CN101353320A - Matrix metalloprotease inhibitors, medicinal composition containing the same, preparation and use thereof - Google Patents

Matrix metalloprotease inhibitors, medicinal composition containing the same, preparation and use thereof Download PDF

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Publication number
CN101353320A
CN101353320A CNA2007101370966A CN200710137096A CN101353320A CN 101353320 A CN101353320 A CN 101353320A CN A2007101370966 A CNA2007101370966 A CN A2007101370966A CN 200710137096 A CN200710137096 A CN 200710137096A CN 101353320 A CN101353320 A CN 101353320A
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isobutyl
succinyl
hydroxylamino
tryptophane
chloro
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Inventor
刘克良
韩寒
梁远军
李�杰
何军林
郑建全
魏晓莉
赵建
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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Priority to CNA2007101370966A priority Critical patent/CN101353320A/en
Priority to PCT/CN2008/001356 priority patent/WO2009012656A1/en
Priority to CN2008800256379A priority patent/CN101932560B/en
Publication of CN101353320A publication Critical patent/CN101353320A/en
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Abstract

The invention relates to a matrix metallo-proteinase inhibitor, a pharmaceutical composition containing the matrix metallo-proteinase inhibitor, and a preparation method thereof and the application thereof. The matrix metallo-proteinase inhibitor has the structure of formula (I), wherein, the definitions of W, X1, X2, R1 and R2 are the same as the instruction book. The matrix metallo-proteinase inhibitor and the pharmaceutical composition containing the matrix metallo-proteinase inhibitor can be used for preventing and treating the diseases adjusted by matrix metalloproteinase, in particular for preventing and treating keratohelcosis, emphysema and skin ulcer caused by chemical injuries or emphysema caused by smoking or drowning.

Description

Matrix metallo-proteinase inhibitor, contain their pharmaceutical composition and its production and use
Technical field
The present invention relates to have the hydroxamic acid and the carboxylic acid derivative of matrix metalloproteinase inhibitory activity and therepic use, the pharmaceutical composition that contains them, their preparation method and this compounds in pharmaceutically application.These compounds are the inhibitor of the matrix metalloproteinase relevant with tissue deterioration particularly.
Background technology
Matrix metalloproteinase (MMP) is the zinciferous proteolytic ferment of a class.It can catalysis extracellular matrix (ECM) hydrolytic cleavage.ECM is the dynamic network structure that is present between the cell, is made of macromolecular substance such as collagen, proteoglycan and glycoprotein.ECM plays important effect in the stability of keeping cell position and the conduction of intercellular signal.MMP and natural inhibitor-tissue inhibitor of metalloproteinase thereof (TIMP) are regulated and control the renewal of ECM jointly, keep the stability of cell.The imbalance of regulatory mechanism can make the ECM excessive degradation cause a series of diseases, as the intrusion of tumour and diffusion transfer, sacroiliitis, periodontitis, multiple sclerosis etc.Effective inhibitors can reduce the activity of MMP, thereby recovers this balance.Therefore, seeking effective MMP inhibitor opens up a new way for capturing these diseases.
Zine ion in the matrix metalloproteinase is the important avtive spot of this enzyme, plays a significant role when protolysate and peptide class substrate.Effectively matrix metallo-proteinase inhibitor structurally generally has following two common features: (1) contains a zine ion conjugated group (ZBG), and chelating zine ion active centre makes enzyme deactivation; (2) molecular skeleton is rich in the atom or the group that can form hydrogen bond, to increase the avidity of compound and enzyme.
The kind of ZBG is a lot, as hydroxamic acid (CONHOH); The anteiso-hydroximic acid (NHOHCHO); Sulfydryl (SH); Phosphoric acid ester [P (O) OROH]; Carboxylic acid (COOH) etc.Hydroxamic acid (CONHOH) be one with the very strong bidentate ligand of catalysis zine ion binding ability, two Sauerstoffatoms wherein and catalysis zine ion form coordinate bond, can suppress its activity well, make it no longer and substrate-function.
The kind of matrix metallo-proteinase inhibitor is a lot, and succinyl hydroxamic acid class is wherein to be studied a class the most widely, and precursor structure can be used formula (VII) expression:
Figure A20071013709600291
Formula (VII)
Wherein W be zine ion conjugated group hydroxamic acid (CONHOH) or carboxylic acid (COOH) group, document illustration change the zine ion conjugated group and the substituent R of this compounds A-R ECan bigger influence be arranged to their inhibition activity.Generally speaking: better to the active hydroxamic acid of the inhibition of various matrix metalloproteinases than carboxylic acid, but hydroxy-acid group can produce the selectivity inhibition to gelatinase with other substituent combination.R A-R EOccupy each sublocus of enzyme respectively, wherein R BSubstituting group is relevant with the selectivity of compound.
Following patent gazette has disclosed the MMP inhibitor based on hydroxamic acid:
The application for a patent for invention mandate specification sheets (patent No.: 95191248.8)
The application for a patent for invention mandate specification sheets (patent No.: 99802593.3)
US?4599361
EP-A-0236872
EP-A-0274453
WO?90/05716
WO?90/05719
WO?90/02716
EP-A-0489577
EP-A-0489579
EP-A-0497192
WO?92/13831
WO?92/17460
WO?92/22523
WO?93/09090
WO?93/09097
WO?93/20047
WO?93/24449
WO?93/24475
EP-A-0574758
Mostly prior art is to introduce hydroxyl or amino and their derivative in the α position of hydroxamic acid group, and these groups mostly are electron-donating group, and its purpose is to improve the dynamic (dynamical) characteristic of compound medicine.Yi Fangmian effort is exactly to seek other group beyond the oxime acid such as anteiso-hydroximic acid (NHOHCHO), (SH), phosphoric acid ester [P (O) OROH], carboxylic acid are (COOH), with some heterocyclic compounds etc. for sulfydryl in addition, as the zine ion conjugated group, in the hope of being used for the design of inhibitors of metalloproteinase.Up to the present, also do not have open in the prior art or the approach that this change hydroximic acid of electron-withdrawing group and the cooperation of zinc huge legendary turtle are used is introduced in prompting in hydroximic acid α position.
Summary of the invention
One of purpose of the present invention provides the even more ideal matrix metallo-proteinase inhibitor of metalloproteinase inhibitory activity.
Another object of the present invention provides a kind of pharmaceutical composition that comprises matrix metallo-proteinase inhibitor of the present invention and pharmaceutically acceptable vehicle or carrier.
An also purpose of the present invention provides the method for preparation matrix metallo-proteinase inhibitor of the present invention.
A further object of the present invention provides matrix metallo-proteinase inhibitor of the present invention and is used for preventing or treats purposes in the medicine of the disease that the Mammals that comprises the people regulated by matrix metalloproteinase in preparation.
For achieving the above object, the present inventor is through long-term deep discovering, by introduce electron-withdrawing group in hydroximic acid α position, changing hydroximic acid and the cooperation of zinc huge legendary turtle uses, formula (III) conformation restriction group is caused shown in the formula (I) in the compound, obtained the better compound of metalloproteinase inhibitory activity.
For example, compound shown in the formula (I), wherein W is a hydroxamic acid group, when introduce electron-withdrawing group in its α position, particularly during halogen atom, the acidic character of strong hydroxamic acid group ever, thereby improve the huge legendary turtle cooperation usefulness of hydroxamic acid group and zine ion, and then increase the enzyme inhibition activity of entire compound.Simultaneously, R in change formula (I), formula (II) and the formula (III) 1-R 5Substituent combination can obtain the even more ideal matrix metallo-proteinase inhibitor of matrix metalloproteinase inhibitory activity.
