DE19719428A1 - New N-sulphonyl-di:amino:carboxylic acid derivatives - Google Patents

Abstract

Phenyl-, thienyl- or furanyl-substituted N( alpha )-sulphonyl-diaminocarboxylic acid derivatives of formula (I) and their stereoisomers and salts are new. R1 = Ar or Het; Ar = phenyl (optionally substituted by 1 or 2 of 1-7C alkyl, 3-7C cycloalkyl, OH, alkyl-COO-, alkyl-O-, alkyl-O-(1-4C alkylene)-O-, halo, CF3, CN, NO2, COOH, alkyl-O-CO-, OCH2O, NR4R5CO and NR4R5); Het = pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, indolyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl or benzotriazolyl (all optionally substituted as for phenyl in Ar); R2,R4,R5 = H, alkyl, carboxyalkyl, Ar-(CH2)o- or picolyl; or NR4R5 = 4-7 membered ring, optionally having one C replaced by O, S or NH; o = 0-2; R3,G = H, alkyl, 3-6C cycloalkyl, 2-6C alkenyl, Ar-(CH2)m-, Het-(CH2)m-, R6CO-, R6OCO-, R6CH(NH2)CO-, NR7R8CO-, R6SO2-, R6SO2NR7CO-. R'6-NHC(=NR'7)- or a heterocyclic group of formula (i); or N(G)R3 = succinimido, maleimido, 2-oxo-pyrrolidino, 1H-1-pyrrolyl, 1H-1-imidazolyl or 2-oxo-2,3-dihydro-1H-1-pyrrolyl, all monosubstituted by R7; phthalimido or 2-oxo-1-indolinyl, both monosubstituted by R10 in the benzene ring; 1-indolyl; 1-benzimidazolyl; pyrrolidino, piperidino, perhydroazepino or perhydroazocino; or a group of formula (ii)-(vi); one ring C in (iv) is optionally replaced by O, S, SO2 or NR2; m = 0-3; r = 1 or 2; R6 = H, alkyl (optionally substituted as for Ar or by 3-6C cycloalkyl), 3-6C cycloalkyl (optionally substituted as for Ar), 2-6C alkenyl (optionally substituted as for Ar, or by Ar or Het (both optionally having a third substituent as above)); Ar-(CH2)m (in which Ar optionally has a third substituent as above and may further be substituted by OCF3, SO2NH2, NHCOCF3 or benzyl; and (CH2)m is optionally substituted by COOH), naphthyl, adamantyl or Het-(CH2)m-; R7 = H or alkyl; R8 = H, alkyl, Ar-(CH2)m- or Het-(CH2)m-; or NR7R8 = optionally substituted 4-7 membered ring, optionally having one C replaced by O, S or NH; R'6,R'7 = as R6,R7; or alkyl-CO-, NO2 or Ar-(CH2)m-SO2-; W = N, S or O; R10 = one or the optional substituents of Ar; A = direct bond, O, CH=CH or C?=C; B = (CH2)m, O(CH2)q or CH=CH; q = 1-5; D = (CH2)s, optionally with one C replaced by optionally substituted NH, O or S; s = 1-6; X = CH=CH, O or S; R9 = H; or can also be alkyl, phenyl, succinimidyl, benzotriazolyl or benzyl if G = H; unless specified otherwise alkyl moieties have 1-6C.

Description

The invention relates to new substituted diaminocarboxylic acids, processes for their Manufacture and use of the same as a medicine.

In the applications EP 0 606 046, WO 95/35276 and WO 96/27583 Arylsulfonaminohydroxamic acids and their effect as matrix metal proteinase Inhibitors described. Special arylsulfonamino carboxylic acids serve as Intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose Reductase inhibitors (EP 0 305 947). In the application EP 0 757 037 the Effect of sulfonylamino acid derivatives as metalloproteinase inhibitors described.

Furthermore, the arylsulfonyl group has proven to be an effective protecting group for the Proven amino function of α-aminocarboxylic acids (R. Roemmele, H. Rapoport, J. Org. Chem. 53 (1988) 2367-2371).

In the pursuit of effective compounds for the treatment of To find connective tissue diseases, it has now been found that the diaminocarboxylic acids according to the invention strong inhibitors of matrix Metalloproteinases are. The inhibition of stromelysin (matrix Metalloproteinase 3) and the neutrophil collagenase (MMP-8) special value laid, since both enzymes are important, especially in the breakdown of proteoglycans Components of the cartilage tissue, are significantly involved (A. J. Fosang et al. J. Clin. Invest. 98 (1996) 2292-2299).  

The invention therefore relates to the compound of the formula I.

and / or a stereoisomeric form of the compound of formula I and / or a physiologically acceptable salt of the compound of formula I, wherein
R ¹ for

• 1. phenyl,
• 2. phenyl which is mono- or disubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, straight, cyclic or branched,
  • 2.2. -OH,
  • 2.3. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.4. (C ₁ -C ₆ ) alkyl-O-,
  • 2.5. 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-OC (O) -,
  • 2.12. Methylenedioxo,
  • 2.13. R ⁴ - (R ⁵ ) NC (O) -,
  • 2.14. R ⁴ - (R ⁵ ) N-, or
• 3. a heteroaromatic from the following group 3.1. to 3.15., which is unsubstituted or substituted as described under 2.1 to 2.14,
  • 3.1. Pyrrole,
  • 3.2. Pyrazole, imidazole,
  • 3.4. Triazole,
  • 3.5. Thiophene,
  • 3.6. Thiazole,
  • 3.7. Oxazole,
  • 3.8. Isoxazole,
  • 3.9. Pyridine,
  • 3.10. Pyrimidine,
  • 3.11. Indole,
  • 3.12. Benzothiophene,
  • 3.13 benzimidazole,
  • 3.14. Benzoxazole or
  • 3.15. Benzothiazole stands,

R ²

, R ⁴

and R ⁵

are the same or different and for

• 1. hydrogen atom,
• 2. (C ₁ -C ₆ ) alkyl,
• 3. HO-C (O) - (C ₁ -C ₆ ) alkyl-,
• 4. Phenyl- (CH ₂ ) _o -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. until 2.14. is substituted and o represents the integer zero, 1 or 2, or
• 5. Picolyl stand or
• 6. R ⁴ and R ⁵ together with the ring-containing amino group form a 4- to 7-membered ring, in which one of the carbon atoms is optionally replaced by -O-, -S- or -NH-,

