Adenosine receptor ligands and their use in the treatment of disease

A method of treatment of a disease state caused by malfunction of the adenosine receptor system comprising administering to a patient in need of such treatment, an effective amount of a composition for treating said disease state, said composition containing a compound that binds to an adenosine receptor and a pharmaceutically acceptable carrier, said compound having the formula:

• 35
• wherein
• A is selected from the group consisting of a bond, —S—, —N(R)—, —(CH2)2—, —CH═CH—, —C≡C— or —O—;
• X and Y each are independently selected from the group consisting of —N═, ═N—,
• —CH═, ═CH—, —C(cyano)═, ═C(cyano)—, —C[C(S)—NH2]═, and ═C[C(S)-NH2]—, wherein at least one of X and Y is nitrogen;
• R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen, cyano, cycloalkyl,
• —(CH2)n—C(O)O-lower alkyl,
• —(CH2)n—C(O)O-lower alkyl-phenyl,
• —(CH2)n—NH—C(O)O-lower alkyl-phenyl,
• —(CH2)n—O-lower alkyl,
• —(CH2)n—O-phenyl,
• —(CH2)n—NH-phenyl,
• —(CH2)n—phenyl,
• —(CH2)n-phenyl substituted by 1 or 2 substituents selected from the group consisting of hydroxy, lower alkoxy, lower alkyl, CF3-lower alkenyl, halogen, CF3, OCF3, and amino,
• —(CH2)n-N-di-lower alkyl, —C(O)NH-lower alkyl, —S(O)2-lower alkyl,
• —(CH2)n-morpholinyl,
• —(CH2)n-amino,
• —(CH2)n-amino substituted by lower alkyl or benzyl,
• —(CH2)n-piperidin-1-yl or —(CH2)n-piperidin-3-yl,
• —(CH2)n-piperidin-1-yl or —(CH2)n-piperidin-3-yl, substituted by lower alkyl,
• —(CH2)n-pyridin-2-yl, —(CH2)n-pyridin-3-yl, —(CH2)n-pyridin-4-yl,
• —(CH2)n-pyridin-2-yl, —(CH2)n-pyridin-3-yl or —(CH2)n-pyridin-4-yl, substitutedtby 1 or 2 substituents, selected from lower alkyl, hydroxy, nitro, cyano, halogen, CF3 or
• —OC(O)N(R)2,
• —(CH2)n—NH-pyridin-2-yl,
• —(CH2)n—NH-pyridin-2-yl, substituted by lower alkyl, halogen,
• —(CH2)n-piperazin-4-yl,
• —(CH2)n-piperazin-4-yl, substituted by lower alkyl, phenyl or carbonyl-phenyl,
• —(CH2)n-phenyl-OC(O)-phenyl,
• —(CH2)n-phenyl—OC(O)-phenyl substituted by halogen, the group 36
• —(CH2)n—S-phenyl or —(CH2)n—S(O)2-phenyl,
• —(CH2)n—S-lower alkyl,
• —(CH2)n(CH═CH)m-phenyl,
• —(CH2)n(CH═CH)m-phenyl,
• —(CH2)n—NH-cycloalkyl,
• —(CH2)n—NH-phenyl,
• —(CH2)n—NH-phenyl, substituted by amino or nitro,
• —(CH2)n-tetrahydro-pyran-4-yl,
• —(CH2)n-quinolin-2-yl,
• —(CH2)n-naphthyl or —(CH2)n—NH-naphthyl,
• —(CH2)n-3,4-dihydro-1H-isoquinolin-2-yl,
• —(CH2)n-benzo[1,3]dioxolyl,
• —(CH2)n—NH—S(O)2-phenyl,
• —(CH2)n—NH—S(O)2-phenyl substituted by halogen,
• —(CH2)n-1,2,3,4-tetrahydro-quinolin-2-yl,
• —(CH2)n-1,2,3,4-tetrahydro-quinolin-2-yl, substituted by lower alkyl or
• —(CH2)n-furanyl;
• R2 is selected from the group consisting of hydrogen, halogen, cyano, nitro, lower alkyl, lower alkenyl, —C(O)-lower alkyl, —C(O)O-lower alkyl, —C(O)O-lower alkyl-phenyl, lower alkynyl-phenyl, lower alkenyl—C(O)O-lower alkyl, lower alkenyl-cyano or phenyl, —C(O)O-lower alkyl, —C(O)O-lower alkyl-phenyl, lower alkynyl-phenyl, lower alkenyl-C(O)O-lower alkyl, lower alkenyl-cyano or phenyl, substituted by halogen;
• R3 is selected from the group consisting of lower alkyl, phenyl, phenyl substituted by lower alkyl, lower alkoxy, or halogen,
• thien-2yl or fur-2yl, thien-2yl or fur-2yl,
• thien-2yl or fur-2yl, substituted by lower alkyl,
• S-lower alkyl, halogen, lower alkoxy, —C(O)O-lower alkyl, —C(═CH2)—O-lower alkyl,
• —(CH2)n-halogen, —(CH2)n—OH, —(CH2)n-lower alkoxy, cyano, CHF2, CH2F,
• 2,3-dihydro-benzo[1.4]dioxin-6-yl,
• benzo[1.3]dioxol-5-yl,
• isoxazol-5-yl, pyridin-2-yl, pyridin-3-yl,
• —C(═CH2)O-lower alkyl,
• 4,5-dihydrofuran-2-yl,
• 5,6-dihydro-4H-pyran-2-yl,
• oxazol-2-yl,
• benzofuranyl,
• pyrazin-2-yl,
• —O—(CH2)n-phenyl,
• —O—(CH2)n-pyridyl,
• —O—(CH2)n-pyridyl substituted by lower alkyl,
• —S—(CH2)n-pyridyl,
• pyrazol-1-yl,
• pyrazol-1-yl substituted by lower alkyl or halogen;
• R4 and R5 are independently from each other selected from the group consisting of hydrogen, —CO—(CH2)n—phenyl, optionally substituted by halogen or —CH2N(R)(CH2)n-lower alkyl, phenyl, phenyl substituted by lower alkoxy, or —C(O)-phenyl;
• R is selected from the group consisting of hydrogen or lower alkyl;
• and A and R2 may be together with the two carbon atoms 37
• and wherein
• n is , 1, 2, 3 or 4;
• m is 1 or 2;
• and pharmaceutically acceptable salts thereof.