Therefore, on the one hand, the invention provides the compound shown in the formula (I), or its pharmaceutically acceptable prodrug, salt, solvate or hydrate,
Figure A20071013709600311
Wherein, R 1Be group shown in the formula (II):
Figure A20071013709600312
Wherein,
R 3The characteristic group of representing natural or non-natural a-amino acid, wherein any functional group of Cun Zaiing is not protected or protected;
R 4Expression (C 1-C 6) alkyl, (C 1-C 6) thiazolinyl, (C 1-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 3-C 8) cycloalkylalkyl, (C 4-C 8) cycloalkenyl group, (C 4-C 8) cycloalkenyl alkyl, heterocyclic radical (C 1-C 6) alkyl, aryl (C 1-C 6) alkyl, aryl (C 1-C 6) thiazolinyl, aryl (C 1-C 6) alkynyl, heterocyclic radical (C 1-C 6) thiazolinyl, heterocyclic radical (C 1-C 6) alkynyl, (C 1-C 6Alkyl) O (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) O (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) O (C 1-C 6) alkyl, (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, wherein any group is not substituted or quilt (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, (C 1-C 6) alkylthio, halogen or cyano group replaces arbitrarily; Or phenyl or 5 or 6 yuan of fragrant heterocycles, it is not oxidized or be oxidized to the N-oxide compound that wherein ring is gone up any nitrogen-atoms, perhaps they and phenyl ring or with 5,6 or 7 yuan heterocyclic fused, wherein any ring be not substituted or by following (a) or (b) group replace:
(a) one or more be independently selected from hydroxyl, halogen, cyano group, carboxyl ,-CO 2(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-CO 2(C 1-C 6) alkyl ,-CONH 2,-CONH (C 1-C 6) alkyl ,-CON[(C 1-C 6) alkyl] 2,-CHO ,-CH 2OH, (C 1-C 4) perfluoroalkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) alkyl ,-SO (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-NO 2,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2With-NHCO (C 1-C 6) group of alkyl;
(b) be selected from (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 4-C 8) group of cycloalkenyl group, phenyl, benzyl, heterocyclic radical or heterocyclyl methyl, any one of these groups is not substituted or by one or more halogen, hydroxyl, amino, carboxyl, (C of being selected from 1-C 4) perfluoroalkyl, (C 1-C 6) alkyl ,-O (C 1-C 6) alkyl and-S (C 1-C 6) substituting group of alkyl replaces;
R 5Be hydrogen or (C 1-C 6) alkyl;
Perhaps, R 1Be group shown in the formula (III)
Figure A20071013709600321
Wherein,
R 4With R 5Identical with definition in the formula (II);
Het represents aromatic ring or fragrant heterocycle, and wherein any one is not substituted or by one or more halogen, hydroxyl, amino, carboxyl, (C of being selected from 1-C 4) perfluoroalkyl, (C 1-C 6) alkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) substituting group of alkyl replaces;
W is-COOH or-CONHOH;
X 1With X 2Be independently selected from hydrogen respectively, comprise F, the halogen of Cl, Br, cyano group, nitro; Work as R 1During expression (II) group, X 1With X 2Be not hydrogen simultaneously; Work as R 1During expression (III) group, X 1With X 2Can be hydrogen simultaneously;
R 2Expression (C 1-C 6) alkyl, (C 1-C 6) thiazolinyl, (C 1-C 6) alkynyl, aryl (C 1-C 6) alkyl, aryl (C 1-C 6) thiazolinyl, aryl (C 1-C 6) alkynyl, heterocyclic radical (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6) thiazolinyl, heterocyclic radical (C 1-C 6) alkynyl, (C 1-C 6Alkyl) O (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) O (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) O (C 1-C 6) alkyl, wherein any group is not substituted or quilt (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, (C 1-C 6) alkylthio, halogen or cyano group replaces.
The steric configuration of compound involved in the present invention is generally as described below:
Load X 1With X 2The C atom, its steric configuration can be R-type, S-type or achirality;
Load R 2The C atom, its steric configuration is the R-type;
Load R 3The C atom, its steric configuration is the S-type.
As previously mentioned, the group that the compound of The compounds of this invention and existing patent gazette announcement is mainly introduced at the alpha-position of zine ion conjugated group (CONHOH) has tangible different, therefore, and radicals R 1, R 2, R 3, R 4, R 5Can be any group of the compound corresponding position of above-listed existing patent gazette announcement.Aforementioned principle is not added restriction, and the corresponding position of original technical compound has been disclosed the substituent R of following type 3, so the suitable R that uses in the The compounds of this invention 3Group can be: (C 1-C 6) alkyl, benzyl, hydroxybenzyl, benzyloxy benzyl, (C 1-C 6) alkoxybenzyl or benzyloxy (C 1-C 6) alkyl; And the characteristic group of natural a-amino acid, wherein any functional group can be protected, and any amino can be by acidylate, and any carboxyl of existence can be by amidation; And-[Alk] nR 6Group, wherein Alk be can be arbitrarily by one or more-O-or-the S-atom or-N (R 7(the C that)-group inserts 1-C 6) alkyl or (C 2-C 6) thiazolinyl (R wherein 7Be hydrogen atom or (C 1-C 6) alkyl), n=0 or 1, R 6Be any substituted cycloalkyl or cycloalkenyl group; And phenyl ring is selected from halogen, nitro, carboxyl, (C 1-C 6) alkoxyl group, cyano group, (C 1-C 6) alkyloyl, (C 1-C 6) alkyl amide, trifluoromethyl (C 1-C 6) alkyl, amino, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, sulfydryl, (C 1-C 6) alkylthio, hydroxyl (C 1-C 6) alkyl, sulfydryl (C 1-C 6) alkyl or (C 1-C 6) benzyl of any replacement of doing of any group of alkyl phenyl methyl.Phenyl ring quilt-OCH 2COR 8The benzyl that group replaces, wherein R 8Be hydroxyl, amino, (C 1-C 6) alkoxyl group, phenyl (C 1-C 6) alkoxyl group, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, phenyl (C 1-C 6) residue of alkylamino, amino acid or its carboxylic acid halides, ester or amide derivatives, described residue connects by amido linkage, and described amino acid is selected from glycine, L-Ala, Methionin, Xie Ansuan, leucine, Isoleucine, phenylalanine, tyrosine, tryptophane, Serine, Threonine, halfcystine, methionine(Met), l-asparagine, glutamine, Methionin, Histidine, arginine, L-glutamic acid and aspartic acid; And heterocycle (C 1-C 6) alkyl, heterocycle and heterocycle (C 1-C 6) alkyl, aromatic ring and heterocycle (C 1-C 6) alkyl, aromatic ring and aromatic ring (C 1-C 6) alkyl, it can be unsubstituted, or any group wherein can be selected from halogen, nitro, carboxyl, (C 1-C 6) alkoxyl group, cyano group, (C 1-C 6) alkyloyl, (C 1-C 6) alkyl amide, trifluoromethyl (C 1-C 6) alkyl, hydroxyl, formyl radical, amino, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, sulfydryl, (C 1-C 6) alkylthio, hydroxyl (C 1-C 6) alkyl, sulfydryl (C 1-C 6) alkyl or (C 1-C 6) any group of alkyl phenyl methyl does arbitrarily and replace.
R 3Also can be-CR aR bR cGroup, wherein: each R a, R b, R cEach is hydrogen (C naturally 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl and R a, R b, R cNot hydrogen simultaneously; Or R cBe hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, R aAnd R bForm 3-8 unit's cycloalkyl or 5-6 unit heterocycle with the carbon atom that links to each other; Or R a, R b, R cForm three rings (as adamantyl) with the carbon atom that links to each other; Or R a, R b(C respectively does for oneself 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl or except hydrogen to R cFollowing definition, perhaps R aAnd R bForm 3-8 unit's cycloalkyl or 3-8 unit heterocycle with the carbon atom that links to each other, and R cBe hydrogen ,-OH ,-SH, halogen ,-CN ,-COOH, (C 1-C 4) perfluoroalkyl ,-CH 2OH ,-CO 2(C 1-C 6) alkyl ,-O (C 1-C 6) alkyl ,-O (C 2-C 6) thiazolinyl ,-S (C 1-C 6) alkyl ,-SO (C 2-C 6) alkyl ,-SO 2(C 2-C 6) alkyl ,-S (C 2-C 6) thiazolinyl ,-SO (C 2-C 6) thiazolinyl ,-SO 2(C 2-C 6) thiazolinyl or-the Q-W group, wherein Q represent a key or-O-,-S-,-SO-,-SO 2-, W represents phenyl, phenylalkyl, (C 3-C 8) cycloalkyl, (C 3-C 8) cycloalkylalkyl, (C 4-C 8) cycloalkenyl group, (C 4-C 8) cycloalkenyl alkyl, heteroaryl or heteroarylalkyl, wherein W can be arbitrarily by one or more be selected from respectively hydroxyl, halogen ,-CN ,-COOH ,-CO 2(C 1-C 6) alkyl ,-CONH 2,-CONH (C 1-C 6) alkyl ,-CONH (C 1-C 6Alkyl) 2,-CHO ,-CH 2OH, (C 1-C 4) perfluoroalkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) alkyl ,-SO (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-NO 2,-NH 2,-NH (C 1-C 6) alkyl ,-N (C 1-C 6Alkyl) 2,-NHCO (C 1-C 6) alkyl, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 4-C 8) substituting group of cycloalkenyl group, phenyl or benzyl replaces.
Work as R 1When representing as general formula (II) group, the X in the formula (I) 1With X 2Group makes up more specifically and is defined as follows: H, F; H, Cl; H, Br; F, F; Cl, Cl; Br, Br; F, Cl; F, Br; Cl, Br; Work as R 1When representing as general formula (III) group, X 1With X 2Combination except that aforesaid combination, X 1With X 2Can also be hydrogen simultaneously.
