Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1996-09-27
2001-10-23
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S237200, C514S238200, C514S255030
Reexamination Certificate
active
06306878
ABSTRACT:
The invention refers to pharmaceutical compositions suitable for the protection of the mitochondrial genom and/or mitochondrium from damages or for the treatment of diseases connected with such damages, said compositions comprising a hydroximic acid derivative of the formula
wherein
R
1
represents a hydrogen or a C
1-5
alkyl group,
R
2
stands for a hydrogen, a C
1-5
alkyl group, a C
3-8
cycloalkyl group or a phenyl group optionally substituted by a hydroxy or a phenyl group, or
R
1
and R
2
together with the nitrogen atom they are attached to form a 5 to 8 membered ring optionally containing one or more further nitrogen, oxygen or sulfur atom(s) and said ring can be condensed with another alicyclic or heterocyclic ring, preferably a benzene, naphthalene, quinoline, isoquinoline, pyridine or pyrazoline ring, furthermore, if desired and chemically possible, the nitrogen and/or sulfur heteroatom(s) are present in the form of an oxide or dioxide,
R
3
means a hydrogen, a phenyl group, a naphthyl group or a pyridyl group wherein said groups can be substituted by one or more halo atom(s) or C
1-4
alkoxy group(s),
Y is a hydrogen, a hydroxy group, a C
1-24
alkoxy group optionally substituted by an amino group, a C
2-24
polyalkenyloxy group containing 1 to 6 double bond(s), a C
1-15
alkanoyl group, a C
3-9
alkenoyl group or a group of the formula R
7
—COO—, wherein R
7
represents a C
2-30
polyalkenyl group containing 1 to 6 double bond(s),
X stands for a halo, an amino group, a C
1-4
alkoxy group, or
X forms with B an oxygen atom, or
X and Y together with the carbon atoms they are attached to and the —NR—O—CH
2
group being between said carbon atoms form a ring of the formula
wherein
Z represents an oxygen or a nitrogen,
R stands for a hydrogen or
R forms with B a chemical bond,
A is a C
1-4
alkylene group or a chemical bond or a group of the formula
wherein
R
4
represents a hydrogen, a C
1-5
alkyl group, a C
3-8
cycloalkyl group or a phenyl group optionally substituted by a halo, a C
1-4
alkoxy group or a C
1-5
alkyl group,
R
5
stands for a hydrogen, a C
1-4
alkyl group or a phenyl group,
m has a value of 0, 1 or 2,
n has a value of 0, 1 or 2,
or a pharmaceutically acceptable acid addition salt thereof as the active ingredient.
HU-P No. 177 578 and its equivalent U.S. Pat. No. 4,308,399 describe hydroximic acid derivatives within the compounds of the formula I suitable for the treatment of diabetic angiopathy.
HU-P No. 207 988 and its equivalent E-P No. 417 210 also describe hydroximic acid halogenides within the formula I having a selective beta-blocking effect, thus, being suitable for the treatment of diabetic angiopathy.
HU-P Application No. 2385/92 published under No. T/66350 describes further hydroximic acid derivatives within the formula I. These known compounds can be used in the treatment of vascular deformations, mainly in the therapy of diabetes mellitus.
It is well-known that the nuclear genom of a human cell encodes about 100 000 genes, but in the cytoplast there is also a small, independent mitochonrial genom/Wellace, D. C., Science, 256, 628-632 (1992)/.
The mitochondrial genom codes only for 13 genes/Clayton, D. A., Cell, 28, 693-705 (1982)/, but without them the cell is unable to consume the oxygen, therefore, as an effect of the damages in the mitochondrial genom, the cell becomes anaerobic. Unlike the nuclear genom, the mitochondrial genom does not have a DNA repair capacity and the mitochondrial DNA (mtDNA) is not surrounded by histons which makes the mitochondrial genes much more vulnerable than the nuclear encoded genes/Tzagoloff, A., Myer, A. M., Annu. Rev. Biochem., 55, 249-285 (1986)/. More than 90% of the oxygen consumption of a cell takes place in the mitochondrial inner membrane where besides normal oxidation also oxygen free radicals are formed /Stryer, L., Biochemistry, 4th edition, W. H. Freeman and Co., New York, 1995/. Such free radicals can easily modify the mitochondrial DNA in the immediate vicinity of their formation. The formation of the reactive oxygen free radicals significantly increases e.g. during the reoxigenation following an ischaemia which increased free radical concentration may cause considerable and irreversible damages to the mitochondrial DNA /Markhund, S. L., J. Mol. Cell. Cardiol., 20, (Supplement II), 23-30 (1988)/. Even under normal circumstances, free radicals cause minor but accumulative damages to the mtDNA. Therefore it is understandable that the damages of mtDNa increase by age /Wellace, D. C., Annu. Rev. Biochem., 61, 1175-1212 (1992)/, although the level of such damages depends on the individual, and that such damages of mtDNA may well cause the development of cardiomyopathy and neurodegenerative diseases in elderly people /Cortopassi, G. A., Arnheim, N., Nucleic Acids Res., 18, 6027-6033 (1990)/.
