Patent EA-001680-B1 (EA)
Title: Tetrahydroquinaline derivatives as eaa antagonists
Inventor: CARGANICO GERMANO
IPC: A61P11/06
Filed: 1997-03-20
Abstract: 1. A compound of formula I   wherein: - A is an oxygen or sulfur atom or a methylene group; - B can be: a) a benzofused heterocycle   wherein: - U is an oxygen or sulfur atom or a NR<5> group, wherein R<5> is hydrogen or (C1-C4)alkyl, the R<5> group being optionally substituted by the substituent containing A when said substituent is bound to the 1-position of the benzofused heterocycle; - Z and Y represent two carbon atoms linked together by a single bond or by a double bond; - T is a single bond, a methylene group or a carbonyl group; and wherein: - the substituent containing A is bound to any one of possible 1-, 2-, 3- or 4-position of the benzofused heterocycle; - the substituent containing C is bound to the 6- or 7- position of the benzofused heterocycle; b) a phenyl group   wherein the substituent containing C is bound to the phenyl group at the 3-, 4- or 5-position; - C is a diradical which represents: a) when B is a benzofused heterocycle, a -CONR<7>-, -CSNR<7>-, -SO2NR<7>-, -CH2O-, -CH=CH- group, wherein R<7> is hydrogen or methyl; b) when B is a phenyl group, a -SO2NR<7>-, -CH2O-, -CH=CH- group, wherein R<7> is hydrogen or methyl; - D is a 5-tetrazolyl or -COOR<8> group, wherein R<8> is hydrogen, a (C1-C4)alkyl or a phenylalkyl group of less than 10 carbon atoms; - R<1>, R<2>, R<3>, R<4> and R<6> are independently hydrogen, halogen, (C1-C4)alkyl, -OCH3 or -OH; - m and n are integers from 0 to 4; as well as the solvates and pharmaceutically acceptable salts thereof and all the possible stereoisomers or mixtures thereof. 2. A compound according to Claim 1, wherein R<1> and R<2> are hydrogen, fluorine or chlorine and D is a 5-tetrazolyl or COOR<8> group, wherein R<8> is hydrogen, methyl, ethyl or benzyl. 3. A compound according to any one of Claims 1 or 2, wherein B is a benzofused heterocycle,   and C is -CONR<7>- or -CH=CH-. 4. A compound according to Claim 3, wherein R<3> is hydrogen or methyl and U is a NR<5> group, wherein R<5> is hydrogen or methyl or can be substituted with the substituent containing A. 5. A compound according to Claim 3, wherein R<3> is hydrogen, R<4> is hydrogen, fluorine, chlorine, methyl or methoxide and U is oxygen. 6. A compound according to Claim 3, wherein the substituent containing C is bound to the 6-position of the central benzofused heterocycle. 7. A compound according to Claims 4 and 6, wherein T is a single bond or a carbonyl group, Y-Z is a -CH=CH- group and the substituent containing A is bound to the 1- or 2-position of the central benzofused heterocycle. 8. A compound according to Claims 5 and 6, wherein the substituent containing A is bound to the 2-position of the central benzofused heterocycle. 9. A compound according to any one of Claims 3 to 8, wherein m and n are integers from 1 to 2. 10. A compound according to any one of Claims 1 or 2, wherein B is a substituted phenyl   and C is -CH=CH-, -CH2O- or -SO2NR<7>-, wherein R<7> is hydrogen or methyl. 11. A compound according to Claim 10, wherein the substituents containing A and C are bound to the phenyl group in a respective para position. 12. A compound according to Claims 10 and 11, wherein R<6> is hydrogen, fluorine, chlorine, methyl or methoxide, n is 0, A is oxygen or sulfur and m is 3 to 5. 13. A compound according to Claim 1 selected from the following ones: 8-[2-(benzyloxymethyl)chromane-6-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-2-(benzyloxymethyl)chromane-6-carboxamide; 8-[2-(3-phenylpropyl)chromane-6-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-2-(3-phenylpropyl)chromane-6-carboxamide; 8-[2-(benzyloxymethyl)benzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-(2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamido)-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-2-benzyloxymethyl-2,3-dihydrobenzofuran-5-carboxamide; 8-[2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamide; 8-(2-benzylthiomethyl-2,3-dihydrobenzofuran-5-carboxamido)-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-5-carboxamide; 8-[7-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamido]-6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[4-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[6-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxamido]-4-oxo-4H-1-benzopyran-2-carboxylic acid; N-[4-oxo-2-(1H-5-tetrazolyl)-4H-1-benzopyran-8-yl]-1-(4-phenylbutyl)-3-methylindole-5-carboxamide; 