Pyrimidinone derivatives as therapeutic agents against acute and chronic inflammatory, ischaemic and remodelling processes
View Patent ↗The invention relates to novel heterocyclic derivatives, processes for their preparation, and their use in medicaments, especially for the treatment of chronic obstructive pulmonary diseases.
1. A compound of the general formula (I)
wherein
A represents an aryl or heteroaryl ring,
R 1 , R 2 and R 3 independently from each other represent hydrogen, halogen, nitro, cyano, C 1 -C 6 -alkyl, hydroxy or C 1 -C 6 -alkoxy, wherein C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy,
R 4 represents trifluoromethylcarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 6 -C 10 -arylaminocarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl can be further substituted with one to three identical or different radicals selected from the group consisting of C 3 -C 8 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, 1-C4-alkylcarbonyl)-C 1 -C 4 -alkylamino, cyano, amino, mono- and di-C 1 -C 4 -alkylamino, heteroaryl, heterocyclyl and tri-(C 1 -C 6 -alkyl)-silyl, and wherein heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl and heterocyclyl can be further substituted with C 1 -C 4 -alkyl,
R 5 represents C 1 -C 4 -alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkenoxy, C 1 -C 6 -alkylthio, amino, mono- and di-C 1 -C 6 -alkylamino, arylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl and the radical —O—C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl,
or
R 5 represents amino,
R 6 represents hydrogen, C 1 -C 6 -alkyl, formyl, aminocarbonyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 3 -C 8 -cycloalkylcarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, N—(C 1 -C 4 -alkylsulfonyl)-aminocarbonyl, N—(C 1 -C 4 -alkylsulfonyl)-N—(C 1 -C 4 -alkyl)-aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C 1 -C 6 -alkyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C 1 -C 4 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, amino, mono- and di-C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonylamino, tri-(C 1 -C 6 -alkyl)-silyl, cyano, mono- and di-C 1 -C 4 -alkylamino-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkylaminocarbonyl and halogen,
or
R 6 represents a moiety of the formula
wherein
R 6A is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, and
n represents an integer of 1 or 2,
R 7 represents halogen, nitro, cyano, C 1 -C 6 -alkyl, hydroxy or C 1 -C 6 -alkoxy, wherein C 1 -C 6 -alkyl is further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy, and C 1 -C 6 -alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy,
and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 independently from each other represent CH or N, wherein the ring contains either 0, 1 or 2 nitrogen atoms,
or a pharmaceutically acceptable salt thereof.
2. The compound of general formula (I) according to claim 1 , wherein
A represents an aryl or heteroaryl ring,
R 1 , R 2 and R 3 independently from each other represent hydrogen, halogen, nitro, cyano, C 1 -C 6 -alkyl, hydroxy or C 1 -C 6 -alkoxy, wherein C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy,
R 4 represents C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, C 1 -C 6 -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 6 -C 10 -arylaminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, heterocyclyl or cyano, wherein C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl can be further substituted with one to three identical or different radicals selected from the group consisting of C 3 -C 8 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonylamino, amino, mono- and di-C 1 -C 4 -alkylamino, heteroaryl, heterocyclyl and tri-(C 1 -C 6 -alkyl)-silyl,
R 5 represents C 1 -C 4 -alkyl, which can be substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy, C 1 -C 6 -alkoxy, C 1 -C 6 -alkenoxy, C 1 -C 6 -alkylthio, amino, mono- and di-C 1 -C 6 -alkylamino, arylamino, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl and the radical —O—C 1 -C 4 -alkyl-O—C 1 -C 4 -alkyl,
or
R 5 represents amino,
R 6 represents hydrogen, C 1 -C 6 -alkyl, formyl, aminocarbonyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 3 -C 8 -cycloalkylcarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, N—(C 1 -C 4 -alkylsulfonyl)-aminocarbonyl, N—(C 1 -C 4 -alkylsulfonyl)-N—(C 1 -C 4 -alkyl)-aminocarbonyl, heteroaryl, heterocyclyl, heteroarylcarbonyl or heterocyclylcarbonyl, wherein C 1 -C 6 -alkyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, heteroaryl and heterocyclyl can be substituted with one to three identical or different radicals selected from the group consisting of aryl, heteroaryl, hydroxy, C 1 -C 4 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, amino, mono- and di-C 1 -C 4 -alkylamino, C 1 -C 4 -alkylcarbonylamino, tri-(C 1 -C 6 -alkyl)-silyl, cyano, mono- and di-C 1 -C 4 -alkylamino-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkylaminocarbonyl and halogen,
or
R 6 represents a moiety of the formula
wherein
R 6A is selected from the group consisting of hydrogen and C 1 -C 6 -alkyl, and
n represents an integer of 1 or 2,
R 7 represents halogen, nitro, cyano, C 1 -C 6 -alkyl, hydroxy or C 1 -C 6 -alkoxy, wherein C 1 -C 6 -alkyl is further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy, and C 1 -C 6 -alkoxy can be further substituted with one to three identical or different radicals selected from the group consisting of halogen, hydroxy and C 1 -C 4 -alkoxy,
and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 independently from each other represent CH or N, wherein the ring contains either 0, 1 or 2 nitrogen atoms.
