Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/013—Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
  • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered

Definitions

• the present invention relates to new therapeutic agents having a protective effect on the protemic complexes of the internal mitochond ⁇ al membrane, and which can be preferably used for the prevention and / or treatment of partial or total ischemia, pathologies associated with ischemia or associated with mitochondrial deficiencies, or apoptosis.
• Ischemia is an interruption of the blood supply to an organ or tissue by obliteration, compression or spasm of an artery. The consequences depend on the nature of the tissue deprived of oxygenated blood and the duration of the phenomenon.
• Total ischemia causes tissue death in a variable time depending on its oxygen requirements.
• Partial ischemia causes either a decrease in the organ's capacities (mental slowing down, insufficiency of the hepatic or renal functions, etc.), or the inability to modify its work at any stimulation, thus showing signs of suffering (crises angina pectoris, cramps of the artery). Ischemia is very harmful to the nervous tissue. Initially, it results in
• the international patent application WO98 / 51291 describes the use of different plant extracts for the treatment and / or prevention of ischemia or of pathologies associated with ischemia or with an energy deficit. This document also describes the mechanism of action of these molecules which allow inhibition of the activation cascade of endothelial cells induced by hypoxia as well as the protective effect of these products on certain mitochond ⁇ al deficiencies, in particular by a protective effect. of complexes I and III of the mitochond ⁇ es. This document proposes a biochemical model making it possible to obtain a protective effect of anti-ischemic compounds.
• Patent application EP-A-0 099 091 describes hexahydrodioxopyrimidme derivatives, their process for obtaining and their use as antiviral, antibacterial and antitumour compounds.
• Patent application FR-2,539,412 describes 5-fluorouracyl derivatives and their therapeutic use as carcostatic agents.
• the publication of Holwood et al. J " . Of Med. Chem. Vol. 10 No. 5 pp. 863-867 (1967)) described as local anesthetics, various derivatives, in particular 2-ethoxycarbonyl aceto-2 ', 6' -xylidide or its corresponding amide.
• Patent application WO97 / 16184 describes methods of treating ischemia consisting of: administration of an acyl inhibitor co-enzyme A cholesterol O acyltransferase (ACAT) such as N (2, 6-d ⁇ sopropyl -phenyl) -2 -phenyl-malonamic acid dodecyl ester and an inhibitor of HMG-co- enzyme A reductase.
• ACAT acyl inhibitor co-enzyme A cholesterol O acyltransferase
• the present invention aims to provide new compounds intended to induce a protective effect on the protemic complexes of the internal mitochond ⁇ al membrane and to be used in particular in the prevention or treatment of partial or total ischemia, of related pathologies ischemia or pathologies related to mitochond ⁇ al deficiencies.
• a particular object of the present invention is to provide compounds having improved activity and / or not having the side effects of molecules of the prior art.
• the present invention relates in particular to new compounds of formula I, their salts or prodrugs of such compounds:
• R 3 and / or R 4 represent:
• - Z represents O or S
• R5 represents H or an alkyl of 1 to 6 carbon atoms (preferably, R ⁇ represents a methyl or an ethyl),
• R ⁇ represents a hydrophobic group, preferably chosen from the group consisting of a terbutyl, an allyl or a ring (aromatic or non-aromatic) of 5, 6 or 7 carbon atoms optionally comprising one or more heteroatoms (preferably N, O or S) and in which the carbon atoms are optionally substituted by:
• an alkyl group R 7 of 1 to 6 carbon atoms preferably a methyl or an ethyl
• a ketone group preferably a methyl or an ethyl
• - Y represents S or O
• - R8 represents an alkyl group of 1 to 6 carbon atoms (preferably methyl or ethyl);
• R 4 represents an alkyl (preferably propene) of 1 to 10 (preferably 1 to 6) carbon atoms, saturated or unsaturated, optionally comprising one or more heteroatoms (preferably N, S or O).
• one or more carbons may optionally be substituted by a halogen element (fluorine, chromium, bromine or iodine) or a trifluoromethyl (CF3).
• R 3 and R 4 preferably represent an amine of formula -NR ⁇ or
• R ⁇ a group of formula -ZR 6 in which R 5 represents H or methyl, Z represents O or S (preferably O), and R ⁇ represents a cyclopentene, a cyclohexane or a benzene group.
