CN1206001A - Substituted diaminocarboxylic acids - Google Patents

Abstract

Compounds of formula (I)are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in the course of which an increased activity of matrix-degrading metalloproteinases is involved.

Description

The diamino monocarboxylic acid that replaces

The invention relates to the diamino monocarboxylic acid and preparation method thereof and the pharmaceutical use of new replacement.

Patent application EP0 606 046, WO95/35276 and WO96/27583 have described Arenesulfonyl amino-iso hydroximic acid and as the effect of matrix metallo-proteinase inhibitor.Specific aryl sulphonyl amino yl carboxylic acid is the intermediate as preparation thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitor (EP 0 305 947).Patent application EP 0 757 037 has also described the effect as the Sulfonylaminocarboxyacids acids derivative of inhibitors of metalloproteinase.

Aryl sulfonyl is proved effective protecting group (R.Roemmele, H.Rapoport, organic chemistry magazine (J.Org.Chem.) 53 (1988) 2367-2371) of the amido functional group that can be used as alpha-amino carboxylic acid in addition.

In the process of the active compound that strives to find the treatment connective tissue disease, have now found that diamino monocarboxylic acid of the present invention is the potent inhibitor of matrix metalloproteinase.Since stromelysin (matrix metalloproteinase 3) and neutrophil collagenase (MMP-8) all fatefully with degraded relevant especially (A.J.Fosang et al. Journal of Clinical Investigation (J.Clin.Invest.) 98 (1996) 2292-2299) as the protein-polysaccharide of the important component of cartilaginous tissue, so especially meaningfully to the restraining effect of stromelysin (matrix metalloproteinase 3) and neutrophil collagenase (MMP-8).

Therefore the present invention relates to formula I compound

And/or the physiologically acceptable salt of the steric isomer of formula I compound and/or formula I compound, wherein R ¹Be 1. phenyl, 2. by single replacement of following radicals or disubstituted phenyl,

2.1. (the C of straight chain, ring-type or side chain ₁-C ₇) alkyl,

2．2．????-OH，

2.3. (C ₁-C ₆) alkyl-C (O)-O-,

2.4. (C ₁-C ₆) alkyl-O-,

2.5. (C ₁-C ₆) alkyl-O-(C ₁-C ₄) alkyl-O-,

2.6. halogen,

2．7．????-CF ₃，

2．8．????-CN，

2．9．????-NO ₂，

2．10．???HO-C(O)-，

2.11. (C ₁-C ₆) alkyl-O-C (O)-,

2.12. methylene radical dioxo (methylenedioxo),

2．13．???R ⁴-(R ⁵)N-C(O)-，

2.14. R ⁴-(R ⁵) N-, or

3. unsubstituted or following by being selected from of replacing of the group described in the 2.1-2.14

3.1-3.16 the heteroaryl of group,

3.1. the pyrroles,

3.2. pyrazoles,

3.3. imidazoles,

3.4. triazole,

3.5. thiophene,

3.6. thiazole,

3.7. oxazole,

3.8. isoxazole,

3.9. pyridine,

3.10. pyrimidine,

3.11. indoles,

3.12. thionaphthene,

3.13. benzoglyoxaline,

3.14. benzoxazole,

3.15. benzothiazole or

3.16. benzotriazole, R ², R ⁴And R ⁵Identical or different, and be

1. hydrogen atom,

2. (C ₁-C ₆) alkyl-,

3.HO-C (O)-(C ₁-C ₆) alkyl-,

4. phenyl-(CH ₂) _o-, wherein phenyl is not substituted or by the base described in the 2.1-2.14

Single group replaces or two replacement, and o is an integer 0,1 or 2, or

Picolyl or

6.R ⁴And R ⁵Go up amino with ring and formed 4 yuan of-7 yuan of rings, wherein carbon atom it

One optional quilt-O-,-S-or-the NH-replacement, R ³Identical or different with G, and be

1. hydrogen atom,

2. straight chain, side chain or cyclic (C ₁-C ₆) alkyl-,

3. (C ₂-C ₆) alkenyl-,

4. phenyl-(CH ₂) m-, wherein phenyl is not substituted or by the base described in the 2.1-2.14

Single group replaces or two replacement, and m is an integer 0,1,2 or 3,

5. heteroaryl-(CH ₂) m-, wherein heteroaryl in the 3.1-3.16 definition and/or as 2.1

Being substituted like that described in-2.14, and m is integer 0,1,2 or 3,

6.R ⁶-C (O)-, R wherein ⁶Be

6.1 (C ₁-C ₆) alkyl-, wherein alkyl is not substituted or is retouched among the 2.1-2.14

The group of stating replaces or quilt (C ₃-C ₆) cycloalkyl substituted

6.2 (C ₃-C ₆) cycloalkyl, wherein cycloalkyl is not substituted or by institute among the 2.1-2.14

The group of describing replaces

6.3 (C ₂-C ₆) alkenyl, wherein alkenyl is not substituted or by following radicals

The single replacement to three replacements

6.3.1 phenyl, it is not substituted or by as the group described in the 2.1-2.14

The single replacement to three replacements

6.3.2 heteroaryl, its definition are not substituted as 3.1-3.16 and its or by 2.1-

2.14 described in the group list replace to three replace or

6.3.3 the group described in the 2.1-2.14,

6.4 phenyl-(CH ₂) m-, wherein phenyl is not substituted or by as institute among the 2.1-2.14

The group list of describing replaces to three replacement or quilt-O-CF ₃,-SO ₂-NH ₂,

-NH-C (O)-CF ₃Or the benzyl list replace to three replace and-(CH ₂)-Ji

Optional quilt-COOH the replacement of a hydrogen atom of group, m be integer 0,

1,2 or 3,

6.5 naphthyl,

6.6 golden steel alkyl,

6.7 heteroaryl-(CH ₂) m-, wherein the heteroaryl definition is as 3.1-3.16 and/or quilt

2.1-2.14 described in group replace, m is an integer 0,1,2

Or 3,7.R ⁶-O-C (O)-, R wherein ⁶Define as above 8.R ⁶-CH (NH ₂)-C (O)-, R wherein ⁶Define as above 9.R ⁸-N (R ⁷)-C (O)-, R wherein ⁸Be 9.1 hydrogen atoms,

9.2 (C ₁-C ₆) alkyl-,

9.3 phenyl-(CH ₂) m-, wherein phenyl is not substituted or by as 2.1-

2.14 described in the group list replace or two replacement and m are whole

Several 0,1,2 or 3, or

9.4 heteroaryl-(CH ₂) m-, wherein decide among heteroaryl such as the 3.1-3.16

Justice and/or replaced, and m by the group described in the 2.1-2.14

Be integer 0,1,2 or 3, R ⁷Be hydrogen atom or (C ₁-C ₆) alkyl, or R wherein ⁷And R ⁸Link to each other with the nitrogen-atoms that is connected them and formed a carbon atom quilt-O-in not being substituted or encircling of 4 yuan-7 yuan rings and this ring ,-S-or-the NH-replacement, 10.R ⁶-SO ₂-, R wherein ⁶Define as above 11.R ⁶-SO ₂-N (R ⁷)-C (O)-, R wherein ⁶And R ⁷Define as above 12.R ⁶-NH-C (=NR ⁷)-, be R wherein ⁶And R ⁷The definition as above or

12.1 (C ₁-C ₆) alkyl-C (O)-,

12.2-NO ₂Or

12.3-SO ₂-(CH ₂) _q-phenyl, wherein phenyl is not substituted or by as 2.1-

2.14 described in the group list replace or two replacement and q are integers

0,1,2 or 3,

13.

