Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-10-28
2002-09-24
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06455589
ABSTRACT:
FIELD OF THE INVENTION
The field of the invention is pharmaceutical compositions of primary N-hyroxylamines.
BACKGROUND OF THE INVENTION
&agr;-Phenyl-N-t-butyl nitrone (PBN) is one of the most widely used spin trapping agents for investigating the existence of free radicals in biological systems. PBN reverses the age-related oxidative changes in the brains of old gerbils (1,2) and delays senescence in senescence-accelerated mice (3) and in normal mice (4). PBN also delays senescence in the normal human lung fibroblast cell line IMR90 (5). In addition, PBN reverses mitochondrial decay in the liver of old rats (38) and exerts a neuroprotective effect in gerbils (1,7) and rats (8,9) after oxidative damage from ischemia/reperfusion injury. The mechanism underlying the biological activity of PBN is still controversial. However, PBN is a well known scavenger of radical species, though a variety of other well known spin trap or anti-oxidants do not mimic its anti-senescence activity in IMR90. PBN at relatively high concentrations reduces the production of hydrogen peroxide in mitochondrial preparations of cerebral cortex (10) and therefore may exert similar properties in vivo. This suggests that PBN possesses special properties that do not exist in other spin traps or antioxidants.
In the course of our study of the affect of PBN on IMR90 cells we observed that old solutions were more effective than fresh solutions in delaying senescence of IMR90 cells. This raised the question about the interaction of PBN's decomposition products with IMR90 cells. This encouraged us to test the anti-senescent effect of the PBN decomposition products, N-t-butyl hydroxylamine and benzaldehyde on IMR90 cells. PBN (or PBN/
−
OH) has been reported to decompose to N-t-butyl hydroxylamine or N-t-butyl hydronitroxide and benzaldehyde (11-13). PBN, as purchased, often contains N-t-butyl hydroxylamine (14). Benzaldehyde, is both mutagenic (15) and carcinogenic (16). N-t-butyl hydroxylamine is a primary hydroxylamine that can be oxidized, under certain conditions (such as with UV or Fe
+3
), to N-(t-butyl)aminoxyl (also referred as N-t-butyl hydronitroxide (10-12). N-(t-butyl)aminoxyl and the corresponding N-hydroxylamine are primary amines and are thus different from the well known cyclic-nitroxides/cyclic-hydroxylamines. The antioxidative and protective features of some cyclic-nitroxides/cyclic-hydroxylamines are known. Probably the most important feature in this regard, is their ability to catalyze superoxide radical dismutation to form H
2
O
2
(17-21). In vitro cyclic-nitroxides can either be oxidized to oxo-ammonium cation or reduced to the corresponding hydroxylamine by superoxide radical, depending on the type of cyclic-nitroxide. Thus cyclic-hydroxylamine or the corresponding oxo-ammonium cation are intermediates during the dismutation of superoxide radical by nitroxide. Interestingly, the oxo-ammonium cation species is reduced to the corresponding cyclic-hydroxylamine by the cellular reductant NADH, which suggests that cyclic-hydroxylamine can be the dominant form inside the cells. In addition the cyclic-nitroxide species can undergo one electron reduction to the corresponding cyclic-hydroxylamine, a reaction proposed to be mediated by mitochondrial coenzyme Q and ascorbic acid (21-23). Mitochondrial cytochrome c oxidase can also oxidize the cyclic-hydroxylamine to the corresponding nitroxide (24). Thus, it appears that mitochondria can contribute to the cycling of cyclic-nitroxides/cyclic-hydroxylamines, which in turn can facilitate dismutation of superoxide radical to H
2
O
2
. The N-t-butyl hydroxylamine and the other N-hydroxylamines tested in this study are primary N-hydroxylamines which have not been previously examined as antioxidants.
SUMMARY OF THE INVENTION
The invention provides pharmaceutical compositions comprising primary N-hydroxylamines and related therapeutic, prophylactic, diagnostic and screening methods.
The pharmaceutical compositions generally comprise a pharmaceutical composition comprising an orally administrable effective unit solid dosage of a primary N-hydroxylamine or a pharmaceutically acceptable salt thereof and substantially free of a nitrone corresponding to the hydroxylamine, wherein the hydroxylamine has the formula:
R
i
NHOH
wherein R
i
is independently selected from: substituted or unsubstituted (C1-C18) alkyl, alkenyl, alkynyl, aryl (carbocyclic and heterocyclic), oxyl, acyl, carboxyl, amino, nitro, nitroso, oxime, hydrazone, azo, thiol, sulfonyl and halide.
