U.S. patent application number 10/698944 was filed with the patent office on 2004-07-29 for nitric oxide donors and pharmaceutical compositions containing them.
Invention is credited to Haj-Yehia, Abdullah.
Application Number | 20040147598 10/698944 |
Document ID | / |
Family ID | 11069962 |
Filed Date | 2004-07-29 |
United States Patent
Application |
20040147598 |
Kind Code |
A1 |
Haj-Yehia, Abdullah |
July 29, 2004 |
Nitric oxide donors and pharmaceutical compositions containing
them
Abstract
The present invention provides a compound containing at least
one sulfhydryl group and at least one NO donor group, wherein said
compound contains one or more protected 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 at least one terminal --ONO.sub.2 group. The
present invention further provides pharmaceutical compositions
comprising one or more of said compounds as an active
ingredient.
Inventors: |
Haj-Yehia, Abdullah;
(Jerusalem, IL) |
Correspondence
Address: |
EITAN, PEARL, LATZER & COHEN ZEDEK LLP
10 ROCKEFELLER PLAZA, SUITE 1001
NEW YORK
NY
10020
US
|
Family ID: |
11069962 |
Appl. No.: |
10/698944 |
Filed: |
November 3, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10698944 |
Nov 3, 2003 |
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10041680 |
Jan 9, 2002 |
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6642260 |
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10041680 |
Jan 9, 2002 |
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09381303 |
Dec 30, 1999 |
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6369071 |
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09381303 |
Dec 30, 1999 |
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PCT/IL98/00144 |
Mar 26, 1998 |
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Current U.S.
Class: |
514/509 ;
514/350; 546/289; 558/250 |
Current CPC
Class: |
A61P 9/08 20180101; C07C
323/12 20130101; C07D 339/04 20130101; C07D 277/14 20130101; C07D
213/70 20130101; C07C 323/56 20130101; A61P 9/10 20180101; C07D
339/08 20130101; C07C 323/19 20130101; C07C 323/62 20130101; C07D
495/04 20130101; C07C 327/32 20130101; C07D 213/80 20130101; C07D
213/82 20130101 |
Class at
Publication: |
514/509 ;
514/350; 546/289; 558/250 |
International
Class: |
C07D 213/84; A61K
031/21; C07C 239/10 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 26, 1997 |
IL |
120531 |
Claims
What is claimed is:
1. A compound containing at least one sulfhydryl group and at least
one NO donor group, wherein said compound contains one or more
protected 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 at least
one terminal --ONO.sub.2 group.
2. A compound according to claim 1, wherein said protected
sulfhydryl group is an acetylated sulfhydryl group.
3. A compound according to claim 1, wherein said compound is:
17
4. A pharmaceutical composition comprising i) as an active
ingredient at least one compound containing at least one sulfhydryl
group and at least one NO donor group, wherein said compound
contains one or more protected 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 at least one terminal --ONO.sub.2 group; and
ii) a pharmaceutically acceptable carrier.
5. A composition according to claim 4, wherein said protected
sulfhydryl group is an acetylated sulfhydryl group.
6. A composition according to claim 4 wherein the active ingredient
is: 18
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation Application of U.S.
application Ser. No. 10/041,680, filed Jan. 9, 2002, which is a
Continuation Application of U.S. application Ser. No. 09/381,303,
filed Dec. 30, 1999, which claims priority of PCT International
Application No. PCT/IL98/00144, International Filing Date Mar. 26,
1998, which claims priority of Application IL 120,531, filed Mar.
26, 1997, which is hereby incorporated by reference
FIELD OF THE INVENTION
[0002] 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
[0003] 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.
[0004] 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 further reaction with
GTN, resulting in tolerance development.
[0005] 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 GIN and other
exogenous and endogenous vasodilators.
[0006] 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
sulfhydryls 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 GIN 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.
[0007] In vitro inhibitory studies provide indirect support for the
involvement of enzymes in GTN bioactivation [glutathione
5-transferase (GST) and cytochrome P450 (P450)]. 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.
[0008] 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.
