CA2512183A1 - Pyrimidine-4,6-dicarboxylic acid diamides for use as selective mmp 13 inhibitors - Google Patents

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

PYRIMIDINE-4, 6-DICARBOXYLIC ACID DIAMIDES FOR USE AS

The invention relates to the use of pyrimidine-4,6-dicarboxylic acid diamides for selectively inhibiting collagenase (MMP 13). The pyrimidine-4,6-dicarboxylic acid diamides can therefore be used for treating degenerative joint diseases.
In diseases such as osteoarthritis and rheumatism, destruction of the joint takes place, with this destruction being caused, in particular, by the proteolytic breakdown of collagen due ,to collagenases. Collagenases belong to the metalloproteinase (MP) or matrix metalloproteinase (MMP) superfamily. Under physiological conditions, MMPs cleave collagen, laminin, proteoglycans, elastin or gelatin and therefore play an important role in bone and connective tissue. A large number of different inhibitors of the MMPs and/or collagenases have been disclosed (EP 0 606 046;
WO 94/28889). Known MMP inhibitors frequently suffer from the disadvantage of lacking the specificity involved in inhibiting only one class of MMPs. As a result, most MMP inhibitors inhibit several MMPs simultaneously because the structure of the catalytic domain in the MMPs is similar. As a consequence, the inhibitors have the undesirable property of acting on many enzymes including those which have a vital function (Massova l., 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 hydroxylase and lysine hydroxylase and thereby bring about an inhibition of collagen biosynthesis by exerting an influence on the collagen-specific hydroxylation reaction (EP 0418797; EP 0463592). This inhibition of collagen biosynthesis results in the formation of a nonfunctional, under-hydroxylated collagen molecule which the cells can only release into the extracellular space in small quantity. fn addition, the under-hydroxylated collagen cannot be incorporated into the collagen matrix and is very readily degraded proteolytically. As a consequence of these effects, the overall quantity of collagen which is deposited extracellularly decreases. It is known from patent applications WO 02/064571 and WO 02/064080 that certain pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can 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.
EP 0418797 also describes pyrimidine-4,6-dicarboxylic acid derivatives and their inhibitory effect on proline hydroxylase. It was possible to confirm this inhibition by pyrimidine-4,6-dicarboxylic acid in in-house experiments. The compounds described in WO 02/064571 and EP 0418797 therefore suffer from the disadvantage that, as a result of proline hydroxylase being inhibited, collagen biosynthesis is also inhibited and a nonfunctional, under-hydroxylated collagen molecule is formed, with the cells only being able to release this molecule into the extracellular space in small quantities.
The object of the present invention is therefore to find compounds which, while selectively inhibiting MMP 13, do not inhibit proline hydroxylase and are therefore better suited for treating degenerative joint diseases more efficiently and more specifically.
It has now been found that the compounds employed in accordance with the invention are powerful inhibitors of matrix metalloproteinase 13 whereas the compounds employed in accordance with the invention have essentially no activity on the MMPs 3 and 8 and do not inhibit proline hydroxylase.
The invention therefore relates to the use of compounds of the formula I
,o 0 R1 ~N ~ R6 U) I
~N

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 tolerated salt of the compound of the formula I

for producing a pharmaceutical for the prophylaxis and therapy of diseases whose course involves an increased activity of matrix metallop~oteinase 13, where R1 is hydrogen atom or -(C~-Cg)-alkyl, R2 is -(C~-Cg)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1 ) hydrogen atom, or 1.2) -(C~-Cg)-alkyl, 2. -(C~-Cg)-alkyl-O-R8, in which R8 is 2.1 ) hydrogen atom, or 2.2) -(C~-Cg)-alkyl, 3. -(Cg-C~4)-aryl, in which aryl is substituted, once, twice or three times, independently of each other, by 3.1 ) -(C2-Cg)-alkyl-C(O)-O-R8, in which R8 is 3.11 ) hydrogen atom, or 3.12) -(C~-Cg)-alkyl, 3.2) -O-(C~-Cg)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C~-Cg)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7 membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-Cg)-alkyl, 3.4) -(CHZ)k-N(R9)-(R10), in which k is 2, 3, 4 or 5 and R9 and R10 are identical or different and are, independently of each other, 3.41 ) hydrogen atom, or 3.42) -(C~-Cg)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-Cg)-alkyl, 3.5) -O-(C2-Cg)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(R8)-C(O)-(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by ~ 3.61 ) halogen, 3.62) cyano, 3.63) vitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C~-Cg)-alkyl, or 3.67) -C(O)-OH, 4. Het, where Het is 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 nitrogen, oxygen and sulfur and is unsubstituted or substituted, once or more than once, by 4.1 ) halogen, 4.2) cyano, 4.3) vitro, 4.4) hydroxyl, 4.5) amino, 4.6) -C(O)-O-(C~-Cg)-alkyl, 4.7) -C(O)-OH, 4.8) -(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 5 4.9) -O-(C~-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.10) pyridyl, or 4.11 ) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, (C~-C6)-alkoxy and (C~-Cg)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4. -O-(C~-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 5. -S-(C~-C6)-alkyl.

The invention also relates to the use of the compounds of the formula I, where R1 is hydrogen atom or -(C~-C4)-alkyl, R2 is -(C~-C4)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1 ) hydrogen atom, or 1.2) -(C~-C4)-alkyl, 2. -(C~-C4)-alkyl-O-R8, in which R8 is 2.1 ) hydrogen atom, or 2.2) -(C~-C4)-alkyl, 3. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 3.1 ) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 3.11 ) hydrogen atom, or 3.12) -(C~-C4)-alkyl, 3.2) -O-(C1-C4)-alkyl-C(O)-O-R8, in which R8 is 3.21 ) hydrogen atom, or 3.22) -(C~-C4)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7 membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-C4)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 3.41) hydrogen atom, or 3.42) -(C~-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-C4)-alkyl, 3.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61 ) halogen, 3.62) cyano, 3.63) vitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C1-Cg)-alkyl, or 3.67) -C(O)-OH, 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, pyrrol, 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 substituted, once, twice or three times, independently of each other, by 4.1 ) halogen, 4.2) amino, 4.3) -C(O)-O-(C~-C4)-alkyl, 4.4) -C(O)-OH, 4.5) -(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.6) -O-(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.7) pyridyl, or 4.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C1-C4)-alkoxy and -(C1-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. -(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 4. -O-(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen.
The invention also relates to the use of the compounds of the formula I, where R1 is hydrogen atom, R2 is -(C1-C2)-alkyl, where alkyl is substituted, once, twice or three times, by 1. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 1.1 ) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 1.11) hydrogen atom, or 1.12) -(C~-C4)-alkyl, 1.2) -O-(C~-C4)-alkyl-C(O)-O-R8, in which R8 is 1.21 ) hydrogen atom, or 1.22) -(C~-C4)-alkyl, 1.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C~-C4)-alkyl, 1.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 1.41) hydrogen atom, or 1.42) -(C~-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C~-C4)-alkyl, 1.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 1.6) -N(H)-C(O)-(C~-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 1.61 ) halogen, 1.62) -C(O)-O-(C~-C4)-alkyl, or 1.63) -C(O)-OH, 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 substituted, once, twice or three times, independently of each other, by 2.1 ) halogen, 2.2) amino, 2.3) -C(O)-O-(C~-C4)-alkyl, 2.4) -C(O)-OH, 2.5) -(C~-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice 5 or three times, by halogen, 2.6) -O-(C~-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.7) pyridyl, 10 2.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C~-C4)-alkoxy and -(C~-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. methyl, ~ 4. trifluoromethyl, 5. methoxy, or 6, trifluoromethoxy.