Wherein m is an integer 0,1,2 or 3, and W is nitrogen, oxygen or sulphur atom, or R ³Formed following formula II a-II p ring with G with the nitrogen-atoms that is connected them,

Wherein r is integer 1 or 2, R ¹⁰Be as the group described in the 2.1-2.14, R ⁷With

A carbon atom in the same and formula II g of the m meaning ring is optional by oxygen, sulphur, SO ₂Or

Nitrogen-atoms is replaced, and described nitrogen-atoms is not substituted or by R ²Replace, A is an a) covalent linkage,

b)-O-，

C)-CH=CH-or

D)-C ≡ C-, B be a)-(CH ₂) _m-, wherein the m implication is the same,

B)-O-(CH ₂) _q-, wherein q is an integer 1,2,3,4 or 5,

Or

C)-and CH=CH-, D is-(CH ₂) _m-, wherein m be integer 1,2,3,4,5 or 6 and one of them

Chain carbon atom is optional be optionally substituted-NH-,-O-or-the former replacement of S-and x be-CH=CH-, Sauerstoffatom or sulphur atom.

Preferred formula I compound, wherein R ¹Be 1. phenyl or

2. by the mono-substituted phenyl of following radicals,

Halogen, particularly chlorine or fluorine or

2.R ⁴-(R ⁵) N-, wherein R ⁴And R ⁵Identical or different and be

2.1. (C ₁-C ₃) alkyl or

2.2.R ⁴And R ⁵Amino has formed 5-6 unit ring and has been somebody's turn to do with encircling upward

Optional quilt-the O-of a carbon atom of ring or-the NH-replacement, R ²Be hydrogen atom, G and R ³Difference, wherein

G is hydrogen atom or (C ₁-C ₄) alkyl and

R ³Be 1. phenyl-(CH ₂) _m, wherein phenyl is not substituted or by as retouching among the 2.1-2.14

The group list of stating replaces or two replacement, and m is an integer 1,

2. heteroaryl-(CH ₂) _n-, wherein heteroaryl such as 3.10 definition and not got

Generation or replaced by the group described in the 2.1-2.14, n is 0,

3.R ⁶-C (O)-, wherein

R ⁶Be 3.1 (C ₁-C ₆) alkyl, wherein alkyl is straight chain, side chain or ring-type

,

3.2 phenyl-(CH ₂) _r-, wherein phenyl is not substituted or by 2.1-

2.14 described in the group list replace or two replacement and-

(CH ₂Optional quilt-the COOH of a hydrogen atom of)-group gets

In generation, r is an integer 0,1,2 or 3, or

3.3 heteroaryl-(CH ₂) _o-, wherein heteroaryl such as 3.1-3.15 decide

Justice and be unsubstituted or by described in the 2.1-2.14

Group replaces, and o is 0,1,2 or 3, or

4.R ⁸-N (R ⁷)-C (O)-, wherein

R ⁸And R ⁷Link to each other with the nitrogen-atoms that is connected them and formed 5-6 unit ring and

This ring is not substituted or a ring carbon atom is replaced by Sauerstoffatom, or

R ³Link to each other with G and the nitrogen-atoms that is connected them and formed formula II g ring, wherein r is 1, and A is a covalent linkage, and B is-(CH ₂) _p-, p is 0, D is-(CH ₂) _q-, q be integer 2,3 or 4 and X be-CH=CH-.

Described " R ⁴And R ⁵With ring go up amino formed one of 4-7 unit ring and/or carbon atom quilt-O-,-S-or-the NH-replacement " be meant and for example be derived from tetramethyleneimine, piperazine, morpholine, the group of piperidines or thiomorpholine.Term " halogen " is meant fluorine, chlorine, bromine or iodine.Term " alkyl " or " alkenyl " are meant that those carbochains are the alkyl of straight or branched.Cycloalkyl is the monocycle system of for example 3-6 unit, for example, and cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Alkenyl can also contain several pairs of keys.The raw material of chemical reaction is knownly maybe easily to prepare with the currently known methods in the document.

The invention still further relates to the preparation method of physiologically acceptable salt steric isomer formula I compound and/or formula I compound and/or formula I compound, this method comprises

If a) in the presence of the alkali or suitable then in the presence of dehydrated reagent, make the diamino monocarboxylic acid of formula III,

R wherein ², R ³, D is identical with the definition in the formula I with G, with the sulfonic acid reaction of formula IV,

R wherein ¹, A is identical with the definition in the formula I with B, Y be halogen atom, imidazolyl or-OR ⁹, R wherein ⁹Be hydrogen atom, (C ₁-C ₆) alkyl, phenyl, succinimido (succinimidyl), benzotriazole base or benzyl and optional being substituted, obtain formula I compound, or

B) under these conditions, make the diamino monocarboxylic acid ester of formula V,

R wherein ², R ³, D, G and R ⁹Implication is the same, with the reaction of formula IV sulfonic acid, obtains formula VI compound, Preferably in the presence of alkali or acid, by removing R ⁹Formula VI compound is converted into formula I compound,

C) make the protected diamino monocarboxylic acid of formula VII,

R wherein ²The same with the D implication, E is the protecting group of amido functional group, with the reaction of formula IV sulfonic acid, obtains formula VIII compound,

By removing protecting group E formula VIII compound is converted into formula I compound by means of the suitable reagent that dissociates then,

R wherein ¹, R ², A, B, D and X implication be the same, R ³With G be hydrogen atom, and if suitable then can in the presence of alkali, make above-mentioned formula I compound and R ³-Y, wherein R ³Have above-mentioned implication with Y, reaction obtains formula I compound,

R wherein ¹, R ², R ³, A, B and X has above-mentioned implication and G is a hydrogen atom, or

D) use and method c) identical method, will be as the protected diamino acid esters of the formula IX of initial compounds,

R wherein ², R ⁹, D and E have above-mentioned implication, is converted into the ester of formula X,

Optional according to method b) ester of formula X is converted into corresponding formula I compound, or

E) make formula XI diamino monocarboxylic acid,

Wherein D and E identical with the definition in the formula I and F are different N-amino protecting groups mutually, are connected gained formula XII compound with the polymer resin of formula PS through intermediate chain L by its carboxyl If after selectivity is removed protecting group F in the presence of alkali or suitable in the presence of dehydrated reagent with formula IV sulfonic acid reaction,

R wherein ¹, A, B and Y have above-mentioned implication, obtains formula X III compound

And formula X III compound is reacted with formula X IV carboxylic acid derivative in the presence of alkali or dehydrated reagent after removing protecting group E,

R ⁶-C (O)-Y (X IV) is R wherein ⁶Have above-mentioned implication with Y, obtain formula X V compound

And after solid support material dissociates, be translated into formula I compound,

R wherein ¹, R ⁶, A, B, D and X have above-mentioned implication.

Used formula III initial compounds, wherein R ², R ³With G be hydrogen atom, preferred 2,3-diaminopropionic acid, 2,4-diamino-butanoic, ornithine, Methionin and high-lysine.If R ³With G be guanidine radicals with amido functional group, then preferably use arginine.

