Classifications

• • 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
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton

Definitions

• the present invention relates to derivatives of 2- ⁇ henylethylamine which have anti-obesity and/or anti-hyperglycaemic activity, to processes for their production and to their use in medicine.
• R 1 is hydrogen, halogen or trifluoromethyl
• R 2 is hydrogen or methyl
• X is -O(CH 2 ) x CO 2 H or -O(CH 2 ) Y M in which x is an integer from 1 to 6, y is an integer from 2 to 7, and
• M is hydroxy , C 1 -6 alkoxy or in which
• R 3 and R 4 are each hydrogen or C 1-6 alkyl ,
• R 1 is halogen, preferably in the metaposition.
• x is 1 and y is 2.
• Particularly preferred compounds are those wherein R 2 is methyl.
• M is one of R 3 and R 4 is preferably hydrogen and the other is C 1- 6 alkyl, preferably methyl or ethyl.
• Pharmaceutically acceptable salts of compounds of formula (I) include acid addition salts formed with a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, orthophosphoric acid, sulphuric acid, methane sulphonic acid, toluenesulphonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid or acetylsalicylic acid.
• Preferred esters of the compounds of formula (I) are C 1-6 alkyl esters of the compounds wherein X is -O(CH 2 ) x CO 2 H. Particularly preferred esters are methyl and ethyl esters.
• Preferred amides of the compounds of formula (I) are those wherein X is converted to a group of the formul -O(CH 2 ) x CONR 3 R 4 , where R 3 and R 4 are as defined in formula (I).
• R 2 When R 2 is methyl, the carbon atom bearing it is asymmetric.
• the compounds may, therefore, exist in two stereoisomeric forms.
• the present invention encompasses both stereoisomers whether free or admixed in any proportion, and thus includes a racemic mixture of isomers.
• the present invention also provides a process for producing a compound of formula (I), or a salt, ester or amide thereof, which process comprises reducing a double bond and/or cleaving a benzyl group of a compound of formula (II):
• R 1 and R 2 are as defined in relation to formula
• R 5 is a group X as defined in relation to formula
• R 6 is hydrogen or together with R 7 forms a bond
• R 7 is hydrogen or benzyl or together with R 6 or
• R 8 forms a bond
• R 8 is hydrogen or together with R 7 forms a bond
• the aforementioned reductions may be effected by conventional chemical methods or by catalytic methods.
• chemical reduction may be effected with lithium aluminium hydride, sodium cyanoborohydride, sodium borohydride or borane methyl sulphide.
• Catalytic hydrogenation may be carried out using catalysts such as palladium on charcoal, or platinum, for instance, as reduced platinum oxide.
• Reduction by sodium borohydride is conveniently effected in a lower alkanolic solvent such as methanol or ethanol.
• the reaction is generally carried out at from 0-20°C.
• Reduction by lithium aluminium hydride is conveniently effected in a dry, ether solvent such as diethyl ether or tetrahydrofuranat ambientorelevatedtemperatures.
• Catalytic reduction is conveniently effected in a conventional hydrogenation solvent such as a lower alkanol, for instance ethanol.
• the hydrogenation is generally carried out under hydrogen gas at about 1 to 10 atmospheres pressure and at ambient or elevated temperatures.
• Reduction of a compound of formula (II) wherein R 7 is benzyl is conveniently effected by catalytic hydrogenation, preferably using palladium on charcoal as catalyst.
• Preferred aspects of the process of the invention comprise reducing a compound of formula (IIA):
• the present invention also provides a further process for producing a compound of formula (I), which comprises reacting an amine of formula (III):
• Z represents a leaving group, preferably halogen or a tosyloxy group
• reaction of a compound of formula (III) with a compound of formula (IV) is conveniently carried out in a solvent, preferably dimethyl sulphoxide, at elevated temperature, preferably 50°C, for about two or three days.
• a solvent preferably dimethyl sulphoxide
• the salts of compounds of formula (I) may be produced by treating the compound of formula (I) with the appropriate acid.
• reaction is conveniently conducted at elevated temperature under conditions resulting in the removal of the water formed during the reaction.
• a particularly suitable method is to perform the reaction in a solvent, such as benzene, under reflux and to remove the water azeotropically using a It is often convenient to prepare the compound of formula (II) and reduce it, in situ, to the desired compound of formula (I) without isolation of the compound of formula (II).
