Carboxamidine derivatives and their use in the treatment of vascular diseases

A method for inhibiting or reversing damage to one or more endothelial cells comprising administering to the one or more endothelial cells an effective amount of a compound of formula I or II as defined below:

• i) a compound of formula I:
• wherein R1 and R2 are independently hydrogen, a straight chained C1-6 alkyl group optionally substituted with a phenyl group, or a branched C1-6 alkyl group optionally substituted with a phenyl group, or R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups;
• A is a phenyl group optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
• n is 0, 1, or 2;
• z is 0 or 1;
• X is halogen or —NR4R5, wherein R4 and R5 are independently hydrogen, a straight chained C1-6 alkyl group or a branched C1-6 alkyl group,
• Y is a hydrogen, hydroxy group, halogen, or C1-22 acyloxy group, wherein if R4 and R5 are both hydrogen, then Y is other than a hydroxy group,
• with the proviso that
• a) if Y is hydrogen and/or X is an —NR4R5 or if X is —NR4R5 group, then
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups, and/or
• A is a nitrogen containing heteroaromatic ring, wherein said ring has an N-oxide structure on the nitrogen heteroatom, or
• b) if X is halogen and Y is hydroxy or acyloxy, then
• n is 1 or 2, and
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo or benzyl groups, or a stereoisomer or salt thereof;
• ii) a compound of formula II
• wherein R1 and R2 are independently hydrogen, a straight chained C1-6 alkyl group optionally substituted with a phenyl group, a branched C1-6 alkyl group optionally substituted with a phenyl group, or R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups,
• A is a phenyl group optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
• n is 0, 1, or 2;
• z is 0 or 1;
• X is oxygen;
• R3 is selected from hydrogen, straight chained C1-6 alkyl group, and branched chained C1-6 alkyl group;
• Y is selected from hydrogen, hydroxy, halogen, and C1-22 acyloxy group,
• with the proviso that if Y is other than halogen, then
• n is 1 or 2, and
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatom, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo or benzyl groups and/or
• A is a nitrogen containing heteroaromatic ring, which has N-oxide structure on the nitrogen heteroatom;
• or a stereoisomer or salt thereof.

A method for increasing vaso-relaxation of a vessel associated with endothelial cells comprising administering to the cells an effective amount of a compound of formula I or II as defined below:

• i) a compound of formula I:
• wherein R1 and R2 are independently hydrogen, a straight chained C1-6 alkyl group optionally substituted with a phenyl group, or a branched C1-6 alkyl group optionally substituted with a phenyl group, or R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups;
• A is a phenyl group optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, nitro or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
• n is 0, 1, or 2;
• z is 0 or 1;
• X is halogen or —NR4R5, wherein R4 and R5 are independently hydrogen, a straight chained C1-6 alkyl group or a branched C1-6 alkyl group,
• Y is a hydrogen, hydroxy group, halogen, or C1-22 acyloxy group, wherein if R4 and R5 are both hydrogen, then Y is other than a hydroxy group,
• with the proviso that
• a) if Y is hydrogen and/or X is an —NR4R5 or if X is —NR4R5 group, then
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein the heterocyclic ring is substituted with one or more hydroxy, oxo, or benzyl groups, and/or
• A is a nitrogen-containing heteroaromatic ring, wherein said ring has an N-oxide structure on the nitrogen heteroatom, or
• b) if X is halogen and Y is hydroxy or acyloxy, then
• n is 1 or 2, and
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo or benzyl groups, or a stereoisomer or salt thereof;
• ii) a compound of formula II
• wherein R1 and R2 are independently hydrogen, a straight chained C1-6 alkyl group optionally substituted with a phenyl group, a branched C1-6 alkyl group optionally substituted with a phenyl group, or R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is optionally substituted with one or more hydroxy, oxo or benzyl groups,
• A is a phenyl group optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, nitro, or halogen, or is a 5-6 membered heteroaromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur, wherein the nitrogen heteroatom is optionally an N-oxide structure;
• n is 0, 1, or 2;
• z is 0 or 1;
• X is oxygen;
• R3 is selected from hydrogen, straight chained C1-6 alkyl group, and branched chained C1-6 alkyl group;
• Y is selected from hydrogen, hydroxy, halogen, and C1-22 acyloxy group,
• with the proviso that if Y is other than halogen, then
• n is 1 or 2, and
• R1 and R2 together with the nitrogen atom attached thereto form a 5-7 membered, saturated heterocyclic ring optionally containing further nitrogen and/or oxygen heteroatoms, wherein said heterocyclic ring is substituted with one or more hydroxy, oxo or benzyl groups and/or
• A is a nitrogen-containing heteroaromatic ring, which has a N-oxide structure on the nitrogen heteroatom;
• or a stereoisomer or salt thereof.