Combinations of selective alpha-adrenergic agonists and antagonists useful in lowering intraocular pressure
AssigneeAllergan, Inc.
InventorJames A. Burke
Life of this patent
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Abstract
Methods and pharmaceutical formulations of alpha.sub.2 agonists and alpha.sub.3 antagonists which are useful in lowering intraocular pressure (IOP) and treatment of intraocular hypertension. Co-administration of a therapeutic amount of alpha.sub.2 agonist with a potentiating amount of alpha.sub.3 agonist is effective in lowering IOP and treatment of intraocular hypertension.
Claims4
A method for lowering intraocular pressure (IOP) comprising co-administering to the eye of a mammal suffering from ocular hypertension a therapeutic amount of alpha.sub.2 agonist and alpha.sub.3 antagonist wherein the amount of alpha.sub.3 potentiates the ocular hypotensive effect of the alpha.sub.2 agonist, and wherein the alpha.sub.2 agonist is a compound selected from compounds having tautomeric formulae (i), (ii) and (iii) ##STR6## where in Formulae (i) R.sub.1 and R.sub.2 independently are C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl;
- and one of R.sub.3 and R.sub.4 is hydrogen and the other is selected from --N(R.sub.5,R.sub.7), --COOR.sub.5, --CO--N(R.sub.5,R.sub.6), --NR.sub.5 COR.sub.6, --CH.sub.2 OH;
- --CN, OH, --OCOR.sub.8, COR.sub.8, --C(R.sub.8)NOH, CHNOH, CHO, CHA and CR.sub.8 A where R.sub.5 and R.sub.6 independently are hydrogen or C.sub.1-6 alkyl, R.sub.7 is hydrogen, C.sub.1-6 alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl, R.sub.8 is C.sub.1-6 alkyl and A represents two alkyl groups, each of which independently has 1 to 6 carbons, or A represents (CH.sub.2).sub.n where n is an integer between 2 to 5;
- in Formulae (ii) R.sub.11 is C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl;
- R.sub.12 is hydrogen;
- R.sub.13 is selected from OH, --N(R.sub.9,R.sub.10) and --NR.sub.9 COR.sub.9 ;
- and R.sub.14 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl where R.sub.9 is hydrogen or C.sub.1-6 alkyl, R.sub.10 is hydrogen, C.sub.1-6 alkyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl;
- in Formulae (iii) R.sub.21 and R.sub.22 are independently H, C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl, and where X represents either one nitrogen atom to form together with the benzene ring a quinoline ring, or X represents two nitrogen atoms in 1,4 position relative to one another to form together with the benzene ring a quinoxaline ring, or a pharmaceutically acceptable salt of said alpha.sub.2 agonist compound;
- and said alpha.sub.3 antagonist is a compound of the formula:
- ##STR7## wherein:
- R.sub.23 is C.sub.1-5 alkyl;
- X.sub.1 is Br, Cl, or F;
- Y.sub.1 is --CH.sub.2 --CH.dbd.C(CH.sub.3).sub.2, --CH.dbd.CH--CH.sub.3, --CH.sub.2 --(CH.sub.3)C.dbd.CH.sub.2, --CH.dbd.C(CH.sub.3).sub.2, --CH.dbd.CH--CH.sub.2 --CH.sub.3, --CH.dbd.CH--CH(CH.sub.3).sub.2 ;
- or a pharmaceutically acceptable salt or hydrate of said alpha.sub.3 antagonist compound.
An ophthalmically acceptable formulation for lowering intraocular pressure (IOP) comprising a therapeutic amount of alpha.sub.2 agonist and alpha.sub.3 antagonist in an amount which potentiates the ocular hypotensive effect of the alpha.sub.2 agonist in a pharmaceutically acceptable excipient, the alpha.sub.2 agonist being selected from compounds having tautomeric formulae (i), (ii) and (iii) ##STR8## wherein in Formulae (i) R.sub.1 and R.sub.2 independently are C.sub.1-6 alkyl, flu or trifluoromethyl;
- and one of R.sub.3 and R.sub.4 is hydrogen and the other is selected from --N(R.sub.5,R.sub.7), --COOR.sub.5, --CO--N(R.sub.5,R.sub.6), --NR.sub.5 COR.sub.6, --CH.sub.2 OH;
- --CN, OH, --OCOR.sub.8, COR.sub.8, --C(R.sub.8)NOH, CHNOH, CHO, CHA and CR.sub.8 A where R.sub.5 and R.sub.6 independently are hydrogen or C.sub.1-6 alkyl, R.sub.7 is hydrogen, C.sub.1-6 alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl, R.sub.8 is C.sub.1-6 alkyl and A represents two alkyl groups, each of which independently has 1 to 6 carbons, or A represents (CH.sub.2).sub.n where n is an integer between 2 to 5;
- in Formulae (ii) R.sub.11 is C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl;
- R.sub.12 is hydrogen;
- R.sub.13 is selected from OH, --N(R.sub.9,R.sub.10) and --NR.sub.9 COR.sub.9 ;
- and R.sub.14 is hydrogen, C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl where R.sub.9 is hydrogen or C.sub.1-6 alkyl, R.sub.10 is hydrogen, C.sub.1-6 alkyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl;
- in Formulae (iii) R.sub.21 and R.sub.22 are independently H, C.sub.1-6 alkyl, fluoro, chloro, bromo or trifluoromethyl, and where X represents either one nitrogen atom to form together with the benzene ring a quinoline ring, or X represents two nitrogen atoms in 1,4 position relative to one another to form together with the benzene ring a quinoxaline ring, or a pharmaceutically acceptable salt of said alpha.sub.2 agonist compound;
- and said alpha.sub.3 antagonist is a compound of the formula:
- ##STR9## wherein:
- R.sub.23 is C.sub.1-5 alkyl;
- X.sub.1 is Br, Cl, or F;
- Y.sub.1 is --CH.sub.2 --CH.dbd.C(CH.sub.3).sub.2, --CH.dbd.CH--CH.sub.3, --CH.sub.2 --(CH.sub.3)C.dbd.CH.sub.2, --CH.dbd.C(CH.sub.3).sub.2, --CH.dbd.CH--CH.sub.2 --CH.sub.3, --CH.dbd.CH--CH(CH.sub.3).sub.2 ;
- or a pharmaceutically acceptable salt or hydrate of said alpha.sub.3 antagonist compound.
Dependencies are inferred from the claim text.