The invention also relates to the compound of the formula I

R1 ~R \ H \ R6 ~ p N~\ j N
R3 Y ~R5 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 tolerated salt-of the compound of the formula l, where R1 is hydrogen atom or -(C~-Cg)-alkyl, R2 is -(C~-Cg)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-0-R8, in which R8 is 1.1 ) hydrogen atom, or 1.2) -(C~-Cg)-alkyl, 2. -(C~-Cg)-alkyl-O-R8, in which R8 is 2.1 ) hydrogen atom, or 2.2) -(C~-Cg)-alkyl, 3. -(Cg-C~4)-aryl, in which aryl is substituted, once, twice or three times, independently of each other, by 3.1 ) -(C2-Cg)-alkyl-C(O)-O-R8, in which R8 is 3.11 ) hydrogen atom, or 3.12) -(C~-Cg)-alkyl, 3.2) -O-(C~-Cg)-alkyl-C(O)-O-R8, in which R8 is 3.21 ) hydrogen atom, or 3.22) -(C~-Cg)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-Cg)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3, 4 or 5 and R9 and R10 are identical or different and are, independently of each other, 3.41 ) hydrogen, or 3.42) -(C~-Cg)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (Cq-C6)-alkyl, 3.5) -O-(C2-Cg)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(R8)-C(O)-(C1-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61 ) halogen, 3.62) cyano, 3.63) vitro, 3.64) hydroxyl, 3.65) amino, 3.67) -C(O)-O-(C1-Cg)-alkyl, or 3.68) -C(O)-OH, 4. Het, where Het is 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 nitrogen, oxygen and sulfur and is unsubstituted or substituted, once or more than once, by 4.1 ) halogen, 4.2) cyano, 4.3) vitro, 4.4) hydroxyl, 4.5) amino, 4.6) -C(O)-O-(C~-Cg)-alkyl, 4.7) -C(O)-OH, 4.8) -(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted,once, twice or three times, by halogen, 4.9) -O-(C~-Cs)-alkyl, wherealkyl is unsubstituted or substituted,once, twice or three times, by halogen, 4.10) pyridyl, or 4.11 ) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, (C~-Cg)-alkoxy and (C~-Cg)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4. -O-(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 5. -S-(C,-C6)-alkyl.
The invention also relates to the compound of the formula I, where R1 is hydrogen atom or-(C~-C4)-alkyl, R2 is -(C~-C4)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1 ) hydrogen atom, or 1.2) -(C~-C4)-alkyl, 2. -(C~-C4)-alkyl-O-R8, in which R8 is 2.1 ) hydrogen atom, or 2.2) -(C~-C4)-alkyl, 3. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 3.1) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 3.11 ) hydrogen atom, or 3.12) -(C~-C4)-alkyl, 3.2) -O-(C~-C4)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C~-C4)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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, where the nitrogen atoms can, independently of each other, be unsubstituted or substituted by -(C~-C4)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 3.41 ) hydrogen atom, or 3.42) -(C~-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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, where the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C~-C4)-alkyl, 3.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(H)-C(O)-(C~-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61 ) halogen, 3.62) cyano, 3.63) vitro, 3.64) hydroxyl, 3.65) amino, 3.67) -C(O)-O-(C~-Cg)-alkyl, or 5 3.68) -C(O)-OH, 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, 10 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, 15 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 substituted, once, twice or three times, independently of each other, by 4.1 ) halogen, 4.2) amino, 4.3) -C(O)-O-(C~-C4)-alkyl, 4.4) -C(O)-OH, , 4.5) -(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.6) -O-(C~-Cg)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.7) pyridyl, or 4.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C~-C4)-alkoxy and -(C~-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. -(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 4. -O-(C~-Cg)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen.
The invention also relates to the compound of the formula I, where R1 is hydrogen atom, R2 is -(C~-C2)-alkyl, where alkyl is substituted, once, twice or three times, by 1. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 1.1 ) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 1.11 ) hydrogen atom, or 1.12) -(C~-C4)-alkyl, 1.2) -O-(C~-C4)-alkyl-C(O)-O-R8, in which R8 is 1.21 ) hydrogen atom, or 1.22) -(C~-C4)-alkyl, 1.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by (C1-C4)-alkyl, 1.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 1.41 ) hydrogen atom, or 17 , 1.42) -(C1-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C1-C4)-alkyl, 1.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 1.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 1.61 ) halogen, 1.62) -C(O)-O-(C1-C4)-alkyl, or 1.63) -C(O)-OH, 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-tr iazole, and Het is unsubstituted or substituted, once, twice or three times, independently of each other, by 2.1 ) halogen, 2.2) amino, 2.3) -C(O)-O-(C1-C4)-alkyl, 2.4) -C(O)-OH, 2.5) -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.6) -O-(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.7) pyridyl, 2.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C~-C4)-alkoxy and -(C~-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. methyl, 4. trifluaromethyl, 5. methoxy, or 6. trifluoromethoxy.
The term "halogen" is understood as meaning fluorine, chlorine, bromine or iodine.
The term "-(C~-Cg)-alkyl" is understood as meaning, in the widest possible sense, hydrocarbon radicals containing 1, 2, 3, 4, 5 or 6 carbon atoms and whose carbon chain is straight or branched or which consist of cyclic hydrocarbon groups or of combinations of linear and cyclic groups. For example, linear and branched hydrocarbon radicals can be methyl, ethyl, propyl, i-propyl, butyl, tertiary butyl, pentyl or hexyl, while cyclic groups can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and a combination of linear and cyclic radicals can be cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl.
The phrase "R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are in each case bonded, a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulfur" is understood as meaning radicals which can be derived, for example, from dioxolane, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan, dihydrofuran, tetrahydrofuran, oxazole, isoxazole, 2-isoxazoline, isoxazolidine, morpholine, oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolidine or thiomorpholine.
The term "-(Cg-C~4)-aryl" is understood as meaning aromatic carbon radicals having from 6 to 14 carbon atoms in the ring. Examples of -(Cg-C~4)-aryl radicals are phenyl, naphthyl, for example 1-naphthyl and 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 as meaning 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 nitrogen, oxygen and sulfur. In the underlying monocyclic or bicyclic heterocyclic ring system, Het contains 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms.
The monocyclic ring system can be a 3-, 4-, 5-, 6- or 7-membered ring. In the bicyclic Het, two rings can be linked to each other, with it being possible for one of the rings to be a 5-membered or 6-membered heterocyclic ring and the other to be a 5- or 6-membered heterocyclic or carbocyclic ring. A
bicyclic Het group can, for example, be composed of 8, 9 or 10 ring atoms.
Het comprises saturated heterocyclic ring systems which do not possess any double bond in the rings and also unsaturated heterocyclic ring systems, including monounsaturated and polyunsaturated heterocyclic ring systems, which possess one or more double bonds and form a stable ring system. Unsaturated rings can be partially unsaturated or form an aromatic system. The Het group contains 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, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithia-zinyl, dihydrofuran[2,3-b]tetrahydrofuran, fuaranyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, 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, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, 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-tirazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-tirazolyl and xanthenyl.
5 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-benzo-10 dioxolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, chromanyl, isochromanyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridoimidazolyl, pyridopyridinyl, pyridopyrimidinyl, purinyl and pteridinyl.
15 Particular preference is given to 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, 20 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, benzothio-phene, 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 or pyridopyrimidines, etc.
and also ring systems which ensue from the listed heterocycles by linking to or annelation with a carbocyclic ring, for example benzoanelated, cycopentaanelated, cycohexaanelated or cycloheptaanelated derivatives of these heterocycles. Suitable nitrogen heterocycles can also be present as N oxides or as quaternary salts in which a suitable nitrogen atom is alkylated with -(C~-C4)-alkyl radicals. The Het groups can be unsubstituted or substituted in accordance with the listed definitions.
The term "osteoarthrosis" is understood as meaning a disease which chiefly develops in connection with a disparity between the strain on and the load capacity of the individual joint components and joint tissues, which is associated with increasing destruction of the cartilage and which is in the main not inflammatory. Damage to the joint cartilage, such as fraying, demedullation and hyalinization, followed by reactive changes in the subchondral bone, and also capsule changes, is prominent in the pathology. The term "spondylosis" is understood as meaning an arthrosis of the vertebral bodies, with this arthrosis being characterized by a noninflammatory loss of cartilage from the vertebral bodies and intervertebral disks.
The compounds of the formula I can be prepared, for example, by reacting a compound of the formula II

