Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Definitions

• the present invention relates to indolo (2, 3-a) quinolizidines, their methods of preparation and the therapeutic compositions containing them.
• R represents -COOC 2 H 5 ; COOH; CN, a primary or secondary amino methylene group, a methylenido group, or in which R, with the indolo ring nitrogen, represents one of the groups N-CO-NH-CH 2 or N-CO; the latter derivatives are D homo azaeburnamonines or D eburnamonines.
• the present invention also relates, where appropriate, to the acid addition salts of the above compounds.
• R can be, for example, a methylenaminocarbalcoxy, a methylaminoaryloxycarbonyl, a methyleaminoalkanoyl, a methyleaminoalkyl or a substituted methylenideido group.
• R can represent COOH, NH 2 , methylenaminocarbethoxy, methylenamino- (trimethoxy-3,4,5) -benzoyl, methylenaminophenoxycarbonyl, methylenideidodiethylaminoethyl, methylenaminopentanoyl, methylenaminopentyl and amidopiperyl.
• compositions therapeutic comprising one or more of these compounds mixed with a diluent or support for therapeutically acceptable reactions.
• the above compounds can be prepared according to the present invention, by condensing together aminoethyl-2-indole-3 and chloro-1-chlorocarbonyl-4- (A) -4-hexane, where A represents -COOC 2 H 5 or -CN, to form the corresponding amide; by subjecting the amide to a strongly basic agent to eliminate HCl and carry out the formation of a cycle with the nitrogen atom on the substituent indole3; by carrying out the formation of a quinolizidine cycle of the product by the action of a dehydrating agent then of a perchlorate; hydrogenating the quinolizidinium perchlorate obtained to produce the isomeric mixture of indolo (2,3-a.) quinolizidine and separating the isomers; the corresponding reaction schemes are represented below under the title "Common initial sequence" and lead only to the compounds where R is -COOC 2 H 5 or -CN (2 isomeric forms in each case, that is to say 4 compounds) .
• - 1 (a) to 1 (i) are references to the different steps of Example 1 where the starting material is the derivative of ethoxycarbonyl-4 and the final products, acids or derivatives thereof, and - 2 (a) to 2 (g) are references to the different steps of Example 2, where the starting product is the cyano-4 derivative and the final products, methylamino derivatives.
• Example 1 The present invention is illustrated by the following examples: Example 1
• a solution of 6.25 g (0.0147 mole) of the perchlorate salt of the previous step in 80 ml of ethanol is hydrogenated for 12 hours in the presence of 0.3 g of platinum oxide. After filtration, the ethanol is evaporated under reduced pressure and the residue taken up with methylene dichloride and stirred with 5% sodium hydroxide. The organic phase is decanted and washed with distilled water.
• the hydrochloride is obtained by treatment with HCl in hydroalcoholic solution. Mp 225 ° C.
• 107.426 C O; -13.712 CH; -82.162 CH.
• the CN peak at around 2250 cm is absent.
• phenoxycarbonylaminomethyl-1-ethyl-1-indolo (2, 3-a) quinolizidine (12b-H; 1-C 2 H 5 trans-isomer) is prepared according to the method of Example 3, but in replacing ethyl chloroformate with phenyl chloroformate.
• the hydrochloride is prepared by treating the above oil, with hydrochloric acid in 20 ml of ethanol, then by centrifuging. The yield is 60%, calculated on the starting amine (II) .F ⁇ 260 ° C. The product precipitates with 1/2 mole of water of crystallization.
• the corresponding derivative of phenoxycarbonylamino-methyl-1-ethyl-1 is prepared, 7 g of the trans II derivative of Example 2 (f) and 100 ml of tetrahydrofuran are placed in a 500 ml three-necked flask, provided with 'an agitator and two bromine bulbs. The flask is cooled to 0-5 ° C. and, at this temperature, 4.25 g of phenyl chloroformate in 50 ml of tetrahydrofuran and 2.9 g of sodium bicarbonate in 50 ml are simultaneously added of water (the quantities added were calculated so as to maintain the pH at 6-7). The mixture is then allowed to warm to ambient temperature, and the mixture is stirred for 3 hours. The product is extracted with 100 ml of methylene chloride, and the extract is washed several times with water before being dried with sodium sulfate and concentrated by evaporation. 11 g of the product, which is an oil, are obtained.
• the ureidomethyl-1 product is prepared as follows:
• the first step gave 4.6 g of crystals, melting at 202 ° C, and the second step, 0.8 g of crystals, melting at 198 ° C.
• the combined products are then recrystallized from benzene to give 4.65 g of the final product.
• Example 5 Using conditions and techniques identical to those of Example 5, a solution of 5.7 g of the trans derivative of Example 2 (f) and 2.1 g of triethylamine in 120 ml of chloride is reacted. methylene, and a solution of 2.45 g of pentanoyl chloride in 20 ml of methylene chloride. 7.8 g of an oil which contains one is therefore obtained. little triethylamine residue.
• the acid addition salt is prepared with maleic acid in solution in a mixture of isopropanol and di-isopropyl ether. Initially, the salt appears as an oil, but can be recrystallized from ethyl acetate to give 6.7 g of dimaleate, melting at 105 ° C.
• the hydrochloride is obtained by adding 4N HCl to a solution of the base in a 1: 1 mixture of ethanol and ethyl ether.
• Example 3 The process of Example 3 is repeated, except that the cis derivative (I) of Example 2 (g) is used instead of the trans derivative (II) of Example 2 (f). 2.1 g of free base are obtained (yield 84%). Mp 210 ° C.
• the hydrochloride is obtained by the action of 4N hydrochloric acid in acetone.
• Example 6 The procedure is first carried out as in the first part of Example 6, using the cis derivative I of Example 2 (g) instead of the trans derivative II of Example 2 (f).
• the LD 50 was determined per os on mice.
• the compounds of the invention have a toxicity comparable to that of vincamine or lower.
• the most toxic (LD 50: 400 mg / kg: vincamine 450 mg / kg) are those of Examples 2 (f), 3 and 4; the least toxic are those of Examples 5, 10 and 12 while the remaining compounds exhibit intermediate toxicity.
• the compounds of the present invention can be administered i.v. or per os in doses comparable to those used for vincamine (dosage units containing from 5 to 40 mg).

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• Organic Chemistry (AREA)
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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• Chemical Kinetics & Catalysis (AREA)
• Bioinformatics & Cheminformatics (AREA)
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• General Chemical & Material Sciences (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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• 1978
  • 1978-11-15 ZA ZA00786426A patent/ZA786426B/xx unknown
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  • 1978-11-24 FR FR7833176A patent/FR2409755A1/fr active Granted
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  • 1978-11-24 FR FR7833175A patent/FR2423492A1/fr active Granted
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• 1979
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• 1980
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• 1982
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• 1984
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• 1985
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