ZA200100277B

ZA200100277B - Phosphinous and phosphonic acid derivatives used as medicaments.

Info

Publication number: ZA200100277B
Application number: ZA200100277A
Authority: ZA
Inventors: Manfred Schudok; Wilfried Schwab; Gerhard Zoller; Eckart Bartnik; Frank Buettner; Klaus-Ulrick Weithmann
Original assignee: Aventis Pharma Gmbh
Priority date: 1998-07-16
Filing date: 2001-01-10
Publication date: 2002-07-10
Also published as: DE19831980A1

Description

®

Description

PHOSPHINIC AND PHOSPHONIC ACID DERIVATIVES USED AS

PHARMACEUTICALS

/

The invention relates to novel sulfonylaminophosphinic and -phosphonic acid derivatives, to processes for their preparation and to their use as pharmaceuticals.

The applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonaminohydroxamic acids and their action as matrix metallo- proteinase inhibitors. Specific arylsulfonaminocarboxylic acids are used as intermediates for preparing thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). The application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metallo- proteinase inhibitors. The arylsulfonyl group has furthermore proved to be an effective protective group of the amino function of a-aminocarboxylic acids (R. Roemmele, H. Rapoport, J. Org. Chem. 53 (1988) 2367-2371).

In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminophosphinic and -phosphonic acid derivatives according to the invention are strong inhibitors of metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3), of neutrophil collagenase (MMP-8) and of aggrecanase, since these enzymes are involved to a considerable extent in the degradation of proteoglycans, as important constituents of the cartilaginous tissue (A.J. Fosang et al. J. Clin,

Invest. 98 (1996) 2292-2299).

The pathological loss of aggrecan, the main proteoglycan of the cartilage, includes proteolytic cleavages in its interglobular domain. Amino acid sequence analyses of proteoglycan metabolites, isolated from the synovial fluid of patients who are suffering from injury to a joint, from osteoarthrosis or from an inflammatory joint condition, showed that a proteolytic cleavage preferably takes place between the amino acids Giu® 3 and A>" in the interglobular domain of human aggrecan (Lohmander et al. Arthritis

Rheum. 36, (1993), 1214-1222). Until now, it was not yet possible to iden- tify the proteolytic activity which is responsible for this cleavage. It is desig- nated as “aggrecanase” and can be inciuded in the metaiioproteinase family.

®

The detection of the expression of MT1-MMP in human cartilaginous tissue for the first time (Bittner et al. Arthritis Rheum. 40, 1997, 704-709), combined with the proof that the catalytic domain of this enzyme cleaves at the “aggrecanase” cleavage site in the recombinant aggrecan fusion protein rAggimut (Buttner et al. Biochem. J. 333, 1998, 159-165), led to the testing of the strong matrix metalloproteinase inhibitors described here with respect to their action against an “aggrecanase” activity. It was possible here to show, using various assay systems, that the sulfonylaminophos- phinic and -phosphonic acid derivatives are also strong inhibitors for the “aggrecanase” activity.

The invention therefore relates to the compound of the formula

R? 3 0 rr LT Y? 0)

X N

: R Y? t and/or a stereoisomeric form of the compound of the formula ! and/or a physiologically acceptable salt of the compound of the formula I, where

R’ is 1. phenyl, 2. phenyl which is mono- or disubstituted by 2.1. (C1-Cg)-alkyl, which is linear, cyclic or branched, 2.2. hydroxyl, 2.3. (C1-Cg)-alkyl-C(O)-O-, 2.4. (C4-Cg)-alkyl-O-, 2.5. (Cq-Cg)-alkyl-O-(C1-C4)-alkyl-O-, 2.6. halogen, 2.7. -CFj3, 2.8. -CN, 2.9. -NOgo, 2.10. HO-C(O)-, 2.11. (C4-Cg)-alkyl-O-C(O)-, 2.12. methylenedioxo, 2.13. R*(R°)N-C(0)-, 2.14. R*(RON- or 2.15. heteroaromatics from the group 3.1. to 3.16,

