CN1261878A - New cysteine derivatives processes for their production, and pharmaceuticals containing them - Google Patents

New cysteine derivatives processes for their production, and pharmaceuticals containing them Download PDF

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CN1261878A
CN1261878A CN98806716A CN98806716A CN1261878A CN 1261878 A CN1261878 A CN 1261878A CN 98806716 A CN98806716 A CN 98806716A CN 98806716 A CN98806716 A CN 98806716A CN 1261878 A CN1261878 A CN 1261878A
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acid
aromatics
aromatic
productive rate
gelucystine
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J·C·D·米勒
E·格拉夫冯勒德恩
L·莫洛德
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Max Planck Gesellschaft zur Foerderung der Wissenschaften eV
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
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Abstract

A compound represented by general formula (I), which binds and inhibits matrix metalloproteinases (MMP), wherein the cysteine moiety contains an unprotected thiol group, the cysteine moiety is in the L- or D-configuration wherein A denotes -CO-, SO2-, -NH-CO-, or -O-CO-, R1 denotes hydrogen, a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms or a C1-C15 alkyl group substituted by halogen, mercapto, hydroxy, alkoxy, amino or nitro, or by carbocyclic non aromatic or aromatic ring systems which are optionally substituted once or several times or aromatic or non aromatic heterocycles, optionally substituted, their pharmacologically acceptable salts, or optically active forms thereof. R denotes hydroxy, a linear or branched saturated or unsaturated alkyl group of 1 to 15 carbon atoms or a C1-C15 alkyl group substituted by carbocyclic non aromatic or aromatic ring systems which are optionally substituted once or several times or aromatic or non aromatic heterocycles, optionally substituted, their pharmacologically acceptable salts, or optically active forms thereof, processes for the preparation, pharmaceutical compositions and their use in medicine.

Description

New cysteine derivative, their preparation method and the medicine that contains them
The present invention relates to new matrix metallo-proteinase inhibitor, this inhibitor so that be used in amino and the carboxyl-functional base on derive and the L-of non-peptide type group or D-halfcystine (formula 1) arranged for basic.The invention still further relates to the preparation method of this inhibitor and in the therapeutics Application for Field.
Matrix metalloproteinase (MMP) family has become the major objective of medicinal design, because these enzymes transform relevant with tissue remodeling and reticular tissue, thereby be involved in following several disease, wherein extracellular matrix degraded fast takes place in (i), for example in congestive heart failure with during highly metastatic cancer cell exosmoses, extracellular matrix degraded slowly perhaps (ii) takes place, and for example the arthrosclerosis infringement forms and breaks, cartilage matrix loss in the osteoarthritis, ground substance of bone in the osteoporosis is degenerated, gum in the periodontopathy is degenerated, matrix during the Alzheimer patch forms is reinvented and deposition and rheumatoid arthritis.
MMP family comprises 14 members at present, and wherein ten is to be formed by emiocytosis with soluble form, and four is membrane bound enzyme.MMP is the enzyme that depends on zinc and need calcium, and they are subjected to one of family member's of tissue inhibitor of metalloproteinase (TIMP) inhibition.Developed as hydroxamic acid ester, N-carboxyalkyl derivative, phosphonic amide acid esters and phosphinate, and with thiol this zymoid synthetic inhibitor as the part of reactive site zinc atom.This propetide of N-end propetide of individual about 80 residues forms an isolating less structural domain, wherein comprises three α-Luo Xuanjiegous and a unfolding peptides that occupies activity site.Catalytic domain in all these structures all contains two Zn 2+Ion, that is, and " structure " zine ion and " catalysis " zine ion." catalysis " zine ion is had the side chain coordination of three histidyl residues of consensus sequence HEXXHXXGXXH.The 4th part of " catalysis " zinc in the downtrod enzyme is the coordinating group of inhibitor, described inhibitor such as hydroxamic acid ester or carboxylicesters; In propetide pro-MMP, the 4th part is the thiol (1) of cysteine residues.
Correspondingly, the collagenase inhibitors based on thiol of Ti Chuing normally comprises the peptide structure of halfcystine or class cysteine amino acids so far, and its design is the binding pattern based on substrate, and is recent then mention the propetide that contains halfcystine.
The present invention relates to a class suc as formula the new MMP inhibitor of being derived and forming in non-peptide mode by halfcystine shown in the I, its preparation method contains the pharmaceutical composition of these compounds and the therepic use in medical science thereof. A representative-CO-wherein ,-SO 2-,-NH-CO-or-O-CO-;
R 1Represent hydrogen, saturated or the unsaturated alkyl of straight or branched that contains 1-15 carbon atom, or replaced by halogen, sulfydryl, hydroxyl, alkoxyl group, amino or nitro or can be chosen wantonly non-aromatics of one or several substituent carbocyclic ring or aromatics ring system or can be chosen wantonly substituted aromatics or C that non-aromatic heterocyclic replaces 1-C 15Alkyl, or acceptable salt or its optically-active form on its pharmacology.
The R representation hydroxy contains the saturated or unsaturated alkyl of straight or branched of 1-15 carbon atom, or can be chosen wantonly one or several substituent carbocyclic aromatic or non-aromatics ring system or can choose substituted aromatics wantonly or the C of non-aromatic heterocyclic replacement 1-C 15Alkyl, or acceptable salt or its optically-active form on its pharmacology.
About formula I, R is or/and R 1Representative contains the saturated or unsaturated alkyl of side chain of 1-15 carbon atom, be selected from methyl, ethyl, propyl group, normal-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc., vinyl etc., and corresponding alkynyl, for example acetylene.
