EP1587803A1

EP1587803A1 - Pyrimidine-4,6-dicarboxylic acid diamides for use as selective mmp 13 inhibitors

Info

Publication number: EP1587803A1
Application number: EP03789359A
Authority: EP
Inventors: Otmar Klingler; Reinhard Kirsch; Jörg Habermann; Klaus-Ulrich Weithmann; Christian Engel; Bernard Pirard
Original assignee: Sanofi Aventis Deutschland GmbH; Aventis Pharma Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 2003-01-03
Filing date: 2003-12-19
Publication date: 2005-10-26
Also published as: TW200505906A; MXPA05006401A; WO2004060883A1; CA2512183A1; BR0317834A; AU2003293951A1; JP2006515595A; DE10300017A1; AR042687A1; PE20040916A1

Abstract

The invention relates to the compounds of formula (I), wherein R1 to R7 are defined as in the claims, and to their use for selectively inhibiting collagenase (MMP 13). The pyrimidine-4,6-dicarboxylic acid diamides can therefore be used for treating degenerative articular diseases.

Description

PYRIMIDIN-4,6-DICARBONE ACID DIAMIDE AS SELECTIVE MMP 13 INHIBITORS

The invention relates to the use of pyrimidine-4,6-dicarboxylic acid diamides for the selective inhibition of collagenase (MMP 13). The pyrimidine-4,6-dicarboxylic acid diamides can therefore be used for the treatment of degenerative joint diseases.

In diseases such as osteoarthritis and rheumatism destruction of the joint takes place, especially due to the proteolytic degradation of collagen by collagenases. Collagenases belong to the superfamily of metalloproteinases (MP) or matrix metalloproteinases (MMPs). MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin under physiological conditions and therefore play an important role in bone and connective tissue. A large number of different inhibitors of MMPs or collagenases are known (EP 0 606 046, WO 94/28888). Disadvantages of the known inhibitors of MMPs are often the lack of specificity of inhibition for only one class of MMPs. Therefore, most MMP inhibitors inhibit multiple MMPs simultaneously because the MMP's catalytic domain has a similar structure. Consequently, the inhibitors undesirably affect many enzymes, including those with vital function (Massova I., et al., The FASEB Journal (1998) 12, 1075-1095).

It is known that pyrimidine-4,6-dicarboxylic acid diamides and 2,4-substituted pyridine N-oxides inhibit the enzymes proline and lysine hydroxylase and thus cause an inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reaction (EP 0418797, EP 0463592). This inhibition of collagen biosynthesis results in the formation of a non-functional, under-hydroxylated collagen molecule which can be released only to a small extent into the extracellular space by the cells. The underhydroxylated collagen also can not be incorporated into the collagen matrix and is very likely proteolytically degraded. As a result of these effects, the amount of extracellularly deposited collagen decreases overall. It is known from the patent applications WO 02/064571 and WO 02/064080 that certain pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides may be allosteric inhibitors of MMP 13.

WO 02/064571 describes pyrimidine-4,6-dicarboxylic acid and pyrimidine-4,6-dicarboxylic acid derivatives and their selective inhibition of MMP 13. Also in EP 0418797 Pyrimidine-4,6-dicarboxylic acid derivatives described and their inhibitory effect on proline hydroxylase. The inhibition of pyrimidine-4,6-dicarboxylic acid could be confirmed in own experiments. Disadvantage of the compounds described in WO 02/064571 and EP 0418797, it is therefore that the collagen biosynthesis is also inhibited by the inhibition of proline hydroxylase and a non-functional, unterhydroxylated collagen molecule is formed, which of the cells only in small amount can be discharged into the extracellular space.

It is therefore an object of the present invention to find compounds which selectively inhibit MMP 13 but do not inhibit proline hydroxylase and are more suitable for more effective and specific treatment of degenerative joint diseases.

It has now been found that the inventively used. Compounds strong inhibitors of the matrix metalloproteinase 13, while the compounds used in this invention are substantially ineffective in the MMP's 3 and 8 and do not inhibit the proline hydroxylase.

The invention therefore relates to the use of compounds of the formula I.

and / or all stereoisomeric forms of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of

Formula I for the manufacture of a medicament for the prophylaxis and therapy of diseases in which

Course an enhanced activity of matrix metalloproteinase 13 is involved, wherein

R 1 is hydrogen or - (C 1 -C 3) -alkyl,

R 2 is - (C 1 -C 6) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1. -C (O) -O-R8, wherein R8

1.1) hydrogen atom or 1.2). - (G | -C ₆ ) -alkyl, 2. - (O | -C ₆ ) -alkyl-O-R 8, wherein R 8

2.1) hydrogen atom or

2.2) - (C ^"ι-C6) -alkyl, 3. - (C5-Ci4) aryl, wherein aryl is mono-, di- or trisubstituted independently of one another, substituted by

3.1) - (C 2 -C 6) -alkyl-C (O) -O-R 8 where R 8

3.11) hydrogen atom or

3.12) - (C 1 -C ₆ ) -alkyl, 3.2) -O- (C 1 -C ₆ ) -alkyl-C (O) -O-R 8, where R 8

3.21) hydrogen atom or

3.22) - (C 1 -C ₆ ) -alkyl,

3.3) -N (R 14) - (R 15) in which R 14 and R 15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein one or two further carbon atoms also have a Heteroatom from the series oxygen, sulfur and nitrogen may be and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (Cj-CgJ-alkyl,

3.4) - (CH ₂ ) k N (R 9) - (R 10) wherein k is 2, 3, 4 or 5 and R 9 and

R10 are the same or different and independently of one another denote 3.41) hydrogen or 3.42) - (C -] - Cs) -alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered one form a saturated ring, wherein for one or two further carbon atoms also a heteroatom from the series oxygen, sulfur and nitrogen may be and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by (G] -Cö) alkyl, 3.5) -O- (C ₂ -C ₆ ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning,

3.6) -N (R8) -C (0) - _(C-j -Cs) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by

3.61) halogen,

3.62) Cyano,

3.63) Nitro,

3.64) hydroxy, 3.65) amino,

3.66) -C (O) -O- (C -] - C ₆ ) -alkyl or

3.67) -C (O) -OH,

4. Het, wherein Het is a saturated or unsaturated monocyclic or bicyclic 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the nitrogen, oxygen and sulfur series and unsubstituted or on or is substituted several times by

4.1) halogen, - 4.2) cyano,

4.3) Nitro,

4.4) hydroxy,

4.5) Amino,

4.6) -C (O) -O- (CC ₆ ) -alkyl, 4.7) -C (O) -OH,

4.8) - (C- ₎ -Cg) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.9) -O- (C-ι-C) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, 4.10) pyridyl or 4.11) phenyl, wherein phenyl is unsubstituted or mono- and polysubstituted and independently of one another by a radical selected from the group consisting of halogen, (C 1 -C 4 -alkoxy and (C 1 -C 5) -alkyl, and R 3, R 4, R 5, R 6 and R 7 are identical or are different and independent of each other

1. hydrogen atom,

2. halogen,

3. - (C -] - C5) -alkyl, in which alkyl is unsubstituted or mono-, di- or trisubstituted by

Is substituted halogen, 4.-O- (Cj -Cß) -Al ky I, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, or 5. -S- (Oι-C ₆ ) alkyl ,

Another object of the invention is the use of the compounds of formula I, wherein

R1 is hydrogen or - (Ci-G-j-alkyl,

R 2 is - (C 1 -C 4) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1.-C (O) -O-R8, wherein R8

1.1) hydrogen atom or 1.2) - (C 1 -C ₄ ) -alkyl,

2. - (C ₁ -C 4) alkyl-O-R 8, wherein R 8

2.1) hydrogen atom or

2.2) - (C 1 -C ₄ ) -alkyl,

3. phenyl, wherein phenyl is mono-, di- or trisubstituted independently of each other

