Patent EA-000987-B1 (EA)
Title: Bicyclic amino derivatives and pgd2 antagonists containing the same
Inventor: OHTANI MITSUAKI
IPC: C07C233/81
Filed: 1996-06-19
Abstract: 1. A compound of general formula (I), its salt or a hydrate thereof:    wherein    is a group of formula            or            A is alkylene which optionally comprises hetero atom or phenylene, contains oxo group and/or has an unsaturated bond; B is hydrogen, alkyl, aralkyl or acyl; R is COOR1, CH2OR2 or CON(R3)R4;  R1 is hydrogen or alkyl; R2 is hydrogen or alkyl; R3 and R4 each are independently hydrogen, alkyl, hydroxy or alkylsulfonyl;  X1 is a single bond, phenylene, naphthylene, thiophenediyl, indolediyl or oxazolediyl; X2 is a single bond, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-O-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C(Cl)=C(Cl)-, -(CH2)n-, ethynylene, -N(R5)-, -N(R51)CO-, -N(R52)SO2-, -N(R53)CON(R54)-, -CON(R55)- -SO2N(R56)-, -O-, -S-, -SO-, -SO2-, -CO-, oxadiisolediyl, thiadiazolediyl or tetrazolediyl;  X3 is alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic group, cycloalkyl, cycloalkenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, -CH=NR6 or -N=C(R7)R8;  R5, R51, R52, R53, R54, R55 and R56 each are hydrogen or alkyl;  R6 is hydrogen, alkyl, hydroxy, alkoxy, carbamoyloxy, thiocarbamoyloxy, ureido or thioureido;  R7 and R8 each are independently alkyl, alkoxy or aryl;  n is 1 or 2;  Z is -SO2- or -CO-; and  m is 0 or 1;  wherein a cyclic substituent may have from one to three substituents selected from the group consisting of nitro, alkoxy, sulfamoyl, substituted or unsubstituted amino group, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mezyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, -N=PPh3, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy, which are antagonists of prostaglandin PGD2. 2. The compound as claimed in claim 1, wherein   is the group of formula   m is 0; and Z is SO2, both X1 and X2 are a single bond; X3 is alkyl, phenyl, naphthyl, stylyl, quinolyl or thienyl; and a cyclic substituent among these substituents optionally has from one to three substituents selected from the group consisting of nitro, alkoxy, substituted or unsubstituted amino group, halogen, alkyl and hydroxyalkyl; or its salt or hydrate thereof. 3. The compound as claimed in claim 1, wherein   is the group of formula    when m is 1, both X1 and X2 are a single bond, X3 is phenyl optionally substituted with halogen; or its salt or hydrate thereof. 4. The compound as claimed in claim 1, wherein   is the group of formula    when m is 1, X1 is phenylene, X2 is -CH2- or -N=N- and X3 is phenyl; or its salt or hydrate thereof. 5. The compounds as claimed in claim 1, which are used for treating nasal occlusion. 6. A compound of the formula (Ia):   wherein A is alkylene, which optionally comprises hetero atom or phenylene, contains oxo group and/or has an unsaturated bond;  B is hydrogen, alkyl, aralkyl or acyl;  R is COOR1, CH2OR2 or CON(R3)R4;  R1 is hydrogen or alkyl;  R2 is hydrogen or alkyl;  R3 and R4 each are independently hydrogen, alkyl, hydroxy or alkylsulfonyl;  X1 is a single bond, phenylene, naphthylene, thiophenediyl, indolediyl or oxazolediyl;  X2 is a single bond, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-O-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C(Cl)=C(Cl)-, -(CH2)n-, ethynylene, -N(R5)-, -N(R51)CO-, -N(R52)SO2-, -N(R53)CON(R54)-, -CON(R55)-, -SO2N(R56)-, -O-, -S-, -SO-, -SO2-, -CO-, oxadiazolediyl, thiadiazolediyl or tetrazolediyl; X3 is alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic group, cycloalkyl, cycloalkenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, -CH=NR6 or -N=C(R7)R8;  R5, R51, R52, R53, R54, R55 and R56 each are hydrogen or alkyl;  R6 is hydrogen, alkyl, hydroxy, alkoxy, carbamoyloxy, thiocarbamoyloxy, ureido or thioureido;  R7 and R8 each are independently alkyl, alkoxy or aryl;  n is 1 or 2;  wherein a cyclic substituent may have from one to three substituents selected from the group consisting of nitro, alkoxy, sulfamoyl, substituted or unsubstituted amino group, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mezyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, -N=PPh3, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy; their salts or hydrates thereof, provided that the compounds, wherein (1) X1 and X2 are a single bond and X3 is substituted or unsubstituted phenyl or naphthyl;  (2) A is 5-heptenylene, R is COOR1 (R1 is hydrogen or methyl), X1 is 1,4-phenylene, X2 is a single bond and X3 is unsubstituted phenyl;  (3) X1 and X2 are a single bond, X3 is methyl, n-hexyl, 2-cyclohexylethyl, benzyl, phenethyl, or substituted or unsubstituted alkenyl; and (4) X1 and X2 are a single bond and X3 is pyridyl are excluded. 