3. a heteroaromatic from the following group 3.1. to 3.16., which is unsubstituted or substituted as described under 2.1. to 2.15,, 3.1. pyrrole, 3.2. pyrazole, 3.3. imidazole, 3.4. triazole, 3.5. thiophene, 3.6. thiazole, : 3.7. oxazole, 3.8. isoxazole, 3.9. pyridine, 3.10. pyrimidine, 3.11. pyrrolidine, 3.12. indole, 3.13. benzothiophene, 3.14. benzimidazole, 3.15. benzoxazole or 3.16. benzothiazole, or 4. -O-(C1-Cg)-alkyl,

RZ R4 and R° are identical or different and are 1. a hydrogen atom, 2. (C1-Ceg)-alkyl-, 3. HO-C(0)-(C1-Cg)-alkyl-, 4. phenyl-(CH2)n-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. or is substituted by -NH-C(0)-(C1-C3)-alky! and n is the integer zero, 1 or 2, or 5. picolyl or 6. R* and R® together with the ring amino group form a 4- to 7-membered ring in which one of the carbon atoms is optionally replaced by -O-, -S- or -NH- or two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical,

R and R® are identical or different and are 1. a hydrogen atom, 2. (C1-C1p)-alkyl-, in which alkyl is unsubstituted, and/or a hydrogen atom of the alkyl radical is replaced by -OH, : 3. (C2-C10)-alkenyl-, in which alkenyl is linear or branched,

4. R°-O-(Cy-Cg)-alkyl-, 5. R%-S(O)n-(C1-Ce)-alkyl-, where n has the abovementioned meaning, 6. R°-S(0)(=NH)-(C1-Cg)-alkyl-, 7. a radical of the formula Ilo

Yam N (CH), I—$ —(C;-Co — Alky— (lio) —w in which n is the integer zero, 1 or 2 and W is a nitrogen, oxygen or sulfur atom, 8. phenyl-(CH2)m-, in which m is the integer zero, 1, 2, 3, 4, 5 or 6 and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and phenyl is unsubstituted or mono- or disubstituted by 8.1. as described under 2.1. to 2.15. 8.2. -O-(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2, 3, 4, 5 or 6, 8.3. -C(O)-(CH2)m-phenyl, in which phenyl is as defined under 8.2., 9. heteroaryl-(CH2)m-, in which heteroaryl is as defined under 3.1. to 3.16, m is as defined above and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and heteroaryl is unsubstituted or mono- or disubstituted by 9.1. as described under 2.1. to 2.15., 9.2. -CH(O), 9.3. -SO2-phenyl, in which phenyl is unsubstituted or as defined under 8.2. or 8.3,, 9.4. -O-(CH2)m-phenyl, 10. -(CH2)m-P(O)(OH)-(C1-Cg)-alkyl, in which m is as defined above, 11. a characteristic residue of an amino acid or 12. R®-C(0)-(Co-Ce)-alkyl-, in which B® is 1. a hydrogen atom,

2. (C1-Ce)-alkyl-, in which alkyl is linear, branched or cyclic, 3. phenyl, in which phenyl is unsubstituted or substituted as described under 2.1. to 2.15., 5 4. heteroaryl, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. or substituted by -(C1-Cg4)-alkyl-COOH, 5. -OH, 6. -OR%, in which R° has the abovementioned meaning, 7. -NR*(R%), in which R* and R° are as defined above, 8. heteroaryl-(CH2)m-NH-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is as defined above, 9. RY*“(RON-NH-, in which R* and R® are as defined above, 10. HO-C(O)-CH(R®)-NH-, in which R> is as defined above, 13. -(CHg)p-N(RI(R'®), in which p is an integer zero, 1, 2, 3 or 4, in which R® and R'° are identical or different and are 1. a hydrogen atom, 2. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3, 3. R"-C(0)-, in which R is 3.1. (C4-Cg)-akkyl-, 3.2. (C2-Cg)-alkenyl-, 3.3. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3, or 3.4. heteroaryl-(CH2)m-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3, 4, R*-0-C(0)-, in which R" is defined as mentioned above, 5. R“CH(NHp)-C(O)-, in which R* is defined as mentioned above,

