NO330345B1 - Pyrimidine-4,6-dicarboxylic acid diamides, process for their preparation and composition containing at least one such compound - Google Patents

Abstract

Pyrimidine-4,6-dicarboxamides of formula (1) are described, the substituents having the defined meanings. The compounds of formula (I) are suitable for the selective inhibition of collagenase (MMP 13). The pyrimidine-4,6-dicarboxamides can thus be used for the treatment of degenerative joint diseases.

Description

The present invention relates to new pyrrinidine-4,6-dicarboxylic acid diamides, a method for production and a pharmaceutical composition containing at least one such compound. The compounds can be used for selective inhibition of collagenase (MMP 13), and they can therefore be used for the treatment of degenerative joint diseases.

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 thereby cause an inhibition of collagen biosynthesis by influencing the collagen-specific hydroxylation reaction (EP 0418797; EP 0463592). Due to this inhibition of collagen biosynthesis, a non-functional, underhydroxylated collagen molecule is formed which can only be released from the cells to the extracellular space to a small extent. In addition, the underhydroxylated collagen cannot be incorporated into the collagen matrix and is very easily broken down proteolytically. As a result of this effect, the overall amount of extracellularly deposited collagen is reduced. From WO 02/064571 and WO 02/064080 it is known that particular pyridine-2,4-dicarboxylic acid diamides and pyrimidine-4,6-dicarboxylic acid diamides can be allosteric inhibitors of MMP 13.

In diseases such as osteoarthritis and rheumatic diseases, there is a destruction of the joints, particularly due to the proteolytic breakdown of collagen due to collagenases. Collagenases belong to the superfamily of the metalloproteinases (MP), respectively. the matrix metalloproteinases (MMP). The 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, resp. the collagenases, are known (EP 0 606 046; WO94/28889). Shortcomings of the known inhibitors of MMPs are often the lack of specificity of the inhibition for only one class of MMPs. Therefore, most MMP inhibitors inhibit several MMPs at the same time, because the catalytic domains of the MMPs have a similar structure. As a result, the inhibitors act in an undesirable manner on several enzymes, including those with vital functions (I. Massova, et al., The FASEB journal (1998) 12, 1075-1095).

In the attempt to find effective compounds for the treatment of connective tissue diseases, it has now been found that the compounds used in the invention are strong inhibitors of matrix metalloproteinase 13, while the compounds used according to the invention are essentially inactive against MMPs 3 and 8.

The object of the present invention is therefore a compound of 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 compounds of formula I, whereby

RI is hydrogen atom or -(Ci-C6)-alkyl,

R 2 is -(C 1 -C 6 )alkyl, wherein alkyl is substituted one, two or three times by

-(C 6 -C 14 )-aryl, wherein aryl is substituted one, two or three times, independently of each other, with

1) -(C0-C6)-alkyl-C(O)-N-(R9)-(R10), wherein R9 and R10 are the same or different and are, independently of each other

i) hydrogen atom or

ii) -(C 1 -C 6 )-alkyl, or

R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated ring, where one heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, the nitrogen atoms may, independently of each other, be unsubstituted or substituted with (C 1 -C 4 -alkyl,

2) -(C0-C6)-alkyl-C(O)-NH-CN,

3) -O(C0-C6)-alkyl-C(O)-N(R9)-R( 10), in which R9 and R10 have the above meaning, 4) -O(Co-C6)-alkyl-C (O)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), wherein R8 is i) hydrogen atom

ii) -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, independently, by -NH2, -CN, -OH, -C(O)-NH-OH, NO2, -C(O)-O(Ci-C6)-alkyl, or halogen or

iii) OH and

wherein R 9 and RIO have the above meaning,

5) -(C0-C6)-alkyl-C(O)- N(R8)-(C0-C6)-alkyl-Het, where R8 has the above meaning and 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, oxygen and sulphur, and is unsubstituted or substituted one, two or three times independently of each other with

a) halogen,

b) cyano,

c) nitro,

d) hydroxy,

e) amino,

f) -C(O)-O-(Ci-C6)-alkyl,

g) -C(0)-OH,

h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted

once, twice or three times with halogen,

i) -O-(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10), or

j) =0,

k) -Hot,

1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), or

m) -(C2-C6)-alkynyl, where alkynyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), or

6) -(Co-C6)-alkyl-C(0)-N(R8)-(C6-Ci4)-aryl, where aryl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned the residues a) to m),

R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogen atom,

2. halogen,

3. -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, 4. -O-(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times with halogen, or

5. -S-(C1-C6)-alkyl or

R4 and R5 or R5 and R6, together with the carbon atoms to which they are attached in each case, independently form a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur, where the ring is unsubstituted or is substituted at one or more carbon atoms, once or twice, with halogen and the other residues R3, R6 and R7 or R3, R4 and R7 have the above-mentioned meaning according to 1. to 5. .

Michael Murray was able to show that compounds containing an unsubstituted benzo[l,3]dioxole ring as a residue inhibit the cytochrome P450 liver enzymes (Michael Murray, Current Drug Metabolism 2000, 67-84). The aforementioned residue is made responsible for this significant, toxicological effect. This is therefore excluded from the compounds of formula I.

A further object of the invention is a compound of formula I, wherein

RI is hydrogen atom or -(Ci-C6)-alkyl,

R 2 is -(C 1 -C 6 )-alkyl, wherein alkyl is substituted one, two, or three times by phenyl, wherein phenyl is substituted one, two, or three times, independently, by

1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10) wherein R9 and R10 are the same or different and are independent of each other

i) hydrogen atom or,

ii) -(C 1 -C 6 )-alkyl, or

R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered, saturated ring, whereby a heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, can the nitrogen atoms, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl,

2) -(C0-C6)-alkyl-C(O)-NH-CN,

3) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 have the above

the meaning,

4) -(Co-C6)-alkyl-C(0)-N(R8)-alkyl-N(R9)-(R10), in which R8 is i) hydrogen atom

ii) -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(O)-OH,

-C(0)-OH, -C(0)-OH, C(0)-NH-OH, NO2, -C(0)-0-(Ci-C6)-alkyl, or halogen or

iii) -OH, and wherein R 9 and R 10 have the above meaning,

5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het, in which R8 has the above meaning and Het is a residue from the group azepine, azetidine, aziridine , benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine , 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3 -oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1 ,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and wherein Het is unsubstituted or substituted one, two or three times, independently of each other, with

a) halogen,

b) cyano,

c) nitro,

d) hydroxy,

e) amino,

f) -C(O)-O-(Ci-C6)-alkyl,

g) -C(0)-OH,

h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted

once, twice, or three times with halogen,

i) -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen or - N(R9)-(R10),

j)<=>o,

k) -Het, in which Het is as defined above,

1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10), or

m) -(C2-C6)-alkynyl, wherein alkynyl is unsubstituted or substituted one, two or three times by halogen or

-N(R9)-(R10), or

6) -(Co-C6)-alkyl-C(0)-N(R8)-(Co-C6)-alkyl-(C6-Ci4)-phenyl, where phenyl

is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned residues a) to m),

R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogen atom,

2. halogen,

3. -(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or 4. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, a , two or three times, with halogen, or

R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached in each case, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring, where the ring is unsubstituted or substituted, at one or more carbon atoms , once or twice, with halogen and the other residues R 3 , R 6 and R 7 or R 3 , R 4 and R 7 have the meaning given above for 1. to 4.