[0009] 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
[0010] The present invention provides a compound containing at
least one sulfhydryl group and at least one NO donor group, wherein
said compound contains one or more protected 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 at least one terminal --ONO.sub.2
group.
[0011] In one embodiment, the protected sulfhydryl group is an
acetylated sulfhydryl group.
[0012] In one embodiment, the compound is: 1
[0013] The present invention further provides a pharmaceutical
composition comprising i) as an active ingredient at least one
compound containing at least one sulfhydryl group and at least one
NO donor group, wherein said compound contains one or more
protected 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 at least
one terminal --ONO.sub.2 group; and ii) a pharmaceutically
acceptable carrier.
[0014] In one embodiment, the protected sulfhydryl group is an
acetylated sulfhydryl group.
[0015] In one embodiment, the active ingredient is: 2
DETAILED DESCRIPTION OF THE PRESENT INVENTION
[0016] The present invention provides a compound containing at
least one sulfhydryl group and at least one NO donor group, wherein
said compound contains one or more protected 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 at least one terminal --ONO.sub.2
group. The present invention further provides pharmaceutical
compositions comprising one or more of said compounds as an active
ingredient.
[0017] In one embodiment, the protected sulfhydryl group is an
acetylated sulfhydryl group.
[0018] In one embodiment, the compound is: 3
[0019] The compounds are in vivo nitric oxide donors and they
contain at least one sulfhydryl group. As defined herein, a
sulfhydryl group is either present in the reduced SH form, or is a
group capable of being converted in-vivo to a sulfhydryl group. In
one embodiment, the compounds contain a sulfhydryl group in the
reduced --SH form. In another embodiment, the compounds contain a
group capable of being converted in-vivo to a sulfhydryl group.
Suitable groups which are capable of being converted in-vivo to a
sulfhydryl group are illustrated in the following embodiments: In
one embodiment, the sulfhydryl group is in the oxidized --S--S
disulfide form. In another embodiment, the sulfhydryl is present in
a separately protected form (acetyl, carbamyl or other). In another
embodiment, the sulfhydryl is present as an atom in a heterocyclic
compound. In cases where the compound contains two sulfhydryl
groups, these can exist in the reduced (SH) or the oxidized
(disulfide) form or in a protected form. However, each one of the
compounds can also be regarded as a parent pro-drug which is
assumed to undergo metabolic reduction or cleavage to provide the
free SH groups in-vivo.
[0020] The present invention further provides a compound containing
at least one nitric oxide (NO) donor group, and at least one
sulfhydryl group as defined herein. In one embodiment, the compound
is 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.sub.2 group. In another
embodiment, the compound is 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.sub.2 group. In another embodiment, the compound is a
5-membered ring compound containing two conjugate S-atoms, which
ring is linked to one or more substituents bearing a terminal
NO.sub.2 group. In another embodiment the compound is 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.sub.2 group. In another embodiment, the
compound is a 6-membered ring compound containing two conjugate
S-atoms which is substituted by one or more --ONO.sub.2 groups or
linked to one or more substituents bearing a terminal --ONO.sub.2
group. In another embodiment the compound is a 6-membered ring
compound containing 2 conjugate S-atoms which is substituted by one
or more --ONO.sub.2 groups or linked to one or more substituents
bearing a terminal --ONO.sub.2 group, wherein said 6-membered ring
is conjugated to at least one carbocyclic aromatic nucleus or at
least one pyridine nucleus. In another embodiment, the compound is
a compound having an S--S group in an open configuration linked to
one or more --ONO.sub.2 groups or linked to one or more
substituents bearing a terminal --ONO.sub.2 group.
[0021] In one embodiment, the compound is: 45
[0022] In another embodiment, the compound is: 6789
[0023] All of the above compounds are such that they will undergo
in vivo metabolic cleavage to provide free --SH groups.
[0024] According to this invention, whenever a compound exists in
the acid form, the term "acid" should also be understood to include
the corresponding acid halide, salts with pharmacologically
acceptable alkali metal (including alkaline earth metal and
ammonium bases), esters and amides. Moreover, the alcohol or the
amines used to form the corresponding ester and amides of the acid
can also bear a nitrate ester.