-Y
N
III) N C-Y
O
a) with a compound of the formula Illa or Illb Illa R5 ~ ~ NHz Illb R6 __ where R1, R2, R3, R4, R5, R6 and R7 have the meanings given in formula I and Y is halogen, hydroxyl or C~-C4-alkoxy or forms, together with the carbonyl group, an active ester or a mixed anhydride, with a compound of the formula I being formed and the reaction products being converted, where appropriate, into their physiologically tolerated salts, or b) reacting a compound of the formula II with a compound of the formula Illa or Illb to give a compound of the formula IVa or IVb \ Y
N
R1 ~N ( \ Y H NON
NON

(IVa) (IVb) where R1 to R7 have the meanings given in formula I and Y is halogen, hydroxyl or C~-C4-alkoxy or forms, together with the carbonyl group, an active ester or a mixed anhydride, and purifying the compound of the formula IVa or IVb, where appropriate, and then using a compound of the formula Illa or Illb to convert it into a compound of the formula I.
The preparation of compounds of the formula I, and the preparation of the starting substances which are required for this purpose - insofar as these substances are not commercially available - are described in more detail below.
The compounds according to the invention are most easily prepared by mixing the two components, i.e. the pyrimidine derivative of the formula (II) and the amine of the formula Ills or Illb in equimolar quantities and reacting them, at temperatures of from -30°C to 150°C, preferably at from 20°C to 100°C, to give a compound of the formula IVa or IVb and then reacting the compounds of the formula IVa or IVb with up to an equimolar quantity of the amine of the formula Illb or Illa in an analogous manner. The termination of the reaction can be determined, for example, by means of thin layer chromatography or HPLC-MS. A variant of this method is that the reaction is carried out in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, choloroform, trichloroethylene or tetrachloroethylene, benzene or toluene, or else polar solvents, such as dimethylformamide, acetone or dimethyl sulfoxide. The reaction temperatures in this connection are between room temperature and the boiling point of the solvent, with temperatures in the range from room temperature up to 130°C being particularly preferred.
Reaction can also take place by way of a mixed anhydride, such as ethyl chloroformate, or by way of an active ester, such as paranitrophenyl ester (Y = CICH2-COO or N02-CgH4-O). Appropriate methods are known and described in the literature.
A compound of the formula II or a compound of the formula IVa or IVb can also react with an amine of the formula Illa or Illb if Y is OH and the corresponding carboxylic acid is activated in situ using customary coupling reagents. Examples of these coupling reagents are carbodiimides, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI), or N,N'-carbonyldiazoles, such as N,N'-carbonyldiimidazole, or a uronium salt, such as O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyl-uroniumtetrafluoroborate (TOTU) or O-(7-azabenzotriazol-1-yl)-1,3,3,-tetramethyluronium hexafluorophosphate (HATU). Appropriate methods are known.
If amines of the formula Illa or Illb are not commercially available, they can be prepared from corresponding, commercially available starting compounds using methods known in the literature. Examples of suitable starting compounds for amines are nitrites, nitro compounds, carboxamides, carboxylic esters, carboxylic acids, aldehydes and bromides. Nitrites, nitro compounds and carboxamides can be reduced to amines using known methods. Carboxylic acids and carboxylic esters can be converted into the carboxamides. Aldehydes can be converted directly into the amines by means of a reductive amination with NH4Ac/NaBH4, or can be initially converted into the oximes using hydroxylamine and then being converted into the amines by reduction.
Where appropriate, the reaction can also take place in the presence of bases. Examples of suitable additional bases are carbonates or hydrogen carbonates, such as sodium carbonate or potassium carbonate or sodium hydrogen carbonate or potassium hydrogen carbonate, or tertiary amines, such as triethylamine, tributylamine or ethyldiisopropylamine, or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylanilines.
Where appropriate, the products, in particular the compound of the formula IVa or IVb can be worked up, for example, by means of extraction or chromatography, e.g. through silica gel. The isolated product can be recrystallized and reacted, where appropriate, with a suitable acid to give a physiologically tolerated salt. Examples of suitable acids are:

