CN101503373A - 2-amino-1-(4-nitro phenyl)-1-ethanol metalloid protease inhibitor, and preparation and use thereof - Google Patents
2-amino-1-(4-nitro phenyl)-1-ethanol metalloid protease inhibitor, and preparation and use thereof Download PDFInfo
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Abstract
The invention relates to a 2-amino-1-(4-nitrobenzophenone)-1-ethanol metalloproteinase inhibitor as well as a preparation and application thereof. The 2-amino-1-(4-nitrobenzophenone)-1-ethanol metalloproteinase inhibitor is a compound with the following general formula (1). Dipeptide-like or kyrine-type compounds of different series can enhance the appetency and metabolization stability of a compound and an enzyme or a receptor and conforms to the basic requirement on inhibitor structures. The invention designs and synthesizes a group of aminopeptidase N inhibitors with totally new structures. A vitro test shows that the inhibitors have no cytotoxin activity, and four compounds which exhibit remarkable vitro inhibitory activity are close to positive control medicine bestatin and can be used as candidate anticancer medicines. The invention also relates to a pharmaceutical composition of a peptide-like compound with a structure indicated by formula (I), and also relates to the pharmacy usage of the pharmaceutical composition.
Description
Technical field
The present invention relates to the composition that a class has class peptide compounds that suppresses the metalloprotease effect and preparation method thereof, activity test and contains such peptide compounds, and the purposes of these compositions.Belong to the synthetic field of medicine.
Background technology
1, 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 can the degradation of cell epimatrix main component of (ECM), and participate in the generation of tumour neovascularity, thereby promote tumor cell invasion and transfer (Sato Y, Biol.Pharm.Bull., 2004,27 (6): 772-776 as a novel signal transduction molecule; 2) APN participates in the inflammatory reaction that the T lymphocyte relies on, and can be expressed in the antigen presenting cell surface, degraded immunologic active material (as interleukin-8); Also 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.(Delmas，B.，et?al.Nature，1992，357,417；Yeager，C.L.；et?al.Nature，1992，357,420)。4) APN can make the chemokine fMLP of HIV-1 auxiliary receptor CCR 5 desensitization by degraded, thereby reduces the natural immunity function of cell, and makes the CCR5 enhanced sensitivity, promotes HIV-1 virus to enter 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, thereby causes the excessive release of P material, causes pain.6) APN degraded Angiotensin, adjusting (Mitsui, the T. of participation body blood pressure; Et al.Biol.Pharm.Bull., 2004,27,768.).
2, 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.etal.Clinical and AppliedImmunology 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.
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.Therefore, aiming is that the inhibitor that designs of action target spot becomes focus in the tumor pharmacother research with these two kinds of enzymes.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, provide a kind of 2,3-diaminostilbene-(4-nitrophenyl)-1-propyl alcohol metalloid protease inhibitor and its production and use.
The english abbreviation of " matrix metalloproteinase " is " MMPs ", and the english abbreviation of Aminopeptidase N is " APN ", followingly all represents matrix metalloproteinase with MMPs for being concise in expression, and represents Aminopeptidase N with APN, and APNi represents aminopeptidase N inhibitor.
Technical scheme of the present invention is:
1. the invention provides a kind of 2-amino-1-(4-nitrophenyl)-1-ethanol metalloid protease inhibitor.Its structure is for having the class peptide compounds of following general formula (I), with and optical isomer, diastereomer and racemic mixture, its pharmacy acceptable salt, solvate or prodrug.
Wherein, W is C (O) NH or CH
2NHC (O);
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 or C1-6 alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, aryl, substituted aryl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or 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 or heteroaryl C2-6 alkynyl, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl or C1-8 carbalkoxy;
Carbon shown in the * has that (1S, 2R) configuration perhaps have (1R, 2S) configuration in the formula (I).
Preferred R
1Be aryl C1-6 alkyl, preferred benzyl, the fragrant ethyl of β, γ virtue propyl group, the C end is protected or do not protected natural or the alpha-non-natural amino acid derivative, and is optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, C1-8 alkoxyl group; R
2Be hydrogen.