Preferred compound includes but not limited to compound as follows according to the present invention:
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-methyl nitrosourea
Figure A20071013709600351
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-methyl nitrosourea
Figure A20071013709600352
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-cyclopropyl amide
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-cyclopropyl amide
Figure A20071013709600354
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-buserelin
Figure A20071013709600355
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-2-furfuryl acid amides
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-buserelin
Figure A20071013709600361
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-2-furfuryl acid amides
Figure A20071013709600362
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-2-picolyl amides
Figure A20071013709600363
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-2-picolyl amides
Figure A20071013709600364
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-phenyl amide
Figure A20071013709600365
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-phenyl amide
Figure A20071013709600366
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-cyclohexyl amide
Figure A20071013709600367
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N1-cyclohexyl amide
Figure A20071013709600368
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-methyl nitrosourea
Figure A20071013709600369
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-methyl nitrosourea
Figure A200710137096003610
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-buserelin
Figure A200710137096003611
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-buserelin
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-cyclopropyl amide
Figure A20071013709600372
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-cyclopropyl amide
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-phenyl amide
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N1-phenyl amide
Figure A20071013709600375
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-methyl nitrosourea
Figure A20071013709600376
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-methyl nitrosourea
Figure A20071013709600377
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-cyclopropyl base acid amides
Figure A20071013709600378
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-cyclopropyl amide
Figure A20071013709600379
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-phenyl amide
Figure A200710137096003710
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N1-phenyl amide
Figure A200710137096003711
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-methyl nitrosourea
Figure A200710137096003712
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-methyl nitrosourea
Figure A20071013709600381
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-cyclopropyl base acid amides
Figure A20071013709600382
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-cyclopropyl amide
Figure A20071013709600383
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-phenyl amide
Figure A20071013709600384
N2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N1-phenyl amide
Figure A20071013709600385
N2-(4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N1-methyl nitrosourea
Figure A20071013709600386
N2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N1-methyl nitrosourea
Figure A20071013709600387
And their prodrug, salt, solvate or hydrate.
More preferably, compound of the present invention is selected from following compound:
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
Or its pharmaceutically acceptable prodrug, salt, solvate or hydrate.
Also more preferably, compound of the present invention is selected from following compound:
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
Or its pharmaceutically acceptable prodrug, salt, solvate or hydrate.
Also more preferably, compound of the present invention is selected from following compound:
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
Or its pharmaceutically acceptable prodrug, salt, solvate or hydrate.
Also more preferably, compound of the present invention is selected from following compound:
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea, and
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
Or its pharmaceutically acceptable prodrug, salt, solvate or hydrate.
Also more preferably, compound of the present invention is selected from following compound:
N 2-(4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3,3 two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3,3 two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea, and
N 2-(3,3 two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea.
On the other hand, the invention provides a kind of pharmaceutical composition, it comprises formula of the present invention (I) compound and pharmaceutically acceptable vehicle or carrier.
Again on the one hand, the invention provides the method for a kind of preparation formula (I) compound.
For example, W is that the The compounds of this invention of hydroxamic acid group-CONHOH can be prepared as follows in the formula (I):
Figure A20071013709600511
(A) make the sour of formula (IVa) or its activated derivatives and azanol or its salt directly carry out condensation reaction and obtain compound shown in the formula (I); Perhaps
(B) earlier with the acid of formula (4a) or its activated derivatives and the protected azanol of O or the two protected azanol condensation of N, O, obtain intermediate shown in the formula (IVb), remove R wherein then a(or) R bProtecting group obtains compound shown in the formula (I);
X wherein 1, X 2, R 1, R 2Definition and formula (I) in identical, R aBe amino protecting group, R bBe the protecting group of hydroxyl, but may with the R of azanol, the protected azanol of O or the two protected azanol of N, O or its reactant salt 1, R 2Substituting group, itself can be protected and make it not participate in this class reaction, then from the hydroxamic acid part and the R of gained 1, R 2Remove any protected substituting group.For method (A), such as dicyclohexylcarbodiimide (DCC)/benzotriazole base, N, N-dimethylaminopropyl-N /Under the condition that condensing agents such as-ethyl carbodiimide (EDC)/benzotriazole base, chloro-formic ester/N-methylmorpholine exist, make the directly sour and azanol condensation of formula (4a) obtain the compound shown in the formula (1); For method (B), such as dicyclohexylcarbodiimide (DCC)/benzotriazole base, N, N-dimethylaminopropyl-N /-ethyl carbodiimide (EDC)/benzotriazole base; under the condition that condensing agents such as chloro-formic ester/N-methylmorpholine exist; make the acid of formula (IVa) and suitable alcohol reaction earlier (IVa) is converted into active derivative; pentafluorophenyl esters as (IVa); hydroxyl succinyl ester or hydroxybenzotriazole base ester; then with protected azanol of O or N; the two protected azanol of O reacts; or the acid that makes (IVa) directly under the condition that above-mentioned condensing agent exists with protected azanol of O or N; the two protected azanol of O reacts; obtain compound shown in the intermediate formula (IVb), remove protecting group again and obtain the compound shown in the formula (I).
The example that is used for the protected azanol of O of aforesaid method (B) comprises O-benzyl hydroxylamine, O-4-methoxy-benzyl azanol, O-trimethyl silyl azanol and O-tertbutyloxycarbonyl azanol.
Be used for the N of aforesaid method (B), the example of the two protected azanol of O comprises N; O-dibenzyl hydroxylamine, N; O-two (4-methoxy-benzyl) azanol, N-tertbutyloxycarbonyl-O-t-butyldimethylsilyl azanol, N-tertbutyloxycarbonyl-O-THP trtrahydropyranyl azanol and N, O-two tertbutyloxycarbonyl azanols.
For method (B), suitable blocking group is the benzyl (as the 4-methoxy-benzyl) of benzyl and replacement.This class protecting group can be removed by hydrogenolysis, and the 4-methoxy-benzyl also can be removed by acid hydrolysis.
It is the method for the The compounds of this invention of carboxyl-COOH that the present invention also provides the middle W of preparation formula (I), and this method may further comprise the steps:
With formula (Va) acid or it activated derivatives and formula (VIa) or (VIb) shown in the amine condensation obtain the intermediate shown in the formula (Vb), remove again the Rc protecting group obtain formula (I, W=COOH) shown in compound.R wherein 1, R 2, R 3, R 4, R 5Definition except the R of potential reaction is arranged in coupled reaction 1, R 2, R 3, R 4, R 5Substituting group itself can be protected and make it not participate in outside this class reaction, other definition with formula (I) is identical, Rc represents hydroxy-protective group.
Condensation reaction can be such as dicyclohexylcarbodiimide (DCC)/I-hydroxybenzotriazole (HOBT), N, N-dimethylaminopropyl-N /-ethyl carbodiimide (EDC)/I-hydroxybenzotriazole (HOBT), DMTMM (structure is seen embodiment abbreviation table), benzotriazole-1-oxygen-three (dimethylin) phosphorus hexafluorophosphate (BOP), 2-(the 1H-benzotriazole-1-)-1,1,3, carry out under the condition that condensing agents such as 3-tetramethyl-urea hexafluorophosphate (HBTU), chloro-formic ester/N-methylmorpholine exist.
Be used for the formula (IVa) and the acid (Va) of aforesaid method, and (VIa) or the intermediate of amine (VIb) can be compound known, also available standards method and the method that is similar to the specific embodiment of preparation here make from known amino acid initial substance.
The compound of formula of the present invention (I), or its pharmaceutically acceptable prodrug, salt, solvate or hydrate have strong matrix metalloproteinase inhibitory activity, therefore can be used for prevention or treatment Mammals, particularly philtrum and MMP regulate diseases associated, comprise the disease that relates to disorganization, shift invasion and attack, neovascular glaucoma, multiple sclerosis or the psoriasis that causes as the growth of keratohelcosis, pulmonary emphysema, skin ulcer, rheumatic arthritis, periodontitis and noumenal tumour with by Secondary cases.The keratohelcosis that causes by chemical damage, pulmonary emphysema, skin ulcer or because smoking or the drowned pulmonary emphysema that cause.Perhaps, the compound of formula of the present invention (I), or its pharmaceutically acceptable prodrug, salt, solvate or hydrate can be used for preparing the medicine that is used for preventing or treats the disease that the Mammals that comprises the people regulated by matrix metalloproteinase.
Used term " (C among the application 1-C 6) alkyl " expression has the straight or branched alkyl of 1-6 carbon atom, for example: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and hexyl etc.
Term " (C 2-C 6) thiazolinyl " expression has the straight or branched thiazolinyl of 2-6 carbon atom, it can have one to have E or stereochemical pair of key of Z in position again.They comprise vinyl, 1-propenyl, 1-or crotyl and 2-methyl-2-propenyl etc.
Term " (C 3-C 8) cycloalkyl " expression has the saturated alicyclic group of 3-8 carbon atom, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.
Term " (C 3-C 8) cycloalkenyl group " expression has the unsaturated cycloaliphatic group of 3-8 carbon atom; for example cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base etc.; for the cyclenes basic ring that 5-8 carbon atom arranged, this ring can contain more than one pair of key.
Do not add the term " heterocyclic radical " of restriction or the first heterocycle of heteroatomic 5-7 that " heterocycle " expression contains one or more S of being selected from, N, O, can be arbitrarily and phenyl ring condense, for example comprise pyrryl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, thiadiazolyl group, pyrazolyl, pyridyl, pyrrolidyl, pyrimidyl, morpholinyl, piperazinyl, indyl, benzimidazolyl-, dimaleoyl imino, succinimido, phthalimide-based etc.