[0025] The present invention further provides a pharmaceutical
composition comprising i) as an active ingredient at least one
compound containing at least one sulfhydryl group and at least one
NO donor group, wherein said compound contains one or more
protected 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 at least
one terminal --ONO.sub.2 group; and ii) a pharmaceutically
acceptable carrier.
[0026] In one embodiment, the protected sulfhydryl group is an
acetylated sulfhydryl group.
[0027] In one embodiment, the active ingredient is: 10
[0028] The present invention further provides a pharmaceutical
composition for the treatment of disorders where nitric oxide
donors are indicated, comprising a) as an active ingredient at
least one compound containing at least one nitric oxide donor
group, and at least one sulfhydryl group as defined herein; and b)
a pharmaceutically acceptable carrier. In one embodiment, the
active ingredient is 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.sub.2 group. In another embodiment, the active ingredient is
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.sub.2 group. In another
embodiment, the active ingredient is a 5-membered ring compound
containing two conjugate S-atoms, which ring is linked to one or
more substituents bearing a terminal --ONO.sub.2 group. In another
embodiment the active ingredient is 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.sub.2 group. In another embodiment, the active ingredient is
a 6-membered ring compound containing two conjugate S-atoms which
is substituted by one or more --ONO.sub.2 groups or linked to one
or more substituents bearing a terminal --ONO.sub.2 group. In
another embodiment the active ingredient is a 6-membered ring
compound containing 2 conjugate S-atoms which is substituted by one
or more --ONO.sub.2 groups or linked to one or more substituents
bearing a terminal --ON.sub.2 group, wherein said 6-membered ring
is conjugated to at least one carbocyclic aromatic nucleus or at
least one pyridine nucleus. In another embodiment, the active
ingredient is a compound having an S--S group in an open
configuration linked to one or more --ONO.sub.2 groups or linked to
one or more substituents bearing a terminal --ONO.sub.2 group.
[0029] In one embodiment, the active ingredient is 1112
[0030] In another embodiment, the active ingredient is:
13141516
[0031] Because of their SH-content (radical scavenging and
anti-oxidant properties), these compounds may also be applied for
other pathologies. Thus, considering their promising chemical and
pharmacological characteristics and the ever-increasing demand for
better therapy for heart diseases, significant potential exists for
compounds of this type to become the next generation of
vasodilators. This is especially true concerning the considerable
amount of recent evidence indicating the involvement of nitric
oxide, reactive oxygen species and thiols in a variety of
conditions, the pathogenesis of as well as the treatment for which
have not been fully resolved. These include (but are not limited
to): atherosclerosis, pulmonary and systemic hypertension, asthma
and other related respiratory diseases, trauma, shock,
neurotoxicity, neurodegenerative and neurologic disorders,
including those involving learning, memory, olfaction and
nociception, Huntington, Alzheimer and Parkinson's diseases,
multiple sclerosis and convulsive (seizure) disorders, AIDS-related
disorders (i.e. dementia), disorders of gastric acid and other
secretory and peristaltic functions of the alimentary system, drug
and disease-induced neuropathy and nephropathy, pathological and
premature uterine contractions, cellular defense impairment, and
insulin-resistance in glucose intolerance and diabetes mellitus,
pregnancy-induced hypertension, chemotaxis and phagocytic
impairment in immunological disorders, cerebrovascular diseases,
aggregation disorders, penile erection and treatment of male
impotence.
[0032] Although the exact mechanisms defining organic nitrates and
other nitric oxide donors' action and tolerance are not completely
elucidated, the primary roles of nitric oxide (being their first
messenger) and cGMP (the second messenger) in mediating
vasorelaxation are universally accepted. Applicant has demonstrated
herein, utilizing example compounds 1 to 6 from pages 9-10, that,
unlike currently available organic and inorganic nitrates, these
compounds possess equipotent or ever superior vasorelaxant
activity. Moreover, using cGMP measurements both in extended
periods of exposure to the drug when used, for example, in
nitroglycerin-equimolar dosing regimens for which tolerance to the
cGMP-inducing activity of nitroglycerin has been documented under
the same experimental conditions (see table on page 26).