® 6. R°-N(R')-C(O)-, in which R® is 6.1. a hydrogen atom, 6.2. (C1-Cg)-alkyl-, 6.3. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1,2 or 3, or 6.4. heteroaryl-(CH2)m-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3 and in which R’ is a hydrogen atom or (C1-Cg)-alkyl- or in which R’ and R® 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 is replaced by -O-, -S- or -NH-, 7. R*-S0Oo, in which R™ is defined as mentioned above, 8. R“NH-C(=NR’)-, in which R* and R’ are defined as mentioned above or are 8.1. (C4-Cg)-alkyl-C(O)-, 8.2. -NOoor 8.3. -SO2-(CHz)qg-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and q is the integer zero, 1, 2 or 3, 9. -S02-(CHz)qg-phenyl-phenyl, in which phenyl is unsub- stituted or mono- or disubstituted as described under 2.1.10 2.15. and q is the integer zero, 1, 2 or 3, or 10. the radical of the formula lip (CH) ON 4 J (lp) wW

I in which m is the integer zero, 1, 2 or 3 and W is a nitrogen atom, or

Rr® and RC together with the nitrogen atom to which they are attached form a ring of the subformula lla to lin

0 0} o} 0)

RL A

Sas : o£ D7 YT N— RL N—

YY o} 0} fo} (la) (ib) (ic) (Id) rR’ (o} RM o lo] .

NA 9

N - r7 N— N— RL: N == a Tr o} lo} Le (Ite) ih) Me) (itn)

RL ee. RINT N—. No = CRT NTT N JE \ bo (Hi) (Hj) (lik) {I))

Oo ya

Ls (CK), N—/ (lin) —N Vi (tm) or 0) where r is the integer 1 or 2, R' is a radical as described under 2.1. to 2.15., and R’ and m have the abovementioned meaning, 14. -OH, 15. =Oor 16. (C1-Ce)-alkyl-, or a -C(R)(R%)- radical for, -NH- or -NR-, in which RZ is as defined above, and tis an integer 1,2, 3 or 4, or

Rr and R> together form a ring with an exocyclic phosphinic or phosphonic acid radical of the subformuila li

®

A

N P Of an i

Oo in which r is the integer zero, 1, 2 or 3 and/or one of the carbon atoms in the ring is replaced by -O-, -S- or -(R’)N-, in which

Rr’ is 1. a hydrogen atom, . 2. (C1-Cg)-alkyl, 3. phenyl, in which phenyl is unsubstituted or substituted as described under 2.1. to 2.15, 4, benzyl, in which benzyl is unsubstituted or substituted as described under 2.1. to 2.15., or 5. RZN-C(=NH)-, where Rr? has the abovementioned meaning, and/or the carbon atoms in the ring of the subformula Il are mono- or polysubstituted by (C1-Cg)-alkyl-, phenyl-, phenyl-(CH2)m- or HO-,

Uis -S02- or -CO-, vy! and v2 are identical or different and independently of one another are a) a hydrogen atom, b) -OH,

C) -(C1-Cy)-alkyl, in which alkyl is linear or branched, d) -(CH2)y-phenyl, in which u is zero or 1, e) -O-(C1-Ca)-alkyl, in which alkyl is linear or branched, or f) -O-(CH2)s-phenyl, in which s is zero or 1,

Ais a) a covalent bond, b) -O-,

C) -CH=CH- or d) -C=C-,

Bis a) -(CH2)m-, in which m has the abovementioned meaning, b) -O-(CH2)p, in which p is an integer from 1 to 5, or

C) -CH=CH-, and

Xis -CH=CH-, an oxygen atom or a sulfur atom.

Preference is given to a compound of the formula | where

R' is 1. phenyl or 2. phenyl which is monosubstituted by

®

A WO 00/04030 PCT/EP99/04740 2.1. (Cq-Cg)-alkyl-, in which alkyl is linear, cyclic or branched, 22. -OH, 2.3. -C(O)-OH, 2.4. -O-(C1-Cg)-alkyl, 2.5. pyrrolidone, 2.6. halogen or 2.7. -CFg, or 3. -O-(C1-Cg)-alkyl, :