Term " heteroaryl " expression replaces or the unsubstituted first heteroaromatic of one or more heteroatomic 5-7 that contains.The example of this class ring is pyrryl, furyl, thienyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, triazolyl, triazinyl, piperazinyl, thiadiazolyl group, oxadiazole base.
Unless do explanation in addition, term " replacement " expression that is used for any group can be replaced by 4 substituting groups nearly, each substituting group (C that can respectively do for oneself 1-C 6) alkoxyl group, hydroxyl, sulfydryl, alkylthio, amino, halogen (comprising fluorine, chlorine, bromine, iodine), trifluoromethyl, nitro, carboxyl, carbamyl or-CONHR A, wherein be R ABe (C 1-C 6) residue of alkyl or natural a-amino acid.
In the following amino acid of term " the feature side chain of natural a-amino acid " expression with-CH (NH 2) the continuous feature side chain of COOH: glycine, L-Ala, Methionin, Xie Ansuan, leucine, Isoleucine, phenylalanine, tyrosine, tryptophane, Serine, Threonine, halfcystine, methionine(Met), l-asparagine, glutamine, Methionin, Histidine, arginine, L-glutamic acid and aspartic acid.
On their feature side chain, contain natural a-amino acid, comprise arginine, Methionin, L-glutamic acid, aspartic acid, tryptophane, Histidine, Serine, Threonine, tyrosine and halfcystine just like amino, carboxyl, hydroxyl, sulfydryl, guanidine radicals, imidazolyl or indyl and so on sense substituent.R in The compounds of this invention 3When being in these side chains, functional group's substituting group is welcome protected.
Here the substituent derivative of non-functionality basically represented in the term " protected " that is used for natural a-amino acid side chain sense substituent.In this article, protected amino comprises amido, and protected hydroxyl or sulfydryl comprise ether and thioether, and protected carboxyl comprises the ester class, and imidazolyl, indyl or guanidine radicals can protected formation tertiary butyloxycarbonyl radical derivatives.These are the example of the known many protection derivatives of prior art, and the personnel that are familiar with this technical field can understand other many examples.
The salt of The compounds of this invention comprises acceptable acid salt on the physiology, example hydrochloric acid salt, hydrobromate, vitriol, mesylate, tosilate, phosphoric acid salt, acetate, Citrate trianion, succinate, lactic acid salt, tartrate, fumarate, malate, maleate.Also can form salt as sodium salt, sylvite, magnesium salts and calcium salt with bases.
Owing to have unsymmetrical carbon, so several chiral centres are arranged among the present invention.The existence of several unsymmetrical carbons has formed each chiral centre generation and has had R-type or the stereochemical a plurality of diastereomers of S-type.Unless do explanation in addition, other structural formula in formula (I) and this specification sheets comprises these steric isomers and their racemic mixture.
Can prepare compound of the present invention and carry out administration for any approach that the pharmacokinetic property with them meets.Oral compositions can be the form of tablet, capsule, powder, granule, lozenge, liquid or gelifying agent, as the solution or the suspension of the parenterai administration of oral, local or sterilization.Oral tablet and capsule can be unit dosage form, can contain conventional vehicle, such as tamanori: as syrup, gum arabic, gelatin, sorbyl alcohol or glycine; Compressing tablet lubricant: as Magnesium Stearate, talcum powder, polyoxyethylene glycol or silica gel; Disintegrating agent: as yam starch or examples of suitable lubricants, as sodium lauryl sulphate.Tablet can be according to general pharmaceutical field known method dressing.Oral liquid can be the form as water-based or butyrous suspension, solution, emulsion or syrup, or provides with the drying products form, and is facing with preceding water or the dilution of other suitable vehicle.These liquid preparations can contain conventional additive, such as suspension agent, as sorbyl alcohol, syrup, methylcellulose gum, dextrose syrup, gelatin, hydrogenation edible fat; Emulsifying agent is as Yelkin TTS, polyoxyethylene-sorbitan mono-oleate or gum arabic; Non-water vehicle (comprising edible oil) is as the oily ester of Prunus amygdalus oil, purified Oleum Cocois, glycerine, propylene glycol or ethanol etc.; Sanitas as methyl p-hydroxybenzoate or propyl ester or Sorbic Acid, also can add conventional seasonings or tinting material when needing.
Oral formulation can contain about 0.1-250 milligram, and suitable per daily dose can be very different according to patient's situation.But the about 0.1-300 milligram/kg body weight of dosage of formula (I) compound, particularly about 0.1-100 milligram/kg body weight may be suitable.
For being applied topically to skin, medicine can be made into creme, lotion or ointment.The creme or the ointment that can be used for medicine are the known conventional formulations of this technical field, as at the preparation described in standard pharmaceutical handbooks such as Chinese Pharmacopoeia.
For being applied topically to eye, medicine can the suitable sterile water-based or non-aqueous vehicle make solution or suspension.Also can comprise additive, as buffer reagent such as sodium metabisulfite or disodium ethylene diamine tetraacetate; The sanitas that comprises sterilant and mycocide as Phenylmercuric Acetate or Phenylmercurinitrate, is pricked benzene oronain or chlohexidine, and thickening material, as hypromellose.
The dosage of topical application will be decided according to the size of processed area certainly.For eyes, typical dosage is in the scope of 0.1-100 milligram medicine.
The also available sterile medium of active ingredient is through parenterai administration.Comprising subcutaneous injection, intravenous injection, intraperitoneal injection or topical application etc.Injection reagent, for example, sterile water for injection suspension agent or oiliness suspension agent can use suitable dispersion agent or wetting agent and outstanding floating agent, prepare according to methods known in the art.Aseptic injection reagent, for example, atoxic thinner or sterile injectable solution in the solvent or suspension that can non-oral administration such as the aqueous solution.As spendable carrier or acceptable solvent, specifiable have: water, Ringer's solution, isotonic saline solution etc.In addition, aseptic volatile oil also can be done conventional solvent or suspension solvent.For this reason, can use any nonvolatile oil or lipid acid, comprise natural or synthetic, semisynthetic fatty oil or lipid acid, and natural or synthetic, semisynthetic single or two or Witepsol W-S 55.
Embodiment
The following example has been set forth technical scheme of the present invention, but does not mean that they have any restriction to claim.
The amino acid that is used for embodiment is commercially available or can makes according to the method for document.
Use following abbreviation in full:
The THF tetrahydrofuran (THF)
DMF N, dinethylformamide
The LDA diisopropylamine lithium
The NMM N-methylmorpholine
The CDI carbonyl dimidazoles
The TFA trifluoroacetic acid
The TLC thin-layer chromatography
R fRf value
PE sherwood oil (60-90 ℃)
The EtOAc ethyl acetate
DMTMM
HOBt N-hydroxy benzo triazole
BOP benzotriazole-1-oxygen-three (dimethylin) phosphorus hexafluorophosphate
HBTU 2-(the 1H-benzotriazole-1-)-1,1,3,3-tetramethyl-urea hexafluorophosphate
1H-NMR is by Varian UNITYThe INOVA600 NMR spectrometer with superconducting magnet is measured; MS is measured by API3000 type LC-MS instrument; Specific rotation is measured by PE-243B type polarimeter.
Embodiment 1
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1 -methyl nitrosourea
Figure A20071013709600572
1.1 N-dissident's acyl-4S-Bian Ji oxazole-2-ketone (aa1)
8.85g (50mmol) 4 (S)-Bian Ji oxazole-2-ketone are placed round-bottomed flask, protection of inert gas.Add 80mL THF, stirring and dissolving, be cooled to-78 ℃, slowly splash into 2.5mol/L normal-butyl Lithium/hexane solution 20mL (50mmol), keep-78 ℃ of stirring reactions after 15 minutes, add 6.6mL (50mmol) dissident acyl chlorides, keep stirring 30min below-45 ℃, naturally heat up, continue reaction 1～2hrs..Add the saturated ammonium chloride solution termination reaction, remove THF under reduced pressure, with ethyl acetate extraction, again respectively with saturated sodium bicarbonate, water and saturated NaCl washing organic layer, anhydrous sodium sulfate drying, concentrating under reduced pressure, product separates (PE: EtOAc=4: 1) through silica gel chromatographic column, obtain colorless oil thick liquid 12.03g, yield 87.3%. 1H-NMR (CDCl 3) δ: 7.33-7.22 (and m, 5H), 4.67～4.64 (m, 1H), 4.19～4.17 (m, 2H), 3.28-3.27 (dd, 1H), 2.94-2.73 (m, 3H), 1.62～1.58 (m, 3H) and 0.95-0.93 (d, 6H).