[0033] For the preparation of pharmaceutical compositions, the
novel compounds are mixed in the usual way with appropriate
pharmaceutical carrier substances, aroma, flavoring and coloring
materials and formed, for example, into tablets or dragees of
immediate or sustained release or, with additions of appropriate
adjuvants, for example water or an oil such as olive or other oil,
are suspended or dispersed or dissolved.
[0034] The compounds or the pharmaceutical composition thereof can
be administered orally (including the sublingual and buccal routes)
or via an injectable form (including the subcutaneous,
intramuscular, intraperitoneal and the parenteral routes). Other
routes of administration such as aerosols and dermal preparations
are also to be considered. As injection medium, water is preferably
used which contains the stabilizing agents, solubilizing agents
and/or buffers usually utilized in the preparation of solutions for
injection. Such additives include, for example, tartarate and
borate buffers, ethanol, ethylene and propylene glycols, glycerol,
dimethyl sulphoxide, complex formers (i.e., ethylenediamine
tetraacetic acid), high molecular weight polymers (such as liquid
polyethylene oxide) for viscosity regulation and polyethylene
derivatives of sorbit anhydrides. Solid carrier materials include,
for example, starch, lactose, mannitol, methyl cellulose, talc,
highly dispersed silicic acid, high molecular weight polymers
(i.e., polyethylene glycol). Compositions suitable for oral
administration (as defined above) can, if necessary, contain
flavoring and sweetening agents.
[0035] The synthesis of the novel compounds was carried out
utilizing conventional organic synthetic methods. The following
examples are given for the purpose of illustrating the present
invention:
EXAMPLE 1
trans-1,2-Dinitrato-4,5-dithiane (Compound 1, Page 9)
[0036] The compound was easily synthesized utilizing the
commercially available precursor trans-1,2-dihydroxy-4,5-dithiane.
0.5 g of the precursor was added portionwise to chilled (-5.degree.
C.) 1:1 mixture of fuming nitric sulfuric acids. Upon completion of
the addition, the ice/salt bath was removed and the mixture brought
to room temperature. This mixture was added dropwise to a cooled
mite of dry diethyl ether:acetonitrile:water (70:20:10) with
vigorous stirring. The lower aqueous phase was separated and
extracted twice with diethyl ether. The combined organic extracts
were washed twice with water and once with cold 1% sodium carbonate
solution. The organic layer was dried over magnesium sulfate and
evaporated to near dryness under reduced pressure. The residual oil
was loaded on a silica column and separated after elution with
hexane. Evaporation under reduced pressure of the eluate yielded a
yellowish oil (0.56 g) with analytical data consistent with the
structure of trans-1,2-dinitrato-4,5-dithiane.
EXAMPLE 2
2,2'-Dithiodiethanol-dinitrate (Compound 2, Page 9)
[0037] The compound was synthesized in a similar fashion to
compound 1 above using the commercially available precursor
2,2'-dithiodiethanol as the starting material. The precursor was
nitrated and separated as above yielding the tide compound
2,2'-dithiodiethanol-dinitrate.
EXAMPLE 3
1,1-Diemethanol-dinitrate-3,4-dithiane (Compound 3, Page 10)
[0038] This compound was synthesized by bishydroxymethylation of
diethyl malonate followed by thiolation of the hydroxyl groups (via
the halide intermediate). The resulting 1,1-dicarboxy-3,4-dithiane
was reduced by borane (catechol borane solution) to the
corresponding 1,1-diemethanol-3,4-dithiane. Direct nitration of
this latter intermediate yielded the title compound 1,1-diemethanol
dinitrate-3,4-dithiane.