Rr? R* and R® are identical or different and are a hydrogen atom or (C1-

Ce)-alkyl-,

Ris a hydrogen atom,

R® is 1. (C1-Ce)-alkyl-, in which alkyl is linear, branched or cyclic, and/or in which a hydrogen atom of the alkyl radical is replaced by -OH, ) 2. R™-S(O)n-(C1-Cg)-alkyl-, in which R™ is (C4-Cg)-alkyl- or phenyl-(CH2)n- and n is the integer zero or 1, 3. -(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and m is the integer 1, 2, 3, 4 or 5, 4. -(CH2)m-heteroaryl, in which heteroaryl is as defined under 3.3, 3.5, 3.6., 3.9. or 3.11 and/or is substituted as described under 2.1. to 2.15 and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and m is the integer 1, 2, 3 or 4, 5. a characteristic residue of an amino acid or 6. -(CHa)p-NRIR'), in which p is an integer zero, 1 or 2, in which R® and R'C are identical or different and are a hydrogen atom or -SO2-(CHz)g-phenyl-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and q is the integer zero, 1, 2 or 3, or 7. R%-C(O)- in which R%is 7.1. -OH, 7.2. R%0-, in which RZ is as defined above, or 7.3. R*-(RO)N-, in which r* and R® are as defined above, 8. a hydrogen atom,

® 9. -OH, 10. =Oor 11. (C1-Cg)-alkyl-, or a -C(R)(R%)- radical for, -NH- or -NR>-, in which R? is as defined above, and tis aninteger1, 2, 3or4,

Uis -SOo-, v'is -OH, . Y? is a) -O-(C1-Cy)-alkyl, in which alkyl is linear or branched, b) -OH or

Cc) -(C1-C4)-alkyl, in which alkyl is linear or branched,

Ais a covalent bond or -O-,

Bis a covalent bond or -(C1-C4)-alkyl and

Xis -CH=CH.

Particular preference is given to a compound of the formula | where

R' is 1. phenyl which is monosubstituted by halogen,

R? is a hydrogen atom,

Ris a hydrogen atom,

Ris 1. (Cy-Ca)-alkyl-, 2. -phenyl, in which phenyl is unsubstituted or mono- or disubstituted by -CF3 or -COOH, 3. a hydrogen atom, 4. -OH or 5. -NH-SO2-phenyl-phenyl, in which phenyl is unsubstituted or substituted by halogen, tis an integer 1, 2, 3 or 4,

Uis -SO02-, vy! and Y? is -OH or -O-CHg,

Ais acovalentbond,

Bis acovalent bond or -(CHo2)o-, in whichois 1,2 or 3 and

Xis -CH=CH-.

Particularly preferred compounds are ( R )-[1-(4 -chlorobiphenyl-4-sulfonyl- amino)-2-methylpropyl]phosphonic acid, dimethyl [3-(4'-chlorobiphenyl- 4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethylphenyl)propyl]phosphonate or [1-(4'-chlorobiphenyl-4-sulfonylamino)-3-methylbutyl]phosphonic acid.

®

The expression Rr and R° together with the ring 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 as meaning radicals which are derived, for example, from azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, indoline, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term "halogen" is understood as meaning fluorine, chlorine, bromine or iodine. The term "alkyl" or "alkenyl" is understood as meaning hydrocarbon radicals whose hydro- carbon chains are straight-chain or branched. Cyclic alkyl radicals are, for example, 3- to 6-membered monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The alkenyl. radicals can furthermore also contain a number of double bonds.

The general structural formula of a-amino acids is as follows: "E—coon

HN

The a-amino acids differ from one another by the radical R, which in the context of the present application is designated as a "characteristic radical" of an amino acid.

The starting substances for the chemical reactions are known or can be easily prepared by methods known from the literature. The amino- phosphinic and -phosphonic acids used as starting substances for the synthesis of the compounds according to the invention are, if not commercially obtainable in the individual case, synthesizable according to known methods (R. S. Rogers, M. K. Stern, Synlett 1992, 708; P. P.

Giannousis, P. A. Bartlett, J. Med. Chem. 30, 1603 (1987); J. P. Genet, M.

Uziel, A. M. Touzin, S. Roland, S. Thorimbert, S. Tanier, Tetrahedron Lett. 33, 77 (1992); E. K. Baylis, C. D. Campbell, J. G. Dingwall, J. Chem. Soc.

Perkin Trans. 1, 1984, 2845).