1.2 N-(4-tertiary butyl oxygen-2R-isobutyl-fourth-1,4-two acyls)-4S-Bian Ji oxazole-2-ketone (aa2)
Under the nitrogen protection; in round-bottomed flask, add two (TMS) amido sodium (Na-HMDS) of 2mol/L/THF 18.75mL (37.5mmol) and 50mL THF; be cooled to-78 ℃; (5.73g, THF solution 25mmol) keep-78 ℃ of stirring reaction 50min to add compound (aa1) under stirring; add 4.4mL (30mmol) bromo-acetic acid tert-butyl; continued to keep the low temperature stirring reaction 1 hour, and rose to room temperature, stirring is spent the night.Add the saturated aqueous ammonium chloride termination reaction, remove THF under reduced pressure, use ethyl acetate extraction, successively with saturated sodium bicarbonate, water, saturated NaCl washing, organic layer anhydrous sodium sulfate drying, concentrating under reduced pressure get thick product, recrystallization in the sherwood oil, filtration obtains the 7.8g white needle-like crystals, yield 80.3%. 1H-NMR (CDCl 3) δ: 7.32～7.26 (m, 5H), 4.65～4.64 (m, 1H), 4.26-4.15 (m, 3H), 3.36～3.32 (dd, 1H), 2.73～2.70 (m, 2H), 2.51～2.50 (dd, 1H), 1.57～1.41 (m, 3H), 1.42 (s, 9H) and 0.94～0.91 (m, 6H).
1.3 2R-isobutyl-fourth-1,4-diacid-uncle 4-. butyl ester (aa3)
In the 250mL flask, 9.7g (25mmol) compound (aa2) is dissolved in 125mLTHF-H 2Among the O (4: 1), the ice bath cooling.Nitrogen protection is stirred down, adds the H of 10.2mL (0.1mol) 2O 2The aqueous solution, and 50mL (40mmol) the 0.8M hydroxide Lithium aqueous solution, stir 1hr. approximately after, add 6.9g (0.1mol) Sodium Nitrite solid, stir 10min.Concentrating under reduced pressure is removed most of solvent, usefulness dichloromethane extraction 3 times, and under the ice bath cooling, to pH2-3, again with ethyl acetate extraction, combining extraction liquid is with anhydrous sodium sulfate drying with aqueous phase as acidified for usefulness 2M hydrochloric acid.Get 5.36g yellow oily liquid after concentrating, yield 93.2% is directly used in next step reaction.Specific rotatory power
Figure A20071013709600591
(c=1, methyl alcohol); 1H-NMR (CDCl 3) δ: 9.44 (s, 1H), 2.89～2.82 (m, 1H), 2.62-2.56 (m, 1H), 2.41～2.35 (m, 1H), 1.43 (s, 9H), 1.63～1.3 (m, 3H) and 0.94～0.89 (m, 6H).
1.4 3-chloro-2R-isobutyl-fourth-1, the 4-diacid-4-tert-butyl ester (aa4)
Diisopropylamine 2.4mL (19mmol) places the anhydrous and oxygen-free reaction flask, is cooled to-78 ℃, stirs.Add 2.5mol/L n-Butyl Lithium/normal hexane 6.8mL (17mmol), stir, slowly be warming up to 0 ℃, continue stir about 15min., make LDA (17mmol) solution.
The LDA solution that obtains is chilled to-78 ℃ again, stirs down, add THF (10ml) solution of (aa3) 2.0g (8.7mmol),-78 ℃ of stirring reaction 45min, THF (1ml) solution that adds tetracol phenixin 0.92mL (9.6mmol) ,-78 ℃ of stirring reaction 30min., stirring at normal temperature 1hr then.
Under cold condition, in bottle, add 2mol/L hydrochloric acid 11.7mL, to wherein adding the 100mL ether, use the separating funnel layering then, tell the ether on upper strata, with less water washing 2 times, use anhydrous MgSO again 4Dry.Be spin-dried for solvent, get coffee-like oily matter 2.12g, productive rate: 92.2% can be directly used in next step reaction.
1H-NMR(CDCl 3)δ：4.41(d，1H)、3.1-3.05(m，1H)、1.8-1.65(m，2H)、1.55(m，1H)、1.48(s，9H)、0.95(d，3H)、0.94(d，3H)。
1.5 L-tryptophane methylamine (aa5)
Take by weighing 5g (20mmol) S-tryptophan methyl ester hydrochloride in flask, add 140mL 30% methylamine/ethanolic soln, stirred overnight at room temperature.Concentrate near doing, add 100mL methylene dichloride and less water, tell organic layer, anhydrous sodium sulfate drying.Underpressure distillation removes and desolvates, and obtains the off-white color solid, the 4.16g that weighs after the drying, yield 94.9%, R f=0.21 (CHCl 3/CH 3OH/CH 3COOH, 10/1/0.5), be directly used in next step reaction.
1.6 N 2-(3-chloro-2R-isobutyl--4-tert-butyl ester succinyl)-S-tryptophane-N 1-methyl nitrosourea (aa6)
In the 100mL flask, take by weighing respectively 4.6g (20mmol) (aa4) and 4.82g (22mmol) (aa5), add the dissolving of 80mL tetrahydrofuran (THF), stirring at room 10min.Add 6.09g (22mmol) DMTMM, stirring is spent the night.Remove solvent under reduced pressure, add ethyl acetate, use saturated aqueous ammonium chloride, water, saturated common salt water washing respectively, tell organic layer, anhydrous sodium sulfate drying, column chromatography gradient elution [AcOEt (1)/PE (2) → AcOEt (1)/PE (1)], get the yellow spumescence solid of 4.55g, productive rate 52%. 1H-NMR (CDCl 3) δ: 8.08 (s, 1H), 7.76～7.74 (d, 1H), 7.36～7.10 (m, 4H), 6.60～6.58 (d, 1H), 5.42 (s, 1H), 4.63～4.62 (m, 1H), 4.36～4.34 (d, 1H), 3.31～3.30 (dd, 1H), 3.1 (m, 1H), 2.83 (m, 1H), 2.63 (d, 3H), 1.52～1.49 (m, 3H) 1.46 (s, 9H) and 0.88～0.86 (m, 6H).
1.7 N 2-(3-chloro-2R-isobutyl--4-maloyl)-S-tryptophane-N 1-methyl nitrosourea (aa7)
In the 100mL flask, 5.6g (13mmol) (aa6) is dissolved in the 20mL methylene dichloride, under the room temperature, slowly add the 20mL trifluoroacetic acid, stirring reaction 25min.With 3～4 organic layers of 20mL water washing, anhydrous sodium sulfate drying.Be spin-dried for, get the orange red solid of 4.5g, yield 93.4%, R f=0.15 (CHCl 3/ CH 3OH/CH 3COOH, 10/1/0.5), be directly used in next step reaction.
1.8 N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea
2.4g (6.5mmol) (aa7) is dissolved among the anhydrous THF of 20mL, be cooled to-15～-20 ℃, stir and add 0.8mL (6.5mmol) N-methylmorpholine (NMM) down, behind the reaction 2min, add 0.6mL (6.5mmol) isobutyl chlorocarbonate, stir 2min, 1mol/L azanol/the methanol solution that adds the 6.5mL prepared fresh again stirs 15min, and room temperature continues to stir 30min, solvent evaporated, add ethyl acetate, successively with water, saturated NaCl washing organic phase, anhydrous sodium sulfate drying, the reclaim under reduced pressure ethyl acetate, add ether and separate out precipitation, filter, product is again with the ether washed twice, the faint yellow solid of gained separates through silicagel column, with chloroform (10)/methyl alcohol (1) wash-out.Final 1.02g oyster white or white solid, the yield 39.6% of getting. 1H-NMR(DMSO-d 6)δ：10.94(s，1H)、10.72(s，1H)、9.12(s，1H)、8.10(d，1H)、7.51-6.94(m，6H)、4.40(m，1H)、4.25(d，1H)、2.98(m，3H)、2.47(m，3H)、1.54-1.40(m，3H)、0.82-0.78(m，6H)。
Embodiment 2
N 2 -(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1 -methyl nitrosourea
2.1 3-bromo-2R-isobutyl-fourth-1, the 4-diacid-4-tert-butyl ester
Operate similarly to embodiment 1.4, wherein replace tetracol phenixin with carbon tetrabromide, other is operated with embodiment 1 corresponding method.
2.2 N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea
Separate and obtain two isomer A and B, TLC (CHCl 3/ CH 3OH/CH 3COOH, 10/1/0.5).
Isomer A:R f=0.40 1H-NMR (DMSO-d 6) δ: 10.98 (s, 1H), 10.78 (s, 1H), 9.26 (s, 1H), 8.49 (d, 1H), 7.76-6.96 (m, 6H), 4.53-4.50 (m, 1H), 4.11 (d, 1H), 3.02 (m, 3H), 2.50 (m, 3H), 1.44-1.34 (m, 3H), 0.85-0.76 (m, 6H).
Isomer B:R f=0.35 1H-NMR (DMSO-d 6) δ: 10.95 (s, 1H), 10.76 (s, 1H), 9.23 (s, 1H), 8.45 (d, 1H), 7.71-7.03 (m, 6H), 4.53-4.52 (m, 1H), 4.12 (d, 1H), 3.03 (m, 3H), 2.51 (m, 3H), 1.44-1.34 (m, 3H), 0.86-0.75 (m, 6H).
