Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-02
2002-12-31
Davis, Brian J. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S237200, C514S307000, C514S315000, C514S318000, C514S343000, C514S357000, C514S428000, C514S637000, C544S124000, C544S162000, C546S145000, C546S193000, C546S231000, C546S232000, C546S233000, C546S276400, C546S332000, C548S566000
Reexamination Certificate
active
06500823
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of PCT International Application No. PCT/HU99/00062 which has an International filing date of Sep. 2, 1999, which designated the United States of America.
The invention refers to novel unsaturated hydroximic acid derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same. The novel compounds have valuable pharmaceutical activities, thus, they can be used, due to their poly(adenosine diphosphate ribose) polymerase inhibiting effect, in states connected with energy deficiency of the cell, in diabetes complications, in oxygen deficient states of the heart and brain, in neurodegenerative diseases as well as in the treatment of autoimmune and/or viral diseases.
Specifically, the invention refers to novel hydroximic acid derivatives of the formula
wherein
R
1
represents a C
1-20
alkyl group, a phenyl group optionally substituted by 1-3 substituents selected from the group consisting of a C
1-2
alkyl group, a C
1-2
alkoxy group, a halo atom, an amino group, a (C
1-4
alkyl)amino group, a di(C
1-4
alkyl)-amino group or a di(C
1-4
alkanoyl)amino group, furthermore R
1
represents a 5- or 6-membered, saturated or unsaturated heterocyclic group containing one or two nitrogen atom(s) or a sulfur atom as the heteroatom, and
R
2
stands for a hydrogen atom, or
R
1
forms together with R
2
a C
5-7
cycloalkyl group optionally condensed with a benzene ring,
Y means a hydrogen atom, a hydroxy group, a C
1-30
alkanoyloxy group or a C
3-22
alkenoyloxy group,
X is a halo atom, a hydroxy group or an amino group,
R
3
represents a C
3-7
cycloalkyl group or a group of the formula —NR
4
R
5
,
wherein
R
4
and R
6
mean, independently, a hydrogen atom, a C
1-5
alkyl group, a C
1-5
alkanoyl group, or
R
4
and R
6
form with the adjacent nitrogen atom a 5- or 6-membered, saturated or unsaturated heterocyclic group that may contain also an oxygen atom and can be condensed with a benzene ring, wherein the heterocyclic group and/or the benzene ring may be substituted by one or two substituent(s) selected from the group consisting of a C
1-2
alkyl group, a C
1-2
alkoxy group or a halo atom,
and pharmaceutically suitable acid addition salts thereof.
From HU-P No. 177 578 and its equivalent U.S. Pat. No. 4,308,399, O-/3-(substituted amino)-2-hydroxy-1-propyl/-(substituted amidoximes) suitable for the treatment of diabetic angiopathy are known, wherein the substituents of the amidoxime are other than an alkenyl group.
The known compounds and other related hydroximic acid derivatives possess other biological activities, too. Thus, they are suitable for the prevention and treatment of diseases of mitochondrial origin (PCT Application No. WO 97/13504); enhance the level of the molecular stress protein of the cells (HU-P Application No. P 95 03141) etc.
In PCT Application No. WO 90/08131, a novel process is described for the preparation of amidoxime derivatives of the formula
wherein R
1
represents a group having 2-15 carbon atoms which can be—among others—an unsaturated and/or cyclic alkyl group. In the cited document, the compounds of the formula A are treated as known ones, however, those compounds of the formula A, wherein R
1
stands for an alkenyl group or a cycloalkylidene group, are novel compounds that have not been prepared and characterized by identification data yet. In the Examples of the cited document, only compounds of the formula A, wherein R
1
is a pyridyl group, a chlorophenyl group, a benzyl group or a dimethoxybenzyl group, are described.
The aim of the invention is to provide novel compounds that can be used for the effective treatment of states connected with energy deficiency of the cell, in diabetes complications, in oxygen deficient states of the heart and brain, in neurodegenerative diseases as well as in the treatment of autoimmune and/or viral diseases.
It was found that the above aim is achieved by the novel unsaturated hydroximic acid derivatives of the formula I and pharmaceutically suitable acid addition salts thereof.
In the description and claims, a C
1-20
alkyl group is, for example, a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, n-decyl, dodecyl, hexadecyl or octadecyl group etc.