The invention furthermore relates to a process for preparing the compound of the formula | and/or a stereoisomeric form of the compound of the formula | and/or of a physiologically tolerable salt of the compound of the formula |, which comprises a) reacting an aminophosphinic or -phosphonic acid of the formula lil

Claims

® Patent Claims

1. A compound of the formula Rr: SEN LT] 0 R—A B—U—N PLY? 0} X RII yr t and/or a stereoisomeric form of the compound of the formula and/or a physiologically acceptable salt of the compound of the formula |, where R'is 1. phenyl,

2. phenyl which is mono- or disubstituted by

2.1. (Cy-Cg)-alkyl, which is linear, cyclic or branched,

2.2. hydroxyl,

2.3. (C1-Cg)-alkyl-C(O)-O-,

2.4. (Cq-Cg)-alkyl-O-,

2.5. (C1-Cg)-alkyl-O-(C1-C4)-alkyl-O-,

2.6. halogen,

2.7. -CFj,

28. -CN,

29. -NOg,

2.10. HO-C(O)-,

2.11. (C1-Cg)-alkyl-O-C(O)-,

2.12. methylenedioxo,

2.13. R*(R%)N-C(O)-,

2.14. R*-(RN- or

2.15. heteroaromatics from the group 3.1. to 3.16.,

3. a heteroaromatic from the following group 3.1. to 3.16., which is unsubstituted or substituted as described under 2.1. to 2.15,

3.1. pyrrole,

3.2. pyrazole,

3.3. imidazole,

3.4. triazole,

3.5. thiophene,

®

3.6. thiazole,

3.7. oxazole,

3.8. isoxazole,

3.9. pyridine,

3.10. pyrimidine,

3.11. pyrrolidine,

3.12. indole,

3.13. benzothiophene,

3.14. benzimidazole,

3.15. benzoxazole or

3.16. benzothiazole, or

4. -O-(C1-Cg)-alkyl, RZ, R4 and Rr are identical or different and are

1. a hydrogen atom,

2. (C1-Cg)-alkyl-,

3. HO-C(0)-(C4-Cg)-alkyl-,

4. phenyl-(CH2)n-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. or is substituted by -NH-C(O)-(C4-C3)-alkyl and n is the integer zero, 1 or 2, or

5. picolyl or

6. Rr and R° together with the ring amino group form a 4- to 7-membered ring in which one of the carbon atoms is optionally replaced by -O-, -S- or -NH- or two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical, R and R3 are identical or different and are

1. a hydrogen atom,

2. (C1-Cqp)-alkyl-, in which alkyl is unsubstituted, and/or a hydrogen atom of the alkyl radical is replaced by -OH,

3. (C2-C1p)-alkenyl-, in which alkenyl is linear or branched,

4. R°-O-(C1-Cg)-alkyl-,

5. RZ-S(0)n-(C1-Ce)-alkyl-, where n has the abovementioned meaning,

6. R°-S(0)(=NH)-(C1-Cg)-alkyl-,

7. a radical of the formula llo am N (CH,) , —S —(C,-Co) — Alkyk— (ilo) —w in which n is the integer zero, 1 or 2 and W is a nitrogen, oxygen or sulfur atom,

8. phenyl-(CH2)m-, in which m is the integer zero, 1, 2, 3, 4, 5 or 6 and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and phenyl is unsubstituted or mono- or disubstituted by

8.1. as described under 2.1. to 2.15.,

8.2. -O-(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2, 3, 4,5 or 6,

8.3. -C(O)-(CH2)m-phenyl, in which phenyl is as defined under 8.2.,

9. heteroaryl-(CH2)m-, in which heteroaryl is as defined under

3.1.t0 3.16, mis as defined above and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and heteroaryl is unsubstituted or mono- or disubstituted by

9.1. as described under 2.1. to 2.15.,

9.2. -CH(O),

9.3. -SO2-phenyl, in which phenyl is unsubstituted or as defined under 8.2. or 8.3,

9.4. -O-(CH2)m-phenyl,

10. -(CH2)m-P(O)(OH)-(C1-Ca)-alkyl, in which m is as defined above,

11. a characteristic residue of an amino acid or

12. R®-C(0)-(Cy-Cg)-alkyl-, in which R® is

1. a hydrogen atom,

2. (C1-Cg)-alkyl-, in which alkyl is linear, branched or cyclic,

3. phenyl, in which phenyl is unsubstituted or substituted as described under 2.1. to 2.15.,

