Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Ion exchange resin
Reexamination Certificate
2001-09-10
2004-01-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Ion exchange resin
C424S078080, C424S078120, C424S078170, C424S422000, C424S718000
Reexamination Certificate
active
06673338
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nitric oxide-releasing imidate and thioimidate diazeniumdiolates, to compositions comprising such compounds, to methods of using such compounds and compositions, and to a method for the preparation of nitric oxide-releasing imidate and thioimidate diazeniumdiolates.
BACKGROUND OF THE INVENTION
Nitric oxide (NO) has been implicated as part of a cascade of interacting agents involved in a wide variety of bioregulatory processes, including the physiological control of blood pressure, macrophage-induced cytostasis and cytotoxicity, and neurotransmission (Moncada et al., “Nitric Oxide from L-Arginine: A Bioregulatory System,”
Excerpta Medica
, International Congress Series 897, Elsevier Science Publishers B. V.: Amsterdam (1990); Marietta et al.,
Biofactors
2: 219-225 (1990); Ignarro,
Hypertension
(Dallas) 16: 477-483 (1990); Kerwin et al.,
J. Med. Chem
. 38: 4343-4362 (1995); and Anggard,
Lancet
343: 1199-1206 (1994)). Given that NO plays a role in such a wide variety of bioregulatory processes, great effort has been expended to develop compounds capable of releasing NO. Some of these compounds are capable of releasing NO spontaneously, e.g., by hydrolysis in aqueous media, whereas others are capable of releasing NO upon being metabolized (Lefer et al.,
Drugs Future
19: 665-672 (1994)).
Several types of compounds of the general structure
have been known for many years. Traube (
Liebigs Ann. Chem
. 300: 81-123 (1898)) reported the preparation of a number of such compounds and noted that treatment of the compounds with acid produced a “brown gas.” Given that the brown gas is nitrogen dioxide which may be produced directly, the release of brown gas by the compounds prepared by Traube is not, in and of itself, evidence of NO release. Compounds of the structural type reported by Traube are known to require harsh treatment with mineral acids to release any gas and such treatment is, of course, incompatible with biological utility.
Another compound, which has the structure
and which has been named cupferron, has been shown by Kubrina et al., (
Izvestia Akademii Nauk SSSR Seriia Biologicheskaia
6: 844-850 (1988) English Trans.: Biol. Bull. Acad. Sci. USSR. 533-538, (1988)) to generate NO in vivo. In addition, the antibiotics alanosine (C(O)(OH)CH(NH
2
)CH
2
N(O)═NOH) and dopastin (CH
3
CH═CHC(O)NHCH
2
CH(i-propyl)-N(O)═NOH), as well as cupferron, have been shown to release NO in vivo by enzymatic oxidation (Alston et al.,
J. Biol. Chem
. 260: 4069-4074 (1985)).
Many of the known diazeniumdiolates and their clinical applications are disclosed in recently issued patents. For example, U.S. Pat. No. 4,954,526 (Keefer et al.) discloses nitric oxide-primary amine complexes useful as cardiovascular agents. U.S. Pat. Nos. 5,039,705 (Keefer et al.) and 5,208,233 (Keefer et al.) disclose anti-hypertensive compositions of secondary amine-nitric oxide adducts. U.S. Pat. Nos. 5,155,137 (Keefer et al.) and 5,250,550 (Keefer et al.) disclose complexes of nitric oxide with polyamines. U.S. Pat. Nos. 5,405,919 (Keefer et al.), 5,525,357 (Keefer et al.) and 5,718,892 (Keefer et al.) disclose polymer-bound nitric oxide
ucleophile adduct compositions. U.S. Pat. No. 5,366,997 (Keefer et al.) discloses oxygen-substituted derivatives of nucleophile-nitric oxide adducts as nitric oxide donor drugs. U.S. Pat. No. 5,389,675 (Christodoulou et al.) discloses mixed ligand complexes of nitric oxide-nucleophile adducts. U.S. Pat. No. 5,632,981 (Saavedra et al.) discloses biopolymer-bound nitric oxide-releasing compositions. U.S. Pat. No. 5,691,423 (Smith et al.) discloses polysaccharide-bound nitric oxide-nucleophile adducts. U.S. Pat. No. 5,721,365 (Keefer et al.) discloses N-substituted piperazine diazeniumdiolates. U.S. Pat. No. 5,185,376 (Diodati et al.) discloses therapeutic inhibition of platelet aggregation by nucleophile-nitric oxide complexes. U.S. Pat. No. 5,650,447 (Keefer et al.) discloses nitric oxide-releasing polymers to treat restenosis and related disorders. U.S. Pat. No. 5,676,963 (Keefer et al.) discloses implants, prostheses, and stents comprising polymer-bound nitric oxide
ucleophile adducts capable of releasing nitric oxide. U.S. Pat. No. 5,700,830 (Korthius et al.) discloses the use of nitric oxide adducts for reducing metastatic risk. U.S. Pat. Nos. 5,714,511 (Saavedra et al.) 5,814,666 (Keefer et al.) disclose selective prevention of organ injury in sepsis and shock using selective release of nitric oxide in vulnerable organs. U.S. Pat. No. 5,731,305 (Keefer et al.) discloses anti-hypertension compositions of secondary amine-nitric oxide adducts. U.S. Pat. No. 5,910,316 (Keefer et al.) discloses encapsulated and non-encapsulated nitric oxide generators useful as antimicrobial agents.