As at method c), d) and e) in; if the amino-functional to formula VII, IX and XI initial compounds provides protecting group E and F; then according to as Houben-Weyl in " organic chemistry method "; the method of describing in the 15/1st volume (Houben-Weyl " Methoden der Org.Chemie ", Volume 15/1) is carried out the amino derivatization of this selectivity.

Be used for the suitable protecting group E of above-mentioned purpose and the N-protected base that F preferably is generally used for chemistry of peptides; for example; the urethanes protecting group; as carbobenzoxy-(Cbz) (Z), tertbutyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc); or amides protecting group, particularly formyl, acetyl or trifluoroacetyl, or alkyls protecting group; for example, benzyl.(trimethyl silyl) ethoxycarbonyl (Teoc) has been proved and has been specially adapted to above-mentioned purpose (P.Koci é nski, Protecting Groups, Thieme Verlag 1994).The compound of many selective derivatizations also is commercially available; so as at method c) described in; the main points of the preparation of formula I compound of the present invention are: introduce sulphonate in alpha-amino group after; carry out the removal of Side chain protective group E, choose wantonly then and carry out the multistage derivatization of the free amine group in the side chain.In described process, carboxyl can the free form or with-OR ⁹Base becomes the form of ester to exist.When-OR ⁹Relate to straight chain (C ₁-C ₃) during alkyl, the ester of described formula I can also the prodrug form be used for the treatment of.

Work as R ⁹When being the tertiary butyl, preferably in last synthesis step, use HCl or trifluoroacetic acid in ether to carry out dissociating of ester according to currently known methods.

Be used for sulfonic acid or its salt of the starting material preference of preparation formula IV sulfonic acid suc as formula X VI a-X VI g,

R ¹⁰It is the group of in phenyl 2.1-2.14 clauses and subclauses, describing.

Aryl sulfonic acid for preparation formula X VI a and b, the preferred Houben-Weyl that uses is in " organic chemistry method ", the 9th volume 450-546 page or leaf (Houben-Weyl " Methoden der Org.Chemie ", Volume 9, pp.450-546) the method for sulfonating vitriol oil of describing in, if suitable then in the presence of catalyzer, sulphur trioxide, and adducts or halosulfonic acid, for example, chlorsulfonic acid carries out sulfonation.When particularly preparing X VI b phenyl ether, now confirmed to use the vitriol oil and diacetyl oxide solvent (with reference to C.M.Suter, JACS (J.Am.Chem.Soc.) 53 (1931) 1114) or use excess chlorine sulfonic acid to react (J.P.Bassin, R.Cremlyn andF.Swinbourne; Phosphorus, sulphur and silicon (Phosphorus, Sulfur and Silicon) 72 (1992) 157) be suitable.Can prepare sulfonic acid with known method according to formula X VI c, X VI d or X VI e, this method be in the aqueous solution or aqueous alcoholic liquid with corresponding aralkyl halogen and sulphite as, S-WAT or ammonium sulphite react, may accelerated reaction in the presence of organic quaternary ammonium salt such as tetrabutylammonium chloride.

Used formula IV sulfonic acid is SULPHURYL CHLORIDE especially.In order to prepare this derivative, under condition of no solvent or under the solvent condition of for example phosphoryl chloride or in the presence of the inert solvent of for example methylene dichloride, hexanaphthene or chloroform, make corresponding sulfonic acid with known method, also can be for example sodium salt, ammonium salt or pyridinium salt of its salt, with phosphorus pentachloride or thionyl chloride reaction, temperature of reaction is generally 20 ℃ of boiling points to used reaction medium.

According to Schotten-Baumann reaction can carry out expediently according to method a), b), c) or the amino acid of the formula IV sulfonic acid d) described and formula III, V, VII or IX between reaction.Especially suitable for this reason alkali is alkali metal hydroxide, for example, and sodium hydroxide, but also can be alkali metal acetate, supercarbonate, carbonate and amine.Be reflected in the water or can be with water miscible or with the immiscible solvent of water, for example, carry out in tetrahydrofuran (THF) (THF), acetone, dioxane or the acetonitrile, temperature of reaction is generally-10 ℃-50 ℃.When reaction is when carrying out in anhydrous medium, especially use tetrahydrofuran (THF) or ethylene dichloride, acetonitrile or dioxane, at alkali, for example, triethylamine, N-methylmorpholine, N-ethyl or diisopropylethylamine exist down, at the N as catalyzer, the N-Dimethylamino pyridine reacts under existing if possible.

In other method, can be by means of sillylation reagent, for example, two-trimethyl silyl trifluoroacetamide (BSTFA), at first the aminocarboxylic acid of formula III, V, VII or IX is converted into their silylanizing form, makes itself and sulfonic acid reaction obtain formula I compound then.

The polymer support that is called PS in the formula XII is the cross-linked polystyrene resin with the connection chain that is called the L intermediate chain, be Wang resin (S.W.Wang, JACS (Journal of theAmerican Chemical Society) (1973), 1328, right-benzyloxy benzylalcohol polystyrene resin).On the other hand, also can adopt the polymer support of the different intermediate chain L of having of other, for example, glass, cotton or Mierocrystalline cellulose.

The intermediate chain that is called L be with covalent linkage be connected on the polymeric carrier and allow with formula XI diamino acid between exist reversible class ester to combine, L keeps stable with combining of diamino monocarboxylic acid in the reaction of further carrying out, but at strong acid, for example, under the reaction conditions of pure trifluoroacetic acid, will the group that be positioned on the connection chain be discharged once more.Can the different steps in reaction carry out by discharging required formula I compound on the connection chain.

1.) for R ³With G be the compound of the formula I of hydrogen, after removing protecting group E, by α-sulfonamido-ω-carboxylic acid derivative being discharged with the trifluoroacetic acid process resin.

2.) if obtain R ³For hydrogen and G are R ⁶-C (O)-formula I compound, then using R ⁶After-C (O)-Y carries out acylation, as 1.) described in discharge this compound from resin.

3.) for R ³With G be R ⁶-C (O)-formula I compound, using acylation catalyst,, carry out behind two acylations completely just as 1. as Dimethylamino pyridine) described in carry out the release of compound.

4.) also allow to use suitable reagent by reaction sequence, for example, alkylogen, alkenyl halogen, chloro-formic ester, isocyanic ester, sulfonic acid or cyclic anhydride make in the formula I and define R ³With the group of the 2-13 of G be coupled on this point of reaction sequence with solid carrier bonded α-sulfoamido-omega-amino-carboxylic acid on.After dissociate the gained compound from carrier, corresponding substituted for example amine, urethane, urea, sulphonamide or acid amides have also just been obtained.

A. according to method e) the protected diamino monocarboxylic acid of formula XI is connected to general method on the solid carrier:

In 20 milliliters of anhydrous methylene chlorides, restrain Wang resin (Nova-Biochem with 2; Charge capacity 0.5 mmole/gram) 30 minutes (bottom has 50 milliliters PET washer (Syringe) of teflon filter) of swelling.After the filter solvents, in washer, be infused in the suitable ω-Teoc-α-Fmoc diamino monocarboxylic acid of 3.5mmol in about 10ml anhydrous methylene chloride (according to D.H.Rich etc., synthetic (Synthesis) 198; 346 preparations), 3.5mmol di-isopropyl carbodiimide and 0.5mmolN, the solution of N-Dimethylamino pyridine and at room temperature (RT) shake 16 hours (h).

After leaching reaction mixture, for several times and dry and weigh to measure output with the washed with dichloromethane resin.