® 4, heteroaryl, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to

2.15. or substituted by -(C1-C4)-alkyl-COOH,

5. -OH,

6. -OR?, in which R? has the abovementioned meaning,

7. NRY(RY), in which Rr and R° are as defined above,

8. heteroaryl-(CH2)m-NH-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is as defined above,

9. R*(R®N-NH-, in which R* and R® are as defined above,

10. HO-C(O)-CH(R%)-NH-, in which R® is as defined above,

13. -(CH2)p-N(R)(R'®), in which p is an integer zero, 1, 2, 3 or 4, in which R® and Rr'C are identical or different and are

1. a hydrogen atom,

2. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3,

3. R-C(O)-, in which R"is

3.1. (C1-Cg)-alkyl-,

3.2. (C2-Cg)-alkenyl-,

3.3. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1,2 or 3, or

3.4. heteroaryl-(CH2)m-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3,

4. R*-0-C(O)-, in which R* is defined as mentioned above,

5. R“-CH(NH2)-C(O)-, in which R* is defined as mentioned above,

6. RC-N(R’)-C(O)-, in which R% is

6.1. a hydrogen atom,

6.2. (Cy-Cg)-alkyl-,

®

6.3. phenyl-(CH2)m-, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3, or

6.4. heteroaryl-(CH2)m-, in which heteroaryl is as defined under 3.1. to 3.16. and/or is substituted as described under 2.1. to 2.15. and m is the integer zero, 1, 2 or 3 and in which R’ is a hydrogen atom or (C1-Cg)-alkyl- or in which R’ and R® 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 is replaced by -O-, -S- or -NH-,

7. R*-SOo, in which R™ is defined as mentioned above,

8. R*-NH-C(=NR’)-, in which R* and R’ are defined as mentioned above or are

8.1. (C1-Ce)-alkyl-C(O)-,

8.2. -NOsor

8.3. -SO2-(CHgz)g-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to

2.15. and q is the integer zero, 1, 2 or 3,

9. -SO02-(CH2)q-phenyl-phenyl, in which phenyl is unsub- stituted or mono- or disubstituted as described under

2.1.10 2.15. and q is the integer zero, 1, 2 or 3, or

10. the radical of the formula lip (CH) 7 ON L jl (Ip) w in which m is the integer zero, 1, 2 or 3 and W is a nitrogen atom, or RY and Rr’ together with the nitrogen atom to which they are attached form a ring of the subformula lla to lim o o lo) 0) 2A 7 —_. 7 —_— —-— 7 —- Ep ; aa : Ee” - a : 0 o lo} (1a) (Itb) (1c) (id) Rr? Oo RM ie} (eo xy Ly, C0 ]7 N— | N— : Ru I ~ © Pa Xen, R? el ° Ie (lle) (1H) (Ig) (in) HO — De (I CO = , > UD] {I (1k) (amy 0] rR’ IL / —N —N pi (im) or (cK) m N— (in) Oo where ris the integer 1 or 2, R' is a radical as described under 2.1. to 2.15, and Rr’ and m have the abovementioned meaning,

14. -OH,

15. =Oor

16. (C1-Cg)-alkyl-, or a -C(R)(R%)- radical for, -NH- or -NR>-, in which R? is as defined above, and tisaninteger 1,2,3 or 4, or

_ R? and Rr together form a ring with an exocyclic phosphinic or phosphonic acid radical of the subformula [i

(CH.) r <N pL oH an on Oo in which r is the integer zero, 1, 2 or 3 and/or one of the carbon atoms in the ring is replaced by -O-, -S- or -RN-, in which R’ is 1. a hydrogen atom,

2. (C1-Ceg)-alkyl,

4. benzyl, in which benzyl is unsubstituted or substituted as described under 2.1. to 2.15., or

5. R®N-C(=NH)-, where R® has the abovementioned meaning, and/or the carbon atoms in the ring of the subformula [I are mono- or polysubstituted by (C1-Cg)-alkyl-, phenyl-, phenyl-(CH2)m- or HO-, Uis -S0O2-or-CO-, v! and Y? are identical or different and independently of one another are a) a hydrogen atom, b) -OH, Cc) -(C1-C4)-alkyl, in which alkyl is linear or branched, d) -(CH2)y-phenyl, in which u is zero or 1, e) -O-(C1-Cg)-alkyl, in which alkyl is linear or branched, or f) -O-(CH2)s-phenyl, in which s is zero or 1, Ais a) a covalent bond, b) -O-, Cc) -CH=CH- or d) -C=C-, Bis a) -(CH2)m-, in which m has the abovementioned meaning, b) -O-(CHz)p, in which pis an integer from 1 to 5, or

® Cc) -CH=CH-, and Xis -CH=CH-, an oxygen atom or a sulfur atom.