A further object of the invention is a compound of formula I, wherein

RI is hydrogen atom,

R 2 is -(C 1 -C 3 )-alkyl, wherein alkyl is substituted by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 1) -(C 0 -C 6 )-alkyl-C(O)- N(R9)-(R10) in which R9 and R10 are hydrogen atoms,

methyl, ethyl, propyl or butyl, or

R9 and R10 form, together with the nitrogen atom to which they are attached, a residue which may be derived from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazolidine and, in the case of nitrogen, the nitrogen atoms may independently be unsubstituted or substituted with (Ci-C4)-alkyl,

2) -(C0-C4)-alkyl-C(O)-NH-CN,

3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10), wherein R9 and R10 have the above

state the meaning,

4) -(Co-C6)-alkyl-C(O)-N(R8)-(Co-C6)-alkyl-N(R9)-(R10), wherein R8 is

hydrogen, methyl, ethyl, propyl or butyl, and R9 and R10 have the meaning given above,

5) -C(O)-N(R8)-(C0-C2)-alkyl-Het, where R8 has the above

meaning and Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochromane, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4- triazine, 1,2,3-triazole or 1,2,4-triazole and Het is unsubstituted or substituted one, two or three times, independently of each other, with

a) halogen,

b) cyano,

c) nitro,

d) hydroxy,

e) amino,

f) -C(O)-O-(Ci-C4)-alkyl,

g) -C(0)-OH,

h) -(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted

once, twice or three times with halogen,

i) -O-(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times, with halogen, or 6) -C(0)-N(R8)-(Co-C4)-alkyl -phenyl, where phenyl is unsubstituted or

substituted one, two or three times independently of each other with the above stated residues a) to i),

R3, R4, R5, R6 and R7 are the same or different and are, independently of each other,

1. hydrogen atom,

2. halogen,

3. -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, 4. -O-(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, with halogen, or

R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring and the other residues are R3, R6 and R7 or R3, R4 and R7 have the above meanings according to 1. to 4.

A further object of the invention is a compound of formula I which is selected from: pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methyloxybenzylamide),

pyrimidine-4,6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-[(2-dimethylaminoethylcarbamoyl)benzylamide] 6-(3-methoxy-benzylamide),

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)amide]-6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide],

Pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[2(4-methylpiperazin-1-yl)-2-oxoethyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-morpholin-4-yl-2-oxoethoxy)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(isopropylcarbamoylmethyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1 -yl-ethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4(3-morpholin-4-yl-propyl-carbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl)amide],

pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-piperazin-1-ylethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-tert-butylcarbamoylbenzylamide) 6-(3-methoxybenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

[4-( {[6-(4-fluoro-3-methylbenzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoylamino]acetic acid methyl ester ester,

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[3(morpholine-4-carbonyl)-benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(piperidin-4-ylmethyl)-carbamoyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)-benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(piperidin-4-ylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide},

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methyl-piperazine-1-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(morpholine-4-carbonyl)-benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide],

Pyrimidin-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide),

pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide],

pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], or

pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide).

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

By the term "-(C6-C14)-aryl" is meant aromatic hydrocarbons with 6 to 14 carbon atoms in the ring. -(C6-C14)-aryl residues are e.g. phenyl, naphthyl, e.g. 1-naphthyl, 2-naphthyl, biphenylyl, such as e.g. 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, anthryl or fluorenyl. Biphenylyl residues, naphthyl residues and especially phenyl residues are preferred aryl residues.

With the term "-R4 and R5, or R5 and R6, together with the carbon atoms to which they are attached, independently of each other, form a 5- or 6-membered ring, which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur", means ring systems that can be derived from dioxole, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, pyran, furan , dihydrofuran, tetrahydrofuran, oxazole, isoxazole, 2-isoxazole, isoxazolidine, morpholine, oxothiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolidine or thiomorpholine.

By the term "Het" is meant 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 or sulfur series. It contains in the underlying monocyclic or bicyclic, heterocyclic ring system 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 bicyclic Het, two rings may be connected to each other, one of which may be a 5-membered or 6-membered heterocyclic ring and the other a 5- or 6-membered heterocyclic or carbocyclic ring. A bicyclic Het group can e.g. consist of 8, 9 or 10 ring atoms.

Het contains saturated, heterocyclic ring systems that have no double bonds in the rings and likewise unsaturated, heterocyclic ring systems including monounsaturated and polyunsaturated, heterocyclic ring systems that have one or more double bonds and form a stable ring system. Unsaturated rings can be partially unsaturated or form an aromatic system. In the Het group there are identical or different heteroatoms from the series nitrogen, oxygen or sulphur. Examples of heterocycles that can be derived from the Het group are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, cromanyl, chromenyl, cinnolyl , decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, lH-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isocromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl . l, pyrazinyl, pyrozolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, 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 and xanthenyl.

Preferred are azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1, 2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole etc. and likewise ring systems which are obtained from the above-mentioned heterocycles by connection or condensation with a carbocyclic ring such as e.g. benzoanellated, cyclopentafused, cyclohexafused or cycloheptafused derivatives of these heterocycles. Suitable nitrogen heterocycles can also be present as N-oxides or as quaternary salts where a suitable nitrogen atom is alkylated with (Ci-C4) alkyl residues.

The Het group may be unsubstituted or substituted according to the definitions given above.

With the term "R9 and R10 or R14 and R15, together with the nitrogen atom to which they are attached, form a 5-, 6- or 7-membered, saturated ring, where one or two carbon atoms may be replaced by a heteroatom from the series oxygen, sulfur or nitrogen", means residues that can be derived from imidazolidine, isothiazolidine, isoxazolidine, morpholine, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine. The present invention further provides a method for the preparation of a compound of formula I, as discussed above, characterized in that a compound of formula II

a) is reacted with a compound Illa or Illb where R1, R2, R3, R4, R5, R6 and R7 have the meaning given in formula I and Y is halogen, hydroxyl or C1-C4 alkoxy or forms, together with the carbonyl group, a active ester or a mixed anhydride, whereby a compound of formula I is formed, and the reaction products are converted, where relevant, into the physiologically acceptable salts, or b) a compound of formula II is reacted with a compound of formula Illa or Illb to a compound of formula IVa or IVb.

whereby R1 to R7 has the meaning 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 the compound of formula IVa or IVb is purified, if appropriate, and is then converted, with a compound of formula Illa or Illb, into a compound of formula I

In the following, the preparation of the compounds according to formula I and the preparation of the starting products necessary for these, as long as they are not commercially available, will be described in more detail.