R ³

and G are the same or different and for

• 1. hydrogen atom,
• 2. (C ₁ -C ₆ ) alkyl-, in which alkyl is straight, branched or cyclic,
• 3. (C ₂ -C ₆ ) alkenyl,
• 4. Phenyl- (CH ₂ ) _m -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. until 2.14. is substituted and m is the integer zero, 1, 2 or 3,
• 5. Heteroaryl- (CH ₂ ) _m -, where heteroaryl as under 3.1. until 3.15. defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3,
• 6. R ⁶ -C (O) -, wherein
  R ⁶ for
  • 6.1 (C ₁ -C ₆ ) alkyl,
  • 6.2 (C ₃ -C ₆ ) alkenyl,
  • 6.3 Phenyl- (CH ₂ ) _m -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. until 2.14. is substituted and m represents the integer zero, 1, 2 or 3, or
  • 6.4 Heteraryl- (CH ₂ ) _m -, in which heteroaryl as under 3.1. until 3.15. defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3,
• 7. R ⁶ -OC (O) -, in which R ^{6 is} as defined above,
• 8. R ⁶ -CH (NH ₂ ) -C (O) -, in which R ^{6 is} as defined above,
• 9. R ⁸ -N (R ⁷ ) -C (O) -, wherein
  R ⁸ for
  • 9.1 hydrogen atom
  • 9.2 (C ₁ -C ₆ ) alkyl,
  • 9.3 Phenyl- (CH ₂ ) _m , in which phenyl is unsubstituted or one or two times as under 2.1. until 2.14. is substituted and m represents the integer zero, 1, 2 or 3, or
  • 9.4 Heteroaryl- (CH ₂ ) _m , where heteroaryl as under 3.1. until 3.15. is defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3, and in which
    R ^{7 represents} hydrogen atom or (C ₁ -C ₆ ) alkyl or wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring and the ring is unsubstituted or a carbon atom in the ring -O-, -S- or -NH- is replaced,
• 10. R ⁶ -SO ₂ -, in which R ⁶ is defined as mentioned above,
• 11. R ⁶ -SO ₂ -N (R ⁷ ) -C (O) -, in which R ⁶ and R ⁷ are defined as mentioned above,
• 12. R ⁶ -NH-C (= NR ⁷ ) -, wherein R ⁶ and R ^{7 are} as defined above or
  • 12.1 (C ₁ -C ₆ ) alkyl-C (O) -,
  • 12.2 NO ₂ or
  • 12.3 -SO ₂ - (CH ₂ ) _q -phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1 to 2.14 and q is the integer zero, 1, 2 or 3,
• 13. wherein m represents the integer zero, 1, 2 or 3 and W represents a nitrogen, oxygen or sulfur atom, or
  R ³ and G together with the nitrogen atom to which they are attached form a ring of the formula IIa to IIm
  form,
  where r is the integer 1 or 2, R ^{10 is} a radical as in 2.1. until 2.14. means, and R ⁷ and m have the meaning given above and, if appropriate, in the sub-formula XIV a carbon atom in the ring is replaced by oxygen, sulfur or nitrogen atom which is optionally substituted by R ² ,
  A for
  • a) a covalent bond,
  • b) -O-,
  • c) -CH = CH- or
  • d) -C∼C- stands,
  B for
  • a) - (CH ₂ ) _m -, where m has the meaning given above,
  • b) -O- (CH ₂ 2) _q , where q is the integer 1, 2, 3, 4 or 5, or
  • c) -CH = CH-,
  D denotes - (CH ₂ ) _m - and wherein m represents the integer 1, 2, 3, 4, 5 or 6 and optionally one of the chain C atoms by an optionally substituted -N-, -O- or - S atom is replaced, and
  X represents -CH = CH-, oxygen atom or sulfur atom.

The term "R ⁴ and R ⁵ together with the ring-shaped amino group form a 4- to 7-membered ring and / or one of the carbon atoms is replaced by -O-, -S- or -NH-" is understood to mean residues which are for example, derived from pyrrolidine, piperazine, morpholine, piperidine or thiomorpholine. The term "halogen" means fluorine, chlorine, bromine or iodine. The term "alkyl" or "alkenyl" is understood to mean hydrocarbon radicals whose carbon chain is straight-chain or branched. Cyclic alkyl radicals are, for example, 3- to 6-membered monocycles such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The alkenyl radicals can also contain a plurality of double bonds. The starting materials for the chemical reactions are known or can be easily prepared using methods known from the literature.

The invention further relates to a process for the preparation of the compound of the formula I and / or a stereoisomeric form of the compound of the formula I and / or a physiologically tolerable salt of the compound of the formula I, which is characterized in that