The carbocyclic aromatic of this alkyl or non-aromatic substituent are selected from C 3-C 6Cycloalkyl, as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or C 6-C 14The carbocyclic aromatic substituting group, as phenyl, naphthyl or anthryl, or the non-aromatic substituent of heterocycle, as pyrrolidyl, piperidyl, piperazinyl or morpholinyl, or the heterocyclic aromatic substituting group, as pyrryl, pyridyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidyl, purine radicals, indyl, quinolyl, carbazyl.
Carbocyclic aromatic or non-aromatics ring system or heterocycle can randomly be replaced described substituting group such as halogen, nitro, hydroxyl, C by one or several substituting group 1-C 6Alkyl, C 1-C 6Alkoxyl group, amino, sulfydryl, carboxyl, cyano group or sulfo group.
If A is representative-CO-, residue R then 1CO-is preferably selected from the residue of following carboxylic acid; Formic acid, acetate, propionic acid, caproic acid, lauric acid, tetradecanoic acid, palmitinic acid, stearic acid, arachidonic acid docosoic, octadecenoic acid, linolic acid, linolenic acid, the 3-thiohydracrylic acid, Glyoxylic acid hydrate, propanedioic acid, succsinic acid, the 4-aminobutyric acid, 6-aminocaprolc acid, 3-nitropropionic acid, naphthyl acetic acid, the 4-aminophenyl acetic acid, vinylformic acid, styracin, the 4-amino-cinnamic acid, amino Ba Dousuan, fumaric acid, toxilic acid, phthalic acid, phenylformic acid, nitrobenzoic acid, the 3-benzaminic acid, the 4-benzaminic acid, anthranilic acid, Whitfield's ointment, the 3-aminosallcylic acid, the 4-aminosallcylic acid, 5-aminosalicylic acid, naphthoic acid, to Phenylbenzoic acid, phenanthrenecarboxylic acid, nicotinic acid, the amino pyrazine of 3--2-carbonic acid, pyridine carboxylic acid, piperazine carboxylic acid, piperidine carboxylic acid.
If A is representative-SO 2, residue R then 1SO 2-be preferably selected from the residue of following sulfonic acid: methylsulfonic acid, ethyl sulfonic acid, propanesulfonic acid, the 3-hydroxy-propanesulfonic acid, ORTHO AMINO PHENOL SULPHONIC (aniline-2-sulfonic acid), naphthene sulfonic acid, napthylamine sulfonic acid, aminomethanesulfonic acid, mistabrom, 2-chloroethene sulfonic acid, N, N '-dimethylamino sulfonic acid, piperidines sulfonic acid, 5-(the amino ethylamino of 2-)-1-naphthalene sulfonic aicd, iodoxy quinoline sulfonic acid, pyridine-3-sulphonic acid, tosic acid, 2-(to toluino) naphthalene-6-sulfonic acid, the decyl methylsulfonic acid, 2-[(2-amino-2-oxygen ethyl) amino] ethyl sulfonic acid, 2-(N-cyclohexyl amino) ethyl sulfonic acid, 2-[two (2-hydroxyethyl) amino] ethyl sulfonic acid, N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid, N-three (methylol) methyl-2-aminoethyl sulfonic acid, 2-(N-morpholino) ethyl sulfonic acid, piperazine-N, N '-two (2-ethanesulfonic acid), 3-(2-pyridyl)-5,6-two (4-Phenylsulfonic acid)-1,2, the 4-triazine.
If A is representative-NHCO-, residue R then 1-NH-CO-is preferably selected from the residue of following urea derivatives: normal-butyl one, and R-(+)-α-styroyl-, R-(-)-1-(1-naphthyl)-ethyl-, ethyl-, propyl group-, hexyl-, octyl group-, benzyl-, the benzyl chloride base-, methyl-benzyl-, the 3-picolyl-, 2-(aminomethyl)-pyridyl urea.
If A is representative-O-CO-, residue R then 1-O-CO-is preferably selected from the residue of following carbamate: Urethylane, urethanum, carboxylamine 9-fluorenyl methyl esters, carboxylamine 9-(2-sulfo group) fluorenyl methyl esters, carboxylamine 9-(2, the 7-dibromo) fluorenyl methyl esters, carboxylamine 4-methoxybenzoyl methyl ester, carboxylamine 2,2,2-three chloro-ethyl esters, carboxylamine 2-phenyl chlorocarbonate, carboxylamine 1-(1-adamantyl)-1-methyl ethyl ester, carboxylamine 1,1-dimethyl-2-halogenated ethyl ester, carboxylamine 1-methyl isophthalic acid-(4-xenyl)-1-methyl ethyl ester, carboxylamine 2-(2 '-pyridyl) ethyl ester, carboxylamine 1-adamantane esters, vinyl carbamate, allyl carbamate, carboxylamine 1-sec.-propyl allyl ester, carboxylamine 4-nitro cinnamic ester, carboxylamine 8-quinolyl ester, carboxylamine cyclohexyl, benzyl carbamate, carboxylamine is to methoxy benzyl ester, carboxylamine is to the nitrobenzyl ester, and carboxylamine is to the bromobenzyl ester, carboxylamine 9-anthryl methyl esters, carboxylamine phenylbenzene methyl esters, carboxylamine 2-sulfonyloxy methyl ethyl ester, carboxylamine 2-(tolysulfonyl) ethyl ester, carboxylamine 4-methylthio group phenyl ester.
