Imidazo[1,2-a]azines and their use as pharmaceuticals

A method of treating a patient for a condition selected from stable or unstable angina pectoris, coronary heart disease, coronary artery disease, Prinzmetal angina, acute coronary syndrome, cardiac insufficiency, heart failure, myocardial infarction, stroke, thrombosis, peripheral artery occlusive disease, endothelial dysfunction, atherosclerosis, restenosis, endothel damage after PTCA, hypertension, essential hypertension, pulmonary hypertension, secondary hypertension, renovascular hypertension, chronic glomerulonephritis, erectile dysfunction, ventricular arrhythmia, diabetes, diabetes complications, nephropathy, retinopathy, angiogenesis, asthma bronchiale, chronic renal failure, cirrhosis of the liver, osteoporosis, restricted memory performance or a restricted ability to learn, or for the lowering of cardiovascular risk of postmenopausal women or after intake of contraceptives, the method comprising administering to the patient a pharmaceutically effective dose of a compound of formula I,

• in which
• X and Y are independently chosen from —N═ and —C(R4)= with the proviso that at least one of X and Y is defined as —N═;
• R is chosen from halogen, (C1-C6)-alkyl which can be substituted by one or more fluorine atoms, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy, (C1-C6)-alkoxy which can be substituted by one or more fluorine atoms, (C1-C6)-alkylmercapto, NR7R8, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C6)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, cyano, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, aminosulfonyl, nitro, pentafluorosulfanyl, (C3-C7)-cycloalkyl and (C6-C14)-aryl, wherein the aryl residue can be substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• or two adjacent R groups form, together with the carbon atoms which carry them, a 4-membered to 7-membered, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R13 and which can contain one or two ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2— which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R1 is chosen from hydrogen and (C1-C6)-alkyl;
• or R and R1 together form a (C1-C2)-alkylene or (C1-C2)-alkenylene chain if R is attached in ortho-position of the phenyl ring;
• R2 is chosen from hydrogen, hydroxy and (C1-C6)-alkyl;
• R3 is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH, (C1-C6)-alkoxycarbonyl and —C(═NR5)-NHR6;
• R4 is each time independently chosen from hydrogen and (C1-C6)-alkyl;
• R5 is chosen from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyloxy, (C1-C18)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, (C6-C14)-arylcarbonyl, (C6-C14)-aryloxycarbonyl, hydroxy, (C1-C6)-alkylcarbonyloxy, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl, (C1-C6)-alkylaminocarbonyloxy, di-((C1-C6)-alkyl)aminocarbonyloxy, (C1-C6)-alkylaminocarbonyl and di-((C1-C6)-alkyl)aminocarbonyl, wherein all aryl groups can be substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• R6 is chosen from hydrogen, cyano, hydroxy, (C1-C6)-alkoxy and (C6-C14)-aryl-(C1-C6)-alkoxy;
• or R5 and R6 form together, with the —N═C—NH— group which carries them, a 4-membered to 7-membered, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R14 and which, in addition to the nitrogen atoms being part of the —N═C—NH— group, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2— which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R7 and R8 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R7 and R8 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R9 and R10 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R9 and R10 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R11 is chosen from hydrogen and (C1-C6)-alkyl;
• R12 is chosen from hydrogen and (C1-C6)-alkyl;
• or R11 and R12 form, together with the carbonylamino group which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R15 and which, in addition to the carbonylamino group connecting R11 and R12, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2— which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R13, R14 and R15 are independently chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• and
• n is chosen from 0, 1, 2, 3, 4 and 5;
• or a physiologically acceptable salt thereof,
• provided that 2-(4-amino-phenyl)-6-chloro-imidazo[1,2-b]pyridazine, 2-(2,4-dimethoxy-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine, 2-(2-methoxy-4-methylsulfinyl-phenyl)-imidazo[1,2-a]pyrimidin-6-ylamine, 6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine, 2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamine and 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamine are excluded.

