Claims
- 1. A pharmaceutical composition for ophthalmic administration comprising a compound of the formula: wherein X1 is C—R6,X2 is C—R7, X3 is C—R8, R1 is hydrogen or halogen, R2 is halogen, R3 is hydrogen; nitro; amino; amino substituted with substituent(s) selected from the group consisting of lower alkyl, acyl, ar(lower)alkyl, carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl and heterocyclic(lower)alkyl; or a heterocyclic group optionally substituted with subtituent(s) selected from the group consisting of halogen, lower alkyl, acyl, aryl, oxo, nitro, amino, ar(lower)alkyl and lower alkoxycarbonyl(lower)alkyl. R4 and R5 are each hydrogen or halogen, R6 and R8 are each hydrogen, halogen, lower alkyl, hydroxy, lower alkylthio, amino optionally substituted with lower alkyl, or lower alkoxy optionally substituted with a substituent selected from the group consisting of hydroxy, lower alkoxy, amino, lower alkylamino and aryl optionally substituted with lower alkoxy, R7 is hydrogen or lower alkyl, A is lower alkylene, and Q is O or N—R9, in which R9 is hydrogen or acyl, provided that R3 is not hydrogen when X1 is C—R6, in which R6 is hydrogen, or pharmaceutically acceptable salts thereof; anda pharmaceutically acceptable, substantially non-toxic carrier or excipient suitable for ophthalmic administration.
- 2. The pharmaceutical composition of claim 1, whereinR3 is a group of the formula in which R10 is hydrogen or lower alkyl, and R11 is acyl, X1 is C—R6, in which R6 is lower alkyl, A is methylene and Q is O or NH.
- 3. The pharmaceutical composition of claim 2, whereinR3 is a group of the formula: in which R10 is hydrogen or lower alkyl, and R11 is an amino acid residue or an amino acid residue substituted with a substituent selected from the group consisting of lower alkyl, alkanoyl, halo(lower)alkanoyl, ar(lower)alkanoyl, aroyl, optionally substituted heterocyclic(lower)alkanoyl, lower alkenoyl, ar(lower)alkenoyl, lower alkoxy-ar(lower)alkenoyl, lower alkylenedioxy-ar(lower)alkenoyl, nitro-ar(lower)alkenoyl, cyano-ar(lower)alkenoyl, halo-ar(lower)alkenoyl, hydroxy-ar(lower)alkenoyl, hydroxy(lower)alkoxy-ar(lower)alkenoyl, amino(lower)alkoxy-ar(lower)alkenoyl, lower alkylamino(lower)alkoxy-ar(lower)alkenoyl, heterocyclic(lower)alkoxy-ar(lower)alkenoyl, heterocyclic-ar(lower)alkenoyl optionally having oxo, amino-ar(lower)alkenoyl, lower alkylamino-ar(lower)alkenoyl, lower alkanoylamino-ar(lower)alkenoyl, N-(lower alkanoyl)-N-(lower alkyl)amino-ar(lower)alkenoyl, cycloalkyl(lower)alkanoylamino-ar(lower)alkenoyl, cycloalkylcarbonylamino-ar(lower)alkenoyl, lower alkenoylamino-ar(lower)alkenoyl, lower alkoxycarbonylamino-ar(lower)alkenoyl, hydroxy(lower)alkanoylamino-ar(lower)alkenoyl, lower alkoxy(lower)alkanoylamino-ar(lower)alkenoyl, halo(lower)alkanoylamino-ar(lower)alkenoyl, amino(lower)alkanoylamino-ar(lower)alkenoyl, lower alkylamino(lower)alkanoylamino-ar(lower)alkenoyl, lower alkanoylamino(lower)alkanoylamino-ar(lower)alkenoyl, carboxy(lower)alkanoylamino-ar(lower)alkenoyl, lower alkoxycarbonyl(lower)alkanoylamino-ar(lower)alkenoyl, lower alkoxycarbonyl(lower)alkenoylamino-ar(lower)alkenoyl, halo(lower)alkoxycarbonylamino-ar(lower)alkenoyl, optionally substituted heterocyclic(lower)alkanoylamino-ar(lower)alkenoyl, aroylamino-ar(lower)alkenoyl, optionally substituted heterocycliccarbonylamino-ar(lower)alkenoyl, lower alkylsulfonylamino-ar(lower)alkenoyl, N-[lower alkoxy(lower)alkanoyl]-N-(lower alkyl)amino-ar(lower)alkenoyl, N-(lower alkanoyl)-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl, N-(lower alkanoyl)-N-[lower alkoxy(lower)alkyl]amino-ar(lower)alkenoyl, N-(lower alkanoyl)-N-[lower alkoxycarbonyl(lower)alkyl]amino-ar(lower)alke noyl, N-(lower alkanoyl)-N-[carboxy(lower)alkyl]amino-ar(lower)alkenoyl, N-[lower alkoxy(lower)alkanoyl]-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl, N-[heterocycliccarbonyl]-N-[lower alkoxy(lower)alkyl]amino-ar(lower)alkenoyl, ureido-ar(lower)alkenoyl, lower