Heterocyclic derivatives
View Patent ↗The invention relates to novel 3,4-dihydropyrimidin-2(1H)-one derivatives having the formula processes for their preparation, and their use in compositions, and in the treatment of chronic obstructive pulmonary diseases, acute coronary syndrome, acute myocardial infarction and heart failure development.
1. A compound of formula (I)
wherein
A represents a phenyl 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 2 -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 -alkyl-carbonyl, 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 -alkoxy-carbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylamino-carbonyl, C 1 -C 4 -alkylcarbonylamino, N—(C 1 -C 4 -alkylcarbonyl)-N—(C 1 -C 4 -alkyl)-amino, 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 2 -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
a group of the formula -T-U wherein
T represents a C 1 -C 6 -alkanediyl or C 2 -C 6 -alkenediyl group and
U represents
C 6 -C 10 -aryl or 5- or 6-membered heteroaryl each of which is substituted by one, two or three radicals independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, 5- or 6-membered heteroaryl and a group of the formula —V—W wherein V represents a bond or a C 1 -C 6 -alkanediyl or C 2 -C 6 -alkenediyl group both of which can be further substituted by C 3 -C 8 -cycloalkyl, and W represents C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl,
a group of the formula —C(═O)—NR a —SO 2 R b wherein R a represents hydrogen or C 1 -C 6 -alkyl, and R b represents C 1 -C 6 -alkyl which can be substituted by trifluoromethyl, or R b represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkyl, halogen, cyano, nitro or trifluoromethyl,
a group of the formula —C(═O)—NR c R d wherein R c represents hydrogen or C 1 -C 6 -alkyl, and R d represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
C 6 -C 10 -arylalkoxy which, in the aryl part, can be substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
R 6 represents
C 3 -C 8 -cycloalkyl which can be substituted by up to three radicals independently selected from the group consisting of C 1 -C 6 -alkyl, hydroxy, oxo, C 1 -C 6 -alkoxy-carbonyl and hydroxycarbonyl,
C 2 -C 6 -alkenyl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxy-carbonyl,
C 1 -C 6 -alkyl or C 1 -C 6 -alkylcarbonyl which are substituted by C 1 -C 6 -alkoxycarbonyl-amino,
C 3 -C 6 -alkoxycarbonyl which is substituted by phenyl-C 1 -C 6 -alkoxycarbonyl which for its part, in the phenyl moiety, can be further substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
a group of the formula —SO 2 —R g wherein R g represents C 1 -C 6 -alkyl which can be substituted by trifluoromethyl, or R g represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkyl, halogen, cyano, nitro, trifluoromethyl, C 1 -C 6 -alkoxy-carbonyl or hydroxycarbonyl,
R 7 represents 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, 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 salt or tautomer thereof.
2. A compound of formula (I) according to claim 1 , wherein
A represents a phenyl 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 2 -C 6 -alkenoxycarbonyl, hydroxycarbonyl, aminocarbonyl, mono- or di-C 1 -C 4 -alkylaminocarbonyl, C 6 -C 10 -arylaminocarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, heteroaryl, hetero-cyclyl 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 2 -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,
R 6 represents
a group of the formula -T-U wherein
T represents a C 1 -C 4 -alkanediyl or C 2 -C 4 -alkenediyl group and
U represents
C 6 -C 10 -aryl or 5- or 6-membered heteroaryl each of which is substituted by one, two or three radicals independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, 5- or 6-membered heteroaryl and a group of the formula —V—W wherein V represents a bond, a C 2 -C 6 -alkenediyl group or a C 1 -C 6 -alkenediyl group the latter of which can be further substituted by C 3 -C 8 -cycloalkyl, and W represents C 1 -C 6 -alkoxycarbonyl or hydroxy-carbonyl,
a group of the formula —C(═O)—NH—SO 2 —R b wherein R b represents C 1 -C 6 -alkyl which can be substituted by trifluoromethyl, or R b represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkyl, halogen, cyano, nitro or trifluoromethyl, or
