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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
  • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • 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
  • A61P9/08—Vasodilators for multiple indications
• • 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
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  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
  • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/37—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
  • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes

Definitions

• the present invention relates mainly to the field of neurology and relates to new derivatives of 1,2-ethylene diamine structure substituted ⁇ and their acharically acceptable salts thereof.
• These compounds are ligands with high af ⁇ finity for sigma receptors and they have a very high selectivity for these receptors. They are useful for the treatment of psychotic disorders, convulsions, dyskinesias and brain suffering consecutive to episodes of hypoxia, anoxia or ischemia associated with cerebral, cardiac or perinatal attacks. . They also have anxiolytic properties and can be used for this purpose.
• these compounds are indicated in inflammatory conditions and more particularly those which involve cell-mediated immune reactions.
• Sigma receptors are therefore currently the subject of intense research, not only in the field of psychotropic substances [JM Walker, WD Bowen, FO Walker, RR Matsumoto, B. De Costa and KC Rice, Pharmacological Reviews, 1990, 42, 355-402], but also in the discovery of new neuroprotectants [MJ Pontecorvo, EW Karbon, S. Goode, DB Cissold, SA Borosky, RJ Patch and JW Ferkany, Brain Research Bul ⁇ letin, 1991, 26, 461-465].
• BMY 14802 opipramol
• 2-methylene-amino-pyrrolidine derivatives such as remoxipride
• European document EP 0290377 describes a class of benzamide derivatives having anti-arrhythmic activities only.
• the present invention is based on the discovery of a new class of compounds of 1,2-ethylene diamine structure substituted at ⁇ by a benzyl radical. Structurally, these molecules show that, compared to other sigma ligands of the pyrrolidinyl type, the aromatic radical Ar surprisingly provides absolute selectivity with respect to dopaminergic receptors. In addition, the amino function in ⁇ , even unsubstituted, confers a strong activity in vitro and in vivo.
• NMDA N-methyl-D-aspartate
• n is a selected number from 0 to 8.
• R 1 represents a hydrogen, an alkyl, branched alkyl, cycloalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl residue;
• 2, R3, R4, Rs and R ⁇ independently represent a hydrogen gene, an alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkoxylyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl , alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfinyl and arylsulfonyl;
• A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen radical, an alkyl radical, branched alkyl, cycloalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl;
• n is a selected number from 1 to 3;
• R2 and R3 taken together can form an unsaturated hydrocarbon ring from C 4 to Cs;
• Y is an alkyl, cycloalkyl, hydroxyalkyl, haalkyl, cycloalkylalkyl, adamantyl, alkoxyalkyl, aralkyl, aryl, alkenyl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, alkylsulfinyl, alkylsulfonyl, arylsulfonylsulfonyl residue aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, aryla ino, heteroarylamino, aralkyla- ino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio; each of the preceding groups Y can additionally carry one or more selected substituents among the hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxy
• Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, arylamino, heteroarylamino, aralkylamino, heteroaralkylamino, arylthio, heteroarylthio, aralkylthio, heteroalkyl; each of the preceding groups Ar can additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl ⁇ alkyl, adamantyl, alkoxyalkyl, haloalkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl, carboxyalkyl, alkanoyl, cyano, amino, nitro, monoalkylamino, dialkylamino, carboxy
• the invention also extends to all pharmaceutically acceptable salts.
• the present invention includes the racemic compounds corresponding to formula I and also the optically active enantiomers, especially those which have the absolute configuration in R 1 which has been fixed by a natural amino acid (L) precursor of synthesis.
• neurological disorders in particular psychotic disorders, dyskinesias, convulsions, episodes of hypoxia, anoxia or ischemia associated with cerebral attacks as well as the prevention of disorders of neurotoxic origin as well as those consecutive to neurodegenerative disorders, can be achieved by the administration of therapeutic doses of compound of formula I.
• n is a selected number from 0 to 8.
• R 1 represents a hydrogen, an alkyl residue from C1 to C3, branched alkyl, al kenyl, cycloal kyle, aral kyle, aryl, al ké ⁇ nyl al kyle, al kynylal kyl e;
• R2, R3, R4, R5 and R ⁇ independently represent a hydrogen, a C1 to C6 alkyl radical, branched alkyl, alkenyl cycloalkyl, hydroxyalkyl cycloalkylalkyl, alkoxyalkyl, aralkyl, aryl, alkenylalkyl, alkynylalkyl;
• A represents a single bond, an oxygen atom or a nitrogen atom substituted by a hydrogen residue, an alkyl residue of C1 to C3;
• R2 and R3 taken together can form an unsaturated hydrocarbon-based cycle from C 4 to C 5.
