Anti-ischemic compounds

Details Anti-ischemic compounds Anti-ischemic compounds

2002-07-30

2004-08-24

Owens, Amelia A. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S300000, C514S301000, C514S302000, C514S421000, C514S457000, C514S464000, C514S465000, C549S283000, C549S285000, C549S305000, C549S306000, C548S453000, C546S113000, C546S114000, C546S115000, C546S183000

Reexamination Certificate

active

06780887

ABSTRACT:

RELATED APPLICATION DATA
This application is a National Phase application under 35 U.S.C. §371 of International Application Number PCT/EP00/10085, filed Oct. 11, 2000 which claims priority to European Application Number 99870212.0 filed Oct. 15, 1999.
OBJECT OF THE INVENTION
The present invention relates to new therapeutic agents with a protective effect on proteinic complexes of the inner mitochondrial membrane and that can be used preferably for preventing and/or treating partial or total ischemia, pathologies associated with ischemia or associated with mitochondrial deficiencies, or apoptosis.
INVENTION-BASED TECHNOLOGICAL BACKGROUND
Ischemia is an interruption of the blood irrigation of an organ or a tissue through artery obliteration, compression or spasma. The consequences depend on the nature of the tissue being deprived of oxygenated blood and the phenomenon duration. Total ischemia leads to tissue necrosis in a period of time variable according to the oxygen needs. Partial ischemia causes either a reduction of the organ capabilities (psychic slowing down, hepatic or kidney function insufficiency, etc.) or the incapability to modify its work at any stimulation, showing then signs of pain (angina pectoris crises, arteritis cramps). Ischemia is very deleterious for the nerve tissue. It is first to be seen in reversible metabolic and functional troubles that can lead to an abnormal nervous activity, for example, an epilepsy crisis or some cerebral cortex ischemic lesions. After a few minutes of ischemia, irreversible lesions of the nervous tissue appear, accompanied with cellular body swelling followed by necrosis thereof. This is called cerebral infarction.
It is known to use agonist molecules for alpha-adrenergic receptors and agonist molecules for alpha-pre-synaptic receptors for treating ischemia. Such compounds are used at the heart level for treating angor, which is a clinical expression of acute myocardial ischemia and the result of a temporary imbalance between the myocardium oxygen demand and the oxygen intake through circulation, leading possibly, in serious cases, to a myocardial infarction.
STATE OF THE ART
The use of various plant extracts for treating and/or preventing ischemia or pathologies associated with ischemia or an energy deficiency is described in International Patent Application WO 98/51291. This document also describes the working mechanism of said molecules that allow an inhibition of the activation cascade of the endothelial cells induced by hypoxia as well as the protective effect of such products on some mitochondrial deficiencies, particularly with a protective effect of the mitochondria complexes I and III. This document gives a biochemical model making it possible to obtain in vitro a protective effect from anti-ischemic compounds.
The Publication by Ukrainets I. et al. (
Tetrahedron Letters
Vol. 50, n° 34, p. 10331-10338 (1994)) describes derivatives and the malonic acid synthesis, particularly an ethyl malonic acid ester and symmetrical diamylides.
Malonic acid derivatives and their use for delaying plant growth are described in International Patent Application WO 87/05898.
The Publication by Venuti et al. (
J. of Med. Chem.
Vol. 31, p. 2145-2152 (1988)) describes, by way of an intermediate compound, a malonic acid derivate involved in the synthesis of compounds being used as prodrugs.
The Publication by Oumar-Mahamat et al. (
Tetrahedron Letters
Vol. 30, n° 3, p. 331-332 (1989)) describes cyclic malonic acid derivates.
Patent Application EP-A-0,099,091 describes hexahydrodioxypyrimidine derivates, the production method thereof and their use as antiviral, anti-bacterial and antitumor compounds.
Patent Application FR-2,539,412 describes 5-fluorouracyl derivates and their therapeutic use as carcinostatic agents.
The Publication by Holwood et al. (