The production of the compounds according to the invention is most successful when the two components, the pyridine derivative of formula II and the amine of formula Illa or Illb, are brought together in equimolar amounts and reacted at temperatures between -30°C and 150°C, preferably from 20°C to 100°C, to compounds of formula IVa or IVb, and that the compounds of formula IVa or IVb are then reacted in an analogous manner with up to an equimolar amount of the amine of formula Illb or Illa. The conditions for the reaction can be determined e.g. by means of thin-layer chromatography or HPLC-MS. A variant of this method consists in working in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, chloroform, tri- or tetrachloroethylene, benzene, toluene or also polar solvents, such as dimethylformamide, acetone or dimethylsulfoxide. The reaction temperatures are therefore between room temperature and the boiling point of the solvent, whereby temperatures in the range of room temperature to 130°C are particularly preferred.

Likewise, the reaction can take place via a mixed anhydride such as chloroformate ethyl ester or via an active ester such as paranitrophenyl ester (Y=ClCH2-COO or NO2-C6H4-O). 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 can take place with an amine of formula Illa or Illb if Y is OH and the corresponding carboxylic acid is activated in situ by usable coupling reagents. Such coupling reagents are e.g. carbodiimides, such as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI) or N,N'-carbonyldiazole, such as N,N'-carbonyldiimidazole or a uronium salt such as O-((cyano(ethoxycarbonyl)methylene)-amino)-1,1,3 ,3-tetramethyluronium tetrafluoroborate (TOTU) or 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). Corresponding methods are known. If the amines of formula IIIa or IIIb are not commercially available, they can be prepared from the corresponding commercially available starting compounds according to methods known in the literature. Suitable starting compounds for amines are e.g. 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 according to known methods. Carboxylic acids and carboxylic acid esters can be transferred to carboxylic acid amides. Aldehydes can via a reductive amination with NUtAc/NaBILt be transferred directly to the amines or first transferred to oximes with hydroxylamine and then transferred to amines by reduction.

If necessary, turnover can also take place in the presence of bases. As additional bases, e.g. mention is made of carbonates or hydrogen carbonates, such as sodium or potassium carbonate or sodium or potassium hydrogen carbonate or tertiary amines, such as triethylamine, tributylamine, ethyldiisopropylamine or heterocyclic amines, such as N-alkylmorpholine, pyridine, quinoline or dialkylaniline.

Optionally, the processing of the products, especially the compounds of formula IVa or IVb, e.g. happen by extraction or chromatography, e.g. over silica gel. The isolated product can be recrystallized and optionally reacted with suitable acids to a physiologically acceptable salt. As suitable acids, e.g. mentioned: mineral acids, such as hydrochloric or hydrobromic acid, as well as sulphurous, phosphoric, nitric or perchloric acid, or organic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric -, maleic, fumaric, phenylacetic, benzoic, methanesulphonic, toluenesulphonic, oxalic, 4-aminobenzoic, naphthalene-1,5-disulphonic or ascorbic acid.

The starting compounds of formula Illa or Illb can, to the extent that they are not commercially available, also be synthesized in a simple way (see, for example, "Organikum", Organische Chemisches Grundpraktikum, 15th edition, VEG Deutscher Verlag der Wissenschaften, 1976; an overview about the different possibilities can be found in the method register, p. 822).

The starting compounds of formula (II) are obtained, e.g. by reaction of pyridine-4,6-dicarboxylic acid, to the corresponding pyridine-4,6-dicarboxylic acid halide, preferably -chloride (according to methods known from the literature), preferably in the presence of a catalyst, such as dimethylformamide. This acid halide can then e.g. reacted with a suitable alcohol, e.g. paranitrobenzyl alcohol to the corresponding active ester, or also with lower alcohols, such as methanol or ethanol, to the corresponding esters. Likewise, the pyrimidine-4,6-dicarboxylic acid can also first, with the addition of a suitable carboxylic acid or a carboxylic acid ester, such as chloroformate ethylase, be transferred to a mixed anhydride which is then reacted with amines of formula Illa or Illb and IVa or IVb to the product according to the invention product. A similar method is also described in the literature.

The preparation of the pyrimidine-4,6-dicarboxylic acid takes place according to methods known from the literature, e.g. by oxidation of 4,6-dimethylpyrimidine which in turn e.g. can be obtained by catalytic hydrogenation of commercially available 2-mercapto-4,6-dimethylpyrimidine.

To the extent that the compounds of formula I allow diastereoisomeric or enantiomeric forms and occur as mixtures of such in the chosen synthesis, the separation into the pure stereoisomers can take place either by chromatography on an optional chiral support material or, if the racemic compound of formula I is capable of to salt formation, by fractional crystallization of those with an optically active base or acid as auxiliaries, formed, diastereomeric salts. As chiral stationary phases for thin-layer or column chromatographic separation of enantiomers, e.g. modified silica gel carriers (so-called Pirkle phases) as well as high-molecular carbohydrates, such as triacetyl cellulose. For analytical purposes, gas chromatographic methods can also be applied to chiral, stationary phases after corresponding derivatizations known to the person skilled in the art. For enantiomer separation of the racemic carboxylic acids, with an optically active, and usually commercially available base such as (-)-nicotine, (+)- or (-)-phenylethylamine, quinine bases, L-lysine or L-or D-arginine, the various soluble diastereomeric salts, the heavier soluble component isolated as a solid and the more easily soluble diastereomer separated from the mother liquor and the thus obtained diastereomeric salts recovered as pure enantiomers. In the same principle, the racemic compounds of formula I, which contain a basic group such as an amino group, can be converted to the pure enantiomers by means of optically active acids such as (+)-camphor-10-sulphonic acid, D- and L-tartaric acid , D- and L-lactic acid as well as (+)- and (-)-mandelic acid. Furthermore, the chiral compounds containing alcohol or amine functions can be transferred to the corresponding esters or amides by means of correspondingly activated or optionally N-protected enantiomeric amino acids or, optionally, the chiral carboxylic acids can be transferred to the amides by means of carboxy-protected, enantiomeric amino acids or, with enantiomerically pure hydroxycarboxylic acids such as lactic acid, are transferred to the corresponding chiral esters. Thus, the chirality of the amino acid or alcohol residue introduced in enantiomeric form can be used to separate the isomers, as the present diastereomers are separated by crystallization or chromatography on suitable stationary phases and then the entrained, chiral molecular part is cleaved using suitable methods.