• Y is an alkyl, cycloalkyl, cycloalkylalkyl, ada ⁇ mantyl, aralkyl, aryl, alkenyl, alkenylalkyl, heteroaryl, aryloxy, heteroarylox, aralkoxy, heteroaralkoxy radical, each of the preceding groups Y can additionally carry one or more substituents selected from the groups hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, adamantyl, halo, haloalkyl, aralkyl, aryl, carboxyalkyl, alkanoyl, cyano, amino, monoalkylamino, dialkylamino, carboxyalkenyl and alkynyl radicals;
• Ar is a radical selected from the following radicals: aryl, heteroaryl, aryloxy, heteroaryloxy, aral ⁇ coxy, heteroaralcoxy, each of the preceding Ar groups may additionally carry one or more substituents selected from the radicals hydrogen, hydroxy, alkyl, branched alkyl, cycloalkyl, adamantyle, halo, haloalkyle, aralkyle, aryle, carboxyalkyle, alkanoyl, cyano, amino, monoalkylamino, dial- kylamino, carboxyalkenyl and alkynyl;
• alkyl used alone or joined with other terms such as "hydroxyalkyl”, extends to linear or branched hydrocarbon chains which can comprise up to 10 atoms such as ethyl, ethyl groups , n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neopentyl.
• cycloalkyl corresponds to cyclic radicals of 3 to 10 carbon atoms such as cyclopropyl and cyclohexyl.
• cycloalkylalkyle corresponds to cyclic radicals of 4 to 20 atoms which can be branched like the methylcyclopropyl radical or else polycyclic like the adamantyl radical.
• haloalkyl describes hydrocarbon chains where one or more carbon atoms of the alkyl chain are substituted by one or more halogen atoms, in particular bromine, chlorine or fluorine. This term also includes the terms monohaloalkyle and polyhaloalkyle where in this case an alkyl chain can be substituted by a combination of the various halogen atoms mentioned, for example it can be a trifluoromethyl group.
• hydroxyalkyl corresponds to linear or branched alkyl groups from Ci to Cio where one of the atoms can be substituted by a hydroxyl group.
• alkenyl and the term “alkenylalkyl” include linear or branched residues having 2 to 10 carbon atoms and containing at least one carbon-carbon double bond such as the allyl group while the group “alkinyl” and “al - kinylalkyl "must itself contain at least one carbon-carbon triple bond, for example the propargyl radical.
• alkoxyalkyl designates linear or branched chains containing an oxygen atom and an alkyl portion which may have up to 10 carbon atoms, such as for example the methoxy group. These latter radicals can themselves be substituted by halogen atoms to lead to the "haloalkoxyalkyl” groups.
• aryl applies to all aromatic hydrocarbon systems of Cs to Cio mono or polycyclic such as phenyl, naphthyl.
• heteroaryl includes aromatic systems containing one or more heteroatoms independently selected from oxygen, nitrogen or sulfur; they may be mono or polycyclic systems having 5 to 10 atoms such as the pyrrolyl, imidazolyl, thiazolyl, furanyl, pyridinyl, indolyl, benzothiophenyl, quinolinyl groups.
• the compounds of the invention correspond to formula I, they can be isolated in the form of a free base or else in the form of addition salts with pharmaceutically acceptable acids as medicaments; by way of nonlimiting examples, they may be mineral acids such as hydrochloric acid, hydrous acid, sulfuric acid, niric acid, or organic acids such as fumaric acid, maleic acid, oxalic acid, aryl or alkyl sulfonic acids. These compounds can be partially solvated, for example hydrated.
• the invention extends not only to racemic compounds, but also to optically active forms of the compounds and their salts.
• the chiral compounds can be prepared from chiral precursors such as natural amino acids, or else by conventional methods of fractional crystallization by reaction of the racemic form with an optically active acid such as levorotatory tartaric acid or dextro- gyre.
• the compounds of the invention correspond to formula I, they can be isolated in the form of a free base or else in the form of addition salts with pharmaceutically acceptable acids as medicaments.