B. the removal of α-Fmoc protecting group

In about 20ml anhydrous dimethyl formamide (DMF) in washer, the resin that will prepare in A. carries out swelling, leach solvent after, be piperidines/DMF solution-treated of 25% with it with concentration and at room temperature shook 45 minutes.The resin that filters the gained mixture and will be retained in the washer washs for several times with dry DMF.(can collect filtrate and whole washing lotion to measure the removal of Fmoc; Operation reference: the method (Solid Phase Peptide Synthesis-aPractical approach) of synthetic-a kind of practicality of solid-phase peptide, E.Atherton and R.C.Sheppard, IRL Press at OxfordUniversity Press 1989).

C. free alpha-amino sulfurization

Inclusion in the washer is assigned to fifty-fifty in 4 less washers that are equipped with the filter plate of packing into subsequently, and is used in different formula IV sulfonic acid (all using 1mmol under every kind of situation) in the 3ml dry DMF and the solution of diisopropylethylamine (all using 1mmol under every kind of situation) was handled and at room temperature shaken 24 hour.Wash reactant solution then off and use the DMF washing resin for several times.The removal of D.Teoc protecting group is used in 1 volumetric molar concentration N-tetrabutyl ammonium fluoride solution among the DMF (under every kind of situation with about 3 milliliters) and handles the resin for preparing and at room temperature shook 2 hours in C..Filtering reaction agent solution and with the washing of the resin that stays for several times with DMF.Then, the inclusion in 4 independent washers is assigned to separately in for example other 3 ready washers (all distributing under every kind of situation) by 1 * 0.05mmol and 2 * 0.1mmol.

E．

1: dissociate from carrier

Under every kind of situation with the inclusion of about 1/5 in the washer with methylene dichloride (about 10 milliliters) washing so that from the solid carrier compound that dissociates, dry and at room temperature shook 1 hour with about 1 milliliter solution of 95% trifluoroacetic acid, 2% water and 3% tri isopropyl silane.Evaporation is precipitated with ether by filtering solution in the washer.Filtration and drying solid resistates are with further purification.

2: use formula R ⁶The acylation that the carboxylic acid derivative of-C (O)-Y carries out

(amine with release is that benchmark is 1 equivalent to add 1 mole of acetic acid anhydride solution under every kind of situation in other washer; or be 3 equivalents during for two acylation) and the triethylamine of the respective amount in DMF and at room temperature shake and (for example can detect finishing of acylation with the Kaiser-Ninhydrin detection method in 16 hours; operation reference: the method (Solid PhasePeptide Synthesis-a practical approach) of synthetic-a kind of practicality of solid-phase peptide; E.Atherton and R.C.Sheppard, JRL Press at Oxford University Press 1989).

3: from the solid carrier formula X V compound that dissociates

With the resin of preparation in the washed with dichloromethane 2, drying is also at room temperature handled it 1 hour with trifluoroacetic acid/water/tri isopropyl silane of 95/2/3 described in 1.Described in 1, handle gained solution.

With known method itself, but, comprise its steric isomer by the physiologically acceptable salt of the salifiable formula I of shape compound.Use alkaline reagents, for example, oxyhydroxide, carbonate, supercarbonate, alkoxide and ammonia or organic bases, for example, Trimethylamine 99 or triethylamine, thanomin or trolamine or basic aminoacids, for example, Methionin, ornithine or arginine, carboxylic acid can form stable an alkali metal salt, alkaline earth salt or optional substituted ammonium.If the compound of formula I has basic group, then also can prepare stable acid salt with strong acid.For this reason, suitable acid is mineral acid and organic acid, for example, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, 4-bromo-benzene sulfonic acid, cyclohexyl thionamic acid, trifluoromethanesulfonic acid, acetate, oxalic acid, tartrate, succsinic acid or trifluoroacetic acid.

The invention still further relates to medicine, it comprise be suitable in the steric isomer of the physiologically acceptable salt of at least a formula I compound of significant quantity and/or formula I compound and/or possible formula I compound and the pharmacy with physiologically acceptable vehicle, additive and/or other active compound and auxiliary agent.

Consider the characteristic of medicine, compound of the present invention is applicable to that prevention and treatment all that increase diseases associated with the matrix degradation MMP activities in its evolution.Described disease comprises degenerative joint disease, for example, behind osteoarthropathy, spondylopathy, the articular trauma or damage of meniscus or kneecap or laceration of ligament after chondrolysis after the long period arthrodesis.And described disease also comprises the disease of reticular tissue, for example, and collagenosis, periodontal disease, wound healing disease and locomotive organ chronic disease, for example, acute or chronic arthritis, joint disease, myalgia and the bone metabolism disease relevant with inflammation, immunity or metabolism.Formula I compound also is applicable to treatment ulcer, atherosclerosis and narrow.Formula I compound also is applicable to formation, emaciation, apocleisis and the septic shock of treatment inflammation, cancer, metastases.

Medicine of the present invention generally is oral administration or administered parenterally.Also can rectum or transdermal administration.

The invention still further relates to the medicine production method, this method comprises uses that be suitable for and physiologically acceptable vehicle in the pharmacy, also use other suitable active compound, additive or auxiliary agent in the time of suitable, at least a formula I compound is mixed with suitable form of administration.

Suitable solid or pharmaceutical formulation type are, for example, the preparation of granula, pulvis, coated tablet, tablet, (little) capsule, suppository, syrup, juice agent, suspension agent, emulsion, drops, injection liquid and active compound slowly-releasing, in described preparation, use common auxiliary agent, for example, vehicle, disintegrating agent, binding agent, Drug coating, swelling agent, releasing agent or lubricant, spices, sweetener and solubilizing agent.The usual auxiliaries that may mention is magnesiumcarbonate, titanium dioxide, lactose, mannitol and other carbohydrate, talcum, milk protein, gelatin, starch, Mierocrystalline cellulose and derivative thereof, animal oil and vegetables oil, for example, Oils,glyceridic,cod-liver, sunflower seed oil, peanut oil or sesame oil, polyoxyethylene glycol and solvent, for example, aqua sterilisa and monohydroxy-alcohol or polyvalent alcohol such as glycerine.

Pharmaceutical preparation preferably is prepared and administration with dose unit, contains the formula I compound of the present invention of doses as each unit of active ingredient.This dosage is up to about 1000 milligrams in solid dosage unit such as tablet, capsule, coated tablet or suppository, but preferably approximately 50-300 milligram, in injection this dosage up to about 300 milligrams, but preferably approximately 10-100 milligram.

According to the effectiveness of formula I compound, the adult patient about 70 kilograms for body weight treats, and the suggestion per daily dose is about 20-1000 milligram, preferably approximately 100-500 milligram.Yet in some cases, higher or lower per daily dose also is fit to.Per daily dose can carry out disposable administration with one dosage unit form or several less dosage unit form, also can carry out multiple dosing with the dosage that separates in particular time interval.