Embodiment 3
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane- N 1 -cyclopropyl amide
Figure A20071013709600621
3.1 S-tryptophane-N 1-cyclopropyl amide
N 2-tertbutyloxycarbonyl-S-tryptophane 6.08g (0.02mole) and carbonyl dimidazoles (CDI) 3.24g (0.02mole) join among the 42mlTHF successively, stirred 2 hours under the room temperature, add the 1.14g cyclopropylamine, room temperature reaction spends the night, alkali is pressed and is steamed solvent, add ethyl acetate, successively with water, saturated sodium bicarbonate, saturated sodium-chloride washing organic phase, anhydrous sodium sulfate drying, alkali is pressed the evaporate to dryness ethyl acetate, and gained oily matter adds 20ml 4NHCl/ dioxane and 20ml methyl alcohol, room temperature reaction 30min, solvent evaporated gets off-white color blister solid 5.6g, TLC R f=0.35 (CHCl 3/ CH 3OH/CH 3COOH, 10/1/0.5), is dissolved in the triethylamine that adds calculated amount in the appropriate solvent and behind the hydrochloric acid and can be directly used in the next step.
Other operation is with embodiment 1 corresponding method.
3.2 N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide
1H-NMR(DMSO-d 6)δ：10.95(s，1H)、10.76(s，1H)、9.15(s，1H)、8.15(d，1H)、7.71-7.64(m，6H)、4.37(m，1H)、4.21(d，1H)、2.94-2.93(m，3H)、2.47(m，3H)、1.54-1.42(m，3H)、0.84-0.83(m，6H)、0.50(m，2H)、0.22-0.16(m，2H)。
Embodiment 4
N 2 -(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane- N 1 -cyclopropyl amide
Figure A20071013709600631
4.1 3-bromo-2R-isobutyl-fourth-1, the 4-diacid-4-tert-butyl ester
Operation is with embodiment 2.1.
4.2 N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide
Separate and obtain two isomer A and B, TLC (CHCl 3/ CH 3OH/CH 3COOH, 10/1/0.5).
Isomer A R f=0.40 1H-NMR (DMSO-d 6) δ: 10.95 (s, 1H), 10.76 (s, 1H), 9.15 (s, 1H), 8.17 (d, 1H), 7.68-6.95 (m, 6H), 4.36 (m, 1H), 4.24 (d, 1H), 3.00 (m, 3H), 2.50 (m, 1H), 1.51-1.45 (m, 3H), 0.85 (m, 6H), 0.50 (m, 2H), 0.21-0.15 (m, 2H).
Isomer B R f=0.35 1H-NMR (DMSO-d 6) δ: 10.96 (s, 1H), 10.76 (s, 1H), 9.23 (s, 1H), 8.43 (d, 1H), 7.80-7.13 (m, 6H), 4.52-4.50 (m, 1H), 4.12 (d, 1H), 3.03-3.2 (m, 3H), 2.51 (m, 1H), 1.43-1.35 (m, 3H), 0.86 (m, 6H), 0.56 (m, 2H), 0.27 (m, 2H).
Embodiment 5
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1 -phenyl amide
Figure A20071013709600632
Operation is with embodiment 3
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide
1H-NMR(DMSO-d 6)δ：11.00(s，1H)、10.78(s，1H)、9.88(s，1H)、9.20(d，1H)、8.48(m，1H)、7.50-7.01(m，10H)、4.5(m，1H)、4.24(d，1H)、3.35-3.01(m，3H)、1.55-1.43(m，3H)、0.86-0.83(m，6H)。
Embodiment 6
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane- N 1 -cyclohexyl amide
Figure A20071013709600641
Operation is with embodiment 3
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide
1H-NMR(DMSO-d 6)δ：11.00(s，1H)、10.78(s，1H)、9.20(s，1H)、8.24(d，1H)、7.50-6.94(m，6H)、4.44(m，1H)、4.22(d，1H)、2.98(m，3H)、1.22-0.86(m，6H)、0.86-0.78(m，6H)。
Embodiment 7
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane- N 1 -furfuryl acid amides
Figure A20071013709600651
Operation is with embodiment 3
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides
1H-NMR(DMSO-d 6)δ：10.96(s，1H)、10.76(s，1H)、9.17(s，1H)、8.25(d，1H)、?8.16(t，1H)、7.52-6.94(m，6H)、6.33(m，1H)、6.05(d，1H)、4.50(m，1H)、4.22(d，2H)、4.16(d，1H)、3.05-2.93(m，3H)、1.56-1.23(m，3H)、0.86-0.78(m，6H)。
Embodiment 8
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3- (2-naphthyl) L-Ala-N 1 -methyl nitrosourea
Figure A20071013709600652
Operation is with embodiment 1
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea
1H-NMR(DMSO-d 6)δ：11.02(s，1H)、9.23(s，1H)、8.36(s，1H)、7.85-7.30(m，8H)、4.44(m，1H)、4.22(d，1H)、3.12-2.93(m，3H)、1.48-1.17(m，3H)、0.73-0.65(m，6H)。
Embodiment 9
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3- (2-naphthyl) L-Ala-N 1 -buserelin
Figure A20071013709600661
Operation is with embodiment 1
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin
1H-NMR(DMSO-d 6)δ：10.98(s，1H)、9.20(s，1H)、8.30(d，1H)、7.85-7.20(m，8H)、4.44(m，1H)、4.23(d，1H)、3.04(m，5H)、1.60-1.20(m，3H)、0.86-0.68(m，9H)。
Embodiment 10
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine- N 1 -methyl nitrosourea
Figure A20071013709600662
Operation is with embodiment 1
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea
1H-NMR(DMSO-d 6)δ：10.99(s，1H)、9.20(s，1H)、8.31(d，1H)、7.62(m，1H)、7.25-7.17(m，5H)、4.30(m，1H)、4.22(d，1H)、3.35(s，3H)、3.53(m，3H)、1.50-1.30(m，3H)、0.80-0.70(m，6H)。
Embodiment 11
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S- Fenclonine-N 1 -methyl nitrosourea
Figure A20071013709600671
Operation is with embodiment 1
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea
1H-NMR(DMSO-d 6)δ：10.99(s，1H)、9.22(s，1H)、8.33(d，1H)、7.66(m，1H)、7.32-7.16(m，4H)、4.30(m，1H)、4.19(d，1H)、2.92-2.86(m，3H)、2.50(s，3H)、1.50-1.20(m，3H)、0.80-0.77(m，6H)。
Embodiment 12
N 2 -(4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin- 3-carboxylic acid-N 1 -methyl nitrosourea
13.1S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
(a) S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid
S-tryptophane 20g (0.098mle) is dissolved in 400ml 0.1N H 2SO 4In the aqueous solution, add the formalin of 8ml 37% under stirring, room temperature reaction 6 hours, strong aqua is transferred PH=7, and refrigerator is placed and is spent the night, and filters, and filter cake is washed the final vacuum drying twice, gets the about 19.79g of khaki color solid, yield: 93%, be directly used in the next step.
B) S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester hydrochloride
The 230ml methyl alcohol suspension cryosel of above-mentioned solid 19.79g (0.092mle) is bathed cooling, and controlled temperature-5-0 ℃ drips thionyl chloride, finish, stirring at room 4 hours, back flow reaction 4 hours, it is closely dried to remove methyl alcohol under reduced pressure, there are a large amount of solids to separate out, add acetone and shift and filter, filter cake with twice of washing with acetone after, vacuum-drying, get khaki color product 17.52g, yield: 67%, 225 ℃ of mp, TLC (chloroform: methyl alcohol=10: 1): R f=0.55, be directly used in the next step.
(c) S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylate methyl ester hydrochloride 17.52g (0.065mle) adds 30% methylamine/ethanolic soln, stirs, muddy immediately after the mixture change clarification earlier, 6 hours after-filtration of room temperature reaction, solid get white thick product 14.7g with an amount of washing with alcohol after the drying, through silica gel column chromatography (chloroform: methyl alcohol=10: 1) be further purified, get white cotton-shaped solid 12.5g, yield: 82%, 245 ℃ of mp.
Other is operated with embodiment 1 corresponding method, the operation of just saving step 1.4, and direct intermediate with 1.3 is used for the next step.
N 2-(4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
1H-NMR (DMSO-d 6) be shown as the non-corresponding isomer mixture of 1: 1 content, δ: 1H-NMR (DMSO-d 6) δ: 10.90 (s, 1H), 10.60 (s, 1H), 8.87 (s, 1H), 8.11 (m, 1H), 7.35 (m, 2H), 7.04 (m, 2H), 5.58-4.83 (m, 2H), 4.08-3.20 (m, 2H), 2.85 (m, 1H), 2.57 (m, 1H), 2.50 (m, 3H), 2.47 (m, 1H), 2.40-2.00 (m, 1H), 1.63-1.01 (m, 3H), 0.90-0.84 (m, 6H).
Embodiment 13
N 2 -(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3, the 4-tetrahydrochysene- β-Ka Lin-3-carboxylic acid-N 1 -methyl nitrosourea
Figure A20071013709600691
Operation is with embodiment 13 corresponding methods, and replaces the intermediate of step 1.3 to react with 1.4 the intermediate of embodiment 1.