a group of the formula —C(═O)—NHR d wherein R d represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
R 6 represents
C 3 -C 8 -cycloalkyl which can be substituted by up to three radicals independently selected from the group consisting of C 1 -C 6 -alkyl, hydroxy, oxo, C 1 -C 6 -alkoxy-carbonyl and hydroxycarbonyl, or
C 2 -C 6 -alkenyl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxy-carbonyl,
R 7 represents 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, and
Y 1 , Y 2 , 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. A compound of formula (I) according to claim 1 , wherein
A represents a phenyl 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, allyloxycarbonyl, hydroxy-carbonyl, aminocarbonyl, mono-C 1 -C 4 -alkylaminocarbonyl, furylcarbonyl, pyridyl-carbonyl 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 6 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, hydroxycarbonyl, amino, mono- and di-C 1 -C 4 -alkylamino,
R 5 represents methyl or ethyl,
R 6 represents
a group of the formula -T-U wherein
T represents a C 1 -C 4 -alkanediyl group and
U represents
phenyl, furyl, thienyl, oxazolyl, thiazolyl or pyridyl each of which is substituted by one or two radicals independently selected from the group consisting of fluoro, chloro, bromo, C 1 -C 4 -alkyl, thienyl, pyridyl and a group of the formula —V—W wherein V represents a bond or a C 1 -C 4 -alkanediyl or C 2 -C 4 -alkenediyl group, and W represents C 1 -C 4 -alkoxycarbonyl or hydroxycarbonyl,
a group of the formula —C(═O)—NH—SO 2 —R b wherein R b represents C 1 -C 4 -alkyl which can be substituted by trifluoromethyl, or R b represents phenyl which can be substituted by C 1 -C 4 -alkyl, fluoro, chloro, bromo, cyano, nitro or trifluoromethyl, or
a group of the formula —C(═O)—NHR d wherein R d represents phenyl which can be substituted by C 1 -C 4 -alkoxycarbonyl or hydroxycarbonyl, or
R 6 represents
C 3 -C 6 -cycloalkyl which can be substituted by up to two radicals independently selected from the group consisting of C 1 -C 4 -alkyl, hydroxy, oxo, C 1 -C 4 -alkoxy-carbonyl and hydroxycarbonyl, or
C 2 -C 4 -alkenyl which is substituted by C 1 -C 4 -alkoxycarbonyl or hydroxycarbonyl,
R 7 represents halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, methyl or ethyl, and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each represent CH.
4. A compound of formula (I) according to claim 1 , wherein
A represents a phenyl ring,
R 1 and R 3 each represent hydrogen,
R 2 represents fluoro, chloro, bromo, nitro or cyano,
R 4 represents cyano, hydroxycarbonyl, furylcarbonyl, pyridylcarbonyl, C 1 -C 4 -alkyl-carbonyl or C 1 -C 4 -alkoxycarbonyl, wherein C 1 -C 4 -alkylcarbonyl and C 1 -C 4 -alkoxy-carbonyl can be substituted with a radical selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxycarbonyl, hydroxycarbonyl, mono- and di-C 1 -C 4 -alkylamino,
R 5 represents methyl,
R 6 represents
a group of the formula -T-U wherein
T represents a —CH 2 — group and
U represents
phenyl, furyl or oxazolyl each of which is substituted by one or two radicals independently selected from the group consisting of fluoro, chloro, bromo, C 1 -C 4 -alkyl and a group of the formula —V—W wherein V represents a bond, a —CH 2 — group or a —CH═CH— group, and W represents C 1 -C 4 -alkoxycarbonyl or hydroxycarbonyl,
a group of the formula —C(═O)—NH—SO 2 —R b wherein R b represents C 1 -C 4 -alkyl which can be substituted by trifluoromethyl, or R b represents phenyl which can be substituted by C 1 -C 4 -alkyl, fluoro, chloro, bromo, cyano, nitro or trifluoromethyl, or
a group of the formula —C(═O)—NHR d wherein R d represents phenyl which can be substituted by C 1 -C 4 -alkoxycarbonyl or hydroxycarbonyl, or
R 6 represents
C 3 -C 6 -cycloalkyl which can be substituted by up to two radicals independently selected from the group consisting of C 1 -C 4 -alkyl, hydroxy, oxo, C 1 -C 4 -alkoxy-carbonyl and hydroxycarbonyl, or
a —CH═CH— group which is substituted by C 1 -C 4 -alkoxycarbonyl or hydroxy-carbonyl,
R 7 represents trifluoromethyl or nitro, and
Y 1 , Y 2 , Y 3 , Y 4 and Y 5 each represent CH.