• R 1 is CH2
• R 3 is a compound of formula ZR 6 in which Z represents O, R ⁇ represents an ethyl
• R 3 is an amine of formula NH-R 6 'in which R ⁇ ' represents a cyclic compound (optionally substituted in position 2 by a hydroxyl group) and the compounds of formula I in which R ⁇ is CH2
• R 3 and R 4 are amines of formula NH-R 6 in which R 6 represents a ring with 6 carbon atoms substituted in position 2 by a hydroxyl group.
• R 1 represents a C1-C6 alkyl group
• A represents a saturated or msaturated ring containing 3 to 7 carbon atoms
• each of the symbols R 2 , R 3 and R 4 independently represents a hydrogen or halogen atom or a group such as a C1-C6 alkoxy group, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxycarbonyl, carboxyl, carboxamido, sulfonic acid, sulfonamido, acylamino, sulfonylammo, C1-C6 alkylsulfonyde, nit ⁇ le, nitro, acyloxy, phenyl or methylene -dioxy and each of the symbols m and n represents an integer ranging from 0 to
• RA represents an alkyl
• R 2 a hydrogen or an alkyl
• the aromatic or non-aromatic rings optionally comprise one or more heteroatoms, preferably one or more oxygen or sulfur atoms, and in which the atoms of carbon are substituted by ketone, hydroxyl or ester groups or by a halogen element as described above.
• the preferred compounds of the invention are chosen from the group consisting of d ⁇ cyclopenten-2 -yle malonate, 2-propenyl 3 -oxa-2 -oxobicyclo
• mineral acids such as hydrochloric, hydrobromic, sulphuric, nitric, phosphoric acids, etc.
• organic acids such as acetic, citric, tartaric, benzoic, salicylic, maleic, etc.
• the present invention also relates to the first application of the compounds of formula I as a medicament, as well as their salts and the prodrugs of said compounds, with the exception of the following known compounds: N- (2, 6-d ⁇ sopropyl- phenyl) -2 -phenyl-malonamic acid dodecyl ester and the compounds of formula I in which R ⁇ is
• R 4 is a group of formula ZR 6 in which Z represents an oxygen and R ° represents an alkyl and in which R 3 is a cord of formula II: NO alkyl
• R -'- represents a C1-C6 alkyl group
• A represents a saturated or unsaturated ring containing 3 to 7 carbon atoms
• each of the symbols R 2 , R 3 and R 4 independently represents a hydrogen or halogen atom or a group such as a C1-C6 alkoxy group, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxycarbonyl, carboxyl, carboxamido, sulfonic acid, sulfonamido, acylamino, sulfonylamino, C1-C6 alkylsulfonate, nitrile, nitro, acyloxy, phenyl or methylene-dioxy and each of the symbols m and n represents an integer ranging from 0 to 4.
• prodrugs means functional derivatives of the compounds of formula I which can be converted, preferably in vivo, in the patient according to the required form of formula I.
• prodrugs of these compounds can be obtained by methods well known to those skilled in the art such as those described in the document "Design and Prodrugs", Ed. H. Bundgaard, Elsevier (1985).
• the compounds of the invention relate to the two enantiomeric forms, the different separate isomers or a mixture of them.
• the new compounds of the invention are advantageously used to obtain a protective effect on the protemic complexes of the internal mitochondrial membrane of the cells of a mammal, preferably a human.
• the compounds of the present invention find particular application in the prevention and / or treatment of partial or total ischemia, of pathologies associated with ischemia or of pathologies associated with mitochondrial deficiencies.
• ischemia partial or total
• pathologies associated with ischemia and pathologies associated with mitochond ⁇ al deficiencies means the diseases, preferably vascular, chosen from the group consisting of myocardial infarction, cerebral ischemia, chronic venous insufficiency, arteriopathies, i.e.
• Another aspect of the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a suitable pharmaceutical vehicle or excipient and a sufficient amount of one or more of the compounds of the invention, that is to say an amount sufficient for at least ameliorate or prevent the above symptoms in a mammal, especially a human.
• the sufficient amount may vary depending on certain factors such as the condition of the animal to be treated, the mode of administration, the severity of the side effects, the stability of the compound in the serum or the circulating blood, etc. .
• the sufficient amount of compound used in the pharmaceutical composition of the invention is between 0.1 and 200 mg / patient, preferably between 1 and 50 mg / patient, preferably between 20 and 30 mg / patient, this quantity being able to be adapted in particular according to the administration doses required and the patient's weight, as can be extrapolated from the examples of application in vivo below
• the pharmaceutical composition comprises a suitable pharmaceutical vehicle which can vary according to the mode of administration and can optionally be combined with an adjuvant so as to improve the therapeutic properties of the compound of the invention or to reduce its possible side effects.