EXAMPLE 4
1,1'-Bisthiomethyl-3,4-dihydroxy-cyclohexane-dinitrate ester
(Compound 4, Page 10)
[0039] This compound was synthesized by thiolation of the
dichloride intermediate of the commercially available
1,1'-bishydroxymethyl-3-cycloh- exene. Oxidation of the double bond
either by hydrogen peroxide/asmium tetroxide to generate the
cis-diol or by a peracid/formic acid mixture to generate the
trans-diol followed by nitration of the diol will generate the
corresponding (cis or trans) form of the title compound.
EXAMPLE 5
Thioctyl Alcohol Nitrate Ester (Compound 5, Page 10)
[0040] This compound was synthesized in a high yield process
utilizing thioctic acid as the precursor. Following reduction of
the acid (or its methyl or ethyl ester) by catechol borane
solution, the resulting thioctyl alcohol was separated and mitrated
as described above to yield the title compound.
EXAMPLE 6
1,2-Dihydroxy-dinitrate-6,8-dithiane (Compound 6, Page 10)
[0041] 2-Hydroxy lipoic (thioctic) acid was synthesized from
thioctic acid via the 2-bromo derivative. This intermediate was
reduced via borane to yield the direct precursor
1,2-dihydroxy-6,8-dithiane which, upon nitration as described
above, yielded the title compound.
Experimental Report
[0042] Representative for the new compounds, the vasorelaxant
activities (measured as the ability of the tested drug to induce an
increase in vascular cGMP) of the example compounds 1 to 6 were
determined and compared to activity of nitroglycerin under the same
experimental conditions following single and sustained exposure of
rats to the compound.
[0043] For this purpose the compound to be tested was administered,
in each case, to 8 male Sprague-Dawley rats (300-400 g) before and
after an 18 hr continuous intravenous infusion of the compound. The
18 hr continuous infusion period was determined based on existing
data demonstrating the development of tolerance to the drug effect
in the case of nitroglycerin. The existence of tolerance to the
drug is demonstrated by the inability of the drug to attain 50% or
more of the cGMP values measured in the vascular tissue after
dosing of the drug to preciously treated animals as compared to
controls (non-treated or vehicle-treated animals). After drug
administration (i.v. push), the rat was sacrificed, the aorta
immediately removed and processed for cGMP measurement as has been
described in detail by us. All of the tested new compounds were
utilized in nitroglycerin equimolar doses, either before of after
the "tolerance" induction period.
[0044] The following table summarizes the results obtained
following administration of either nitroglycerin or the tested
compounds before and after an 18 hr continuous exposure to the same
compound:
1 cGMP (pmol/g tissue) Tested Compound Pre-infusion Post-infusion
Nitroglycerin 153 .+-. 13 68 .+-. 9** Compound 1 196 .+-. 14 189
.+-. 13* Compound 2 169 .+-. 12 174 .+-. 13* Compound 3 171 .+-. 14
174 .+-. 16* Compound 4 149 .+-. 11 169 .+-. 13* Compound 5 123
.+-. 13 113 .+-. 11* Compound 6 193 .+-. 17 179 .+-. 12*
**Significantly different from the pre-infusion values and denotes
tolerance. *Not significantly different from pre-infusion levels
and denotes the lack of tolerance.
[0045] Besides their expected superior vasorelaxant activity, these
results clearly demonstrate that whereas tolerance to the
cGMP-inducing activity of nitroglycerin developed early (18 hr)
following its continuous in vivo administration, no tolerance was
observed to the cGMP-increasing effects of the novel compounds
under the same experimental conditions used for the induction of in
vivo tolerance. In fact, Applicant shows in preliminary results
that no tolerance to this cGMP-inducing effect of these novel
SH-containing-NO-donors develops even after exposure of the animals
to the compounds for extended periods of time (i.e., not even after
168 hr of continuous intravenous infusions).
[0046] It will be understood that the compounds shown demonstrate
the principle upon which this invention is based. Thus, the
specification and examples given in this application are
illustrative but not limitative of the present invention and
embodiments within the spirit and scope of the invention will
suggest themselves to those skilled in the art. Rather, the scope
of this invention is defined by the claims which follow.
* * * * *