Other diazeniumdiolates useful in a host of applications include those described in U.S. patent application Ser. No. 09/254,301 (Saavedra et al.), which discloses O
2
-arylated and O
2
-glycosylated diazeniumdiolates, and U.S. Pat. No. 6,232,336 (Hrabie et al.), which discloses amidine- or enamine-derived diazeniumdiolates.
Despite the extensive literature available on NO and nitric oxide-releasing compounds, there remains a need for stable nitric oxide-releasing compounds in which the nitric oxide-releasing group N
2
O
2
31
is bonded directly to a carbon atom and that serve as versatile intermediates in the preparation of a wide variety of therapeutic nitric oxide-releasing compounds.
BRIEF SUMMARY OF THE INVENTION
The invention described herein provides for a novel class of imidate and thioimidate diazeniumdiolates and their preparation. The imidate and thioimidate diazeniumdiolates are useful therapeutic compounds and serve as important building blocks in the synthesis of other biologically important NO-releasing compounds. These and other advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided below.
The invention provides NO− or NO
−
-releasing imidate or thioimidate diazeniumdiolates in which the N
2
O
2
−
functional group is bonded to a carbon atom. The invention also provides compositions comprising such diazeniumdiolate compounds, and methods of using such compounds and compositions. The invention further provides a method for the preparation of NO— or NO
−
-releasing imidate or thioimidate diazeniumdiolates.
DETAILED DESCRIPTION OF THE INVENTION
The novel class of imidate and thioimidate diazeniumdiolates is capable of releasing nitric oxide under physiological conditions. These compounds are useful for treating biological conditions where a release of nitric oxide is beneficial.
The invention provides a novel class of NO-releasing imidate and thioimidate diazeniumdiolates of the formula:
wherein X is O or S; R
1
is hydrogen, an unsubstituted or substituted C
1-12
straight chain alkyl, an unsubstituted or substituted C
3-12
branched chain alkyl, an unsubstituted or substituted C
3-12
straight chain alkenyl, an unsubstituted or substituted C
3-12
branched chain alkenyl, an unsubstituted or substituted alkoxy, nitrile, halo, an unsubstituted or substituted benzyl, an unsubstituted or substituted phenyl, an unsubstituted or substituted naphthyl, an unsubstituted or substituted piperazino, an unsubstituted or substituted morpholino, amino, an unsubstituted or substituted alkylamino, an unsubstituted or substituted arylamino, an unsubstituted or substituted dialkylamino, an unsubstituted or substituted diarylamino, carboxyalkylamino, carboxydialkylamino, an unsubstituted or substituted tolyl, xylyl, anisyl, mesityl, an unsubstituted or substituted acetoxy, carboxy, an unsubstituted or substituted carboxyethyl, an unsubstituted or substituted alkylcarbonyl, thiol, an unsubstituted or substituted alkylthio, an unsubstituted or substituted alkyloxy, carboxamido, an unsubstituted or substituted alkylcarboxamido, an unsubstituted or substituted dialkylcarboxamido, an unsubstituted or substituted phenoxy, an unsubsti
Arnold Ernst V.
Hrabie Joseph A.
Keefer Larry K.
Di Nola-Baron Liliana
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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