• the invention extends not only to racemic compounds, but also to optically active forms.
• the compounds having the formula I can be prepared in a known manner. Two synthetic routes are illustrated in the examples below.
• R2 and / or R3 may represent a protective group for the primary amino function.
• the preferred protecting group is a t-Butyl carbamate (BOC).
• a deprotection step is therefore added after the acylation reaction when at least one of the R ⁇ and R3 is H.
• the starting compounds of ethylene-diamino structure corresponding to formula III generally come from ⁇ -amino- ⁇ -arylalkyl-carboxamides which are derivatives of aci ⁇ of natural amines or obtained by synthesis according to conventional methods.
• the precursor amino acids are chiral, the synthesis leads to optically active compounds.
• activation methods such as methods using the formation of a mixed anhydride or an imidazole derivative.
• a preferred method is that using a carbodimimide, such as dicyclohexylcarbodiimide in the presence of 1-hydroxybenzotriazole, which is an agent which limits the racemization phenomena.
• an additional deprotection step is carried out before or after the reduction.
• Diagram 2 represents the condensation of a derivative of natural or synthetic amino acid, on an amino part. This reaction is carried out according to the methods mentioned above, however, preference will be given to methods using a carbodimimide and combining a reagent to minimize the risks of racemization.
• Diagram 2 represents the condensation of a derivative of natural or synthetic amino acid, on an amino part. This reaction is carried out according to the methods mentioned above, however, preference will be given to methods using a carbodimimide and combining a reagent to minimize the risks of racemization.
• the derivative of formula VI leads to the type I compounds claimed after a reduction step, carried out according to the methods described above.
• a deprotection step can possibly be carried out before or after the reduction of the carboxamido function.
• the compound VI may be alkylated, for example according to conventional methods using alkyl halides in the presence of a base, by methods of reductive amination using sant an aldehyde and sodium cyanoborohydride, or to lead to an unsaturated heterocycle of pyrrole type according to the process described by M. Artico, F. Corelli, S. Massa and G. Stefancich, Synthesis, 1983, 931.
• R2 and / or R3 represent a hydrogen atom and R4 an alkyl residue
• the compound I thus substituted can itself serve as a substrate for conventional acylation or alkylation reactions depending on the final product of desired structure I .
• the chromatograms are observed in ultraviolet light with a wavelength of 254 nm and / or after revelation by spraying of common reagents. The observed Rf are indicated as well as the migration conditions.
• Example 1 Analogously to Example 1 (b), it is synthesized from 12 g (43 mM) of previous amide. 9.3 g (81.9%) of a colorless oil are obtained, which is used as described below.
• Example 1 (d) from 9.3 g (35 mM) of amine 2 (b) and from 6.9 g (35 mM) of 5-phenylvaleric acid chloride. Is isolated after chromatography on a silica column (eluent: 40% ethyl acetate - 60% hexane), 3.7 g (25%) of the expected product in the form of an oil.
• Example 1 (b) Similarly to Example 1 (b), starting from 6.4 g (31 mM) of the preceding product, 6.0 g of crude product used for the next step are isolated.
• the hydrochloride is produced in ether, from 1.4 g of product, after recrystallization from a dichloromethane mixture 70 ml - ether 30 ml, 1.4 g of (S) - (-) - N- hydrochloride are obtained ( 2-dimethylamino-3-phenylpropyl) -N- methyl-N- (5-phenyl) -valeramide.
• F 86-88 * C, pasty, hygroscopic.
• the N-dimethylation of methyl ester of (S) -phenyl-alanine is carried out according to the method described in 3 (b), starting from 21.55 g (100 M) of methyl ester of (S) -pheny- lananine, 16.7 g (80.6%) of (S) -N- (dimethylamino) -phenylalanine methyl ester are obtained.
• the medium is stirred for 24 hours, allowing it to gradually rise to ambient temperature, then filtered to remove the dicyclohexylurea formed during the reaction.
• the solvent is evaporated, the residue is taken up in ethyl acetate and after several washes with a saturated aqueous solution of NaHCO 3, the organic phase is dried over sodium sulfate and concentrated in vacuo.
• chromatography on a silica column eluent: 95% dichl oromethane - 5% methanol, 4.7 g (61.1%) of the expected product are obtained in the form of an oil, Rf: 0.5 in the eluent used for the purification .
