Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
  • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
  • C07C49/782—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic
  • C07C49/788—Ketones containing a keto group bound to a six-membered aromatic ring polycyclic with keto groups bound to a condensed ring system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides

Definitions

• This invention comprises novel derivatives of malearnic acid and in particular those derivatives wherein a hydrogen of the amino group of nraleamic acid is replaced by a naphthyl-lower alkyl radical and more particularly by derivatives wherein the lower alkylene chain of the naphthyl-lower alkyl substituent is additionally substituted by one or more groups such as by a lower alkyl, phenyl, benzyl, and the like radicals, or is substituted by any combination of these radicals.
• R is a straight chain alkylene radical having at least one and no more than three carbon atoms in the chain connecting the naphthyl radical and the nitrogen of the amino group of maleamic acid; in other words, R is a methylene, ethylene or propylene radical, each valence of the said alkylene radicals being satisfied by one of the following: (a) hydrogen, (b) a lower alkyl radical having from 1 to 10 carbon atoms, and preferably having up to 6 carbon atoms in a straight or branchedchain or alicyclic, such as a methyl, isoor normal-propyl, isoor normal-butyl, amyl, hexyl, cyclopentyl, cyclohexyl, and the like, (c) a mononuclear aryl, preferably a phenyl radical
• the compounds of this invention posses a 'variety of properties and are especially useful because they inhibit the excretion of penicillin through the kidney tubules thus providing prolonged blood levels of penicillin. Because of this property the new compounds of this invention are useful as adjuvants for use in conjunction with the administration of penicillin to provide an increase in the blood plasma pencillin concentration with a given dose of penicillin, thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin for providing, a given blood level, or permitting less frequent administration of penicillin while maintaining a penicillin blood level adequate for bactericidal or bacteriostatic purposes.
• Some of the compounds additionally enhance the excretion of uric acid from the body and therefore are useful agents in the treatment of gout or gouty arthritis and in alleviating symptoms of these conditions and of complications associated with gout and gouty arthritis.
• naphthylalkyl-maleamic acids or their salts or simple esters can be administered in conventional dosage forms such as in a capsule, pill or tablet either with or without therapeutically inert materials and with or without other therapeutically active substances or in the form of a sterile solution and the like.
• the maleamic acid'derivatives of this invention possess one or more of the above properties to varying degrees, the compounds having a (l-naphthyl)-lower alkylene or a (2-naphthyl)-lower alkylene radical attached to the amino nitrogen of rnaleamic acid, and especially 1- or 2-naph-thylethylmaleamic acids which also have attached to the ethylene chain a lower alkyl group, and especially a methyl radical, possess one or more of the above described properties to a marked degree.
• the maleamic acid derivatives of this invention are easily prepared by bringing together a solution of the selected naphthyl-lower-alkylamine and a solution of maleic anhydride.
• the reaction between the ingredients occurs quite readily at room temperature accompanied by the precipitation of the maleamic acid derivative from the reaction mixture, which then can be separated by known conventional methods, as by filtration or evaporation of the solvent and the like.
• Ether has been found to be an effective solvent for the naphthyl-lower-alkylamine as well as for maleic anhydride, although other solvents could be used in its place.
• naphthylalkylamines used in preparing the :rnaleamic acid derivatives of this invention are new compounds which can readily be prepared by one or another of the many well-known methods for preparing naphthylalkylamines.
• a carbonyl compound is converted by means of the Leuckart reaction to the desired naphthylalkylamine. This reaction involves heating the carbonyl compound (i.e., a ketone or an aledhyde) with formamide and formic acid preferably under reflux conditions to form the formamide derivative of the desired naphthylalkylamine.
• This compound after hydrolysis with a mineral acid, such as hydrochloric acid, generally is isolated either (a) as an acid addition salt thereof, such as the hydrochloride salt, which may be insoluble in the reaction medium or (b) by treatment of the reaction medium with alkali, such as sodium hydroxide, to obtain the free base, which then is extracted with a solvent, such as ether, and purified by distillation of the base.
• a mineral acid such as hydrochloric acid
• the selected nitriles can be reacted with a Grignard reagent thus forming the corresponding ket-imine.
• the ketimine then is hydrolyzed to the corresponding carbonyl .compound and the latter product converted by means of the Leuckart reaction (supra) to the naphthylalkylamine.
• novel maleamic acid derivatives of this invention as well as their intermediate naphthylalkylamines, which contain one asymmetric carbon atom in the ethylene or propylene radical will-.be obtained as racemic mixtures which can be separated into the dextrorotatory and levorotatory isomers by known methods.