Preferably, above-mentioned class peptide compounds (I) is one of following:
(2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl)-N-propyl group propionic acid amide (5a),
(2R, 3S)-2-amino-3-hydroxy-n-sec.-propyl-3-(4-nitrophenyl) propionic acid amide (5b),
(2R, 3S)-2-amino-N-butyl-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5c),
(2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl)-N-amyl group propionic acid amide (5d),
(2R, 3S)-2-amino-N-cyclohexyl-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5e),
(2R, 3S)-2-amino-N-benzyl-3-hydroxyl-3-(4-nitrophenyl) propylamine (5f),
(2R, 3S)-2-amino-N-(4-luorobenzyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5g),
(2R, 3S)-2-amino-N-(4-methoxy-benzyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5h),
(2R, 3S)-2-amino-N-(styroyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5i),
(2R, 3S)-2-amino-N-(2-chlorobenzene ethyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5j),
(2R, 3S)-2-amino-N-(2-leptodactyline)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5k),
(2R, 3S)-2-amino-3-hydroxy-n-((S) 1-hydroxyl-3-hydrocinnamyl-2-yl)-3-(4-nitrophenyl) propionic acid amide (51),
(2R, 3S)-2-amino-3-hydroxy-n-((S) 1-hydroxyl-3-hydrocinnamyl-2-yl)-3-(4-nitrophenyl) propionic acid amide (5m),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propylamine)-4-methylvaleric acid (5n),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3-phenylpropionic acid (5o),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3 Methylbutanoic acid (5p),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3 Methylbutanoic acid (5q),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3-(1H-indoles-2-yl) propionic acid (5r),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-N-hydroxy-4-methyl valeramide (7n),
(2R, 3S)-2-amino-3-hydroxy-n-((S)-1-(hydroxylamino)-1-oxygen-3-phenylpropyl alcohol alkane-2-yl)-3-(4-nitrophenyl) propionic acid amide (7o),
(S)-2-((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-4-methylpent acid amides)-3-phenylpropionic acid (5s),
(S)-2-((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionyl ammonia)-3-phenylpropyl alcohol acyl ammonia)-3-phenylalanine (5t),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) benzamide (12a),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-methyl benzamide (12b),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-chlorobenzamide (12c),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-chlorobenzamide (12d),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-nitrobenzamide (12e),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-methoxy benzamide (12f),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2,4 dichloro benzene methane amide (12g),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2,4-dinitrobenzamide (12h),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3,4,5-trimethoxy-benzamide (12i),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-gallamide (12g),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-phenylacetamide (12k),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) cinnamide (121),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-(4-hydroxy 3-methoxybenzene base) acrylamide (12m),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-hydrocinnamamide (12n),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-fenbutyramidum (12o),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-methylpent acid amides (12p),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-Phenylpropionamide (12q),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylbutyryl amine (12r),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylpent acid amides (12s),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) propionic acid amide (12t),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-sulfydryl propionic acid amide (12u),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-hydroxyl propionic acid amide (12v),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylthio group propionic acid amide (12w),
(S)-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl propyl group)-2-((S)-2-amino-3-Phenylpropionamide base)-4-methylpent acid amides (12x) or
(S)-2-amino-N-((S)-1-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group amino)-1-oxygen-3-phenyl third-2-yl)-3-Phenylpropionamide (12y).
2. the invention provides a kind of method for preparing compound (I), its step is as follows:
With dextrorotation chlorine enzyme amine 1 is raw material, at first uses the amino compound 2 that gets of N-tertbutyloxycarbonyl (Boc) protection, and compound 2 obtains intermediate 3 through selective oxidation; In methylene dichloride (DCM), contract and agent as compound with N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBT), intermediate 3 reacts with the amine of various replacements, after generating intermediate 4a～4t, intermediate 4a～4m takes off the Boc protecting group in the hydrochloric ethyl acetate saturated solution, obtain the compound 5a～5m in compound (I) series; Intermediate 3 obtains intermediate 4n～4t with the methyl ester hydrochloride reaction of each seed amino acid and dipeptides, at last in NaOH solution, saponification reaction takes place, the decarboxylize methyl esters, and obtain target compound 5n～5t in compound (I) series after the Boc protecting group of deaminize end; Wherein intermediate 4n～4o carboxyl ester generates compound 6n～6o, and obtains target compound 7n～7o in (I) series after the Boc protecting group of deaminize end under the effect of azanol potassium.
Synthetic route can design in conjunction with the state of the art according to certain concrete compound that will prepare with reference to following route 1.
Route 1:
The invention provides a kind of method for preparing compound (I), perhaps its step is as follows:
With compound 2 is raw material, gets compound 8 through primary hydroxyl selectivity bromo; Compound 8 and NaN
3Carry out S
N2 substitution reactions generate compound 9; Compound 9 usefulness triphenyl phosphorus are made reductive agent, reduce intermediate 10; The amino acid and the dipeptides of intermediate 10 and various carboxylic acids or Boc protection; contract and agent as compound with N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBT); obtain intermediate 11a～11y; intermediate 11a～11y takes off the Boc protecting group, generates (I) serial target compound 12a～12y.