• a 1 M alane (A1H3) solution is prepared by adding dropwise 0.5 equivalents of sulfuric acid at room temperature to a 1 M solution of lithium aluminum hydride maintained under stirring and at 20 ' vs. 60 ml of this freshly prepared solution are introduced into a 250 ml three-necked flask kept under a nitrogen atmosphere.
• the di-oxalate is prepared from 2.7 g (7.1 mM) of this oil and 1.26 g (14 mM) of oxalic acid.
• the product obtained is recrystallized from an ethanol-ether mixture (10-90). 2 g (50%) of a hygroscopic white powder of (S) - (+) - N- [2- (4-morpholino) -3-phenylpropyl] -N- methyl-N- ( 5-phenyl) -pentanam ne.
• F 82-84 "C.
• the pH of the solution is maintained at 5 by addition of acetic acid, then after stirring overnight at room temperature, the solution is cooled and the mixture is extracted with 2 times 100 ml of dichloromethane after having added sufficient potassium hydroxide. as a tablet to make it basic.
• the organic phase is washed with saturated sodium bicarbonate solution, then dried over sodium sulfate. After evaporation to dryness, 6.6 g of colorless oil are obtained. This oily residue is taken up in 60 ml of 6N hydrochloric acid and brought to reflux for 2 hours. After evaporation to dryness, the product is taken up in 70 ml of ethanol and 30 ml of propylene glycol and then brought to reflux.
• Example 4 According to the procedure described for Example 4 (e), the reduction of 2.0 g (5.26 M) of Tamide described in Example 13 used in its base form leads to 1.85 g (96 %) colorless oil.
• the di-oxalate is prepared according to the usual operating protocol, starting from the preceding oily residue, 1.85 g (67.7%) of di-oxalate from (S) - (+) - N- [2] are isolated - (1-buta- namino) -3-phenylpropyl] -N-methyl-N- (5-phenyl) -pentanamine under form of a very hygroscopic white powder.
• Table I represents the most remarkable compounds corresponding to formula I. The preparation of these representative compounds has been described in detail in the examples above.
• the binding of the compounds of the invention to the sigma sites is measured according to the technique described by BL Largent, AL Gundlach, and SH Snyder [Proc. Natl. Acad. USA., 1984, 81, 4983].
• the membrane preparations are made from rat brains (Sprague-Dawley, 150-170 g). Brains were weighed and homogenized with a Polytron in 25 volumes of Tris-HCl buffer pH 7.7 at + 4 ° C. The homogenate is then centrifuged at 45 000 g during 10 min and the supernatant removed.
• the centrifugation pellet is rinsed twice with Tris-HCl buffer pH 7.7 at +4 * C and then taken up in 80 volumes of Tris-HCl buffer pH 8.0 at +25 * C,
• the membrane fractions (0.4 ml) are then incubated in the presence of increasing concentrations of the reference drug (pe ⁇ tazocine 10 ⁇ 10 to 10 " 5 M) or of the products to be tested (10 ⁇ 10 to 10 " 5 M) and the ra ⁇ dioactive ligand ( [ 3 H] -Propyl-3- (3-hydroxyphenyl) piperidine ([ 3 H] - PPP), 3 nM, 90-120 Ci / mmol, New England Nuclear, Dupont de Nemours) for 120 min at room temperature.
• the reference drug pe ⁇ tazocine 10 ⁇ 10 to 10 " 5 M
• the products to be tested 10 ⁇ 10 to 10 " 5 M
• the ra ⁇ dioactive ligand [ 3 H] -Propyl-3- (3-hydroxypheny
• test ends by filtration through a Whatman GF / B filter under suction using a Brandel apparatus.
• the filters are rinsed 3 times with Tris-HCl buffer pH 7.7 at + 4 ° C.
• Non-specific binding is determined in the presence of 10 microM pentazo- film.
• the filters are distributed in counting bottles.
• the 3 H radioactivity was counted by scintillation in liquid medium using the scintillating medium Formula 989 (New England Nuclear, Dupont de Nemours) and a scintillation counter LS 6000 TA (Beckman).
• the binding of the compounds to the dopaminergic D 2 receptor is measured according to the method described by M. Terai, K. Hidaka, and Y. Nakamura. [Eur. J. Pharmacol. , 1989, 173, 177].
