New diamides pyrimidin-4,6 of dicarboxylic acid for selective inhibition of collagenases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns to new diamides of pyrimidine-4,6-dicarboxylic acid of I formula, selective inhibitors of collagenases possessing properties which concern to the metalloproteinase superfamily and the matrix metalloproteinases. The bonds render influence on hyperactivity of the matrix metalloproteinase-13 (MMP-13) and thus do not render influence on MMP-3 and MMP-8. In the formula I R1 means an atom of hydrogen, R2 means - (C1-C6)-alkyl where alkyl is unitary replaced by phenyl where phenyl is replaced 1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 identical or different and independently from each other mean i) atom of hydrogen or ii) - (C1-C6)-alkyl or R9 and R10 together with atom of nitrogen to which they are bound, form 5, 6-links the sated cycle, and instead of one or two other atoms of carbon there can be also a heteroatom from an oxygen row, sulphur and nitrogen, and in case of nitrogen atoms of nitrogen independently from each other can be unsubstituted or substituted with (C1-C6)-alkyl, 2) -(C0-C6)-alkyl-C(O)-NH-SN, 3) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10) where R9 and R10 have the specified above value, 4) -(C0-C6)-alkyl-C(O)-N (R8)-(C0-C6)-alkyl-N(R9)-(R10) where R8 means hydrogen, R9 and R10 have the specified above value, 5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the specified above value, and Het means the sated or nonsaturated monocyclic heterocyclic system with number of links from 3 to 6 which contains in a cycle of 1 or 2 identical or different heteroatoms from a number nitrogen, oxygen and sulphur and unsubstituted or one-, two- or triple independently from each other is replaced by halogen, b) hydroxy,) -(C1-C6)-alkyl, and alkyl is unsubstituted or one-, two- or triple is substituted by halogen, d)=0,e)-Het, R4 and R5 or R5 and R6 together with atom of Carboneum to which they are bound, independently from each other form 5 or 6-unit cycle which is sated and contains one or two heteroatoms from an oxygen row.

EFFECT: obtaining of bonds which can find application for treatment of degenerate diseases of joints, such as osteoarthritis, rheumatic disease.

7 cl, 3 tbl, 117 ex

 

The invention relates to new diamide pyrimidine-4,6-dicarboxylic acid and their use for the selective inhibition of collagenase (MMP-13). So diamides pyrimidine-4,6-dicarboxylic acid can be used for the treatment of degenerative joint disease.

It is known that the diamide pyrimidine-4,6-dicarboxylic acid and 2,4-substituted pyridine-N-oxides inhibit the enzymes Proline - and lizingodatelyu and thus causes inhibition of collagen biosynthesis by influencing collegespecific hydroxylation reactions (EP 0418797; EP 0463592). Due to this inhibition of the biosynthesis of collagen are formed inactive, incomplete gidroksilirovanii collagen molecule, which can come from cells into the extracellular space only in small quantities. Not fully gidroksilirovanii collagen cannot, moreover, be embedded in the collagen matrix and is very easy proteoliticeski split. Due to these effects, the amount deposited outside the cells collagen will in General decrease. Patent applications WO 02/064571 and WO 02/064080 it is known that certain diamides pyridine-2,4-dicarboxylic acid diamide pyrimidine-4,6-dicarboxylic acid can be allosteric inhibitors of MMP-13.

For diseases such as osteoarthritis and rheumatism, is the destruction of the joint, in particular, is stipulated by the Noah proteolytic cleavage of collagen by collagenases. Collagenase belong to the superfamily of metalloproteinases (MP) or matrix metalloproteinases (MMP). MMPs break down collagen, laminin, proteoglycan, elastin or gelatin in physiological conditions and therefore play an important role in bone and connective tissue. There are many different MMP inhibitors or collagenases (EP 0606046; WO 94/28889). The disadvantages of the known MMP inhibitors are often insufficient specificity of inhibition of only one class of MMP. So most of MMP inhibitors inhibit multiple MSEs, since the catalytic domains of MMP have a similar structure. As a consequence, the inhibitors are undesirable way for many enzymes, including enzymes with vital functions (I. Massova et al., The FASEB Journal(1998) 12,1075-1095).

In trying to find effective compounds for the treatment of diseases of the connective tissue was found that the compounds used according to the invention, are strong inhibitors of matrix metalloproteinase 13, and compounds used according to the invention, essentially no effect on MMP-3 and-8.

Therefore, an object of the invention is a compound of formula I,

and/or all stereoisomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or the physiologically priemysel the compounds of formula I, and

for the case (a)

R1 means a hydrogen atom or -(C1-C6)-alkyl,

R2 denotes -(C1-C6)-alkyl, and alkyl of one, two or three times substituted

1. -(C1-C6)-alkyl-O-(C6-C14)-aryl,

2. -(C0-C6)-alkyl-N(R8)-C(O)-O-(C1-C6)-alkyl, in which R8 means

(i) a hydrogen atom, or

ii) -(C1-C6)-alkyl,

3. -C(O)-N(R9)-(R10), where R9 and R10 are the same or different and independently from each other mean

(i) a hydrogen atom, or

ii) -(C1-C6)-alkyl or

R9 and R10 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)-alkyl,

4. -(C6-C14)-aryl, where the aryl with one, two or three times, independently from each other substituted

4.1) -CH2-C(O)-O-R8, where R8 has the above value,

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

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

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

4.5) -S(O)y-(C1-C6)-alkyl-C(O)-O-R8, where R8 has the above meaning and y OSN which denotes 1 or 2,

4.6) -S(O)z-(C1-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 have the above meaning and z is zero, 1 or 2,

4.7) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-N(R9)-(R10), where R8, R9 andR10 have the above meaning,

4.8) -C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the above meaning, and Het denotes a saturated or unsaturated monocyclic or bicyclic heterocyclic system with the number of links from 3 to 10, which contains in the cycle 1, 2 or 3 identical or different heteroatoms from the series nitrogen, oxygen and sulfur, and may be unsubstituted or have one, two or three times, independently from each other substituted

a) halogen,

b) cyano,

c) nitro,

(d) hydroxy,

e) amino,

f) -C(O)-O-(C1-C6)-alkyl,

g) -C(O)-OH,

h) -(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

i) -O-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4.9) -C(O)-N(R8)-(C0-C6)-alkyl-(C6-C14)-aryl, and aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

4.10) -CH2-N(R9)-(R10), where R9 and R10 have the abovementioned meaning,

4.11) -(CH2)y-N(R8)-C(O)-(C1-C6)-alkyl, where alkyl unsubstituted or have one, two or three times, independently of one another substituted by the above-mentioned residues from a) to i), and y is 1 or 2,

4.12) -(CH2)x-N(R8)-C(O)-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x represents 0, 1, 2, 3,or 4

4.13) -(CH2)x-N(R8)-C(O)-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x represents 0, 1, 2, 3,or 4

4.14) -(CH2)x-N(R8)-C(O)-O-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x represents 0, 1, 2, 3,or 4

4.15) -(CH2)x-N(R8)-C(O)-O-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x represents 0, 1, 2, 3,or 4

4.16) -(CH2)x-N(R8)-C(O)-O-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x represents 0, 1, 2, 3,or 4

4.17) -(CH2)X-N(R8)-C(O)-N(R11)-R12, where R8 and x have the above meaning, and R11 and R12 are the same or different and independently from each other mean

4.17.1) a hydrogen atom,

4.17.2) -(C1-C6)-alkyl,

4.17.3) -(C0-C6)-alkyl-(C6 -C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

4.17.4) -(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

4.17.5)-C(O)-(C1-C6)-alkyl,

4.17.6) -C(O)-(C0-C6)-alkyl-(C6-C14)-aryl,

4.17.7) -C(O)-(C0-C6)-alkyl-Het,

4.17.8) -SO2-(C1-C6)-alkyl,

4.17.9) -SO2-(C0-C6)-alkyl-(C6-C14)-aryl,

4.17.10) -SO2-(C0-C6)-alkyl-Het,

4.18) -(CH2)x-N(R8)-S(O)2-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x and R8 have the above meaning,

4.19) -(CH2)x-N(R8)-S(O)2-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and x and R8 have the above meaning,

4.20) -(CH2)x-N(R8)-S(O)2-N(R8)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x and R8 independently of one another have the above meaning,

4.21) -CH 2)x-N(R8)-S(O)2-N(R8)-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x and R8 independently of one another have the above meaning,

4.22) -(CH2)x-N(R8)-S(O)2-N(R8)-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x and R8 independently of one another have the above meaning,

4.23) -(CH2)X-N(R8)-C(O)-N(R8)-SO2-R13, where x and R8 independently of one another have the above significance, and R13 denotes -(C1-C6)-alkyl or -(C0-C6)-alkyl-(C6-C14)-aryl,

4.24) -S(O)2-N(R8)-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and R8 has the above value,

4.25) S(O)2-N(R8)-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and R8 has the above value,

4.26) -S(O)2-N(R8)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), the R8 has the above value,

4.27) -S(O)2-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

4.28) -S(O)2-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

4.29) -O-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), or

4.30) -Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), or

4.31) -phenyl, and the phenyl ring is unsubstituted or one-, two - or three-replaced

4.31.1) halogen,

4.31.2) -(C1-C6)-alkyl,

4.31.3) -O-(C1-C6)-alkyl,

4.31.4) -S(O)2-R16, where R16 means (C1-C6)-alkyl or-NH2,

5. -C(O)-N(R8)-(C0-C6)-alkyl-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from 4.1) to 4.31) or 4.8) (a) to 4.8) (i)and R8 has the above value, or

6. -C(O)-N(R8)-(C0-C6)-alkyl-Het, where Het has the above significance and unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues with 4.1) at 4.31) or 4.8a) 4.8) (i), and R8 has the above value, or

7. -NH-(C6-C14)-aryl, where aryl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues with 4.1) by 4.30) or 4.8). (a) 4.8) (i), or

8. -NH-Het, where Het has the above significance and unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues with 4.1) at 4.31) or 4.8). (a) 4.8) (i),

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

1. a hydrogen atom,

2. halogen,

3. -(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4. -O-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen, or

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

R4 and R5 or R5 and R6 together with the carbon atom to which they are respectively bound, independently from each other to form a 5 - or 6-tier cycle, which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulphur, whereby the cycle unsubstituted or on one or more carbon atoms by one or twice substituted by halogen, and the other residues R3, R6 and R7 or R3, R4 and R7 have the above in paragraphs 1. 5. value

or for the case b)

R1 means a hydrogen atom or -(C1-C6)-alkyl,

R2 denotes -(C1-C6)-alkyl, the rich one alkyl-, two or three times substituted

1. -C(O)-O-R8', where R8' means

1.1) a hydrogen atom, or

1.2) -(C1-C6)-alkyl,

2. -(C1-C6)-alkyl-O-R8', where R8' has the abovementioned meaning,

3. -(C6-C14)-aryl, where the aryl with one, two or three times, independently from each other substituted

3.1) -(C2-C6)-alkyl-C(O)-O-R8', where R8' has the abovementioned meaning,

3.2) -O-(C1-C6)-alkyl-C(O)-O-R8', where R8' has the abovementioned meaning,

3.3) -N(R14)-(R15), where R14 and R15 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)-alkyl,

3.4) -(CH2)k-N(R9')-(R10'), where k is 2, 3, 4 or 5 and R9' and R10' are the same or different and independently from each other mean

3.4.1) hydrogen or

3.4.2) -(C1-C6)-alkyl, or

R9' and R10' together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)alkyl,

