Claims
- 1. A compound of the formula: whereinR1 is carboxy or protected carboxy, R2 is aryl which may have suitable substituent(s), R3 is aryl which may have suitable substituent(s), R4 is hydrogen, lower alkyl, hydroxy or aryl, A1 is lower alkylene, (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have suitable substituent(s)) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, lower alkyl or acyl) and A6 is lower alkylene which may have suitable substituent(s)], and n is 0 or 1, and a pharmaceutically acceptable salt thereof.
- 2. A compound of claim 1, whereinR2 is phenyl or lower alkylphenyl, R3 is phenyl or lower alkylphenyl, R4 is hydrogen, lower alkyl, hydroxy or phenyl, and —A3— is (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one to three suitable substituent(s) selected from the group consisting of imino, oxo, acyl and imino protective group) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, lower alkyl or acyl) and A6 is lower alkylene which may have one to three suitable substituent(s) selected from the group consisting of lower alkyl and hydroxy(lower)alkyl].
- 3. A compound of claim 2, wherein (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or two suitable substituent(s) selected from the group consisting of imino, oxo, lower alkanoyl and mono(or di or tri)phenyl(lower)alkyl) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, lower alkyl or lower alkanoyl) and A6 is lower alkylene which may have a suitable substituent selected from the group consisting of lower alkyl and hydroxy(lower)alkyl].
- 4. A compound of claim 3, whereinR1 is carboxy or esterified carboxy, and (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicyclo[2.2.1]heptane, bicyclo(2.2.1]hept-2-ene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or two suitable substituent(s) selected from the group consisting of imino, oxo, lower alkanoyl and phenyl(lower)alkyl) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, lower alkyl or lower alkanoyl) and A6 is lower alkylene which may have a suitable substituent selected from the group consisting of lower alkyl and hydroxy(lower)alkyl].
- 5. A compound of claim 4, whereinR1 is carboxy or lower alkoxycarbonyl, R2 is phenyl or C1-C4 alkylphenyl, R3 is phenyl or C1-C4 alkylphenyl, R4 is hydrogen, C1-C4 alkyl, hydroxy or phenyl, A1 is C1-C4 alkylene, and —A3— is (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicyclo[2.2.1]heptane, bicyclo[2.2.l]hept-2-ene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or two suitable substituent(s) selected from the group consisting of imino, oxo, C1-C4 alkanoyl and phenyl(C1-C4)alkyl) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, C1-C4 alkyl or C1-C4 alkanoyl) and A6 is C1-C4 alkylene which may have a suitable substituent selected from the group consisting of C1-C4 alkyl and hydroxy-(C1-C4)alkyl].
- 6. A compound of claim 1, which is a compound of the formula: whereinR1 is carboxy or protected carboxy, R2 is phenyl or lower alkylphenyl, R3 is phenyl or lower alkylphenyl and A1 is lower alkylene, or a pharmaceutically acceptable salt thereof.
- 7. A compound of claim 6, which is selected from the group consisting of(1) sodium salt of (1R)-1-[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-carboxymethoxy-1,2,3,4-tetrahydronaphthalene and (2) sodium salt of (1S)-1-[(2S)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]-5-carboxymethoxy-1,2,3,4-tetrahydronaphthalene.
- 8. A compound of claim 1, which is a compound of the formula: whereinR1 is carboxy or protected carboxy, R2 is phenyl or lower alkylphenyl, R3 is phenyl or lower alkylphenyl and A1 is lower alkylene, or a pharmaceutically acceptable salt thereof.
- 9. A compound of claim 8, which is selected from the group consisting of(1) sodium [3-[[(2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]methyl]phenoxy]acetate and (2) sodium [3-[[(2S)-2-(4,5-diphenyloxazol-2-yl)pyrrolidin-1-yl]methyl]phenoxy]acetate.
- 10. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers.
- 11. A method for treating or preventing arterial obstruction, restenosis after percutaneous transluminal coronary angioplasty, hepatitis, hepatic insufficiency, hepatic cirrhosis, arteriosclerosis, cerebrovascular disease or ischemic heart disease which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to humans or animals.
- 12. The method of claim 11, wherein said compound is a prostaglandin I2 agonist.
- 13. A method for agonising prostaglandin I2 activity, which comprises administering an effective amount of a compound of claim 1 or pharmaceutically acceptable salts thereof to human or animals.
- 14. A method for inhibiting platelet aggregation, which comprises administering an effective amount of a compound of claim 1 or pharmaceutically acceptable salts thereof to human or animals.
- 15. A method for suppressing blood pressure, which comprises administering an effective amount of a compound of claim 1 or pharmaceutically acceptable salts thereof to humans or animals.
- 16. A process for preparing a compound of the formula: whereinR1 is carboxy or protected carboxy, R2 is aryl which may have suitable substituent(s), R3 is aryl which may have suitable substituent(s), R4 is hydrogen, lower alkyl, hydroxy or aryl, A1 is lower alkylene, (in which —A4— is bond, —CH2— or —CO—, and is cyclo(C5-C8)alkene, cyclo(C7-C8)alkane, bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have suitable substituent(s)) or —X—A6— [in which —X— is —O—, —S— or (in which R5 is hydrogen, lower alkyl or acyl) and A6 is lower alkylene which may have suitable substituent(s)], and n is 0 or 1, or a salt thereof, which comprises (1) reacting a compound of the formula: wherein R2, R3, R4, and —A3— are each as defined above, or a salt thereof with a compound of the formula:Y1—A1—R1 wherein R1 and A1 are each as defined above, and Y1 is acid residue, or a salt thereof to give a compound of the formula: wherein R1, R2, R3, R4, A1, and —A3— are each as defined above, or a salt thereof, or(2) subjecting a compound of the formula: wherein R2, R3, R4, n, A1, and —A3— are each as defined above, andRa1 is protected carboxy, or a salt thereof to elimination reaction of the carboxy protective group to give a compound of the formula: wherein R2, R3, R4, n, A1, and —A3— are each as defined above, or a salt thereof, or(3) subjecting a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, or a salt thereof to oxidation reaction to give a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, or a salt thereof, or(4) subjecting a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, andR6 is imino protective group, or a salt thereof to elimination reaction of the imino protective group to give a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, or a salt thereof, or(5) subjecting a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, and is cyclo(C7-C8)alkene, or a salt thereof to reduction reaction to give a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, and is cyclo(C7-C8)alkane, or a salt thereof, or(6) reacting a compound of the formula: wherein R1, R4, n, A1, and —A4— are each as defined above, andY2 is halogen, or a salt thereof with a compound of the formula: wherein R2 and R3 are each as defined above, or a salt thereof to give a compound of the formula: wherein R1, R2, R3, R4, n, A1, and —A4— are each as defined above, or a salt thereof.
- 17. A process for preparing a pharmaceutical composition which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.
Priority Claims (2)
Number |
Date |
Country |
Kind |
9515085 |
Jul 1995 |
GB |
|
PN9002 |
Mar 1996 |
AU |
|
Parent Case Info
This application is a Div. of Ser. No. 08/983,139 filed Jan. 21, 1998 now U.S. Pat. No. 5,972,965.
US Referenced Citations (3)
Number |
Name |
Date |
Kind |
5348969 |
Romine et al. |
Sep 1994 |
|
5763489 |
Taniguchi et al. |
Jun 1998 |
|
5863918 |
Taniguchi et al. |
Jan 1999 |
|
Foreign Referenced Citations (2)
Number |
Date |
Country |
0434034 |
Jun 1991 |
EP |
9517393 |
Jun 1995 |
WO |