Route 2
The compound of general formula (I) in the medicine of preparation treatment tumour as the application of inhibitors of metalloproteinase.
It is as follows that above-mentioned general formula (I) compound external presses down enzyme test:
Target compound suppresses gelatinase activity test (external)
MMPs suppresses active test description in Vijaykumar, M.B. etc., and Matrix Biol.2000 is in 19,26.The own proof of succinyl gelatin 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.Test principle and detailed test procedure are referring to CN 1528745A pyrrolidinyl metalloprotease inhibitor and preparation method thereof.
Target compound suppresses the activity test (external) of Aminopeptidase N
APN suppresses active test description in Lejczak, and .Biochemistry such as B are in 1989,28,3549.Substrate L-leucyl-p-N-methyl-p-nitroaniline 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.Test principle and detailed test procedure are referring to CN1974554A cyclin imide peptidyl metalloprotease inhibitor and application thereof.
The activity test of the vitro inhibition cell proliferation of above-mentioned general formula (I) compound is as follows:
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.
People's acute myeloblastic leukemia cell HL60 is introduced by Chinese Academy of Sciences's Shanghai cell.Adopt conventional the cultivation.All use the logarithmic phase cell during experiment.The HL-60 cell suspension 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:
The structure activity study of above-mentioned general formula (I) compound is as follows:
Application software Sybyl 7.0 docks with the active region of APN having best active compound 5u in (I) series, certain similarity is arranged when as shown in Figure 1, the configuration of compound 5u combines in the active region with APN with the configuration of ubenimex (dark structure among the left figure).5u can occupy the hydrophobicity pocket S1 of APN well, S1 ', S2 ', 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 5u, and we can obtain from figure, the amino acid conserved sequence (HEXXHX of 5u and APN catalytic center
18E) three amino acid His
297, Glu
298, His
301Formed hydrophobic bond respectively; Arg among 5u and the S2 ' in addition
825Also formed
Stronger ionic bond effect.Thereby these constitutional featuress carry out the structure activity study rational expectation for us and design has better pressing down
Make active APN inhibitor foundation is provided.
4. the invention still further relates to the pharmaceutical composition that contains general formula (I) structural compounds.
A kind of pharmaceutical composition comprises arbitrary class peptide compounds and (2) one or more pharmaceutically acceptable carriers or the vehicle of (1) general formula (I).
In addition, the present invention also comprises a kind of mammiferous pharmaceutical composition of orally give that is suitable for, and comprises arbitrary class peptide compounds and (2) pharmaceutically acceptable carrier of (1) general formula (I), 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 arbitrary class peptide compounds and (2) pharmaceutically acceptable carrier of (1) general formula (I), optional (3) one or more the pharmaceutically acceptable vehicle that comprise.
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.
The present invention general formula (I) also be provided the class peptide compounds at preparation prevention or treatment and metalloprotease, comprise matrix metalloproteinase or Aminopeptidase N, 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.
Detailed Description Of The Invention
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, is monocycle or the bicyclic radicals that contains 5-12 atom.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 VanNostrand Chemist ' s Dictionary, p.650 (1953).The pharmaceutically acceptable solvent that the present invention adopts comprises bioactive those solvents of not disturbing inhibitors of metalloproteinase (solvent known to for example water, ethanol, acetate, the N, dinethylformamide, dimethyl sulfoxide (DMSO) and this those skilled in the art or that determine easily).
" optical isomer " used herein, " enantiomorph ", " diastereomer ", " raceme " etc. have defined the form of The compounds of this invention or all possible steric isomer of its physiological derivative.Unless indication is arranged in addition, the chemical name of The compounds of this invention comprises the mixture of all possible stereochemical form, affiliated mixture comprises all diastereomers and the enantiomorph of basic structure molecule, and the single isomeric forms of the The compounds of this invention of substantially pure, promptly wherein contain and be lower than 10%, preferably be lower than 5%, particularly be lower than 2%, most preferably be lower than other isomer of 1%.The various stereoisomer forms of class peptide compounds of the present invention all obviously are contained in the scope of the present invention.
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.
Description of drawings
Fig. 1 be compound (S)-2-((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionyl ammonia)-3-phenylpropyl alcohol acyl ammonia)-3-phenylalanine (5u) dock with the active region of APN the result by Sybyl 7.0 with the 3-D display synoptic diagram.