3.5) -O-(C2-C 6)-alkyl-N(R9')-R10', and R9' and R10' have the above meaning,

3.6) -N(R8')-C(O)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two - or three-replaced

3.6.1) halogen,

3.6.2) cyano,

3.6.3) nitro,

3.6.4) hydroxy,

3.6.5) amino,

3.6.6) -C(O)-O-(C1-C6)-alkyl or

3.6.7) -C(O)-OH and R8' has the abovementioned meaning,

3.7) -phenyl, and the phenyl ring is unsubstituted or one-, two - or three-replaced

3.7.1) halogen,

3.7.2) -(C1-C6)-alkyl,

3.7.3) -O-(C1-C6)-alkyl,

3.7.4) -S(O)2-R16', and R16' means (C1-C6)-alkyl or-NH2,

4. Het, and Het denotes a saturated or unsaturated mono - or bicyclic heterocyclic system with the number of links from 3 to 10, which contains in the cycle 1, 2 or 3 identical or different heteroatoms from the series nitrogen, oxygen and sulfur, unsubstituted or one-, two - or three-replaced

4.1) halogen,

4.2) cyano,

4.3) nitro,

4.4) hydroxy,

4.5) amino,

4.6) -C(O)-(C1-C6)-alkyl,

4.7) -C(O)-OH,

4.8) -(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4.9) -O-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4.10) pyridium or

4.11) phenyl, and phenyl unsubstituted or mono - or megatr the IDT and independently from each other substituted by a residue from the series halogen, -(C1-C6)-alkoxy and -(C1-C6)-alkyl, and

R4 and R5 or R5 and R6 together with the carbon atom to which they are respectively bound, independently from each other to form a 5 - or 6-tier cycle, which is saturated or contains one or two heteroatoms from the series oxygen, nitrogen or sulphur, whereby the cycle unsubstituted or on one or more carbon atoms with one or doubly substituted with halogen, and other residues R3, R6 and R7 or R3, R4 and R7 denote hydrogen, provided that excluded unsubstituted benzo[1,3]DIOXOLANYL cycle.

Michael Murray was able to show that compounds that contain unsubstituted cycle benzo[1,3]dioxole as balance, inhibit the liver enzyme cytochrome P450 (Michael Murray, Current Drug Metabolism 2000, 67-84). The specified residue is responsible for these significant Toxicological effects. He was therefore excluded from the compounds of formula I.

Another object of the invention is a compound of formula I, and for the case (a)

R1 means a hydrogen atom or -(C1-C6)-alkyl,

R2 denotes -(C1-C6)-alkyl, and alkyl of one, two or three times substituted

1. -(C1-C6)-alkyl-O-(C6-C14)-aryl,

2. -(C0-C6)-alkyl-N(R8)-C(O)-O-(C1-C6)-alkyl, where R8 means

(i) a hydrogen atom

ii) -(C1-C6)-alkyl, where alkyl unsubstituted or have one, two or three n is independently from each other substituted-NH 2, -CN, -OH, -C(O)-OH, -C(O)-O-(C1-C6)-alkyl, -C(O)-NH-OH, NO2or halogen, or

iii) -OH,

3. -C(O)-N(R9)-(R10), where R9 and R10 are the same or different and independently from each other mean

(i) a hydrogen atom, or

ii) -(C1-C6)-alkyl or

R9 and R10 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)-alkyl,

4. by phenyl, where the phenyl with one, two or three times, independently from each other substituted

4.1) -(C0-C6)-alkyl-C(O)-O-R8, where R8 has the above value,

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

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

4.4) -(C0-C6)-alkyl-C(O)-(C0-C6)-alkyl-Het, and Het denotes a residue from the group of azepine, azetidine, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxole, 4H-benzo[1,4]oxazine, benzoxazole, benzothiazole, benzothiophene, heatline, quinoline, cinoxacin, chromane, cinnoline, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazole, isoxazol, m is Halina, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, oxirane, piperazine, piperidine, phthalazine, Piran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, predominate, pyridopyrimidines, pyridopyrimidines, 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 where Het unsubstituted or one-, two -, or three independently other substituted

a) halogen,

b) cyano,

c) nitro,

(d) hydroxy,

e) amino,

f) -C(O)-O-(C1-C6)-alkyl,

g) -C(O)-OH,

h) -(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

i) -O-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen or

-N(R9)-(R10), or

j) =0,

k) -Het, where Het is defined as above,

l) -(C2-C6-alkenyl, and alkenyl unsubstituted or one-, two - or three-fold substituted with halogen or-N(R9)-(R10), or

m) -(C2-C6-quinil, and quinil unsubstituted or one-, two -, or three times substituted by halogen or

-N(R9)-(R10),

4.5) -(C0-C6)-alkyl-C(O)-(C0-C6)-alkyl-OH,

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

4.7) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6/sub> )-alkyl-N(R9)-(R10), where R8, R9 and R10 have the above meaning,

4.8) -(C0-C4)-alkyl-N(R8)-S(O)2-(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m) and R8 has the above value,

4.9) -(C0-C4)-alkyl-S(O)2-(C0-C6)-alkyl-(C6-C14)-phenyl, where phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.10) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the above meaning, and Het has the above significance and unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.11) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-(C6-C14)-phenyl, and phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.12) -(C0-C6)-alkyl-N(R9)-(R10), where R9 and R10 have the abovementioned meaning,

4.13) -(CH2)y-N(R8)-C(O)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m) and y represents 1 or 2,

4.14) -(C0-C4)-alkyl-N(R8)-C(O)-(C0/sub> -C6)-alkyl-(C6-C14)-phenyl, where phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.15) -(C0-C4)-alkyl-N(R8)-C(O)-(C0-C6)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.16) -(C0-C4)-alkyl-N(R8)-C(O)-O-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.17) -(C0-C4)-alkyl-N(R8)-C(O)-O-(C1-C6-alkenyl, where alkenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.18) -(C0-C4)-alkyl-N(R8)-C(O)-O-(C1-C6-quinil where quinil unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.19) -(C0-C4)-alkyl-N(R8)-C(O)-O-(C0-C6)-alkyl-(C6-C14)-phenyl, where phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.20) -(C0-C4)-alkyl-N(R8)-C(O)-O-(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted the above OST tchami a) to m),

4.21) -(C0-C4)-alkyl-N(R8)-C(O)-(C0-C6)-alkyl-N(R11)-R12, where R8 has the above meaning, and R11 and R12 are the same or different and independently from each other mean

4.21.1) a hydrogen atom,

4.21.2) -(C1-C6)-alkyl,

4.21.3) -(C0-C6)-alkyl-(C6-C14)-phenyl, where phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.4) -(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.5) -C(O)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.6) -C(O)-(C3-C6-cycloalkyl where cycloalkyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.7) -C(O)-(C0-C6)-alkyl-(C6-C14)-phenyl, where phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.8) -C(O)-(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.9) -SO2-(C0-C6)-alkyl, where alkyl is independently is substituted or mono-, two or three times, independently from each other substituted above the remnants of a) to m),

4.21.10) -NH-SO2-(C0-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.11) -SO2-(C0-C6)-alkyl-(C6-C14)-phenyl-(C0-C6)-alkyl, where the phenyl unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.21.12) -SO2-(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

4.22) -O-(C0-C6)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m), or

4.23) -(C0-C4)-alkyl-Het, where Het is defined above and is unsubstituted or one-, two -, or three times, independently from each other substituted above the remnants of a) to m),

5. -C(O)-N(R8)-(C0-C6-alkylphenyl, where phenyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues with 4.1) at 4.23) or 4.4)a) to 4.4)m)and R8 has the above value, or

6. -C(O)-N(R8)-(C0-C6)-alkyl-Het, where Het means azepin, azetidin, aziridine, benzimidazole, Ben is furan, benzo[1,4]dioxin, 1,3-benzodioxol, 4H-benzo[1,4]oxazin, benzoxazole, benzothiazole, benzothiophene, hinzelin, quinoline, cinoxacin, chroman, cinnolin, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazol, isoxazol, morpholine, 1,2-oxazin, 13-oxazin, 1,4-oxazin, oxazol, oxiran, piperazine, piperidine, phthalazine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, predominate, iridoviridae, pyridopyrimidines, pyrrole, pyrrolidine, tetrazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 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 unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from 4.1) to 4.4) or 4.4)a) to 4.4)m)and R8 has the above value,

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

1. a hydrogen atom,

2. halogen,

3. -(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen, or

4. -O-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen, or

R4 and R5 or R5 and R6 together with the carbon atom to which they relate, independently of each form dioxane, DIOXOLANYL, dihydrofuran or furan cycle, and the cycle of nezame the EN or on one or more carbon atoms with one or doubly substituted with halogen, and other residues R3, R6 and R7 or R3, R4 and R7 have the above in paragraphs 1 through 4 the value

or for the case b)

R1 means a hydrogen atom or -(C1-C4)-alkyl,

R2 denotes -(C1-C4)-alkyl, and alkyl of one, two or three times substituted

1. -C(O)-O-R8', where R8' means

1.1) a hydrogen atom, or

1.2) -(C1-C4)-alkyl,

2. -(C1-C4)-alkyl-O-R8', where R8' has the abovementioned meaning,

3. phenyl, where the phenyl with one, two or three times, independently from each other substituted

3.1) -(C2-C4)-alkyl-C(O)-O-R8', where R8' has the abovementioned meaning,

3.2) -O-(C1-C4)-alkyl-C(O)-O-R8', where R8' has the abovementioned meaning,

3.3) -N(R14)-(R15), where R14 and R15 together with the nitrogen atom to which they are bound, form a residue that can be derived from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, research, isothiazolinone or thiomorpholine, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C4)-alkyl,

3.4) -(CH2)k-N(R9')-(R10'), where k is 2, 3, 4 or 5, and R9' and R10' are the same or different and independently from each other mean

3.4.1) a hydrogen atom, or

3.4.2) -(C1-C6)-alkyl or

R9' and R10' together with the nitrogen atom to which they are bound, form a residue that can be images of the n from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, research, isothiazolinone or thiomorpholine, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C4)-alkyl,

3.5) -O-(C2-C6)-alkyl-N(R9')-R10', and R9' and R10' have the above meaning,

3.6) -N(R8')-C(O)-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two - or three-replaced

3.6.1) halogen,

3.6.2) cyano,

3.6.3) nitro,

3.6.4) hydroxy,

3.6.5) amino,

3.6.7) -C(O)-O-(C1-C6)-alkyl or

3.6.8) -C(O)-OH, and R8' has the abovementioned meaning,

3.7) -phenyl, and the phenyl ring is unsubstituted or one-, two - or three-replaced

3.7.1) halogen,

3.7.2) -(C1-C6)-alkyl,

3.7.3) -O-(C1-C6)-alkyl, or

3.7.4) -S(O)2-R16', where R16' means (C1-C6)-alkyl or-NH2,

4. Het, and Het means azepin, azetidin, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxol, 4H-benzo[1,4]oxazin, benzoxazole, benzothiazole, benzothiophene, hinzelin, quinoline, cinoxacin, chroman, cinnolin, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazol, isoxazol, morpholine, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol oxiran, piperazine, n is peridin, phthalazine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, predominate, iridoviridae, pyridopyrimidines, pyrrole, pyrrolidine, tetrazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 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 unsubstituted or one-, two -, or three times, independently from each other substituted

4.1) halogen,

4.2) cyano,

4.3) nitro,

4.4) hydroxy,

4.5) amino,

4.6) -C(O)-O-(C1-C6)-alkyl,

4.7) -C(O)-OH,

4.8) -(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4.9) -O-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4.10) pyridium or

4.11) phenyl, and phenyl unsubstituted or one-, two -, or three times, independently of one another substituted by a residue from the series halogen, -(C1-C6)-alkoxy and -(C1-C6)-alkyl, and

R4 and R5 or R5 and R6 together with the phenyl ring and the carbon atom to which they are respectively bound, independently from each other to form a cyclic system from a number of benzo[1,4]dioxane, 2,3-dihydrobenzofuran and 2,2-debtorrent[1,3]dioxol, and other residues R3, R6 and R7 or R3, R4 and R7 means a hydrogen atom.