mineral acids, such as hydrochloric acid and hydrobromic acid, and also sulfuric acid, phosphoric acid, nitric acid or perchloric acid, or organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, malefic acid, fumaric acid, phenylacetic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid, oxalic acid, 4-aminobenzoic acid, naphthalene-1,5-disulfonic acid or ascorbic acid.
Insofar as they are not commercially available, the starting compounds of the formula Illa or Illb can be prepared readily (e.g. Organikum, Organisch Chemisches Grundpraktikum [Organicum, basic practical course in organic chemistryJ, 15th edn, VEB Deutscher Verlag der Wissenschaften, 1976; the methods index contains a review of the different possibilities on 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-dicarbonyl halide or pyridine-2,4-dicarbonyl halide, preferably chloride (using methods known from the literature), preferably in the presence of a catalyst such as dimethyl-formamide. This acid halide can then be reacted, for example, either with a suitable alcohol, e.g. paranitrobenzyl alcohol to give the corresponding active ester, or else with lower alcohols, such as methanol or ethanol, to give the corresponding esters. The pyrimidine-4,6-dicarboxylic acid can also initially be converted, in the added presence of a suitable carboxylic acid or of a carboxylic ester, such as ethyl chloroformate, into a mixed anhydride, which is then reacted with the amines of the compound of the formulae Illa or Illb and IVa or IVb to give the products according to the invention. A corresponding method is also described in the literature.
The pyrimidine-4,6-dicarboxylic acid is prepared in accordance with methods known from the literature, for example by oxidizing 4,6-dimethyl-pyrimidine, which, for its part, can be obtained, for example, by catalytically hydrogenating commercially available 2-mercapto-4,6-dimethylpyrimidine.
Insofar as compounds of the formula I permit diastereoisomeric or enantiomeric forms and accrue as their mixtures in the synthesis which is selected, separation into the pure stereoisomers is achieved either by chromatography on an optionally chiral support material or, provided the racemic compound of the formula I is capable of salt formation, by fractionally crystallizing the diastereomeric salts which are formed using an optically active base or acid as auxiliary substance. Examples of suitable chiral stationary phases for the thin-layer or column chromatographic separation of enantiomers are modified silica gel supports (what are termed 5 Pirkle phases) and also high molecular weight carbohydrates, such as triacetyl cellulose. Following appropriate derivatization, which is known to the skilled person, gas-chromatographic methods on chiral stationary phases can also be used for analytical purposes. In order to separate the enantiomers of the racemic carboxylic acids, the diastereomeric salts, 10 which differ in solubility, are formed using an optically active, as a rule commercially available, base such as (-)-nicotine, (+)- and (-)-phenylethylamine, quinine bases, L-lysine or L- and D-arginine, the more sparingly soluble component is isolated as a solid, the more readily soluble diastereomer is separated out from the mother liquor, and the pure 15 enantiomers are isolated from the diastereomer salts which have been obtained in this way. The racemic compounds of the formula I which contain a basic group, such as amino group, can, in what is in principle the same manner, be converted into the pure enantiomers using optically active acids, such as (+)-camphor-10-sulfonic acid, D- and L-tartaric acid, 20 D- and L-lactic acid and (+) and (-)-mandelic acid. Chiral compounds which contain alcohol or amine functions can also be converted into the corresponding esters or amides using appropriately activated or optionally N-protected enantiomerically pure amino acids or, conversely, chiral carboxylic acids can be converted into the amides using carboxyl-protected 25 enantiomerically pure amino acids or into the corresponding chiral esters using enantiomerically pure hydroxycarboxylic acids such as lactic acid.
The chirality of the amino acid or alcohol radical which has been introduced in enantiomerically pure form can then be used for separating the isomers by the diastereomers, which are now present, being separated by means of crystallization or chromatography on suitable stationary phases and, after that, using suitable methods to once again eliminate the entrained chiral molecule moiety.
Acidic or basic products of the compound of the formula I may be present in the form of their salts or in free form. Preference is given to pharmacologically tolerated salts, e.g. alkali metal salts or alkaline earth metal salts or hydrochorides, hydrobromides, sulfates, hemisulfates, all possible phosphates and also salts of the amino acids, natural bases or carboxylic acids.