Acidic or basic products of the compounds of formula I can be present in the form of the respective salts or in free form. Pharmacologically acceptable salts are preferred, e.g. alkali or alkaline earth metal salts, such as hydrochlorides, hydrobromides, sulphates, hemisulphates, all possible phosphates as well as salts of amino acids, natural bases or carboxylic acids.

The preparation of physiologically acceptable salts from compounds of formula I which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. The carboxylic acids form with basic reagents, such as hydroxides, carbonates, hydrogen carbonates, alcoholates as well as ammonia or organic bases such as trimethyl or triethylamine, ethanol or triethanolamine, or also basic amino acids such as lysine, ornithine or arginine, stable alkali or alkaline earth metal or optionally substituted ammonium salts . To the extent that the compounds of formula I exhibit basic groups, stable acid addition salts can also be prepared with strong acids. For this purpose, both inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzene, p-toluenesulfonic acid, 4-bromobenzenesulfonic acid, cyclohexylamidosulfonic acid, trifluoromethylsulfonic acid, acetic acid, oxal -, tartaric, succinic or trifluoroacetic acid.

Due to the pharmacological properties, the compounds of formula I are suitable for the prophylaxis and treatment of all such diseases in the course of which an enhanced activity of matrix metalloproteinase 13 is involved.

These include degenerative joint diseases, such as osteoarthritis, spondylosis, cartilage loss after joint trauma or long-term joint stiffness after meniscus or patella injuries or torn ligaments. This also includes diseases in connective tissue such as collagenoses, periodontal diseases, wound healing disorders and chronic diseases of the musculoskeletal system such as inflammatory, immunological or metabolic acute and chronic arthritis, arthropathies, myalgias and disorders in bone metabolism or cancers such as breast cancer.

The present invention consequently also provides a pharmaceutical composition, characterized in that it comprises an effective content of at least one compound of formula I, as discussed above, together with a pharmaceutically suitable and physiologically acceptable carrier substance, additive and/or other active compound and excipients.

The pharmaceutical composition according to the invention can be used subcutaneously, intra-articularly, intraperitoneally or intravenously. The intra-articular injection is preferred. Reactal, oral, inhalation, or transdermal delivery is also possible.

The pharmaceutical composition according to the invention can be prepared by bringing at least one compound of formula I, together with a pharmaceutically suitable and physiologically acceptable carrier and any further active ingredient, additives or auxiliaries, into a suitable administration form.

The compounds of formula I are mixed with the suitable additives such as carriers, stabilizers or inert diluents and brought by suitable methods into suitable administration form such as tablets, dragees, suppositories, aqueous alcoholic or oil suspensions or aqueous or oil solutions. Examples of inert carriers include gum arabic, magnesium oxide, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Thereby, the preparation can take place both as dry and moist granules. Vegetable or animal oils, such as sunflower oil or cod liver oil, can be mentioned as oily carriers or solvents.

For subcutaneous, intra-articular, intraperitoneal or intravenous administration, the active ingredients are, if desired, brought into solution, suspension or emulsion with substances suitable for this purpose, such as dissolution agents, emulsifiers or further auxiliaries. As a solvent, e.g. mention is made of physiological saline solution or alcohols such as ethanol, propanol, glycerine, in addition also sugar solutions such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

You can also use common auxiliaries, such as carriers, blasting, binding, coating, swelling, sliding or lubricating agents, flavourings, sweeteners and solubilizing agents. Frequently used excipients include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk egg white, gelatin, starch, cellulose and derivatives thereof, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents, which e.g. sterile water and mono or polyhydric alcohols such as glycerin.

The compounds of formula I are preferably prepared and administered as pharmaceutical preparations in dosage units whereby each unit, as active ingredient, contains a special dose of the compounds of formula I. For this purpose, they can e.g. administered orally in doses from 0.01 to 25.0 mg/kg/day, preferably 0.01 to 5.0 mg/kg/day, or parenterally in doses of 0.001 to 5 mg/kg/day and preferably 0.001 to 2 .5 mg/kg/day. In severe cases, the dosage can also be increased. In most cases, however, lower doses are sufficient. This information concerns the treatment of adults.

The invention will be explained in more detail below with the help of the following illustrative examples.

Example 1:

[4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyridine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester a) 6-(4-fluoro-3-methyl- benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester 8.81 g (0.045 mol) pyrimidine-4,6-dicarboxylic acid dimethyl ester are dissolved in 200 ml DMF and 6.25 g (0.045 mol) 4-fluoro-3-methyl-benzylamine are added and the the whole is stirred for 48 hours at 60°C. The solvent is removed under vacuum and the residue is taken up in ethyl acetate. The organic phase is washed with sat sodium bicarbonate solution and 0.5N HCl and dried over MgSO 4 . After filtering off and evaporating the solvent under vacuum, the residue is stirred in isopropanol. 8.75 g of product is obtained, which is used further without further purification. b) 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid 8.75 g (0.02 mol) 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester (70%) is taken up in 150 ml of ethanol and 1.89 g (0.022 mol) NaOH in 6 ml of water is added. After 3 hours at room temperature, the solvent is removed under reduced pressure, the residue is added to water and brought to pH <2 with concentrated HCl. The precipitate is sucked off and dried. 5.5 g (94%) of 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid is obtained.

MS (ES<+>): m/e = 289.09.

c) (4-aminomethyl-phenyl)-acetic acid ethyl ester

0.5 g (2.6 mmol) (4-cyano-phenyl)-acetic acid ethyl ester is dissolved in 70 ml of ethanolic ammonia solution and hydrated with Raney nickel at room temperature and under normal pressure. After 45 minutes, it is all filtered and evaporated. 0.42 g (82%) of (4-aminomethyl-phenyl)-acetic acid ethyl ester is obtained.

MS (ES+): m/e = 194.11.

d) [4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester

1.3 g (4.5 mmol) of 6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carboxylic acid and 1.042 g (5.4 mmol) of (4-aminomethyl-phenyl)-acetic acid ethyl ester are dissolved in 30 ml of DMF and 1.02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0.607 g (4.5 mmol) of hydroxybenzotriazole are added at 5°C. The whole thing is stirred for 5 hours and sucked off. The solvent is removed under vacuum, the residue is taken up in ethyl acetate and washed with saturated aqueous NaHCO 3 solution. The organic phase is dried over MgSO4, filtered and evaporated under reduced pressure. 2.66 g of product is obtained, which is further worked up by preparative HPLC.

MS (ES+): m/e = 464.19.

Example 2: [4-( {[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid

2.4 g (5.2 mmol) of [4-({[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid ethyl ester is taken up in 150 ml of water and add 10 ml of water and 0.227 g (5.7 mmol) of NaOH. After 5 days of stirring at room temperature, the solvent is removed under reduced pressure and the residue is stirred with ethanol and filtered. 1.51 g (67%) of [4-({[6-(4-fluoro-3-methyl-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid is obtained.