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
MS?m/z：479.12、480.12、481.12[M+H] +
Biology embodiment
With Ilomastat (structure shows below) as the positive control medicine, adopt following method that described compound is carried out experiment in vitro: the drug screening kit MMP-2 colorimetric analysis test kit that adopts the development of Biomol company, with reference to the experimental implementation explanation, at first MMP-2, inhibitor NNGH, specimen and reaction substrate thereof are diluted to working concentration, and with MMP-2, reaction substrate, 96 orifice plates, sample etc. heat to 37 ℃ standby; Then 20 μ L MMP-2 are added in contrast, inhibitor and the specimen plate hole, other establishes blank hole (not containing MMP-2); Secondly the specimen solution 20 μ L with respective concentration add in the specimen hole and mixing, incubate warm 30-60min under 37 ℃ of conditions; At last 10 μ L substrate solutions are added in contrast, inhibitor and the specimen hole, light absorption value (OD value) when 1min reads 412nm continuously at interval continues record 10-20min.The OD value of each sample is figure to the time and is calculated its speed of reaction (V, the i.e. slope of data scatter diagram straight line portion), represent with OD/min.Calculate the inhibiting rate=(1-V of specimen Inhibitor/ V Contrast) * 100.
Figure A20071013709600701
The Ilomastat structural formula
Table 1. vitro inhibition active testing result
Figure A20071013709600702

Claims (24)

1. the compound shown in the formula (I), or its pharmaceutically acceptable prodrug, salt, solvate or hydrate,
Figure A2007101370960002C1
Wherein, R 1Be group shown in the formula (II):
Figure A2007101370960002C2
Wherein,
R 3The characteristic group of representing natural or non-natural a-amino acid, wherein any functional group of Cun Zaiing is not protected or protected;
R 4Expression (C 1-C 6) alkyl, (C 1-C 6) thiazolinyl, (C 1-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 3-C 8) cycloalkylalkyl, (C 4-C 8) cycloalkenyl group, (C 4-C 8) cycloalkenyl alkyl, heterocyclic radical (C 1-C 6) alkyl, aryl (C 1-C 6) alkyl, aryl (C 1-C 6) thiazolinyl, aryl (C 1-C 6) alkynyl, heterocyclic radical (C 1-C 6) thiazolinyl, heterocyclic radical (C 1-C 6) alkynyl, (C 1-C 6Alkyl) O (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) O (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) O (C 1-C 6) alkyl, (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) NH (C 1-C 6) alkyl, wherein any group is not substituted or quilt (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, (C 1-C 6) alkylthio, halogen or cyano group replaces arbitrarily; Or phenyl or 5 or 6 yuan of fragrant heterocycles, it is not oxidized or be oxidized to the N-oxide compound that wherein ring is gone up any nitrogen-atoms, perhaps they and phenyl ring or with 5,6 or 7 yuan heterocyclic fused, wherein any ring be not substituted or by following (a) or (b) group replace:
(a) one or more be independently selected from hydroxyl, halogen, cyano group, carboxyl ,-CO 2(C 1-C 6) alkyl ,-(C 1-C 6) alkyl-CO 2(C 1-C 6) alkyl ,-CONH 2,-CONH (C 1-C 6) alkyl ,-CON[(C 1-C 6) alkyl] 2,-CHO ,-CH 2OH, (C 1-C 4) perfluoroalkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) alkyl ,-SO (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-NO 2,-NH 2,-NH (C 1-C 6) alkyl ,-N[(C 1-C 6) alkyl] 2With-NHCO (C 1-C 6) group of alkyl;
(b) be selected from (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 4-C 8) group of cycloalkenyl group, phenyl, benzyl, heterocyclic radical or heterocyclyl methyl, any one of these groups is not substituted or by one or more halogen, hydroxyl, amino, carboxyl, (C of being selected from 1-C 4) perfluoroalkyl, (C 1-C 6) alkyl ,-O (C 1-C 6) alkyl and-S (C 1-C 6) substituting group of alkyl replaces;
R 5Be hydrogen or (C 1-C 6) alkyl;
Perhaps, R 1Be group shown in the formula (III)
Wherein,
R 4With R 5With defined identical in the formula (II);
Het represents aromatic ring or fragrant heterocycle, and wherein any one is not substituted or by one or more halogen, hydroxyl, amino, carboxyl, (C of being selected from 1-C 4) perfluoroalkyl, (C 1-C 6) alkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) substituting group of alkyl replaces;
W is-COOH or-CONHOH;
X 1With X 2Be independently selected from hydrogen respectively, comprise F, the halogen of Cl, Br, cyano group, nitro; Work as R 1During expression (II) group, X 1With X 2Be not hydrogen simultaneously; Work as R 1During expression (III) group, X 1With X 2Can be hydrogen simultaneously;
R 2Expression (C 1-C 6) alkyl, (C 1-C 6) thiazolinyl, (C 1-C 6) alkynyl, aryl (C 1-C 6) alkyl, aryl (C 1-C 6) thiazolinyl, aryl (C 1-C 6) alkynyl, heterocyclic radical (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6) thiazolinyl, heterocyclic radical (C 1-C 6) alkynyl, (C 1-C 6Alkyl) O (C 1-C 6) alkyl, aryl (C 1-C 6Alkyl) O (C 1-C 6) alkyl, heterocyclic radical (C 1-C 6Alkyl) O (C 1-C 6) alkyl, wherein any group is not substituted or quilt (C 1-C 6) alkyl, (C 1-C 6) alkoxyl group, (C 1-C 6) alkylthio, halogen or cyano group replaces.
2. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, the stereochemical structure of wherein said compound is as follows:
Load X 1With X 2The C atom, its steric configuration is R-type, S-type or achirality;
Load R 2The C atom, its steric configuration is the R-type;
Load R 3The C atom, its steric configuration is the S-type;
In the formula (III) with R 4R 5The C atom that NCO-links to each other, its steric configuration is R-type or S-type.
3. compound according to claim 1 and 2, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate are wherein worked as R 1During expression (II) group, X 1With X 2Combination can be: H, F; H, Cl; H, Br; F, F; Cl, Cl; Br, Br; F, Cl; F, Br; Cl, Br; H, CN; CN, CN; H, NO 2NO 2, NO 2Work as R 1During expression (III) group, X 1With X 2Combination except that being the aforesaid combination in this claim, X 1With X 2Can also be hydrogen simultaneously.
4. compound according to claim 1 and 2, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 2Expression isobutyl-, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, cyclohexyl and base, phenyl propyl 4-chloro-phenyl-propyl group, 4-aminomethyl phenyl propyl group, 4-p-methoxy-phenyl propyl group, phenyl butyl, propoxy-methyl or third sulfydryl.
5. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 3The characteristic group of representing natural or non-natural a-amino acid; Or the characteristic group of natural a-amino acid, wherein any functional group of Cun Zaiing is not subjected to or is protected, and any amino is acidylate or by acidylate not, the not amidation or by amidation of any carboxyl; Or-[Alk] nR 6Group, wherein Alk is (C 1-C 6) alkyl or (C 2-C 6) thiazolinyl, or by one or more-O-or-the S-atom or-N (R 7(the C that)-group inserts 1-C 6) alkyl or (C 2-C 6) thiazolinyl, wherein R 7Be hydrogen atom or (C 1-C 6) alkyl, n=0 or 1, R 6Be not to be substituted or substituted cycloalkyl or cycloalkenyl group; Or phenyl ring is selected from halogen, nitro, carboxyl, (C 1-C 6) alkoxyl group, cyano group, (C 1-C 6) alkyloyl, (C 1-C 6) alkyl amide, trifluoromethyl (C 1-C 6) alkyl, amino, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, sulfydryl, (C 1-C 6) alkylthio, hydroxyl (C 1-C 6) alkyl, sulfydryl (C 1-C 6) alkyl or (C 1-C 6) benzyl that replaces arbitrarily of any group of alkyl phenyl methyl; Phenyl ring quilt-OCH 2COR 8The benzyl that group replaces, wherein R 8Be hydroxyl, amino, (C 1-C 6) alkoxyl group, phenyl (C 1-C 6) alkoxyl group, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, phenyl (C 1-C 6) residue of alkylamino, amino acid or its carboxylic acid halides, ester or amide derivatives, described residue connects by amido linkage, and described amino acid is selected from glycine, L-Ala, Methionin, Xie Ansuan, leucine, Isoleucine, phenylalanine, tyrosine, tryptophane, Serine, Threonine, halfcystine, methionine(Met), l-asparagine, glutamine, Methionin, Histidine, arginine, L-glutamic acid and aspartic acid; Or heterocycle (C 1-C 6) alkyl, heterocycle and heterocycle (C 1-C 6) alkyl, aromatic ring and heterocycle (C 1-C 6) alkyl, aromatic ring and aromatic ring (C 1-C 6) alkyl, it is not by generation or be selected from halogen, nitro, carboxyl, (C 1-C 6) alkoxyl group, cyano group, (C 1-C 6) alkyloyl, (C 1-C 6) alkyl amide, trifluoromethyl (C 1-C 6) alkyl, hydroxyl, formyl radical, amino, (C 1-C 6) alkylamino, two (C 1-C 6) alkylamino, sulfydryl, (C 1-C 6) alkylthio, hydroxyl (C 1-C 6) alkyl, sulfydryl (C 1-C 6) alkyl or (C 1-C 6) any group of alkyl phenyl methyl replaces.