• suitable pharmaceutical vehicles or adjuvants are well known to those skilled in the art and can be prepared according to the procedures generally applied by pharmacists and can include any non-toxic, solid (including powdered), liquid pharmaceutical vehicle.
• the percentage of active pharmaceutical compound can vary depending on the frequency of administration and possible side effects on animals, including humans.
• compositions in the form of tablets, granules, capsules or cachets, suspensions, etc., it is possible to incorporate elements such as corn starch, lactose, sucrose, sorbitol , talc, stearic acid, magnesium stearate, gums or diluents comprising a variable percentage of water or a solvent such as a syrup, oily or aqueous suspensions, perfumed emulsions, etc.
• Dispersible agents used in aqueous compositions can include gums, algae, dextrans, carboxymethyl cellulose derivatives, etc.
• the present invention also relates to a method of therapeutic or preventive treatment of ischemia or pathologies linked to ischemia as mentioned above comprising the administration of a sufficient amount of the compound of formula I or of the pharmaceutical composition of the invention to said patient, preferably a human, so as to prevent, reduce or eliminate the symptoms of ischemia, pathologies linked to ischemia or associated with mitochondrial deficiencies, or apoptosis, with the additional condition that the compound is not N- (2, 6-d ⁇ sopropyl -phenyl) -2 -phenyl - malonamic acid dodecyl ester nor a compound of formula I in which R 1 is CH2, R 4 is a group of formula
• a final aspect of the present invention relates to the use of these compounds or of the pharmaceutical composition of the invention for the preparation of a medicament intended for the treatment or prevention of ischemia, pathologies linked to the 'ischemia or associated with mitochond ⁇ ale deficiencies as mentioned above or apoptosis with the additional condition mentioned in the previous paragraph.
• the present invention also relates to the process for the preparation of the compounds of the invention of formula I, comprising the following steps: - esterification of an intermediate compound R 3 -H by a group of formula
• Step 1 In a 250 ml t ⁇ col flask, equipped with an addition funnel and a condenser, the diethyl malonate (20.00 g; 124.87 mmol) is dissolved in 80 ml ethanol (commercial). The colorless mixture obtained is stirred at room temperature and a KOH solution
• a milky white mixture is obtained which is stirred at 0 ° C for 1 hour then at room temperature until complete reaction (control of the progress of the reaction by TLC, eluent Pentane / ethyl acetate: 8/2).
• the precipitate is removed by filtration on celite and washed with dichloromethane.
• the filtrate is washed with a saturated aqueous solution of NaHCO3 (10 ml).
• the phases are separated and the aqueous phase is extracted with dichloromethane (3x10 ml).
• the combined organic phases are washed successively with a saturated aqueous NaCl solution and with water, then dried over anhydrous MgS04 and concentrated.
• the precipitate is again removed by filtration on celite and washed with pentane.
• the purification of the reaction crude is carried out by chromatography on a silica column (elution Pentane / Ethyl acetate: 8/2) to give the compound of the invention (MCR2P45) (1.39 g; 84%) in the form of an oil colorless.
• Step 2 In a 50 ml three-necked flask, equipped with a magnetic stirrer, an addition funnel and a thermometer, the potassium methyl malonate (10.27 g; 65.76 mmol) is dissolved in 10 ml of water. The reaction mixture is cooled using an ice-cold bath and 5.5 ml of concentrated hydrochloric acid are slowly added. The reaction mixture is filtered and the KCl precipitate is washed with ether (3x10 ml). The filtrate is decanted and the aqueous phase is extracted with ether (3x10 ml).
• a milky white mixture is obtained which is stirred at 0 ° C for 1 hour then at room temperature until complete reaction (control of the progress of the reaction by TLC, eluent Pentane / ethyl acetate: 8/2).
• the precipitate is removed by filtration on celite and washed with dichloromethane.
• the filtrate is washed with a saturated aqueous solution of NaHC ⁇ 3 (10 ml).
• the phases are separated and the aqueous phase is extracted with dichloromethane (3x10 ml).
• the combined organic phases are washed successively with a saturated aqueous NaCl solution and with water, then dried over anhydrous MgSO4 and concentrated.
• the precipitate is again removed by filtration on celite and washed with pentane.
• the purification of the reaction crude is carried out by chromatography on a silica column (elution Pentane / ethyl acetate: 8/2) to give the compound of the invention (MCR2P85) (1.40 g; 83%) in the form of an oil colorless.