5. A compound of formula (I) according to claim 1 , wherein R 1 is hydrogen.
6. A compound of formula (I) according to claim 1 , wherein R 2 is cyano.
7. A compound of formula (I) according to claim 1 , wherein R 3 is hydrogen.
8. A compound of 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 -alkyl-carbonyl, hydroxycarbonyl or cyano.
9. A compound of formula (I) according to claim 1 , wherein R 5 is methyl.
10. A compound of formula (I) according to claim 1 , wherein R 7 is trifluoromethyl or nitro.
11. A compound of formula (IA)
wherein
Z represents CH, and
R 1 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 2 -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 -alkyl-carbonyl, 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 -alkoxy-carbonyl, hydroxycarbonyl, aminocarbonyl, mono- and di-C 1 -C 4 -alkylamino-carbonyl, C 1 -C 4 -alkylcarbonylamino, N—(C 1 -C 4 -alkylcarbonyl)-N—(C 1 -C 4 -alkyl)-amino, 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, and,
R 6 represents
a group of the formula -T-U wherein
T represents a C 1 -C 6 -alkanediyl or C 2 -C 6 -alkenediyl group and
U represents
C 6 -C 10 -aryl or 5- or 6-membered heteroaryl each of which is substituted by one, two or three radicals independently selected from the group consisting of halogen, C 1 -C 6 -alkyl, 5- or 6-membered heteroaryl and a group of the formula —V—W wherein V represents a bond or a C 1 -C 6 -alkanediyl or C 2 -C 6 -alkenediyl group both of which can be further substituted by C 3 -C 8 -cycloalkyl, and W represents C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl,
a group of the formula —C(═O)—NR a —SO 2 —R b wherein R a represents hydrogen or C 1 -C 6 -alkyl, and R b represents C 1 -C 6 -alkyl which can be substituted by trifluoromethyl, or R b represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkyl, halogen, cyano, nitro or trifluoromethyl,
a group of the formula —C(═O)—NR c R d wherein R c represents hydrogen or C 1 -C 6 -alkyl, and R d represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl,
C 6 -C 10 -arylalkoxy which, in the aryl part, can be substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
R 6 represents
C 3 -C 8 -cycloalkyl which can be substituted by up to three radicals independently selected from the group consisting of C 1 -C 6 -alkyl, hydroxy, oxo, C 1 -C 6 -alkoxy-carbonyl and hydroxycarbonyl,
C 2 -C 6 -alkenyl which can be substituted by C 1 -C 6 -alkoxycarbonyl or hydroxy-carbonyl,
C 1 -C 6 -alkyl or C 1 -C 6 -alkylcarbonyl which are substituted by C 1 -C 6 -alkoxycarbonyl-amino,
C 3 -C 6 -alkoxycarbonyl which is substituted by phenyl-C 1 -C 6 -alkoxycarbonyl which for its part, in the phenyl moiety, can be further substituted by halogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxycarbonyl or hydroxycarbonyl, or
a group of the formula —SO 2 —R g wherein R g represents C 1 -C 6 -alkyl which can be substituted by trifluoromethyl, or R g represents C 6 -C 10 -aryl which can be substituted by C 1 -C 6 -alkyl, halogen, cyano, nitro, trifluoromethyl, C 1 -C 6 -alkoxy-carbonyl or hydroxycarbonyl
or a salt or tautomer thereof.
12. A process for synthesizing compound of formula (I) according to claim 1 , by condensing a compound of formula (II)
wherein A, R 1 and R 2 have the meaning indicated in claim 1 , with a compound of formula (III)
wherein R 4 and R 5 have the meaning indicated in claim 1 , and a compound of formula (IV)
wherein R 3 , R 7 , and Y 1 to Y 5 have the meaning indicated in claim 1 , to give a compound of formula (IB)
wherein A, R 1 to R 5 , R 7 , and Y 3 to Y 5 have the meaning indicated in claim 1 , followed by reaction of the compound of formula (IB) with a compound of formula (V)
R 6 —X (V),
wherein
R 6 has the meaning indicated in claim 1 , and
X represents a leaving group,
in the presence of a base.
13. A composition comprising at least one compound of formula (I) according to claim 1 and a pharmacologically acceptable diluent.