7. The compound of claim 6, its salt or hydrate thereof, wherein X1 and X2 are a single bond, X3 is isoxazolyl, thiadiazolyl, isothiazolyl, morpholyl, indolyl, benzofuryl, dibenzofuryl, dibenzodioxynyl, benzothienyl, dibenzothienyl, carbazolyl, xanthenyl, phenanthridinyl, dibenzoxepinyl, dibenzothiepinyl, cinnolyl, chromenyl, benzimidazolyl, dihydrobenzothiepinyl, dibenzopyranyl. 8. The compound of claim 6, its salt or hydrate thereof, wherein X2 is a single bond, X1 is phenylene, X3 is alkenyl, alkynyl, -CH=NR6 or -N=C(R7)R8. 9. The compound of claim 6, its salt or hydrate thereof, wherein R is COOR1, X1 is phenylene, thiophenediyl or indolediyl, X2 is a single bond, -N=N-, -CH=CH-, -CONH-, -NHCO-, ethynylene, -N=CH-, -(CH2)n- (n is as defined above), -N(R5)- (R5 is as defined above), -O-, -S-, -SO2-, -CO-, oxadiazolediyl or tetrazolediyl; X3 is phenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, thienyl, cyclohexyl, 1-cyclohexenyl, n-hexyl, indolyl or benzoxazolyl. 10 . A compound of the formula (Ib):    wherein    is the group of the formula   wherein A is alkylene which optionally comprises hetero atom or phenylene, contains oxo group and/or has an unsaturated bond; B is hydrogen, alkyl, aralkyl or acyl; R is COOR1, CH2OR2 or CON(R3)R4;  R1 is hydrogen or alkyl; R2 is hydrogen or alkyl; R3 and R4 each are independently hydrogen, alkyl, hydroxy or alkylsulfonyl; X1 is a single bond, phenylene, naphthylene, thiophenediyl, indolediyl or oxazolediyl; X2 is a single bond, -N=N-, -N=CH-, -CH=N-, -CH=N-N-, -CH=N-O-, -C=NNHCSNH-, -C=NNHCONH-, -CH=CH-, -CH(OH)-, -C(Cl)=C(Cl)-, -(CH2)n-, ethynylene, -N(R5)-, -N(R51)CO-, -N(R52)SO2-, -N(R53)CON(R54)-, -CON(R55)-, -SO2N(R56)-, -O-, -S-, -SO-, -SO2-, -CO-, oxadiazolediyl, thiadiazolediyl or tetrazolediyl;  X3 is alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclic group, cycloalkyl, cycloalkenyl, thiazolinylidenemethyl, thiazolidinylidenemethyl, -CH=NR6 or -N=C(R7)R8; R5, R51, R52, R53, R54, R55 and R56 each are hydrogen or alkyl; R6 is hydrogen, alkyl, hydroxy, alkoxy, carbamoyloxy, thiocarbamoyloxy, ureido or thioureido; R7 and R8 each are independently alkyl, alkoxy or aryl;  n is 1 or 2;  wherein a cyclic substituent may have from one to three substituents selected from the group consisting of nitro, alkoxy, sulfamoyl, substituted or unsubstituted amino group, acyl, acyloxy, hydroxy, halogen, alkyl, alkynyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, mezyloxy, cyano, alkenyloxy, hydroxyalkyl, trifluoromethyl, alkylthio, -N=PPh3, oxo, thioxo, hydroxyimino, alkoxyimino, phenyl and alkylenedioxy, or their salts or hydrates thereof, provided that compounds, wherein X1 and X2 are a single bond and X3 is unsubstituted phenyl, and wherein X1 is a single bond, X2 is -O- and X3 is benzyl, are excluded. 11. The compound of claim 10, its salt or hydrate thereof, wherein    is the group of the formula   12. The compound of claim 11, its salt or hydrate thereof, wherein R is COOR1. 13. The compound of claim 11, its salt or hydrate thereof, wherein X1 is phenylene or thiophenediyl, X2 is a single bond, -N=N-, -CH=CH-, ethynylene, -O-, -S-, -CO-, -CON(R55)-, -N(R51)CO-and X3 is phenyl or thienyl. 14. The compound of claim 10, its salt or hydrate thereof, wherein    is the group of the formula   15. The compound of claim 14, its salt or hydrate thereof, wherein B is hydrogen, both X1 and X2 are a single bond, X3 is thienyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrrolyl, pyridyl, benzofuryl, benzimidazolyl, benzothienyl, dibenzofuryl, dibenzothienyl, quinolyl or indolyl. 16. The compound of claim 14, its salt or hydrate thereof, wherein X1 is phenylene, thiophenediyl, indolediyl or oxazolediyl, X2 is a single bond, -N=N-, -CH=CH-, ethynylene, -S- or -O- and X3 is aryl or heterocyclic group. 17. The compound of claim 10, its salt or hydrate thereof, wherein    is the group of the formula   A is is alkylene which optionally comprises oxo group and/or has an unsaturated bond; B is hydrogen; R is COOH or CH2OH;  X1 is a single bond;  X3 is substituted or unsubstituted benzothienyl.