3.1) - (C ₂ -C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

3.11) hydrogen atom or

3.12) - (C- _| -C ₄₎ -alkyl,

3.2) -O- (CτC ₄ ) -alkyl-C (O) -O-R8, wherein R8 is 3.21) hydrogen atom or

3.22) - (C 1 -C ₄ ) -alkyl, 3.3) -N (R 14) - (R 15) wherein R 14 and R 15, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered saturated ring, with one or two further carbon atoms as well a heteroatom from the series oxygen, sulfur and nitrogen can be and in the case of

Nitrogen, the nitrogen atoms may be unsubstituted or substituted by - (0] -C4) -alkyl,

3.4) - (CH 2) k "N (R 9) - (R 10), wherein k is 2, 3 or 4 and R 9 and R 10 are the same or different and independently

3.41) hydrogen or 3.42) - (0 | -C4) -alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to stand for an oxygen, sulfur and nitrogen heteroatom and Trap of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by (C -) - C4) -alkyl,

3.5) -O- _(C2-C4) alkyl-N (R9) -R10, wherein R9 and R10 have the abovementioned meaning, 3.6) -N (H) -C (0) - (O] -C4) Alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by 3.61) halogen,

3.62) Cyano,

3.63) Nitro,

3.64) hydroxy,

3.65) amino, 3.66) -C (O) -O- (CC ₆ ) -alkyl or

3.67) -C (O) -OH, 4. Het, wherein het is azepine, azetidine, aziridine, benzimidazole, benzo [1,4] dioxin, 1,3-benzodioxole, benzofuran, 4H-benzo [1,4] oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline , Quinoxaline, chroman, cinnoline, oxirane, 1,2-diazepine, 1, 3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole,, indazole, indole, isoquinoline, isochroman, isoindole, Isoxazole, isothiazole, 1,2-

Oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, phthalazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, tetrazole, 1,2-thiazine, 1, 3-thiazine, 1,4-thiazine, thiazole, thiophene, thiopyran, 1, 2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole or 1, 2,4-triazole and Het is unsubstituted or monosubstituted or trisubstituted independently of one another by

4.1) halogen,

4.2) Amino,

4.3) -C (O) -O- (C -] - C ₄ ) -alkyl, 4.4) -C (O) -OH,

4.5) - (C-j-C J-alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen

4.6) -O- (C 1 -C) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, 4.7) pyridyl or

4.8) phenyl, wherein phenyl is unsubstituted or monosubstituted and polysubstituted and independently of one another by a radical selected from halogen, - (C -) - C4) -alkoxy and - (G | -C4) -alkyl, and

R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen,

3. - (0] -C6) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trihydric

Is halogen, or 4.-O- (G] -C5) alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen. Another object of the invention is the use of the compounds of formula I, wherein

R 1 is hydrogen, R 2 is - (O-C 2) -alkyl, wherein alkyl is monosubstituted, disubstituted or trisubstituted by

1. phenyl, wherein phenyl is mono-, di- or trisubstituted independently of each other

1.1) - (C ₂ -C 4) -alkyl-C (O) -O-R 8, wherein R 8

1.11) hydrogen atom or 1.12) - (C 1 -C ₄ ) -alkyl,

1.2) -0- (G] -C ₄₎ -alkyl-C (0) -0-R8, wherein R8

1.21) hydrogen atom or

1.22) - (C -C ₄ ) -alkyl,

1.3) -N (R 14) - (R 15) in which R 14 and R 15, together with the nitrogen atom to which they are attached, form a residue other than

Imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by (D | -C 4) alkyl,

1.4) - (CH ₂ ) kN (R 9) - (R 10) where k is 2, 3 or 4 and R 9 and R 10 are the same or different and independently of one another 1.41) hydrogen or 1.42) - (G | -C 4) - Alkyl or R9 and R10 together with the nitrogen atom,. to which they are attached form a radical derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine; and in the case of nitrogen, the nitrogen atoms are independently unsubstituted or substituted by (C -] - C4) -alkyl may be substituted, 1.5) -O- (C 2 -C 4) -alkyl-N (R 9) -R 10 where R 9 and R 10 are those mentioned above

Meaning, 1.6) -N (H) -C (0) - (C- _| -C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by 1.61) halogen,

1.62) -C (O) -O- (CC ₄ ) -alkyl or

1.63) -C (O) -OH,

2. Het, wherein Het is furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, 1,2,3-triazole or 1,2,4-

Triazole and Het is unsubstituted or mono- or trisubstituted independently of each other is substituted by

2.1) halogen,

2.2) amino, 2.3) -C (O) -O- (C ₁ -C ₄ ) -alkyl,

2.4) -C (O) -OH,

2.5) - (0 _| -C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen,

2.6) -O- (-O-C4) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

2.7) pyridyl,

2.8) phenyl, wherein phenyl is unsubstituted or mono- or polysubstituted and independently of one another by a radical selected from halogen, - (C -) - C4) -alkoxy and - (C- _| -C4) -alkyl, and

R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen,

3. methyl, 4. trifluoromethyl,

5. Methoxy or

6. trifluoromethoxy, stand. The invention also relates to the compound of the formula

and / or all stereoisomeric forms of the compound of formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of formula I, wherein

R1 is hydrogen atom or - (C- _| -CG) is alkyl,

R 2 is - (C 1 -C 4) alkyl, wherein alkyl is mono-, di- or trisubstituted by 1 -C (O) -O-R 8, where R 8

1.1) hydrogen atom or

1.2) - (G] -C ₆ ) -alkyl,

2. - (G] -C6) alkyl-0-R8 wherein R8

2.1) is hydrogen or 2.2) - (G] -C6) -alkyl,

3. - (C6-C- | 4) -aryl, wherein aryl is mono-, di- or trisubstituted independently of each other

3.1) - (C ₂ -C ₆ ) -AlkyI-C (O) -O-R 8, wherein R 8

3.11) is hydrogen or 3.12) - (C 1 -C 6) -alkyl,

3.2) -O- (O | -C ₆ ) -alkyl-C (O) -O-R 8, wherein R 8

3.21) hydrogen atom or

3.22) - (C _r C ₆ ) -alkyl,

3.3) -N (R 14) - (R 15) wherein R 14 and R 15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein for one or two Further carbon atoms can also be a heteroatom from the series oxygen, sulfur and nitrogen and in the case of nitrogen, the nitrogen atoms can be independently unsubstituted or substituted by (C -] - Cg) alkyl, 3.4) - (CH) kN (R9 ) - (R10) wherein k is 2, 3, 4 or 5 and R9 and

R10 are the same or different and are independently of one another 3.41) hydrogen or 3.42) - (G] -C5) -alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to stand for an oxygen, sulfur and nitrogen heteroatom and Trap of nitrogen, the nitrogen atoms may be unsubstituted independently or substituted by (Ci-CgJ-alkyl,

3.5) -O- (C ₂ -C ₆ ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning,

3.6) -N (R8) -C (O) - (O | -C6) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by

3.61) halogen,

3.62) Cyano,

3.63) Nitro,

3.64) hydroxy, 3.65) amino,

3.67) -C (O) -O- (C ₁ -C ₆ ) -alkyl or

3.68) -C (0) -OH,

4. Het, wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, Contains oxygen and sulfur and is unsubstituted or mono- or polysubstituted by

4.1) halogen,

4.2) Cyano, 4.3) Nitro,

4.4) hydroxy,

4.5) Amino,

4.6) -C (O) -O- (C 1 -C ₆ ) -alkyl,

4.7) -C (O) -OH, 4.8) - (Cq-CgJ-alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.9) -O- (O] -C5) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.10) pyridyl or 4.11) phenyl, wherein phenyl is unsubstituted or mono- and polysubstituted and independently of one another by a radical from the series halogen, (O | -C5) -alkoxy and (-CC) -alkyl, and

R3, R4, R5, R6 and R7 are the same or different and are each independently of one another the first hydrogen atom, the second halogen,

3. - (0 _| C5) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by

Halogen is substituted,

4. - O- (C -] - C3) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trihydric

Halogen is substituted, or 5. -S- (C- _| -C) -Alky I stand.