• a) a diaminocarboxylic acid of the formula III
  wherein R ² , R ³ , D and G are as defined in formula I, with a sulfonic acid derivative of formula IV
  wherein R ¹ , A and B are as defined in formula I and Y is a halogen atom, imidazoyl or -OR ⁹ , wherein R ^{9 is} hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, succinimidyl, benzotriazolyl or benzyl, optionally substituted represents, in the presence of a base or optionally a dehydrating agent to a compound of formula I, or
• b) a diaminocarboxylic acid ester of the formula V
  wherein R ² , R ³ , D, G and R ^{9 have} the meaning given above, with a sulfonic acid derivative of the formula IV under the abovementioned conditions to give a compound of the formula VI
  and the compound of the formula VI is converted into a compound of the formula I with elimination of the radical R ⁹ , preferably in the presence of a base or acid.
• c) the protected diaminocarboxylic acids of the formula VII,
  wherein R ² and D have the meanings given above and E represents a protective group of the amino function, with a sulfonic acid derivative of the formula IV to a compound of the formula VIII
  then the compound of the formula VIII is converted into a compound of the formula I with the splitting off of the protective group E using suitable cleaving reagents,
  wherein R ¹ , R ² , A, B, D and X have the meaning given above and R ³ and G represent a hydrogen atom, and this compound of formula I optionally with the help of R ³ -Y, in which R ³ and Y the have the meanings given above, in the presence of a base to give a compound of the formula I,
  wherein R ¹ , R ² , R ³ , A, B and X have the meanings given above and G represents a hydrogen atom, or
• d) in the event that protected diamino acid esters of the formula IX are used as starting compounds,
  wherein R ² , R ⁹ , D and E have the meaning given above, in the same way as described in process variant c) into the esters of the formula X,
  which are optionally converted into the corresponding compounds of the formula I according to process variant b), or
• e) a diaminocarboxylic acid of the formula XI,
  wherein D is as defined in formula I and E and F represent mutually different N-amino protective groups, with their carboxyl group coupled via an intermediate chain L to a polymeric resin of the general formula PS, a compound of the formula XII
  arises, which after selective removal of the protective group F with a sulfonic acid derivative of the formula IV
  where R ¹ , A, B and Y have the meanings given above, in the presence of a base or optionally a dehydrating agent to give a compound of the formula XIII
  and the compound of the formula XIII after splitting off the protective group E with a carboxylic acid derivative of the formula XIV
  R ⁶ -C (O) -Y (XIV)
  wherein R ⁶ and Y have the meaning given above, in the presence of a base or a dehydrating agent to give a compound of formula XV
  implements, and this after cleavage from the carrier material in a compound of formula I,
  wherein R ¹ , R ⁶ , A, B, D and X have the meaning given above.

The starting compounds of the formula III in which R ² , R ³ and G represent a hydrogen atom are preferably 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, orinitin, lysine and homolysin. If R ³ and G together with the amino function represent a guanidyl group, arginine is preferably used. If, as in process variant c), d) and e), the amino functions of the starting compounds of the formulas are provided with a protective group E or F, this selective amino group derivatization takes place according to methods as described in Houben-Weyl "Methods of Org. Chemistry", Volume 15/1 are described.

Suitable protective groups E and F are preferably the N-protective groups customary in peptide chemistry, for example protective groups of the urethane type, such as benzyloxycarbonyl (Z), t-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc) and allyloxycarbonyl (Aloc) or of acid amide type, in particular formyl, acetyl or trifluoroacetyl of alkyl type such as benzyl. The (trimethylsilyl) ethoxycarbonyl (Teoc) group (P. Kociénski, Protecting Groups, Thieme Verlag 1994) has also been particularly suitable for this. Many of the selectively derivatized compounds are also commercially available, so that the preparation of the compounds of the formula I according to the invention as described in process variant c) consists in the elimination of the side chain protective group E after the introduction of the sulfonic acid esters into the α-amino group , which may be followed by a multistage derivatization of the free amino group in the side chain. During this procedure, the carboxyl group can be in free form or in the form of an ester with the radical -OR ⁹ . In the event that the radical -OR ⁹ is a straight-chain (C ₁ -C ₃ ) alkyl radical, these esters of the general formula I can also be used in therapy in this form (prodrug).

In the event that R ^{9 is} a tert-butyl radical, the ester cleavage is preferably carried out on the last synthesis stage by known methods using HCl in diethyl ether or trifluoroacetic acid.

The starting products used to prepare the sulfonic acid derivatives of the formula IV are preferably sulfonic acids or their salts of the formula XVIa-XVIg, for example

where R ^{10 is} a phenyl 2.1. until 2.14. described rest means.

The arylsulfonic acids of the formulas XVIa and b are used preferably the one in Houben / Weyl "Methods of Organic Chemistry" Volume 9, p. 450-546 described sulfonation process with concentrated sulfuric acid if necessary in Presence of a catalyst, sulfur trioxide and its addition compounds or Halogen sulfonic acids such as chlorosulfonic acid. Especially in the case of the diphenyl ether Formula XVIb has the use of concentrated sulfuric acid and Acetic anhydride as solvent (see C.M. Suter, J. Am. Chem. Soc. 53 (1931) 1114), or the reaction with excess chlorosulfonic acid (J.P. Bassin, R. Cremlyn and F. Swinbourne; Phosphores, Sulfur and Silicon 72 (1992) 157) proven. Sulfonic acids according to the formulas XVIc, XVId, or XVIe can be in themselves produce in a known manner by using the corresponding arylalkyl halide Sulfites such as sodium sulfite or ammonium sulfite in aqueous or aqueous / alcoholic Reacts solution, the reaction in the presence of tetraorganoammonium salts how tetrabutylammonium chloride can be accelerated.

Sulfonic acid chlorides are particularly found as sulfonic acid derivatives according to formula IV Use. The corresponding sulfonic acids, also in Form of their salts such as sodium, ammonium or pyridinium salts in a known manner Phosphorus pentachloride or thionyl chloride without or in the presence of a solvent such as Phosphorus oxytrichloride or an inert solvent such as methylene chloride, cyclohexane  or chloroform in general at reaction temperatures from 20 ° C to Boiling point of the reaction medium used implemented.

The reaction of the sulfonic acid derivatives of the formula IV with the amino acids of the Formula III, V, VII or IX runs according to process variants a), b), c) or d) advantageous in the manner of the Schotten-Baumann reaction. Suitable as a base for this especially alkali hydroxides such as sodium hydroxide, but also alkali acetates, -hydrogen carbonates, -carbonates and amines. The reaction takes place in water or in a water-miscible or immiscible solvent such as tetrahydrofuran (THF), acetone, dioxane or acetonitrile instead, the reaction temperature in is generally kept from -10 ° C to 50 ° C. In the event that the reaction in anhydrous medium is carried out, especially tetrahydrofuran or Methylene chloride, acetonitrate or dioxane in the presence of a base such as triethylamine, N- Use methylmorpholine, N-ethyl or diisopropyletheramine, possibly in Presence of N, N-dimethylaminopyridine as a catalyst.

In another variant, the aminocarboxylic acids of the formula III, V, VII or IX first using a silylating agent such as bis-trimethylsilyltrifluoroacetamide (BSTFA) convert them into their silylated form and then add them with sulfonic acid derivatives Implement compounds of formula I.