A pharmaceutical composition comprising at least one compound of formula Ia,

• or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier, in which
• X and Y are independently chosen from —N═ and —C(R4)=, with the proviso that at least one of X and Y is defined as —N═;
• R is chosen from halogen, (C1-C6)-alkyl which can be substituted by one or more fluorine atoms, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy, (C1-C6)-alkoxy which can be substituted by one or more fluorine atoms, (C1-C6)-alkylmercapto, NR7R8, mono-(C1-C6)-alkylaminocarbonyl, di-(C2-C6)-alkylaminocarbonyl, (C1-C6)-alkoxycarbonyl, cyano, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, aminosulfonyl, nitro, pentafluorosulfanyl, (C3-C7)-cycloalkyl and (C6-C14)-aryl, wherein the aryl residue can be substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• or two adjacent R groups form, together with the carbon atoms which carry them, a 4-membered to 7-membered, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R13 and which can contain one or two ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2— which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R1 is chosen from hydrogen and (C1-C6)-alkyl;
• or R and R1 together form a (C1-C2)-alkylene or (C1-C2)-alkenylene chain if R is attached in ortho-position of the phenyl ring;
• R2 is chosen from hydrogen, hydroxy and (C1-C6)-alkyl;
• R3 is chosen from Cl, Br, cyano, nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH, (C1-C6)-alkoxycarbonyl and —C(═NR5)-NHR6;
• R4 is each time independently chosen from hydrogen and (C1-C6)-alkyl;
• R5 is chosen from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyloxy, (C1-C18)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, (C6-C14)-arylcarbonyl, (C6-C14)-aryloxycarbonyl, hydroxy, (C1-C6)-alkylcarbonyloxy, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl, (C1-C6)-alkylaminocarbonyloxy, di-((C1-C6)-alkyl)aminocarbonyloxy, (C1-C6)-alkylaminocarbonyl and di-((C1-C6)-alkyl)aminocarbonyl, wherein all aryl groups can be substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• R6 is chosen from hydrogen, cyano, hydroxy, (C1-C6)-alkoxy and (C6-C14)-aryl-(C1-C6)-alkoxy;
• or R5 and R6 form, together with the —N═C—NH— group which carries them, a 4-membered to 7-membered, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R14 and which, in addition to the nitrogen atoms being part of the —N═C—NH— group, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2—, which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R7 and R8 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R7 and R8 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R9 and R10 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R9 and R10 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R11 is chosen from hydrogen and (C1-C6)-alkyl;
• R12 is chosen from hydrogen and (C1-C6)-alkyl;
• or R11 and R12 form, together with the carbonylamino group which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R15 and which, in addition to the carbonylamino group connecting R11 and R12, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2—, which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R13, R14 and R15 are independently chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• and
• n is chosen from 0, 1, 2, 3, 4 and 5;
• provided that compounds are excluded in which X is N, Y is CH, R1 and R2 are hydrogen, R3 is amino, n is 2 and at least one of the substituents R is methoxy,
• provided that compounds are excluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Cl, n is 1 or 2 and at least one of the substituents R is amino or acetamido,
• provided that compounds are excluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Cl, n is 0 or 1 and R is halogen, (C1-C6)-alkyl, methoxy, cyclohexyl, phenyl or methylsulfonyl,
• provided that compounds are excluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is Br, n is 0 or 1 and R is Br, Cl, tert-butyl or methoxy,
• provided that compounds are excluded in which X is CH, Y is N, R1 and R2 are hydrogen, R3 is amino, n is 0 or 1 and R is Br, Cl or methoxy,
• and provided that 6-chloro-2-p-tolyl-imidazo[1,2-a]pyrimidine, 6-chloro-2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazine, 2-(3-fluoro-3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamine and 2-(3′,4′-dimethyl-biphenyl-4-yl)-imidazo[1,2-b]pyridazin-6-ylamine are excluded.

A compound of formula Ib,

• in which
• X and Y are independently chosen from —N═ and —C(R4)=, with the proviso that at least one of X and Y is defined as —N═;
• R is chosen from fluorine, (C1-C3)-alkyl which can be substituted by one or more fluorine atoms, hydroxy, NR7R8, cyano and pentafluorosulfanyl;
• R1 is chosen from hydrogen and (C1-C6)-alkyl;
• R2 is chosen from hydrogen, hydroxy and (C1-C6)-alkyl;
• R3 is chosen from Br, cyano, nitro, —C(═O)—NR9R10, amino, —N(R11)-C(═O)—R12, COOH, (C1-C6)-alkoxycarbonyl and —C(═NR5)-NHR6;
• R4 is each time independently chosen from hydrogen and (C1-C6)-alkyl;
• R5 is chosen from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, (C1-C6)-alkoxycarbonyloxy, (C1-C18)-alkylcarbonyloxy-(C1-C6)-alkoxycarbonyl, (C6-C14)-arylcarbonyl, (C6-C14)-aryloxycarbonyl, hydroxy, (C1-C6)-alkylcarbonyloxy, (C6-C14)-aryl-(C1-C6)-alkoxycarbonyl, (C1-C6)-alkylaminocarbonyloxy, di-((C1-C6)-alkyl)aminocarbonyloxy, (C1-C6)-alkylaminocarbonyl and di-((C1-C6)-alkyl)aminocarbonyl, wherein all aryl groups can be substituted by one or more identical or different substituents chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• R6 is chosen from hydrogen, cyano, hydroxy, (C1-C6)-alkoxy and (C6-C14)-aryl-(C1-C6)-alkoxy;
• or R5 and R6 form, together with the —N═C—NH— group which carries them, a 4-membered to 7-membered, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R14 and which, in addition to the nitrogen atoms being part of the —N═C—NH— group, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2—, which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R7 and R8 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R7 and R8 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R9 and R10 are independently chosen from hydrogen and (C1-C6)-alkyl;
• or R9 and R10 form, together with the nitrogen atom which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring;
• R11 is chosen from hydrogen and (C1-C6)-alkyl;
• R12 is chosen from hydrogen and (C1-C6)-alkyl;
• or R11 and R12 form, together with the carbonylamino group which carries them, a 4-membered to 7-membered, saturated, partially unsaturated or aromatic heterocyclic ring which can be substituted by one or more identical or different substituents R15 and which, in addition to the carbonylamino group connecting R11 and R12, can contain one or two further ring members chosen from ═N—, —N(R4)-, —C(═O)—, —O—, —S—, —S(O)— and —S(O)2—, which can be identical or different, with the proviso that two ring members from the series —O—, —S—, —S(O)—, —S(O)2— cannot be present in adjacent ring positions;
• R14 and R15 are independently chosen from halogen, (C1-C6)-alkyl, (C1-C6)-alkoxy and trifluoromethyl;
• and
• n is chosen from 0, 1, 2, 3, 4 and 5;
• or a physiologically acceptable salt thereof.