At room temperature (RT) uses tetramethyl silane (TMS) to be internal standard substance as usual, record on the instrument of 200MHz Varian Associates, Inc. (US) 611 Hansen Way, Palo Alto, California 94303, U.S.A. (Firma Varian) ¹The H-NMR spectrum.Indicate solvent for use in all cases.As usual, measure final product with mass spectroscopy (FAB-, ESI-mass spectroscopy).Temperature numerical is meant centigradetemperature, and RT refers to room temperature (22-26 ℃).Used abbreviation or made an explanation or consistent with conventional usage.Embodiment 1 (R)-(4-chlordiphenyl sulphonyl) citrulline a) prepares according to method

The R-citrulline of 1.7g (9.7mmol) is dissolved among the NaOH of 19.4ml 0.5N, after adding 40ml THF, also slowly handles with 1 mole of 4-chlordiphenyl chloride solution of 9.7ml simultaneously at 0 ℃ of hydrogen-oxygen sodium solution with other 19.4ml.After stirring 16 hours (h) under the room temperature, reaction mixture is concentrated on rotary evaporator and handle with the ethyl acetate of 20ml.Use the 1MHCl acidifying, be settled out white precipitate, suction filtration is also dry.Output: 2.26g (theoretical yield 54%) ¹H-NMR (DMSO-d ₆): 1.2-1.7 (2m, 4H); 2.9 (dd, 2H); 3.7 (dd, 1H); 5.4 (s, 2H); 5.9 (t, 1H); 7.5-7.9 (2d, s, 8H); (8.2 d, 1H) embodiment 2 R-(4-chlordiphenyl sulphonyl)-Lys (Boc)-OH is according to method c) preparation

Press method described in the embodiment 1, carry out obtaining the reaction of (4-chlordiphenyl sulphonyl)-R-Lys (Boc)-OH by H-D-Lys (Boc)-OH of 5.15g (21mmol); By handling with ethyl acetate extraction and solvent evaporated under reduced pressure.Output: 9.3g (theoretical yield 89%) ¹H-NMR (DMSO-d ₆): 1.1-1.7 (m, 15H); 2.8 (dd, 2H); 3.7 (m, 1H); 6.7 (t, 1H); 7.6; 7.8 (2d, 4H); 7.9 (m, 4H); 8.2 (d, 1H) embodiment 3 R-(4-chlordiphenyl sulphonyl)-Lys-OH

Handle the compound 30 minutes that 4.97g (10mmol) obtains by embodiment 2 with the dichloromethane solution of the TFA of 15ml 50% concentration under the room temperature.Reduction vaporization obtains required compound.Output: 3.73g (theoretical yield 94%) ¹H-NMR (DMSO-d ₆): 1.1-1.7 (m, 6H), 2.8 (dd, 2H), 3.7 (m, 1H), 6.6 (m, 2H), 7.6; 7.8 (2d, 4H), 7.9 (m, 4H), 8.2 (d, 1H) embodiment 4 4-chlordiphenyl sulphonyl-N-ε-(5-methyl-isoxazole-4-carbonyl)-Lys-OH

0.15g (0.345mmol) (4-chlordiphenyl sulphonyl) Methionin that will obtain from embodiment 3 under the room temperature and 50.1mg (0.345mmol) 5-methyl-isoxazole-4-carbonyl chlorine and 86.9mg (1.035mmol) NaHCO the 5ml acetonitrile ₃Solution together stir 6h.Underpressure distillation solvent, resistates are dissolved in the ethyl acetate and sway this solution of extraction for several times under hydrochloric acid and neutrallty condition.In dry organic phase and after filtering siccative, this solution of reduction vaporization.Output: 0.11g (theoretical yield 63%) ¹H-NMR (DMSO-d ₆): 1.1-1.7 (mm, 7H); 2.6 (2s, 3H); 2.8; 3.1 (2m, 2H); 3.7 (m, 1H); 7.6; 7.8 (2d, 4H); 7.9 (m, 5H); 8.2 (d, 1H); 8.8 (2s, 1H) embodiment 5 (4-chlordiphenyl sulphonyl)-N-δ-(phenylsulfonamido-carbonyl)-Orn-OH is according to method d) preparation 5a. is obtained the reaction of 4-chlordiphenyl sulphonyl-Orn (Z)-OtBu by H-Orn (Z)-OtBu:

At 0 ℃, in 200mlTHF, make H-Orn (Z)-OtBu hydrochloride and 9.02g (31.4mmol) 4-chlordiphenyl SULPHURYL CHLORIDE and the reaction of 10.7ml (61.8mmol) diisopropylethylamine of 11.27g (31.4mmol).After 4 hours, evaporation under reduced pressure is dissolved in resistates in the ethyl acetate and under hydrochloric acid, neutrality and alkalescence (sodium carbonate solution) condition and sways extraction.Dry organic phase is evaporated to the dried required product that obtains.Output: 16.7g (theoretical yield 93%) ¹H-NMR (DMSO-d ₆): 1.5 (s, 9H); 1.3-1.5 (m, 4H); 2.9 (m, 2H); 3.6 (m, 1H); 5.0 (s, 2H); 7.3 (m, 6H); 7.5; 7.7 (2d, 4H); 7.8 (s, 4H); 8.2 (d, 1H) 5b. removes benzyloxycarbonyl protecting group (Z)

To be dissolved in from 16.7g (29mmol) product that 5a obtains methyl alcohol-ethyl acetate of 1: 1, under overpressure condition slightly with 4g10%Pd/C hydrogenation 16h.Leach catalyzer and reduction vaporization resistates.Output: 11.2g (theoretical yield 91%) ¹H-NMR: the characteristic signal (5.0 that does not have protecting group; 7.3).5c. obtain the reaction of benzene sulfonyl urea derivatives from 5b:

Compound of in N,N-dimethylacetamide, 0.5g (1.14mmol) being mentioned in 5b under the room temperature and the reaction of 0.23ml benzenesulfonyl isocyanate.Behind the 16h, except that desolvating and will from ethyl acetate, carrying out aftertreatment with ether by sedimentary crystalline product.The ether resistates is removed in decompression.Output: 0.53g (theoretical yield 75%) ¹H-NMR (DMSO-d ₆): 1.1 (s, 9H); 1.3-1.5 (m, 4H); 2.9 (m, 2H); 3.6 (m, 1H); 6.5 (t, 1H); 7.4-7.9 (mm, 14H); 8.2 (d.1H); 10.6 (s, 1H) removal of the protecting group of 5d. embodiment 5c:

Product 5c that 0.52g is above-mentioned stirred 45 minutes with the TFA of 5ml under the room temperature.TFA is removed in decompression; Resistates with toluene coevaporation twice, is suspended in it in ether and isolates product with white crystalline solid as described in example 5 above.Output: 0.4g (theoretical yield 84%) ¹H-NMR (DMSO-d ₆): 1.3-1.5 (m, 4H); 2.9 (m, 2H); 3.6 (m, 1H); 6.5 (t, 1H); 7.4-7.9 (mm, 14H); 8.2 (d, 1H); 10.6 (s, 1H) embodiment 6 2-(2R)-(4-chlordiphenyl sulfonamido)-5-phthalimido-valeric acid

2-(2R)-(4-chlordiphenyl sulfonamido)-5-amino-valerate hydrochlorate (according to method c) preparation with 0.7g (1.67mmol)) Tetra hydro Phthalic anhydride with 0.358g (2.42mmol) heats 1h at 150 ℃.After not having gas to produce, reaction mixture is dissolved in the methylene dichloride and through silica gel column chromatography separates (elutriant: ethyl acetate/petroleum ether/Glacial acetic acid 10/10/1).Output: 29.6mg (theoretical yield 34.6%) fusing point: 178 ℃ ¹H-NMR (DMSO-d ₆): 1.3-1.7 (m, 4H); 3.4-3.6 (t, 2H); 3.7-3.8 (m, 1H); 7.5 (d, 2H); 7.7 (d, 2H); 7.7-7.9 (m, 8H); 8.2 (d, 1H, NH); 12.6 (s, 1H, broad, OH) embodiment 7 2-(2R)-(4-chlordiphenyl sulfonamido)-5-(1-oxo-1,3-xylylenimine-2-yl)-valeric acid