Physiologically tolerated salts are prepared in a manner known per se from compounds of the formula I, including their stereoisomeric forms, which are capable of salt formation. The carboxylic acids form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides; carbonates, hydrogencarbonates, alkoxides and ammonia or organic bases, for example trimethylamine, triethylamine, ethanolamine or triethanolamine, or else basic amino acids, for example lysine, ornithine or arginine. Insofar as the compounds of the formula I possess basic groups, stable acid addition salts can also be prepared using strong acids. Both inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid, acetic acid, oxalic acid, tartaric acid, succinic acid and trifluoroacetic acid are suitable for this purpose.
As a result of their pharmacological properties, the compounds of the formula I are suitable for the prophylaxis and therapy of all those diseases whose course involves an increased activity of matrix metalloproteinase 13.
These diseases include degenerative joint diseases, such as osteoarthroses, spondyloses and cartilage loss following joint trauma or relatively long joint immobilization following meniscus or patella injuries or ligament rupture. They also include diseases of the connective tissue, such as collagenoses, periodontal diseases, wound healing disturbances and chronic diseases of the locomotory apparatus such as inflammatory, immunologically determined or metabolism-determined, acute and chronic arthritides, arthropathies, myalgias and disturbances of bone metabolism, or cancers, such as breast cancer.
The pharmaceuticals according to the invention can be administered by subcutaneous, intraarticular, intraperitoneal or intravenous injection.
Intraarticular injection is preferred. Rectal, oral, inhalative or transdermal administration is also possible.
The invention also relates to a process for producing a pharmaceutical, wherein at least one compound of the formula I is brought, together with a pharmaceutically suitable and physiologically tolerated carrier and, where appropriate, other suitable active compounds, additives or auxiliary substances, into a suitable form for administration.
The compounds of the formula I are mixed with the additives, such as carrier substances, stabilizers or inert diluents, which are suitable for the purpose and brought into suitable administration forms, such as tablets, sugar-coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions or aqueous or oily solutions, using the customary methods.
Examples of inert carrier substances which can be used are gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. In this connection, the preparation can be effected either as dry granules or as wet granules.
Examples of suitable oily carrier substances or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil.
For subcutaneous, intraarticular, intraperitoneal or intravenous administration, the active compounds are, if desired, brought into solution, suspension or emulsion using the substances which are suitable for this purpose, such as solubilizers, emulsifiers or other auxiliary substances.
Examples of suitable solvents are physiological sodium chloride solution or alcohols, e.g. ethanol, propanol or glycerol, and, in addition, sugar solutions, such as solutions of glucose or mannitol, or else a mixture which is composed of the different solvents mentioned.
Customary adjuvants, such as carrier substances, disintegrants, binding agents, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are also used. Auxiliary substances which are frequently employed and which may be mentioned 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 oil, peanut oil or sesame seed oil, polyethylene glycol and solvents such as sterile water and monohydric or polyhydric alcohols, such as glycerol.
The compounds of the formula I are preferably prepared as pharmaceutical preparations and administered in dosage units, with each unit containing a defined dose of the compound of the formula I as the active constituent.
For this purpose, the compounds of the formula I can be administered orally in doses of from 0.01 mg/kg/day to 25.0 mg/kg/day, preferably from 0.01 mg/kg/day to 5.0 mg/kg/day, or parenterally in doses of from 0.001 mg/kg/day to 5 mg/kg/day, preferably of from 0.001 mg/kg/day to 2.5 mg/kg/day. The dosage can also be increased in severe cases.
However, smaller doses are also adequate in many cases. These figures relate to the treatment of an adult.
The invention is explained in more detail below with the aid of examples.
Example 1: tert-Butyl [4-(f[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]amino}methyl)phenoxy]acetate tert-Butyl (4-formylphenoxy)acetate: 10 g (0.0819 mol) of 4-hydroxybenz-aldehyde and 15.97 g (0.0819 mol) of tert-butyl bromoacetate were dissolved in 200 ml of 2-butanone, after which 11.32 g (0.0819 mol) of potassium carbonate were added and the mixture was heated under reflux for 2 hours (h). The mixture was then concentrated under reduced pressure and the residue was taken up in water and the solution was extracted three times with dichloromethane. The organic phase was dried (MgS04), filtered and concentrated under reduced pressure.
Yield: 18.72 g (97%) tert-Butyl [4-(hydroxyiminomethyl)phenoxy]acetate: 18.72 g (0.0792 mol) of tert-butyl (4-formylphenoxy)acetate were dissolved in 200 ml of water/ethanol (1:1), after which 6.056 g (0.0872 mol) of hydroxyammonium chloride and 3.169 (0.0792 mol) of sodium hydroxide were added and the mixture was stirred under reflux for 2.5 hours (h). The mixture was concentrated under reduced pressure and the residue was taken up in water and the solution was extracted with ethyl acetate. The organic phase was dried (MgS04), filtered and concentrated under reduced pressure.
Yield: 19.9 g (100%) MS (ES+): m/e = 251.12 tert-Butyl (4-aminomethylphenoxy)acetate: 6 g (0.0239 mol) of tert-butyl [4-(hydroxyiminomethyl)phenoxy]acetate were dissolved in 10 ml of water/ethanol (1:1 ) and hydrogenated, under a pressure of 5 bar and at room temperature, over 0.06 g of Pd/C (10%). After 3 hours (h), the mixture was filtered through Celite and concentrated under reduced pressure.
Yield: 4.26 g (75%) Methyl 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylate: the compound was prepared in analogy with methyl 6-benzylcarbamoylpyrimi-dine-4-carboxylate.
6-(4-Fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid: 0.889 g (0.0222 mol) of sodium hydroxide in 6 ml of water was added to 8.75 g (0.0202 mol) of methyl 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylate in 80 ml of methanol and the mixture was stirred at room temperature (RT). After 2.5 hours, the solvent was removed under reduced pressure and the residue was dissolved in 300 ml of water and the solution was acidified with concentrated HCI. The precipitate was filtered off and dried.
Yield: 5.43 g (95%) MS (ES+): m/e = 289.09 tert-Butyl [4-({[6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]-amino}methyl)phenoxy]acetate: 150 mg (0.519 mmol) of 6-(4-fluoro-3-methylbenzylcarbamoyl)pyrimidine-4-carboxylic acid were dissolved in 5 ml of DMF, after which 170 mg (0.519 mmol) of TOTU were added and the mixture was stirred at RT for 30 minutes. 147.6 mg (0.62 mmol) of tert-butyl (4-aminomethylphenoxy)acetate and 119.55 mg (1.038 mmol) of N-ethyl-morpholine were then 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 homogeneous 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-methylbenzylcarbamoyl)pyrimidine-4-carbonyl]-amino}methyl)phenoxy]acetic acid 83.6 mg (0.16 mmol) of tert-butyl [4-({[6-(4-fluoro-3-methylbenzylcarba moyl)pyrimidine-4-carbonyl]amino~methyl)phenoxy]acetate (Example 31 ) were stirred at RT for 4 hours in 90% trifluoroacetic acid. Acetonitrile/water was then added and the precipitate was filtered off and dried.
Yield: 55 mg (76%) MS (ES+): m/e = 452.15 The following compounds were prepared in analogy with Example 1.

Table 1:
Example Structure MS (ESI+) 1 508.21 o' v /
I
\ N/~ N / I F
NI / H \

2 452.15 w o~
o \
I ~ N~ N
I
O O
3 477.00 N~ f N/~N / F
N I / N \ I
O O
4 ~0 396.13 S N~N /
N I / N \ I ~~a O
O O
5 H,c 463.OZ
s N~N / F
N~~N

6 382.11 s o \ /N o-N
O
7 ~ 384.11 i'~NI / I F
N~~N

8 N/ N~N / F 433.05 a \ I N I / N \ ( a 9 411.11 N I NI~N / I
CI ~ N N ~ O~CH~
O O

10 ~c~ 407.16 N~N
\ I N I ~ N \
O O
11 H,c~o 473.05 N ~ I Br \ N~ N / F I
N I / N \ I
O O
1 Z S 6r 448.00 N~N ~ F
N I~~N ~
O O
13 380.15 ~~ lol i N ~ I ~
o~c 14 ~ ~ F - 399.09 ~ I N I ~ N
G

15 ~ , F 404.05 I N I / N ~
a 16 382.14 Gi, O N/~N / F
N I / N
O O

443.04 N 9r \ I N I/~N N / I F
/ \
O O
18 448.00 /i i~N / I F
N / N \
O O

19 ~O 418.07 N~ / F
N I / N \
CI
O O
2p o~~ 429.10 F
N/ N ~N /
\ I N ( / N \ d O O
21 382.11 NON /
N I / \

22 377.15 N/ I ~~N ~ I
\ N / N \ ~Cfi3 O
O O
23 ~ F 404.05 N N /
N 4 / N \ I a 24 a N 477.00 ~f / N/~N / F
N I / N \
O O
25 ~,c 449.03 sr NON / F
N I / N ~

26 ~ I cri, 368.13 F
~hN / I
N"~~N \
'O~ ~ ~O
27 F 443.04 % N~N
\ ~ N I / N'Wgr O O