A C
1-2
alkyl group is a methyl or ethyl group, while a C
1-2
alkoxy group is a methoxy or ethoxy group.
A halo atom is, primarily, a fluoro, chloro or bromo atom, preferably a chloro atom or a bromo atom.
A C
1-4
alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group.
A C
1-5
alkyl group may include, for example, a n-pentyl group in addition to the ones listed under C
1-4
alkyl.
A C
1-4
alkanoyl group is preferably a formyl, acetyl, propionyl or butiryl group.
A C
1-5
alkanoyl group may include, for example, a n-pentanoyl group in addition to the ones listed under C
1-4
alkanoyl.
A 5- or 6-membered saturated or unsaturated heterocyclic group containing one or two nitrogen atom(s) or a sulfur atom as the heteroatom is, for example, a pyrrolyl, pyrazolyl, imidazolyl, thienyl, pyridyl, piperidyl, pirimidinyl, piperazinyl group etc.
A C
3-7
cycloalkyl group is, for example, a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl group.
A C
5-7
cycloalkyl group optionally condensed with a benzene ring is, for example, a cyclopentyl, cyclohexyl, cycloheptyl, indanyl or tetralinyl group.
A C
1-30
alkanoyloxy group is, for example, a formyloxy, acetoxy, propionyloxy, butiryloxy, palmityloxy or steryloxy group etc.
A C
3-22
alkenoyloxy group may contain 1-6 double bond(s) and can be preferably a linolenoyloxy, linoloyloxy, docosahexaenoyloxy, eicosapentaenoyloxy or arachidonoyloxy group.
A 5- or 6-membered saturated or unsaturated heterocyclic group containing a nitrogen atom or a nitrogen and an oxygen atom as the heteroatom is, for example, a pyrrolyl, pyridyl, piperidyl or morpholino group.
The pharmaceutically acceptable acid addition salts of the unsaturated hydroximic acid derivatives of the formula I are the acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid etc., or with pharmaceutically acceptable organic acids such as acetic acid, fumaric acid, lactic acid, tartaric acid, succinic acid, malic acid, benzene sulfonic acid, p-toluene sulfonic acid etc.
Due to the double bond present in formula I, the novel unsaturated hydroximic acid derivatives of the invention may exist in the form of geometrical isomers i.e. cis or trans isomers or any mixtures thereof. The invention includes the pure geometrical isomers and the mixtures thereof.
In addition, certain compounds of the formula I contain one or more chiral carbon atom(s), consequently, these compounds may exist in the form of optical isomers, too. The invention includes also the optical isomers and any mixtures thereof.
A preferred subgroup of the unsaturated hydroximic acid derivatives of the invention consists of the compounds of the formula I, wherein
X represents an amino group,
Y stands for a hydroxy group,
R
3
means a C
3-7
cycloalkyl group or a group of the formula —NR
4
R
5
,
wherein
R
4
and R
6
represent, independently, a C
1-5
alkanoyl group, but one of them can be also a hydrogen atom, or
R
4
and R
6
form together with the adjacent nitrogen atom a 5- or 6-membered saturated or unsaturated heterocyclic group that is condensed with a benzene ring and may contain also an oxygen atom, wherein the heterocyclic group and/or the benzene ring may be substituted by one or two substituent(s) selected from the group consisting of a C
1-2
alkyl group, a C
1-2
alkoxy group or a halo atom, and R
1
represents a C
14-20
alkyl group, a phenyl group optionally substituted by 1-3 substituent(s) selected from the group consisting of a C
1-2
alkyl group, a C
1-2
alkoxy group, a halo atom, an amino group, a (C
1-4
alkyl)amino group, a di(C
1-4
alkyl)-amino group or a di(C
1-4
alkanoyl)amino group, furthermore R
1
represent
Literáti Nagy Péter
Sümegi Balázs
Takács Kálmán
Birch & Stewart Kolasch & Birch, LLP
Davis Brian J.
N-Gene Research Laboratories Inc.
LandOfFree
Unsaturated hydroximic acid derivatives as per abstract... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Unsaturated hydroximic acid derivatives as per abstract..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Unsaturated hydroximic acid derivatives as per abstract... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2928937