The next object of the invention is a compound of formula I, and

in case (a)

R1 means the atom bodoro is and,

R2 denotes -(C1-C3)-alkyl, and alkyl substituted

1. by phenyl, where the phenyl with one, two or three times, independently from each other substituted

1.1) -CH2-C(O)-O-R8, where R8 means hydrogen, methyl, ethyl, propyl or butyl,

1.2) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 denote a hydrogen atom, methyl, ethyl, propyl or butyl, or R9 and R10 together with the nitrogen atom to which they are bound, form a residue that can be formed from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, research, isothiazolinone or thiomorpholine, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C4)-alkyl,

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

1.4) -O-(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 have the meanings set out in 1.2),

1.5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-N(R9)-(R10), where R8, R9 and R10 have the above meaning,

1.6) -C(O)-N(R8)-(C0-C2)-alkyl-Het, and R8 has the above meaning, and Het means azepin, azetidin, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxol, 4H-benzo[1,4]oxazin, benzoxazole, benzothiazole, benzothiophene, hinzelin, quinoline, cinoxacin, chroman, cinnolin, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoh the nolin, isochroman, isoindole, isothiazol, isoxazol, morpholine, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxiran, piperazine, piperidine, phthalazine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, predominate, iridoviridae, pyridopyrimidines, pyrrole, pyrrolidine, tetrazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 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 unsubstituted or one-, two -, or three times, independently from each other substituted

a) halogen,

b) cyano,

c) nitro,

(d) hydroxy,

e) amino,

f) -C(O)-O-(C1-C4)-alkyl,

g) -C(O)-OH,

h) -(C1-C4)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

i) -O-(C1-C4)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen, or

1.7) -C(O)-N(R8)-(C0-C4-alkylphenyl, and phenyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

1.8) -CH2-N(R9)-(R10), where R9 and R10 have the above meaning,

1.9) -(CH2)y-N(R8)-C(O)-(C1-C4)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i) and y represents 1 or 2,

1.10) -(CH2)x-N(R8)-C(O)-(C0-C2-alkylphenyl, the de phenyl unsubstituted or mono-, two or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x is 0, 1 or 2,

1.11) -(CH2)x-N(R8)-C(O)-(C0-C2)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x is 0, 1 or 2,

1.12) -(CH2)x-N(R8)-C(O)-O-(C1-C4)-alkyl, where alkyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x is 0, 1 or 2,

1.13) -(CH2)x-N(R8)-C(O)-O-(C0-C4-alkylphenyl, where phenyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x is 0, 1 or 2,

1.14) -(CH2)x-N(R8)-C(O)-O-(C0-C4)-alkyl-Het, where Het unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i), and x is 0, 1 or 2,

1.15) -(CH2)X-N(R8)-C(O)-N(R11)-R12, where R8 and x have the above meaning, and R11 and R12 are the same or different and independently from each other mean

1.15.1) a hydrogen atom,

1.15.2) methyl, ethyl, propyl or butyl,

1.15.3) -(C0-C2-alkylphenyl, where phenyl unsubstituted or one-, two -, or three times, independently of one another substituted by the above-mentioned residues from a) to i),

1.15.4) -(C0-C2)-alkyl-Het, the de Het unsubstituted or mono-, two or three times, independently of one another substituted by the above-mentioned residues from a) to i),

1.15.5) -C(O)-(C1-C4)-alkyl,

1.15.6) -C(O)-(C0-C2-alkylphenyl,

1.15.7) -C(O)-(C0-C2)-alkyl-Het,

1.15.9) -SO2-(C0-C4-alkylphenyl or

1.15.10) -SO2-(C0-C2)-alkyl-Het,

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

1. a hydrogen atom,

2. halogen,

3. -(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen,

4. -O-(C1-C6)-alkyl, where alkyl unsubstituted or one-, two -, or three times substituted by halogen, or

R4 and R5 or R5 and R6 together with the carbon atoms to which they are linked, independently of each form dioxane, DIOXOLANYL, dihydrofuran or furan cycle, and other residues R3, R6 and R7 or R3, R4 and R7 have the meanings specified above in paragraphs 1. to 4.,

or for the case b)

R1 means a hydrogen atom,

R2 denotes -(C1-C2)-alkyl, and alkyl of one, two or three times substituted

1. -C(O)-O-R8', where R8' means

1.1) a hydrogen atom, or

1.2) -(C1-C2)-alkyl,

2. by phenyl, where the phenyl with one, two or three times, independently from each other substituted

2.1) -O-(C2-C4)-alkyl-N(R9')-R10', and R9' and R10' independently of one another mean a hydrogen atom, methyl or ethyl, or R9 and R10' together with the nitrogen atom, with which they are linked, form a residue that can be formed from pyrrolidine, piperidine, piperazine, research or thiomorpholine, and in the case of piperazine second nitrogen atom may be replaced by stands or ethyl,

2.2) -O-(C1-C2)-alkyl-C(O)-O-R8', where R8' independently of one another mean a hydrogen atom, methyl or ethyl, or

2.3) -N(R14)-(R15), where R14 and R15 together with the nitrogen atom to which they are linked, form a residue that can be formed from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, research, isothiazolinone or thiomorpholine, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted by stands or ethyl,

2.4) -(CH2)k-N(R9')-(R10'), where k represents 2, 3 or 4 and R9' and R10' are the same or different and independently from each other mean a hydrogen atom, methyl or ethyl, or R9' and R10' together with the nitrogen atom to which they are linked, form a residue that can be formed from pyrrolidine, piperidine, piperazine, research or thiomorpholine, and in the case of piperazine second nitrogen atom may be replaced by stands or ethyl, and

R4 and R5 or R5 and R6 together with the phenyl ring and the carbon atom to which they are respectively bound, independently from each other to form a cyclic system from a number of benzo[1,4]dioxane, 2,3-dihydrobenzo the furan and 2,2-debtorrent[1,3]dioxol, and other residues R3, R6 and R7 or R3, R4 and R7 means a hydrogen atom.

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

4-(3-methoxybenzamido)-6-(4-profilirovannymi) pyrimidine-4,6-carboxylic acid,

4-(4-isopropylcarbodiimide)-6-(3-methoxybenzylamine) pyrimidine-4,6-carboxylic acid,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxyhemoglobinemia ether,

4-(3-methoxybenzamido)-6-[(2-phenoxyethyl)-amide] pyrimidine-4,6-carboxylic acid,

(5-{[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-pentyl)-carboxypolymethylene ether,

4-[4-(2-dimethylaminoethanol)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[4-(2-dimethylaminoethanol)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(3-chloro-4-forbindelse)-6-[4-(2-dimethylaminoethanol)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-dimethylcarbamoyl-6-(3-methoxybenzylamine) pyrimidine-4,6-carboxylic acid,

[4-({[6-(3-aminobenzoylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-tert-butyl ether,

4-(3-chlorobenzylamino)-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-[(2-chloropyridin-4-ylmethyl)-amide]-6-(4-fluoro-3-methylbenzylamine) PI is kidin-4,6-dicarboxylic acid,

4-benzylated-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[(pyridine-4-ylmethyl)-amide] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[(pyridine-3-ylmethyl)-amide] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]-benzylamine} pyrimidine-4,6-carboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-morpholine-4-yl-2-oksidoksi)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(4-diethylcarbamazine)-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-carboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(isopropylaminomethyl)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[(2-morpholine-4-yl-ethylcarbamate)-methyl]-benzylamine} pyrimidine-4,6-carboxylic acid,

4-(4-diethylcarbamazine)-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-carboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-morpholine-4-yl-2-oxoethyl)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(isopropylcarbamate)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(3-methoxybenzamido)-6-[(pyridine-3-ylmethyl)-amide] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-({[(pyridine-4-ylmethyl)-carbarnoyl]-methyl}-amide) pyrimidine-4,6-carboxylic acid,

4-({[(2-what lipiridy-4-ylmethyl)-carbarnoyl]-methyl}-amide)-6-(3-methoxybenzylamine) pyrimidine-4,6-carboxylic acid,

4-(3-chloro-4-forbindelse)-6-({[(2-chloropyridin-4-ylmethyl)-carbarnoyl]-methyl}-amide) pyrimidine-4,6-carboxylic acid,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamidotryptamine ether,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxylesterases ether,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxyquinolone ether,

4-(3-chloro-4-forbindelse)-6-[4-(1-methylpiperidin-3-yloxy)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(3-chloro-4-forbindelse)-6-({[(pyridine-3-ylmethyl)-carbarnoyl]-methyl}-amide) pyrimidine-4,6-carboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[(2'-sulfamoylbenzoyl-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(thiophene-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(5-methylfuran-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(5-methylfuran-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran the-5-ylmethyl)-amide]-6-[(5-pyridin-2-yl-thiophene-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(pyridine-3-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[(pyridine-3-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[(5-methylfuran-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[(thiophene-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(5-methyl-isoxazol-3-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(1-methyl-1H-pyrazole-4-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(2,5-dimethylfuran-3-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-[(6-aminopyridine-3-ylmethyl)-amide]-6-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(1-methyl-1H-pyrrol-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(1H-benzoimidazol-2-ylmethyl)-amide]-6-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(pyrazin-2-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,2-debtorrent[1,3]dioxol-5-ylmethyl)-amide]-6-[(pyridine-4-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

methyl ether ({6-[(23 dihydrobenzo[1,4]dioxin-6-ylmethyl)-carbarnoyl]-pyrimidine-4-carbonyl}-amino)-acetic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(2-methyl-1H-imidazol-4-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(2-pyridin-2-retil)-amide] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-{[3-(4-forfinal)-1H-pyrazole-4-ylmethyl]-amide} pyrimidine-4,6-carboxylic acid;

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[4-(3-dimethylaminopropoxy)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[4-(2-dimethylaminoethoxy)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[3-(2-dimethylaminoethoxy)-benzylamine] pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(pyridine-4-ylmethyl)-amide] pyrimidine-4,6-carboxylic acid;

4-(3-chloro-4-forbindelse)-6-(4-[3'-methylsulphonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(4-oxopiperidin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(4-oxopiperidin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-[4-(4-hydroxypiperidine-1-carbonyl)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dick is Borovoy acid,

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

4-(4-fluoro-3-methylbenzylamino)-6-[4-(4-hydroxypiperidine-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(thiomorpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(thiomorpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(3-methoxybenzamido)-6-[4-(3-oxopiperidin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(4-fluoro-3-methylbenzylamino)-6-[4-(3-oxopiperidin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-hydrooximethylcarbamil)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[(pyridine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(4-sankarnarayanan)-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-dicarboxylic key is lots

4-(3-methoxybenzamido)-6-[4-(3-morpholine-4-yl-propellerblades)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(3-morpholine-4-yl-propellerblades)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(4-methylpiperazin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-{4-[(pyridine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-(4-[3'-methylsulphonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