Another object of the invention is the compound of formula I, wherein R 1 is hydrogen or R 2 is - (C 1 -C 4) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1. -C (O) -O-R8, wherein R8 1.1). Hydrogen atom or

1.2) - (-CC) alkyl,

2. - (C 1 -C 4) -alkyl-0-R 8, wherein R 8

2.1) hydrogen or 2.2) - (0 _| -C4) -alkyl,

3.1) - (C ₂ -C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

3.11) hydrogen atom or 3.12) - (0 _| -C4) alkyl,

3.2) -O- (C 1 -C 4) -alkyl-C (O) -O-R 8 where R 8

3.21) hydrogen atom or

3.22) - (C 1 -C ₄ ) -alkyl,

3.3) -N (R 14) - (R 15) wherein R 14 and R 15, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered saturated ring derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine , Piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, where the nitrogen atoms may each be unsubstituted or substituted by - (O-C4) -alkyl, 3.4) - (CH ₂ ) kN (R 9) - (R10) wherein k is 2, 3 or 4 and R9 and

R 10 are the same or different and independently of one another denote 3.41) hydrogen or 3.42) - (G] -C ₄ ) -alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring of imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or Derive thiomorpholine, the Nitrogen atoms may each be unsubstituted or substituted by - (G] - (- 4) -alkyl,

3.5) -O- (C ₂ -C ₄ ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning,

3.6) -N (H) -C (O) - (Gj-C4) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by

3.61) halogen,

3.62) Cyano, 3.63) Nitro,

3.64) hydroxy,

3.65) Amino,

3.67) -C (O) -O- (O | -C ₆ ) -alkyl or.

3.68) -C (O) -OH,

4. Het, wherein Het-azepine, azetidine, aziridine, benzimidazole, benzo [1,4] dioxin, 1, 3-benzodioxole, benzofuran, 4H-benzo [1,4] oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, Quinoline, quinoxaline, chroman, cinnoline, oxirane, 1,2-diazepine, 1, 3-diazepine, 1, 4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole , Isoxazole, isothiazole, 1,2-

Oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, phthalazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, tetrazole, 1, 2-thiazine, 1, 3-thiazine, 1, 4-thiazine, thiazole, thiophene, thiopyran, 1, 2,3-triazine, 1, 2,4-triazine, 1,3,5-triazine, 1, 2,3-triazole or 1, 2,4-triazole and Het is unsubstituted or monosubstituted or trisubstituted independently of one another by

4.1) halogen,

4.2) Amino,

4.3) -C (O) -O- (CC ₄ ) -alkyl, 4.4) -C (O) -OH,

4.5) - _(C-j -C J--alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen 4.6) -O- (G 1 -C 6) -alkyl, where alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.7) Pyridyl or

4.8) phenyl, wherein phenyl is unsubstituted or one or more times and independently of one another by a radical from the series

Halogen, and - (0] -C4) -alkyl, and

R3, R4, R5, R6 and R7 are the same or different and represent, for the 1st hydrogen atom, 2nd halogen,

3. - (O-Cβ) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by

Halogen is substituted, or

4. -O- (O] -C6) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen.

Another object of the invention is the compound of formula I, wherein

R1 is hydrogen,

R 2 is - (C -) - C 2) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by 1-phenyl in which phenyl is monosubstituted, disubstituted or trisubstituted independently of one another

1.1) - (C ₂ -C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

1.11) hydrogen atom or

1.12) - (C-ι-C means ₄₎ -alkyl, 1.2) -0- (C- _| _-C4) alkyl-C (0) -0-R8, wherein R8

1.21) hydrogen atom or

1.22) - (C -] - C4) -alkyl,

1.3) -N (R 14) - (R 15) in which R 14 and R 15, together with the nitrogen atom to which they are attached, form a residue derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine,

Piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or Derive thiomorpholine and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (G | -C4) alkyl,

1.4) - (CH ₂ ) kN (R 9) - (R 10), where k is 2, 3 or 4 and R 9 and R 10 are the same or different and independently of one another

1.4.1) hydrogen atom or 1.42) - (Gι-C4) alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a radical derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine,

Pyrrolidine, tetrazine or thiomorpholine derived can and in the case of nitrogen, the nitrogen atoms are unsubstituted or independently of one another by - may be substituted (C _j -G ^ alkyl,

1.5) -O- (C 2 -C 4) -alkyl-N (R 9) -R 10, where R 9 and R 10 have the abovementioned meaning,

1.6) -N (H) -C (O) - (C 1 -C 4) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by

1.61) halogen,

1.62) -C (0) -0- (Oj-C ₄₎ -alkyl or 1.63) -C (0) -0H,

2. Het, wherein Het is furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole,

Pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, 1,2,3-triazole or 1, 2,4-triazole, and Het is unsubstituted or monosubstituted or trisubstituted independently of one another by 2.1) halogen,

2.2) Amino,

2.3) -C (O) -O- (C 1 -C ₄ ) -alkyl,

2.4) -C (O) -OH,

2.5) - _(C-j-C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, 2.6) -O- (C -] - C4) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

2.7) pyridyl,

2.8) phenyl, wherein phenyl is unsubstituted or one or more times and independently of one another by a radical from the series

Halogen, - (C -] - C].) - Alkoxy and - (C -] - C4) -alkyl substituted, and

R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen, 3. methyl,

4. trifluoromethyl,

5. Methoxy or

6. trifluoromethoxy, stand.

By the term "halogen" is meant fluorine, chlorine, bromine or iodine.

By the term "- (C-i-CgJ-alkyl" are in the broadest sense hydrocarbon radicals with 1, 2, 3,

4, 5 or 6 carbon atoms whose carbon chain is straight-chain or branched or which consist of cyclic hydrocarbon groups or of combinations of linear and cyclic groups. For example, linear and branched hydrocarbon radicals may be methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl or hexyl, cyclic groups may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a combination of linear and cyclic radicals may cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl. By the term "R4 and R5 or R5 and R6 together with the carbon atoms to which they are respectively attached form a 5- or 6-membered ring which is aromatic or saturated and zero, one or two heteroatoms selected from oxygen, nitrogen or Sulfur contains "radicals are understood, for example, of dioxolane, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan, dihydrofuran , Tetra hydrofuran, oxazole, isoxazole, 2-isoxazoline, isoxazolidine, morpholine, oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolidine or thiomorpholine. By the term "- (Cg-C - ^ - aryl" are meant aromatic carbon radicals with 6 to

14 carbon atoms in the ring. - (Cg-O ^ -Arylreste are for example phenyl, naphthyl, for

Example 1-naphthyl, 2-naphthyl, biphenylyl, for example 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl radicals, naphthyl radicals and, in particular, phenyl radicals are preferred aryl radicals. The term "Het" is understood to mean a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system which contains 1, 2 or 3 identical or different ring heteroatoms from the series consisting of nitrogen, oxygen and sulfur monocyclic or bicyclic

10 heterocyclic ring system 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. The monocyclic

Ring system may be a 3-, 4-, 5-, 6- or 7-membered ring. In the bicyclic Het two rings may be linked together, one of which may be a 5-membered or 6-membered heterocyclic ring and the other may be a 5- or 6-membered heterocyclic or carbocyclic ring. For example, a bicyclic Het group may be selected from 8, 9 or

15 10 ring atoms exist.

Het includes saturated heterocyclic ring systems which do not have a double bond in the rings and also unsaturated heterocyclic ring systems including monounsaturated and polyunsaturated heterocyclic ring systems which have one or more double bonds and form a stable ring system. Unsaturated rings can

20 be partially unsaturated or form an aromatic system. In the Het group are identical or different heteroatoms from the series nitrogen, oxygen and sulfur. Examples of heterocycles from which the het group can be derived are the radicals acridinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,

25 benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,2,2-dithiazinyl, dihydrofuran [2,3-b] tetrahydrofuran, fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, Imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,

30 octahydroisoquinolinyl, oxadiazolyl, 1, 2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl , Phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, Piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, Quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- Thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl. Preference is given to pyridyl; such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl; such as 2-pyrrolyl and 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl; thienyl; such as 2-thienyl and 3-thienyl; Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, 1,3-benzodioxol, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, Cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, purinyl and pteridinyl.