8-[[4-(4-phenylbutoxy)phenyl]methyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[[4-(4-phenylbutoxy)phenyl]sulfonylamino]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[(E)-2-[4-(4-phenylbutoxy)phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[(E)-2-[4-[4-(4-fluorophenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-(4-phenylbutoxy)-2-fluorophenyl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[(E)-2-[2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-5-yl]ethen-1-yl]-4-oxo-4H-1-benzopyran-2-carboxylic acid; 8-[(E)-2-[2-(4'-fluorobenzyloxymethyl)-2,3-dihydrobenzofuran-5-yl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-chlorophenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-methylphenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-methoxyphenyl)butoxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-[4-(iso-propyl)phenyl]butoxy]phenyl]-ethen-l-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-[4-(tert-butyl)phenyl]butoxy]phenyl]-ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-chlorophenyl)propyloxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-fluorophenyl)propyloxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-methylphenyl)propyloxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-(4-methoxyphenyl)propyloxy]phenyl]ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-[4-(iso-propyl)phenyl]propyloxy]phenyl]-ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran; 8-[(E)-2-[4-[4-[4-(tert-butyl)phenyl]propyloxy]phenyl]-ethen-1-yl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran. 14. A process for the preparation of the compounds of general formula I of Claim 1, and the pharmaceutically acceptable salts thereof, in which process: when in general formula I D is -COOR<8>, a compound of general formula II,   wherein R<1>, R<2>, A, B, C, m and n have the above mentioned meanings, is reacted with a commercial compound III,   wherein R<9> is the residue R<8> with the exception of hydrogen, in the presence of a base, to obtain a compound IV,   which is subjected to an acid treatment to obtain compound V,   which coincides with I wherein D is COOR<8> or, when D is COOH in formula I, is converted into I by cleavage of the R<9> group through alkali hydrolysis; and, if necessary, the compound of formula I is converted into the desired salt, by treatment with a base or a suitable ion exchanger according to conventional methods. 15. The method for obtaining compounds of general formula I according Claim 1 and pharmaceutically acceptable salts thereof, wherein when in general formula I D is a 5-tetrazolyl group, a compound of formula VI,   wherein R<1>, R<2>, A, B, C, m and n have the above mentioned meanings, is reacted with sodium azide to obtain a compound VII,   which coincides with I wherein D is the 5-tetrazolyl group; and, if necessary, the compound of formula I is converted into the desired salt, by treatment with a base or a suitable ion exchanger according to conventional methods. 16. The method for obtaining compounds of general formula I according Claim 1 and pharmaceutically acceptable salts thereof, wherein when in general formula I C is -CO-NR<7>-, a compound VIII,   wherein R<1>, A, B, m and n have the above mentioned meanings, is reacted with a compound IX,   wherein R<2> and R<7> have the above mentioned meanings and E can be equivalent to the group D in I or, when D in formula I is COOH, then E contains a suitable carboxy-protecting group, the reaction being carried out previously preparing the acid chloride of the compound VIII according to conventional processes, then reacting it with compound IX in the presence of a base, to obtain thereby a compound of formula X,   which coincides with I, wherein C is -CONR<7>- or is converted in I, wherein C is -CONR<7>-, removing any COOH-protecting group present in E; and, if necessary, the compound of formula I is converted into the desired salt, by treatment with a base or a suitable ion exchanger according to conventional methods. 17. The method for obtaining compounds of general formula I according Claim 1 and pharmaceutically acceptable salts thereof, wherein when in general formula I C is -CH2O-, then a compound of formula XI,   wherein R<1>, A, B, m and n have the above mentioned meanings and X is a chlorine or bromine atom or an alkyl- or aryl- sulfonate group, is reacted with a compound XII,   wherein R<2> and E have the above mentioned meanings, in the presence of a base, to obtain a compou