• Those compounds of formula (I) having an asymmetric carbon atom may be separated into individual stereoisomers by conventional means such as by the use of an optically active acid as a resolving agent.
• Suitable optically active acids which may be used as resolving agents are described in 'Topics in Stereochemistry', Vol. 6, Wiley Interscience, 1971, Allinger, N.L., and Eliel, W.L. Eds.
• individual stereoisomers may be prepared by stereospecific syntheses using optically active starting materials.
• a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof may be administered as the pure drug, however, it is preferred that the drug be administered as a pharmaceutical composition also comprising a pharmaceutically acceptable carrier.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof with a pharmaceutically acceptable carrier therefor.
• compositions of the present invention embracecompositions and ingredients for both human and Usually the compositions of the present invention will be adapted for oral administration although compositions for administration by other routes, such as by injection are also envisaged.
• compositions for oral administration are unit dosage forms such as tablets and capsules.
• Other fixed unit dosage forms, such as powders presented in sachets, may also be used.
• the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or the like.
• Typical carriers may, therefore, comprise such agents as microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate, sucrose and the like.
• composition will be provided in unit dose form.
• unit doses will normally comprise 0.1 to 1000 mg of the drug, more usually 0.1 to 550 mg and favourably 0.1 to 250 mg.
• the present invention further provides a method for treating obesity in human or non-human animals, which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof to obese humans or non-human animals.
• the present invention further provides a method for treating hyperglycaemia in humans or non-human animals which method comprises administering an effective, non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof to hyperglycaemic humans or non-human animals.
• the drug may be administered as a pharmaceutical composition as hereinbefore defined, and this forms a particular aspect of the present invention.
• the drug may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be about 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
• the drug may be administered by mouth, usually once or twice a day and at about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.
• Methyl 4-(2-oxopropyl) phenoxyacetate (2.22g) and 2-(3chlorophenyl) ethanamine (1.56g) in methanol (80ml) were hydrogenated in the presence of platinum (from platinum oxide, 50mg) until hydrogen uptake ceased.
• the mixture was filtered through diatomaceous earth and the solvent was removed under reduced pressure.
• the residue in diethyl ether was treated with a solution of hydrogen chloride in ether and the solvent removed under reduced pressure to give the title compound m.p. 132-3°C (methanol/ethyl acetate).
• mice Female CFLP mice, weighing approximately 25 g, were fasted for 24 hours prior to the study. The compounds under study were administered orally as an aqueous solution to each of 6 mice. 30 minutes later a blood sample (10 ul) was obtained from the tail for the analysis of blood glucose. Immediately after taking this blood sample, glucose ( lg/Kg body weight) was administered subcutaneously to each mouse. 6 mice were given water as a control. Blood samples were then obtained from each mouse at 30 minute intervals for 120 minutes.
• mice Female CFLP mice, each weighing approximately 24 g were given food and water ad lib before and during the experiment. The compounds were dissolved in water by addition of one mole of hydrochloric acid per mole of compound and these solutions were administered orally to each of 12 mice. A further 12 mice were dosed orally with water. The mice were placed in boxes through which air was drawn and the oxygen content of the air leaving the boxes was measured. The energy expenditure of the mice was calculated for 3 hours after dosing from the volume of air leaving the boxes and its oxygen content, following the principles described by J.B. de V. Weir, J. Physiol. (London), 109, 1-9 (1949).

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Citations (5)

• 1983
  • 1983-04-19 GB GB838310556A patent/GB8310556D0/en active Pending
• 1984
  • 1984-03-27 EP EP19840901385 patent/EP0140922A1/de not_active Withdrawn
  • 1984-03-27 WO PCT/GB1984/000101 patent/WO1984004091A1/en unknown

Patent Citations (5)

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