2-(2R)-(4-chlordiphenyl sulfonamido)-5-amino-valerate hydrochlorate of 0.32g (0.76mmol) is dissolved in 30ml to be contained in the Glacial acetic acid of 0.186g (1.35mmol) phthalaldehyde and at 100 ℃ and stirs 3h.Cooling solution to 0 ℃, suction filtration are removed precipitation and are separated (elutriant: ethyl acetate/petroleum ether/Glacial acetic acid 10/10/2) through silica gel column chromatography.Output: 185mg (theoretical yield 52%) fusing point:＞234 ℃ (decomposition) ¹H-NMR (DMSO-d ₆): 1.4-1.7 (m, 4H); 3.1 (m, 1H); 3.4-3.6 (m, 2H); 4.4 (d, 1H); 4.5 (d, 1H); 6.9 (s, 1H, broad, OH); (7.4-7.9 m, 13H) embodiment 8 R-(4-biphenyl second sulphonyl)-Lys-OH is according to method e) preparation

Under these conditions, α-Fmoc-ε-Teoc-D-Lys-OH (0.18mmol) is coupled on 100mg (0.05mmol) the Wang resin, removes after α-Fmoc protecting group 4-biphenyl ethyl sulfonyl chloride/diisopropylethylamine reaction with 0.18mmol.Removing ε-Teoc protecting group with 1 mole of tetrabutylammonium/DMF solution and from the resin gained lysine derivative (trifluoroacetic acid (TFA)/H that dissociates ₂The O/ tri isopropyl silane, 95/2/3) after, evaporation gained solution.Wash solid residue with ether, be dissolved in the acetic acid aqueous solution of 10% concentration and lyophilize, obtain the amorphous white powdered title compound of 20mg.High pressure liquid chromatography (RP18; UV210nm): gradient 0-15 minute .B=5-70% (A=100%H ₂The O/0.1% trifluoroacetic acid; B=100% acetonitrile/0.1% trifluoroacetic acid) T _R=9.49 minutes. (95%) embodiment 9 R-(4-biphenyl second sulphonyl)-N-ε-ethanoyl-Lys-OH

As method as described in the embodiment 8, α-Fmoc-ε-Teoc-D-Methionin of 0.35mmol is coupled on the Wang resin of 200mg (0.10mmol), slough after the Fmoc protecting group and 4-biphenyl ethyl sulfonyl chloride/diisopropylethylamine reaction.After removing ε-Teoc protecting group, at room temperature gained lysine derivative and 0.15mmol diacetyl oxide/0.15mmol diisopropylethylamine are together stirred 15h.After thoroughly washing with DMF, methylene dichloride and resin drying (0.1mmHg) spent the night, with trifluoroacetic acid/H ₂The solution of O/ tri isopropyl silane=95/2/3 dissociates the gained compound and handle product with method the same the embodiment 8 from solid carrier.Obtain the amorphous white powdered compound of 40mg.High pressure liquid chromatography (RP18; UV210nm): gradient 0-15 minute .B=5-70% (A=100%H ₂The O/0.1% trifluoroacetic acid; B=100% acetonitrile/0.1% trifluoroacetic acid) T _R=10.39 minutes. (93%) use with the foregoing description in similar methods prepared the hereinafter compound of embodiment described in the table 1.

Table 1

The mensuration of the preparation of medicine embodiment human body stromelysin and neutrophil collagenase and the enzymatic activity of catalyst structure domain thereof

Method according to Ye etc. prepares stromelysin (MMP-3) and two kinds of enzymes of neutrophil collagenase (MMP-8) (biological chemistry (Biochemistry); 31 (1992) 11231-11235 pages or leaves).Be to measure enzymic activity or enzyme inhibitors effect, the enzyme solution that makes the buffered soln of 70 μ l and 10 μ l was with the methyl-sulphoxide aqueous solution incubation of the concentration 10% (V/V) of choosing the 10 μ l that contain enzyme inhibitors wantonly 15 minutes.After adding contains the methyl-sulphoxide aqueous solution of 10 μ l concentration 10% (V/V) of 1mmol/l matrix, with fluorescence spectrum (328nm (ex)/393nm (em)) monitoring enzyme reaction.

Enzymic activity is with delustring increased value/minute represent.Listed IC in the table 2 that mensuration is represented with inhibitor concentration ₅₀Value, this inhibitor concentration causes the inhibition of 50% enzyme in each case.

Buffered soln contains 0.05% Brij (Sigma, Deisenhofen, Germany) and tris/HCl, 0.1mol/lNaCl, the 0.01mol/lCaCl of 0.1mol/l ₂With 0.1mol/l piperazine-N, N '-two [2-ethanesulfonic acid] (pH=6.5).

Enzyme solution contains 5 μ g/ml according to one of enzymatic structure territory of preparation such as Ye; matrix solution contains fluorescence matrix (ayapanin-4-yl) ethanoyl-Pro-Leu-Gly-Leu-3-(2 ' of 1mmol/l; 4 '-dinitrophenyl)-and L-2,3-diamino propionyl-Ala-Arg-NH ₂(Bachem, Heidelberg, Germany).

Table 2

Embodiment	IC50MMP-3[×10 -9???Mol/l	IC50MMP-8[×10 - ??9Mol/l]
			????1	????50	????7
????2	????20	????6
			????4	????90	????20
????5	????50	????4
			????6	????5	????2
????7	????4	????2
			????9	????60	????70
????12	????60	????10
			????14	????5	????3
????15	????20	????8
			????16	????20	????10
????18	????70	????10
			????19	????20	????5
????20	????40	????7
			????21	????70	????20
????22	????80	????80
			????23	????40	????5
????24	????30	????5
			????25	????60	????10
????26	????60	????7
			????28	????40	????6
????29	????6	????3
			????30	????30	????5
????31	????5	????2
			????32	????6	????2
????34	????4	????2
			????36	????5	????2
????38	????5	????2
			????39	????20	????30
????41	????5	????2
			????42	????10	????3

????43	????40	????20
			????44	????30	????6
????45	????20	????4
			????46	????10	????3
????47	????10	????3
			????48	????20	????7
????49	????20	????3
			????50	????6	????2
????51	????20	????3
			????52	????20	????10
????53	????30	????6
			????55	????7	????3
????56	????10	????8
			????57	????40	????8
????59	????5	????1
			????60	????10	????10
????61	????6	????2
			????62	????5	????2
????63	????10	????2
			????64	????30	????2
????65	????20	????4
			????66	????10	????2
????69	????4	????2
			????70	????10	????3
????71	????10	????3
			????72	????20	????6
????73	????4	????2
			????74	????10	????3
????75	????20	????4
			????76	????40	????40
????77	????10	????2
			????79	????5	????2
????80	????10	????3
			????81	????30	????3

????82	????20	????4
			????83	????7	????3
????84	????20	????4
			????85	????20	????5
????86	????20	????4
			????87	????30	????10
????88	????10	????3
			????89	????30	????10
????90	????20	????5
			????91	????30	????5
????92	????40	????20
			????93	????20	????4
????94	????30	????5
			????95	????20	????4
????96	????20	????6
			????97	????20	????4
????98	????10	????3
			????99	????5	????2
????100	????4	????2
			????101	????40	????10
????102	????20	????5
			????103	????70	????60
????104	????30	????8
			????105	????40	????10
????106	????60	????30
			????107	????10	????4
????108	????20	????5
			????109	????20	????7
????110	????40	????20
			????111	????10	????3
????113	????5	????3
			????114	????5	????2
????115	????5	????3
			????116	????20	????4