2. A compound of the formula | as claimed in claim 1, wherein R' is 1. phenyl or

2. phenyl which is monosubstituted by

2.1. (C41-Cg)-alkyl-, in which alkyl is linear, cyclic or branched,

2.2. -OH,

2.3. -C(O)-OH,

2.4. -0O-(C1-Cg)-alkyl,

2.5. pyrrolidone,

2.6. halogen or

2.7. -CF3, or

3. -0O-(C1-Cg)-alkyl, R%, Rr? and RY are identical or different and are a hydrogen atom or (C1-Ce)-alkyl-, Ris a hydrogen atom, Rr is 1. (C1-Cg)-alkyl-, in which alkyl is linear, branched or cyclic, and/or in which a hydrogen atom of the alkyl radical is replaced by -OH,

2. R2-§(0)n-(C1-Ceg)-alkyl-, in which R is (C1-Ce)-alkyl- or phenyl-(CH2)n- and n is the integer zero or 1,

3. -(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted as described under 2.1. to 2.15. and/or a hydrogen atom of the -(CHz)m- chain is replaced by -OH and m is the integer 1, 2, 3, 4 or 5, 4, -(CH2)m-heteroaryl, in which heteroaryl is as defined under 3.3, 3.5., 3.6, 3.9. or 3.11 and/or is substituted as described under 2.1. to 2.15 and/or a hydrogen atom of the -(CH2)m- chain is replaced by -OH and m is the integer 1, 2, 3 or 4,

5. a characteristic residue of an amino acid or

6. -(CH2)pNR)R'®, in which p is an integer zero, 1 or 2, in which R® and R'C are identical or different and are a hydrogen atom or -SO2-(CH2)q-phenyl-phenyl, in which phenyl is unsubstituted or mono- or disubstituted

_ as described under 2.1. to 2.15. and q is the integer zero, 1,2 or 3, or

7. R®-C(O)-, in which R® is

7.1. -OH,

7.2. RCO-, in which R? is as defined above, or

7.3. RY (RON-, in which r and Rr are as defined above,

8. a hydrogen atom,

9. -OH,

10. =Oor :

11. (C1-Cg)-alkyl-, or a _C(R)(RY)- radical for, -NH- or NR, in which R? is as defined above, and tis an integer 1, 2, 3 or 4, Uis -SOo-, v'is -OH, v2 is a) -0O-(C4-Cy)-alkyl, in which alkyl is linear or branched, b) -OH or Cc) -(C1-C4)-alkyl, in which alkyl is linear or branched, Ais a covalent bond or -O-, Bis a covalent bond or -(C1-C4)-alkyl and Xis -CH=CH.

3. A compound of the formula | as claimed in claim 1 or 2, wherein R’ is 1. phenyl which is monosubstituted by halogen, Rr? is a hydrogen atom, Ris a hydrogen atom, Ris 1. (Cy-Ca)alkyl-,

2. -phenyl, in which phenyl is unsubstituted or mono- or disubstituted by -CF3 or -COOH,

3. a hydrogen atom,

4. -OH or

5. -NH-SO2-phenyl-phenyl, in which phenyl is unsubsti- tuted or substituted by halogen, tis anintegeri, 2, 3 or4, Uis -SOo-, Y and v2 is -OH or -O-CHg, Ais a covalent bond,

® Bis a covalent bond or -(CH2)o-, in whichois 1, 2 or 3 and Xis -CH=CH-.