• ethyl malonic acid (1.00 g; 7.57 mmol) is introduced into 8 ml of dry dichloromethane.
• the flask is cooled to 0 ° C by means of an ice bath.
• 1.5 equivalents (0.83 ml; 11.35 mmol) of thiony chloride diluted in 5 ml of dichloromethane are slowly added.
• the reaction mixture is stirred at 0 ° C for 10 minutes and then heated at reflux for 2 days.
• concentration ethyl chloroformyl ethanoate (0.99 g; 87%) is isolated, which is used without additional purification in the next step.
• the colorless mixture obtained is cooled to 0 ° C. via an ice bam and added slowly syringe with ethyl chloroformyl ethanoate (1.3 ml; 10.15 mmol).
• An intense red / orange solution is obtained which is stirred at 0 ° C for 1 night (monitoring the progress of the reaction by TLC) (eluent Pentane / Ethyl acetate: 1/9), then, approximately 4 ml of a 10% HCl solution are added.
• the two phases are separated and the organic phase is washed with water (3x10 ml).
• the combined aqueous phases are extracted with dichloromethane.
• the organic phase is washed with a saturated aqueous solution of NaCl and then dried over anhydrous MgSO4. After filtration and concentration, the crude ester amide is obtained in the form of an orange solid.
• the purification is carried out by recrystallization from a Pentane / ethyl acetate mixture to provide the compound of the invention (MCR2P255) (1.67 g; 67%) in the form of an unbleached powder.
• Example 8 Synthesis of N-methyl -N-cyclohexamido ethanoate of ethyl e
• N-methyl N-cyclohexylamme (0.41 ml; 3.12 mmol) in 20 ml of dry dichloromethane
• the triethylamme (0.54 ml; 3.91 mmol).
• the colorless mixture obtained is cooled to 0 ° C. by means of an ice bam and ethyl chloroformyl ethanoate (0.5 ml; 3.91 mmol) is slowly added to it with a syringe.
• the purification is carried out by chromatography on a silica column (eluent Pentane / ethyl acetate: 1/9) to provide the compound of the invention (MCR2P237) (0.71 g; 100%) in the form of an orange liquid.
• the compounds of the invention are characterized by the inhibition of the decrease in ATP content, of the activation of phospholipase A2 and adhesion of polymorphonuclear neutrophils (PMN) on human umbilical vein endothelial cells in culture when these are incubated under hypoxic conditions.
• the inhibition by the compounds of the invention of the activation cascade of endothelial cells induced by hypoxia and the maintenance of the ATP content in endothelial cells under hypoxia are obtained by the compounds of the invention which preserve mitochond ⁇ ale respiratory activity.
• RCR respiratory control
• the mitochondria are isolated according to the method described by Nowicki et al. , J. of Cerebral Blood Flow and Metabolism 2, pp. 33-40 (1982).
• Mitochondrial respiration is measured by an oxygen electrode linked to a recorder.
• the RCR represents respiratory control, and represents the relationship between oxygen consumption in the presence of endogenous substrate (glutamate / malate) and consumption after phosphorylation of ADP to ATP. This technique has been described by Chance & William (Na ture 175, pp. 1120-1121 (1955)).
• Example 1 significantly increases the RCR of mitochond ⁇ es, and this because this molecule greatly decreases stage IV of respiration.
• the effect is optimal at 10 " ⁇ mol / 1 and decreases with concentration to be negligible at 10 " ⁇ mol / 1.
• the table below summarizes the effect of other compounds of the invention with the optimal concentrations at which these effects have been observed.
• the results show that the compounds of the invention are capable of reproducibly protecting the decrease in ATP content induced by hypoxia in endothelial cells.
• the maximum average protection of 92.5% is observed at a concentration by 10 -4 mol / 1 for the compound of Example 2. This protection decreases with the concentration of this compound to be negligible at 10 -8 mol / 1.
• the results also show that the compound of Example 1 is capable of reproducibly protecting the decrease in ATP content induced by hypoxia in endothelial cells.
• the average maximum protection of 92.1% is observed at concentrations of 10 -4 to 10- ⁇ mol / 1. This protection decreases with the concentration of this compound to be negligible at 10 -8 mol / 1.