28 F 418.07 N~N /
\ N ~ / N \ I d Z9 ~, 473.05 O N
I ~ r NON / F
N
O O
30 377.15 N N/~N /
\ I N I / N~O

O O
31 _ 366.13 I O I N I /N N \ ( i~
O
O O
32 "-- H 382.16 HOC-N
N/~N ~ F
N ~ / N

33 ~ - ~ 409.15 O i N~N / F
\ I N I / N \ I
O O
446.05 N
Br i~N / I F
N / N \
O O
35 - 398.1 Z
I w NON S
i N I ~ N

36 396.00 NII~N
N~~N \ ~ Oil O~ ~ ~O
37 ~ F 418.07 s N ~N /
/ N I / N
G
C
f'Ls 0 0 38 396.13 N~N /
~~N ( / N \ I OiC~
hi~CIY \/ \
39 / ~ 379.14 N~ N~N / F
N I / N \ I

40 ~i B~ 449.00 </ F
S~ N~N /
N I / N \ I
O O
41 H,c N~ cH 394.16 I
~N N~N / F
N I / N \
O O
42 F 394.08 N~ N /
i0 N I / N \
H,C ~ ~~~ G

43 405.05 F
N N~N
~N I / N \ I G

44 383.00 N N~N /
~~N I / N \ I O~C~
O O

45 F / N/yN N 365.13 \ I N I / N \

46 Ha 393.16 F
N~N /
wN ~ N~~~N \ I
O~ '' ~O
47 ~H~ 388.15 H C O\ ~ / F
~ ~O IN NI /N N \ I
O O
48 380.07 ~N / F
HO N I / N \ I
O O O
49 392.16 i ~C~N~N I /N \
O O
50 399.09 N~N / F
N ~ N ~ / N \ d 51 434.16 O N~N
~CwO~N N \
Clip O 0 52 391.16 N~N /
N \ N I / N \ I OiC~
( /

5~- ' 358.13 0 N~N
~C~O~N I / N \
O O
54 F 380.07 I1~C N / N
I~N / ~ G
O O
55 ~c~ 360.12 cH, I~ N / I F
N~~N \
O O
56 394.08 F
O N~N /
~C~O N I / N \ ~ d Giy O O
57 392.16 \ ~ N I / N
N~ N~N
N
O O
5g 391.16 N~N
N~~N \
O O
5g 408.15 N~N
~N. N~~~N \ I OiC
[/
N O O
hi~C
60 372.14 N~N /
N I / N

61 ~o\ 346.14 N~ / F
N~~N \ I
O O
62 393.00 '1 \ N
N~N / F
N~~N \ I

63 ~~, 461.00 N
\ /
NInN / I F
N'~~N \
O O
6q OH CH3 332.13 N N / F
N I / N \
O O
65 N--, 382.16 N
N~N / F
N~~N \

66 330.13 N~N
HON I / N \ I O~C~

67 N, 434.03 Br vN N~N / F
N I / N \
O O
68 H,~~N~~, S19.12 O
Br ~C~O~ N~N ~ ~ F
N / N
O O
69 ~ 463.22 w I r~ N ~ w 70 \~ 463.00 N~ N /
\ I " i ~- b \ I

71 477.24 I
/N
N 'N /
\ I / \ ~ O/
O O
72 527.17 \ ~' N \ i F
a 73 420.14 ai O ~N
\( ~ \I

74 452.15 o\ / a-i I
~N / I F
/ \
O O
75 505.23 N~ N
~i y ~I
J o 76 a 416.07 /
N-~'~
\ /N
O
O
O
77 465.05 s e~
i ' N / I F
t-N / N \
O O
78 399.22 s ~N / F
~f ' \
O O

79 413.11 a N~
\ N~ N / I F
I / H \

80 418.07 F
I ~ N~ N
O O
81 / 380.15 N
O
NH _ O
O-82 399.09 N~ N / F
\ I H I / \ a O O

404.05 ~ F
I I N i N H
a 382.14 N~ N / F
i /

85 443.04 N~
I
\ ~ ~ F
~-r~ I , b \ I

86 448.00 j S 8' / i 'N / I F
/ \
O O
87 418.07 5 H i 'N H / I F
/ N~., a gg 384.11 r~~ N /
/ ~ \
O O
89 377.15 N~ N / I
H I N \ O/

90 404.05 N~ N / F
I / \
a 91 477.00 a I
F
I / H \
O O
92 379.14 F
N \\~N
I / N ~ / N ~~~I .
O O
93 449.03 o a / F
I/
I

Pharmacological examples Determining the enzyme activity of the catalytic domain of human collagenase 3 (MMP-13).
This protein is obtained as an inactive proenzyme from INVITEK, Berlin (Catalog No. 30 100 803). Activating the proenzyme:
2 parts by volume of proenzyme are incubated with 1 part by volume of APMA solution at 37°C for 1.5 hours. The APMA solution is prepared from a 10 mmol/l solution of p-aminophenylmercuric acetate in 0.1 mmol/l NaOH
by diluting with 3 parts by volume of tris/HCl buffer, pH 7.5 (see below).
The pH is adjusted to between 7.0 and 7.5 by adding 1 mmol/I HCI. After the enzyme has been activated, it is diluted to a concentration of 1.67 ~g/ml using the tris/HCl buffer.
In order to measure the enzyme activity, 10 NI of enzyme solution are incubated for 15 minutes with 10 NI of a 3% (v/v) buffered solution of dimethyl sulfoxide (reaction 1). In order to measure the enzyme inhibitor activity, 10 NI of enzyme solution are incubated with 10 NI of a 3% (v/v) buffered solution of dimethyl sulfoxide containing the enzyme inhibitor (reaction 2).
In the case of both reaction 1 and reaction 2, the enzyme reaction is monitored by fluorescence spectroscopy (328 nm (extinction)1393 nm (emission)) after adding 10 NI of a 3% (v/v) aqueous solution of dimethyl sulfoxide containing 0.75 mmol of the substrate/I.
The enzyme activity is depicted as increase in extinction/minute.
The effect of the inhibitor is calculated as a percentage inhibition using the following formula:
inhibition = 100 - [(increase in extinction/minute in reaction 2)/(increase in extinction/minute in reaction 1 ) x 100].
The ICSp, i.e. the inhibitor concentration which is required for inhibiting the enzyme activity by 50%, is determined graphically by plotting the percentage inhibitions at different inhibitor concentrations.
The buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) and 0.1 mol of tris/HCl/l, 0.1 mol of NaCl/l and 0.01 mol of CaCl2/I (pH = 7.5).
The enzyme solution contains 1.67 ~,g of the enzyme domain/ml.

