Claims for Patent: 7,205,302

Summary for Patent: 7,205,302

Title:	Heterocyclic compound derivatives and medicines
Abstract:	The present invention provides a compound which is useful as a PGI2 receptor agonist, and a pharmaceutical composition.
Inventor(s):	Tetsuo Asaki, Taisuke Hamamoto, Keiichi Kuwano
Assignee:	Nippon Shinyaku Co Ltd
Application Number:	US10/476,196
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 7,205,302
Patent Claims:	1. A pharmaceutical composition comprising a heterocyclic compound represented by the following general formula (1) or a salt thereof as an active ingredient: wherein R1 and R2 are the same or different and each represents an optionally substituted aryl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro, Y represents N or N→O, Z represents CR6; and R6 represents hydrogen, alkyl, or halogen, A represents NR7 or SO, and R7 represents hydrogen, alkyl, alkenyl or cycloalkyl, D represents alkylene or alkenylene which are optionally substituted with hydroxy, or A and D are combined with each other to form a divalent group represented by the following formula (2): r represents an integer of 0 to 2, q represents an integer of 2 to 3, and t represents an integer of 0 to 4, E represents phenylene or single bond, or D and E are combined with each other to form a divalent group represented by the following formula (3): u represents an integer of 0 to 2, and v represents 0 or 1, G represents O, S, SO, SO2, or C(R8)(R9), and R8 and R9 are the same or different and each represents hydrogen or alkyl, R3 and R4 are the same or different and each represents hydrogen or alkyl, Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by the following formula (22): R10 represents amino, monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro; and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to claim 1, wherein, in the formula (1), R1 and R2 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and alkoxy, Y and Z correspond to either of the following cases (1) and (2): (1) Y is N, and Z is CH, and (2) Y is N→O, and Z is CH, A represents NR7, and R7 represents hydrogen, alkyl, or cycloalkyl, D represents alkylene or alkenylene, E represents single bond, G represents O, S, SO, SO2, or C(R8)(R9), and R8 and R9 each represents hydrogen, R3 and R4 are the same or different and each represents hydrogen or alkyl, and Q represents carboxy, alkoxycarbonyl, tetrazolyl, or a group represented by the formula (22), and R10 represents amino, monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 3. The pharmaceutical composition according to claim 1, wherein, in the formula (1), R1 and R2 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and alkoxy, Y is N, and Z is CH, A represents NR7, and R7 represents hydrogen or alkyl, D represents alkylene, E represents single bond, G represents O, R3 and R4 are the same or different and each represents hydrogen or alkyl, Q represents carboxy, tetrazolyl, or a group represented by the formula (22), and R10 represents amino, monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 4. The pharmaceutical composition according to claim 1, wherein, in the formula (1), R1 and R2 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and alkoxy, Y represents N, and Z represents CH, A represents NR7, and R7 represents alkyl, D represents alkylene, E represents single bond, G represents O, R3 and R4 are the same or different and each represents hydrogen or alkyl, and Q represents carboxy or a group represented by the formula (22), and R10 represents amino monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 5. The pharmaceutical composition according to claim 1, wherein the hetero cyclic compound is selected from the group consisting of the following compounds (1) to (27): (1) 2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid, (2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid, (3) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, (4) 2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, (5) 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine 1-oxide, (6) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid, (7) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic acid, (8) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}acetic acid, (9) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acid, (10) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}acetic acid, (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide, (12) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide, (13) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide, (14) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide, (15) N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (16) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (17) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide, (18) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide, (19) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide, (20) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (21) N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (22) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide, (23) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide, (24) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid phenyl ester, (25) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid, (26) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid sodium salt, and (27) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide. 6. A method of inhibiting platelet aggregation, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1. 7. A method of treating arteriosclerosis obliterans, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1. 8. A method of treating intermittent claudication, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1. 9. A method of treating peripheral arterial embolism, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1. 