Fig. 2 is that ((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionyl ammonia)-3-phenylpropyl alcohol acyl ammonia)-3-phenylalanine (5u) docks the result with the active region of APN and shows synoptic diagram by Ligplot with two dimension compound (S)-2-.
Embodiment
The present invention is described further below in conjunction with embodiment, but be not limited thereto.
Embodiment 1. (S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propylamine)-4-methylvaleric acid (5n) synthetic
(1) (1S, 2S)-2-N-tertbutyloxycarbonyl amido-1-(4-nitrophenyl)-1, ammediol (2)
(2.12g 10mmol) is dissolved among the anhydrous THF of 10mL, under the stirring at room, slowly is added dropwise to and drips tert-Butyl dicarbonate (2.93g, THF solution (5mL) 11mmol), room temperature reaction 24h with dextrorotation chlorine enzyme amine (1).Filter insolubles, with Rotary Evaporators pressure reducing and steaming solvent, cooling crystallization obtains the thick 2.80g of white solid, productive rate 90%, mp115～116 ℃.(2) (2R, 3S)-2-tertbutyloxycarbonyl amido-3-hydroxyl-3-(4-nitrophenyl) propionic acid (3)
With compound 2 (3.12g, 10mmol) and TEMPO (0.16g 1mmol) is dissolved in the acetone of 50ml, stirs down, adds 5% NaHCO
3(50ml), the solution becomes muddiness, ice bath cooling reaction solution to 0 ℃, drip in the 15min NaOCl solution (20.5mL, ca.10%w/w).After dripping, stirring reaction 12 hours, remove acetone under reduced pressure after, reaction solution is with EtOAc (10mL) washed twice, it is 2 that the phosphoric acid solution of 1mol/L is acidified to pH, (3 * 30mL), extraction merges organic phase Na to EtOAc
2SO
4After the drying, concentrating under reduced pressure gets crude product.It is white solid 0.97g that column chromatography purification obtains final product, productive rate 30%, mp80～82 ℃.
(3) (S)-methyl-2-((2R, 3S)-2-(uncle-butoxy carbonyl amino)-3-hydroxyl-3-(4-nitrophenyl) propylamine)-4-methyl pentyl ester (4n)
With compound 3 (3.26g, 10mmol), leucine methyl ester hydrochloride (1.81g, 10mmol), and HOBt (1.62g 12mmol) is dissolved in the 150ml anhydrous methylene chloride, is added dropwise to TEA (2.22g, 22mmol,) ice bath is cooled to 0 ℃, slowly drips EDCI (3.82g, dichloromethane solution 20mmol), about 1h dropwises, and removes ice bath room temperature continuation stirring and spends the night.The reaction solution priority is with the citric acid of 1mol/L, saturated NaHCO
3, saturated brine washing, anhydrous Na
2SO
4Drying, column chromatography purification obtain pure product, are white solid 4.08g, productive rate 88.7%, mp141～143 ℃, ESI-MS m/z:454.3[M+H]
+
(4) (S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propylamine)-4-methylvaleric acid (5n)
(4.53g 10mmol) in the easy 100ml methyl alcohol, is cooled to 5 ℃ with compound 4n, stir the NaOH solution that slowly drips the 1mol/L of 12ml down, after dripping, stirring reaction 6h, steam and remove methyl alcohol, adding 20ml distilled water, is that acid pH is 1 with the phosphoric acid solution conditioned reaction liquid of 1mol/L, has a large amount of white solids to separate out, leave standstill 1h, filter, the filter residue distilled water wash gets white solid after the drying.Under the ice bath, gained solid powder is dissolved in anhydrous ethyl acetate (10ml), drips the HCl/EtOAc saturated solution, continues to stir 12h, the TLC detection reaction, and after reaction finished, steaming desolventized, and adds the 10ml ethyl acetate again, boils off solvent.Add the distilled water of 10ml, use saturated Na
2CO
3It is 6 that solution is regulated the pH value, and the adularescent solid is separated out.Leave standstill filtration, filter residue is the white solid crude product after the vacuum-drying with distilled water wash twice.The pure product of recrystallizing methanol are white crystal 3.20g, productive rate 60%, 203～205 ℃ of mp.ESI-MS?m/z：340.4[M+H]
+；
1H-NMR(DMSO-d
6)δ?0.731(d，J＝12.10，6H)，1.121-1.142(m，1H)，1.336-1.354(m，2H)，3.417(d，J＝4.50，1H)，4.094-4.113(m，1H)，4.882(d，J＝4.50，1H)，7.631(d，J＝8.70，2H)，8.092(d，J＝7.50，1H)，8.180(d，J＝8.70，2H).