????117	????9	????2
			????118	????10	????4
????120	????20	????4
			????122	????3	????2
????123	????60	????10
			????125	????10	????10
????126	????30	????10
			????127	????20	????3
????128	????5	????2
			????129	????10	????2
????130	????20	????4
			????131	????20	????5
????132	????30	????10
			????133	????5	????2
????134	????5	????2
			????135	????30	????8
????136	????10	????7
			????137	????20	????7
????138	????30	????10
			????139	????50	????20
????140	????60	????20
			????141	????10	????10
????142	????10	????4
			????143	????5	????2
????144	????10	????3
			????145	????10	????5
????146	????30	????3
			????151	????30	????10
????152	????60	????10
			????154	????30	????9
????155	????50	????10
			????156	????60	????20
????157	????40	????7
			????158	????7	????2

160	70	10
	161	40	4
162	50	6
168	40	20
170	20	10
171	30	10

Claims (8)

1. the compound of formula I

And/or the physiologically acceptable salt of the steric isomer of formula I compound and/or formula I compound, wherein R ¹Be 1. phenyl,

2. replaced or disubstituted phenyl by the following radicals list,

2.1. (the C of straight chain, ring-type or side chain ₁-C ₇) alkyl,

2．2．?-OH，

2.3. (C ₁-C ₆) alkyl-C (O)-O-,

2.4. (C ₁-C ₆) alkyl-O-,

2.5. (C ₁-C ₆) alkyl-O-(C ₁-C ₄) alkyl-O-,

2.6. halogen,

2．7．?-CF ₃，

2．8．?-CN，

2．9．?-NO ₂，

2．10．HO-C(O)-，

2.11. (C ₁-C ₆) alkyl-O-C (O)-,

2.12. the methylene radical dioxo,

2．13．R ⁴-(R ⁵)N-C(O)-，

2.14.R ⁴-(R ⁵) N-, or

3. unsubstituted or following by being selected from of replacing of the group described in the 2.1-2.14

3.1-3.16 the heteroaryl of group,

3.1. the pyrroles,

3.2. pyrazoles,

3.3. imidazoles,

3.4. triazole,

3.5. thiophene,

3.6. thiazole,

3.7. oxazole,

3.8. isoxazole,

3.9. pyridine,

3.10. pyrimidine,

3.11. indoles,

3.12. thionaphthene,

3.13. benzoglyoxaline,

3.14. benzoxazole,

3.15. benzothiazole or,

3.16. benzotriazole,

R ², R ⁴And R ⁵Identical or different, and be

1. hydrogen atom,

2. (C ₁-C ₆) alkyl-,

3.HO-C (O)-(C ₁-C ₆) alkyl-,

4. phenyl-(CH ₂) _o-, wherein phenyl is not substituted or is replaced or two replacement by the group list described in the 2.1-2.14, and o is an integer 0,1 or 2, or

Picolyl or

6.R ⁴And R ⁵Go up amino with ring and formed 4 yuan of-7 yuan of rings, wherein the optional quilt-O-of one of carbon atom ,-S-or-the NH-replacement,

R ³Identical or different with G, and be

1. hydrogen atom,

2. straight chain, side chain or cyclic (C ₁-C ₆) alkyl-,

3. (C ₂-C ₆) alkenyl-,

4. phenyl-(CH ₂) m-, wherein phenyl is not substituted or is replaced or two replacement by the group list described in the 2.1-2.14, and m is an integer 0,1,2 or 3,

5. heteroaryl-(CH ₂) m-, wherein heteroaryl in the 3.1-3.16 definition and/or replaced by the group described in 2.1-2.14, and m is integer 0,1,2 or 3,

6.R ⁶-C (O)-, R wherein ⁶Be

6.1 (C ₁-C ₆) alkyl-, wherein alkyl is not substituted or is replaced or quilt (C by the group described in the 2.1-2.14 ₃-C ₆) cycloalkyl substituted

6.2 (C ₃-C ₆) cycloalkyl, wherein cycloalkyl is not substituted or is replaced by the group described in the 2.1-2.14

6.3 (C ₂-C ₆) alkenyl, wherein alkenyl is not substituted or is replaced to three replacements by following radicals is single

6.3.1 phenyl, it is not substituted or is replaced to three replacements by the group list described in the 2.1-2.14

6.3.2 heteroaryl, its definition as 3.1-3.16 and heteroaryl is not substituted or by the group list described in the 2.1-2.14 replace to three replacements or

6.3.3 the group described in the 2.1-2.14,

6.4 phenyl-(CH ₂) m-, wherein phenyl is not substituted or is replaced to three replacement or quilt-O-CF by the group list described in the 2.1-2.14 ₃,-SO ₂-NH ₂,-NH-C (O)-CF ₃Or the benzyl list replace to three replace and-(CH ₂Optional quilt-the COOH of a hydrogen atom of)-group replaces, and m is an integer 0,1,2 or 3,

6.5 naphthyl,

6.6 adamantyl,

6.7 heteroaryl-(CH ₂) m-, wherein heteroaryl such as 3.1-3.16 define and/or are replaced by the group described in the 2.1-2.14, and m is an integer 0,1,2 or 3,

7.R ⁶-O-C (O)-, R wherein ⁶Define as above,

8.R ⁶-CH (NH ₂)-C (O)-, R wherein ⁶Define as above,

9.R ⁸-N (R ⁷)-C (O)-, wherein

R ⁸Be 9.1 hydrogen atoms,

9.2 (C ₁-C ₆) alkyl-,

9.3 phenyl-(CH ₂) m-, wherein phenyl is not substituted or is replaced by the group list described in the 2.1-2.14 or two replacement and m are integers 0,1,2 or 3, or

9.4 heteroaryl-(CH ₂) m-, wherein heteroaryl in the 3.1-3.16 definition and/or replaced by the group described in the 2.1-2.14, and m is integer 0,1,2 or 3,

R ⁷Be hydrogen atom or (C ₁-C ₆) alkyl, or wherein

R ⁷And R ⁸With the nitrogen-atoms that connects them formed a carbon atom quilt-O-in not being substituted or encircling of 4 yuan-7 yuan rings and this ring ,-S-or-the NH-replacement,

10.R ⁶-SO ₂-, R wherein ⁶Define as above,

11.R ⁶-SO ₂-N (R ⁷)-C (O)-, R wherein ⁶And R ⁷Define as above,

12.R ⁶-NH-C (=NR ⁷)-, be R wherein ⁶And R ⁷The definition as above or

12.1 (C ₁-C ₆) alkyl-C (O)-,

12.2-NO ₂Or

12.3-SO ₂-(CH ₂) _q-phenyl, wherein phenyl is not substituted or is replaced by the group list described in the 2.1-2.14 or two replacement and q are integers 0,1,2 or 3,

13.

