Patent EA-004373-B1 (EA)
Title: 1-AMINO[4,3-a] QUINAZOLINE-5-ONES AND/OR -5-THIONES INHIBITING PHOSPHODIESTERASE IV
Inventor: GAUDILLIERE BERNARD
IPC: A61P25/36
Filed: 2000-04-28
Abstract: 1. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones of formula I or II: I and II being positional isomers of the group R on nitrogens 3 or 4, in which: - A1 is O or S; - X1 and X2, which may be identical or different, represent: - hydrogen, hydroxyl, halogen, amino, nitro, mercapto, cyano, carboxyl, - lower alkyl, lower alkoxy or -CO-Q1-Q2-Q3 in which: -Q1- is: a single valency bond, -O-, in which p is an integer which can range from 0 to 3, and Z1 is CH, N, O or S, -Q2- is: a) -(CH2)q-, q being equal to 0, 1, 2, 3, or 4, and -Q3 is: -H, -OH, -NHX3 or in which X3 and X4, which may be identical or different, represent a lower alkyl group, - -NH-R1 in which R1 represents a lower alkyl group, optionally substituted with one or more groups chosen from halogen, hydroxyl, cyano, lower alkoxy and -CO-Q1-Q2-Q3, or - -NR2R3 in which R2 and R3, which may be identical or different, represent a lower alkyl, wherein R2 and R3 are optionally linked to form a ring, comprising one to seven carbon atoms and one N hetero atom; - R represents: - lower alkyl, lower alkenyl, lower alkynyl, arylalkynyl, 2-, 3- or 4-pyridylalkyl or amino group, in which: - n is an integer from 1 to 5, - Ar is an aromatic ring comprising 5 or 6 atoms including from 0 to 3 hereto atoms chosen from O, S and N, - Y1, Y2 and Y3, which may be identical or different, represent: - hydrogen, hydroxyl, amino, nitro, halogen, -(CH2)s-CN, or -(CH2)sCO-Q1-Q2-Q3 in which s is an integer from 0 to 1; - lower alkyl, lower alkoxy, it being possible for each to be optionally substituted with one or more halogen atoms; and - R4 and R5, represent: - lower alkyl when R4 and R5 are identical, aralkyl, cycloalkyl or cycloalkylalkyl, when R4 and R5 are identical, - lower alkyl, it being possible for R4 and R5 to be linked to form a saturated ring or a ring including one or more double bonds comprising one to seven hetero atoms chosen from O, S and N and optionally substituted with a lower alkyl, a hydroxyl or a lower alkoxy or bridged with a lower alkyl, gem-dialkylated or substituted with one or more groups being a lower alkyl, wherein said ring is optionally condensed with another ring which is phenyl; optionally the racemic forms thereof and the isomers thereof, as well as the pharmaceutically acceptable salts thereof, where - lower alkyl group is a linear or branched group comprising from 1 to 6 carbon atoms, - lower alkoxy group is a linear or branched group comprising from 1 to 5 carbon atoms, - lower alkenyl group comprising from 3 to 6 carbon atoms, - lower alkynyl group comprising from 3 to 6 carbon atoms, - 2-, 3- or 4-pyridylalkoxy group comprises alkyl comprising from 1 to 5 carbon atoms, - aryl group comprising from 5 to 8 carbon atoms. 2. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones according to Claim 1, in which: A1 represents an oxygen atom; X1 represents a hydrogen atom and X2 is a halogen, amino, lower alkyl, hydroxyl or -NHR1 group, R1 being as defined above, R represents: - a lower alkyl, lower alkenyl, arylalkynyl, 2-, 3- or 4-pyridylalkyl group; n is an integer from 1 to 3, - Y1, Y2 and Y3 each represent a hydrogen atom or a lower alkoxy group, more particularly methoxy, - Y1 and Y2 each represent a hydrogen atom and Y3 represents a lower alkoxy group, an amino group, nitro, hydroxyl, a group -(CH2)sCO-Q1-Q2-Q3, a group (CH2)s-CN in which s, Q1, Q2, and Q3 are as defined above, or a lower alkyl group optionally substituted with one or more halogen atoms, the position which is particularly preferred for the substituent Y3 being position 4, or - Y1 represents a hydrogen atom and Y2 and Y3, which may be identical or different, represent a hydroxyl, halogen or lower alkoxy group, or in which: - Ar is as defined above; - Y1, Y2 and Y3 each represent a hydrogen atom, or - Y1 and Y2 each represent a hydrogen atom and Y3 is lower alkoxy or halogen; R4 and R5 represent: - lower alkyl when R4 and R5 are identical, - lower alkyl, wherein R4 and R5 are optionally linked to form a saturated ring or a ring including one or more double bonds comprising one to seven carbon atoms and one or more hetero atoms chosen from O, S and N and optionally substituted with a lower alkyl, a hydroxyl or bridged with lower alkyl, gem-dialkylated or substituted with one or more groups being a lower alkyl, wherein said ring is optionally condensed with another ring which is phenyl; 3. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones according to Claim 1 or 2, in which: X1 represents a hydrogen atom, X2 represents a halogen, amino, lower alkyl, hydroxyl or -NHR1 group; R represents: in which: - n is an integer from 1 to 3, - Y1, Y2 and Y3 each represent a hydrogen atom or a lower alkoxy group, more particularly methoxy and in particular 3, 4, 5-trimethoxy, - Y1 and Y2 each represent a hydrogen atom and Y3 represents a lower alkoxy, amino, nitro, or hydroxyl group, a lower alkyl group optionally substituted with one or more halogen atoms, a group -(CH2)sCO-Q1-Q2-Q3 in which s is 0 or 1, Q1 is O, -NH- or a valency bond, Q2 is -(CH2)q-, q being equal to 0 1, 2, 3 or 4 and Q3 is H, OH or NX3X4 in which X3 and X4 are as defined above, a group (CH2)s-CN in which s is 0 or 1, the position particularly preferred for the substituent Y3 being position 4 or - Y1 represents a hydrogen atom and Y2 and Y3, which may be identical or different, represent a hydroxyl, halogen or lower alkoxy group; or in which: - Ar1 is an aromatic ring comprising 6 atoms which can include a nitrogen atom in position 2, 3 or 4 and preferably in position 3; - Y1, Y2 and Y3 each represent a hydrogen atom, or - Y1 and Y2 each represent a hydrogen atom and Y3 is lower alkoxy group or a halogen group when Ar1 does not comprise a nitrogen atom; and R4 and R5 represent: - lower alkyl, when R4 and R5 are identical, lower alkyl, wherein it being possible for R4 and R5 to be linked to form a saturated ring or a ring including one or more double bonds comprising two to seven carbon atoms and one or more hetero atoms chosen from O, S and N and optionally substituted with a lower alkyl, a hydroxyl or a lower alkoxy or bridged with a lower alkyl, gem-dialkylated or substituted with one or more groups, being a lower alkyl, wherein said ring is optionally condensed with another ring which is phenyl. 4. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones according to any one of Claims 1 to 3, in which: - the halogen group is chosen from F, C1, Br and I, - the lower alkyl group or lower alkoxy groups substituted with one or more halogen atoms are chosen from the groups -(CH2)pCF3, or -O-(CH2)pCF3 in which p is an integer from 0 to 3. 5. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones according to Claim 1, in which: - A1 is O or S; - X1 and X2, which may be identical or different, represent: - hydrogen, hydroxyl, halogen, amino, nitro, mercapto, cyano, carboxyl, - lower alkyl or lower alkoxy; - R represents: in which: - n is an integer from 1 to 5, Ar is an aromatic ring comprising 5 or 6 atoms including from 0 to 3 hetero atoms chosen from O, S and N, - Y1, Y2 and Y3, which may be identical or different, represent: - hydrogen, hydroxyl, mercapto, amino, nitro, halogen, -(CH2)sCO-Q1-Q2-Q3, or -(CH2)s-CN in which s is an integer from 0 to 6; - lower alkyl, lower alkoxy it being possible for each to be optionally substituted with one or more halogen atoms; - R4 and R5, which may be identical or different, represent: - lower alkyl, it being possible for R4 and R5 to be linked to form a saturated ring or a ring including one or more double bonds comprising one or more hetero atoms chosen from O, S and N and optionally bridged with a lower alkyl, gem-dialkylated or substituted with one or two lower alkyl. 6. Triazolo[4,3-a]quinazolin-5-ones and/or -5-thiones according to any one of Claims 1 to 5, chosen from the group comprising: 1-(Azepan-1-yl)-7-chloro-4-(3-phenylallyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-3-(3-phenylallyl)-3H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 7-Bromo-1-dimethylarnino-4-((E)-3-pyrid-3-ylallyl)-4H-[1,2,4]triazolo[4, 3a]quinazolin-5-one; 7-Bromo-4-pyrid-3-ylmethyl-1-pyrrolidin-1-yl-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 7-Bromo-3-pyrid-3-ylmethyl-1-pyrrolidin-1-yl-3H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-Azepan-1-yl-4-(3-phenylallyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-allyl-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-methylbenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(2-chlorobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(3-chlorobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-chlorobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-bromobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-fluorobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-(trifluoromethyl)benzyl)-4H-[1,2,4]triazolo[4,3-a]-quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-cyanobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(2-methoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(3-methoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-methoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(3,4-dichlorobenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(3,4-dimethoxybenzyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(2-pyridylmethyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(3-pyridylmethyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(4-pyridylmethyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-(2-phenylethyl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one; 1-(Azepan-1-yl)-7-chloro-4-[2-(4-methoxypheny