• striata of rats were weighed and homogenized with a Polytron in nine volumes of buffer 50 mM Tris, 5 mM EDTA, 8 mM MgCl2, pH 7.15 to 4 * C. The homogenate is then centrifuged at 18 000 g for 20 min and the supernatant is removed.
• the centrifugation pellet is taken up in 200 volumes of incubation buffer (Tris 50 mM, EDTA 1 mM, MgCl ⁇ 5 mM, CaCl2 1.5 mM, NaCl 120 M, 5 M KC1, 0.1% ascorbate and 10 ⁇ M pargyline, pH 7.15 at +25 "C.)
• the membrane fractions (0.4 ml) are then in ⁇ cubed in the presence of increasing concentrations of the reference drug.
• NMDA N-methyl1-D-aspartic acid
• the survival time (time of appearance of the 1st respiratory gasp) is measured in male Swiss mice (20 -25 g) exposed to an oxygen-poor atmosphere (96- * "N2, 4% O2) according to the technique described by JC Lamar, H. Poignet, M. Beaughard and G. Dureng, [Drug Development Research, 1988, 14, 297-304].
• the test products and the reference drug (vincamine 20 mg / kg) are injected i.p. 30 min before the start of the test.
• mice Male Swiss mice (20-25 g) are treated with dexamphetamine sulfate (8 mg / kg, ip) and then placed in 25 x 19.5 x 13.5 cm cages (10 mice per cage) [ MRA Chance, J. Pharmacol. , 1946, 87, 289-296]. Dead animals are counted 1, 2, 3, 4, 5 and 24 hours later. The products to be tested are injected i.p. 30 minutes before Tamphetamine. At a dose of 30 mg / kg, the compounds described in Examples 1 and 2 protect 90% of the animals.
• mice Male Swiss mice (20-25 g) are treated with dexamphetamine sulfate (8 mg / kg, i.p.) and placed in individual cages.
• the products to be tested are administered i.p. 30 mins before amphetamine. A significant decrease in stereotyped movements is observed with the molecules corresponding to Examples 2, 5 and 6 at a dose of 1 mg / kg.
• the doses administered to patients are between 0.1 and 10,000 mg per day. For a normal adult weighing 70 kg, these doses are between 0.001 to 100 mg / kg of body weight per day.
• the therapeutic doses can vary according to the clinical condition of the patient and are established by the person skilled in the art. Administration can be by enteral, parenteral, topical or ocular route.
• This invention also includes all of the pharmaceutical compositions containing the compounds of formula I in combination with all of the pharmaceutically acceptable adjuvants and ingredients.
• the drugs can be in the form of tablets, capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions.
• the preparation of oral forms may combine one or more of the following products: lactose, sucrose, starch, cellulose esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium or magnesium salts of phosphoric acid or of sulfuric acid, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohols nyl ic.
• compositions can be in the form of aqueous or nonaqueous sterile solutions or suspensions for infusion or for injection, these solutions or these suspensions can be prepared extemporaneously from sterile powders or granules which may contain one or more of the adjuvants mentioned above as well as an aqueous or non-aqueous vehicle.
• the pharmaceutical compositions based on the compounds according to the invention are in the form of ointments, tincture, cream, ointments, powders, suspensions, solutions, lotions, gels.
• the topical compositions preferably contain from 0.001 to about 5% by weight of compound (s) of formula (I).
• eye these are mainly eye drops or ointments.
• compositions according to the invention may also contain flavor-improving agents, preserving agents, stabilizing agents, moisture regulating agents, pH regulating agents, agents modifying osmotic pressure, agents, antioxidants.
• Example 2 the compound of Example 2 can be replaced by the same amount of compound of Examples 1 to 15.

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• 1993
  • 1993-04-20 ZA ZA932761A patent/ZA932761B/xx unknown
  • 1993-04-22 WO PCT/CH1993/000106 patent/WO1993022279A1/fr not_active Application Discontinuation
  • 1993-04-22 EP EP93907750A patent/EP0605667A1/de not_active Withdrawn
  • 1993-04-22 JP JP5518810A patent/JPH06509586A/ja active Pending
  • 1993-04-22 CA CA002112490A patent/CA2112490A1/en not_active Abandoned
  • 1993-04-22 AU AU38866/93A patent/AU3886693A/en not_active Abandoned

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