Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-28
2001-10-09
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S912000, C514S913000
Reexamination Certificate
active
06300328
ABSTRACT:
This invention concerns compounds which inhibit the enzyme adenosine monophosphate deaminase (AMPDA) for the treatment of optic nerve and retinal damage resulting from ischaemia and hypoxia.
BACKGROUND OF THE INVENTION
The cytoprotective effects resulting from adenosine receptor activation, such as, vasodilation, neurotransmission inhibition, reduced oxygen consumption, and reduced inflammation are well known in the art (see for example: Erion, M. D., Ann. Rep. Med. Chem. 1993, 288, 295; DeNinno, M. P., Ann. Rep. Med. Chem. 1998, 33, 111). Several compounds which are either agonists at one of the adenosine receptor sub-types or which maintain/increase adenosine levels in affected tissue by preventing adenosine catabolism have been evaluated in animals and man for the treatment of damage resulting from stroke, brain trauma, and heart attack. One method of increasing adenosine concentration in the affected tissue is to inhibit the AMPDA-catalyzed deamination of adenosine monophosphate (AMP), an intermediate in the biochemical pathway between adenosine triphosphate and adenosine, to inosine monophosphate. However, such inhibition needs to be selective for AMPDA over adenosine deaminase (ADA), as potent ADA inhibition has been observed to result in severe immunosuppresion.
Compounds which inhibit the uptake of adenosine have been claimed for the treatment of retinal and optic neuropathy (Shade, U.S. Pat. No. 5,780,450), and a method for preventing retinal damage by administering a purine nucleoside analog has been claimed (Gruber, U.S. Pat. No. 4,912,092). The effect of elevated adenosine concentration on tissue damage in animal models of retinal ischaemia-reperfusion injury has been reviewed (Ghiardi, G. J.; Gidday, J. M.; Roth, S. Vision Research 1999, 39, 2519). Also, the compounds of the present invention have been claimed for the treatment of heart and nerve tissue damage resulting from ischaemic events (Erion, U.S. Pat. No. 5,731,432; Erion et. al., J. Am Chem. Soc. 1999, 121, 308). However, the compounds of the present invention have not been claimed or disclosed for the treatment of retinal and optic nerve damage resulting from ischaemia or hypoxia.
SUMMARY OF THE INVENTION
The present invention is directed to certain compounds which selectively inhibit AMPDA over the enzyme ADA for use in treating persons suffering from chronic or acute optic nerve and/or retinal damage resulting from hypoxia or ischaemia related to glaucoma, edema, or trauma. The present invention discloses compositions and methods for systemic, topical, and intraocular administration of at least one AMPDA inhibitor in an amount effective to prevent or to treat retinal and/or optic nerve head tissue damage.
DETAILED DESCRIPTION PREFERRED EMBODIMENTS
In accordance with the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise.
The term “aryl” refers aromatic groups which have at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are carbon atoms. Carbocyclic aryl groups include monocyclic carbocyclic aryl groups and polycyclic or fused compounds such as optionally substituted naphthyl groups.
Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl, and the like, all optionally substituted.
The term “biaryl” represents aryl groups containing more than one aromatic ring including both fused ring systems and aryl groups substituted with other aryl groups.
The term “alicyclic” means compounds which combine the properties of aliphatic and cyclic compounds and include but are not limited to aromatic, cycloalkyl and bridged cycloalkyl compounds.
The term “optionally substituted” or “substituted” includes groups substituted by one to four substituents, independently selected from lower alkyl, lower aryl, lower aryloxy, aralkyl, perhaloakloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azido, amino, guanidino, tetrazolo, 3H-1,2,3,5-oxythiodiazolo, thiazolidine-2,4-diono, oxazolidin-2,4-diono, halogen, hydroxy, lower alkoxy, lower alkylthio, carboxyalkyl, carboxyl, carboxamido, carboxamidoalkylaryl, carboxamidoaryl, aminocarboxainidoalkyl, cyano, and lower perhaloalkyl.
The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, and may be optionally substituted.
The term “lower” referred to herein in connection with organic radicals or compounds respectively defines such as with up to and including 10, preferably up to and including and advantageously one or two carbon atoms. Such groups may be straight chain or branched.
The terms “arylamino” (a), and “aralkylamino” (b), respectively, refer to the group —NRR
1
wherein respectively, (a) R is aryl and R
1
is hydrogen or aryl, and (b) R is aralkyl and R
1
is hydrogen or aralkyl.
The term “alkylamino” refers to —NRR
1
where R and R
1
are independently selected from hydrogen or lower alkyl.
The term “carboxamide” or “carboxamido” refers to —CONR
2
where each R is independently hydrogen or alkyl.
The term “alkyl” refers to saturated aliphatic groups including straight chain, branched chain and cyclic groups.
The terms “alkenyl” refers to unsaturated groups which contain at least one carbon-carbon double bond and includes straight chain, branched-chain and cyclic groups.
The term “alkynyl” refers to unsaturated groups which contain at least one carbon-carbon triple bond and includes straight chain, branched-chain and cyclic groups.
The terms “alkylene” refers to a divalent straight chain or branched chain saturated aliphatic radical.
The term “acyloxy” refers to the ester group —O—C(O)R.
The term “thioacyloxy” refers to the thioester group —S—C(O)R.
The term “alkylenylaryl” refers to an alkylene group substituted with an aryl group. “Lower alkylenylaryl” refers to such groups where alkylene is lower alkylene.
The term “alkylenylamino” refers to the group —alk— wherein alk is an alkylene group.
The term “alkylenylaminoalkylene” refers to the group —alk—NH—alk— wherein each alk is an independently selected alkylene. “Lower alkylenylaminoalkylene” refers to groups where each alkylene group is lower alkylene.
The term “alkylenylaminoaryl” refers to an alkylene group substituted with an arylamino group. In “lower alkenylaminoaryl”, the alkylene group is lower alkylene.
The term “alkylenyloxyaryl” refers to an alkylene group substituted with an aryloxy group. In “lower alkylenyloxyaryl”, the alkylene group is lower alkylene.
The term “alkylenylacylamino” refers to the group —alk—NH—(COR)— wherein alk is alkylene and R is lower alkyl. In “lower alkylenylacylamino”, the alkylene group is lower alkylene.
The term “alkylenyloxyalkylenylaryl” refers to an alkylene group substituted with an aralkenyloxy group. “Lower alkylenyloxyalkylenylaryl” refers to such groups where the alkylene group is lower alkylene.
The term “alkylenylacylaminoalkylene” refers to the group —alk—NH—(COR)—alk— where each alk is an independently selected alkylene group. In “lower alkylenylacylaminoalkylene” the alkylene groups are lower alkylene.
The term “alkenyloxy” refers to the group —alk—O— wherein each alk is an alkylene group.
The term “alkoxyalkyl” refers to the group —alk—O—alk wherein each alk is an independently selected alkylene group. In “lower alkoxyalkyl”, each alkylene is lower alkylene.
The term “alkylenethio” refers to the group —alk—S— wherein alk is alkylene group.
The term “alkylthioalkyl” refers to the group —alk—S—alk wherein each alk is an independently selected alkylene group. In “lower alkylthioalkyl” each alkylene is lower alkylene.
The term “alkyl
Alcon Universal Ltd.
Fay Zohreh
Yeager Sally S.
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