• Example 11 Stability in Human Plasma The compounds of Examples 1 and 2 were subjected to stability tests in order to evaluate their behavior in contact with the plasma after an incubation of 3 and 24 hours at a temperature of 37 ° C. These tests were carried out by GC following the evolution of the chromatograms of the different esters compared to an internal standard as a function of time. The injection of the pure products in GC / MF was carried out under the following conditions:
• the different compounds were prepared as follows. 10 ⁇ l of pure compound were dissolved in 100 ⁇ l of plasma at a temperature of 37 ° C.
• the sample is centrifuged for 10 mm at a speed of 13,000 rpm. 1 ⁇ l of the supernatant phase
• Example 12 In vi tro effect on the adhesion of neutrophils to endothelial cells incubated under hypoxia
• Endothelial cells were incubated under hypoxia in the presence of different concentrations of the compounds of the invention. After incubation, the cells are co-incubated with a suspension of unstimulated human neutrophils. Under normoxic conditions, the adhesion of neutrophils to endothelial cells is low (5 to 10%), but it increases on the order of 3 times under hypoxia.
• the effect of the compound of Example 1 on the adhesion of neutrophils to endothelial cells incubated under hypoxia is characterized by an inhibition of the adhesion induced by hypoxia, and this in a manner dependent on the concentration between 10 " ⁇ and 10 -8 mol / 1.
• An optimum activity should be obtained between 10 ⁇ 7 and 10 " 5 mol / 1.
• the compound of Example 2 inhibits the increase in the adhesion of neutrophils induced by hypoxia between 10 " ⁇ and 10 -8 mol / 1 with a maximum of 71% at 10 -8 mol / 1 .
• EXAMPLE 13 In Vivo Effect on the Liver After Treatment of Rats Per Orally for 5 Days The rats were treated per os either with solutions of increasing concentration of each of the compounds of the invention, or with batches containing DMSO at the same concentration as that used to dissolve the molecules (control rats) once a day for 5 days. Following the treatment, the rats are sacrificed. The mitochond ⁇ es are isolated from the liver and their respiratory activity is measured every 15 mm during the 75 mm following the isolation procedure.
• the optimal pre-mcubation concentration for the compound of Example 1 is 10 ⁇ mol / 1 (0.236 ⁇ g / 1).
• the dose used to treat rats is therefore 2.36 mg / kg, and doses 5 times less, 5 times higher and 20 times higher were also tested.
• the optimal concentration in pre-mcubation is 10 " 'mol / 1 (0.0183 ⁇ g / ml).
• the doses tested are therefore 0.18 mg / kg Given that this dose was weakly active, doses 5 times higher and 20 times higher were also tested.
• the compound of example 1 increases in a dose-dependent and significant manner the RCR of the hepatic mitochond ⁇ es after a treatment of 5 days with a 25% increase to 2.36 mg / kg At a higher dose, the molecule becomes slightly toxic and the RCR drops slightly below the control values. This increase in RCR is due to a marked decrease in stage IV of breathing.
• the compound of Example 2 increases dose-dependent and significantly the RCR of the mitochondria with a maximum of 17% at 3.6 mg / kg. This increase in CPR is also due to a decrease in stage IV breathing.
• EXAMPLE 14 In Vivo Effect on the Heart After Treatment of Rats Per Orally for One Day The rats were treated per os with the concentrations of 2.36 mg / kg of compound of Example 1 or 3, 6 mg / kg of compound of Example 2, either with batches containing DMSO at the same concentration as that used to dissolve the molecules (control rats) at a rate of once.
• the compound of Example 1 increases the RCR of the cardiac mitochondria after a day's treatment with an increase of 41% at 2.36 mg / kg
• the compound of Example 2 increases the RCR of the mitochondria after a one day treatment with an increase of 56% to 3.6 mg / kg.
• Promyelocytic cells are incubated in the presence of agents inducing apoptosis such as etoposide, a type II topoisomerase inhibitor. After incubation, various parameters indicative of apoptosis are detectable: activation of caspases, release by the mitochond ⁇ es of cytochrome c, DNA fragmentation, etc. Unexpectedly, if the cells are incubated in the presence of etoposide and in the presence of the compound of Example 1, an inhibition of the induction of apoptosis is observed. This inhibition is dependent on the dose between 10 -5 and 10 "8 mol / 1. Thus, the activation of caspase 3, the release by the mitochondria of cytochrome c and the fragmentation of DNA are inhibited.
• agents inducing apoptosis such as etoposide, a type II topoisomerase inhibitor.
• various parameters indicative of apoptosis are detectable: activation of caspases, release by the mit

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• 1999
  • 1999-10-15 EP EP99870212A patent/EP1092432A1/de not_active Withdrawn
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