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 PGI.sub.2 receptor agonist, and a pharmaceutical composition. The present invention is directed to a pharmaceutical composition comprising a compound represented by the following formula [1]: ##STR00001## (R.sup.1 and R.sup.2 are the same or different and each represents optionally substituted aryl, Y represents N or CH, Z represents N or CH, A represents NH, NR.sup.5, O, S, or ethylene, R.sup.5 represents alkyl, D represents alkylene or alkenylene, E represents phenylene or single bond, G represents O, S, or CH.sub.2, R.sup.3 and R.sup.4 are the same or different and each represents hydrogen or alkyl, Q represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, or N-(alkylsulfonyl)carbamoyl), or a pharmaceutically acceptable salt thereof as an active ingredient.
Inventor(s):	Asaki; Tetsuo (Kyoto, JP), Hamamoto; Taisuke (Osaka, JP), Kuwano; Keiichi (Osaka, JP)
Assignee:	Nippon Shinyaku Co., Ltd. (Kyoto, JP)
Application Number:	10/476,196
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: ##STR00030## wherein R.sup.1 and R.sup.2 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.fwdarw.O, Z represents CR.sup.6; and R.sup.6 represents hydrogen, alkyl, or halogen, A represents NR.sup.7 or SO, and R.sup.7 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): ##STR00031## 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): ##STR00032## u represents an integer of 0 to 2, and v represents 0 or 1, G represents O, S, SO, SO.sub.2, or C(R.sup.8)(R.sup.9), and R.sup.8 and R.sup.9 are the same or different and each represents hydrogen or alkyl, R.sup.3 and R.sup.4 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): ##STR00033## R.sup.10 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), R.sup.1 and R.sup.2 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.fwdarw.O, and Z is CH, A represents NR.sup.7, and R.sup.7 represents hydrogen, alkyl, or cycloalkyl, D represents alkylene or alkenylene, E represents single bond, G represents O, S, SO, SO.sub.2, or C(R.sup.8)(R.sup.9), and R.sup.8 and R.sup.9 each represents hydrogen, R.sup.3 and R.sup.4 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 R.sup.10 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), R.sup.1 and R.sup.2 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 NR.sup.7, and R.sup.7 represents hydrogen or alkyl, D represents alkylene, E represents single bond, G represents O, R.sup.3 and R.sup.4 are the same or different and each represents hydrogen or alkyl, Q represents carboxy, tetrazolyl, or a group represented by the formula (22), and R.sup.10 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), R.sup.1 and R.sup.2 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 NR.sup.7, and R.sup.7 represents alkyl, D represents alkylene, E represents single bond, G represents O, R.sup.3 and R.sup.4 are the same or different and each represents hydrogen or alkyl, and Q represents carboxy or a group represented by the formula (22), and R.sup.10 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}ac- etic 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}pyraz- ine 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}a- cetic acid, (8) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}ace- tic 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}ac- etic acid, (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluen- esulfonyl)acetamide, (12) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropy- lsulfonyl)acetamide, (13) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluor- omethanesulfonyl)acetamide, (14) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluen- esulfonyl)acetamide, (15) N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]b- utyloxy}acetamide, (16) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropy- lamino]butyloxy}acetamide, (17) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methox- ybenzenesulfonyl)acetamide, (18) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluoro- benzenesulfonyl)acetamide, (19) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thioph- enesulfonyl)acetamide, (20) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]but- yloxy}acetamide, (21) N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopro- pylamino]butyloxy}acetamide, (22) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholi- n-4-ylsulfonyl)acetamide, (23) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolid- in-1-ylsulfonyl)acetamide, (24) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid phenyl ester, (25) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid, (26) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid sodium salt, and (27) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsu- lfonyl)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: ##STR00034## wherein: R.sup.91 