Particularly preferred is a Het from the group aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, Pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine, 1,4-dioxin, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine, 1, 4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, Isoindole, benzofuran, benzothiophene, 1,3-benzodioxole, benzo [1,4] dioxin, 4H-benzo [1,4] oxazine, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, chroman, isochroman, cinnoline, quinazoline, Quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines, pyridopyrimidines, etc. and also ring systems resulting from the heterocycles listed by linkage or condensation with a carbocyclic ring, such as benzo-fused, cyclopenta-fused, cyclohexa fused or cyclohepta fused D derivatives of these heterocycles. Suitable nitrogen heterocycles may also be present as N-oxides or as quaternary salts in which a suitable nitrogen atom is alkylated by - (C 1 -C 4) -alkyl radicals.

The het groups may be unsubstituted or substituted according to the definitions given. The term "osteoarthrosis" is understood to mean a disease that arises predominantly in the case of a mismatch between the stress and load capacity of the individual joint parts and joint tissue, which is associated with an increasing cartilaginous destruction and is predominantly non-inflammatory , Demarcation or hyalinization, followed by reactive changes in the subchondral bone as well as capsular changes The term "spondylosis" is understood to mean arthrosis of the vertebral bodies, which is characterized by a noninflammatory loss of cartilage in the vertebral bodies and intervertebral discs.

The compounds of the formula I can be prepared, for example, by reacting a compound of the formula II

a) with a compound of the formula IIIa or IIIb

where R1, R2, R3, R4, R5, R6 and R7 are those indicated in formula I.

And Y is halogen, hydroxyl or G | -C4-alkoxy or together with the carbonyl group forms an active ester or a mixed anhydride, wherein a compound of formula I is formed and the reaction products optionally converted into their physiologically acceptable salts, or

b) a compound of the formula II with a compound of the formula IIIa or IIIb to give a compound of the formula IVa or IVb.

(IVa) (IVb), where R1 to R7 have the meanings given in formula I and Y is halogen, hydroxyl or 0] -C -alkoxy or together with the

Carbonyl group forms an active ester or a mixed anhydride and the compound of formula IVa or IVb optionally purifies and then converted with a compound of formula IIIa or IIIb in a compound of formula I.

In the following, the preparation of compounds of formula I and the preparation of the starting materials required for this purpose - if they are not commercially available - described in more detail.

The preparation of the compounds according to the invention is most simply achieved by combining the two components, the pyrimidine derivative of the formula (II) and the amine of the formula IIIa or IIIb, in equimolar amounts and at temperatures from -30.degree. C. to 150.degree. preferably be reacted at 20 ° C to 100 ° C to give compound of formula IVa or IVb and then the compounds of formula IVa or IVb are reacted with up to an equimolar amount of the amine of formula IIIb or IIIa in an analogous manner. The termination of the reaction can be determined, for example, by thin-layer chromatography or HPLC-MS. A variant of this method is that in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons such as methylene chloride, chloroform, tri-nor tetrachlorethylene ,. Benzene, toluene or polar solvents such as dimethylformamide, acetone or dimethyl sulfoxide works. The reaction temperatures are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature to 130 ° C being particularly preferred. Likewise, the reaction via a mixed anhydride such as ethyl chloroformate or via an active ester such as Paranitrophenylester (Y = CICH2-COO or NO2-C5H4-O) take place. Corresponding methods are known and described in the literature.

Likewise, the reaction of a compound of formula II or a compound of formula IVa or IVb with an amine of the formula IIIa or IIIb take place, if Y is OH and the corresponding carboxylic acid is activated in situ by conventional coupling reagents. Such coupling reagents are, for example, carbodiimides such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI) or N, N'-carbonyldiazoles such as N, N'-carbonyldiimidazole or a uronium salt such as 0 - ((cyano (ethoxycarbonyl) methylene) amino) -1, 1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or 0- (7-azabenzotriazol-1-yl) -1,3,3,3-tetramethyluronium hexafluorophosphate (HATU). Appropriate methods are known. If amines of the formula IIIa or IIIb are not commercially available, they can be prepared from corresponding commercially available starting compounds by methods known from the literature. Suitable starting compounds for amines are, for example, nitriles, nitro compounds,

Carboxylic acid amides, carboxylic acid esters, carboxylic acids, aldehydes and bromides. Nitriles, nitro compounds and carboxylic acid amides can be reduced to amines by known methods. Carboxylic acids and carboxylic acid esters can be converted into the carboxylic acid amides. Aldehydes can be converted via a reductive amination with NH4Ac / NaBH4 directly to the amines or hydroxylamine first to the oximes and then converted by reduction to the amines.

Optionally, the reaction can also be carried out in the presence of bases. Suitable additional bases are, for example, carbonates or bicarbonates, such as sodium or potassium carbonate or sodium or potassium bicarbonate, or tertiary amines, such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.

Optionally, the workup of the products, in particular the compound of formula IVa or IVb, for example by extraction or chromatography z. B. on silica gel. The isolated product can be recrystallized and optionally with a suitable Acid be converted to a physiologically acceptable salt. Suitable acids include, for example:

Mineral acids such as hydrochloric and hydrobromic acid and sulfuric, phosphoric, nitric or perchloric acid or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic -, fumaric, phenylacetic, benzoic, methanesulfonic, toluenesulfonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulfonic or ascorbic acid.

The starting compounds of the formula IIIa or IIIb can, insofar as they are not commercially available, be easily synthesized (eg Organikum, Organisch Chemisches Grundpraktikum, 15th ed., VEB Deutscher Verlag der Wissenschaften, 1976, an overview of the various possibilities can be found in the Methods Register, p. 822).

The starting compounds of the formula (II) are obtained, for example, by reacting pyrimidine-4,6-dicarboxylic acid or pyridine-2,4-dicarboxylic acid to give the corresponding pyrimidine-4,6-dicarboxylic acid halide or pyridine-2,4-dicarboxylic acid halide , preferably - chloride (according to literature methods), preferably in the presence of a catalyst such as dimethylformamide. This acid halide can then be added, for example, either with a suitable alcohol, e.g. B. paranitrobenzyl alcohol to the corresponding active ester, or be reacted with lower alcohols such as methanol or ethanol to the corresponding esters. Likewise, the pyrimidine-4,6-dicarboxylic acid can also be initially converted with the addition of a suitable carboxylic acid or a carboxylic acid ester such as ethyl chloroformate in a mixed anhydride, which then with the amines of the compounds of formulas IIIa or IIIb and (IVa or IVb to the products of the invention A corresponding method is also described in the literature.

The preparation of pyrimidine-4,6-dicarboxylic acid is carried out by literature methods, for example by oxidation of 4,6-dimethylpyrimidine, which in turn is obtainable, for example, by catalytic hydrogenation of commercially available 2-mercapto-4,6-dimethylpyrimidine.

If compounds of the formula I allow diastereoisomeric or enantiomeric forms and accumulate as their mixtures in the selected synthesis, the separation into the pure stereoisomers is possible either by chromatography on an optionally chiral Carrier material, or, if the racemic compound of the formula I is capable of salt formation, by fractional crystallization of diastereomeric salts formed as an auxiliary with an optically active base or acid. Suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are, for example, modified silica gel carriers (so-called Pirkle phases) and high molecular weight carbohydrates such as triacetylcellulose. For analytical purposes, gas chromatographic methods can also be used on chiral stationary phases according to appropriate derivatization known to the person skilled in the art. To separate the enantiomers of the racemic carboxylic acids with an optically active, usually commercially available base such as (-) - nicotine, (+) - and (-) - phenylethylamine, quinine bases, L-lysine or L- and D-arginine which have different solubility formed diastereomeric salts, the less soluble component as a solid isolated, the more readily soluble diastereomer from the mother liquor deposited, and obtained from the thus obtained diastereomeric salts, the pure enantiomers. In principle, the racemic compounds of the formula I, which contain a basic group such as an amino group, with optically active acids, such as (+) - camphor-10-sulfonic acid, D- and L-tartaric acid, D- and L- Convert lactic acid and (+) and (-) - mandelic acid into the pure enantiomers. Also, one can chiral compounds containing alcohol or amine functions, with appropriately activated or optionally N-protected enantiomerically pure amino acids in the corresponding esters or amides, or conversely chiral carboxylic acids with carboxy-protected enantiomerically pure amino acids in the amides or with enantiomerically pure hydroxycarboxylic acids such as lactic acid, in the convert appropriate chiral ester. Then, the chirality of introduced in enantiomerically pure form amino acid or alcohol residue can be used to separate the isomers by performing a separation of the diastereomers now present by crystallization or chromatography at suitable stationary phases and then splits off the entrained chiral moiety by suitable methods again.