MS (ES+): m/e = 436.15.

Example 3:

Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxybenzylamide)

a) Synthesis of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid

26 g (88 mmol) 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid methyl ester

(prepared by reacting pyrimidine-4,6-dicarboxylic acid dimethyl ester with 3-methoxybenzylamine) is dissolved in 100 ml of tetrahydrofuran and 104 ml (1.2 equivalents) of a 1 molar aqueous lithium hydroxide solution is added, after which the reaction mixture is then stirred for 18 hours at room temperature.

Then most of the solvent used was distilled off under reduced pressure, the remainder filtered off from insoluble by-products and the filtrate acidified with a 10% aqueous citric acid solution. Then 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid crystallized out in the form of pale yellow crystals which were filtered off.

19 g (66.2 mmol) of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid were obtained in a yield of 75% of the theoretical.

MS (ES<+>): m/e = 287.8).

b) 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester

4.3 g of 6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carboxylic acid (15 mmol) from a) was dissolved in 50 ml of absolute N,N-dimethylformamide and with stirring and at 0°C, it was successively added 3.3 g (16.5 mmol) methyl-4-(aminomethyl)-benzoate hydrochloride, 5.4 g (16.5 mmol) 0-[(cyanethoxycarbonylmethylene)-amino]-N,N,N',N' -tetramethyluronium tetrafluoroborate (TOTU) and 4.6 ml of triethylamine (33 mmol). The reaction mixture was then stirred for 1 hour at 0°C and finally for 12 hours at room temperature.

For work-up, the solvent was distilled off under reduced pressure and the residue taken up with 100 ml of dichloromethane. The organic phase was washed with 100 ml of saturated aqueous sodium bicarbonate solution and then with 3 x 100 ml of water. After drying the organic phase with Na 2 SO 4 , the solvent was distilled off under reduced pressure. The oily residue was rubbed with a little diethyl ether whereby colorless crystals crystallized out. After filtering off the reaction product and washing with n-pentane, 6.6 g of 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid methyl ester were obtained in the form of pale yellow crystals . The reaction product had a purity of 88% according to LC-MS analysis.

MS (ES<+>): m/e = 435.2).

c) 4-( {[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid

6.6 g of the methyl ester produced under b) was dissolved in 100 ml of tetrahydrofuran and 36 ml (2.4 equivalents) of a 1 molar lithium hydroxide solution was added, after which the reaction mixture was stirred for 4 hours under reflux.

The solvent was then distilled off under reduced pressure. After adding 50 ml of water, the whole was filtered over celite filter aid and the filtrate acidified with 2N aqueous hydrochloric acid. The reaction product precipitated on acidification and was filtered off.

3.05 g of 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid were obtained in the form of light yellow crystals in a yield of 48% of the theoretical.

MS (ES+): m/e = 421.31.

d) Pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxybenzylamide)

420 mg of the 4-({[6-(3-methoxy-benzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid from c) was dissolved in 5 ml of absolute N,N-dimethylformamide and with stirring at 0 °C successively added 115 µl of diethylamine, 361 mg of O-[(cyano-ethoxycarbonylmethylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 153 µl of triethylamine, after which the reaction mixture was stirred for 1 hour at 0°C and then 12 hours at room temperature.

For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 100 ml of dichloromethane. The organic phase was washed with 30 ml of saturated aqueous sodium bicarbonate solution and then with 3 x 30 ml of water. After drying the organic phase over Na 2 SO 4 , the solvent was distilled off under reduced pressure. The oily residue was purified by column chromatography on silica gel (40-63 u) with ethyl acetate/n-heptane, 2:1 as mobile phase. After distilling off the solvent, an oily residue was obtained which slowly crystallized after the addition of a little diethyl ether.

270 mg of pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoyl-benzylamide) 6-(3-methoxy-benzyl)amide were obtained in the form of colorless crystals in a yield of 57% of the theoretical.

MS (ES): m/e = 476.40.

Example 62:

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide]

a) Synthesis of 6-[(pyridin-4-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid 9.7 g (35.7 mmol) 6-[(pyridin-4-ylmethyl)-carbamoyl]-pyrimidine-4 -carboxylic acid

methyl ester (obtained by reaction of pyrimidine-4,6-dicarboxylic acid dimethyl ester with pyridin-4-yl-methylamine) was dissolved in 80 ml of tetrahydrofuran and 40 ml of water, 40 ml of a 1 molar aqueous NaOH solution was added, after which the reaction mixture was stirred in a further 2 hours at room temperature.

For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure to half the original volume. It was then acidified with 22 ml of aqueous 2 N hydrochloric acid solution and the reaction mixture was further evaporated to dryness on a rotary evaporator.

12.2 g of colorless solid was obtained, which was directly reacted further according to 62

b).

b) Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide]

12.2 g of the compound prepared under 62a) was dissolved in 15 ml of absolute DMF and, with stirring and at 0°C (ice cooling), 6.63 g (35.7 mmol) of 5-aminomethyl-2,3- dihydrobenzofuran hydrochloride, 11.7 g (35.7 mmol) of O-[(cyano-ethoxycarbonylmethylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 20 ml of triethylamine. After the addition was complete, the reaction mixture was stirred for 1 hour at 0°C and 4 hours at room temperature.

For work-up, the solvent was distilled off under reduced pressure and the residue taken up with 200 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate, after which the solvent was removed under reduced pressure on a rotary evaporator. The reaction product formed as an oily residue crystallized after the addition of a little diethyl ether in the form of pink crystals. For further purification, it was recrystallized twice more from 200 ml of isopropanol each time.

10 g (25.6 mmol) of pyrimidin-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide] 6-[(pyridin-4-ylmethyl)-amide] were obtained in a yield of 72% of the theoretical, calculated for the two reaction steps.

MS (ES<+>): 390.08.

1H-NMR (400 MHz, d^-DMSO): δ = 3.13 (t, J = 8.6 Hz, 2H), 4.42 (d, J = 6.4 Hz, 2H), 4.48 (t, J = 8.6 Hz, 2H ), 4.54 (d, J = 6.4 Hz, 2 H), 6.69 (d, J = 8 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.31 (m, 2 H ), 8.46 (m, 1 H), 8.50 (m 2 H), 9.47 (m, 1 H), 9.58 (t, J = 6.4 Hz, 1 H), 9.80 (t, J = 6.4 Hz, 1 H) .

Example 117:

Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-aryl] 6-[4-(morpholine-4-carbonyl)-benzylamide]

a) Synthesis of 6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid

16.1 g (51 mmol) 6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carboxylic acid methyl ester (prepared by reaction of pyrimidine-4,6-dicarboxylic acid dimethyl ester with 5-aminomethyl- 2,3-dihydrobenzofuran) was dissolved in 150 ml of tetrahydrofuran, 62 ml of a 1 molar aqueous LiOH solution was added and then the reaction mixture was stirred for a further 2 hours at room temperature.

