hydroxyl-L-prolineamide,
(2S)-2, the 6-diamino-N-[(2R)-and 2-amino-3-hydrocinnamyl] hexanamide,
(2S)-2-amino-4-methylthio group-N-[(2R)-2-amino-3-hydrocinnamyl] butyramide,
4-amino-N-[(2R)-2-amino-3-hydrocinnamyl] butyramide,
6-amino-N-[(2R)-2-amino-3-hydrocinnamyl] hexanamide,
(2S)-2-amino-3-hydroxy-n-[(2R)-and 2-amino-3-hydrocinnamyl] propionic acid amide,
N-[(2R)-2-amino-3-hydrocinnamyl]-the 3-hydrocinnamamide,
(2S)-2, the 5-diamino-N-[(2R)-and 2-amino-3-hydrocinnamyl] valeramide,
N-[(2R)-2-amino-3-hydrocinnamyl]-L-histidyl-amine,
N-[(2R)-2-amino-3-hydrocinnamyl]-4-methyl-benzsulfamide,
N-[(2R)-2-amino-3-hydrocinnamyl]-4-chloro-butyramide,
(2S)-2-amino-3-sulfydryl-N-[(2R)-2-amino-3-hydrocinnamyl] propionic acid amide,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-phenylallene acid amides,
N-[(2R)-and 2-amino-3-hydrocinnamyl]-3,4,5-trimethoxy-benzamide,
N-[(2R)-2-amino-3-hydrocinnamyl]-the 2-phenylacetamide,
N-[(2R)-2-amino-3-hydrocinnamyl]-the 4-fenbutyramidum,
N-[(2R)-and 2-amino-3-hydrocinnamyl]-3, the 5-dichloro-benzamide,
N-[(2R)-2-amino-3-hydrocinnamyl]-2-(2-naphthyl)-methane amide,
N-[(2R)-2-amino-3-hydrocinnamyl]-2-[2-(2, the 6-dichlorophenyl) amino] phenylacetamide,
N-[(2R)-and 2-amino-3-hydrocinnamyl] benzamide,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3, the 4-dimethoxy) phenylallene acid amides,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3-methoxyl group-4-hydroxyl) phenylallene acid amides,
(2E)-N-[(2R)-2-amino-3-hydrocinnamyl]-3-(3, the 4-dihydroxyl) phenylallene acid amides,
N-[(2R)-2-amino-3-hydrocinnamyl]-4-nitro-benzamide,
N-[(2R)-and 2-amino-3-hydrocinnamyl]-3,5-dinitrobenzene-benzamide,
4-{N-[(2R)-and 2-amino-3-hydrocinnamyl] formamido-} methyl benzoate.
7. prepare the intermediate of the described compound of claim 1, it is characterized in that: this intermediate is (2R)-2-tertiary butyloxycarbonyl amide group-3-phenyl-propylamine, or 2-tertiary butyloxycarbonyl amido-N-[(2R)-and 2-tertiary butyloxycarbonyl amido-3-hydrocinnamyl] ethanamide.
8. the preparation method of the described compound of claim 1, it is characterized in that: reactions steps and reaction formula are as follows:
(1) reduction of nitrine:
(2) mixed anhydride method is carried out condensation reaction:
Above-mentioned R
1, R
2And R
3Such as claim 1 definition.
9. each compound of claim 1-3 comprises matrix metalloproteinase or Aminopeptidase N at 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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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 |
| CN112341356A (en) * | 2019-08-09 | 2021-02-09 | 成都苑东生物制药股份有限公司 | (2S,3R) -3-amino-2-hydroxy-4-phenylbutylamide derivative, and preparation method and application thereof |
| US11197908B2 (en) | 2018-07-17 | 2021-12-14 | The Board Of Trustees Of The University Of Arkansas | Peptoids and methods for attenuating inflammatory response |
| EP3765442A4 (en) * | 2018-03-12 | 2021-12-22 | The Regents of The University of California | Amphiphilic thiol compounds and uses thereof |
| EP3964497A1 (en) * | 2020-09-04 | 2022-03-09 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Substituted vicinal diamine compounds and their use in the treatment, amelioration or prevention of pain |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1294120C (en) * | 2003-10-21 | 2007-01-10 | 山东大学 | Pyrrolidinyl metalloprotease inhibitor and its application |
| 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 |
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Cited By (7)
| 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 |
| EP3765442A4 (en) * | 2018-03-12 | 2021-12-22 | The Regents of The University of California | Amphiphilic thiol compounds and uses thereof |
| US11197908B2 (en) | 2018-07-17 | 2021-12-14 | The Board Of Trustees Of The University Of Arkansas | Peptoids and methods for attenuating inflammatory response |
| CN112341356A (en) * | 2019-08-09 | 2021-02-09 | 成都苑东生物制药股份有限公司 | (2S,3R) -3-amino-2-hydroxy-4-phenylbutylamide derivative, and preparation method and application thereof |
| CN112341356B (en) * | 2019-08-09 | 2023-04-28 | 成都苑东生物制药股份有限公司 | (2S, 3R) -3-amino-2-hydroxy-4-phenylbutyramide derivative, preparation method and application thereof |
| EP3964497A1 (en) * | 2020-09-04 | 2022-03-09 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Substituted vicinal diamine compounds and their use in the treatment, amelioration or prevention of pain |
| WO2022048922A1 (en) * | 2020-09-04 | 2022-03-10 | Friedrich-Alexander-Universität Erlangen-Nürnberg | Substituted vicinal diamine compounds and their use in the treatment, amelioration or prevention of pain |
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