Wherein m is an integer 0,1,2 or 3, and W is nitrogen, oxygen or sulphur atom, or R ³Formed following formula II a-II p ring with G with the nitrogen-atoms that is connected them,

Wherein r is integer 1 or 2, R ¹⁰Be as the group described in the 2.1-2.14, R ⁷A carbon atom with the m meaning in the same and formula II g ring is optional by oxygen, sulphur, SO ₂Or nitrogen-atoms replaces, and described nitrogen-atoms is not substituted or by R ²Replace,

A is an a) covalent linkage,

b)?-O-，

C)-CH=CH-or

d)?-C≡C-，

B be a)-(CH ₂) _m-, wherein the m implication is the same,

B)-O-(CH ₂) _q-, wherein q is an integer 1,2,3,4 or 5, or c)-CH=CH-,

D is-(CH ₂) _m-, wherein m be integer 1,2,3,4,5 or 6 and one of them chain carbon atom is optional is optionally substituted-NH-,-O-or-the S-atom replace and

X is-CH=CH-, Sauerstoffatom or sulphur atom.

2. according to the formula I compound of claim 1, wherein

R ¹Be 1. phenyl or

2. by the mono-substituted phenyl of following radicals,

2.1 halogen, particularly chlorine or fluorine or

2.2 R ⁴-(R ⁵) N-, wherein R ⁴And R ⁵Identical or different and be

2.2.1. (C ₁-C ₃) alkyl or

2.2.2.R ⁴And R ⁵With ring go up an amino carbon atom that has formed 5-6 unit ring and this ring choose wantonly quilt-O-or-the NH-replacement,

R ²Be hydrogen atom,

G and R ³Difference, wherein

G is hydrogen atom or (C ₁-C ₄) alkyl and

R ³Be 1. phenyl-(CH ₂) _m, wherein phenyl is not substituted or is replaced or two replacement by the group list described in the 2.1-2.14, and m is an integer 1,

2. heteroaryl-(CH ₂) _n-, wherein heteroaryl such as 3.10 definition and be unsubstituted or replaced that n is 0 by the group described in the 2.1-2.14,

3.R ⁶-C (O)-, wherein

R ⁶Be 3.1 (C ₁-C ₆) alkyl, wherein alkyl is straight chain, side chain or ring-type,

3.2 phenyl-(CH ₂) _r-wherein phenyl be not substituted replaced by the group list described in the 2.1-2.14 or two replacement and-(CH ₂Optional quilt-the COOH of a hydrogen atom of)-group replaces, and r is an integer 0,1,2 or 3, or

3.3 heteroaryl-(CH ₂) _o-, wherein heteroaryl defines as 3.1-3.15 and is unsubstituted or is substituted as described in the 2.1-2.14, and o is 0,1,2 or 3, or

4.R ⁸-N (R ⁷)-C (O)-, wherein

R ⁸And R ⁷Formed 5-6 unit ring and this ring is not substituted or a ring carbon atom is replaced by Sauerstoffatom with the nitrogen-atoms that connects them, or

R ³Formed formula II g ring with G with the nitrogen-atoms that is connected them, wherein r is 1,

A is a covalent linkage,

B is-(CH ₂) _p-, p is 0,

D is-(CH ₂) _q-, q be integer 2,3 or 4 and

X is-CH=CH-.

3. the compound of formula X And/or the physiologically acceptable salt of the steric isomer of formula X compound and/or formula X compound, wherein R ¹, A, X, B, R ², R ³Identical with the implication in the compound of D and claim 1 Chinese style I, R ⁹Be hydrogen atom, (C ₁-C ₆) alkyl, phenyl, succinimido, benzotriazole base or benzyl.

4. the method for or multinomial claimed formula I compound among the preparation claim 1-3, this method comprise,

If a), make the diamino monocarboxylic acid of formula III in the presence of the alkali or be suitably in the presence of the dehydrated reagent,

R wherein ², R ³, D is identical with the definition in the formula I with G, with the sulfonic acid reaction of formula IV,

R wherein ¹, A is identical with the definition in the formula I with B, Y be halogen atom, imidazolyl or-OR ⁹, R wherein ⁹Be hydrogen atom, (C ₁-C ₆) alkyl, phenyl, succinimido, benzotriazole base or benzyl, optionally be substituted and obtain formula I compound, or

B) under these conditions, make the diamino monocarboxylic acid ester of formula V,

R wherein ², R ³, D, G and R ⁹Implication is the same, with the reaction of formula IV sulfonic acid, obtains formula VI compound,

Preferably in the presence of alkali or acid, by removing R ⁹Formula VI compound is converted into formula I compound,

C) make the protected diamino monocarboxylic acid of formula VII,

R wherein ²The same with the D implication, E is the protecting group of amido functional group, with the reaction of formula IV sulfonic acid, obtains formula VIII compound,

By removing protecting group E formula VIII compound is converted into formula I compound by means of the suitable reagent that dissociates then, R wherein ¹, R ², A, B, D and X implication be the same, R ³With G be hydrogen atom, and if suitable then can in the presence of alkali, make above-mentioned formula I compound and R ³-Y reaction, wherein R ³Have above-mentioned implication with Y, obtain formula I compound,

R wherein ¹, R ², R ³, A, B and X has above-mentioned implication and G is a hydrogen atom, or

D) use and method c) identical method, will be as the protected diamino acid esters of the formula IX of initial compounds,

R wherein ², R ⁹, D and E have above-mentioned implication, is converted into the ester of formula X, Optional according to method b) ester of formula X is converted into corresponding formula I compound, or

E) make formula XI diamino monocarboxylic acid, Wherein D and E identical with the definition in the formula I and F are different N-amino protecting groups mutually, are connected gained formula XII compound with the polymer resin of formula PS through intermediate chain L by its carboxyl

If after selectivity is removed protecting group F in the presence of alkali or suitable in the presence of dehydrated reagent with formula IV sulfonic acid reaction,

R wherein ¹, A, B and Y have above-mentioned implication, obtains formula X III compound And make formula X III compound after removing protecting group E, in the presence of alkali or dehydrated reagent, react R with formula X IV carboxylic acid derivative ⁶-C (O)-Y (X IV) is R wherein ⁶Have above-mentioned implication with Y, obtain formula X V compound

And after solid support material dissociates, be translated into formula I compound, R wherein ¹, R ⁶, A, B, D and X have above-mentioned implication.

5. medicine, at least a that in claim 1-3, be suitable in one or multinomial claimed formula I compound and the pharmacy and physiologically acceptable vehicle, additive and/or other active compound and the auxiliary agent that comprise significant quantity.

6. one or multinomial claimed formula I compound increase purposes in the drug manufacture of diseases associated with the matrix degradation MMP activities being applicable to prevention and treating those among at least a claim 1-3 in its evolution.

7. according to the purposes of claim 6, described medicine is used for the treatment of degenerative joint disease, for example, osteoarthropathy, spondylopathy, behind the articular trauma or damage of meniscus or kneecap or laceration of ligament after chondrolysis after the long period arthrodesis, the disease of reticular tissue, for example, collagenosis, periodontal disease, wound healing disease and locomotive organ chronic disease, for example, with inflammation, acute or the chronic arthritis that immunity or metabolism are relevant, joint disease, myalgia and bone metabolism disease, ulcer, atherosclerosis and narrow and be used for the treatment of inflammation, cancer, the formation of metastases, emaciation, apocleisis and septic shock.

8. medicine production method; this method comprises uses that be suitable for and physiologically acceptable vehicle in the pharmacy; also use other suitable active compound, additive or auxiliary agent in the time of suitable, one or multinomial claimed formula I compound among at least a claim 1-3 are mixed with suitable form of administration.