For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure. The crude product was then taken up in 100 ml of water and, after adding activated charcoal, filtered over a celite clarification layer. The obtained mother liquor was then acidified by the addition of 2N aqueous HCl whereby the reaction product slowly precipitated in the form of colorless crystals.

After filtering off and drying the reaction product, 8.3 g (27 mmol) of colorless solid was obtained, which was reacted directly further to 117b). Yield was 53% of the theoretical.

MS(ES<+>): 300.1.

b) Synthesis of 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidin-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester

4.7 g (15.7 mmol) of the compound prepared under a) was dissolved in 30 ml of absolute DMF and, while stirring and at 0°C, 3.5 g (17.3 mmol) of 4-amino-methyl were successively added -benzoic acid methyl ester, 5.7 g (17.3 mmol) 0-[(cyano-ethoxy-carbonyl-methylene)-

amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 4.8 ml of trimethylamine. The reaction mixture was stirred for a further 1 hour at 0°C and 8 hours at room temperature after the addition was complete.

For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 100 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and the solvent was then removed under reduced pressure on a rotary evaporator. The resulting reaction product as an oily residue crystallized out in the form of pale yellow crystals after the addition of a little diethyl ether.

6.8 g (15.2 mmol) of 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]- benzoic acid methyl ester, in a yield of 97% of the theoretical.

MS (ES+): 447.1.

c) 4-[( {6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid

6.28 g (14 mmol) 4-[({6-[(2,3-dihydro-benzofuran-5-ylmethyl)-carbamoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid methyl ester (see 117b )) was suspended in 150 ml of tetrahydrofuran and 70 ml of water, 16.9 ml of a 1N aqueous NaOH solution was added and the reaction mixture was then stirred for 24 hours at room temperature.

For work-up, the reaction mixture was evaporated on a rotary evaporator under reduced pressure to a volume of approx. 50 ml, after which 100 ml of ice water was added. It was then acidified with 2N aqueous hydrochloric acid solution, and the reaction product precipitated in the form of pale yellow crystals.

After filtration, washing with a little water and drying of the reaction product, 5.4 g (12.5 mmol) of colorless solid was obtained, which was carried on directly to 117d). Yield was 89% of the theoretical.

MS (ES<+>): 433.2.

1H-NMR (400 MHz, dé-DMSO): δ = 3.13 (t, J = 8.7 Hz, 2 H), 4.43 (d, J = 6.1 Hz, 2 H), 4.48 (t, J = 8.7 Hz, 2 H), 4.59 (d, J = 6.3 Hz, 2 H), 6.69 (d, J = 8.1 Hz, 1 H), 7.07 (m, 1 H), 7.22 (m, 1 H), 7.44 (m , 2 H), 7.88 (m, 1 H), 7.90 (m, 1 H), 8.47 (d, J = 1.5 Hz, 1 H), 9.46 (d, J = 1.3 Hz, 1 H), 9.56 (t , J = 6.3 Hz, 1 H), 9.76 (t, J = 6.3 Hz, 1 H), 12.90 (br s, 1H)

d) Pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydro-benzofuran-5-ylmethyl)-amide] 6-[4-(morpholine-4-carbonyl)-benzylamide]

432 mg (1 mmol) of the compound prepared under c) was dissolved in 5 ml of absolute DMF and, with stirring and at 0°C, 96 µl (1.1 mmol) of morpholine, 361 mg (1.1 mmol) of O - [(cyano-ethoxy-carbonyl-methylene)-amino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) and 155 (l of triethylamine. The reaction mixture was stirred further after the addition was complete for 1 hour at 0° C and 8 hours at room temperature.

For work-up, the solvent was distilled off under reduced pressure and the residue taken up in 30 ml of dichloromethane. The organic phase was then washed twice with saturated aqueous sodium bicarbonate solution and once with water, dried over sodium sulfate and the solvent was then removed under reduced pressure on a rotary evaporator. The crude product formed as an oily residue was purified by chromatography on silica gel (40-63 (i) and with ethyl acetate:methanol 20:1 as mobile phase. After removal of the mobile phase by distillation under reduced pressure, an oily reaction product was obtained which, after addition of diethyl ether, crystallized out in the form of colorless crystals.

340 mg (0.68 mmol) of colorless crystals were obtained in a yield of 68% of the theoretical.

MS (ES<+>): 502.27.

1H-NMR (500 MHz, dé-DMSO): δ = 2.60 (m, 2 H), 3.4 - 3.6 (br m, 8 H), 4.42 (d, J = 6.5 Hz, 2 H), 4.48 ( t, J = 8.6 Hz, 2 H), 4.56 (d, J = 6.5 Hz, 2 H), 6.68 (d, J = 8.3 Hz, 1 H), 7.07 (d, J = 6.5 Hz, 1 H), 7.22 (s, 1 H), 7.88 (m, 4 H), 8.46 (m, 1 H), 9.46 (m, 1 H), 9.57 (t, J = 6.5 Hz, 1 H), 9.75 (t, J = 6.5 Hz, 1 H).

The following compounds were prepared in a comparable manner.

Pharmacological examples

Determination of the enzymatic activity of the catalytic domain of the human collagenase-3 (MMP-13).

This protein was obtained as inactive pro-enzyme from the company INVITEK, Berlin, (catalog no. 30 100 803). Activation of the proenzyme: 2 volumes of proenzyme were incubated with 1 volume of APMA solution at 37°C for 1.5 hours. The APMA solution was prepared from a 10 mmol/l p-aminophenylmercuric acetate solution in 0.1 mmol/l NaOH diluted with 3 volumes of Tris/HCl buffer pH 7.5 (see below). The pH value was adjusted to 7.0 to 7.5 by the addition of 1 mmol/l HCl. After activation of the enzyme, this was diluted with the Tris/HCl buffer to a concentration of 1.67 µg/ml.

For measurement of enzyme activity, 10 µl of enzyme solution is incubated with 10 ml of a 3% by volume, buffered dimethylsulfoxide solution (reaction 1) for 15 minutes. To measure the enzyme inhibitor activity, 10 µl of enzyme solution is incubated with 10 µl of a 3% by volume buffered dimethyl sulphide solution containing the enzyme inhibitor (reaction 2).

Both in reaction 1 and in reaction 2, the enzyme reaction, after the addition of 10 µl of a 3 volume-% aqueous dimethylsulfoxide solution containing 0.75 mmol/1 of the substrate, is followed fluorescence spectroscopically (extinction 328 nm/emission/393 nm).

The enzyme activity is indicated as extinction increase per minute.

The inhibitory effect is calculated as percentage inhibition according to the following formula: % inhibition = 100 - [(extinction increase/minute in reaction

2)/(extinction increase/minute in reaction 1) x 100].