Acidic or basic products of the compound of formula I may be in the form of their salts or in free form. Preference is given to pharmacologically acceptable salts, for. As alkali or alkaline earth metal salts or hydrochlorides, hydrobromides, sulfates, hemisulfates, all sorts of phosphates and salts of amino acids, natural bases or carboxylic acids. The preparation of physiologically acceptable salts of compounds capable of salt formation of the formula I, including their stereoisomeric forms, takes place in a manner known per se. The carboxylic acids form with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or basic amino acids, such as lysine, ornithine or arginine, stable alkali, alkaline earth or optionally substituted ammonium salts , If the compounds of the formula I have basic groups, it is also possible to prepare stable acid addition salts with strong acids. For this purpose, both inorganic and organic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfone, Cyclohexylamidosulfon-, trifluoromethylsulfone, acetic, oxal come -, wine, succinic or trifluoroacetic acid in question.

On account of the pharmacological properties, the compounds of the formula I are suitable for the prophylaxis and therapy of all such diseases, in whose course increased activity of matrix metalloproteinase 13 is involved.

These include degenerative joint diseases such as osteoarthrosis, spondylosis, loss of cartilage after joint trauma or prolonged joint restraint after meniscal or patella injuries or torn ligaments. It also includes connective tissue disorders such as collagenosis, periodontal disease, wound healing disorders and chronic musculoskeletal disorders such as inflammatory, immunological or metabolic acute and chronic arthritides, arthropathies, myalgia and bone metabolism disorders or cancers such as breast cancer.

The application of the medicaments according to the invention can be effected by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Preference is given to intra-articular injection. Rectal, oral, inhalation or transdermal administration is also possible.

The invention also relates to a process for the preparation of a medicament, which comprises at least one compound of the formula I with a pharmaceutically suitable and physiologically tolerated carrier and optionally brings further suitable active ingredients, additives or excipients in a suitable dosage form.

The compounds of the formula I are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and brought by the usual methods into suitable dosage forms, such as tablets, dragees, capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions. As inert carriers z. Gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, especially corn starch. The preparation can be carried out both as a dry and as a wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod liver oil.

For subcutaneous, intra-articular, intraperitoneal or intravenous administration, the active compounds are, if desired, brought into solution, suspension or emulsion with the substances suitable therefor, such as solubilizers, emulsifiers or other excipients. As a solvent come z. B. in question physiological saline or alcohols, eg. For example, ethanol, propanol, glycerol, besides sugar solutions such as glucose or mannitol solutions, or ^ a mixture of the various solvents mentioned.

Further, common auxiliaries such as carriers, disintegrants, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used. Commonly used adjuvants 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 mono- or polyhydric alcohols such as glycerol, called.

The compounds of formula I are preferred as pharmaceutical preparations in

Dosage units are prepared and administered, each unit containing as active ingredient a certain dose of the compound of formula I. For this purpose, they may be administered orally at doses of 0.01 mg / kg / day to 25.0 mg / kg / day, preferably 0.01 mg / kg / day to 5.0 mg / kg / day or parenterally at doses of 0.001 mg / kg / day to 5 mg / kg / day, preferably 0.001 mg / kg / day to 2.5 mg / kg / day. The dosage can also be increased in severe cases. In many cases, however, smaller doses are sufficient. This information refers to the treatment of an adult.

The invention is explained in more detail with reference to examples.

Example 1: [4 - ({[6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl] -amino} -methyl) -phenoxy-acetic acid tert-butyl ester

(4-Formyl-phenoxy) -acetic acid tert-butyl ester: 10 g (0.0819 mol) of 4-hydroxybenzaldehyde and 15.97 g (0.0819 mol) of bromoacetic acid tert-butyl ester were dissolved in 200 mL of 2-butanone and It was admixed with 11.32 g (0.0819 mol) of potassium carbonate and refluxed for 2 hours (h), then concentrated under reduced pressure and the residue was taken up in water and extracted three times with dichloromethane The organic phase was dried (MgSO 4). , filtered off and concentrated under reduced pressure Yield: 18.72 g (97%)

[4- (Hydroxyimino-methyl) -phenoxy] -acetic acid tert-butyl ester: 18.72 g (0.0792 mol) of (4-formyl-phenoxy) -acetic acid tert-butyl ester were dissolved in 200 ml of water / ethanol (1 : 1) and treated with 6.056 g (0.0872 mol) of hydroxylammonium chloride and 3.169 (0.0792 mol) of sodium hydroxide and 2.5 hours (h) under. Reflux stirred. It was concentrated under reduced pressure, the residue taken up in water and extracted with ethyl acetate. The organic phase was dried (MgSO 4), filtered off and concentrated under reduced pressure. Yield: 19.9 g (100%) MS (ES +): m / e = 251, 12

(4-Aminomethyl-phenoxy) -acetic acid tert-butyl ester: 6 g (0.0239 mol) of tert-butyl [4- (hydroxyimino-methyl) -phenoxy] -acetate were dissolved in 10 ml of water / ethanol (1: 1 ) and hydrogenated over 0.06 g Pd / C (10%) at a pressure of 5 bar at room temperature. After 3 hours (h), it was filtered through Celite and concentrated under reduced pressure. Yield: 4.26 g (75%)

6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylic acid methyl ester: The compound was prepared analogously to methyl 6-benzylcarbamoyl-pyrimidine-4-carboxylate. 6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylic acid: 8.75 g (0.0202 mol) of methyl 6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylate To 80 ml of methanol were added 0.889 g (0.0222 mol) of sodium hydroxide in 6 ml of water and stirred at room temperature (RT). After 2.5 hours, the solvent was removed under reduced pressure, the residue dissolved in 300 mL of water and acidified with concentrated HCl. The precipitate was filtered off and dried. Yield: 5.43 g (95%) MS (ES +): rh / e

= 289.09

[4 - ({[6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl] -amino} -methyl) -phenoxy] -acetic acid tert-butyl ester: 150 mg (0.519 mmol) 6 (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carboxylic acid were dissolved in 5 mL of DMF, treated with 170 mg (0.519 mmol) of TOTU and stirred at RT for 30 minutes. Subsequently, 147.6 mg (0.62 mmol) of tert-butyl (4-aminomethylphenoxy) acetate and 119.55 mg (1.038 mmol) of N-ethylmorpholine were added and the mixture was stirred at RT for 12 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC (water / acetonitrile). The uniform fractions were concentrated under reduced pressure and freeze-dried. Yield: 126 mg (48%) MS (ES-): m / e = 508.21

Example 2: [4 - ({[6- (4-Fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl-1-amino} -methyl) -phenoxy-acetic acid 83.6 mg (0.16 mmol) [4 Tert-butyl ({[6- (4-fluoro-3-methyl-benzylcarbamoyl) -pyrimidine-4-carbonyl] -amino} -methyl) -phenoxy-acetic acid (Example 31) was reacted in 90% for 4 hours.

Trifluoroacetic acid stirred at RT. Subsequently, it was mixed with acetonitrile / water, the

Precipitate filtered off and dried.

Yield: 55 mg (76%) MS (ES +): m / e = 452.15 Analogously to Example 1, the following compounds were prepared.

Table 1 :

Determination of enzymatic activity of the catalytic domain of human collagenase

-3 (MMP-13).