R is preferably selected from following group: ethyl-, propyl group-, hexyl-, octyl group-, benzyl-, 4-benzyl chloride base-, the 4-methyl-benzyl-, the 3-picolyl-, 2-(methyl)-pyridyl-, 4-(methyl) pyridyl-, the 3-phenyl propyl-, the 4-phenyl butyl-, 2-(p-methylphenyl) ethyl-, the 3-nitrobenzyl-, the benzyl ethyl-, the 2-styroyl-, adamantyl-, pyridyl-, phenyl-, cholesteryl-, naphthyl-, 4-Phenoxyphenyl or indyl ethyl-.
Preferred formula I compound is the compound of embodiment 5-22 and the compound in the following table:
????R 1-CO ??R
Formyl radical- Benzyl-
Phenyl- Naphthyl-
The naphthalene ethanoyl- The 3-picolyl-
The 4-xenyl- The 2-styroyl-
????R 1-SO 2 ??R
Pyridine-3-alkylsulfonyl- Hydrocinnamyl-
P-toluenesulfonyl- P-chlorobenzyl-
????R 1-NH-CO ??R
Benzyl- Pyridyl-
????R 1-O-CO ??R
The 2-styroyl- The 4-Phenoxyphenyl-
Benzyl- The 2-styroyl-
2-(tolysulfonyl) ethyl- Benzyl-
Formula I compound is made up of different structure and three parts of different nature.Chelation group SH is used for the Zn of activated positions 2+Ion, hydrophobic grouping R 1Or R and hydrophobic S ' 1The protein bag interacts, and for exerting an influence along the additional hydrophobic interaction of p ' substrate in conjunction with the crack.
The inhibitor of general formula I can develop into the selective depressant of the desired different MMP of different pathological implication (for example osteoporosis, rheumatoid arthritis, periodontopathy, arthrosclerosis, congestive heart failure, tumor invasion and transfer and vascularization).
Mentioned similar compounds in the known references.But they are peptide compounds, and the transformation period in human plasma is very poor.
Consider to select the chemical structure of cysteine derivative by improving metabolic stability.Correspondingly, amino is produced acid amides with the carboxylic acid acidylate, but preferably known to the more stable urethane groups derivative of enzymatic metabolism.Similarly, the carboxyl of C-end is derivatized to acid amides rather than esterification, so that avoid the quick clearance rate that caused by the lipase hydrolysis owing to fat.In addition, selection is known to peptase more stable N-alkyl and N-arylamide.
Adopt classical organic synthesis step to come synthetic inhibitor (2).Relevant formula II L-and D-cystine derivatives then according to synoptic diagram 1, are used the EDCI/HOBt amidation according to the standard method preparation of chemistry of peptides.Shown in flow process 1, utilize reductive agent such as mercaptan or preferably use phosphine class such as tributylphosphine subsequently, with formula III Gelucystine compound reduction accepted way of doing sth I cysteine derivative.
Figure A9880671600071
The general route of flow process 1. synthetic MMP inhibitor of the present invention
The compounds of this invention suppresses MMP specifically, they are applicable to that on pharmacology treatment rheumatoid arthritis and CA are the diseases related of promoting factor therein, for example, loosen disease, bulla formation, general ulcer, epidermis ulcer, stomach ulcer etc. of keratohelcosis, osteoporosis, periodontopathy, pendant Gee disease, oulitis, tumor invasion, dystrophic epidermolysis.These compounds be specially adapted to treat rheumatoid arthritis (former chronic polyarthritis, PCP), systemic lupus erythematosus (SLE), children's's rheumatoid arthritis, Xiao Gelun syndromes (mouthful xerophthalmia scheorma sacroiliitis syndromes), polyarteritis nodosa and relevant vasculitis such as Wegner granulomatosis, giant cell arteritis, pulmonary apoplexy ephritis syndromes, allergic angiitis, PM-DM, systemic scleroderma, Behcet syndrome, urethrooculosynovial syn (sacroiliitis+urethritis+conjunctivitis), mixed connective tissue disease (Sharp syndrome), ankylosing spondylitis (M.Bechterew).
The compounds of this invention can be through any suitable way administration, preferably with the pharmaceutical compositions of suitable this approach with to the predetermined effective dosed administration of treatment.For preventing or suppress the illness progress that the treatment effective dose of required The compounds of this invention can easily be determined by those of ordinary skills.
Therefore, the invention provides the new pharmaceutical composition of a class, wherein contain one or more The compounds of this invention and one or more pharmaceutically useful non-toxic carriers that cooperate with it and/or assistant agent (this paper is referred to as " solid support material ") and if necessary, contain other activeconstituents.The compounds of this invention and composition for example in the blood vessel, intraperitoneal, subcutaneous, intramuscular or topical.
For all administrations, pharmaceutical composition can be tablet, capsule, suspension or liquid form.Pharmaceutical composition is preferably made the dosage unit form that contains the specific quantity active ingredient.The example of this class dose unit is tablet or capsule.For Mammals, suitable per daily dose can great changes have taken place with patient's situation and other factor.But the about 0.1-300mg of every kg body weight, the particularly dosage of the about 1-30mg of every kg body weight may be suitable.Activeconstituents also can be used the injection system administration.
Dosage during with The compounds of this invention and/or composition therapeuticing disease is selected according to multiple factor, the type, age, weight, sex and the healthy state that comprise the patient, the seriousness that infects, the approach of administration and the particular compound of use therefore can great changes have taken place.
