Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-01-09
2002-12-10
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S298000, C546S299000, C546S261000, C546S301000, C548S200000, C549S039000, C549S032000, C564S300000, C568S023000, C514S335000, C514S348000, C514S351000, C514S356000, C514S365000, C514S369000, C514S440000
Reexamination Certificate
active
06492405
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to nitric oxide donors containing at least one sulfhydryl group or a group capable of being converted in-vivo to a sulfhydryl group, and at least one nitric oxide donor group. The novel compounds are effective substitutes for existing tolerance-inducing organic or inorganic nitric oxide donors.
BACKGROUND OF THE INVENTION
For over a century, the nitric oxide (NO) donor nitroglycerin (GTN) has been the mainstay in the treatment of angina and related heart diseases. However, the existing mechanisms proposing the mediation of GTN action by free NO, intracellular or extracellular S-nitrosothiol formation and subsequent activation of guanylyl cyclase (GC), as well as those describing GTN tolerance, have become increasingly controversial. The phenomenon of tolerance to GTN, however, is of special clinical importance. In fact, early tolerance to the anti-anginal effects of the drug is the major drawback of nitrate therapy, especially during acute myocardial infarction. This is particularly important since alternative non-tolerance inducing agents have not yet been developed to successfully replace therapy with GTN.
Based on accumulating evidence, Applicant hypothesized that GTN may directly interact with SH-group/s located on its target enzyme (GC) resulting in its S-nitrosylation and activation. However, subsequent auto-oxidation (disulfide formation) of these SH-groups renders the enzyme inert towards farther reaction with GIN, resulting in tolerance development.
Additionally, evidence has recently been provided to support an involvement of the superoxide anion in the mechanism/s underlying GTN tolerance and cross-tolerance. According to these reports, increased production of superoxide anion was found to accompany tolerance development to GTN in vascular tissue. Treatment with superoxide dismutase (SOD) significantly enhanced relaxation of control and tolerant vascular tissue to GTN and other exogenous and endogenous vasodilators.
While the precise mechanism for the vasorelaxant effect of GTN is unknown, a consensus exists regarding the primary involvement of cGMP in mediating the nitrate-induced relaxation. However, the roles of sulfhydryl groups [reduced glutathione (GSH) and cysteine (Cys)] and of various enzymes in the bioconversion of GIN and subsequent activation of guanylyl cyclase (GC) leading to relaxation have become increasingly controversial. Cysteine was found to be the specific sulfhydryl required for activation of soluble coronary arterial GC and to be the only one of several sulfhydryl to react non enzymatically with GTN at physiologic pH resulting in formation of S-nitrosocysteine. Since S-nitrosothiols were shown to be potent activators of GC, S-nitrosocysteine/thiols were proposed as the intracellular mediators of organic nitrate-induced vasorelaxation. Additionally, N-acetylcysteine (NAC, an immediate donor of Cys thereby increasing GSH) was reported to potentiate GTN activity in vitro and in vivo. The enhanced reaction of thiols with GTN in plasma and blood versus buffer suggested that activation of GC by GTN may be mediated via extracellular formation of S-nitrosothiol/s. In either case (intra- or extracellular S-nitrosothiol formation), this association between sulfhydryls and GTN activity has long been recognized as evidence for the “thiol depletion hypothesis”. However, recent studies by the Applicant and those of Boesgard et al. revealed a dissociation between tissue thiol content (measured as Cys and GSH) and nitrate tolerance in vivo.
In vitro inhibitory studies provide indirect support for the involvement of enzymes m GTN bioactivation [glutathione S-transferase (GST) and cytochrome P-450 (P-450)]. However, in view of several other reports suggesting the lack of any significant role of GST and P-450 in GTN bioactivation, the reduced bioactivation of GTN is unlikely to be the main factor underlying nitrate tolerance in vivo. In fact, reduced cGMP production was also shown to follow exposure of vascular preparation to direct NO-donors, for which no definitive metabolic pathway has been reported.
Furthermore, Applicant has recently presented in vivo evidence excluding the involvement of any particular metabolic pathway since reduced cGMP was also shown to follow treatment with S-alkylating agents in the absence of GTN.
Heart disease is the leading cause of death in Western society and is rapidly approaching this leading position worldwide. Ischemic heart disease is the most common heart disease. For over a century, nitroglycerin and other organic nitrates have been used for the treatment of various types of myocardial ischemia, including acute myocardial infarction (AMI) and as adjuncts in the treatment of other heart diseases (congestive heart failure and resistant hypertension). Chronic prophylaxis and acute treatment are necessary to prevent complications of ischemic heart disease with potential fatal outcomes (~25% death for AMI). Tolerance to the anti-ischemic effect of these drugs is, by far, the most serious drawback of therapy with currently available organic nitrates. The compounds proposed in this application constitute a novel approach to overcome tolerance.
SUMMARY OF THE INVENTION
The present invention provides a compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound is a) a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group; b) a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group; c) a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal —ONO
2
group; or d) a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group.
In one embodiment, the compound is:
In another embodiment, the compound is:
The present invention further provides a pharmaceutical composition comprising a) as an active ingredient at least one compound containing at least one sulfhydryl group and at least one NO donor group, wherein said compound is 1) a compound containing one or more sulfhydryl groups linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group; 2) a 5-membered ring heterocyclic compound containing a sulfur atom and a nitrogen atom, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group; 3) a 5-membered ring compound containing two conjugate S-atoms, which ring is linked to one or more substituents bearing a terminal —ONO
2
group; or 4) a compound containing an acyclic —S—S group, linked to at least one aromatic ring or a heteroaromatic ring with a nitrogen in the ring structure, which ring is substituted by one or more substituents bearing a terminal —ONO
2
group; and b) a pharmaceutically acceptable carrier.
In one embodiment, the active ingredient is:
In another embodiment, the active ingredient is:
REFERENCES:
Dhami, Kawal S., Addition products of various halogens and carbomethoxymethyl malonate monothioallylamide, Correction., 1975, Indian J. Chem., 13 (9), 989.
Coppins Janet L
Eitan Pearl Latzer & Cohen-Zedek
Rotman Alan L.
Yissum Research Development Company of the Hebrew University of
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