6. the compound of stating according to claim 5, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 3Expression (C 1-C 6) alkyl, benzyl, hydroxybenzyl, benzyloxy benzyl, (C 1-C 6) alkoxybenzyl or benzyloxy (C 1-C 6) alkyl.
7. compound according to claim 5, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 3Expression-CR aR bR cGroup, wherein each R a, R b, R cEach is hydrogen (C naturally 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, and R a, R b, R cNot hydrogen simultaneously, or R cBe hydrogen, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl, (C 3-C 8) cycloalkyl, R aAnd R bForm 3-8 unit's cycloalkyl or 5-6 unit heterocycle with the carbon atom that links to each other; Or R a, R b, R cForm three rings with the carbon atom that links to each other; Or R a, R b(C respectively does for oneself 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, phenyl (C 1-C 6) alkyl or following R cDefinition in group except hydrogen, perhaps R aAnd R bForm 3-8 unit's cycloalkyl or 3-8 unit heterocycle, R with the carbon atom that links to each other cBe hydrogen ,-OH ,-SH, halogen ,-CN ,-COOH, (C 1-C 4) perfluoroalkyl ,-CH 2OH ,-CO 2(C 1-C 6) alkyl ,-O (C 1-C 6) alkyl ,-O (C 2-C 6) thiazolinyl ,-S (C 1-C 6) alkyl ,-SO (C 2-C 6) alkyl ,-SO 2(C 2-C 6) alkyl ,-S (C 2-C 6) thiazolinyl ,-SO (C 2-C 6) thiazolinyl ,-SO 2(C 2-C 6) thiazolinyl or-the Q-W group, wherein Q represent a key or-O-,-S-,-SO-,-SO 2-, W represents phenyl, phenylalkyl, (C 3-C 8) cycloalkyl, (C 3-C 8) cycloalkylalkyl, (C 4-C 8) cycloalkenyl group, (C 4-C 8) cycloalkenyl alkyl, heteroaryl or heteroarylalkyl, wherein W can be arbitrarily by one or more be selected from respectively hydroxyl, halogen ,-CN ,-COOH ,-CO 2(C 1-C 6) alkyl ,-CONH 2,-CONH (C 1-C 6) alkyl ,-CONH (C 1-C 6Alkyl) 2,-CHO ,-CH 2OH, (C 1-C 4) perfluoroalkyl ,-O (C 1-C 6) alkyl ,-S (C 1-C 6) alkyl ,-SO (C 1-C 6) alkyl ,-SO 2(C 1-C 6) alkyl ,-NO 2,-NH 2,-NH (C 1-C 6) alkyl ,-N (C 1-C 6Alkyl) 2,-NHCO (C 1-C 6) alkyl, (C 1-C 6) alkyl, (C 2-C 6) thiazolinyl, (C 2-C 6) alkynyl, (C 3-C 8) cycloalkyl, (C 4-C 8) substituting group of cycloalkenyl group, phenyl or benzyl replaces.
8. according to claim 1,5,6 or 7 described compounds, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 3Expression benzyl, 4-benzyl chloride base, 4-hydroxybenzyl, 4-methoxy-benzyl, 4-kharophen benzyl, 2-picolyl, 3-picolyl, 4-picolyl, 1-menaphthyl, 2-menaphthyl, 2-quinoline methyl, 3-quinoline methyl, 4-quinoline methyl, 3-indole methyl, 3-benzo [b] thenyl, 3-cumarone methyl, isobutyl-or the tertiary butyl.
9. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 4Be methyl, ethyl, cyclopropyl, morpholine-N-propyl group, benzyl, the 2-picolyl, the 3-picolyl, the 4-picolyl, furfuryl or phenyl, the 1-naphthyl, the 2-naphthyl, furyl, thienyl, pyrroles woods base, tetrahydrofuran base, imidazolyl oxadiazole base, thiazolyl, thiadiazolyl group, pyridyl, pyridyl-N-oxide compound, piperazinyl, indyl, benzimidazolyl-, the benzotriazole base, pyrazinyl, pyridazinyl, pyrimidyl, the dithiane base, benzo [b] thienyl isoxazolyl or quinolyl, above-mentioned any group be not substituted or by in the claim 1 about R 4Defined substituting group replaces arbitrarily.
10. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein Het is phenyl ring, naphthalene nucleus, indole ring or benzo [b] thiphene ring or phenyl ring, naphthalene nucleus, indole ring or benzo [b] thiphene ring for closing with adjacent piperidine ring a pair of horses going side by side shown in any possible form and the formula (III).
11. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein R 5Be hydrogen.
12. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide.
13. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide.
14. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide.
15. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-buserelin,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-2-picolyl amides,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-phenylalanine-N 1-phenyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl base acid amides,
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-cyclopropyl amide,
N 2-(3,3-two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide,
N 2-(3,3-two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide, and
N 2-(3,3-two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-S-fenclonine-N 1-phenyl amide.
16-compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea, and
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea.
17. compound according to claim 1, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate, wherein this compound is selected from following compound:
N 2-(4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3R-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea
N 2-(3R-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3R-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3S-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3,3 two fluoro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea,
N 2-(3,3 two chloro-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea, and
N 2-(3,3 two bromo-4-N-hydroxylaminos-2R-isobutyl-succinyl)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid-N 1-methyl nitrosourea.
18. a pharmaceutical composition, it comprises each described compound of claim 1 to 17 and pharmaceutically acceptable vehicle or carrier.
19. according to the pharmaceutical composition of claim 18, wherein said compound is selected from following compound:
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea, and
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea.
20. one kind prepares the described W of claim 1 is the method for the compound of hydroxamic acid group-CONHOH, this method comprises:
Figure A2007101370960024C1
(A) (IV acid or its activated derivatives and azanol or its salt a) directly carries out condensation reaction and obtains compound shown in the formula (I) to make formula; Perhaps
(B) earlier with the acid of formula (4a) or its activated derivatives and the protected azanol of O or the two protected azanol condensation of N, O, obtain intermediate shown in the formula (IV b), remove R wherein then a(or) R bProtecting group obtains compound shown in the formula (I);
X wherein 1, X 2, R 1, R 2Definition identical with the definition in the formula (I), R aBe amino protecting group, R bBe the protecting group of hydroxyl, but with the R of azanol, the protected azanol of O or the two protected azanol of N, O or its reactant salt 1, R 2Substituting group itself can be protected and make it not participate in this class reaction, then from the hydroxamic acid part and the R of gained 1, R 2Remove any protected substituting group.
21. one kind prepares the described W of claim 1 is the method for the compound of carboxyl-COOH, this method may further comprise the steps:
Figure A2007101370960025C1
With formula (V a) acid or its activated derivatives and formula (VI a) or the amine condensation shown in (VI b) obtains the intermediate shown in the formula (V b), remove again the Rc protecting group obtain formula (I, W=COOH) shown in compound.R wherein 1, R 2, R 3, R 4, R 5Definition except the R of potential reaction is arranged in coupled reaction 1, R 2, R 3, R 4, R 5Substituting group itself can be protected and make it not participate in outside this class reaction, other definition with formula (I) is identical, Rc represents hydroxy-protective group.
22. each described compound of claim 1 to 17, or its pharmaceutically acceptable prodrug, salt, solvate or hydrate are used for preventing or treat purposes in the medicine of the disease that the Mammals that comprises the people regulated by matrix metalloproteinase in preparation.
23. according to the purposes of claim 22, wherein said compound is selected from following compound:
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea, and
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea.
24. according to the purposes of claim 22, wherein said compound is selected from following compound:
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-bromo-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclopropyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-furfuryl acid amides,
N 2-(3-fluoro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-phenyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-tryptophane-N 1-cyclohexyl amide,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-methyl nitrosourea,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-3-(2-naphthyl) L-Ala-N 1-buserelin,
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-phenylalanine-N 1-methyl nitrosourea, and
N 2-(3-chloro-4-N-hydroxylamino-2R-isobutyl-succinyl)-S-fenclonine-N 1-methyl nitrosourea.
25. purposes according to claim 22, wherein said disease are the growth of keratohelcosis, pulmonary emphysema, skin ulcer, rheumatic arthritis, periodontitis and noumenal tumour and invasion and attack, neovascular glaucoma, multiple sclerosis or the psoriasis that is caused by the Secondary cases transfer.
CNA2007101370966A 2007-07-24 2007-07-24 Matrix metalloprotease inhibitors, medicinal composition containing the same, preparation and use thereof Pending CN101353320A (en)

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