Novel Pyrimidine-4,6-dicarboxylic acid diamides for selectively inhibiting collagenases

A compound of the formula I

• 169
• wherein, for the case a)
• R1 is hydrogen or —(C1-C6)-alkyl,
• R2 is —(C1-C6)-alkyl, wherein, alkyl is substituted, one, two or three times, by
• 1. —(C1-C6)-alkyl-O—(C6-C14)-aryl,
• 2. —(C0-C6)-alkyl-N(R8)—C(O)—O—(C1-C6)-alkyl, wherein, R8 is
• i) hydrogen,
• ii) —(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by —NH2, —CN, —OH, —C(O)—OH, —C(O)—O—(C1-C6)-alkyl, —C(O)—NH—OH, NO2 or halogen, or
• iii) OH,
• 3. —(C(O)—N(R9)—(R10), wherein, R9 and R10 are identical or different and are, independently of each other,
• i) hydrogen or
• ii) —(C1-C6)-alkyl, or
• R9 and R10 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring, where a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl,
• 4. —(C6-C14)-aryl, wherein, aryl is substituted, one, two or three times, independently of each other, by
• 4.1) —(C0-C6)-alkyl-C(O)—O—R8, wherein, R8 has the abovementioned meaning,
• 4.2) —(C0-C6)-alkyl-C(O)—N(R9)—(R10), wherein, R9 and R10 have the abovementioned meaning,
• 4.3) —(C0-C6)-alkyl-C(O)—NH—CN,
• 4.4) —(C0-C6)-alkyl-C(O)—(C0-C6)-alkyl-Het, wherein, Het is a saturated or unsaturated, monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system which contains 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, oxygen and sulfur and is unsubstituted or substituted, one, two or three times, independently of each other, by
• a) halogen,
• b) cyano,
• c) nitro,
• d) hydroxyl,
• e) amino,
• f) —C(O)—O—(C1-C6)-alkyl,
• g) —C(O)—OH,
• h) —(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen,
• i) —O—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen, or —N(R9)—(R10),
• j) ═O,
• k) —Het,
• l) —(C2-C6)-alkenyl, wherein, alkenyl is unsubstituted or substituted, one, two or three times, by halogen, or —N(R9)—(R10), or
• m) —(C2-C6)-alkynyl, wherein, alkynyl is unsubstituted or substituted, one, two or three times, by halogen or —N(R9)—(R10),
• 4.5) —(C0-C6)-alkyl-C(O)—(C0-C6)-alkyl-OH,
• 4.6) —O—(C0-C6)-alkyl-C(O)—N(R9)—(R10), wherein, R9 and R10 have the abovementioned meaning,
• 4.7) —S(O)y—(C1-C6)-alkyl-C(O)—O—R8, wherein, R8 has the abovementioned meaning and y is 1 or 2,
• 4.8) —S(O)z—(C1-C6)-alkyl-C(O)—N(R9)—(R10), wherein, R9 and R10 have the abovementioned meaning and z is zero, 1 or 2,
• 4.9) —(C0-C6)-alkyl-C(O)—N(R8)—(C0-C6)-alkyl-N(R9)—(R 10), wherein, R8, R9 and R10 have the abovementioned meaning,
• 4.10) —(C0-C6)-alkyl-C(O)—N(R8)—(C0-C6)-alkyl-Het, wherein, R8 has the abovementioned meaning and Het has the abovementioned meaning and is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.11) —(C0-C6)-alkyl-C(O)—N(R8)—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.12) —(C0-C6)-alkyl-N(R9)—(R10), wherein, R9 and R10 have the abovementioned meaning,
• 4.13) —(CH2)y—N(R8)—C(O)—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and y is 1 or 2,
• 4.14) —(C0-C4)-alkyl-N(R8)—C(O)—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.15) —(C0-C4)-alkyl-N(R8)—C(O)—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.16) —(C0-C4)-alkyl-N(R8)—C(O)—O—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.17) —(C0-C4)-alkyl-N(R8)—C(O)—O—(C1-C6)-alkenyl, wherein, alkenyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.18) —(C0-C4)-alkyl-N(R8)—C(O)—O—(C1-C6)-alkynyl, wherein, alkynyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.19) —(C0-C4)-alkyl-N(R8)—C(O)—O—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.20) —(C0-C4)-alkyl-N(R8)—C(O)—O—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21) —(C0-C4)-alkyl-N(R8)—C(O)—(C0-C6)-alkyl-N(R11)—R12, wherein, R8 has the abovementioned meaning and R11 and R12 are identical or different and are, independently of each other,