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

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

4-(4-N-cyanocarbonimidate)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-(3[3'-methylsulphonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

4-(4-hydroxycarbonylmethyl)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(hydroxycarbonylmethyl)-benzylamine] pyrimidine-4,6-dicarboxylic sour is s,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(1-methylpiperidin-3-yloxy)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-piperazine-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-(4-hydroxycarbonylmethyl) pyrimidine-4,6-dicarboxylic acid,

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

4-(4-fluoro-3-methylbenzylamino)-6-[4-(1-methylpiperidin-3-yloxy)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-tert-butylcarbamoyl)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[methyl-(1-methylpiperidin-4-yl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

{4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoylamine}-acetic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-{4-[4-(2-dimethylaminoethyl)-piperazine-1-carbonyl]-benzylamine}-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-(4-[3'-methylsulphonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[3-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic key is lots

[4-({[6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoylamine]-acetic acid,

4-(3-methoxybenzamido)-6-[4-(2-piperazine-1-yl-acetylamino)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(3-methoxybenzamido)-6-[3-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[(piperidine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(piperidine-4-ylcarbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(piperidine-4-ylcarbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[methyl-(1-methylpiperidin-4-yl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-7-ylmethyl)-amide] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[(piperidine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(4-methylpiperazin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(4-pyridin-4-yl-piperazine-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2-morpholine-4-yl-acetylamino)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(3-methoxybenzamido)-6-(4-[p-toluensulfonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

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

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-(4-[3'-phenylsulfonyl]-ureidopenicillin) pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-pyrrolidin-1-yl-ethoxy)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[4-(3-cyclohexanecarbonitrile)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[3-(pyridine-3-carbonyl)-ureido]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-[4-(3-isobutylamino)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarbo the OIC acid,

4-(3-methoxybenzamido)-6-[4-(2-pyrrolidin-1-yl-acetylamino)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

4-(3-methoxybenzamido)-6-{4-[2-(2-oxopyrrolidin-1-yl)-acetylamino]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

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

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

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

4-[4-(2-dimethylaminoacetyl)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-morpholine-4-yl-ethoxy)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[4-(3-cyclohexylurea)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-{4-[3-(2,6-dichloropyridine-4-yl)-ureido]-benzylamine}-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-[4-(3-tert-butylurea)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-but-2-injuly ether,

4-(4-ethanolamines lamed)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(thiophene-2-sulfonylamino)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2,2,2-cryptgethashparam)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxypolymethylene ether,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-2-injuly ether,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-2-methoxyethylamine ether,

[4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-4-forfinally ether,

4-[4-(3-benzoylamino)-benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

[3-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-2-injuly ether,

[3-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxamido-prop-2-injuly ether,

[3-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-carboxyhemoglobinemia ether,

4-(3-chloro-4-forbindelse)-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzyl the MFA)-6-{4-[(pyridine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-(4-diethylcarbamazine) pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-[4-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-{4-[2-(2,6-dimethylpiperidin-1-yl)-2-oxoethyl]-benzylamine}-6-(4-fluoro-3-methylbenzylamine) pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(1-methylpiperidin-3-yloxy)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-diethylcarbamazine)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid,

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

4-(3-chloro-4-forbindelse)-6-(4-methanesulfonylaminoethyl) pyrimidine-4,6-dicarboxylic acid, or

4-(4-methanesulfonanilide)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid.

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

and/or all stereoisomeric forms of the compounds of formula I and/or mixtures of these forms in any ratio, and/or physiologically acceptable salts of the compounds of formula I to obtain drugs for prevention and treatment of diseases, in the course of which the effect of increasing the military activity of matrix metalloproteinase-13.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to hydrocarbon residues in the broadest sense, the carbon chain which is linear or branched, or which consist of cyclic hydrocarbon groups or combinations of linear and cyclic groups. For example, linear and branched hydrocarbon residues may be the stands, ethyl, propylene, isopropyl, bootrom, tert-bootrom, Pentium or hexyl, a cyclic group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a combination of linear and cyclic residues can be cyclopropylmethyl, cyclobutylmethyl or cyclopentylmethyl. However, the alkyl may be single or multiply unsaturated, as (C2-C6)-alkenyl, for example, ethylene, propylene, butene, methylpropan, isobutylene, 1,3-butadiene or 1,3-pentadiene, or (C2-C6)-quinil, for example, acetylene, profilin, butyn, 2-methyl-3-hexyne, 1,4-pentadien or 2-HEXEN-4-in. The term "-(C0-C6)-alkyl" refers to hydrocarbon residues, carbon chain which is linear or branched and contain from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl or hexyl. "-C0-alkyl" is a covalent bond.

The term "-(C6-C14)-Ari is understood to mean an aromatic carbon residues, containing from 6 to 14 carbon atoms in the cycle. -(C6-C14)-aryl residues are, for example, phenyl, naphthyl, for example 1-naphthyl, 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl and 4-biphenylyl, antrel or fluorenyl. Biphenylene residues, raftiline residues and, in particular, phenyl residues are preferably aryl residues.

The term "R4 and R5 or R5 and R6 together with the carbon atom to which they relate, independently of each other to form a 5 - or 6-tier cycle, which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulfur" refers to a cyclic system, which may be formed of dioxole, pyrrole, pyrrolidine, pyridine, piperidine, dioxane, tetrahydropyridine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, pyridazine, pyrimidine, pyrazine, piperazine, Piran, furan, dihydrofuran, tetrahydrofuran, oxazole, isoxazol, 2-isoxazoline, isoxazolidine, research, oxathiolane, thiopyran, thiazole, isothiazole, 2-isothiazoline, isothiazolinone or thiomorpholine.

The term "Het" refers to saturated or unsaturated monocyclic or bicyclic heterocyclic system with the number of links from 3 to 10, which contains in the cycle 1, 2 or 3 identical or different heteroatoms from the series I is t, oxygen and sulfur. Het contains the main monocyclic or bicyclic heterocyclic system 3, 4, 5, 6, 7, 8, 9 or 10 atoms in the cycle. Monocyclic system can be 3-, 4-, 5-, 6 - or 7-tier cycle. In bicyclic Het can be combined with each other two rings, of which one may be 5-tier or 6-tier a heterocycle, and the other may be 5 - or 6-tier a heterocycle or carbocycle. Bicyclic Het group can be, for example, of 8, 9 or 10 atoms in the loop.

Het includes saturated heterocyclic system that cycles do not contain double bonds and unsaturated heterocyclic systems, including monounsaturated and polyunsaturated heterocyclic system containing one or more double bonds and form stable cyclic system. Unsaturated cycles can be partially unsaturated, or to form an aromatic system. In Het-group includes identical or different heteroatoms from the series nitrogen, oxygen and sulfur. Examples of the heterocycles that can be formed by Het-group are acridines, azocines, benzimidazolyl, benzofuranyl, benzothiophene, benzothiophene, benzoxazole, benzothiazole, benzotriazole, betterall, benzisoxazole, benzisothiazole, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolines, bromanil, bromanil, zinno inil, decahydroquinoline, 2H,6H-1,5,2-detainer, dihydrofuro[2,3-b]-tetrahydrofuran, furanyl, furutani, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridines, phenanthrolines, phenazines, phenothiazinyl, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, pteridinyl, pyrenyl, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridoxal, predominate, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, 2H-pyrrolyl, pyrrolyl, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 6H-1,2,5-thiadiazine, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl and xantinol.

Preferred azepin, azetidin, aziridine, benzimidazole, benzofuran, benzo[1,4]dioxin, 1,3-benzodioxol, 4H-benzo[1,4]oxazin, benzoxazole, benzothiazole, benzothiophene, hinzelin, quinoline, cinoxacin, chroman, cinnolin, 1,2-diazepine, 1,3-d is azepin, 1,4-diazepine, 1,4-dioxin, dioxole, furan, imidazole, indazole, indole, isoquinoline, isochroman, isoindole, isothiazol, isoxazol, morpholine, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxiran, piperazine, piperidine, phthalazine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, predominate, iridoviridae, pyridopyrimidines, pyrrole, pyrrolidine, tetrazole, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 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 loop system, which is obtained from the above heterocycles by combining or condensation with carbocycles, as, for example, Antonelliana, cyclopent-condensed, cyclohexa-condensed or cyclohepta-condensed derivatives of these heterocycles. Suitable nitrogen heterocycles can also be present as N-oxides or Quaternary salts, in which a suitable nitrogen atom is alkylated (C1-C4)-alkyl residues.

Het group can be unsubstituted or substituted in accordance with the above definitions.

The term "R9 and R10 or R14 and R15 together with the nitrogen atom to which they are bound, form a 5-, 6 - or 7-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulfur and nitrogen" refers to the remains, who may be formed of imidazolidine, isothiazolinone, isoxazolidine, research, piperazine, piperidine, pyrazine, pyrazolidine, pyrrolidine, tetrazine or thiomorpholine.

The compounds of formula I can be obtained, for example, the fact that the compound of formula II

a) is subjected to interaction with the compound of the formula IIIa or IIIb

and R1, R2, R3, R4, R5, R6 and R7 have the meanings indicated in formula I and Y is halogen, hydroxyl or C1-C4-alkoxy, or together with the carbonyl group forms an active ester or a mixed anhydride, forming a compound of formula I, and the reaction products, if necessary, translated into their physiologically acceptable salts, or

b) the compound of formula II is subjected to interaction with the compound of the formula IIIa or IIIb with the formation of compounds of formula IVa or IVb,

and residues from R1 to R7 have the meanings indicated in formula I and Y is halogen, hydroxyl or With the1-C4-alkoxy, or together with the carbonyl group forms an active ester or a mixed anhydride, and a compound of formula IVa or IVb, if necessary, cleaned, and then the compound of the formula IIIa or IIIb is transferred to the compound of formula I.

Next, obtain the compounds of formula I and obtain the necessary source is x substances because they are not commercially available are described in more detail.

Obtaining the compounds according to the invention manages the easiest way so that both components, pyrimidine derivative of the formula (II) and the amine of the formula IIIa or IIIb are combined in equimolar amounts and at temperatures from -30 to 150°C, preferably from 20 to 100°C is transferred to the compound of formula IVa or IVb, and then the compounds of formula IVa or IVb similar lead by reaction with an amine of the formula IIIb or IIIa in an amount up to equimolar. The end of the reaction can be determined, for example, using thin-layer chromatography or HPLC-MS. One variant of this method is that is carried out in a suitable solvent, such as diethyl ether, dimethoxyethane or tetrahydrofuran, chlorinated hydrocarbons like methylene chloride, chloroform, tri - or tetrachloroethylene, benzene, toluene, or in polar solvents such as dimethylformamide, acetone or dimethylsulfoxide. When the reaction temperature is between room temperature and the boiling point of the solvent, particularly preferred temperature in the range from room temperature up to 130°C.

Similarly, the transformation can occur through a mixed anhydride as ethyl ether of Harborview acid, or via an active ester as a couple-nitrophenyloctyl ether (Y=ClCH2-COO or NO 2-C6H4-O). Corresponding methods are known and described in literature.