alkylureido-ar(lower)alkenoyl, heterocyclicureido-ar(lower)alkenoyl, lower alkanoyl-ar(lower)alkenoyl, carboxy-ar(lower)alkenoyl, lower alkoxycarbonyl-ar(lower)alkenoyl, carbamoyl-ar(lower)alkenoyl, lower alkylcarbamoyl-ar(lower)alkenoyl, hydroxy(lower)alkylcarbamoyl-ar(lower)alkenoyl, N-[hydroxy(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, lower alkoxy(lower)alkylcarbamoyl-ar(lower)alkenoyl, N-[lower alkoxy(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, heterocyclic(lower)alkylcarbamoyl-ar(lower)-alkenoyl, N-[heterocyclic(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, heterocycliccarbamoyl-ar(lower)alkenoyl, optionally substituted heterocyclicarbonyl-ar(lower)alkenoyl, lower alkenylcarbamoyl-ar(lower)alkenoyl, lower alkynylcarbamoyl-ar(lower)alkenoyl, amino(lower)alkylcarbamoyl-ar(lower)alkenoyl, lower alkylamino(lower)alkylcarbamoyl-ar(lower)alkenoyl, lower alkylcarbamoyloxy-(lower)alkylcarbamoyl-ar(lower)alkenoyl, lower alkylcarbamoyl(lower)alkylcarbamoyl-ar(lower)alkenoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl-ar(lower)alkenoyl, carboxy(lower)alkyl carbamoyl-ar(lower)alkenoyl, [lower alkylcarbamoyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl, [lower alkoxycarbonyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl, [carboxy-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl, N-[lower alkylcarbamoyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, N-[lower alkoxycarbonyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, N-[carboxy(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl, arylcarbamoyl-ar(lower)alkenoyl, ar(lower)alkynoyl, heterocyclic(lower)alkenoyl, heterocyclicthio(lower)alkanoyl, aminoheterocyclic(lower)alkenoyl, lower alkylamino-heterocyclic(lower)alkenoyl, lower alkanoylamino-heterocyclic(lower)alkenoyl, lower alkenoylaminoheterocyclic(lower)alkenoyl, heterocyclic(lower)alkanoylamino-heterocyclic(lower)alkenoyl, heterocycliccarbonylamino-heterocyclic(lower)alkenoyl, lower alkanoylamino(lower)alkanoylamino-heterocyclic(lower)alkenoyl, lower alkoxycarbonyl(lower)alkanoylamino-heterocyclic(lower)alkenoyl, lower alkoxy(lower)alkanoylamino-heterocyclic(lower)alkenoyl, lower alkylureido-heterocyclic(lower)alkenoyl, carboxy-heterocyclic(lower)alkenoyl, lower alkoxycarbonyl-heterocyclic(lower)alkenoyl, lower alkylcarbamoyl-heterocyclic(lower)alkenoyl, lower alkoxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl, hydroxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl , heterocycliccarbamoyl-heterocyclic(lower)alkenoyl, heterocyclic(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl, heterocycliccarbonyl-heterocyclic(lower)alkenoyl, lower alkenylcarbamoyl-heterocyclic(lower)alkenoyl, lower alkynylcarbamoyl-heterocyclic(lower)alkenoyl, optionally substituted heterocycliccarbonyl, cyclo(lower)alkylcarbonyl, lower alkoxycarbonyl, aryloxycarbonyl, aroyl(lower)alkanoyl, nitro-aryloxycarbonyl, carbamoyl, lower alkylcarbamoyl, lower alkoxycarbonyl(lower)alkylcarbamoyl, lower alkenylcarbamoyl, cyclo(lower)alkylcarbamoyl, arylcarbamoyl, lower alkoxy-arylcarbamoyl, halo(lower)alkyl-arylcarbamoyl, halo-arylcarbamoyl, lower alkanoyl-arylcarbamoyl, hydroxy(lower)alkyl-arylcarbamoyl, heterocycliccarbonyl-arylcarbamoyl, carboxy-arylcarbamoyl, lower alkoxycarbonyl-arylcarbamoyl, carbamoyl-arylcarbamoyl, lower alkylcarbamoyl-arylcarbamoyl, nitro-arylcarbamoyl, cyano-arylcarbamoyl, amino-arylcarbamoyl, lower alkylamino-arylcarbamoyl, lower alkanoylamino-arylcarbamoyl, N-(lower alkanoyl)-N-(lower alkyl)amino-arylcarbamoyl, lower alkoxy(lower)alkanoylamino-arylcarbamoyl, loweralkoxycarbonyl(lower)alkanoylamino-arylcarbamoyl, carboxyamino-arylcarbamoyl, lower alkoxycarbonylamino-arylcarbamoyl, aroylamino-arylcarbamoyl, heterocycliccarbonylamino-arylcarbamoyl, heterocyclic(lower)alkanoylamino-arylcarbamoyl, ureido-arylcarbamoyl, lower alkylureido-arylcarbamoyl, hydroxyimino(lower)alkyl-arylcarbamoyl, lower