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-NH2 (Bachem, Heidelberg, Germany).
Table 2 below shows the results.
Table 2:
Example IC5p MMP13 (nM) Example IC5p MMP13 (nM) Determining the enzyme 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, were also carried out as described in that publication.
When determining human neutrophil collagenase and human stromelysin, the compounds described in the above examples in each ~ case had IC50 values of more than 100 000 nM. These compounds are therefore virtually without activity as regards inhibiting MMP 3 and 8.
Determining prolyl hydroxylase inhibition by the method of Majamaa Eur. J.
Biochem. 138 (1984) 239-245 using the version of Kaule and Guenzler Analytical Biochemistry 184 (1990) 291-297.
0.03 pg of prolyl 4-hydroxylase, which was prepared, by the method of Kedersa, Collagen Relat. Res. 1 (1981 ) 345-353, from homogenized 14-day-old chick embryos by ammonium sulfate precipitation and affinity chromatography on poly-L-proline-coupled Sepharose 4B and subsequent DEAE cellulose chromatography, was incubated, at 37°C for one hour, in 0.05 ml of an 0.04 M tris-HCI solution (pH = 7.5) containing 0.05 mM

FeS04, 0.1 mM 2-oxo-[5-C-14]glutarate (100 000 dpm), 20 pg (0.4 mg/ml) of (Pro-Pro-Gly)~p (Protein Research Foundation, Minoh, Osaka, Japan), 1 mM ascorbic acid, 0.4 mg of catalase/ml, 0.5 mM dithiothreitol and 2 mg of bovine serum albumin/ml, as well as the concentration of the inhibitor to be measured (the comparison experiment was carried out without any inhibitor). After that, 25 pl of a 20 mM succinate and 2-oxaglutarate solution, and also 25 pl of a 0.16 M 2,4-DNPH solution containing 30%
HC104, were added. After the mixture had been incubated at room temperature for a further 30 minutes, it was centrifuged at 3000 g for 5 minutes. The radioactivity of 100 p.l of the supernatant was determined by liquid scintillation. Production of the [1-C-14] succinate was given in dpm.
Unless otherwise indicated, all the chemicals and reagents were obtained from Sigma, Sigma D-82024 Taufkirchen.
The compounds tested in Table 3 were used at concentrations of from 0.1 wM to 1 mM. Where it was possible, the IC50 value was determined by graphic extrapolarization of the individual results. This value denotes the concentration of active inhibitors which led to 50% inhibition of the enzyme.
Table 3:
Example Prolyl hydroxylaseExample Prolyl hydroxylase Pyrimidine-4,6-1.2 70 No inhibition dicarbox lic acid 7 No inhibition 71 No inhibition 14 No inhibition 72 No inhibition 16 No inhibition 83 No inhibition 22 No inhibition 84 No inhibition 69 No inhibition

Claims (9)

claims 1. A 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 tolerated salt of the compound of the formula I, where R1 is hydrogen atom or -(C1-C6)-alkyl, R2 is -(C1-C6)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1) hydrogen atom, or 1.2) -(C1-C6)-alkyl, 2. -(C1-C6)-alkyl-O-R8, in which R8 is 2.1) hydrogen atom, or 2.2) -(C1-C6)-alkyl, 3. -(C6-C14)-aryl, in which aryl is substituted, once, twice or three times, independently of each other, by 3.1) -(C2-C6)-alkyl-C(O)-O-R8, in which R8 is 3.11) hydrogen atom, or 3.12) -(C1-C6)-alkyl, 3.2) -O-(C1-C6)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C1-C6)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15-form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3, 4 or 5 and R9 and R10 are identical or different and are, independently of each other, 3.41) hydrogen, or 3.42) -(C1-C6)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl, 3.5) -O-(C2-C6)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(R8)-C(O)-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61) halogen, 3.62) cyano, 3.63) nitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C1-C6)-alkyl, or 3.67) -C(O)-OH, 4. Het, where Het is 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 nitrogen, oxygen and sulfur and is unsubstituted or substituted, once or more than once, by 4.1) halogen, 4.2) cyano, 4.3) nitro, 4.4) hydroxyl, 4.5) amino, 4.6) -C(O)-O-(C1-C6)-alkyl, 4.7) -C(O)-OH, 4.8) -(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.9) -O-(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.10) pyridyl, or 4.11) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, (C1-C6)-alkoxy and (C1-C6)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4. -O-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 5. -S-(C1-C6)-alkyl.

2. A compound of the formula 1 as claimed in claim 1, where R1 is hydrogen atom or -(C1-C4)-alkyl, R2 is -(C1-C4)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1) hydrogen atom, or 1.2) -(C1-C4)-alkyl, 2. -(C1-C4)-alkyl-O-R8, in which R8 is 2.1) hydrogen atom, or 2.2) -(C1-C4)-alkyl, 3. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 3.1) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 3.11) hydrogen atom, or 3.12) -(C1-C4)-alkyl, 3.2) -O-(C1-C4)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C1-C4)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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, where the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C4)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 3.41) hydrogen atom, or 3.42) -(C1-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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, where the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C4)-alkyl, 3.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, 3.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61) halogen, 3.62) cyano, 3.63) nitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C1-C6)-alkyl, or 3.67) -C(O)-OH, 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, pyrrol, 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 substituted, once, twice or three times, independently of each other, by 4.1) halogen, 4.2) amino, 4.3) -C(O)-O-(C1-C4)-alkyl, 4.4) -C(O)-OH, 4.5) -(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.6) -O-(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.7) pyridyl, or 4.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C1-C4)-alkoxy and -(C1-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. -(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 4. -O-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen.

3. A compound of the formula I as claimed in claims 1 or 2, where R1 is hydrogen atom, R2 is -(C1-C2)-alkyl, where alkyl is substituted, once, twice or three times, by 1. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 1.1) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 1.11) hydrogen atom, or 1.12) -(C1-C4)-alkyl, 1.2) -O-(C1-C4)-alkyl-C(O)-O-R8, in which R8 is 1.21) hydrogen atom, or 1.22) -(C1-C4)-alkyl, 1.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C1-C4)-alkyl, 1.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 1.41) hydrogen atom, or 1.42) -(C1-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C1-C4)-alkyl, 1.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, or 1.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 1.61) halogen, 1.62) -C(O)-O-(C1-C4)-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 substituted, once, twice or three times, independently of each other, by 2.1) halogen, 2.2) amino, 2.3) -C(O)-O-(C1-C4)-alkyl, 2.4) -C(O)-OH, 2.5) -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.6) -O-(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.7) pyridyl, or 2.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C1-C4)-alkoxy and -(C1-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. methyl, 4. trifluoromethyl, 5. methoxy, or 6. trifluoromethoxy.