Similarly, interactions can occur the compounds of formula II or the compound of formula IVa or IVb with an amine of the formula IIIa or IIIb, if Y denotes OH, and the corresponding carboxylic acid is activated in situ in the usual agents of the combination. Such agents combinations are, for example, carbodiimide as dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DCI), or N,N'-carbonyldiimidazole as N,N'-carbonyldiimidazole, or salt Urania as O-((cyano(etoxycarbonyl)methylene)-amino)-1,1,3,3-tetramethylethylenediamine (TOTU) or O-(7-asobancaria-1-yl)-1,1,3,3-tetramethylhexadecane (HATU). Corresponding methods are known. If amines of the formula IIIa or IIIb not available for sale, you can get them by known literature methods from the appropriate commercially available starting compounds. Suitable parent compounds to amines are, for example, NITRILES, nitro compounds, amides, carboxylic acids, esters of carboxylic acids, carboxylic acids, aldehydes and bromides. NITRILES, nitro compounds, and amides of carboxylic acids can be recovered by known methods to amines. Carboxylic acids and esters of carboxylic acids can be converted into amides of carboxylic acids. Aldehydes can be converted to amine is directly through reductive amination of NH 4Ac/NaBH4or hydroxylamine first Axemen and then recovery in amines.

If necessary, the transformation can be carried out also in the presence of bases. As additional grounds are considered, for example, carbonates or bicarbonates like sodium carbonate or potassium or sodium bicarbonate or potassium, or tertiary amines like triethylamine, tributylamine, ethyldiethanolamine, or heterocyclic amines as N-alkylboronic, pyridine, quinoline or dialkylanilines.

If necessary, can be further processed products, in particular, compounds of the formula IVa or IVb, for example, extraction or chromatography, for example, silica gel. The isolated product can be recrystallized and, if necessary, converted to the appropriate acid in a physiologically acceptable salt. As suitable acids are considered, for example:

inorganic acids such as hydrochloric and Hydrobromic acid, and sulfuric, phosphoric, nitric or perchloric acid, or organic acids as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric, phenylacetic, benzoic, methansulfonate, toluensulfonate, oxalic acid, 4-aminobenzoic, naphthalene-1,5-disulfonate or ascorbic acid.

The source connection of the texts of the formula IIIa or IIIb, in the absence of a sale, can be simply synthesized (for example, Organikum, Organisch Chemisches Grundpraktikum, 15. Aufl., VEB Deutscher Verlag der Wissenschaften, 1976; an overview of the different possibilities is the index methods, S. 822).

The initial compounds of the formula (II) are obtained, for example, the conversion of pyrimidine-4,6-dicarboxylic acid to the corresponding gelegenheid pyrimidine-4,6-dicarboxylic acid, preferably the acid chloride (known from the literature method), preferably in the presence of a catalyst as dimethylformamide. This gelegenheid acid may then be converted, for example, or a suitable alcohol, for example, para-nitrobenzyl alcohol into the corresponding active ester, or lower alcohols like methanol or ethanol, the corresponding esters. Similarly, pyrimidine-4,6-dicarboxylic acid can also be translated first by adding a suitable carboxylic acid, or a complex ester of carboxylic acid as ethyl ether of Harborview acid mixed anhydride, which can then interact with amines of compounds of formula IIIa or IIIb and IVa or IVb with a transformation in the products according to the invention. A corresponding method is also described in the literature.

Getting pyrimidine-4,6-dicarboxylic acid is known from the literature, for example, by oxidation of 4,6-di is ethylpyrimidine, which, in turn, can be obtained, for example, by catalytic hydrogenation of commercially available 2-mercapto-4,6-dimethylpyrimidine.

Since the compounds of formula I admit diastereoisomers or enantiomeric form, and when the selected synthesis are obtained in the form of their mixtures, the separation of the pure stereoisomers possible or by chromatography on a carrier, it is possible chiral, or as racemic compound of the formula I are capable of forming salts by fractional crystallization of the diastereomeric salts formed with optically active base or acid as an excipient. As chiral stationary phases for the separation of enantiomers using thin-layer or column chromatography are suitable, for example, the modified media of silica (so-called phase Pirkle), and high molecular weight carbohydrates as triacetylcellulose. For analytical purposes after appropriate known to the specialist, obtaining the derivative can also be used chromatographic methods on chiral stationary phases. For the separation of enantiomers of racemic carboxylic acids with optically active, as a rule, commercially available base, (- )- nicotine, (+)- and (-)-phenylethylamine, Hinn bases, L-lysine or L - and D-arginine, which form the soluble diastereomeric salt, allocate more difficultly soluble components in the form of a solid substance, which brings more easily soluble diastereoisomer from the mother liquor, and of thus obtained diastereoisomeric salts pure enantiomers. In principle, the same method can racemic compounds of the formula I which contain a basic group in the amino group, translated using optically active acid such as (+)-campher-10-sulfonic acid, D - and L-tartaric acid, D - and L-lactic acid and (+) and (-)-mandelic acid, in the pure enantiomers. You can also chiral compounds that contain alcohol or amino group, with the corresponding activated or possibly N-protected pure enantiomeric amino acids translated into the corresponding esters or amides, or, on the contrary, chiral carboxylic acids using carboxyamide pure enantiomeric amino - amides, or by using pure enantiomeric hydroxycarbonic acid, lactic acid, into the corresponding chiral esters. Then the chirality of the amino acid or alcohol residue, shown in pure enantiomeric form, can be used to separate the isomers, the fact that the separation available now diastereomers is carried out by crystallization or chromatography on suitable stationary phases, the village is e which simultaneously obtained chiral part of the molecule is again separated by suitable methods.

Acidic or basic products of the compounds of formula I can be in the form of their salts or in free form. Preferred pharmacologically acceptable salts, for example, salts of alkaline or alkaline earth metals or hydrochloride, hydrobromide, sulphates, polysulfate, various phosphates, and salts of amino acids, natural substrates or carboxylic acids.

Obtaining physiologically acceptable salts of the compounds of formula I are capable of forming salts, including their stereoisomeric forms, is known by. Carboxylic acids form with basic reagents, as hydroxides, carbonates, bicarbonates, alcoholate, and ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine or triethanolamine, or basic amino acids, in the case of lysine, ornithine or arginine, stable alkaline, alkaline earth or perhaps substituted ammonium salt. Since the compounds of formula I have a basic group with a strong acid to obtain a stable kislotoupornye salt. For this purpose, suitable inorganic and organic acids as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, benzolsulfonat, p-toluensulfonate, 4-bromobenzophenone, cyclohexanesulfonyl, cryptomaterial the new, acetic, oxalic, tartaric, succinic or triperoxonane acid.

Due to the pharmacological properties of the compounds of formula I are suitable for the prevention and treatment of all diseases on the course which are affected by enhanced activity of matrix metalloproteinase-13.

These include degenerative joint diseases like osteoarthritis, spondylosis, atrophy of cartilage after joint injuries or long Immobilise the knee joint after injury meniscus or kneecap or torn ligaments. Further, these are also diseases of connective tissue, as collagenoses, periodontal disease, impaired wound healing and chronic diseases of the musculoskeletal system as inflammatory, immunological or caused by the metabolism of acute and chronic airtricity, arthropathies, myalgias and disturbances of bone metabolism, or cancers such as breast cancer.

The administration of a medicinal product according to the invention can be carried out using subcutaneous, intraarticular, intraperitoneal or intravenous injection. Preferably intra-articular injection. It is also possible rectal, oral, inhalation, or transdermal administration.

The invention relates also to a method for producing a medicinal product, which is characterized by the fact that less is th least one compound of formula I with a pharmaceutically suitable and physiologically acceptable carrier and, if necessary, further active substances, additives or auxiliary substances result in appropriate form application.

The compounds of formula I are mixed with appropriate additives such as carriers, stabilizers or inert diluents, and conventional methods result in suitable forms of applications, such as tablets, pills, swallowing capsules, aqueous-alcoholic or oily suspensions or aqueous or oil solutions. As inert carriers may be used, for example, gum Arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This composition may be either dry or moist granules. As oily carriers or solvents are considered, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneous, intraarticular, intraperitoneal or intravenous receiving active compounds with suitable substances as agents of dissolution, emulsifiers or other auxiliaries, if necessary, translated into a solution, suspension or emulsion. As a suitable solvent, for example, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerin, along with this also solutions of sugars, as R is the cross-sections of glucose or mannitol, or also a mixture of the mentioned solvents.

In addition, the use of conventional auxiliary substances as carriers, spray agents, astringents, means for coating agents, swelling, glidant or lubricants, flavorings, sweeteners and agents of dissolution. As commonly used excipients can be called magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and other derivatives, animals, vegetable oil, like fish oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and one - or polyhydric alcohols as glycerol.

The compounds of formula I receive and accept preferably in the form of pharmaceutical preparations in dosage units, each unit contains as an active ingredient a specific dose of a compound of formula I. For this purpose, they can be taken orally in a dose of from 0.01 to 25.0 mg/kg/day, preferably from 0.01 to 5.0 mg/kg/day, or parenterale in a dose of from 0.001 to 5 mg/kg/day, preferably from 0.001 to 2.5 mg/kg/day. In severe cases, the dosage may be increased. However, in many cases sufficient smaller doses. These figures are based on the adult treatment.

Further, the invention is Ronnie is illustrated by means of examples.

Example 1:

Ethyl ester [4-({[6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid

a) Methyl ester of 6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carboxylic acid

8,81 g (0.045 mol) of dimethyl ether pyrimidine-4,6-dicarboxylic acid was dissolved in 200 ml of DMF, mixed with 6.25 g (0.045 mol) of 4-fluoro-3-methylbenzylamine and stirred for 48 hours at 60°C. the Solvent was removed in vacuum and the residue was combined with ethyl ester of acetic acid. The organic phase was washed with a saturated solution of sodium bicarbonate and 0.5 N. HCl and dried (MgSO4). After filtration and concentration of the solvent in vacuo the residue is stirred in isopropanol. Received of 8.75 g of product, which without further purification was further transformed.

b) 6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carboxylic acid

of 8.75 g (0.02 mol) of methyl ester of 6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carboxylic acid (70%) was combined with 150 ml ethanol and mixed with 1.89 g (0,022 mol) of NaOH in 6 ml of water. After 3 hours at room temperature the solvent was removed under reduced pressure, the residue was mixed with water and using concentrated HCl was set at pH < 2. The residue was pumped out and dried. Obtained 5.5 g (94%) of 6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carboxylic acid. M is (ES +): m/e=289,09

c) Ethyl ester (4-aminomethylphenol)-acetic acid

0.5 g (2.6 mmol) of ethyl ether (4-cyanophenyl)-acetic acid was dissolved in 70 ml of ethanolic ammonia solution and was first made over Raney Nickel at room temperature and normal pressure. After 45 minutes, was filtered and was concentrated. Received 0,42 g (82%) of ethyl ester (4-aminomethylphenol)-acetic acid. MS (ES+): m/e=194,11

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

1.3 g (4.5 mmol) of 6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carboxylic acid and 1,042 g(5.4 mmol) of the ethyl ester (4-aminomethylphenol)-acetic acid was dissolved in 30 ml DMF and combined with 1,02 g (4.9 mmol) of dicyclohexylcarbodiimide and 0,607 g (4.5 mmol) of hydroxybenzotriazole in 5°C. Stirred 5 (h) hours and was pumped. The solvent was removed in vacuo, the residue was combined with ethyl ester of acetic acid and washed with saturated aqueous NaHCO3. The organic phase was dried (MgSO4), filtered, and concentrated under reduced pressure. Received 2.66 g of product which was further purified using preparative HPLC. MS(ES+): m/e=464,19

Example 2:

[4-({[6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid

2.4 g (5.2 mmol) of the ethyl ester [4-({[6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid was combined with 150 ml of water was added 10 ml of water and 0,227 g (5.7 mmol) of NaOH. After 5 days of stirring at room temperature the solvent was removed under reduced pressure and the residue was mixed with ethanol and filtered. Obtained 1.51 g (67%) of [4-({[6-(4-fluoro-3-methylbenzylamino)-pyrimidine-4-carbonyl]-amino}-methyl)-phenyl]-acetic acid. MS (ES+): m/e=436,15

Example 3

4-(4-diethylcarbamazine)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid

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

26 g (88 mmol) of methyl ester of 6-(3-methoxybenzylidene)-pyrimidine-4-carboxylic acid (obtained by the interaction of the methyl ester pyrimidine-4,6-dicarboxylic acid 3-methoxybenzylamine) was dissolved in 100 ml of tetrahydrofuran and combined with 104 ml (1.2 equivalents) of 1-molar aqueous solution of the hydrochloride lithium and then the reaction mixture was stirred 18 hours at room temperature.