The polymeric support designated PS in Formula XII is a cross-linked Polystyrene resin with a linker called intermediate chain L, known as Wang Harz (S.W. Wang, Joumal of the American Chemical Society (1973), 1328 p-benzyloxybenzyl alcohol polystyrene resin). Alternatively, other polymeric carriers such as glass, cotton or cellulose with various intermediate chains L. will.

The intermediate chain labeled L is covalently bound to the polymeric support and allows a reversible, ester-like bond with the diamino acid of the formula XI remains stable on the bound diaminocarboxylic acid during the further reaction; however under strongly acidic reaction conditions, e.g. B. pure trifluoroacetic acid, which on Group on the left releases again.  

The desired compound of general formula I can be released from the linker at various points in the reaction sequence.

• 1) In the event that a compound of general formula I in which R ³ and G are hydrogen, the α-sulfonylamino-ω-carboxylic acid derivative is released after the protective group E has been removed by treating the resin with trifluoroacetic acid.
• 2) If a compound of general formula I with R ³ equal to hydrogen atom and G equal to R ⁶ -C (O) - is to be obtained, the release of the compound from resin after simple acylation with R ⁶ -C (O) -Y, as in 1).
• 3) In the event that a compound of general formula I in which R ³ and G are R ⁶ -C (O) -, the cleavage is only after extensive diacylation with the aid of an acylation catalyst, for. B. dimethylaminopyridine, as in 1).
• 4) Furthermore, this procedure allows that the radicals defined in formula I 2 to 13 for R ³ and G using suitable reagents, eg. B. alkyl halides, alkenyl halides, chloroformates, isocyanates, sulfonic acid derivatives or cyclic anhydrides, can be coupled at this point in the reaction sequence to the α-sulfonyl-amido-ω-aminocarboxylic acid bound to the solid support. After the compounds obtained have been split off from the solid support, the corresponding substituted amines, urethanes, ureas, sulfonamides or amides are also obtained, for example.

A. General procedure for coupling protected diaminocarboxylic acids of the formula XI to the solid support according to procedure e)

2 g of Wang resin (Nova-Biochem; loading 0.5 mmol / g) are dried in 20 ml Allow dichloromethane to swell for 30 min (50 ml PET syringe with Teflon filter on Syringe base). After filtering the solvent, the syringe is filled with a solution  of 3.5 mmol of the corresponding ω-Teoc-α-Fomc-diaminocarboxylic acid (prepared after: D.H. Rich et al., Synthesis 198; 346), 3.5 mmol diisopropylcarbodiimide and 0.5 mmol N, N-dimethylaminopyridine and about 10 ml of dry dichloromethane Shaken for 16 hours (h) at room temperature (RT).

After filtering off the reaction mixture, the resin is washed several times with dichloromethane washed and dried and weighed to determine yield.

B. Cleavage of the α-Fmoc protecting group

The resin prepared as in A. is dried in the syringe in about 20 ml Dimethylformamide (DMF) allowed to swell and then, after filtering off the Solvent, mixed with a 25% piperidine / DMF solution and 45 minutes (min) shaken at RT. The resulting mixture is filtered and this in the syringe remaining resin washed several times with dry DMF. (Filtrate and all Wash solutions can be stored to determine Fmoc release; For implementation see: Solid Phase Peptide Synthesis - a practical approach, E. Atherton and R.C. Sheppard, IRL Press at Oxford University Press 1989).

C. Sulfonation of the Free α-Amino Group

The syringe content is now z. B. on 4 smaller, provided with inserted filter plate Syringes divided equally and with solutions from different Sulfonic acid derivatives of the formula IV (each 1 mmol) and diisopropylethylamine (each 1 mmol) in 3 ml of dry DMF and shaken at RT for 24 h. Then will washed out the reagent solution and washed the resin several times with DMF.

D. Teoc protecting group split off

The resin prepared as in C. is mixed with a molar N-tetrabutylammonium fluoride Solution in DMF (about 3 ml each) was added and shaken at RT for 2 hours. The Reagent solutions are filtered and the remaining resin several times with DMF  washed. The syringe content of each of the 4 individual syringes is now z. B. each additional 3 prepared syringes divided. (1 × 0.05 mmol and 2 × 0.1 mmol each).

E. 1: separation from the solid support

Approximately 1/5 of each syringe content is washed with dichloromethane (approximately 10 mol) to separate the substance from the solid carrier, dried and with approximately 1 ml of a solution of 95% trifluoroacetic acid, 2% H ₂ O and 3% triisopropylsilane for 1 hour at RT shaken. The solution filtered from the syringe is evaporated and precipitated with diethyl ether. The solid residue is filtered and dried for further purification.

2: Acylation with carboxylic acid derivatives of the formula R ⁶ -C (O) -Y

The remaining syringes are each filled with 1 molar solutions of acetic anhydride (1st Equivalent based on released amine, or 3 equivalents for bis-acylation) and appropriate amount of triethylamine in DMF and shaken at RT for 16 hours (Completeness of the acylation can be carried out e.g. by Kaiser-Ninhydrin test / implementation see: Solid Phase Peptide Synthesis - a practical approach, E. Atherton and R.C. Sheppard, JRL Press at Oxford University Press 1989).

3: Elimination of the compounds of formula XV from the solid support

The resins prepared as in 2: are, as described in 1:, washed with dichloromethane, dried and treated with trifluoroacetic acid / H ₂ O / triisopropylsilane 9512/3 for 1 h at RT. The solutions obtained are worked up as described in 1 :.

The production of physiologically compatible salts from those capable of salt formation Compounds of formula I, including their stereoisomeric forms, are given in well-known way. The carboxylic acids form with basic reagents such as Hydroxides, carbonates, hydrogen carbonates, alcoholates and ammonia or organic bases, for example trimethylamine or triethylamine, ethanolamine or Triethanolamine or also basic amino acids, such as lysine, omithine or arginine, stable alkali, alkaline earth or optionally substituted ammonium salts. If the Compounds of formulas I having basic groups can be with strong acids  also produce stable acid addition salts. Both inorganic and also organic acids such as hydrogen chloride, hydrogen bromide, sulfur, Phosphorus, methanesulfone, benzenesulfone, p-toluenesulfone, 4-bromobenzene-sulfone, Cyclohexylamido sulfone, trifluoromethyl sulfone, vinegar, oxal, wine, amber or Trifluoroacetic acid in question.