alkoxyimino(lower)alkyl-arylcarbamoyl, lower alkylhydrazono(lower)alkyl-arylcarbamoyl, heterocyclic-arylcarbamoyl optionally having oxo, heterocycliccarbonyl-arylcarbamoyl having lower alkyl, heterocycliccarbonyl-arylcarbamoyl having aryl, heterocycliccarbonyl-arylcarbamoyl having a heterocyclic group, heterocycliccarbonyl-arylcarbamoyl having lower alkanoyl, heterocycliccarbonyl-arylcarbamoyl having lower alkoxycarbonyl, heterocycliccarbonyl-arylcarbamoyl having lower alkylamino, heterocycliccarbonyl-arylcarbamoyl having lower alkylcarbamoyl, hydroxy(lower)alkylcarbamoyl-arylcarbamoyl, N-[hydroxy(lower)alkyl]-N-(lower alkyl)carbamoyl-arylcarbamoyl, lower alkoxy(lower)alkylcarbamoyl-arylcarbamoyl, N-[lower alkoxy(lower)alkyl]-N-(lower alkyl)carbamoylarylcarbamoyl, lower alkylamino(lower)alkylcarbamoyl-arylcarbamoyl, N-[lower alkylamino(lower)alkyl]-N-(lower alkyl)carbamoyl-arylcarbamoyl, heterocycliccarbamoyl-arylcarbamoyl, N-(heterocyclic)-N-(lower alkyl)carbamoyl-arylcarbamoyl, heterocyclic(lower)alkylcarbamoyl-arylcarbamoyl, N-[heterocyclic(lower)alkyl]-N-(lower alkyl)carbamoyl-arylcarbamoyl, N-[heterocyclic(lower)alkyl-N-lower alkoxy(lower)alkyl]carbamoyl-arylcarbamoyl, arylcarbamoyl-arylcarbamoyl, lower alkylaminoarylcarbamoyl-arylcarbamoyl, arylthiocarbamoyl, ar(lower)alkylcarbamoyl, aroylcarbamoyl, heterocycliccarbamoyl, heterocyclic(lower)alkylcarbamoyl, arylaminocarbamoyl, ar(lower)alkenylsulfonyl, lower alkylsulfonyl, phthaloyl, amino acid residue, amino acid residue substituted with lower alkyl, amino acid residue substituted with a heterocyclic group, amino acid residue substituted with heterocyclic(lower)alkyl, amino acid residue substituted with cycloalkyl, amino acid residue substituted with aryl, amino acid residue substituted with alkanoyl, amino acid residue substituted with lower alkoxycarbonyl, amino acid residue substituted with ar(lower)alkyl and amino acid residue substitued with phthaloyl.
- 4. The pharmaceutical composition of claim 1, wherein the compound is 8-[3-[N-[(E)-3 -(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline or its acid addition salt.
- 5. A method for the prevention and/or treatment of bradykinin or its analogues mediated diseases in the eye, comprising administering an effective amount of the pharmaceutical composition of claim 1 to a patient via ophthalmic administration.
- 6. The method of claim 5, wherein the diseases are selected from the group consisting of allergy, inflammation, and pain of the eye.
- 7. The method of claim 6, wherein the diseases are selected from the group consisting of conjunctivitis, vernal conjunctivitis, uveitis, iritis, and iridocyclitis.
- 8. A method for the prevention and/or treatment of bradykinin or its analogues mediated diseases in the eye, comprising administering an effective amount of the pharmaceutical composition of claim 4 to a patient via ophthalmic administration.
- 9. The method of claim 8, wherein the diseases are selected from the group consisting of allergy, inflammation, and pain of the eye.
- 10. The method of claim 9, wherein the diseases are selected from the group consisting of conjunctivitis, vernal conjunctivitis, uveitis, iritis, and iridocyclitis.
Priority Claims (2)
Number |
Date |
Country |
Kind |
9308804 |
Apr 1993 |
GB |
|
9318929 |
Sep 1993 |
GB |
|
Parent Case Info
This application is a continuation of U.S. Ser. No. 08/933,354, filed Sep. 19, 1997 now U.S. Pat. No. 5,922,711 which is a divisional of U.S. Ser. No. 08/660,393 filed Jun. 7, 1996 now U.S. Pat. No. 5,708,173, which is a divisional of U.S. Ser. No. 08/233,771 filed Apr. 26, 1994, now U.S. Pat. No. 5,563,162.
US Referenced Citations (5)
Foreign Referenced Citations (1)
Number |
Date |
Country |
WO 9951245 |
Oct 1999 |
WO |
Continuations (1)
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Number |
Date |
Country |
Parent |
08/933354 |
Sep 1997 |
US |
Child |
09/228973 |
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US |