Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-02
2003-04-01
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S394000, C546S118000, C548S305700
Reexamination Certificate
active
06541486
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds and methods for inhibiting cell death, such as neuronal or myocardial cell death. The compounds and pharmaceutical compositions thereof are particularly effective in inhibiting apoptotic cell death, and thus may be used to protect cells from cell death associated with ischemia, trauma, neurodegeneration, and inflammation.
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BACKGROUND OF THE INVENTION
Apoptosis has been associated with ischemic injury, such as typically occurs in cases of stroke, myocardial infarction, and reperfusion injury (Walton et al., 1997; MacManus et al., 1993). Apoptosis is also associated with immunoreactive and immunodegenerative states and a variety of neurodegenerative disorders. Recent studies on the mechanism of retinal ganglion cell death in experimental glaucoma also indicate that the cells die by apoptosis (Nickells, 1996; Garcia-Valenzuela et al., 1995; Laquis et al., 1998).
Apoptosis is a programmed cell death, occurring in normally functioning human and animal cells when age or state of cell health and condition dictates. It is an active process requiring metabolic activity by the dying cell, and is often characterized by cleavage of the DNA into fragments that give a so called laddering pattern on gels. Cells that die by apoptosis do not usually elicit the inflammatory responses that are associated with necrosis, a passive process in which collapse of internal homeostasis leads to cellular dissolution.
Apoptosis can have particularly devastating consequences when it occurs pathologically in cells that do not normally regenerate, such as neurons. Because such cells are not replaced when they die, their loss can lead to debilitating and sometimes fatal dysfunction of the affected organ.
Various drug strategies have been proposed for treatment of stroke and other neuronal conditions related to ischemia. To date, however, these drugs have been either relatively ineffective or effective only at dosage levels where undesired side effects are observed. For example, anti-coagulants, such as heparin, antivasoconstriction agents, such as flunarazine, excitatory neurotransmitter antagonists, such as MK-801 and AP7, and anti-edemic compounds have shown mixed results, with no clear benefits to outweigh a variety of side effects, including neurotoxicity or increased susceptibility to infection. Verapamil and related compounds, which prevent calcium entry into smooth and striated muscles, appear to be effective only at high drug concentrations, where serious cardiotoxicity effects may ensue. Increased cerebral edema has been observed as a side effect in treatment with dihydropyridines, such as nimodipine. Benzothiazepines, as exemplified by diltiazem, have shown moderate protective effects, but these drugs also appear to cause undesired side effects, such as hypotension, which may be inimical to treatment.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a pharmaceutical composition, useful for inhibiting cell death, which comprises an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
In formula I, X, X′, Z and Z′ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, cyano, carboxylic acid or ester, sulfonic acid or ester, amino, alkylamino, nitro, and halogen. The linker L is NR
1
, carbonyl, CR
2
R
3
, or a direct bond, where R
1
and R
2
are independently selected from hydrogen, alkyl, aryl, and aralkyl, and R
3
is selected from hydrogen, lower alkyl, amino, lower alkylamino, nitro, halogen, and lower alkyl sulfonate. The moiety A
B represents a three-atom linkage effective to form an imidazole, pyrrole, oxazole or thiazole ring fused to the adjacent six-membered ring, where one of A and B is nitrogen or carbon and the other is selected from NR
1
, O, or S, wherein at least one of A and B is nitrogen, and where A
B groups on opposing sides of the linker L may be the same or different. The groups Y and Y′ are independently selected from carbon and nitrogen.
In selected embodiments, the linker L is CH
2
, CHCH
3
, or carbonyl, and is preferably CH
2
. In further embodiments, in which A
B represents a three-atom linkage effective to form an imidazole ring fused to the adjacent six-membered ring, NR
1
is preferably NH, NCH
3
, or NCH
2
C
6
H
5
(N-benzyl). Y and Y′ are preferably carbon.
In further embodiments, X, X′, Z and Z′ are independently selected from hydrogen, alkyl, carboxylic acid or ester, amino, nitro, chloro, and fluoro. Preferably, at least one of X and X′ is amino or nitro, and Z and Z′ are independently selected from hydrogen, carboxylic acid, chloro, and fluoro. Not included are compositions in which, in Formula I, L is CH
2
, Y is carbon, A
B represents a three-atom linkage effective to form an imidazole or pyrrole ring, X, X′ and R
1
are hydrogen, and Z and Z′ are each selected from hydrogen, nitro, amino, or halogen. However, methods of administering these compositions to inhibit cell death, as described below, are included in the invention.
Alternatively, the pharmaceutical compositions of the invention may comprise an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
In formula II, L is NR
1
, carbonyl, CR
2
R
3
, or a direct bond, where R
1
and R
2
are independently selected from hydrogen, alkyl, aryl, and aralkyl, and R
3
is selected from hydrogen, lower alkyl, amino, lower alkylamino, nitro, halogen, and lower alkyl sulfonate. R
4
is selected from hydrogen, alkyl, aryl, and aralkyl; and R
5
is selected from an electron pair, hydrogen, alkyl, aryl, and aralkyl. It is understood that when R
5
is not an electron pair, the compound has a positive charge (e.g. compound SNX-980). L is preferably CR
2
R
3
, where R
2
and R
3
are selected independently from hydrogen and lower alkyl.
As in formula I, A
B represents a three-atom linkage effective to form an imidazole, pyrrole, oxazole or thiazole ring fused to the adjacent six-membered ring, where one of A and B is nitrogen or carbon and the other is selected from NR
1
, O, or S, wherein at least one of A and B is nitrogen; and Y is carbon or nitrogen.
The group W represents a two- to four-carbon alkyl chain linking the two depicted nitrogen atoms to form a five- to seven-membered heterocyclic ring. Each carbon atom of the alkyl chain is unsubstituted or substituted with one or two lower alkyl groups or a hydroxyl group. Preferably, each carbon atom of the alkyl chain is unsubstitut
Anstine Duran T.
Bitler Catherine M.
Khan Mohamed A.
Meyer-Franke Anke
Wood Paul L.
Elan Pharma International Ltd.
Gorthey LeeAnn
Perkins Coie LLP
Stockton Laura L.
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