The invention also relates to pharmaceuticals characterized by an effective content on at least one compound of the formula I and / or one physiologically compatible salt of the compound of formula I and / or an optionally stereoisomeric form of the compound of formula I, together with a pharmaceutical suitable and physiologically compatible carrier, additive and / or others Active and auxiliary substances.

The pharmacological properties of the invention make them suitable Connections for the prophylaxis and therapy of all such diseases, on their course increased activity of matrix-degrading metalloproteinases is involved. To include degenerative joint diseases such as osteoarthritis, spondylosis, Cartilage shrinkage after joint trauma or long immobilization after Meniscus or patella injuries or ligament tears. It also includes Diseases of the connective tissue such as collagenosis, periodontal diseases, Wound healing disorders and chronic diseases of the musculoskeletal system such as inflammatory, immunological or metabolic acute and chronic Arthritis, arthropathy, myalgia and disorders of bone metabolism. Further the compounds of the formula I are suitable for the treatment of ulceration, Atherosclerosis and stenosis. The compounds of the formula I are also suitable for Treatment of inflammation, cancer, tumor metastasis, Cachexia, anorexia and septic shock.

The pharmaceuticals according to the invention are generally orally or parenterally administered. Rectal or transdermal application is also possible.

The invention also relates to a method for producing a medicament which characterized in that at least one compound of formula I with a  pharmaceutically suitable and physiologically compatible carriers and, if appropriate other suitable active ingredients, additives or auxiliaries in a suitable dosage form brings.

Suitable solid or pharmaceutical preparation forms are, for example, granules, Powders, coated tablets, tablets (micro) capsules, suppositories, syrups, juices, suspensions, Emulsions, drops or injectable solutions as well as preparations with protracted Active ingredient release, in the production of common auxiliaries such as carriers, explosives, Binding agents, coating agents, swelling agents, lubricants or lubricants, flavorings, Sweeteners and solubilizers. As frequently used Auxiliaries are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, Talc, milk protein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, Polyethylene glycol and solvents such as sterile water and one or polyhydric alcohols such as glycerin.

The pharmaceutical preparations are preferably in dosage units manufactured and administered, each unit as an active ingredient a specific Contains dose of the compound of formula I according to the invention. With fixed Dosage units such as tablets, capsules, coated tablets or suppositories, these can Dose up to about 1000 mg, but preferably about 50 to 300 mg and at Injection solutions in ampoule form up to about 300 mg, but preferably about 10 to 100 mg.

For the treatment of an adult patient weighing approximately 70 kg, depending on the effectiveness of the compounds according to formula I, daily doses of about 20 mg up to 1000 mg of active ingredient, preferably about 100 mg to 500 mg. In certain circumstances however, higher or lower daily doses may also be appropriate. The Administration of the daily dose can be done both as a single dose Dosage unit or several smaller dosage units as well Multiple doses are divided at certain intervals.  

¹ H-NMR spectra were recorded on a 200 MHz device from Varian, usually with tetramethylsilane (TMS) as the internal standard and at room temperature (RT). The solvents used are given in each case. End products are usually determined by mass spectroscopic methods (FAB-, ESI-MS). Temperatures in degrees Celsius, RT means room temperature (22-26 ° C). Abbreviations used are either explained or correspond to the usual conventions.

Example 1 (R) - (4-chlorobiphenylsulfonyl) citrulline Manufactured according to process variant a)

1.7 g (9.7 mmol) of R-citrulline are dissolved in 19.4 ml of 0.5 N NaOH and, after adding 40 ml of THF, slowly at 0 ° C. with a further 19.4 ml of sodium hydroxide solution and at the same time with 9.7 ml of a 1 molar solution of 4-chlorobiphenylsulfonic acid chloride are added. After 16 hours (h) of stirring at room temperature, the reaction mixture is concentrated on a rotary evaporator and 20 ml of ethyl acetate are added. When acidified with 1 M HCl, a white precipitate precipitates, which is filtered off and dried.
Yield: 2.26 g (54% of theory)
¹ H 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 (2 d, s, 8H); 8.2 (d, 1H)

Example 2 R- (4-Chlorobiphenylsulfonyl) -Lys (Boc) -OH Manufactured according to process variant c)

5.15 g (21 mmol) of HD-Lys (Boc) -OH is converted into (4-chlorobiphenylsulfonyl) -R-Lys (Boc) -OH as described in Example 1; however, working up is carried out by extraction with ethyl acetate and evaporation of the solvent under reduced pressure.
Yield: 9.3 g (89% of theory)
¹ H 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)

Example 3 R- (4-chlorobiphenylsulfonyl) -Lys-OH

4.97 g (10 mmol) of the compound from Example 2 are treated for 30 min at RT with 15 ml of 50% TFA in methylene chloride. Evaporation under reduced pressure gives the desired connection.
Yield: 3.73 g (94% of theory)
¹ H 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)

Example 4 4-Chlorobiphenylsulfonyl-N-epsilon- (5-methylisoxazole-4-carbonyl) -Lys-OH

0.15 g (0.345 mmol) of the (4-chlorobiphenylsulfonyl) lysine from Example 3 are mixed with 50.1 mg (0.345 mmol) of 5-methylisoxazole-4-carboxylic acid chloride and 86.9 mg (1.035 mmol) of NaHCO ₃ in 5 ml of acetonitrile Stirred at RT for 6 h. The solvent is then distilled off under reduced pressure, the residue is taken up in ethyl acetate and extracted repeatedly with hydrochloric acid and neutral. After the organic phase has dried and the desiccant has been filtered off, it is evaporated under reduced pressure.
Yield: 0.11 g (63% of theory)
¹ H NMR (DMSO-d ₆ ): 1.1-1.7 (mm, 7 H); 2.6 (2s, 3H); 2.8; 3.1 (2 m, 2H); 3.7 (m, 1H); 7.6; 7.8 (2 d, 4H); 7.9 (m, 5H); 8.2 (d, 1H); 8.8 (2 s, 1 h)