4. The 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 tolerated salt of the compound of the formula I

for producing a pharmaceutical for the prophylaxis and therapy of diseases whose course involves an increased activity of matrix metalloproteinase 13, where R1 is hydrogen atom or -(C1-C6)-alkyl, R2 is -(C1-C6)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1) hydrogen atom, or 1.2) -(C1-C6)-alkyl, 2. -(C1-C6)-alkyl-O-R8, in which R8 is 2.1) hydrogen atom, or 2.2) -(C1-C6)-alkyl, 3. -(C6-C14)-aryl, in which aryl is substituted, once, twice or three times, independently of each other, by 3.1) -(C2-C6)-alkyl-C(O)-O-R8, in which R8 is 3.11) hydrogen atom, or 3.12) -(C1-C6)-alkyl, 3.2) -O-(C1-C6)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C1-C6)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3, 4 or 5 and R9 and R10 are identical or different and are, independently of each other, 3.41) hydrogen, or 3.42) -(C1-C6)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl, 3.5) -O-(C2-C6)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, or 3.6) -N(R8)-C(O)-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61) halogen, 3.62) cyano, 3.63) nitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C1-C6)-alkyl, or 3.67) -C(O)-OH, 4. Het, where Het is 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 nitrogen, oxygen and sulfur and is unsubstituted or substituted, once or more than once, by 4.1) halogen, 4.2) cyano, 4.3) nitro, 4.4) hydroxyl, 4.5) amino, 4.6) -C(O)-O-(C1-C6)-alkyl, 4.7) -C(O)-OH, 4.8) -(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.9) -O-(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.10) pyridyl, or 4.11) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, (C1-C6)-alkoxy and (C1-C6)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4. -O-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 5. -S-(C1-C6)-alkyl.

5. The use of the compound of the formula 1 as claimed in claim 4, where R1 is hydrogen atom or -(C1-C4)-alkyl, R2 is -(C1-C4)-alkyl, where alkyl is substituted, once, twice or three times, by 1. -C(O)-O-R8, in which R8 is 1.1) hydrogen atom, or 1.2) -(C1-C4)-alkyl, 2. -(C1-C4)-alkyl-O-R8, in which R8 is 2.1) hydrogen atom, or 2.2) -(C1-C4)-alkyl, 3. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 3.1) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 3.11) hydrogen atom, or 3.12) -(C1-C4)-alkyl, 3.2) -O-(C1-C4)-alkyl-C(O)-O-R8, in which R8 is 3.21) hydrogen atom, or 3.22) -(C1-C4)-alkyl, 3.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C1-C4)-alkyl, 3.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 3.41) hydrogen atom, or 3.42) -(C1-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by (C1-C4)-alkyl, 3.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, or 3.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 3.61) halogen, 3.62) cyano, 3.63) nitro, 3.64) hydroxyl, 3.65) amino, 3.66) -C(O)-O-(C1-C6)-alkyl, or 3.67) -C(O)-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, pyrrol, 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 substituted, once, twice or three times, independently of each other, by 4.1) halogen, 4.2) amino, 4.3) -C(O)-O-(C1-C4)-alkyl, 4.4) -C(O)-OH, 4.5) -(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.6) -O-(C1-C6)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 4.7) pyridyl, or 4.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C1-C4)-alkoxy and -(C1-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are 1. hydrogen atom, 2. halogen, 3. -(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen, or 4. -O-(C1-C6)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by halogen.

6. The use of the compounds of the formula I as claimed in claims 4 and 5, where R1 is hydrogen atom, R2 is -(C1-C2)-alkyl, where alkyl is substituted, once, twice or three times, by 1. phenyl, in which phenyl is substituted, once, twice or three times, independently of each other, by 1.1) -(C2-C4)-alkyl-C(O)-O-R8, in which R8 is 1.11) hydrogen atom, or 1.12) -(C1-C4)-alkyl, 1.2) -O-(C1-C4)-alkyl-C(O)-O-R8, in which R8 is 1.21) hydrogen atom, or 1.22) -(C1-C4)-alkyl, 1.3) -N(R14)-(R15), in which R14 and R15 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by (C1-C4)-alkyl, 1.4) -(CH2)k-N(R9)-(R10), in which k is 2, 3 or 4 and R9 and R10 are identical or different and are, independently of each other, 1.41) hydrogen atom, or 1.42) -(C1-C4)-alkyl, or R9 and R10 form, together with the nitrogen atom to which they are bonded, 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 can, independently of each other, be unsubstituted or substituted by -(C1-C4)-alkyl, 1.5) -O-(C2-C4)-alkyl-N(R9)-R10, where R9 and R10 have the abovementioned meaning, or 1.6) -N(H)-C(O)-(C1-C4)-alkyl, in which alkyl is unsubstituted or substituted, once, twice or three times, by 1.61) halogen, 1.62) -C(O)-O-(C1-C4)-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 substituted, once, twice or three times, independently of each other, by 2.1) halogen, 2.2) amino, 2.3) -C(O)-O-(C1-C4)-alkyl, 2.4) -C(O)-OH, 2.5) -(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.6) -O-(C1-C4)-alkyl, where alkyl is unsubstituted or substituted, once, twice or three times, by halogen, 2.7) pyridyl, 2.8) phenyl, where phenyl is unsubstituted or substituted, once or more than once and independently of each other, by a radical from the series halogen, -(C1-C4)-alkoxy and -(C1-C4)-alkyl, and R3, R4, R5, R6 and R7 are identical or different and are

1. hydrogen atom,

2. halogen,

3. methyl,

4. trifluoromethyl,

5. methoxy, or

6. trifluoromethoxy.

7. A process for preparing the compound of the formula I as claimed in one or more of claims 1 to 6, which comprises 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 have the meanings given in formula I and Y is halogen, hydroxyl or C1-C4-alkoxy or forms, together with the carbonyl group, an active ester or a mixed anhydride, with a compound of the formula I being formed and the reaction products being converted, where appropriate, into their physiologically tolerated salts, or b) reacting 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 where R1 to R7 have the meanings given in formula I and Y
is halogen, hydroxyl or C1-C4-alkoxy or forms, together with the carbonyl group, an active ester or a mixed anhydride, and purifying the compound of the formula IVa or IVb, where appropriate, and then using a compound of the formula IIIa or IIIb to convert it into a compound of the formula I.

8. A pharmaceutical, which comprises an effective content of at least one compound of the formula I as claimed in one or more of claims 1 to 3 together with a pharmaceutically suitable and physiologically tolerated carrier substance, additive and/or other active compounds and auxiliary substances.

9. The use of the compound of the formula I as claimed in one or more of claims 4 to 6 for producing a pharmaceutical for the prophylaxis and therapy of diseases whose course involves an increased activity of matrix metalloproteinase 13, where the diseases involved are degenerative joint diseases such as osteoarthroses, spondyloses and cartilage loss following joint trauma or relatively long joint immobilization following meniscus or patella injuries or ligament rupture, or diseases of the connective tissue, such as collagenoses, periodontal diseases, wound healing disturbances and chronic diseases of the locomotory apparatus such as inflammatory, immunologically determined or metabolism-determined, acute and chronic arthritides, arthropathies, myalgias and disturbances of bone metabolism or cancer diseases such as breast cancer.