The IC50, i.e. the inhibitor concentration required for a 50% inhibition of the enzyme activity, is determined graphically by plotting the percentage inhibition at different inhibitor concentrations.

The buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany) as well as 0.1 mol/l Tris/HCl, 0.1 ml/l NaCl, 0.01 mol/l CaCl2 (pH = 7.5).

The enzyme solution contains 1.67 µg/ml of the enzyme domain.

The substrate solution contains 0.75 mmol/1 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).

The following table 2 shows the results.

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

The enzymes human neutrophil collagenase and human stromelysin were carried out as described by Weithmann et al. in Inflamm. Res., 46 (1997), pp. 246-252, as active, catalytic domains. The measurement of the enzyme activity as well as the determination of the inhibitory effect of the inhibitors on the enzyme activity took place in the same way as described there.

The compounds according to the above examples, in the determination of the human neutrophil collagenase and the human stromelysin, in each case showed IC 50 values of more than 100,000 nm. Thereby, these compounds are practically inactive when inhibiting MMP-3 and MMP-8.

Claims (6)

1. Connection, characterized by formal 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 compounds of formula I, whereby RI is hydrogen atom or -(Ci-C6)-alkyl, R 2 is -(C 1 -C 6 )alkyl, wherein alkyl is substituted one, two or three times by -(C 6 -C 14 )-aryl, wherein aryl is substituted one, two or three times, independently of each other, by 1) -( C0-C6)-alkyl-C(O)-N-(R9)-(R10), wherein R9 and RI 0 are the same or different and are, independently of each other i) hydrogen atom or ii) -(Ci-C6)- alkyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a 5-, 6- or 7-membered saturated ring, where one heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -O(C0-C6)- alkyl-C(O)-N(R9)-R(10), in which R9 and R10 have the above meaning, 4) -O(Co-C6)-alkyl-C(0)-N(R8)-( C 0 -C 6 )-alkyl-N(R 9 )-(R 10 ), in which R 8 is i) hydrogen atom ii) -(C 1 -C 6 )-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(O)-NH-OH, NO2, -C(0)-O(Ci-C6)-alkyl, or halogen or iii) OH and wherein R 9 and R 10 have the above-mentioned meaning, 5) -(Co-C 6 )-alkyl-C(O)- N (R 8 )-(C 0-C 6 )-alkyl-Het, where R 8 has the above-mentioned meaning and 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, oxygen, and sulfur, and is unsubstituted or substituted one, two, or three times independently of each other with a) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -CCOXMCrCéValkyl, g) -C(0)-OH, h) -(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen, i) -O-(Ci-C6)-alkyl, where alkyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)-(R10 ), or j)<=>o, k) -Het, 1) -(C2-C6)-alkenyl, where alkenyl is unsubstituted or substituted one, two or three times by halogen or -N(R9)-(R10) , or m) -(C2-C6)-alkynyl, where alkynyl is unsubstituted or substituted one, two or three times with halogen or -N(R9)-(R10), or 6)-(Co-C6)-alkyl-C(0)-N(R8)-(C6-C14)-aryl, where aryl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned residues a) to m), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 1. hydrogen atom, 2. halogen, 3. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times , with halogen, 4. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times by halogen, or 5. -S-(Ci-C6)-alkyl or R4 and R5 or R5 and R6, together with the carbon atoms to which they are attached in each case, independently form a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur, where the ring is unsubstituted or is substituted at one or more carbon atoms, once or twice, with halogen and the other residues R3, R6 and R7 or R3, R4 and R7 have the above-mentioned meaning according to 1. to 5. . 2. Compound with formula I according to claim 1, characterized in that RI is hydrogen atom or -(Ci-C6)-alkyl, R 2 is -(C 1 -C 6 )-alkyl, wherein alkyl is substituted one, two or three times by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 1) -(C 0 -C 6 )-alkyl -C(O)-N(R9)-(R10) in which R9 and R10 are the same or different and are independent of each other i) hydrogen atom or, ii) -(C1-C6)-alkyl, or R9 and R10 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered, saturated ring, whereby a heteroatom from the series of oxygen, sulfur and nitrogen can also replace one or two carbon atoms and, in the case of nitrogen, can the nitrogen atoms, independently of each other, be unsubstituted or substituted with (Ci-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-CN, 3) -(C0-C6)-alkyl- C(O)-N(R9)-(R10), where R9 and R10 have the above meaning, 4) -(C0-C6)-alkyl-C(O)-N(R8)-alkyl-N(R9 )-(R10), in which R8 is i) hydrogen atom ii) -(Ci-C6)-alkyl, in which alkyl is unsubstituted or substituted one, two or three times, independently of each other, with -NH2, -CN, -OH, -C(0)-OH, -C(0)-OH, -C(0)-OH, C(0)-NH-OH, NO2, -C(0)-0-(Ci-C6)-alkyl , or halogen or iii) -OH, and wherein R 9 and R 10 have the above meaning, 5) -(C0-C6)-alkyl-C(O)—N(R8)-(C0-C6)-alkyl-Het , in which R8 has the above meaning and Het is a residue from the group azepine, azetidine, aziridine, benzimidazole, benzofuran, be nzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chroman, cinnoline, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochrome, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and wherein Het is unsubstituted or substituted one, two or three times, independently of each other, with a) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -C(0)-0-(C1-C6)-alkyl, g) -C(0)-OH, h) -(C1-C6)-alkyl , wherein alkyl is unsubstituted or substituted one, two, or three times by halogen, i) -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two, or three times, by halogen or - N(R9 )-(R10), j)<=>o, k) -Het, wherein Het is as defined above, 1) -(C2-C6)-alkenyl, wherein alkenyl is unsubstituted or substituted one, two or three times by halogen or - N(R9)- (R 10 ), or m) -(C 2 -C 6 )-alkynyl, wherein alkynyl is unsubstituted or substituted one, two or three times by halogen or -N(R 9 )-(R 10 ), or 6) -(C 0 -C 6 ) -alkyl-C(O)-N(R8)-(Co-C6)-alkyl-(C6-C14)-phenyl, where phenyl is unsubstituted or substituted one, two or three times, independently of each other, with the above-mentioned the residues a) to m), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 5. hydrogen atom, 6. halogen, 7. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or 8. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted, one, two or three times, with halogen, or R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached in each case, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring, where the ring is unsubstituted or substituted, at one or more carbon atoms , once or twice, with halogen and the other residues R 3 , R 6 and R 7 or R 3 , R 4 and R 7 have the meaning given above for 1. to 4. 