Through damages of the energy metabolism of a cell, the damages of the mitochondrial genom can cause severe illnesses such as myopathy /Luft, R., Proc. Natl. Acad. Sci. USA, 91, 8731-8738 (1994)/, dilatative or hypertrofic cardiomyopathy /Ozawa, T. et. al., Biochem. Biophys. Res. Commun., 170, 830-836 (1990)/, furthermore may have a role in the aggravation by age of a number of neurodegenerative diseases (such as Parkinson's disease, Huntington's disease, Alzheimer's disease) and of the severe symptoms of diabetes /Luft, R., cited publication/.
In a number of the above diseases (e.g. the myopathy), a treatment with antioxidants was applied (treatment with coenzyme Q and vitamin C) /Shoffner, J. M., Wallace, D. C., Adv. Hum. Genet., 19, 267-330 (1990)/. These treatments bring results only occasionally. Further test treatments were made to avoid damages of after-ischaemia reoxidation applying antioxidant and metabolic therapy, using lipoamid. Lipoamid corrects the damages to the heart caused by the ischaermia on one hand by its antioxidant effect, on the other hand by its positive influence on the mitochondrial metabolish /S{overscore (u)}megi, Balazs et al., Biochem. J., 297, 109-113 (1994)/. Without a profound knowledge of the damaging process, no breakthrough therapy has been developed yet.
Based on the above, there is a need for the development of a pharmaceutical product which can protect the mitochondrial genom from damages or also prevent such damages.
It was found that the compounds of the formula I are able to protect the mitochondrial genom from damages, thus, they are suitable for the protection of the mitochonrial genom and/or mitochondrium from damages or for the treatment of diseases connected with such damages. Examples of diseases of mitochondrial origin:
KSS
(Kearns-Sayre's syndrome),
MERRF
(myoclonus epilepsy and ragged red fibers
syndrome),
LHON
(Leber's hereditary optic neuropathy),
MELAS
(mitochondrial myopathy, encephalopathy,
lactic acidosis and stroke-like episodes),
Leigh disease,
(chronic progressive external phthalmoplegia),
CPEO,
Alper's syndrome.
Examples of age-dependent degenerative diseases where the mitochondrial genom has been damaged:
Neurodegenerative diseases:
Alzheimer's disease,
Parkinson's disease,
ALS
(amyotrophic lateral sclerosis),
HD
(Huntington's disease),
Cardiomiopathies and other myopathies.
Thus, the invention refers to pharmaceutical compositions comprising 0.1 to 95% by mass of a hydroximic acid derivative of the formula I or a pharmaceutically acceptable acid addition salt thereof as the active ingredient in admixture with one or more conventional carrier(s).
In the specification and Claims, a C
1-5
alkyl group is, for example, a methyl, ethyl, n-propyl, isorpopyl, n-butyl or n-pentyl group, preferably a methyl or an ethyl group.
A C
308
cycloalkyl group is, for example, a cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, preferably a cyclopentyl or a cyclohexyl group.
A 5 to 8 membered ring containing one or more heteroatom(s) can be, for example a pyrrole, pyrazole, imidazole, oxazole, thiazole, pyridine, pyridazine, pyrimidine, piperazine, morpholine, indole, quinolime etc. ring.
A C
Literáti Nagy Péter
Maresca Bruno
Sumegi Balazs
Vigh Laszlo
Birch & Stewart Kolasch & Birch, LLP
Fay Zohreh
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