This protein is obtained as an inactive pro-enzyme from INVITEK, Berlin (catalog no. 30 100 803). Activation of the proenzyme:

2 volumes of proenzyme are incubated with 1 volume of APMA solution at 37 ° C for 1.5 hours. The APMA solution is prepared from a 10 mmol / L p-aminophenyl-mercuric acetate solution in 0.1 mmol / L NaOH by dilution with 3 volumes of Tris / HCl buffer pH7.5 (see below). The pH is adjusted by adding 1 mmol / L HCl between 7.0 and 7.5. After activation of the enzyme, it is diluted with the Tris / HCl buffer to a concentration of 1.67 μg / ml.

To measure the enzyme activity, 10 .mu.l of enzyme solution are incubated with 10 .mu.l of a 3% (v / v) buffered dimethyl sulphoxide solution (reaction 1) for 15 minutes. To measure the

Enzyme inhibitor activity will be 10 μL enzyme solution with 10 μL of a 3% (v / v) buffered

Dimethylsulfoxide solution containing the enzyme inhibitor, incubated (reaction 2).

Both in reaction 1 and in reaction 2, the enzyme reaction is monitored by fluorescence spectroscopy after addition of 10 μL of a 3% (v / v) aqueous dimethylsulfoxide solution containing 0.75 mmol / L of the substrate (328 nm (absorbance)). / 393 nm (emission)).

The enzyme activity is expressed as the increase in absorbance / minute.

The inhibitor activity is calculated as percent inhibition according to the following formula:

% Inhibition = 100 - [(extinction increase / minute in reaction 2) /

(Extinction increase / minute in Reaction 1) x 100]. The IC50, ie the inhibitor concentration required for 50% inhibition of enzyme activity, is graphically determined by plotting the percent inhibitions at various inhibitor concentrations.

The buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol / L Tris / HCl, 0.1 mol / L NaCl, 0.01 mol / L CaCl ₂ (pH = 7.5). The enzyme solution contains 1.67 μg / mL of the enzyme domain.

The substrate solution contains 0.75 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 (Bachern, Heidelberg, Germany).

Table 2 below shows results.

Table 2:

Determination of the enzymatic activity of the catalytic domain of human neutrophil collagenase (MMP-8) and of human stromelysin (MMP-3).

The enzymes human neutrophil collagenase and human stromelysin were prepared as active catalytic domains as described in Weithmann et al Inflamm Res, 46 (1997), pages 246-252. The measurement of the enzyme activity and the determination of the inhibitory effect of inhibitors on the enzyme activity was also carried out as described there.

The compounds according to the above examples each showed IC50 values of. In the determination of human neutrophil collagenase and human stromelysin more than 100000 nM. Thus, these compounds are virtually ineffective in inhibiting MMP 3 and 8.

Determination of prolyl hydroxylase inhibition according to Majamaa Eur. J. Biochem. 138 (1984) 5 239-245 in the design of Kaule and Guenzler Analytical Biochemistry 184 (1990) 291-297.

0.03 μg prolyl 4-hydroxylase, which according to Kedersa, Collagen Relat. Res. 1 1981) 345-353, prepared from homogenized 14-day-old chick embryos by ammonium sulfate precipitation and 0 affinity chromatography on poly-L-proline-coupled Sepharose 4B followed by DEAE-cellulose chromatography in 0.05 ml of a 0.04 M Tris-HCl solution (pH = 7.5) containing 0.05 mM FeS0 ₄ , 0.1 mM 2-oxo- [5-C-14] glutarate (100,000 dpm), 20 μg (0.4 mg / ml) (Pro-Pro-Gly) ιo (Protein Research Foundation, Minoh, Osakajapan), 1 mM ascorbic acid, 0.4 mg / ml Katalasae, 0.5 M dithiothreitol and 2 mg / ml bovine serum albumin, and the concentration of contained inhibitor (the

Comparative experiment was performed without inhibitor), incubated for one hour at 37 ° C. Subsequently, 25 μl of a 20 mM succinate and 2-oxoglutarate solution and 25 μl of a 0.16 M 2,4-DNPH solution containing 30% HCIO4 were added. After another half hour

Incubation at room temperature was centrifuged at 3000 g for 5 minutes. The radioactivity of 100 μl of the supernatant was determined by liquid scintillation. The preparation of [1-C-14] succinate was reported in dpm. Unless otherwise stated, all chemicals and reagents were obtained from Sigma, Sigma D-82024 Taufkirchen. The compounds tested in Table 3 were used at concentrations of 0.1 μM to 1 mM. Where possible, the IC 50 value was determined by extrapolarization of the 5 individual results. This value means that concentration of effective inhibitors that resulted in a 50% inhibition of the enzyme. Table 3:

Claims

claims

1. Compound of formula I

and / or all stereoisomeric forms of the compound of the formula. I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of formula I, wherein R 1 is hydrogen or - (C -) - C 6) -alkyl,

R 2 is - (C -) - C 6) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1. -C (O) -O-R8, wherein R8

1.1) hydrogen atom or

1.2) - (G | -C ₆ ) -alkyl,

2. - (C 1 -C 6) alkyl-O-R 8, wherein R 8

2.1) hydrogen atom or

2.2) - (CC ₆ ) -alkyl,

3. - (COE 0 _| 4) -aryl, wherein aryl is mono-, di- or trisubstituted independently of one another, substituted by

3.1) - (C ₂ -C 6) -alkyl-C (O) -O-R 8, wherein R 8

3.11) hydrogen atom or

3.12) - (G | -C ₆ ) -alkyl,

3.2) -O- (C 1 -C ₆ ) -alkyl-C (O) -O-R 8 where R 8

3.21) hydrogen atom or

3.22) - (C 1 -C ₆ ) -alkyl,

3.3) -N (R 14) - (R 15) wherein R 14 and R 15 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein for one or two Further carbon atoms can also be a heteroatom from the series oxygen, sulfur and nitrogen and, in the case of nitrogen, the nitrogen atoms are unsubstituted or substituted independently 3.4) - (CH ₂ ) k N (R 9) - (R 10) in which k is 2, 3, 4 or 5 and R 9 and

R10 are the same or different and are independent of each other

3.41) hydrogen atom or

3.42) - (C-j-Cg) -AlkyΙ or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to be a heteroatom from the series consisting of oxygen, sulfur and nitrogen, and Trap of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (C 1 -C 6) -alkyl,

3.6) -N (R 8) -C (O) - (C 1 -C 6) -alkyl, in which alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by 3.61) halogen,

3.62) Cyano,

3.63) Nitro,

3.64) hydroxy,

3.65) amino, 3.66) -C (O) -O- (CC ₆ ) -alkyl or

3.67) -C (O) -OH, 4. Het, wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system, the 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, Contains oxygen and sulfur and is unsubstituted or mono- or polysubstituted by

4.1) halogen,

4.2) Cyano,

4.3) Nitro,

4.4) hydroxy,

4.5) amino, 4.6) -C (O) -O- (CC ₆ ) -alkyl,

4.7) -C (0) -OH,

4.8) - (Cq-C, J-alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.9) -O- (G 1 -C 6) -alkyl, where alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.10) Pyridyl or

4.11) phenyl, where phenyl is unsubstituted or mono- and polysubstituted and independently of one another by a radical from the series halogen, (C 1 -C 6) -alkoxy and (C 1 -C 3 -alkyl), and R 3, R 4, R 5, R6 and R7 are the same or different and are each independently

1. hydrogen atom,

2. halogen,

3. (C 1 -C 6) -alkyl, in which alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, 4.-O- (C 1 -C -g) -alkyl, in which alkyl is unsubstituted or mono-, or substituted by halogen in triplicate, or 5.S- (CC ₆ ) alkyl.