3. Compound of formula I according to claim 1 or 2, characterized in that RI is hydrogen atom, R 2 is -(C 1 -C 3 )-alkyl, wherein alkyl is substituted by phenyl, wherein phenyl is substituted one, two or three times, independently of each other, by 2) -(C 0 -C 6 )-alkyl-C(O)- N(R9)-(R10) in which R9 and R10 are hydrogen, methyl, ethyl, propyl or butyl, or R9 and R10 form, together with the nitrogen atom to which they are attached, a residue which may be derived from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, morpholine, isothiazolidine and, in the case of nitrogen, the nitrogen atoms may independently be unsubstituted or substituted with (Ci-C4)-alkyl, 2) -(C0-C4)-alkyl-C(O)-NH-CN, 3) -O-(C0-C6)-alkyl-C(O) -N(R 9 )-(R 10 ), wherein R 9 and R 10 have the meaning given above, 4) -(Co-C 6 )-alkyl-C(O)-N(R 8 )-(Co-C 6 )-alkyl-N (R 9 )-(R 10 ), wherein R 8 is hydrogen, methyl, ethyl, propyl or butyl, and R 9 and R 10 have the above meaning, 5) -C(O)-N(R 8 )-(C 0 -C 2 )- alkyl-Het, where R 8 has the above meaning and Het is azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[l,4]dioxin, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, quinazoline, quinoline, quinoxaline, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxol, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazole, morpholine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidine, tetrazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, thiazole, thiomorpholine, thiophene, thiopyran, 1,2,3-triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazole or 1,2,4-triazole and Het is unsubstituted or substituted one, two or three times, independently of each other, with a ) halogen, b) cyano, c) nitro, d) hydroxy, e) amino, f) -C(0)-0-(Ci-C4)-alkyl, g) -C(0)-OH, h) - (Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times with halogen, i) -O-(Ci-C4)-alkyl, where alkyl is unsubstituted or substituted one, two or three times, with halogen, or 6) -C(O)-N(R8)-(C0-C4)-alkyl-phenyl, where phenyl is unsubstituted or substituted one, two or three times independently of each other with the above-mentioned residues a) to i), R 3 , R 4 , R 5 , R 6 and R 7 are the same or different and are, independently of each other, 5. hydrogen atom, 6. halogen, 7. -(C 1 -C 6 )-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen, 8. -O-(Ci-C6)-alkyl, wherein alkyl is unsubstituted or substituted one, two or three times, with halogen, or R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are attached, independently of each other, a dioxane, dioxole, dihydrofuran or furan ring and the other residues are R3, R6 and R7 or R3, R4 and R7 have the above meanings according to 1. to 4. 4. Compounds of formula I according to one or more of claims 1 to 3, characterized in that one of the following compounds is selected: pyrimidine-4,6-carboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methyloxybenzylamide), pyrimidine-4, 6-carboxylic acid 4-(3-methoxybenzylamide) 6-(4-propylcarbamoylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-isopropylcarbamoylbenzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-[ (2-dimethylaminoethylcarbamoyl)benzylamide] 6-(3-methoxy-benzylamide), pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzo[ 1,4]dioxin-6-ylmethyl)amide]-6-[ 4-(2-dimethylaminoethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-dimethylaminoethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4- (4-fluoro-3-methylbenzylamide) 6- {4-[2(4-methylpiperazin-1-yl)-2-oxoethyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide ) 6-[4(2-morpholin-4-yl-2-oxoethoxy)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoy lmethoxybenzylamide) 6-(4-fluoro-3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(isopropylcarbamoylmethyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4 -(4-fluoro-3-methylbenzylamide) 6-{4-[(2-morpholin-4-ylethylcarbamoyl)methyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylmethylbenzylamide) 6-(4-fluoro -3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-yl-2-oxoethyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(isopropylcarbamoylmethoxy)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-morpholine-4- ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(2-pyrrolidin-1 -yl-ethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4- fluoro-3-methylbenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(thiomorpholine-4-carbonyl)benzylamide], pyrimidine-4,6-d icarboxylic acid 4-(4-cyanocarbamoylbenzylamide) 6-(4-fluoro-3-methylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(3-morpholin-4-ylpropylcarbamoyl)benzylamide] , pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4(3-morpholin-4-yl-propyl-carbamoyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(4-methylpiperazin-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl )amide] 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-[(2,3-dihydrobenzofuran-5-ylmethyl )amide], pyrimidine-4,6-dicarboxylic acid 4-(4-N-cyanocarbamoylbenzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4 -(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4(2-piperazin-1-ylethylcarbamoyl)benzylamide], pyrimidine-4,6 -dicarboxylic acid 4-(4-tert-butylcarbamoylbe nzylamide) 6-(3-methoxybenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-{4-[methyl-( 1 -methylpiperidin-4-yl)carbamoyl]benzylamide}, pyrimidine-4, 6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-pyrrolidin-1-yl-ethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[ 3-(2-morpholin-4-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], [4-( {[6-(4-fluoro-3-methylbenzylcarbamoyl)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoylamino]acetic acid methyl ester ester, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6 -[3(morpholine-4-carbonyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(piperidin-4-ylmethyl)-carbamoyl]benzylamide}, Pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(piperidin-4-ylcarbamoyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- [4-(piperidin-4-ylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6-{4-[methyl-(1-methylpiperidin-4-yl)carbamoyl]benzylamide}, Pyrimidin-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamide) 6- {4-[(piperidin-4-ylmethyl)carbamoyl]benzylamide}, pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6-[4-(4-methyl-piperazine-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4- [(2,3-dihydrobenzofuran- 5-ylmethyl)amide] 6-[4-(morpholine-4-carbonyl)-benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(4-methylpiperazine-1-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-[(2,3-dihydrobenzofuran-5-ylmethyl)amide] 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-pyrrolidin-1-ylethylcarbamoyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- [4-(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-methoxybenzylamide) 6- {4-[(pyridin-4-ylmethyl)carbamoyl]benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-(4-diethylcarbamoylbenzylamide), pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(morpholine-4-carbonyl)benzylamide], pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-fluorobenzylamide) 6-[4-(2-morpholin-4-ylethylcarbamoyl)benzylamide], or pyrimidine-4,6-dicarboxylic acid 4-(4-diethylcarbamoylbenzylamide) 6-(3-methoxybenzylamide). 5. Process for producing the compound of formula I according to one or more of claims 1 to 4, characterized in that a compound of formula II a) is reacted with a compound of formula Illa or Illb where R1, R2, R3, R4, R5, R6 and R7 have the meaning 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, being a compound of formula I is formed, and the reaction products are converted, where appropriate, into the physiologically acceptable salts, or b) a compound of formula II is reacted with a compound of formula IIIa or IIIb to give a compound of formula IVa or IVb where R1 to R7 have the meaning 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 the compound of formula IVa or IVb is purified, if appropriate, and then converted, with a compound of formula Illa or Illb, to a compound of formula I. 6. Pharmaceutical composition, characterized in that it comprises an effective content of at least one compound of formula I according to any one of claims 1 to 4, together with a pharmaceutically suitable and physiologically acceptable carrier substance, additive and/or other active compound and excipients.