Patent EA-002156-B1 (EA)
Title: 4,5-diaryl oxazole derivatives, process for preparing and use as medicaments
Inventor: TANIGUCHI KIYOSHI
IPC: C07D413/04
Filed: 1996-07-18
Abstract: 1. A compound of the formula:   wherein R<1> is carboxy or protected carboxy, R<2> is aryl or substituted aryl, R<3> is aryl or substituted aryl, R<4> is hydrogen, C1-C6 alkyl, hydroxy or aryl, A<1> is C1-C6 alkylene,   -A<3>- is   (in which -A<4>- is bond, CH2 - or -CO-, and   is cyclo(C5-C8)alken, cyclo(C7-C8)alkan, bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or more suitable substituents), or -X-A<6>- [ wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C6-alkyl or acyl) and A<6> is lower alkylene which can be substituted with one or more acceptable substituents], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or more suitable substituents), and  n is 0 or 1, and a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1, wherein R<2> is phenyl or C1-C6 -alkylphenyl, R<3> is phenyl or C1-C6 -alkylphenyl, R<4> is hydrogen, C1-C6 -alkyl, hydroxy or phenyl, and    -A<3>- is   (in which -A<4>- is bond, CH2- or -CO-, and   is bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one to three substituents, selected from the group consisting of imino-, oxo-, hydroxy-, acyl and iminoprotective group) or -X-A<6>- [wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C6-alkyl or acyl) and A<6> is C1-C6-alkylene which can be substituted with one to three substituents, selected from the group, comprising C1-C6-alkyl and hyrdoxy-C1-C6-alkyl], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or more substituents, selected from the group consisting of imino-, oxo-, hydroxy-, acyl and iminoprotective groups). 3. A compound of Claim 2, wherein   -A<3>- is   (in which -A<4>- is bond, CH2- or -CO-, and   is bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or two substituents, selected from the group consisting of imino, oxo, hydroxy, C1-C6-alkanoyl and mono- (or di-, or three)phenyl(C1-C6)alkyl or -X-A<6>- [wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C6-alkyl or C1-C6-alkanoyl) and A<6> is C1-C6-alkylene which can have a substituent, selected from the group, comprising C1-C6-alkyl and hyrdoxy-C1-C6-alkyl], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is 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 more substituents, selected from the group consisting of imino-, oxo-, hydroxy-, C1-C6-alkanoyl and mono- (or di-, or three)phenyl(C1-C6)alkyl). 4. A compound of Claim 3, wherein R<1> is carboxy or esterified carboxy, and  , -A<3>- is   (in which -A<4>- is bond, CH2- or -CO-, and   is 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 substituents, selected from the group consisting of imino, oxo, hydroxy, C1-C6-alkanoyl and phenyl(C1-C6)alkyl) or -X-A<6>- [wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C6-alkyl or C1-C6-alkanoyl) and A<6> is C1-C6-alkylene which can have a substituent, selected from the group, comprising C1-C6-alkyl and hyrdoxy-C1-C6-alkyl], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is 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 more substituents, selected from the group consisting of imino-, oxo-, hydroxy-, C1-C6-alkanoyl and mono- (or di-, or three)phenyl(C1-C6)alkyl). 5. A compound of Claim 4, wherein R<1> is carboxy or C1-C6-alkoxycarbonyl, R<2> is phenyl or C1-C4-alkylphenyl, R<3> is phenyl or C1-C4-alkylphenyl, R<4> is hydrogen, C1-C4-alkyl, hydroxy or phenyl, A<1> is C1-C2-alkylene, and   -A<3>- is   (in which -A<4>- is bond, CH2- or -CO-, and   is 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 substituents, selected from the group consisting of imino, hydroxy, oxo, C1-C4-alkanoyl and phenyl(C1-C4)alkyl) or -X-A<6>- [wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C4-alkyl or C1-C4-alkanoyl) and A<6> is C1-C4-alkylene which can have a substituent, selected from the group, comprising C1-C4-alkyl and hyrdoxy-C1-C4-alkyl], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is 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 more substituents, selected from the group consisting of imino-, oxo-, hydroxy-, C1-C4-alkanoyl and phenyl(C1-C4)alkyl). 6. A compound of Claim 1, which is a compound of the formula:   wherein R<1> is carboxy or protected carboxy, R<2> is phenyl or C1-C6-alkylphenyl, R<3> is phenyl or C1-C6-alkylphenyl and A<1> is C1-C6-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 of the formula:   wherein R<1> is carboxy or protected carboxy, R<2> is phenyl or C1-C6-alkylphenyl, R<3> is phenyl or C1-C6-alkylphenyl and A<1> is C1-C6-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. 9. A process for preparing a compound of the formula:   wherein R<1> is carboxy or protected carboxy, R<2> is aryl or substituted aryl, R<3> is aryl or substituted aryl, R<4> is hydrogen, C1-C6 alkyl, hydroxy or aryl, A<1> is C1-C6 alkylene,   -A<3>- is   (in which -A<4>- is bond, CH2- or -CO-, and   is bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or more suitable substituents), or -X-A<6>- [wherein -X- is -O-, -S- or   (wherein R<5> is hydrogen, C1-C6-alkyl or acyl) and A<6> is C1-C6-alkylene which can be substituted with one or more acceptable substituents], with proviso that when   is  , then -A<3>- is   (wherein -A<4>- is -CH2- or -CO-, and   is bicycloheptane, bicycloheptene, tetrahydrofuran, tetrahydrothiophene, azetidine, pyrrolidine or piperidine, each of which may have one or more suitable substituents), and n is 0 or 1, and salts thereof, characterised in that the compound of formula:   wherein each of R<2>, R<3>, R<4>, n, A<1>,   and -A<3>- has the above-mentioned meanings or salts thereof. 11. A pharmaceutical composition which comprises, as an active ingredient, a compound of Claim 1 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carriers. 12. The use of compound of Claim 1 or a pharmaceutically acceptable salt thereof as a prostaglandin I2 agonist. 13. 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. 14. A process for modulation of a prostaglandin I2 activity by treating its antagonist, comprising administering an effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof to humans or animals. 15. A process for inhibition of platelets aggregation which comprises administering an effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof to humans or animals. 16. A process for blood pressure suppression which comprises administering an effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof to humans or animals.