Embodiment 2. (S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-N-hydroxy-4-methyl valeramide (7n) synthetic
(4.53g 10mmol), is dissolved in the anhydrous methanol of 20ml, stirs the H of the 1.5mol/L of room temperature dropping 10ml down with compound 4n
2N-OK solution after dropwising, continue to stir 50min, is 7 with the vinegar acid for adjusting pH value, remove methyl alcohol under reduced pressure after, must faint yellow solid.Post isolating 6n, pure product are white solid mp150～153 ℃.With gained solid powder, be dissolved in anhydrous ethyl acetate (10ml), drip the HCl/EtOAc saturated solution, continue to stir 12h, the TLC detection reaction, after reaction finished, steaming desolventized, and adds the 10ml ethyl acetate again, boils off solvent.Add the distilled water of 10ml, use saturated Na
2CO
3It is 6 that solution is regulated the pH value, and the adularescent solid is separated out.Leave standstill filtration, filter residue is white solid 7n crude product after the vacuum-drying with distilled water wash twice.Pure product are white crystal 3.20g behind the recrystallization, productive rate 74.2%, mp212～213 ℃.ESI-MS?m/z：355.6[M+H]
+；
1H-NMR(DMSO-d
6)δ?0.548-0.609(m，6H)，0.701-0.811(m，1H)，0.911-1.198(m，2H)，3.967(d，J＝3.50，1H)，4.063-4.081(m，1H)，4.968(d，J＝3.50，1H)，7.651(d，J＝8.70，2H)，8.244(d，J＝8.70，2H)，8.746(d，J＝8.10，2H).
Embodiment 3. (S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-methylpent acid amides (12p) synthetic
(1) (1S, 2R)-preparation (8) of 2-N-tertbutyloxycarbonyl amido-3-bromo-1-(4-nitrophenyl)-1-propyl alcohol
In the round-bottomed flask of 250mL, and adding compound 2 (3.12g, 10mmol), Ph
3P (3.93g 15mmol), with the anhydrous THF of 100mL dissolving, immerses flask during cryosel bathes then, stirs, measure the 0.8ml pyridine (0.79g 10mmol) drops in the solution, divides three adding NBS solids (2.67g, 15mmol).Cryosel is bathed stirring reaction 1h down, removes ice bath room temperature reaction 8h.Filter insolubles, with Rotary Evaporators pressure reducing and steaming solvent, add the 100ml ether in the residue, leave standstill 1h, filter, filtrate is used 1mol/LH successively
3PO
4, saturated NaHCO
3, saturated aqueous common salt washed twice, anhydrous Na
2SO
4Dry.Filter, concentrate with Rotary Evaporators, obtain reddish-brown oily matter, the crude product post separates, white crystals 1.87g, productive rate 50%, mp116～119 ℃.
(2) (1S, 2S)-preparation (9) of 2-N-tertbutyloxycarbonyl amido-3-nitrine-1-(4-nitrophenyl)-1-propyl alcohol
(3.75g 10mmol) is dissolved in the 10mL dry DMF, adds (0.97g, 15mmol) NaN of porphyrize with compound 8
3, under 55 ℃～60 ℃ of nitrogen protections, stirring reaction 12h under this mixed system.Reaction solution is chilled to room temperature, and impouring 60ml gets in the frozen water, stirs fast with glass stick, and visible white crystals is separated out.Left standstill 2 hours, suction filtration, filter residue distilled water wash twice, vacuum-drying gets white crystals 2.93g, productive rate 87%, 143～145 ℃ of mp.
(3) (1S, 2S)-preparation (10) of 2-N-tertbutyloxycarbonyl amido-3-amino-1-(4-nitrophenyl)-1-propyl alcohol
With compound 9 (3.37g, 10mmol) be dissolved in THF (80mL, 0.5%water) after, add triphenyl phosphorus (3.14g, 12mmol). reaction solution stirring at room 24 hours.The pressure reducing and steaming solvent adds 40ml ethyl acetate dissolution residual substance, the H of 1mol/L
3PO
4Solution extraction organic phase three times, each 10ml is associated with water, and the NaOH of 1mol/L regulates pH value to 10, and water extracts three times with ethyl acetate, each 20ml.Merge ethyl acetate, anhydrous Na
2SO
4Dry.Filter, concentrate with Rotary Evaporators, obtain the faint yellow solid crude product, the ether recrystallization gets pure product 2.27g, productive rate 73%, 197～201 ℃ of mp.