Be the purpose of treatment, common and one or more the suitable assistant agents combinations of specifying routes of administration of The compounds of this invention.If it is oral, compound can mix with cellulose ester, Mierocrystalline cellulose alkyl ester, talcum, stearic acid, Magnesium Stearate, magnesium oxide, phosphoric acid and vitriolic sodium salt and calcium salt, gelatin, gum arabic, sodiun alginate, polyvinylpyrrolidone and/or the polyvinyl alcohol of lactose, sucrose, starch, paraffinic acid, then compressing tablet or pour into capsule conveniently to take.Or, can compound is water-soluble, in polyoxyethylene glycol, propylene glycol, ethanol, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, phenylcarbinol, sodium-chlor and/or the various buffer reagent.Other assistant agent and administering mode also are to be widely known by the people in the pharmaceutical field.Certainly, the suitable dose under any appointment situation all depends on essence and seriousness, the approach of medication and the related mammiferous species of the illness of being treated, and comprises its size and any individual specificity.
Representational carrier, thinner and assistant agent comprise for example water, lactose, gelatin, starch, Magnesium Stearate, talcum, vegetables oil, natural gum, polyalkylene glycol, Vaseline etc.Pharmaceutical composition can make solid form, for example particle, powder or suppository, or make liquid form, for example solution, suspension or milk sap.Can add conventional pharmaceutical adjuvant in the pharmaceutical composition, for example sanitas, stablizer, wetting agent, emulsifying agent, buffer reagent etc.
For being used for the treatment of rheumatoid arthritis, The compounds of this invention can be with any administration easily, preferably with the pharmaceutical compositions of suitable this approach with for the effective dosed administration of envisioning of treatment.When treatment of arthritis, can adopt the oral or intra-articular injection mode administration in the affected joint easily.
As mentioned above, dosage of taking and treatment plan will depend on for example disease, its severity, the patient who is treated and the response to treating thereof, and therefore very big variation can be arranged.Enzyme test
Use MMP8 (Phe 79-MMP8) catalytic domain with MMP3 carries out inhibition test.Enzyme test is in 10mM CaCl under 25 ℃ 2, carry out among 100mM NaCl, the 50mMTris/HCl (pH7.6), enzyme concn is 8nM, uses fluorogenic substrate Dnp-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH respectively for MMP8 and MMP3 2(Bachem M-1855,1 * 10 -5M) and Mca-Arg-Pro-Lys-Pro-Val-Glu-Nva-Trp-Arg-Lys (Dnp)-NH 2(Bachem M-2110,4 * 10 -6M).Basically measure according to (4) described (for MMP3) such as (3) such as Stack described (to MMP8) and Nagase.In 100 seconds, monitor 350nm (MMP8) or 390nm (MMP3) and locate the enhancing of fluorescence, to determine the original speed of hydrolysis.The evaluation of dynamics data is carried out according to (5) such as Copeland are described.
Table I. with the non-peptide L-halfcystine of general formula I
Derivative suppresses the example of MMP8 and MMP3
Figure A9880671600101
Synthetic general method
A) amidation: with 1mmol N, N '-urethane groups Gelucystine, 2mmol HOBT (hydroxybenzotriazole) and 2.08mmol EDCI (N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride) dissolve or are suspended among the 10ml THF.The add-on of amine is superfluous (2.5-5mmol), in the situation of hydrochloride, adds the N-methylmorpholine of equivalent.Reaction mixture at room temperature stirred spend the night, be concentrated into small volume, be distributed among ethyl acetate and the water.Organic layer 5% NaHCO 3, 5%KHSO 4With the washing secondary, use MgSO 4Dry.Evaporating solvent, resistates precipitate with suitable solvent (as sherwood oil, Di Iso Propyl Ether, t-butyl methyl ether or pentane) in ethyl acetate.
B) reduction: Gelucystine compound (1mmol) reacts with the 1.5mmol tributylphosphine in 10ml 95% trifluoroethanol.Reaction mixture at room temperature stirred spend the night, be evaporated to small volume, after the ethyl acetate dilution, product is precipitated with suitable solvent such as sherwood oil, Di Iso Propyl Ether, t-butyl methyl ether or pentane.N, N '-two benzyloxy carbonyl-L-Gelucystine hydroxamic acid ester (5a)
By N, N '-two benzyloxy carbonyl-L-Gelucystine (2) and azanol prepare according to step (A).Productive rate: 22%; The last homogeneous of TLC (solvent system: chloroform/methanol, 4: 1; R f=0.5).