In a first particular embodiment of the general compositions, R
i
is substituted or unsubstituted methyl group having the general formula,
NHOHCR
1
R
2
R
3
wherein R
1
, R
2
and R
3
are independently selected from: substituted or unsubstituted (C0-C10) alkyl, alkenyl, alkynyl, aryl (carbocyclic and heterocyclic), oxyl, acyl, carboxyl, amino, nitro, nitroso, oxime, hydrazone, azo, thiol, sulfonyl and halide.
The invention provides more specific aspects of this embodiment:
wherein at least one R of R
1
, R
2
and R
3
is selected from unsubstituted (C0-C10) alkyl, alkenyl and alkynyl;
wherein at least one R of R
1
, R
2
and R
3
is selected from unsubstituted (C0-C18) alkyl, cycloalkyl, alkenyl and alkynyl, and the R is selected from: CH
3
—(CH
2
)
n1
, (CH
3
—(CH
2
),2—)
2
CH, (CH
3
—(CH
2
)
2
—)
3
, cyclopentyl, cyclohexyl, (CH
2
═CH—CH
2
)
n3
and (CH
═
C—CH
2
—)
n3
, wherein n1=1 to 18, n2=1 to 17and n3=1 to 3;
wherein at least one R of R
1
, R
2
and R
3
is selected from unsubstituted (C0-C10) alkyl, alkenyl and alkynyl, and the hydroxylamine is selected from:
N-methylhydroxylamine,
N-(n-decahexyl)hydroxylamine,
N-ethylhydroxylamine,
N-(n-decaoctyl)hydroxylamine,
N-n-propylhydroxylamine,
N-isopropylhydroxylamine,
N-(n-butyl) hydroxylamine,
N-sec-butylhydroxylamine,
N-(n-pentyl)hydroxylamine,
N-tert-butylhydroxylamine,
N-(n-hexyl)hydroxlamine,
N-cyclohexylhydroxylamine,
N-(n-heptyl)hydroxylamine,
N-cyclopentylhydroxylamine,
N-(n-octyl)hydroxylamine,
N-(2-propene)hydroxylamine,
N-(n-nonyl)hydroxylamine,
N-(3-butene)hydroxylamine,
N-(n-decyl)hydroxylamine,
N-(2-propyne)hydroxylamine and
N-(n-dodecyl)hydroxylamine,
N-(3-butyne)hydroxylamine;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted aryl;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted aryl, and the R is selected from: mono, di, or tri methyl, methoxy, halo, nitro, amino, hydroxyl and substituted or unsubstituted phenyl, naphthyl, anthryl, phenanthryl, pyridyl, quinolinyl, imidazolyl, benzoxazolyl, pyrrolyl, furanyl, piperidinolyl and tetrahydrofuranyl;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted aryl, and the hydroxylamine is selected from:
N-benzylhydroxylamine,
N-(1,3-diaminobenzyl)hydroxyl-
amine,
N-(n-nitrobenzyl)hydroxylamine,
N-(1,3-hydroxybenzyl)hydroxyl-
amine,
N-(n-methylbenzyl)hydroxylamine,
N-(2,4-diaminobenzyl)hydroxyl-
amine,
N-(n-chlorobenzyl)hydroxylamine,
N-(2,4-dihydroxybenzyl)hydroxyl-
amine,
N-(n-aminobenzyl)hydroxylamine,
Imidazole-2-methylhydroxylamine
and
N-(n-hydroxybenzyl)hydroxylamine,
Benzoxazole-2-methylhydroxyl-
amine,
wherein n is selected from 1, 2, 3, 4, 5 and 6;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted (C0-C18) oxyl;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted (C0-C18) oxyl and the R is selected from: hydroxyl, hydroxyalkyl (HO—(CH
2
)
n1
), hydroxyaryl selected from benzylalcohol, phenol and naphthol, alkoxy (O—(CH
2
)
n1
) and aryloxy selected from phenoxy, benzyloxy and naphthyloxy, wherein n1=1 to 18;
wherein at least one R of R
1
, R
2
and R
3
is substituted or unsubstituted (C0-C18)alkyl hydroxyl or arylhydroxyl and the hydroxylamine is selected from:
N-(hydroxymethyl)hydroxylamine,
N-(methoxymethyl)hydroxyl-
amine,
N-(2-hydroxyethyl)hydroxylamine,
N-(methoxyethyl)hydroxyl-
amine,
N-(3-hydroxypropyl)hydroxylamine,
N-(methoxyisopropyl)hydroxyl-
amine,
N-(4-hydroxybutyl)hydroxylamine,
N-(benzylo
Ames Bruce N.
Atamna Hani
Jones Dwayne C.
Osman Richard Aron
The Regents of the University of California
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