Then a large part of the used solvent drove away under reduced pressure, the residue was filtered from the insoluble by-products and the filtrate was acidified using 20%aqueous citric acid solution. It was crystallized 6-(3-methoxybenzylidene)-pyrimidine-4-carboxylic acid as light yellow crystals, which were filtered off.

Received 19 g (66,2 mmol) 6-(3-methoxybenzylidene the l)-pyrimidine-4-carboxylic acid (yield 75% of theoretical; MS (ES+): m/e=287,8).

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

4.3 g of 6-(3-methoxybenzylidene)-pyrimidine-4-carboxylic acid (15 mmol) of a) was dissolved in 50 ml of absolute N,N-dimethylformamide, and under stirring at 0°C sequentially connected from 3.3 g (16.5 mmol) of methyl-4-(aminomethyl)-benzotrichloride, 5,4 g (16.5 mmol) of O-[(canadachloromycetin)-amino]-N,N,N',N'-tetramethylethylenediamine (TOTU) and 4.6 ml of triethylamine (33 mmol). The reaction mixture was stirred 1 hour at 0°C and then 12 hours at room temperature.

For further processing solvent drove under reduced pressure and the residue was combined with 100 ml dichloromethane. The organic phase is washed with 100 ml saturated aqueous sodium hydrogen carbonate solution and then three times washed with water, using each time 100 ml After drying the organic phase by means of Na2SO4the solvent is kept at reduced pressure. The oily residue is triturated with a little diethyl ether, and crystallized colorless crystals. After filtration of the reaction product and washing with n-pentane obtained 6.6 g of methyl ester of 4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid (light yellow crystals). The reaction product, according to the on LC-MS analysis, has a purity of 88% (MS (ES+): m/e=435,2).

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

6.6 g of the methyl ester obtained in (b), was dissolved in 100 ml of tetrahydrofuran and mixed with 36 ml (2.4 equivalents) of 1-molar solution of hydrochloride lithium, and then the reaction mixture was stirred 4 hours at the return flow of solvent.

The solvent is then drove away under reduced pressure. After it was added 50 ml of water was filtered through Celite filter® and the filtrate was acidified using 2n aqueous solution of hydrochloric acid. The reaction product upon acidification to precipitate and was filtered.

Received of 3.05 g of 4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid, pale yellow crystals [exit 48% of theoretical; MS (ES+): m/e=421,31]

d) 4-(4-diethylcarbamoyl-benzylamine)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid

420 mg of 4-({[6-(3-methoxybenzylidene)-pyrimidine-4-carbonyl]-amino}-methyl)-benzoic acid from c) was dissolved in 5 ml of absolute N,N-dimethylformamide, and under stirring at 0°C was sequentially added 115 μl of diethylamine, 361 mg of O-[(canadachloromycetin)amino]-N,N,N',N'-tetramethylethylenediamine (TOTU) and 153 μl of triethylamine and the reaction mixture was stirred 1 hour at 0°C and then 12 hours at room Tempe is the atur.

For further processing solvent drove under reduced pressure and the residue was combined with 100 ml dichloromethane. The organic phase is washed with 30 ml saturated aqueous sodium hydrogen carbonate solution and then three times with water, each time in 30 ml. After drying the organic phase by means of Na2SO4the solvent is kept at reduced pressure. The oily residue was cleaned by chromatography on silica gel (40 - 63 μ) a mixture of ethyl acetate/n-heptane 2:1, as mobile phase. After removal of the solvent the obtained oily residue, which after addition of a small amount of diethyl ether was slowly crystallized.

Obtained 270 mg of 4-(4-diethylcarbamoyl-benzylamine)-6-(3-methoxybenzylamine) pyrimidine-4,6-dicarboxylic acid, colorless crystals (yield 57% of theoretical [MS (ES+): m/e=476,40]).

Example 62

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

a) Synthesis of 6-[(pyridine-4-ylmethyl)-carbarnoyl]-pyrimidine-4-carboxylic acid

9.7 g (35,7 mmol) of methyl ester of 6-[(pyridine-4-ylmethyl)-carbarnoyl]-pyrimidine-4-carboxylic acid (obtained by the reaction of methyl ester pyrimidine-4,6-dicarboxylic acid and pyridine-4-ylmethylamino) was dissolved in 80 ml of tetrahydrofuran and 40 ml of water, the MCA is ivali with 40 ml of 1-molar aqueous NaOH solution and then the reaction mixture was stirred 2 hours at room temperature.

For further processing the reaction mixture was concentrated on a rotary evaporator under reduced pressure to half the original volume. Then acidified 22 ml of 2 N. aqueous solution of hydrochloric acid and the reaction mixture was then concentrated until dry in a rotary evaporator.

Obtained 12.2 g of colorless solid product, which was immediately converted further in accordance with 62b).

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

12.2 g of the compound obtained in 62a), was dissolved in 150 ml of absolute DMF and stirring at 0°C (cooling with ice) was sequentially added 6,63 g (35,7 mmol) 5-aminomethyl-2,3-dihydrobenzofuranyl, 11,7 g (35,7 mmol) of O-[(canadachloromycetin)-amino]-N,N,N',N'-tetramethylethylenediamine (TOTU) and 20 ml of triethylamine. After the addition was finished the reaction mixture was stirred 1 hour at 0°C and 4 hours at room temperature.

For further processing solvent drove under reduced pressure and the residue was combined with 200 ml dichloromethane. Then the organic phase is twice washed with a saturated aqueous solution of sodium bicarbonate and once with water, dried with sodium sulfate and the solvent was removed on a rotary evaporator under reduced pressure. The reaction product, in the drop-down filemakerstore sediment, after adding a small amount of diethyl ether was crystallized in the form of pink crystals. For additional purification recrystallized twice using 200 ml of isopropanol.

Received 10 g (25.6 mmol) of 4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[(pyridine-4-ylmethyl)-amide] pyrimidine-4,6-dicarboxylic acid (yield 72% of theory, based on both reaction stages; MS (ES+): 390,08)

1H-NMR (400 MHz, d6-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, 2H), 6,69 (d, J=8 Hz, 1H), 7,07 (m, 1H), 7,22 (m, 1H), 7,31 (m, 2H), 8,46 (m, 1H), and 8.50 (m, 2H), for 9.47 (m, 1H), 9,58 (t, J=6,4 Hz, 1H), 9,80 (t, J=6,4 Hz, 1H).

Example 117

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

a) Synthesis of 6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carboxylic acid

16,1 g (51 mmol) of methyl ester of 6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carboxylic acid (obtained by the interaction of the methyl ester pyrimidine-4,6-dicarboxylic acid 5-aminomethyl-2,3-dihydrobenzofuran) was dissolved in 150 ml of tetrahydrofuran, mixed with 62 ml of 1-molar aqueous solution of LiOH and then the reaction mixture was stirred 2 hours at room temperature.

For further processing the reaction mixture was concentrated on rotation the second evaporator under reduced pressure. Then the crude product was combined with 100 ml of water and after the addition of activated carbon was filtered through a clarifying filter Celite©. Then the obtained mother liquor was acidified by adding 2 N. aqueous solution of HCl, and the reaction product slowly precipitated in the form of colorless crystals.

After filtering off and drying the reaction product obtained 8,3 g (27 mmol) of colorless solid product, which is then immediately converted into 117b; yield 53% of theory.

MS (ES+): 300,1

b) Synthesis of methyl ester 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid

4.7 g (15.7 mmol) of the compound obtained in a)was dissolved in 30 ml of absolute DMF and stirring at 0°C was added sequentially 3.5 g (17.3 mmol) of methyl ester 4-aminometilbensana acid, 5.7 g (17.3 mmol) of O-[(canadachloromycetin)-amino]-N,N,N',N'-tetramethylethylenediamine (TOTU) and 4.8 ml of triethylamine. After the addition was finished the reaction mixture was stirred 1 hour at 0°C and 8 hours at room temperature.

For further processing solvent drove under reduced pressure and the residue was combined with 100 ml dichloromethane. Then the organic phase is twice washed with a saturated aqueous solution of sodium bicarbonate and once with water, dried with sodium sulfate and removed Rast is oritel on a rotary evaporator under reduced pressure. The reaction product obtained in the form of oily sludge after addition of a small amount of diethyl ether was crystallized in the form of light yellow crystals.

Obtained 6.8 g (15,2 mmol) of methyl ester 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid, the yield of 97% of theory.

MS (ES+): 447,1

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

6,28 g (14 mmol) of methyl ester 4-[({6-[(2,3-dihydrobenzofuran-5-ylmethyl)-carbarnoyl]-pyrimidine-4-carbonyl}-amino)-methyl]-benzoic acid (see 117b) suspended in 150 ml of tetrahydrofuran and 70 ml of water and mixed with 16.9 ml of 1 n aqueous NaOH solution, then the reaction mixture for 24 hours was stirred at room temperature.

For further processing the reaction mixture was concentrated on a rotary evaporator under reduced pressure to a volume of about 50 ml and mixed with 100 ml of ice water. Then acidified 2 N. aqueous solution of HCl, and the reaction product precipitated in the form of light yellow crystals.

After filtration, washing with water and drying of the reaction product obtained is 5.4 g (12.5 mmol) of colorless solid product, which is then immediately converted into 117d; yield 89% of theory. MS (ES+): 433,2

1H-NMR (400 MHz, d6-DMSO): δ = ,13 (t, J=8.7 Hz, 2H), 4,43 (d, J=6,1 Hz, 2H), 4,48 (t, J=8.7 Hz, 2H), 4,59 (d, J=6.3 Hz, 2H), 6,69 (d, J=8,1 Hz, 1H), 7,07 (m, 1H), 7,22 (m, 1H), 7,44 (m, 2H), 7,88 (m, 1H), of 7.90 (m, 1H), of 8.47 (d, J=1.5 Hz, 1H), 9,46 (d, J=1.3 Hz, 1H), 9,56 (t, J=6.3 Hz, 1H), 9,76 (t, J=6.3 Hz, 1H), 12,90 (Shir. s, 1H).

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

432 mg (1 mmol) of the compound obtained in c), was dissolved in 5 ml of absolute DMF and stirring at 0°C was added sequentially 96 μl (1.1 mmol) of the research, 361 mg (1.1 mmol) of O-[(canadachloromycetin)-amino]-N,N,N',N'-tetramethylethylenediamine (TOTU) and 155 μl of triethylamine. After the addition was finished the reaction mixture was stirred 1 hour at 0°C and 8 hours at room temperature.