• 4.21.1) hydrogen,
• 4.21.2) —(C1-C6)-alkyl,
• 4.21.3) —(C0-C6)-alkyl-(C6-C 14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.4) —(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.5) —C(O)—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.6) —C(O)—(C3-C6)-cycloalkyl, wherein, cycloalkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.7) —C(O)—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.8) —C(O)—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.9) —SO2—(C0-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.10) —NH—SO2—(C0-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.11) —SO2—(C0-C6)-alkyl-(C6-C14)-aryl-(C0-C6)-alkyl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.21.12) —SO2—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.22) —(C0-C4)-alkyl-N(R8)—S(O)2—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.23) —(C0-C4)-alkyl-N(R8)—S(O)2—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.24) —(C0-C4)-alkyl-N(R8)—S(O)2—N(R8)—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.25) —(C0-C4)-alkyl-N(R8)—S(O)2—N(R8)—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.26) —(C0-C4)-alkyl-N(R8)—S(O)2—N(R8)—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.27) —(C0-C4)-alkyl-N(R8)—C(O)—N(R8)—SO2—R13, wherein, R8 has the abovementioned meaning and R13 is —(C1-C6)-alkyl or —(C0-C6)-alkyl-(C6-C14)-aryl,
• 4.28) —(C0-C4)-alkyl-S(O)2—N(R8)—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.29) —(C0C4)-alkyl-S(O)2—N(R8)—(C0—C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.30) —(C0-C4)-alkyl-S(O)2—N(R8)—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m) and R8 has the abovementioned meaning,
• 4.31) —(C0-C4)-alkyl-S(O)2—(C0-C6)-alkyl-(C6-C14)-aryl, wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.32) —(C0-C4)-alkyl-S(O)2—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.33) —O—(C0-C6)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m),
• 4.34) —(C0-C4)-alkyl-Het, wherein, Het is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals a) to m), or
• 4.35)-phenyl, wherein, the phenyl is unsubstituted or substituted, one, two or three times, by
• 4.35.1) halogen,
• 4.35.2) —(C1-C6)-alkyl,
• 4.35.3) —O—(C1-C6)-alkyl or
• 4.35.4) —S(O)2—R16, wherein, R16 is (C1-C6)-alkyl or —NH2,
• 5. —C(O)—N(R8)—(C0-C6)-alkyl-(C6-C14)-aryl wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals 4.1) to 4.35) or 4.4) a) to 4.4) m) and R8 has the abovementioned meaning,
• 6. —C(O)—N(R8)—(C0-C6)-alkyl-Het wherein, Het has the abovementioned meaning and is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals 4.1) to 4.35) or 4.4)a) to 4.4)m) and R8 has the abovementioned meaning, or
• 7. —NH—(C6-C14)-aryl wherein, aryl is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals 4.1) to 4.35) or 4.4) a) to 4.4) m), or
• 8. —NH-Het wherein, Het has the abovementioned meaning and is unsubstituted or substituted, one, two or three times, independently of each other, by the abovementioned radicals 4.1) to 4.35) or 4.4) a) to 4.4) m),
• R3, R4, R5, R6 and R7 are identical or different and are, independently of each other,
• 1. hydrogen,
• 2. halogen,
• 3. —(C1-C6)-alkyl wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen,
• 4. —O—(C1-C6)-alkyl wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen, or
• 5. —S—(C1-C6)-alkyl, or