J. of Med. Chem.
Vol. 10, n° 5, p. 863-867 (1967)) describes as local anesthetics, various derivates, more particularly 2-ethoxycarbonyl-aceto-2′,6′-xylidide or its corresponding amide.
The Publication by McLaughlin et al. (
J. of Neurochem.
Vol. 70, p. 2406-2415 (1998)) describes the effect of dopamine on the mitochbndrial inhibition compared to that of methylmalonate.
Patent Application WO97/16184 describes methods for treating ischemia comprising the step of administrating an acyl-co-enzyme A cholesterol O acyltransferase (ACAT) inhibitor such as dodecyl N-(2,6-diisopropylphenyl)-2-phenyl-malomanic acid ester and a HMG-co-enzyme A reductase inhibitor.
AIMS OF THE INVENTION
The aim of the present invention is to provide new compounds designed to induce a protective effect on protein complexes of the inner mitochondrial membrane and designed to be used particularly for preventing or treating partial or total ischemia, pathologies associated with ischemia or pathologies associated with mitochondrial deficiencies.
A particular aim of the present invention is to provide compounds with an improved activity and/or with no side effects of molecules in the state of the art.
CHARACTERISTIC ELEMENTS OF THE INVENTION
The present invention relates particularly to new compounds of formula I, the salts thereof and prodrugs of such compounds:
wherein:
R
1
is CH
2
, NH or a ligand, preferably a carbon atom, forming together with R
3
and/or R
4
an aromatic or non-aromatic ring having 5 or 6 carbon atoms (n=1 or 2), optionally comprising on each ring an heteroatom, preferably a nitrogen, oxygen or sulfur atom;
R
3
and/or R
4
represent:
an amine with the formula:
a group having the formula —Z—R
6
wherein:
Z represents O or S,
R
5
represents H or an alkyl group with 1 to 6 carbon atoms (preferably, R
5
represents a methyl or ethyl group),
R
6
represents an hydrophobic group, preferably selected amongst the group consisting of a tert-butyl group, an allyl group or a (aromatic or non aromatic) ring having 5, 6 or 7 carbon atoms optionally comprising one or more heteroatoms (preferably N, O or S) and wherein the carbon atoms are optionally substituted for by:
an alkyl group R
7
having 1 to 6 carbon atoms (preferably, a methyl or ethyl group),
a ketone group,
a hydroxyl group,
an ester group,
a halogen element (F, Cl, Br or I),
a trifluoromethyl (CF
3
) group, or
a group having the formula:
wherein:
W represents CH or a nitrogen atom,
Y represents S or O, and
R
8
represents an alkyl group having 1 to 6 carbon atoms (preferably a methyl or ethyl group),
with the additional condition that, if R
3
forms together with R
1
said above-mentioned ring or if R
3
is either an amine of formula:
R
4
represents an alkyl group (preferably a propene) having 1 to 10 (preferably 1 to 6) carbon atoms, either saturated or unsaturated, optionally comprising one or more heteroatoms (preferably N, S or O). Additionally, in said alkyl group, one or more carbons can optionally be substituted for by an halogen element (fluorine, chlorine, bromine or iodine) or a trifluoromethyl group (CF3).
In the compounds having formula I, R
3
and R
4
preferably represent an amine having the formula:
a group having the formula —Z—R
6
wherein R
5
represents H or a methyl group, Z represents O or S (preferably O) and R
6
represents a cyclopentene, a cyclohexane or a benzene group.
According to the invention, are excluded as compounds already described in the state of the art, compounds having the formula I wherein R
1
is CH
2
, R
3
is a compound having the formula Z—R
6
wherein Z represents O, R
6
represents an ethyl group, R
3
is an amine having the formula NH—R
6′
wherein R
6′
represents a cyclic compound (optionally 2-substituted with an hydroxyl group) and compounds having formula I wherein R
1
is CH
2
, R
3
and R
4
are amines having the formula NH—R
6
wherein R
6
represents a ring having 6 carbon atoms 2-substituted by an hydroxyl group.
Also excluded from the invention, as already described compounds, are the compounds described in tables 1, 2, and A in the Application WO87/05898, the dodecyl N-(2,6-diisopropylphenyl)-2-phenyl-malonamic acid ester and the compound having the formul

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