FAB-MS:m/z=539.2[M+H +]; C 22H 26N 4O 8S 2Calculated value M=538.2.Carbobenzoxy-(Cbz)-L-halfcystine hydroxamic acid ester (5)
(B) prepared by 5a according to step.With flash chromatography method purifying (eluent: CH 2Cl 2/ MeOH, 95: 5,45: 5 subsequently).Productive rate 18%. 1H-NMR (d 6-DMSO): 10.7 (bs, 1H, NHOH); 8.89 (bs, 1H, OH); 7.50 (d, 1H, NHureth.); 7.38 (arom.H ' s) for m, 5H; 5.03 (s, 2H, CH 2V.Z); (3.99 m, 1H, H-C (α)); 2.75/2.66 (2xm, 2H, β-CH 2); 2.29 (bs, 1H, SH). two tertbutyloxycarbonyls-L-Gelucystine dibenzyl acid amides (6a)
By N, N '-two tertbutyloxycarbonyls-L-Gelucystine (12) and benzylamine prepare according to step (A).Productive rate: 77%.(the solvent system: hexanaphthene/chloroform/acetate, 45: 45: 10, R of homogeneous on TLC f=0.7).L-Gelucystine dibenzoyl amine hydrochlorate (6b)
13.87g (22.4mmol) 6a stirs under room temperature in 100ml 4.6M HCl/ diox and spends the night, collecting precipitation is fully washed with ether.Output 11g (quantitatively).N, N '-diacetyl-L-Gelucystine dibenzamide (6c)
300mg (0.61mmol) 6b is distributed in ethyl acetate and 40ml NaHCO 3(5%) among, then with diacetyl oxide (0.27g, 2.6mmol) reaction.Organic layer washes with water, uses MgSO 4Drying is evaporated to dried.Productive rate: 94%; Homogeneous on TLC (solvent system: hexanaphthene/chloroform/acetate: 45: 45: 10, R f=0.4).N-ethanoyl-L-cysteine benzamide (6)
6c is reduced according to step (B).Productive rate: 65%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.7); Fusing point 186-189 ℃. 1H-NMR (d 6-DMSO): 8.56 (t, 1H, NH, acid amides), 8.23 (d, 1H NH urethanes); 7.32-7.09 (fragrant H ' s) for m, 5H; 4.56, or 4.38 (m, 1H, H-C α); 4.28 (m, 2H, CH 2-Bn); 3.12/2.89, or 2.79/2.69 (2xm, 2H, β-CH 2); 2.30 (bs, 1H, SH); 1.87 (d, 3H, CH 3) .FAB-MS:m/z=253.1[M+H +]; C 12H 16N 2O 2S calculated value M=252.1N, N-two formyls-L-Gelucystine dibenzamide (7a)
Prepare according to step (A) by 6b and formic acid.Productive rate: 59%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10; R f=0.1).N-formyl-L-cysteine benzamide (7)
According to step (B) reduction 7a.Productive rate: 62%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate; 45: 45: 10; R f=0.45); Fusing point 180-183 ℃. 1H-NMR (d 6-DMSO): 8.58 (t, 1H, NH, acid amides); (8.35 d, 1H, NH urethane); 8.10 (s, 1H, formyl radical-H); 7.33-7.21 (fragrant H ' s) for m, 5H; 4.49, (m, 1H, H-C α); 4.30 (d, 2H, CH 2-Bn); 2.82/2.72 (2xm, 2H, β-CH 2); 2.26 (bs, 1H, SH) .FAB-MS:m/z=239.0[M+H +]; C 11H 14N 2O 2S calculated value M=238.3 tertbutyloxycarbonyl-L-cysteine benzamide (8)
According to step (B) reduction 6a.Productive rate: 38%, (the solvent system: heptane/trimethyl carbinol/acetate, 5: 1: 1, R of homogeneous on TLC f=0.7); Fusing point 97-100 ℃; 1H-NMR (d 6-DMSO): 8.38 (m, 1H, NH, acid amides); 7.32-7.21 (fragrant H ' s) for m, 5H; (6.95 d, 1H, NH-urethane); 4.29 (d, 2H, CH 2-Bn); 4.08 (m, 1H, H-C α); 2.81/2.68 (2xm, 2H, β-CH 2); 2.29 (bs, 1H, SH); 1.40 (s, 9H, t-Bu) .FAB-MS:m/z=311.1[M+H +]; C 15H 22N 2O 3S calculated value M=310.1N, N '-two benzyloxy carbonyl-L-Gelucystine dibenzamide (9a)
By N, N '-two benzyloxy carbonyl Gelucystine and benzene methanamine obtain according to (A).Productive rate: 90%.N-carbobenzoxy-(Cbz)-L-cysteine benzamide (9)
According to (B) reduction 9a.Productive rate: 41%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10; R f=04); Fusing point 148-152 ℃; 1H-NMR (d 6-DMSO): 8.50 (m, 1H, NH, acid amides); (7.49 d, 1H, NH urethane); 7.37-7.23 (m, 10H, fragrance, H ' is s); 5.06 (dd, 2H, CH 2V.Z); 4.30 (d, 2H, CH 2-Bn); 4.16 (m, 1H, H-C α); 2.84/2.70 (2xm, 2H, β-CH 2); 2.33 (bs, 1H, SH) .FAB-MS:m/z=345.0[M+H +]; C 18H 20N 2O 3S calculated value M=344.4N, N '-two benzyloxy carbonyl-L-Gelucystine two-4-pyridyl methane amide (10a)
By N, N '-two benzyloxy carbonyl-L-Gelucystine and 4-(aminomethyl) pyridine prepare according to step (A).Productive rate: 59%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.65).N-carbobenzoxy-(Cbz)-L-halfcystine-4-pyridyl methane amide (10)