(4) (1S, 2S)-preparation (12p) of 2-N-tertbutyloxycarbonyl amido-3-amino-1-(4-nitrophenyl)-1-propyl alcohol
With compound 10 (3.11g, 10mmol), Boc-Leu (2.31g, 10mmol), and HOBt (1.62g 12mmol) is dissolved in the 150ml anhydrous methylene chloride, is added dropwise to TEA (2.22g, 22mmol,) ice bath is cooled to 0 ℃, slowly drips EDCI (3.82g, dichloromethane solution 20mmol), about 1h dropwises, and removes ice bath room temperature continuation stirring and spends the night.The reaction solution priority is with the citric acid of 1mol/L, saturated NaHCO
3, saturated brine washing, anhydrous Na
2SO
4Drying, column chromatography purification obtain pure product 11p, are white solid 3.43g, productive rate 65.4%, 200～203 ℃ of mp, ESI-MS m/z:525.3[M+H]
+
Under the ice bath, (2.07g 5mmol) is dissolved in anhydrous ethyl acetate (10ml) to compound 11p, drips the HCl/EtOAc saturated solution, continues to stir, and the adularescent solid is separated out behind the 10min.The TLC detection reaction, after reaction finished, steaming desolventized, and adds the 10ml ethyl acetate again, boils off solvent.Add the distilled water of 10ml, use saturated Na
2CO
3It is 10 that solution is regulated the pH value, and the adularescent solid is separated out.Leave standstill filtration, filter residue is white solid 7n crude product after the vacuum-drying with distilled water wash twice.Pure product 12p is white crystal 1.06g behind the recrystallization, productive rate 65.9%, 160～163 ℃ of mp, ESI-MS m/z:325.3[M+H]
+ 1H-NMR (DMSO-d
6) δ 0.886-0.906 (m, 6H), 1.592-1.553 (m, 2H), 1.554-1.573 (m, 1H), 3.097-3.143 (m, 1H), 3.481-3.549 (m, 1H), 3.737 (m, 1H), 4.970 (d, J=3.50,1H), 6.649 (d, J=3.50,1H), 7.750 (d, J=8.70,2H), 8.241 (m, 1H), 8.250 (s, 2H), 8.433 (s, 2H), 8.260 (d, J=8.70,2H), 8.746 (d, J=8.10,2H) .9.145 (s, 1H).
Embodiment 4 presses down enzyme test
(I) the external enzyme test result that presses down of series compound is as follows:
The external enzyme test table 1 as a result that presses down
The external enzyme test table 2 as a result that presses down
The external enzyme test table 3 as a result that presses down
Numerical value is the mean value of three tests in the table, the numeric representation standard deviation after " ± ".
Last table test data shows: 2-amino-1-(4-nitrophenyl)-1-alcohol compound all demonstrates metalloprotease APN and the certain inhibition activity of MMP.Wherein, compound 12u, 12w, 12y, 5t demonstrate and suppress Aminopeptidase N activity (IC preferably
50=4.3～21.3 μ mol.L-1), near the inhibition activity (IC of positive control Bestatin
50The value that further research is arranged=3.0 μ mol.L-1).
Embodiment 5 target compounds suppress the activity test (In vitro) of cell proliferation
Part of compounds in the compound (I) (IC50＜60 μ mol/L) has been carried out the test of vitro inhibition HL-60 cancer cell multiplication, and the result is as follows: Compound I C
50(mmol/L)
Table 4:
| Compound | IC 50(mM) | Compound | IC 50(mM) |
| Ubenimex | 1.65±0.09 | ||
| 7n | 0.98±0.08 | 5s | 2.02±0.13 |
| 7o | 0.51±0.11 | 5t | 2.21±0.11 |
Numerical value is the mean value of three tests in the table, the numeric representation standard deviation after " ± ".
As can be seen from the results, compound 7n, 7o, 5s and 5t demonstrate stronger activity in the test of extracorporeal anti-tumor cell proliferation, are expected to become the anticancer drug candidate of non-cytotoxicity class.