Example 5 (4-chlorobiphenylsulfonyl) -N-delta- (phenylsulfonylamino-carbonyl) -Orn-OH Manufactured according to process variant d) 5 a. Conversion of H-Orn (Z) -OtBu to 4-chlorobiphenylsulfonyl-Orn (Z) -OtBu

11.27 g (31.4 mmol) of H-Orn (Z) -OtBu hydrochloride are mixed with 9.02 g (31.4 mmol) of 4-chlorobiphenylsulfonic acid chloride and 10.7 ml (61.8 mmol) of diisopropylethylamine at 0 ° C implemented in 200 ml THF. After 4 hours, the mixture is evaporated under reduced pressure and the residue, after being taken up in ethyl acetate, is shaken out in hydrochloric acid, neutral and basic (sodium carbonate solution). After drying the organic phase, the desired product is obtained after evaporation to dryness.
Yield: 16.7 g (93% of theory)
¹ H 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. Removal of the benzyloxycarbonyl protective group (Z)

16.7 g (29 mmol) of the product from 5a is dissolved in methanol / ethyl acetate 1: 1 and hydrogenated with 4 g of 10% Pd / C under a slight excess pressure for 16 h. The catalyst is then filtered off and the residue is evaporated under reduced pressure.
Yield: 11.2 g (91% of theory)
¹ H-NMR: The characteristic signals of the protective group are missing (5.0; 7.3).

5c. Conversion of Sb to the phenylsulfonylurea derivative

0.5 g (1.14 mmol) of the compound mentioned under 5 b are reacted in dimethylacetamide at RT with 0.23 ml of phenylsulfonyl isocyanate. After 16 h the solvent is removed and the crystalline product which precipitates from ethyl acetate is aftertreated with ether. Diethyl ether residues are removed under reduced pressure.
Yield: 0.53 g (75% of theory)
¹ H 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)

5d. Removal of the protective group from Example 5c

0.52 g of the above-mentioned product 5 c is stirred with 5 ml of TFA for 45 min at RT. TFA is removed under reduced pressure; is coevaporated twice with toluene, the residue is suspended in diethyl ether and, as in Example 5, separated as a white crystalline solid.
Yield: 0.4 g (84% of theory)
¹ H 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)

Example 6 2- (2R) - (4-Chlorobiphenylsulfonylamino) -5-phthalimidoyl-pentanoic acid

0.7 g (1.67 mmol) of 2- (2R) - (4-chlorobiphenylsulfonylamino) -5-amino-pentanoic acid hydrochloride (prepared according to process variant c) are mixed with 0.358 g (2.42 mmol) of phthalic anhydride for 1 hour 150 ° C heated. After the evolution of gas has subsided, the reaction mixture is taken up in dichloromethane and chromatographed on a silica gel column (eluent: ethyl acetate / petroleum ether / glacial acetic acid 10/10/1).
Yield: 29.6 mg (34.6% of theory)
Melting point: 178 ° C
¹ H 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)

Example 7 2- (2R) - (4-chlorobiphenylsulfonylamino) -5- (1-oxo-1,3-dihydro-isoindol-2-yl) - pentanoic acid

0.32 g (0.76 mmol) of 2- (2R) - (4-chlorobiphenylsulfonylamino) -5-aminopentanoic acid hydrochloride are dissolved with 0.186 g (1.35 mmol) of phthaldialdehyde in 30 ml of glacial acetic acid and 3 hours at 100 ° C stirred. The solution is cooled to 0 ° C., the precipitate is filtered off and chromatographed on a silica gel column (eluent: ethyl acetate / petroleum ether / glacial acetic acid 10/10/2).
Yield: 185 mg (52% of theory)
Melting point: <234 ° C (decomposition)
¹ H 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)

Example 8 R- (4-Biphenylethylsulfonyl) -Lys-OH Manufactured according to process variant e)

a-Fmoc-e-Teoc-D-Lys-OH (0.18 mmol) is coupled to 100 mg (0.05 mmol) of Wang resin under the conditions mentioned above, and with 0 after the a-Fmoc protective group has been split off , 18 mmol of 4-biphenylethyl sulfonyl chloride / diisopropylethylamine. After splitting off the e-Teoc protective group with 1 molar tetrabutylammonium / DMF solution and splitting off the lysine derivative obtained from the resin (trifluoroacetic acid (TFA) / H ₂ O / triisopropylsilane, 95/2/3), the solution obtained is evaporated. The solid residue is washed with diethyl ether, dissolved in a 10% aqueous acetic acid, lyophilized to dryness and provides 20 mg of the title compound in the form of an amorphous white powder.
HPLC (RP 18; UV 210 nm): gradient 0-15 min. B = 5-70% (A = 100% H ₂ O / 0.1% trifluoroacetic acid; B = 100% acetonitrile / 0.1% trifluoroacetic acid)
T _R = 9.49 min. (95%)

Example 9 R- (4-Biphenylethylsulfonyl) -N-epsilon-acetyl-Lys-OH

As described in Example 8, 0.35 mmol of a-Fmoc-epsilon-Teoc-D-lysine are coupled to 200 mg (0.10 mmol) of Wang resin, Fmoc is deprotected and reacted with 4-biphenlethylsulfonyl chloride / diisopropylethylamine. After the e-Teoc protective group has been split off, the lysine derivative obtained is stirred for 15 hours at room temperature with 0.15 mmol of acetic anhydride / 0.15 mmol of diisopropylethylamine. After extensive washing with DMF; Dichloromethane and drying of the resin (0.1 Torr) overnight, the desired compound with trifluoroacetic acid / H ₂ O / triisopropylsilane = 95/2/3 is split off from the solid support and worked up as in Example 8. 40 mg of the compound are obtained as an amorphous white powder.
HPLC (RP 18; UV 210 nm): gradient 0-15 min. B = 5-70% (A = 100% H ₂ O / 0.1%
Trifluoroacetic acid; B = 100% acetonitrile / 0.1% trifluoroacetic acid)
T _R = 10.39 min (93%).