3. The compound of general formula (I) according to claim 1 , wherein
A represents a phenyl, naphthyl or pyridyl ring,
R 1 , R 2 and R 3 independently from each other represent hydrogen, fluoro, chloro, bromo, nitro, cyano, methyl, ethyl, trifluoromethyl or trifluoromethoxy,
R 4 represents C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono-C 1 -C 4 -alkylaminocarbonyl or cyano, wherein C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl and mono-C 1 -C 4 -alkylaminocarbonyl can be substituted with one to three identical or different radicals selected from the group consisting of C 3 -C 8 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, amino, mono- or di-C 1 -C 4 -alkylamino, heteroaryl and heterocyclyl,
R 5 represents methyl or ethyl,
R 6 represents hydrogen, C 1 -C 6 -alkyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl or heterocyclylcarbonyl, wherein C 1 -C 6 -alkyl and C 1 -C 6 -alkoxycarbonyl can be substituted with one to three identical or different radicals selected from the group consisting of heteroaryl, hydroxy, C 1 -C 4 -alkoxy, hydroxycarbonyl, C 1 -C 6 -alkoxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, cyano, amino, mono- and di-C 1 -C 4 -alkylamino,
or
R 6 represents a moiety of the formula
wherein
R 6A is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl, and
n represents an integer of 1 or 2,
R 7 represents halogen, nitro, cyano, trifluoromethyl, or trifluoromethoxy,
and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each represent CH.
4. The compound of general formula (I) according to claim 1 , wherein
A represents a phenyl or a pyridyl ring,
R 1 and R 3 each represent hydrogen,
R 2 represents fluoro, chloro, bromo, nitro or cyano,
R 4 represents cyano, C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl, wherein C 1 -C 4 -alkoxycarbonyl can be substituted with a radical selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, mono- and di-C 1 -C 4 -alkylamino, heteroaryl and heterocyclyl,
R 5 represents methyl,
R 6 represents hydrogen, C 1 -C 4 -alkyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl, wherein C 1 -C 4 -alkyl and C 1 -C 4 -alkoxycarbonyl can be substituted with a radical selected from the group consisting of heteroaryl, hydroxy, C 1 -C 4 -alkoxy, hydroxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylaminocarbonyl, amino, mono- and di-C 1 -C 4 -alkylamino,
or
R 6 represents a moiety of the formula
wherein
R 6A is selected from the group consisting of hydrogen and methyl,
R 7 represents trifluoromethyl or nitro,
and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each represent CH.
5. The compound of general formula (I) according to claim 1 , wherein A is phenyl or pyridyl.
6. The compound of general formula (I) according to claim 1 , wherein R 1 is hydrogen.
7. The compound of general formula (I) according to claim 1 , wherein R 2 is cyano.
8. The compound of general formula (I) according to claim 1 , wherein R 3 is hydrogen.
9. The compound of general formula (I) according to claim 1 , wherein R 4 is C 1 -C 4 -alkoxycarbonyl optionally substituted by hydroxy or wherein R 4 is C 1 -C 4 -alkylcarbonyl.
10. The compound of general formula (I) according to claim 1 , wherein R 5 methyl.
11. The compound of general formula (I) according to claim 1 , wherein R 6 is hydrogen.
12. The compound of general formula (I) according to claim 1 , wherein R 7 is trifluoromethyl or nitro.
13. A compound of general formula (IA)
wherein
Z represents CH or N, and
R 1 , R 3 , R 4 and R 6 have the meaning indicated in claim 1 .
14. A process for synthesizing the compounds of general formula (I), as defined in claim 1 by condensing compounds of general formula (II)
wherein
A, R 1 and R 2 the meaning indicated in claim 1 ,
with compounds of general formula (III)
wherein
R 4 and R 5 have the meaning indicated in claim 1 ,
and compounds of general formula (IV)
wherein
R 3 , R 7 , and Y 1 to Y 5 have the meaning indicated in claim 1 , in the presence of an acid either in a three-component/one-step reaction or sequentially to give compounds of the general formula (IB)
wherein
A, R 1 to R 5 , R 7 , and Y 1 to Y 5 have the meaning indicated in claim 1 , optionally followed by reaction of the compounds of general formula (IB) with compounds of the general formula (V)
R 6 *—X (V),
wherein
R 6 * has the meaning of R 6 as indicated in claim 1 , but does not represent hydrogen, and
X represents a leaving group,
in the presence of a base.
15. A composition containing at least one compound of general formula (I) as defined in claim 1 and a pharmacologically acceptable diluent.
16. A process for preparation of a composition, said process comprising a step of bringing the compounds of general formula (I) as defined in claim 1 together with customary auxiliaries into a suitable application form; wherein said composition contains at least one compound of general formula (I) and a pharmacologically acceptable diluent.
17. A method of treating chronic obstructive pulmonary disease or acute myocardial infarction, said method comprising administering a therapeutically effective amount of a compound of claim 1 .
18. The method of claim 17 , wherein a neutrophil elastase inhibitory amount is administered.
19. A composition containing at least one compound of general formula (IA) as defined in claim 13 and a pharmacologically acceptable diluent.
20. A process for preparation of a composition, said process comprising a step of bringing the compounds of general formula (IA) as defined in claim 13 together with customary auxiliaries into a suitable application form; wherein said composition contains at least one compound of general formula (IA) and a pharmacologically acceptable diluent.
21. Ethyl 4-(4-cyanophenyl)-6-methyl-1-(3-methylphenyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate, or a pharmaceutically acceptable salt thereof.
22. A compound according to claim 1 , having the following structure:
(5-{5-Acetyl-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4- pyrimidinyl}-2-pyridinecarbonitrile)
or a pharmaceutically acceptable salt thereof.
23. A compound according to claim 22 , having the formula (+)-5-{5-Acetyl-6- methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-4-pyrimidinyl}-2- pyridinecarbonitrile, or a pharmaceutically acceptable salt thereof.