Claims (10)
1. compound of Formula I and pharmaceutical salts thereof,
Wherein, W is C (O) NH or CH
2NHC (O);
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 or C1-6 alkyl, optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, aryl, substituted aryl, halogen C1-8 alkyl, the C1-8 alkoxyl group, C1-6 alkyl-carbonyl, C1-8 carbalkoxy or 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 or heteroaryl C2-6 alkynyl, optional by one or more following groups replacements: halogen, nitro, cyano group, halogen C1-8 alkyl, C1-8 alkoxyl group, C1-6 alkyl-carbonyl or C1-8 carbalkoxy.
2. compound as claimed in claim 1 is characterized in that: the carbon shown in the * has that (1S, 2R) configuration perhaps have (1R, 2S) configuration in the formula (I).
3. compound as claimed in claim 1 or 2 is characterized in that: R
1Be aryl C1-6 alkyl, preferred benzyl, the fragrant ethyl of β, γ virtue propyl group, the C end is protected or do not protected natural or the alpha-non-natural amino acid derivative, and is optional by one or more following groups replacements: hydroxyl, halogen, nitro, cyano group, C1-8 alkoxyl group.
4. compound as claimed in claim 1 or 2 is characterized in that: R
2Be hydrogen.
5. as the compound of claim 1 or 2, it is one of following:
(2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl)-N-propyl group propionic acid amide (5a),
(2R, 3S)-2-amino-3-hydroxy-n-sec.-propyl-3-(4-nitrophenyl) propionic acid amide (5b),
(2R, 3S)-2-amino-N-butyl-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5c),
(2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl)-N-amyl group propionic acid amide (5d),
(2R, 3S)-2-amino-N-cyclohexyl-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5e),
(2R, 3S)-2-amino-N-benzyl-3-hydroxyl-3-(4-nitrophenyl) propylamine (5f),
(2R, 3S)-2-amino-N-(4-luorobenzyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5g),
(2R, 3S)-2-amino-N-(4-methoxy-benzyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5h),
(2R, 3S)-2-amino-N-(styroyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5i),
(2R, 3S)-2-amino-N-(2-chlorobenzene ethyl)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5j),
(2R, 3S)-2-amino-N-(2-leptodactyline)-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide (5k),
(2R, 3S)-2-amino-3-hydroxy-n-((S) 1-hydroxyl-3-hydrocinnamyl-2-yl)-3-(4-nitrophenyl) propionic acid amide (5l),
(2R, 3S)-2-amino-3-hydroxy-n-((S) 1-hydroxyl-3-hydrocinnamyl-2-yl)-3-(4-nitrophenyl) propionic acid amide (5m),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propylamine)-4-methylvaleric acid (5n),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3-phenylpropionic acid (5o),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3 Methylbutanoic acid (5p),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3 Methylbutanoic acid (5q),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-3-(1H-indoles-2-yl) propionic acid (5r),
(S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-N-hydroxy-4-methyl valeramide (7n),
(2R, 3S)-2-amino-3-hydroxy-n-((S)-1-(hydroxylamino)-1-oxygen-3-phenylpropyl alcohol alkane-2-yl)-3-(4-nitrophenyl) propionic acid amide (7o),
(S)-2-((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionic acid amide)-4-methylpent acid amides)-3-phenylpropionic acid (5s),
(S)-2-((S)-2-((2R, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propionyl ammonia)-3-phenylpropyl alcohol acyl ammonia)-3-phenylalanine (5t),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) benzamide (12a),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-methyl benzamide (12b),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-chlorobenzamide (12c),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-chlorobenzamide (12d),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-nitrobenzamide (12e),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-methoxy benzamide (12f),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2,4 dichloro benzene methane amide (12g),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2,4-dinitrobenzamide (12h),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3,4,5-trimethoxy-benzamide (12i),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-gallamide (12g),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-2-phenylacetamide (12k),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) cinnamide (12l),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-(4-hydroxy 3-methoxybenzene base) acrylamide (12m),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-hydrocinnamamide (12n),
N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-fenbutyramidum (12o),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-4-methylpent acid amides (12p),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-Phenylpropionamide (12q),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylbutyryl amine (12r),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylpent acid amides (12s),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group) propionic acid amide (12t),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-sulfydryl propionic acid amide (12u),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-hydroxyl propionic acid amide (12v),
(S)-2-amino-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group)-3-methylthio group propionic acid amide (12w),
(S)-N-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl propyl group)-2-((S)-2-amino-3-Phenylpropionamide base)-4-methylpent acid amides (12x) or
(S)-2-amino-N-((S)-1-((2S, 3S)-2-amino-3-hydroxyl-3-(4-nitrophenyl) propyl group amino)-1-oxygen-3-phenyl third-2-yl)-3-Phenylpropionamide (12y).