The examples given in Table 1 below are analogous to the previous ones Examples have been prepared.

Table 1

Pharmacological examples Representation and determination of the enzymatic activity of the catalytic domain of human stromelysin and neutrophil collagenase

The two enzymes - stromelysin (MMP-3) and neutrophil collagenase (MMP-8) - were presented according to Ye et al. (Biochemistry; 31 (1992) pages 11231-11235). For Measuring the enzyme activity or the enzyme inhibitor effect, 70 µl buffer solution, and 10 ul enzyme solution with 10 ul of a 10% (v / v) aqueous dimethyl sulfoxide solution, which optionally contains the enzyme inhibitor, incubated for 15 minutes. After encore of 10 ul of a 10% (v / v) aqueous dimethyl sulfoxide solution containing 1 mmol / l of Contains substrate, the enzyme reaction is monitored by fluorescence spectroscopy (328 nm (ex) / 393 nm (em)).

The enzyme activity is shown as the increase in extinction / minute. The IC ₅₀ values listed in Table 2 are determined as those inhibitor concentrations which in each case lead to 50% inhibition of the enzyme.

The buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) as well as 0.1 mol / l Tris / HCl, 0.1 mol / l NaCl, 0.01 mol / l CaCl ₂ and 0.1 mol / l piperazine -N, N'-bis [2-ethane sulfonic acid] (pH = 6.5).

The enzyme solution contains 5 µg / ml of one of the Ye et al. enzyme domains shown. The substrate solution contains 1 mmol / l of the fluorogenic substrate (7-methoxycoumarin-4-yl) acetyl-Pro-Leu-Gly-Leu-3- (2 ', 4'-dinitrophenyl) -L-2, 3-diaminopropionyl-Ala -Arg-NH ₂ (Bachem, Heidelberg, Germany).

Table 2

Claims (7)

1. Compound of formula I.
and / or a stereoisomeric form of the compound of the formula I and / or a physiologically tolerable salt of the compound of the formula I, where R ^{1 is}

• 1. phenyl,
• 2. phenyl which is mono- or disubstituted by
  • 2.1. (C ₁ -C ₆ ) alkyl, straight, cyclic or branched,
  • 2.2. -OH,
  • 2.3. (C ₁ -C ₆ ) alkyl-C (O) -O-,
  • 2.4. (C ₁ -C ₆ ) alkyl-O-,
  • 2.5. 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-OC (O) -,
  • 2.12. Methylenedioxo,
  • 2.13. R ⁴ - (R ⁵ ) NC (O) -,
  • 2.14. R ⁴ - (R ⁵ ) N-, or
• 3. a heteroaromatic from the following group 3.1. to 3.15., which is unsubstituted or substituted as described under 2.1 to 2.14,
  • 3.1. Pyrrole,
  • 3.2. Pyrazole, imidazole,
  • 3.4. Triazole,
  • 3.5. Thiophene,
  • 3.6. Thiazole,
  • 3.7. Oxazole,
  • 3.8. Isoxazole,
  • 3.9. Pyridine,
  • 3.10. Pyrimidine,
  • 3.11. Indole,
  • 3.12. Benzothiophene,
  • 3.13 benzimidazole,
  • 3.14. Benzoxazole or
  • 3.15. Benzothiazole stands,

R ² , R ⁴ and R ^{5 are the} same or different and are for

• 1. hydrogen atom,
• 2. (C ₁ -C ₆ ) alkyl,
• 3. HO-C (O) - (C ₁ -C ₆ ) alkyl-,
• 4. Phenyl- (CH ₂ ) ₀ -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. to 2.14 is substituted and o represents the integer zero, 1 or 2, or
• 5. Picolyl stand or
• 6. R ⁴ and R ⁵ together with the ring-containing amino group form a 4- to 7-membered ring, in which one of the carbon atoms is optionally replaced by -O-, -S- or -NH-,

R ³ and G are the same or different and are for

• 1. hydrogen atom,
• 2. (C ₁ -C ₆ ) alkyl-, in which alkyl is straight, branched or cyclic,
• 3. (C ₃ -C ₆ ) alkenyl,
• 4. Phenyl- (CH ₂ ) _m -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. until 2.14. is substituted and m is the integer zero, 1, 2 or 3,
• 5. Heteroaryl- (CH ₂ ) _m -, where heteroaryl as under 3.1. until 3.15.
• defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3,
• 6. R ⁶ -C (O) -, wherein R ^{6 is}
  • 6.1 (C ₁ -C ₆ ) alkyl,
  • 6.2 (C ₃ -C ₆ ) alkenyl,
  • 6.3 Phenyl- (CH ₂ ) _m -, in which phenyl is unsubstituted or mono- or disubstituted as under 2.1. until 2.14. is substituted and m represents the integer zero, 1, 2 or 3, or
  • 6.4 Heteraryl- (CH ₂ ) _m -, in which heteroaryl as under 3.1. until 3.15. defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3,
• 7. R ⁶ -OC (O) -, in which R ^{6 is} as defined above,
• 8. R ⁶ -CH (NH ₂ ) -C (O) -, in which R ^{6 is} as defined above,
• 9. R ⁸ -N (R ⁷ ) -C (O) -, wherein
  • R ⁸ for
  • 9.1 hydrogen atom
  • 9.2 (C ₁ -C ₆ ) alkyl,
  • 9.3 Phenyl- (CH ₂ ) _m , in which phenyl is unsubstituted or one or two times as under 2.1. until 2.14. is substituted and m represents the integer zero, 1, 2 or 3, or
  • 9.4 Heteroaryl- (CH ₂ ) _m , where heteroaryl as under 3.1. until 3.15. is defined and / or substituted as described under 2.1 to 2.14 and m represents the integer zero, 1, 2 or 3, and in which
  R ^{7 represents} hydrogen atom or (C ₁ -C ₆ ) alkyl or wherein R ⁷ and R ⁸ together with the nitrogen atom to which they are attached form a 4- to 7-membered ring and the ring is unsubstituted or a carbon atom in the ring -O- -S- or -NH- is replaced,
• 10. R ⁶ -SO ₂ -, in which R ⁶ is defined as mentioned above,
• 11. R ⁶ -SO ₂ -N (R ⁷ ) -C (O) -, in which R ⁶ and R ⁷ are defined as mentioned above,
• 12. R ⁶ -NH-C (= NR ⁷ ) -, wherein R ⁶ and R ^{7 are} as defined above or
  • 12.1 (C ₁ -C ₆ ) alkyl-C (O) -,
  • 12.2 NO ₂ or
  • 12.3 -SO ₂ - (CH ₂ ) _q -phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1 to 2.14 and q is the integer zero, 1, 2 or 3,
• 13. wherein m represents the integer zero, 1, 2 or 3 and W represents a nitrogen, oxygen or sulfur atom, or
  R ³ and G together with the nitrogen atom to which they are attached form a ring of the partial formula IIa to IIm,
  where r is the integer 1 or 2, R ^{10 is} a radical as in 2.1. until 2.14. means described and R ⁷ and m have the meaning given above and, if appropriate, in the sub-formula XIV a carbon atom in the ring is replaced by oxygen, sulfur or unsubstituted or substituted by R2,