Prepare according to step (B) by 10a.Productive rate: 65%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.8); Fusing point 122-125 ℃. 1H-NMR (d 6-DMSO): 8.61 (t, 1H, NH, acid amides); 8.48/7.37/7.25 (m is respectively, 9H, and fragrant H ' is s); (7.56 d, 1H, NH-urethane); 5.08 (dd, 2H, CH 2, Z); 4.32 (d, 2H, CH 2-Bn); 4.18 (m, 1H, H-C α), 2.87/2.72 (2xm, 2H, β-CH 2); 2.40 (bs, 1H, SH) .FAB-MS:m/z=346.2[M+H +]; C 17H 19N 3O 3S calculated value M=345.1N, N '-two benzyloxy carbonyl-L-Gelucystine two-3-pyridyl methane amide (11a)
By N, N '-two benzyloxy carbonyl Gelucystine and 3-(aminomethyl) pyridine obtain according to step (A).Productive rate: 69%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.2).N-carbobenzoxy-(Cbz)-L-halfcystine-3-pyridyl methane amide (11)
According to step (B) reduction 11a.Productive rate: 14%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.8); Fusing point 125-127 ℃; 1H-NMR (d 6-DMSO): 8.58 (t, 1H, NH, acid amides); 8.50/8.45/7.65/7.36 (m is respectively, 9H, and fragrance, H ' is s); (7.52 d, 1H, NH-urethane); 5.07 (dd, 2H, CH 2V.Z); 4.42 (d, 2H, CH 2-Bn); 4.15 (m, 1H, H-C α); 2.82/2.71 (2xm, 2H, β-CH 2); 2.36 (bs, 1H, SH) .FAB-MS:m/z=346.1[M+H +]; C 17H 19N 3O 3S calculated value M=345.1N, N '-two benzyloxy carbonyl-L-Gelucystine two-2-pyridyl methane amide (12a)
By N, N '-two benzyloxy carbonyl Gelucystine and 2-(aminomethyl) pyridine obtain according to step (A).Productive rate: 96%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.7).N-carbobenzoxy-(Cbz)-L-halfcystine-2-pyridyl methane amide (12)
According to (B) reduction 12a.Productive rate: 33%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.8); Fusing point 129-131 ℃. 1H-NMR (d 6-DMSO): 8.59 (t, 1H, NH, acid amides); 8.48/7.72/7.36-7.22 (m is respectively, 9H, and fragrant H ' is s); (7.52 d, 1H, NH-urethane); 5.07 (dd, 2H, CH 2V.Z); 4.49 (d, 2H, CH 2-Bn); 4.20 (m, 1H, H-C α); 2.85/2.72 (2xm, 2H, β-CH 2); 2.42 (bs, 1H, SH) .FAB-MS:m/z=346.1[M+H +]; C 17H 19N 3O 3S calculated value M=345.1N, N '-dibenzoyl-L-Gelucystine dibenzamide (13a)
Prepare according to (A) by 6a and phenylformic acid.Productive rate: 78%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate; 45: 45: 10, R f=0.65).N-benzoyl-L-cysteine benzamide (13)
According to step (B) reduction 13a.Productive rate: 57%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate; 45: 45: 10, R f=0.55); Fusing point 174-176 ℃;
1H-NMR (d 6-DMSO): 8.56 (t, 1H, NH, acid amides); (7.92 d, 1H, NH urethane); 7.57-7.22 (m,
10H, fragrant H ' is s); 4.59, (m, 1H, H-C α), 4.31 (d, 2H, CH 2-Bn); 2.98/2.89 (2xm, 2H, β-CH 2); 2.41 (t, 1H, SH) FAB-MS:m/z=315.1[M+H +]; C 17H 18N 2O 2S calculated value M=314.1N, N '-two (tosyl group)-L-Gelucystine dibenzamide (14a)
390mg (0.794mmol) 6b and 180mg (0.952mmol) toluene sulfonyl chloride react in the 6ml pyridine.Stir under the room temperature after 12 hours, leach solid, filtrate is added toluene, adds t-butyl methyl ether at last and be evaporated to dried.Productive rate: 81%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.7).N-sulfonyloxy methyl-L-cysteine benzamide (14)
According to (B) reduction 14a.Productive rate: 54%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 4: 1, R f=0.6); Fusing point 180-182 ℃; 1H-NMR (d 6-DMSO): 8.41 (t, 1H, NH, acid amides); (7.98/7.68/7.35-7.14 m is respectively and d ' s, 10H, fragrant H ' s, NH urethane); 4.13 (d, 2H, CH 2-Bn); 3.86 (m, 1H, H-C α); 2.59 (m, 2H, β-CH 2); 2.38 (s, 3H, CH 3); 2.17 (t, 1H, SH) .FAB-MS:m/z=365.1[M+H +]; C 17H 20N 2O 3S calculated value M=364.1N, N '-two benzyloxy carbonyl-L-Gelucystine two-2-phenyl-acetamides (15a)
By N, N '-two benzyloxy carbonyl-L-Gelucystine and 2-phenyl-ethyl amine obtain according to step (A).Productive rate: 34%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 19: 1, R f=0.8).N-carbobenzoxy-(Cbz)-L-halfcystine-2-phenyl-acetamides (15)
According to (B) reduction 15a.Productive rate: 61%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.6); Fusing point 119-121 ℃; 1H-NMR (d 6-DMSO): 8.02 (t, 1H, NH, acid amides); (7.39-7.18 m, 11H, fragrant H ' s, NH urethane); 5.03 (dd, 2H, CH 2V.Z), 4.06 (m, 1H, H-C α); 2.72/2.61 (2xm, 4H, CH 2-CH 2); 2.22 (bs, 1H, SH) .FAB-MS:m/z=359.1[M+H +]; C 19H 22N 2O 3S calculated value M=358.1.N, N '-two benzyloxy carbonyl-L-Gelucystine-two-2-(4-acenol) (16a)