6. the intermediate of preparation claim 1 or 2 described compounds, its be (2R, 3S)-2-tertbutyloxycarbonyl amido-3-hydroxyl-3-(4-nitrophenyl) propionic acid, or (1S, 2S) 2-N-tertbutyloxycarbonyl amido-3-amino-1-(4-nitrophenyl)-1-propyl alcohol.
7. the preparation method of the described compound of claim 1 is characterized in that comprising the steps:
With dextrorotation chlorine enzyme amine (1) is raw material, at first uses the amino compound (2) that gets of N-tertbutyloxycarbonyl (Boc) protection, and compound (2) obtains intermediate (3) through selective oxidation; In methylene dichloride (DCM), contract and agent as compound with N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBT), intermediate (3) reacts with the amine of various replacements, generate intermediate (behind the 4a～4t), (4a～4m) take off the Boc protecting group in the hydrochloric ethyl acetate saturated solution obtains the compound (5a～5m) in compound (I) series to intermediate; The methyl ester hydrochloride reaction of intermediate (3) and each seed amino acid and dipeptides obtains intermediate (4n～4t), at last in NaOH solution, saponification reaction takes place, the decarboxylize methyl esters, and obtain (the 5n～5t) of target compound in compound (I) series after the Boc protecting group of deaminize end; Wherein (carboxyl ester of 4n～4o) is under the effect of azanol potassium, generates compound (6n～6o), the and obtain (7n～7o) of target compound in (I) series after the Boc protecting group of deaminize end for intermediate;
Reaction formula is as follows:
8. the preparation method of the described compound of claim 1 is characterized in that comprising the steps:
With compound (2) is raw material, gets compound (8) through primary hydroxyl selectivity bromo; Compound (8) and NaN
3Carry out S
N2 substitution reactions generate compound (9); Compound (9) is made reductive agent with triphenyl phosphorus, reduce intermediate (10); The amino acid and the dipeptides of intermediate (10) and various carboxylic acids or Boc protection, contract and agent as compound with N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCI) and 1-hydroxy benzo triazole (HOBT), obtain intermediate (11a～11y), (11a～11y) takes off the Boc protecting group to intermediate, generates (I) serial target compound (12a～12y);
Reaction formula is as follows:
9. each compound of claim 1-5 comprises matrix metalloproteinase or Aminopeptidase N at preparation prevention or treatment and metalloprotease, the application in the medicine of the mammalian diseases that active unconventionality expression is relevant; Described and the related mammalian disease metal proteinase activity unconventionality expression comprises: inflammation, cancer, multiple sclerosis, various tissue ulcers or tissue ulcer venereal disease disease, periodontopathy, epidermolysis bullosa and leukemia.
10. pharmaceutical composition comprises each compound and one or more pharmaceutically acceptable carriers or vehicle of claim 1-5.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009109850A3 (en) * | 2008-03-06 | 2009-12-10 | Novaremed Ltd. | N-substitutedbenzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation |
| US8252843B2 (en) | 2004-03-26 | 2012-08-28 | Novaremed Limited | Compounds for the treatment of AIDS and other viral diseases |
| US8309606B2 (en) | 2002-10-03 | 2012-11-13 | Novaremed Limited | Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection |
| 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 |
| US8802734B2 (en) | 2009-09-09 | 2014-08-12 | Novaremed Limited | Method of treating or preventing pain |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1566065A (en) * | 2003-06-27 | 2005-01-19 | 中国医学科学院药物研究所 | Alpha position heteroatom substituted gamma aryl ketobutyric acid derivative, process, pharmaceutical combination and uses thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8309606B2 (en) | 2002-10-03 | 2012-11-13 | Novaremed Limited | Compounds for use in the treatment of autoimmune diseases, immuno-allergical diseases and organ or tissue transplantation rejection |
| US8252843B2 (en) | 2004-03-26 | 2012-08-28 | Novaremed Limited | Compounds for the treatment of AIDS and other viral diseases |
| WO2009109850A3 (en) * | 2008-03-06 | 2009-12-10 | Novaremed Ltd. | N-substitutedbenzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation |
| US8883853B2 (en) | 2008-03-06 | 2014-11-11 | Novaremed Limited | N-substituted benzenepropanamide or benzenepropenamide derivatives for use in the treatment of pain and inflammation |
| US8802734B2 (en) | 2009-09-09 | 2014-08-12 | Novaremed Limited | Method of treating or preventing pain |
| 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 |
| 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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| CN101503373B (en) | 2013-07-24 |
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