For further processing solvent drove under reduced pressure and the residue was combined with 30 ml dichloromethane. Then the organic phase is twice washed with a saturated aqueous solution of sodium bicarbonate and once with water, dried with sodium sulfate and the solvent was removed on a rotary evaporator under reduced pressure. The crude product, in the form of oily sludge was cleaned by chromatography on silica gel (40-63 μ; mobile phase: ethyl acetate/methanol=20/1). After removal of the mobile phase by distillation under reduced pressure, the obtained oily product of the reaction, after dilution with diethyl ether vegetali who was avivasa in the form of colorless crystals.

Received 340 mg (of 0.68 mmol) of colorless crystals, yield 68% of theory. MS (ES+): 502,27

1H-NMR (500 MHz, d6-DMSO): δ = 2,60 (m, 2H), 3,4-3,6 (SIRM, 8H), 4,42 (d, J=6,5 Hz, 2H), 4,48 (t, J=8.6 Hz, 2H), 4,56 (d, J=6,5 Hz, 2H), of 6.68 (d, J=8,3 Hz, 1H), 7,07 (d, J=6,5 Hz, 1H), 7,22 (s, 1H), 7,88 (m, 4H), 8,46 (m,1H), 9,46 (m, 1H), to 9.57 (t, J=6,5 Hz, 1H), 9,75 (t, J=6,5 Hz, 1H)

The following compounds were obtained in the same way

17437,17
18437,17
19519,48
20522,41
21508,44
22478,44
23549,50

24492,45
25506,45
26494,32
27 435,38
28435,38
29469,37
30491,31
31492,26
32464,20

33476,23
34512,38
35457,29
36533,30
37517,27
38560,20
39395,30
40393,27
41486,15

td align="center"> 42
472,12
43390,38
44406,16
45409,16
46411,17
47394,04
48393,28
49407,10

50405,31
51392,09
52429,12
53391,05
54428,14
55387,18
56393,24
5 404,36

58473, 30
59506, 26
60492, 39
61492,31
62390, 08
63535,06
64502,19
65503,9

66473,30
67506,26
68492,39
69492,31
70390,08
71 535,06
72502,19
73503,9
74514,15
75504,14
75a516,19
76506,16
77508,16
78506,09
79518,1
80503,14
81515,14
82505,13
83476,14
84466,12
85513,05
86 464,12
87547,16
88559,18
89505,13
90523,15
91515,12
92525,28
93457,21
94445,13
95492,39
96513,28
97436,18
98505,23
99502,25
100534,21
101438,18
102 448,15
103492,23
104476,27
105531,31
106490,26
107519,28
108560,31
109513,25
110533,23
111480,29
112518,25
113535,25
114494,18
115490,25
116517,28
117503,28
118505,23
119533,26
120450,31
121519,27
122503,24
123566,25
125519,25
126502,27
127589,25
128515,36
129529,29
130575,23
131545,24
132502,2
133545,25
134 540,25
135505,25
136503,35
137429,13
138517,32
139395,23
140409,27
141409,17
142477,3
143518,34
144517,49
145580,35
146491,34
147488,22
148484,35
149538,15
150538,34
150A450,34
151474,41
152494,45
153530,43
154539,23
155488,41
156474,41
157478,41
158539,4
159490,43
160511,41
161498,36
512,37
555,4
532,46
490,35
476,4
424,21
492,12
455,1

The drugs examples

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

This protein is obtained as inactive proferment manufactured by INVITEK, Berlin (catalogue number 30 100 803). Activating proferment:

2 volume fraction of proferment incubated with 1 volume fraction of solution APMA at 37°C for 1.5 hours. The APMA solution was obtained from a solution of 10 mmol/l acetate p-aminophenylacetate in 0.1 mmol/l NaOH by diluting 3 volume fractions buffer Tris/HCl pH 7,5 (see below). The pH was determined from 7.0 to 7.5 by adding 1 mmol/l HCl. After activation of the enzyme was diluted with buffer Tris/HCl concentrations up to 1.67 mg/ml

To measure the enzymatic activity was incubated with 10 μl of an enzyme solution with 10 μl of 3% (vol./about.) buffer solution of dimethyl sulfoxide (reaction 1) for 15 minutes. For measuring the activity of an inhibitor of the enzyme was incubated with 10 μl of an enzyme solution with 10 μl of 3% (vol./about.) buffer solution of dimethyl sulfoxide, which contains the inhibitor of the enzyme (reaction 2).

As in reaction 1 and reaction 2 after EXT is compliance with 10 μl of 3% (vol./about.) aqueous solution of dimethyl sulfoxide, which contains 0.75 mmol/l substrate, the enzymatic reaction proceeds fluorescently-by a spectroscope (328 nm (extinction)/ 393 nm (emission)).

Enzymatic activity is expressed as the increase in extinction per minute.

The inhibitory effect is calculated as the inhibition percentage by the following formula:

% inhibition=100 - [(increase in extinction / minute in reaction 2) /(increase in extinction / minute in reaction 1) x 100].

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

Buffer solution contains 0.05% Brij (Sigma, Deisenhofen, Germany)and 0.1 mol/l Tris/HCl, 0.1 mol/l NaCl, 0.01 mol/l CaCl2(pH=7,5).

The enzyme solution contains 1,67 mg/ml of the enzymatic domain.

The substrate solution contains 0.75 mmol/l fluorogenic substrate (7-methoxycoumarin-4-yl)acetyl-Pro-Leu-Gly-Leu-3-(2',4'-dinitrophenyl)-L-2,3-diaminopropionic-Ala-Arg-NH2(Bachem, Heidelberg, Germany).

The results are shown in Table 2.

Table 2
ExampleIC50< / br>
MMP-13< / br>
(nm)
ExampleIC50MMP-13< / br>
(h is)
ExampleIC50MMP-13< / br>
(nm)
ExampleIC50MMP-13< / br>
(nm))
34732596501262,3
413743098201273,3
6207570995012860
361075a34101212922
393076231052313520
442007831064013620
622082301095013740
6398351124513850
6410843,211450139 10
6515853,5115201449
6610862,511781473
671587241182,415080
68228833119351519
693289181213015315
702493201224315422
719942012541584
7210

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

The enzyme neutrophil collagenase person and stromelysin person were obtained as described in Weithman et al. Inflamm Res, 46 (1997), Seiten 246-252 get active catalytic domains. Measurement of enzyme activity and determination of the inhibitory effect of inhibitors on enzyme activity were carried out as described therein.

Compounds according to the above examples show when determining neutrophil collagenase person and stromelysin person corresponding values IC50more than 100000 nm. Thus, these compounds are essentially ineffective in the inhibition of MMP-3 and-8.

1. The compound of the formula I

or a physiologically acceptable salt of the compounds of formula I,

where R1 means a hydrogen atom,

R2 denotes -(C1-C6)-alkyl, where alkyl substituted once by phenyl, where phenyl is substituted by an

1)-(C0-C6)-alkyl-C(O)-N(R9)-(R10),

where R9 and R10 are the same or different and independently from each other mean

(i) a hydrogen atom, or

ii)-(C1-C6)-alkyl or

R9 and R10 together with the nitrogen atom to which they are bound, form a 5-, 6-tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)-alkyl,

2)-C 0-C6)-alkyl-C(O)-NH-CN,

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

4)-(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-N(R9)-(R10), where R8 means hydrogen, R9 and R10 have the above meaning,

5)-(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, and R8 has the above meaning, and Het denotes a saturated or unsaturated monocyclic heterocyclic system with the number of links from 3 to 6, in the cycle which contains 1 or 2 identical or different heteroatoms from the series nitrogen, oxygen and sulfur and is unsubstituted or one-, two -, or three times, independently from each other substituted

a) halogen,

b) hydroxy,

(C)-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two -, or three times substituted by halogen,

d)=0,

e)-Het,

R4 and R5 or R5 and R6 together with the carbon atom to which they relate, independently of each other to form a 5 - or 6-tier cycle, which is saturated and contains one or two heteroatoms from the series oxygen.

2. The compound of formula I according to claim 1,

where R1 means hydrogen,

R2 denotes -(C1-C6)-alkyl, where alkyl substituted once by phenyl, where phenyl is substituted by an

1) -(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 are the same or different and independently from others who ha mean (i) hydrogen atom or (ii)-(C 1-C6)-alkyl, or R9 and R10 together with the nitrogen atom to which they are bound, form a 5-, 6 - tier rich loop, and instead of one or two other carbon atoms may be a heteroatom from the series oxygen, sulphur and nitrogen, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C6)-alkyl,

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

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

4)-(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-N(R9)-(R10), where R8 means hydrogen, R9 and R10 have the above meaning,

5) -(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-Het, where R8 has the abovementioned meaning, and Het means the rest of the group azepine, azetidine, aziridine, dioxin, dioxole, furan, isothiazol, isoxazol, morpholine, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxiran, piperazine, piperidine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, thiazole, thiophene, and where Het unsubstituted or one-, two -, or three times, independently of one another substituted by (a) halogen, (b) hydroxy with a)-(C1-C6)-alkyl, and alkyl unsubstituted or one-, two - or three-fold substituted with halogen, d)=0, f)-Het,

R4 and R5 or R5 and R6 together with the carbon atom to which they relate, independently of each other clicks the form dioxane, doxology, dihydrofuran or furan cycle.

3. The compound of formula I according to claim 1 or 2, where R1 denotes hydrogen, R2 denotes -(C1-C3)-alkyl, and alkyl substituted by phenyl, where the phenyl once, two or three times, independently from each other substituted

1)-(C0-C6)-alkyl-C(O)-N(R9)-(R10), where R9 and R10 denote a hydrogen atom, methyl, ethyl, propyl or butyl, or R9 and R10 together with the nitrogen atom to which they are bound, form a residue that can be formed from pyrrolidine, piperidine, pyrazolidine, pyrazine, tetrazine, imidazolidine, piperazine, isoxazolidine, research, isothiazolinone or thiomorpholine, and in the case of nitrogen, the nitrogen atoms independently from each other may be unsubstituted or substituted (C1-C4)-alkyl,

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

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

4)-(C0-C6)-alkyl-C(O)-N(R8)-(C0-C6)-alkyl-N(R9)-(R10), where R8 means hydrogen, a R9 and R10 have the above meaning,

5)-C(O)-N(R8)-(C0-C2)-alkyl-Het, and R8 has the above value, a Het means azepin, azetidin, aziridine, dioxin, dioxole, furan, isothiazol, isoxazol, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, oxazol, oxiran, piperazine, piperidine, Piran, pyrazin, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, who irreligion, the thiazole, thiophene, and Het unsubstituted or one-, two -, or three times, independently from each other substituted

a) halogen,

b) hydroxy,

(C)-(C1-C4)-alkyl, and alkyl unsubstituted or one-, two - or three-replaced

halogen,

and

R4 and R5 or R5 and R6 together with the carbon atoms to which they are linked, independently of each form dioxane, DIOXOLANYL, dihydrofuran or furan cycle.