and R.sup.92 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, Y.sup.9 represents N or N.fwdarw.O, Z.sup.9 represents CR.sup.96, and R.sup.96 represents hydrogen, alkyl, or halogen, A.sup.9 represents NR.sup.97 or SO, and R.sup.97 represents hydrogen, alkyl, alkenyl, or cycloalkyl, D.sup.9 represents alkylene or alkenylene which are optionally substituted with bydroxy, or A.sup.9 and D.sup.9 are combined with each other to form a divalent group represented by the following formula (2z): ##STR00035## 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, E.sup.9 represents phenylene or single bond, or D.sup.9 and E.sup.9 are combined with each other to form a divalent group represented by the following formula (3z): ##STR00036## w represents an integer of 0 to 2, and x represents 0 or 1, G.sup.9 represents O, S, SO, SO.sub.2, or C(R.sup.98)(R.sup.99), and R.sup.98 and R.sup.99 are the same or different and each represents hydrogen or alkyl, R.sup.93 and R.sup.94 are the same or different and each represents hydrogen or alkyl, Q.sup.9 represents carboxy, alkoxycarbonyl, tetrazolyl, carbamoyl, monoalkylcarbamoyl, dialkylcarbamoyl, or a group represented by the following formula (22z): ##STR00037## R.sup.910 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: R.sup.91 and R.sup.92 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.sup.9 and Z.sup.9correspond to either of the following cases (1) and (2): (1) Y.sup.9 is N, and Z.sup.9 is CH, and (2) Y.sup.9 is N.fwdarw.O, and Z.sup.9 is CH, A.sup.9 represents NR.sup.97, and R.sup.97 represents hydrogen, alkyl, or cycloalkyl, D.sup.9 represents alkylene, E.sup.9 single bond, G.sup.9 represents O, S. SO, SO.sub.2, or C(R.sup.98)(R.sup.99), and R.sup.98 and R.sup.99 each represents hydrogen, R.sup.93 and R.sup.94 are the same or different and each represents hydrogen or alkyl, and Q.sup.9 represents carboxy, alkoxycarbonyl, tetrazolyl, or a group represented by the formula (22z), R.sup.910 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), R.sup.91 and R.sup.92 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.sup.9 represents N, Z.sup.9 represents CH, A.sup.9 represents NR.sup.97, and R.sup.97 represents hydrogen or alkyl, D.sup.9 represents alkylene, E.sup.9 represents single bond, G.sup.9 represents O, R.sup.93 and R.sup.94 are the same or different and each represents hydrogen or alkyl, Q.sup.9 represents carboxy, tetrazolyl, or a group represented by the formula (22z), R.sup.910 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 R.sup.91 and R.sup.92 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.sup.9 represents N, and Z.sup.9 represents CH, A.sup.9 represents NR.sup.97, and R.sup.97 represents alkyl, D.sup.9 represents alkylene, E.sup.9 single bond, G.sup.9 represents O, R.sup.93 and R.sup.94 are the same or different and each represents hydrogen or alkyl, Q.sup.9 represents carboxy or a group represented by the formula (22z), R.sup.910 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}ace- tic 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}a- cetic acid, (8) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-(Z)-2-buten-1-yloxy}ace- tic 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}ac- etic acid, (11) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(p-toluen- esulfonyl)acetamide, (12) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(isopropy- lsulfonyl)acetamide, (13) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(trifluor- omethanesulfonyl)acetamide, (14) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(o-toluen- esulfonyl)acetamide, (15) N-(benzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]b- utyloxy}acetamide, (16) N-(4-chlorobenzenesulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropy- lamino]butyloxy}acetamide, (17) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-methox- ybenzenesulfonyl)acetamide, (18) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(4-fluoro- benzenesulfonyl)acetamide, (19) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(2-thioph- enesulfonyl)acetamide, (20) N-(aminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]but- yloxy}acetamide, (21) N-(N,N-dimethylaminosulfonyl)-2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopro- pylamino]butyloxy}acetamide, (22) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(morpholi- n-4-ylsulfonyl)acetamide, (23) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(pyrrolid- in-1-ylsulfonyl)acetamide, (24) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid phenyl ester, (25) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid, (26) N-[2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetyl]su- lfamic acid sodium salt, and (27) 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}-N-(methylsu- lfonyl)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.