2. A compound of the formula I as claimed in claim 1, where R 1 is hydrogen or - (C 1 -C 6 -alkyl,

R 2 is - (C -] - C 4) -alkyl, wherein alkyl is mono-, di- or trisubstituted by

1.-C (O) -O-R8, wherein R8

1.1) represents hydrogen or 1.2) - (C 1 -C ₄ ) -alkyl,

2. - (Oj-C4) -alkyl-0-R8, wherein R8

2.1) hydrogen atom or

2.2) - (G | -C ₄₎ -alkyl,

3. phenyl, wherein phenyl is mono-, di- or trisubstituted independently by 3.1) - (C ₂ -C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

3.11) hydrogen atom or

3.12) - (CC ₄ ) -alkyl,

3.2) -O- (C 1 -C 4) -alkyl-C (O) -O-R 8 where R 8 is 3.21) hydrogen or 3.22) - (CC ₄ ) -alkyl,

3.3) -N (R14) - (R15), wherein R14 and R15 together with the

Nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring which can be derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, wherein the Nitrogen atoms may be unsubstituted or independently substituted by - (O-C4) -alkyl, 3.4) - (CH2) | <- N (R9) - (R10), where k is 2, 3 or 4 and R9 and R10 are the same or different and independent of each other

3.41) hydrogen atom or

3.42) - (G | -C4) -alkyl or

R 9 and R 10, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered saturated ring composed of imidazolidine, isothiazolidine, isoxazolidine,

Morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, wherein the nitrogen atoms may be independently unsubstituted or substituted by - (C -] - C4) -alkyl, 3.5) -O- (C ₂ -C ₄ ) -alkyl-N (R9) -R10, wherein R9 and R10 have the abovementioned meaning, or

3.6) -N (H) -C (O) - (Oι-C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by

3.61) halogen,

3.62) Cyano, 3.63) Nitro,

3.64) hydroxy,

3.65) amino, 3.66) -C (O) -O- (O | -C ₆ ) -alkyl or

3.67) -C (0) -OH, or 4. Het, where Het is azepine, azetidine, aziridine, benzimidazole, benzo [1, 4] dioxin,

1,3-benzodioxole, benzofuran, 4H-benzo [1,4] oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chroman, cinnoline, oxirane, 1,2-diazepine, 1,3-diazepine, 1, 4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isoxazole, isothiazole, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole , Phthalazine, piperidine, pyran, pyrazine,

Pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, tetrazole, 1,2-thiazine, 1, 3-thiazine, 1,4-thiazine, thiazole, thiophene, thiopyran, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1, 2,3-triazole or 1,2,4-triazole and Het is unsubstituted or mono- or trisubstituted independently of each other by

4.1) halogen,

4.2) Amino,

4.3) -C (O) -O- (C 1 -C ₄ ) -alkyl,

4.4) -C (O) -OH, 4.5) - (C 1 -C 6) -alkyl, where alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen

4.6) -O- (C 1 -C 5) -alkyl, where alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.7) pyridyl or 4.8) phenyl, where phenyl is unsubstituted or monosubstituted and polysubstituted and independently of one another by a radical selected from halogen, - (O _| -C 4) -alkoxy and - (C- _| -C 4) -alkyl, and R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen,

3. - (C-j-CgJ-alkyl wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, or

4. -O- (C -] - C6) alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen.

3. A compound of formula I according to claims 1 or 2, wherein R 1 is hydrogen,

R _{2 is} - (G ₁ -C ₂ ) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1. phenyl, wherein phenyl is mono-, di- or trisubstituted independently by 1.1) - (C ₂ -C) alkyl C (0) -O-R 8, wherein R 8

1.11) hydrogen atom or

1.12) - (C -] - C ₄ ) -alkyl,

1.2) -O- (CC ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

1.21) is hydrogen or 1.22) - (G] -C ₄ ) -alkyl,

1.3) -N (R 14) - (R 15) in which R 14 and R 15, together with the nitrogen atom to which they are attached, form a residue consisting of imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, Pyrrolidine, tetrazine or thiomorpholine can be derived and in the case of nitrogen, the

Nitrogen atoms may be unsubstituted or substituted by (C 1 -C 4) -alkyl independently of one another,

1.4) - (CH ₂ ) kN (R 9) - (R 10) in which k is 2, 3 or 4 and R 9 and R 10 are the same or different and independently of one another 1.41) hydrogen atom or

1.42) - (C -] - C4) -Alkyl mean or R 9 and R 10 together with the nitrogen atom to which they are attached form a radical which can be derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine and, in the case of nitrogen, the nitrogen atoms may be unsubstituted or substituted by - (O-C4) -alkyl,

1.5) -O- (C ₂ -C 4) -alkyl-N (R 9) -R 10 where R 9 and R 10 are those mentioned above

Meaning, or

1.61) halogen, 1.62) -C (O) -O- (CC ₄ ) -Alkyl or

1.63) -C (0) -OH, or 2. Het, wherein Het furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, 1, 2,3-triazole or 1,2,4

2.1) halogen,

2.2) amino, 2.3) -C (O) -O- (CC ₄ ) -alkyl,

2.4) -C (O) -OH,

2.5) - (-O-C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen,

2.6) -O- (C 1 -C 4) -alkyl, where alkyl is unsubstituted or mono-, di- or trisubstituted by halogen,

2.7) Pyridyl, or

2.8) phenyl, wherein phenyl is unsubstituted or mono- or polysubstituted and independently of one another by a radical selected from halogen, - (G-C4) -alkoxy and - (O-C4) -alkyl, and R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen,

3. methyl,

4. trifluoromethyl,

5. Methoxy or

6. trifluoromethoxy, stand.

4. Use of the compound of the formula I, and / or all stereoisomeric forms of the compound of the formula I and / or mixtures of these forms in any ratio, and / or a physiologically acceptable salt of the compound of the formula I for the preparation of a medicament for prophylaxis and therapy of diseases in whose course an increased activity of matrix metalloproteinase 13 is involved, wherein

R 1 is hydrogen or - (C 1 -C 6) -alkyl, R 2 is - (C 1 -C -g) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by

1. -C (O) -O-R8, wherein R8

1.1) hydrogen atom or

1.2) - (C <ι-C6) -alkyl, 2. - (O | -C 6) -alkyl-O-R8, wherein R8

2.1) hydrogen atom or

2.2) - (C ^« -C6) -alkyl,

3. - (C -C-) -aryl, in which aryl is monosubstituted, disubstituted or trisubstituted independently of each other by 3.1) - (C ₂ -C ₆ ) -alkyl-C (O) -O-R 8, wherein R8

3.11) hydrogen atom or

3.12) - (G | -C 6) -alkyl, 3.2) -O- (C 1 -C ₆ ) -alkyl-C (O) -O-R 8, in which R 8

3.21) hydrogen atom or

3.22) - (C 1 -C ₆ ) -alkyl, '3,3) -N (R 14) - (R 15), wherein R 14 and R 15 together with the

Nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, wherein one or two further carbon atoms can also be a heteroatom from the series oxygen, sulfur and nitrogen and in the case of nitrogen, the nitrogen atoms independently of one another unsubstituted or may be substituted by (Cj -Cg) -alkyl,

3.4) - (CH ₂ ) k N (R 9) - (R 10) wherein k is 2, 3, 4 or 5 and R 9 and

R10 are the same or different and are independently 3.41) hydrogen or 3.42) - (C _r C ₆ ) alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered saturated ring, it also being possible for one or two further carbon atoms to stand for an oxygen, sulfur and nitrogen heteroatom and Trap of nitrogen, the

Nitrogen atoms can be unsubstituted or independently substituted by (G _| -Cg) -alkyl,

3.5) -O- (C ₂ -C ₆ ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning, or 3.6) -N (R 8) -C (O) - (O? - C 6) alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by

3.61) halogen,

3.62) Cyano,

3.63) Nitro, 3.64) hydroxy,

3.65) Amino,

3.66) -C (O) -O- (CC ₆ ) -alkyl or

3.67) -C (O) -OH, wherein Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system containing 1, 2 or 3 identical or different ring heteroatoms from the

Contains nitrogen, oxygen and sulfur and is unsubstituted or mono- or polysubstituted by

4.1) halogen,

4.2) Cyano, 4.3) Nitro,

4.4) hydroxy,

4.5) Amino,

4.6) -C (O) -O- (CC ₆ ) -alkyl,

4.7) -C (O) -OH, 4.8) - (C -] - C5) -AlkyI, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.9) -O- (C -] - C) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

4.10) pyridyl, or 4.11) phenyl, where phenyl is unsubstituted or substituted one or more times independently from each other by a radical from the series halogen, _(C-j -CG) alkoxy and (C-ι-Cg) alkyl, and

3. - (C 1 -C 8) -alkyl, in which alkyl is unsubstituted or mono-, di- or trisubstituted by halogen,

4. - O- (C 1 -C 8) -alkyl, in which alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen, or 5.S- (CC ₆ ) -alkyl.