By N, N '-two benzyloxy carbonyl Gelucystine and 2-(4-hydroxyphenyl) ethamine prepares according to step (A).Productive rate: 71%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.5).N-carbobenzoxy-(Cbz)-L-halfcystine-2-(4-hydroxyphenyl) ethanamide (16)
According to step (B) reduction 16a.Productive rate: 24%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.6); Fusing point 133-135 ℃; 1H-NMR (d 6-DMSO): 9.11 (s, 1H, phenol, OH); (7.98 t, 1H, NH, acid amides); (7.38 m, 6H, fragrant .v.Z, NH urethane); 6.99/6.68 (fragrant phenol .H ' s) for 2xd, 4H; 5.04 (dd, 2H, CH 2VZ); 4.05 (m, 1H, H-C α); 2.73/2.60 (2xm, 4H, CH 2-CH 2); 2.26 (bs, 1H, SH) FAB-MS:m/z=357.2[M+H +]; C 19H 22N 2O 4S calculated value M=374.1.N, N '-two benzyloxy carbonyl-L-Gelucystine-two-4-chlorobenzamide (17a)
By N, N '-two benzyloxy carbonyl Gelucystine and 4-chlorobenzamide obtain according to (A).Productive rate: 99%; (the solvent system: CHCl of homogeneous on TLC 3/ MeOH, 19: 1, R f=0.8).N-carbobenzoxy-(Cbz)-L-halfcystine-4-chlorobenzamide (17)
According to step (B) reduction 17a.Productive rate: 71%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.85); Fusing point 137-139 ℃; 1H-NMR (d 6-DMSO): 8.53 (t, 1H, NH, acid amides); (7.51 d, 1H, NH urethane); 7.38-7.26 (fragrant .H ' s) for m, 9H; 5.06 (dd, 2H, CH 2V.Z), 4.29 (d, 2H, CH 2-Bn); 4.13 (m, 1H, H-C α); 2.82/2.70 (2xm, 2H, β-CH 2); 2.53 (bs, 1H, SH) .FAB-MS:m/z=379.1[M+H +]; C 18H 19CIN 2O 3S calculated value M=378.1.N, N '-two benzyloxy carbonyl-L-Gelucystine-two-3-Phenylpropionamide (18a)
By N, N '-two benzyloxy carbonyl Gelucystine and 3-phenylpropylamine obtain according to step (A).Productive rate: 94%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.7).N-carbobenzoxy-(Cbz)-L-halfcystine-3-Phenylpropionamide (18)
According to (B) reduction 18a.Productive rate: 76%; (the solvent system: hexanaphthene/CHCl of homogeneous on TLC 3/ acetate, 45: 45: 10, R f=0.7); Fusing point 104-106 ℃; 1H-NMR (d 6-DMSO): 8.02 (t, 1H, NH, acid amides); (7.43 d, 1H, NH urethane); 7.38-7.15 (fragrant H ' s) for m, 10H; 5.05 (dd, 2H, CH 2V.Z); 4.09 (m, 1H, H-C α); 3.12 (m, 2H, N-CH 2); 2.70/2.69 (2xm, 2H, β-CH 2); 2.58 (t, 2H, CH 2-Ph); 2.32 (bs, 1H, SH); 1.70 (m, 2H, CH 2-CH 2-CH 2) .FAB-MS:m/z=373.2[M+H +]; C 20H 24N 2O 3S calculated value M=372.2.N, N '-two benzyloxy carbonyl-L-Gelucystine-two-Se acid amides (19a)
By N, N '-two benzyloxy carbonyl Gelucystine and tryptamines obtain according to (A).Productive rate: 75%; The last homogeneous of TLC (solvent system: hexanaphthene/CHCl 3/ acetate, 45: 45: 10, R f=0.6).Carbobenzoxy-(Cbz)-L-halfcystine look acid amides (19)
According to step (B) reduction 19a.Productive rate: 62%; The last homogeneous of TLC (solvent system: hexanaphthene/CHCl 3/ acetate, 45: 45: 10, R f=0.7); Fusing point 150-152 ℃; 1H-NMR (d 6-DMSO): 10.80 (s, 1H, NH-tryptamines); (8.09 t, 1H, NH acid amides); (7.54-6.96 m, 11H, fragrant H ' s, urethane NH); 5.05 (dd, 2H, CH 2, v.Z); (4.08 m, 1H, H-C (α)); 3.32 (m, 2H, NHCH 2CH 2); 2.82 (t, 2H, NHCH 2CH 2); 2.77/2.65 (2xm, 2H, β-CH 2); 2.26 (m, 1H, SH) .FAB-MS:m/z=398.2[M+H +]; C 21H 23N 3O 3S calculated value M=397.2.N, N '-two hexanoyls-L-Gelucystine-two-benzamide (20a)
Obtain according to step (A) by 6b and caproic acid.Productive rate: 86%; Last homogeneous (the solvent system of TLC; Hexanaphthene/chloroform/acetate, 45: 45: 10, Rf=0.6). 1H-NMR (d 6-DMSO): 8.48 (t, 1H, NH, acid amides); (8.02 d, 1H, NH urethane); 7.3-7.2 (fragrant H ' s) for m, 5H; 4.41 (m, 1H, H-C α); 4.28 (d, 2H, CH 2-Bn); 2.80/2.70 (2xm, 2H, β-CH 2); 2.25 (t, 1H, SH); 2.17 (m, 2H ,-CH 2-CO-); (1.49-1.21 m, 10H, alkyl), 0.87 (t, 3H ,-CH 3) .N-hexanoyl-L-cysteine benzamide (20)