4. The compound (R)-[1-(4’-chlorabiphenyl-4-sulfonylamino)-2-methyl- propyllphosphonic acid, dimethyl [3-(4’-chlorobiphenyl-4-sulfonyl- amino)-1-hydroxy-3(4-trifluoromethylphenyl)propyllphosphonate, [1- (4’-chlorobiphenyl-4-sulfonylamino)-3-methylbutyl]phosphonic acid or monoethy! (R,S)-[1-(4’-chlorobiphenyl-4-sulfonylamino)-1-phenyl- methyl]phosphonate. :

5. A compound of the formula VI Rr 3 R nebo v1) X R| “ve t and/or a stereoisomeric form of the compound of the formula VI and/or a physiologically acceptable salt of the compound of the formula VI, where R' A X B,U, v2, t, RZ and R® have the meaning mentioned in the compound of the formula | as claimed in claim 1 and R® has the meaning mentioned in the compound of the formula IV as claimed in claim 6.

6. A process for preparing the compound of the formula | as claimed in one or more of claims 1 to 5, which comprises a) reacting an aminophosphinic or -phosphonic acid of the formula Ill r2| R3IY? 11 Le N P— v2 ({1)} R t in which RZ, Y', Y2, R and R® are as defined in formula !, with a sulfonic acid or carbonyl derivative of the formula IV oad MN a-u—y (IV) X in which R' A, X, U and B are as defined in formula | and Z is a halogen atom, imidazolyl or -OR®, in which Re is a hydrogen atom, (C1-Ceg)-alkyl, phenyl or benzyl, if appropriate substituted, in the presence of a base or optionally of a dehydrating agent to give a compound of the formula |, or b) reacting an aminophosphinic or -phosphonic acid ester of the formula V R2| R3|Y? RIRIE: N PZ-0—RS (V) H R t in which R?, RS, t, v2 and Rr? have the abovementioned meaning, with a sulfonic acid or carbonyl derivative of the formula IV to give a compound of the formula VI 2 ii Wo 0 VY, ad Vey PLo—R (VI) X rR | ye t and converting the compound of the formula VI with removal of the . 8 . Ly radical R™, preferably in the presence of a base or acid, into a compound of the formula |, or Cc) reacting the compound of the formula VII

(cH),

Clg. N Pp —OR® L where n is the integer zero, 1 or 2, with the aid of a protective group E to give a compound of the formula VII E I (cH) N 5 (Vi) N Pp —OR® Ho Y2 and converting the compound of the formula VIII, using a compound of the formula IV, into a compound of the formula IX 0

1 . Y2— Pp —OR / C X £E—N N—u—s— A= (1X) cH) =~ n and then converting the compound of the formula IX, with removal of the protective group E and of the radical R® with the aid of suitable cleavage reagents, into the compound of the formula |, or d) separating a compound of the formula | prepared by one of the processes a), b) or c¢), which on account of its chemical structure occurs in enantiomeric forms, into the pure enantio- mers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure com-

@ pounds such as amino acids, separation of the diastereomers thus obtained, and removal of the chiral auxiliary groups, or e) isolating the compound of the formula | prepared by one of the processes a), b), ¢) or d) either in free form, or in the case of the presence of acidic or basic groups, converting it into physiologically acceptable saits.

7. A pharmaceutical, comprising an efficacious amount of at least one compound of the formula | as claimed in one or more of claims 1 to 5 together with a pharmaceutically suitable and physiologically accept- able excipient, additive and/or other active compounds and auxiliaries.

8. The use of at least one compound of the formula | as claimed in one or more of claims 1 to 5 for producing pharmaceuticals for the prophylaxis and therapy of disorders in the course of which an increased activity of matrix-degrading metalloproteinases is involved.

9. The use as claimed in claim 8 for the treatment of degenerative joint disorders such as osteoarthroses, spondyloses, chondrolysis after joint trauma or relatively long joint immobilization after meniscus or patella injuries or torn ligaments, disorders of the connective tissue such as collagenoses, periodontal disorders, wound healing dis- orders and chronic disorders of the locomotory apparatus such as inflammatory, immunological or metabolically related acute and chronic arthritis, arthropathies, myalgias and disorders of the bone metabolism, ulceration, atherosclerosis and stenoses, but also for the treatment of inflammations, carcinomatous disorders, tumor metastasis formation, cachexia, anorexia and septic shock.

10. A process for preparing a pharmaceutical, which comprises bringing at least one compound of the formula | as claimed in one or more of claims 1 to 5 into a suitable administration form using a pharma- ceutically suitable and physiologically acceptable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.