• R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are in each case bonded, independently of each other, a 5- or 6-membered ring which is aromatic or saturated and contains zero, one or two heteroatoms from the series oxygen, nitrogen or sulfur, wherein, the ring is unsubstituted or is substituted, at one or at several carbon atoms, one or two times, by halogen, and the other radicals R3, R6 and R7 or R3, R4 and R7 have the abovementioned meaning of 1. to 5;
• or wherein, for the case b)
• R1 is hydrogen or —(C1-C6)-alkyl,
• R2 is —(C1-C6)-alkyl, wherein, alkyl is substituted, one, two or three times, by
• 1. —C(O)—O—R8′, wherein, R8′ is
• 1.1) hydrogen or
• 1.2) —(C1-C6)-alkyl,
• 2. —(C1-C6)-alkyl-O—R8′, wherein, R8′ has the abovementioned meaning,
• 3. —(C6-C14)-aryl wherein, aryl is substituted, one, two or three times, independently of each other, by
• 3.1) —(C2-C6)-alkyl-C(O)—O—R8′ wherein, R8′ has the abovementioned meaning,
• 3.2) —O—(C1-C6)-alkyl-C(O)—O—R8′ wherein, R8′ has the abovementioned meaning,
• 3.3) —N(R14)—(R15) wherein, R14 and R15 form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring, wherein, a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl,
• 3.4) —(CH2)k—N(R9′)—(R10′) wherein, k is 2, 3, 4 or 5 and R9′ and R10′ are identical or different and are, independently of each other,
• 3.4.1) hydrogen or
• 3.4.2) —(C1-C6)-alkyl, or
• R9′ and R10′ form, together with the nitrogen atom to which they are bonded, a 5-, 6- or 7-membered saturated ring, wherein, a heteroatom from the series oxygen, sulfur and nitrogen can also replace one or two further carbon atoms and, in the case of nitrogen, the nitrogen atoms can, independently of each other, be unsubstituted or substituted by (C1-C6)-alkyl,
• 3.5) —O—(C2-C6)-alkyl-N(R9′)—R10′, wherein, R9′ and R10′ have the abovementioned meaning,
• 3.6) —N(R8′)—C(O)—(C1-C6)-alkyl wherein, alkyl is unsubstituted or substituted, one, two or three times, by
• 3.6.1) halogen,
• 3.6.2) cyano,
• 3.6.3) nitro
• 3.6.4) hydroxyl,
• 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, wherein, phenyl is unsubstituted or substituted, one, two or three times, by
• 3.7.1) halogen,
• 3.7.2) —(C1-C6)-alkyl,
• 3.7.3) —O—(C1-C6)-alkyl,
• 3.7.4) —S(O)2—R16′, wherein, R16′ is (C1-C6)-alkyl or —NH2,
• 4. Het, wherein, Het is a saturated or unsaturated monocyclic or bicyclic, 3- to 10-membered heterocyclic ring system which contains 1, 2 or 3 identical or different ring heteroatoms from the series nitrogen, oxygen and sulfur and is unsubstituted or substituted, one, two or three times, by
• 4.1) halogen,
• 4.2) cyano,
• 4.3) nitro,
• 4.4) hydroxyl,
• 4.5) amino,
• 4.6) —C(O)—O(C1-C6)-alkyl,
• 4.7) —C(O)—OH,
• 4.8) —(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen,
• 4.9) —O—(C1-C6)-alkyl, wherein, alkyl is unsubstituted or substituted, one, two or three times, by halogen,
• 4.10) pyridyl, or
• 4.11) phenyl, wherein, phenyl is unsubstituted or substituted, at least one time and independently of each other, by a radical from the series halogen, —(C1-C6)-alkoxy and —(C1-C6)-alkyl, and
• R4 and R5 or R5 and R6 form, together with the carbon atoms to which they are in each case bonded, independently of each other, a 5- or 6-membered ring which is saturated and contains one or two heteroatoms from the series oxygen, nitrogen or sulfur, where the ring is unsubstituted or substituted, at one or at several carbon atoms, one or two times, by halogen, and the other radicals R3, R6 and R7 or R3, R4 and R7 are hydrogen,
• or a stereoisomer or a mixture of stereoisomers in any ratio of the compound of the formula I, or a pharmaceutically acceptable salt of the compound, stereoisomer or mixture of stereoisomers of the compound;
• and a pharmaceutically acceptable carrier;
• provided that the unsubstituted benzo[1,3]dioxole ring is excluded.