According to step (B) reductase 12 0a.Productive rate: 69%; Fusing point 141-143 ℃; 1H-NMR (d 6-DMSO): 1H-NMR (d 6-DMSO): 8.48 (t, 1H, NH acid amides); 8.02 (d, 1H, NH-ureth.); 7.31-7.2 (fragrant H ' s) for m, 5H; 4.40 (m, 1H, H-C α); 4.22 (d, 2H, CH 2-Bn); 2.80/2.70 (2xm, 2H, β-CH 2); 2.3 (bs, 1H, SH); 2.12 (m, 2H ,-CH 2-CO-); (1.50-1.19 m, 6H, alkyl), 0.85 (t, 3H ,-CH 3) FAB-MS:m/z=309.2[M+H +]; C 16H 24N 2O 2S calculated value M=308.2.N, N '-two decoyls-L-Gelucystine-dibenzamide (21a)
By 6a with sadly prepare according to step (A).Productive rate: 86%; The last homogeneous of TLC (solvent system: hexanaphthene/chloroform/acetate, 45: 45: 10, Rf=0.6).N-decoyl-L-cysteine benzamide (21)
According to step (B) reductase 12 1a.Productive rate: 73%; Fusing point 137-139 ℃; 1H-NMR (d 6-DMSO): 1H-NMR (d 6-DMSO): 8.48 (t, 1H, NH, acid amides); (8.02 d, 1H, NH-urethane); 7.3-7.2 (fragrant H ' s) for m, 5H; 4.41 (m, 1H, H-C α); 4.28 (d, 2H, CH 2-Bn); 2.80/2.70 (2xm, 2H, β-CH 2); 2.25 (t, 1H, SH); 2.17 (m, 2H ,-CH 2-CO-); (1.49-1.21 m, 10H, alkyl), 0.87 (t, 3H ,-CH 3) .FAB-MS:m/z=337.2[M+H +]; C 18H 28N 2O 2S calculated value M=336.2.N, N '-two caprinoyls-L-Gelucystine-two-benzamide (22a)
Prepare according to step (A) by 6b and capric acid.Productive rate: quantitatively; The last homogeneous of TLC (solvent system: hexanaphthene/chloroform/acetate, 45: 45: 10; R f=0.9).N-caprinoyl-L-cysteine benzamide (22)
According to step (B) reductase 12 2a.Productive rate: 33%; R f=0.7; Fusing point: 138-140 ℃; 1H-NMR (d 6-DMSO): 8.46 (t, 1H, NH, acid amides); (8.02 d, 1H, NH-urethane); 7.3-7.2 (fragrant H ' s) for m, 5H; 4.4 (m, 1H, H-C α); 4.29 (d, 2H, CH 2-Bn); 2.80/2.70 (2xm, 2H, β-CH 2); 2.25 (t, 1H, SH); 2.18 (m, 2H ,-CH 2-CO-); (1.49-1.19 m, 14H, alkyl), 0.85 (t, 3H ,-CH 3) .FAB-MS:m/z=365.2[M+H +]; C 20H 32N 2O 2S calculated value M=364.2.1.Beckett.R.P.; Davidson, A.H.; Drummond.A.H.; Huxley, P; Whittaker, M.Drug Disc.Today (contemporary drug discovery) 19962.W ü nsch, E.in Houben-Weyl, Methoden der Organischen Chemie (organic chemistry method), Vol.15/I, Springer Verlag, Stuttgart, 1974.3.Stack, M.S.; Gray, R.D.J.Biol.Chem. (journal of biological chemistry) 1989,264,4277.4.Nagase, H.; Fields, C.G.; Fields, G.B.J.Biol.Chem. (journal of biological chemistry) 1994,269,20952.5.Copeland, R.A.; Lombardo, D.; Giannaras, J.; Decicco.C.P.Bioorg.Med.Chem.Lett. (biological organic medicinal chemistry wall bulletin) 1995,5,1947.

Claims (5)

1. the compound of general formula I representative This compound combination also suppresses matrix metalloproteinase (MMP), and wherein halfcystine partly contains not protected thiol, and this halfcystine partly is L-or D-form, wherein
A representative-CO-,-SO 2-,-NH-CO-or-O-CO-,
R 1Represent hydrogen, saturated or the unsaturated alkyl of straight or branched that contains 1-15 carbon atom, or replaced by halogen, sulfydryl, hydroxyl, alkoxyl group, amino or nitro or can be chosen wantonly non-aromatics of one or several substituent carbocyclic ring or aromatics ring system or can be chosen wantonly substituted aromatics or C that non-aromatic heterocyclic replaces 1-C 15Alkyl, or acceptable salt or its optically-active form on its pharmacology;
The R representation hydroxy contains the saturated or unsaturated alkyl of straight or branched of 1-15 carbon atom, or can be chosen wantonly the C that non-aromatics of one or several substituent carbocyclic ring or aromatics ring system or optional substituted aromatics or non-aromatic heterocyclic replace 1-C 15Alkyl, or acceptable salt or its optically-active form on its pharmacology.
2. pharmaceutical composition contains the compound of claim 1 in this pharmaceutical composition, or acceptable salt on its pharmacology, or its optically-active form, and pharmaceutically useful carrier.
3. the therapeutic composition of claim 2, being used for the treatment of rheumatoid arthritis and CA is other diseases related of promoting factor therein.
4. according to the purposes of claim 3, wherein the dosage of therapeutical agent is every kg body weight 0.1-300mg.
5. according to the purposes of claim 3 or 4, wherein in therapeutical agent oral administration, the blood vessel, intraperitoneal, subcutaneous, intramuscular or topical.
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