• novel maleamic acid derivatives of this invention as well as the corresponding naphthylalkylamines, which contain two asymmetric carbon atoms in the ethylene or propylene radical will be obtained as diasterioisomers.
• diasterioisomer having the higher melting point is considered to be the wisomer and that having the lower melting point is considered to be the fl-isomer.
• While greater activity may reside in one or another of the oc-isomer or fi-isomer or in the dextroor levorotatory antipode of one or another of these isomers, in general, mixtures of their racemates can be employed for one or another of the uses identified above for which the individual compound may possess the desired property.
• the acid extract is refluxed for two hours, cooled and extracted with a mixture of ether and benzene 1:1) (250 ml.). The extract is washed with sodium carbonate and saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is distilled to give 10.4 g. of 1-(1-naphthyl)-l-hexanone, B.P. 133 C. at 0.4 mm. pressure.
• Step B Preparation of 1 -(1 -naphthyl -hexylamine.-A mixture of the ketone prepared in Step A 10.2 g., 0.045 mole), formamide (8.1 g., 0.18 mole) and a few drops of formic acid is placed in a flask equipped with a condenser set for downward distillation. The mixture is heated at l75l80 C. (internal temperature) for 14 hours. Whenever the vapors above the reaction mixture become basic, a few ml. of formic acid is added. The reaction mixture then is extracted with benzene, the henzene evaporated and the residue mixed with concentrated hydrochloric acid (10 ml.).
• Step C Preparation of N-[1-(1-naphthyl)-1-hexyl]- maleamic acid.An ether (30 ml.) solution of the amine prepared in Step B (5.68 g., 0.025 mole) is added slowly to an ether (30 ml.) solution of maleic anhydride (2.45 g., 0.025 mole). A clear solution results which gradually deposits a solid. After 16 hours, the precipitate is collected and Washed with ether. The solid is crystallized from a mixture of methanol and water to give 4.46 g. of N-[1-(1-naphthyl)-l-hexyl]-maleamic acid, M.P. 136- 137 C.
• Step A Preparation of l -(L-naplithj l)Z-methylpropylamine-By replacing theketone employed in Example 5, Step 13, by l naphthyl isopropyl ketone (10.8 g., 0.053 mole) and following substantially the same procedure described in Step B of Example 5 there is obtained 7.5 g. of 1-(l-naphthyl)-2-methylpropylamine, B.P. 112-114" C. at 0.2 mm; pressure.
• Step B Preparation of N-[1-(I-naphthyl)-2-methyl-I- propyl] analeamic acid.
• the amine (4.97 g., 0.025 mole) prepared in Step A is reacted with maleic anhydride (2.45 g., 0.025 mole) by substantially the same procedure de scribed in Example 5, Step C, to give N-[l-(l-naphthyl) 2-methyl-1-propyl]-maleamic acid which, after crystallization from a mixture of benzene and hexane, melts at 141-142 C.
• Step A Preparation of 1 -(1 -naphthyl -amylam'ine.By replacing the ketone used in Example 5, Step B, by naphthyl)-l-pentanone (10.0 g., 0.047 mole), (prepared from butyl magnesium bromide and l-naphthyl cyanide by the method described in Example 5, Step A) and following subs ant a ly the same procedure described in Example 5, Step B, there is obtained 7.1 g. of 1-( l-naphthyl) amylamine, B.P. 119123 C. at 0.1-0.2 mm. pressure.
• Step B Preparation of N-[1-(1-naphthyl)-1-amyl]- maleamic acid.-The amine (6.94 g., 0.03 mole) obtained in Step A is reacted with maleic anhydride (2.94 g., 0.03 mole) by substantially the same method described in Example 5, Step C, to give N-[1-(1-naphthyl) 1-amyl]-maleamic acid which, after crystallization from a mixture of isopropyl alcohol and water, yields 7 g. of product, M.P. 153-154 C.
• Step B Preparation of N-[a-(l-naphthyl)-hexahydr0- benzyl1-maleamic acid.
• the amine (6.0 g., 0.025 mole) obtained in Step A is reacted with maleic anhydride (2.45 g., 0.025 mole) by substantially the same method described in Example 5, Step C, to give N-[a-(1-naphthyl)- hexahydrobenzyH-maleamic acid that separates as an oil and then solidifies after standing at room temperature for several hours.
• Step B Preparation of N[] -(1-Naphthyl) -3-butyl]- maleamic acid.-Reaction of equimolecular quantities of the above amine and maleic anhydride by substantially the same procedure described in Example 5, Step C, gives N[1-(l-naphthyl)-3-butyl]-maleamic acid.
• Step A Preparation of 1-(Z-naphthyl)-3-butylamine.
• Step B By replacing the ketone used in Example 5, Step B, by an equimolecular quantity of 1-(2-naphthyl)-3butanone, and following substantially the same procedure described in 6 Example 5, Step B, there is obtained 1-(2-naphthy1)-3- butylamine.
• Step B Preparation of N-[I-(Z-naphthyl)-3-batyl]- maleamic acid.Reaction of equimolecular quantities of the above amine and maleic anhydride by substantially the same procedure described in Example 5, Step C, gives N[ l-(2-naphthyl)-3-butyl]-ma1eamic acid.
• N-(napht-hyl-R)-ma1eamic acid having the structural wherein R is an alkylene group having from 1 to 3 carbon atoms linked together in a straight chain between the naphthyl radical and the nitrogen atom of the maleamic acid residue, each remaining valence of said alkylene group being satisfied by a radical selected from the group consisting of hydrogen, lower alkyl, cyclohexy-l and phenyl.
• N-( 1-naphthyl-3 -lower alkyl) -maleamic acid N-( 1-naphthyl-3 -lower alkyl) -maleamic acid.

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• 1962
  • 1962-02-08 US US171829A patent/US3277166A/en not_active Expired - Lifetime
• 1963
  • 1963-02-06 FR FR923926A patent/FR1519485A/fr not_active Expired
  • 1963-05-03 FR FR933674A patent/FR2584M/fr not_active Expired

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