4. The compound of formula I according to claim 1, selected from the following compounds:

4-(4-diethylcarbamazine)-6-(3-methoxybenzylamine)pyrimidine-4,6-

dicarboxylic acid,

4-(3-methoxybenzamido)-6-(4-profilirovannymi)pyrimidine-4,6-dicarboxylic acid,

4-(4-isopropylcarbodiimide)-6-(3-methoxybenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-[4-(2-dimethylaminoethanol)benzylamine]-6-(3-methoxybenzylamine) pyrimidine-4,6-carboxylic acid,

4-[(2,3-dihydrobenzo[1,4]dioxin-6-ylmethyl)-amide]-6-[4-(2-dimethylaminoethanol)-benzylamine]pyrimidine-4,6-dicarboxylic acid 4-(3-chloro-4-forbindelse)-6-[4-(2-dimethylaminoethanol)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl] -benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-METI benzilate)-6-[4-(2-morpholine-4-yl-2-oksidoksi)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-diethylcarbamazine)-6-(4-fluoro-3-methylbenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(isopropylaminomethyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[(2-morpholine-4-yl-ethylcarbamate)-methyl]-benzylamine }pyrimidine-4,6-dicarboxylic acid,

4-(4-diethylcarbamazine)-6-(4-fluoro-3-methylbenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-morpholine-4-yl-2-oxoethyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(isopropylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2-morpholine-4-iletileri)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(2-pyrrolidin-1-iletileri)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(thiomorpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(thiomorpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-sankarnarayanan)-6-(4-fluoro-3-methylbenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(3-morpholine-4-yl-propellerblades)-benzylamine] pyrimidine-4,6-di is arbonboy acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(3-morpholine-4-yl-propellerblades)-benzylamine] pyrimidine-4,6-dicarboxylic acid 4-(4-fluoro-3-methylbenzylamino)-6-[4-(4-methylpiperazin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-{4-[(pyridine-4-ylmethyl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

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

4-(4-N-cyanocarbonimidate)-6-(3-methoxybenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(morpholine-4-carbonyl)-benzylamine]pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-piperazine-1-iletileri)benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-tert-butylcarbamoyl)-6-(3-methoxybenzylamine)pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[methyl-(1-methylpiperidin-4-yl)-carbarnoyl]-benzylamine }pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-pyrrolidin-1-iletileri)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[3-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(2-morpholine-4-yl-Amilcar mail)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[3-(morpholine-4-carbonyl)-benzylamine]pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[(piperidine-4-ylmethyl)-carbarnoyl]benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(piperidine-4-ylcarbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-[4-(piperidine-4-ylcarbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[methyl-(1-methylpiperidin-4-yl)-carbarnoyl]-benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(4-fluoro-3-methylbenzylamino)-6-{4-[piperidine-4-ylmethyl)carbarnoyl-benzylated} pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(4-methylpiperazin-1-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

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

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

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-[(2,3-dihydrobenzofuran-5-ylmethyl)-amide]-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-FPO is benzylated)-6-[4-(2-pyrrolidin-1-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-[4-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-methoxybenzamido)-6-{4-[(pyridine-4-ylmethyl)-carbarnoyl] -benzylamine} pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-(4-diethylcarbamazine)pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-[4-(morpholine-4-carbonyl)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(3-chloro-4-forbindelse)-6-[4-(2-morpholine-4-yl-ethylcarbamate)-benzylamine] pyrimidine-4,6-dicarboxylic acid,

4-(4-diethylcarbamazine)-6-(3-methoxybenzylamine)pyrimidine-4,6-dicarboxylic acid.

5. The method of obtaining the compounds of formula I according to one or more of claims 1 to 4, characterized in that the compound of formula II

subjected to interaction with the compound of the formula IIIa or IIIb

obtaining the compounds of formula IVa or IVb

and balances with R1for R7have the meanings indicated in formula I, a Y means halogen, hydroxyl or With the1-C4-alkoxy, or together with the carbonyl group forms an active ester or a mixed anhydride, and the connection IVa or IVb, if necessary, cleaned and then translated using the compounds of formula IIIa or IIIb in the compound of formula I.

6. Drug, possess inhibitory activity against increased activity of matrix metalloproteinases -13, characterized in that it contains an effective amount of at least one of the compounds of formula I according to one or more of claims 1 to 4 together with a pharmaceutically suitable and physiologically acceptable carrier, additive and/or other active and auxiliary substances.

7. The use of the compounds of formula I according to one or more of claims 1 to 4 to obtain drugs for prevention and treatment of diseases, in the course of which is influenced by increased activity of matrix metalloproteinase-13.

Priority items:

02.11.2002 - pp.5-7;

20.11.2002 - p.1;

02.11.2002 and 20.11.2002 - apply equally to claim 2 to 4.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: claimed invention relates to derivatives of 4-[1-arylimidazol-4-yl ethynyl]-2-alkylpyridine and 4-[1-heteroarylimidazol-4-yl ethynyl]-2-alkylpyridine of general formula I having general formula I in which R1 stands for C1-C6alkyl; R2 stands for C1-C6alkyl or C3-C12cycloalkyl; R3 stands for aryl or heteroaryl, where aryl or heteroaryl are unsubstituted or contain substituents, selected from group, including halogen, C1-C6alkyl, S-C1-C6alkyl, C1-C6alkylhlogen, C1-C6alkoxygroup, halogen- C1-C6lkoxygroup, C3-C12cycloalkyl, C2-C11heterocycloakyl, C1-C6alkylminogroup,di- C1-C6alkylaminogroup, C1-C6alkoxyaminogroup, (C1-C6 alkoxy) C1-C6alkylaminogroup, C3-C12cycloalkylaminogroup, benzylaminogroup and cyanogroup, where said "aryl" represents phenyl, and said " heteroaryl" represents aromatic 5- or 6- member ring or one or more condensed rings, containing one or more heteroatoms, selected from group, which includes nitrogen, oxygen and sulfur; and R4 stands for hydrogen, C(O)H or CH2R5 , where R stands for hydrogen or its pharmaceutically acceptable salt. Invention also relates to method of obtaining compounds of general formula I, their application as anxiolytic, to based on them pharmaceutical composition and method of treatment or prevention of disorders, fully or partly mediated by metabotropic glutamate receptor of subtype 5.

EFFECT: obtaining novel heterocyclic compounds possessing useful biological properties.

15 cl, 18 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 ex

FIELD: chemistry.

SUBSTANCE: claimed are novel pyrazole derivatives of formula II or its pharmaceutically acceptable salts, where C ring is selected from phenyl or pyridinyl ring and R2, R2', Rx and Ry are such as said in given description. C ring has ortho-substituent and is optionally substituted in non-ortho positions. R2 and R2' , optionally taken with their intermediate atoms, form condensed ring system, such s indazole ring, and Rx and Ry, optionally taken together with their intermediate atoms, form condensed ring system, such a quinazoline ring.

EFFECT: possibility to use compositions as inhibitors of protein kinases as inhibitors GSK-3 and other kinases and apply them for protein kinase-mediated diseases.

41 cl, 8 tbl, 423 ex

Crystal form // 2339634

FIELD: chemistry.

SUBSTANCE: (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide in essentially crystal form has powder radiograph, expressed in angle values 20, and obtained by means of difractometer, including peaks, located in the following positions expressed in angles 2θ: 9.1-9.2 (±0.1), 16.0-16.1(±0.1), 18.0-18.2 (±0.1) and 18.3-18.4 (±0.1) degrees, and term "essentially crystal form" means that said form is mainly free from amorphous form of (E)-2-(5-Chlorothiene-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethensulfonamide, and by term "mainly free from" content of amorphous form less than 50% is meant.

EFFECT: increased activity.

15 cl, 2 dwg, 5 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of 2-pyridinecarboxamide and their pharmaceutical salts, which have glucokinase activating properties. In formula (I): D represents O or S; R2 and R3 each represents a hydrogen atom; formula (II) represents triazole group, imidazole group, thiazole group and pyridine group, which can have in the ring, 1 or 2 substitutes; formula (III) represents a thiazole group, thiadiazole group, isoxazolyl group, pyrazine group, pyridothiazolyl group or pyridyl group, ring B can have 1 or 2 substitutes. The invention also relates to pharmaceutical compositions based on the invented compounds.

EFFECT: new derivatives can be used for treating such diseases as sugar diabetes.

19 cl, 5 tbl, 165 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to compounds of formula (I) or their pharmaceutically acceptable salts, where Q represents optionally substituted with 1-3 substituents, determined in formula, phenyl or pyridyl or pyrodazinyl; R2 represents C1-6alkyl or aminogroup, determined in item 1 of formula or C1-6alkyl, substituted with said aminogroup; bond between oxygen atom O* and adjacent carbon atom C1 or (i) is double bond, which determines carbonyl group [C(=O)], where R6 represents C1-6alkyl or cyclopropyl; or (ii) represents simple bond, where, in case of simple bond, said oxygen atom O*, is in addition bound to group R6 and, taken together with R6 and with adjacent nitrogen atom, determines optionally substituted with C1-6alkyl, oxadiazolyl ring, bond between C1 and adjacent nitrogen atom being double bond.

EFFECT: obtaining medications which are useful in obtaining medications for treatment of conditions connected with p38 kinase and/or in obtaining medications for treatment of inflammatory diseases or conditions in patient.

8 cl, 6 tbl, 88 ex

FIELD: medicine; pharmacology.

SUBSTANCE: presented are anilides of nicotinic acid of general formula I , where R means atom of hydrogen, halogen or benzyloxy-group, R' means atom of hydrogen or halogen, X means 2-furyl, 2-pyridyl, 3-pyridyl unsubstituted or substituted with phenyl halogen atom with fungicidal activity.

EFFECT: new compound are effective for hazardous fungi.

3 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in pyridylmethylanilides of heterocyclic acids of general formula I R stands for atom of hydrogen halogen or benzyloxy-group, R' stands for atom of hydrogen or halogen, X stands for 2-phuryl or 2-pyridyl.

EFFECT: increase of compound efficiency against harmful fungi.

1 cl, 3 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

Carbonyl compounds // 2337099

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to novel compounds of general formula(I) , where D represents phenyl, pyridyl or tienyl, each of which is single-substituted or double-substituted with Hal; R1 represents H, =O, COOR3, OH, OA, NH2, alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms, N3, ethinyl, vinyl, allyloxy, -OCOR3, NHCOA or NHSO2A; R2 represents H, =O, OH, OA or alkyl, which has 1, 2, 3, 4, 5 or 6 carbon atoms; R1 and R2 together alternatively represent spirocyclically linked 3-6-member carbocyclic ring, R3 represents H or A, R4 represents H or A; represents pyrrolidine-1,2-diyl, piperidine-1,2-diyl, oxazolidine-3,4 or 3,5-diyl, thiazolidine-3,4-diyl, 2,5-dihydro-1H-pyrrol-1,5-diyl, 1,3-dioxolane-4,5-diyl; G represents (CH2)n or (CH2)nNH-; X represents CONH; Y represents 1,3- or 1,4-phenylene, which is not substituted or is single-substituted with methyl, trifluoromethyl, ethyl, propyl, Cl or F; T represents morpholine-4-yl, which is single-substituted or double-substituted with carbonyl oxygen; A represents non-branched or branched alkyl, which has 1-10 carbon atoms and in which 1-7 hydrogen atoms can be substituted with F; Hal represents F, CI, Br or I, n represents 0, 1 or 2; and their pharmaceutically acceptable derivatives, solvates, salts or sterioisomers, including their mixtures in all ratios. Invention also relates to method of obtaining formula I compounds, to medication based on formula I compound and application of formula I compounds for preparation of medication, which has inhibiting activity with respect to coagulation factors Xa and VIla.

EFFECT: obtained novel compounds have inhibiting activity with respect to said coagulation factors.

11 cl, 1 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns to 3,4-disubstituted tsiklobuten-1,2-diones of the formula I or their pharmaceutically to comprehensible salts or solvates, . A is chosen from the group including

X=-O-, -NH-, -S-,

.

n=1-5

B is chosen from the group including

. The bonds can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and a cancer. The pharmaceutical composition and application of bonds I are also described.

EFFECT: obtaining of bonds which can be used at treatment of mediated chemokine diseases, such as acute both chronic inflammatory diseases and cancer.

50 cl, 31 ex

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