10. A heterocyclic compound represented by the following general formula (1z) or a salt thereof: wherein: R91 and R92 are the same or different and each represents optionally substituted aryl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro, Y9 represents N or N→O, Z9 represents CR96, and R96 represents hydrogen, alkyl, or halogen, A9 represents NR97 or SO, and R97 represents hydrogen, alkyl, alkenyl, or cycloalkyl, D9 represents alkylene or alkenylene which are optionally substituted with bydroxy, or A9 and D9 are combined with each other to form a divalent group represented by the following formula (2z): m represents an integer of 0 to 2, k represents an integer of 2 to 3, and n represents an integer of 0 to 4, E9 represents phenylene or single bond, or D9 and E9 are combined with each other to form a divalent group represented by the following formula (3z): w represents an integer of 0 to 2, and x represents 0 or 1, G9 represents O, S, SO, SO2, or C(R98)(R99), and R98 and R99 are the same or different and each represents hydrogen or alkyl, R93 and R94 are the same or different and each represents hydrogen or alkyl, Q9 represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by the following formula (22z): R910 represents amino, monoalkylamino, dialkylaxuino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 11. The heterocyclic compound according to claim 10, wherein, in the formula (1z), substituents correspond to the following case: R91 and R92 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and. alkoxy, Y9 and Z9correspond to either of the following cases (1) and (2): (1) Y9 is N, and Z9 is CH, and (2) Y9 is N→O, and Z9 is CH, A9 represents NR97, and R97 represents hydrogen, alkyl, or cycloalkyl, D9 represents alkylene, E9 single bond, G9 represents O, S. SO, SO2, or C(R98)(R99), and R98 and R99 each represents hydrogen, R93 and R94 are the same or different and each represents hydrogen or alkyl, and Q9 represents carboxy, alkoxycarbonyl, tetrazolyl, or a group represented by the formula (22z), R910 represents amino, monoalkylarnino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 12. The heterocyclic compound according to claim 10, wherein, in the formula (1z), R91 and R92 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and alkoxy, Y9 represents N, Z9 represents CH, A9 represents NR97, and R97 represents hydrogen or alkyl, D9 represents alkylene, E9 represents single bond, G9 represents O, R93 and R94 are the same or different and each represents hydrogen or alkyl, Q9 represents carboxy, tetrazolyl, or a group represented by the formula (22z), R910 represents amino, monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionally substituted aryloxy, or optionally substituted heterocyclic group, and the substituents of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 13. The heterocyclic compound according to claim 10, wherein R91 and R92 are the same or different and each represents optionally substituted phenyl, and the substituents are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl and alkoxy, Y9 represents N, and Z9 represents CH, A9 represents NR97, and R97 represents alkyl, D9 represents alkylene, E9 single bond, G9 represents O, R93 and R94 are the same or different and each represents hydrogen or alkyl, Q9 represents carboxy or a group represented by the formula (22z), R910 represents amino, monoalkylamino, dialkylamino, hydroxy, optionally substituted alkyl, optionally substituted aryl, optionaiiy substituted aryloxy, or optionally substituted heterocyclic group, and the substitunets of alkyl, aryl, aryloxy or heterocyclic group are the same or different and 1 to 3 substituents are selected from the group consisting of halogen, alkyl, haloalkyl, arylalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylsulfonyl, hydroxy, amino, monoalkylamino, dialkylamino, carboxy, cyano and nitro. 14. The heterocyclic compound according to claim 10, wherein the heterocyclic compound is selected from the following compounds (1) to (27): (1) 2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid, (2) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]butyloxy}acetic acid, (3) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, (4) 2-{4-[N-(5,6-di-p-tolylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid, (5) 2,3-diphenyl-5-{N-[4-(carboxymethoxy)butyl]-N-methylamino}pyrazine 1-oxide, (6) 7-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]heptanoic acid, (7) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylthio}acetic acid, (8) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}acetic acid, (9) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-ethylamino]butyloxy}acetic acid, (10) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butylsulfinyl}acetic acid, (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluenesulfonyl)acetamide, (12) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropylsulfonyl)acetamide, (13) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluoromethanesulfonyl)acetamide, (14) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluenesulfonyl)acetamide, (15) N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (16) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (17) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methoxybenzenesulfonyl)acetamide, (18) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluorobenzenesulfonyl)acetamide, (19) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thiophenesulfonyl)acetamide, (20) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (21) N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetamide, (22) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholin-4-ylsulfonyl)acetamide, (23) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolidin-1-ylsulfonyl)acetamide, (24) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid phenyl ester, (25) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid, (26) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]sulfamic acid sodium salt, and (27) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsulfonyl)acetamide. 15. A method of treating pulmonary hypertension, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition according to claim 1.