5. Use of the compound of the formula I according to claim 4, wherein R 1 is hydrogen or - (C 1 -C 4) -alkyl,

R 2 is - (G 1 -C 4) -alkyl, where alkyl is monosubstituted, disubstituted or trisubstituted by 1-C (O) -O-R 8, where R 8

1.1) hydrogen atom or

1.2) - (G _| -C ₄ ) -alkyl,

2. - (C 1 -C 4) alkyl-0-R 8, wherein R 8

2.1) hydrogen atom or 2.2) - (C 1 -C ₄ ) -alkyl,

3.1) - (C ₂ -C 4) -alkyl-C (O) -O-R 8, wherein R 8

3.11) is hydrogen or 3.12) - (C 1 -C ₄ ) -alkyl,

3.2) -O- (C 1 -C 4) -alkyl-C (O) -O-R 8 where R 8 is 3.21) hydrogen atom or ^' 3.22) - (0] -C 4) -alkyl,

3.3) -N (R 14) - (R 15) in which R 14 and R 15 together with the nitrogen atom to which they are attached form a radical consisting of imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, Pyrrolidine, tetrazine or thiomorpholine can be derived and in the case of nitrogen, the nitrogen atoms independently unsubstituted or by can be substituted

3.4) - (CH ₂ ) k N (R 9) - (R 10) where k is 2, 3 or 4 and R 9 and

R10 are the same or different and are independent of each other

3.41) hydrogen atom or

3.42) - (O _j-C4) -alkyl means alkyl or R9 and R10 together with the nitrogen atom to which they are attached form a radical derived from imidazolidine Isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (C-1-C4) -alkyl,

3.5) -O- (C ₄ -C ₄ ) -alkyl-N (R 9) -R 10, wherein R 9 and R 10 have the abovementioned meaning, or 3.6) -N (H) -C (O) - (C- _| C4) -alkyl, in which alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by 3.61) halogen,

3.62) Cyano,

3.63) Nitro,

3.64) hydroxy,

3.65) amino, 3.66) -C (O) -O- (Gι-C ₆ ) alkyl or

3.67) -C (0) -OH, or 4. Het, where Het is azepine, azetidine, aziridine, benzimidazole, benzo [1,4] dioxin, 1,3-benzodioxole, benzofuran, 4H-benzo [1, 4] oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chroman, cinnoline, oxirane, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, .

Indazole, indole, isoquinoline, isochroman, isoindole, isoxazole, isothiazole, 1, 2-oxazine, 1, 3-oxazine, 1,4-oxazine, oxazole, phthalazine, piperidine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, Pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, tetrazole, 1, 2-thiazine, 1,3-thiazine, 1, 4-thiazine, thiazole, thiophene, thiopyran, 1,2,3-triazine, 1, 2,4-triazine, 1, 3,5-triazine, 1, 2,3-triazole or 1, 2,4-triazole and Het is unsubstituted or mono- or trisubstituted independently of each other by

4.1) halogen,

4.2) amino, 4.3) -C (O) -O- (C 1 -C ₄ ) -alkyl,

4.4) -C (0) -OH,

4.5) - (-CC) alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen,

4.6) -O- (C-ι-Cg) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen, 4.7) pyridyl or

Wherein phenyl is unsubstituted or and 4.8) phenyl one or more times independently from each other by a radical from the series halogen, -] - - C4) alkoxy and - _(C-j ^ -C alkyl is substituted, and (C

R3, R4, R5, R6 and R7 are the same or different and are each hydrogen atom,

2. halogen,

3. - (C 1 -C 6) -alkyl, in which alkyl is unsubstituted or mono-, di- or trisubstituted

Halogen is substituted, or

4. -O- (C -] - C) alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by halogen.

6. Use of the compounds of the formula I according to claims 4 and 5, wherein R 1 is hydrogen, 'R _{2 is} - (C ₁ -C ₂ ) -alkyl, where alkyl is mono-, di- or trisubstituted by

1.1) - (C ₂ -C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

1.11) is hydrogen or 1.12) - (C -] - C ₄ ) -alkyl,

1.2) -O- (C _r C ₄ ) -alkyl-C (O) -O-R 8, wherein R 8

1.21) hydrogen atom or

1.22) - (C 1 -C 4) -alkyl,

Imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, Piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (O-C4) -alkyl, 1.4) - (CH ₂ ) kN (R 9) - (R10), wherein k is 2, 3 or 4 and R9 and R10 are the same or different and are independently 1:41) hydrogen atom or 1:42) - mean (G] -C ₄₎ -alkyl or

R 9 and R 10 together with the nitrogen atom to which they are attached form a radical derived from imidazolidine, isothiazolidine,

Isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine, and in the case of nitrogen, the nitrogen atoms may be independently unsubstituted or substituted by - (Cj-C4) -alkyl, 1.5) -O- ( C ₂ -C 4) -alkyl-N (R 9) -R 10 where R 9 and R 10 are those mentioned above

Or 1.6) -N (H) -C (O) - (O] -C4) -alkyl, wherein alkyl is unsubstituted or mono-, di- or trisubstituted by 1.61) halogen, 1.62) -C (0 ) -O- (G | -C ₄ ) -alkyl or

1.63) -C (O) -OH, or 2. Het, where Het is furan, imidazole, isothiazole, isoxazole, oxazole, pyrazole,

Pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, 1,2,3-triazole or 1,2,4-triazole and Het is unsubstituted or mono- or trisubstituted independently substituted by

2.1) halogen,

2.2) Amino,

2.3) -C (0) -0- (C- _| -C4) alkyl,

2.4) -C (O) -OH, 2.5) - (C 1 -C 4) -alkyl, where alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

2.6) -O- (O-C4) -alkyl, wherein alkyl is unsubstituted or monosubstituted, disubstituted or trisubstituted by halogen,

2.7) pyridyl,

Halogen, - (C-i-Gj-alkoxy and - (C -] - C4) -alkyl substituted, and

R3, R4, R5, R6 and R7 are the same or different and for

1. hydrogen atom,

2. halogen, 3. methyl,

4. trifluoromethyl,

5. Methoxy or

6. trifluoromethoxy, stand.

7. A process for the preparation of the compound of the formula I according to one or more of claims 1 to 6, characterized in that a compound of the formula II

a) with a compound of the formula IIIa or IIIb

wherein R1, R2, R3, R4, R5, R6 and R7 have the meanings given in formula I and Y is halogen, hydroxyl or 0] -C4-alkoxy or together with the carbonyl group forms an active ester or a mixed anhydride, wherein a compound of formula I is formed and the Optionally converted into their physiologically acceptable salts, or reaction products

(IVa) (IVb) is reacted, wherein R1 to R7 have the meanings given in formula I and Y is halogen, hydroxyl or C-i-Gψ alkoxy or together with the

8. A pharmaceutical composition, characterized by an effective content of at least one compound of the formula I according to one or more of claims 1 to 3 together with a pharmaceutically suitable and physiologically acceptable carrier, additive and / or other active ingredients and excipients.

9. Use of the compound of the formula I according to one or more of claims 4 to 6 for the manufacture of a medicament for the prophylaxis and therapy of

Diseases in which an increased activity of matrix metalloproteinase 13 is involved, which are degenerative joint diseases such as osteoarthrosis, spondylosis, cartilage shrinkage after joint trauma or prolonged joint rest after meniscal or patella injuries or torn ligaments or connective tissue diseases such as collagenosis,

Periodontal diseases, wound healing disorders and chronic diseases of the musculoskeletal system such as inflammatory, immunological or metabolic acute and chronic arthritides, arthropathies, myalgia and disorders of bone metabolism or cancers such as breast cancer.