A for

• a) a covalent bond,
• b) -O-,
• c) -CH = CH- or
• d) -C∼C- stands,

B for

• a) - (CH ₂ ) _m -, where m has the meaning given above,
• b) -O- (CH ₂ 2) _q , where q is the integer 1, 2, 3, 4 or 5, or
• c) -CH = CH-,

D is - (CH ₂ ) rn- and where m is the integer 1, 2, 3, 4, 5 or 6 and optionally one of the chain C atoms by an optionally substituted -N-, -O- or - S. Atom is replaced, and
X represents -CH = CH-, oxygen atom or sulfur atom. 2. Compound of formula X
and / or a stereoisomeric form of the compound of the formula X and / or a physiologically tolerable salt of the compound of the formula X, where R ¹ , A, X, ER ² , R ³ and D are those mentioned in the compound of the formula I according to claim 1 Have meaning and R ^{9 is} hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, succinimidyl, benzotriazolyl or benzyl. 3. A process for the preparation of the compound of formula I according to one or more of claims 1 or 2, characterized in that

• a) a diaminocarboxylic acid of the formula III
  wherein R ² , R ³ , D and G are as defined in formula I, with a sulfonic acid derivative of formula IV
  wherein R ¹ , A and B are as defined in formula I and Y is a halogen atom, imidazoyl or -OR ⁹ , wherein R ^{9 is} hydrogen, (C ₁ -C ₆ ) alkyl, phenyl, succinimidyl, benzotriazolyl or benzyl, optionally substituted represents
  in the presence of a base or optionally a dehydrating agent to give a compound of formula I, or
• b) a diaminocarboxylic acid ester of the formula V
  wherein R ² , R ³ , D, G and R ^{9 have} the meaning given above, with a sulfonic acid derivative of the formula IV under the abovementioned conditions to give a compound of the formula VI
  and the compound of the formula VI is converted into a compound of the formula I, with elimination of the radical R ⁹ , preferably in the presence of a base or acid, or
• c) the protected diaminocarboxylic acids of the formula VII,
  wherein R ² and D have the meanings given above and E represents a protective group of the amino function, with a sulfonic acid derivative of the formula IV to a compound of the formula VIII
  then the compound of the formula VIII is converted into a compound of the formula I with the splitting off of the protective group E using suitable cleaving reagents,
  wherein R ¹ , R ² , A, B, D and X have the meaning given above and R ³ and G represent a hydrogen atom, and this compound of formula I optionally with the aid of R ³ -Y, wherein R ³ and Y have the above have the meanings given, in the presence of a base to give a compound of the formula I,
  wherein R ¹ , R ² , R ³ , A, B and X have the meanings given above and G represents a hydrogen atom, or
• d) in the event that protected diamino acid esters of the formula IX are used as starting compounds,
  wherein R ² , R ⁹ , D and E have the meaning given above, in the same way as described in process variant c) into the esters of the formula X,
  which are optionally converted into the corresponding compounds of the formula I according to process variant b), or
• e) a diaminocarboxylic acid of the formula XI,
  wherein D is as defined in formula I and E and F are mutually different N-amino protecting groups, with their carboxyl group coupled via an intermediate chain L to a polymeric resin of the general formula PS, a compound of the formula XII
  arises, which after selective removal of the protective group F with a sulfonic acid derivative of the formula IV
  where R ¹ , A, B and Y have the meanings given above, in the presence of a base or optionally a dehydrating agent to give a compound of the formula XIII
  and the compound of the formula XIII after splitting off the protective group E with a carboxylic acid derivative of the formula XIV
  R ⁶ -C (O) -Y (XIV)
  wherein R ⁶ and Y have the meaning given above, in the presence of a base or a dehydrating agent to give a compound of formula XV
  implements, and this after cleavage from the carrier material in a compound of formula I,
  wherein R ¹ , R ⁶ , A, B, D or X have the meaning given above.

4. Medicinal product, characterized by an effective content of at least one Compound of formula I according to one or more of claims 1 or 2 together with a pharmaceutically suitable and physiological compatible carrier, additive and / or other active substances and auxiliaries. 5. Use of at least one compound of the formula I according to one or more of claims 1 or 2, for the manufacture of medicaments for Prophylaxis and therapy of diseases, on the course of which an intensified Activity of matrix-degrading metalloproteinases is involved. 6. Use according to claim 5, for the treatment of degenerative Joint diseases such as osteoarthritis, spondylosis, cartilage loss after Articular trauma or prolonged immobilization after meniscus or Patella injuries or torn ligaments, diseases of the connective tissue such as Collagenosis, periodontal diseases, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, acute and chronic arthritis caused by immunology or metabolism, Arthropathy, myalgia and disorders of bone metabolism, the Ulceration, atherosclerosis and stenosis, but also for the treatment of Inflammation, cancer, tumor metastasis, cachexia, Anorexia and septic shock.   7. A process for the manufacture of a medicament, characterized in that at least one compound of the formula I according to one or more of the Claims 1 or 2 with a pharmaceutically suitable and physiological compatible carrier and, if appropriate, other suitable active, additional or Brings excipients in a suitable dosage form.