EP0140922A1 - Pharmaceutically active 2-phenylethylamine derivatives - Google Patents

Pharmaceutically active 2-phenylethylamine derivatives

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Publication number
EP0140922A1
EP0140922A1 EP19840901385 EP84901385A EP0140922A1 EP 0140922 A1 EP0140922 A1 EP 0140922A1 EP 19840901385 EP19840901385 EP 19840901385 EP 84901385 A EP84901385 A EP 84901385A EP 0140922 A1 EP0140922 A1 EP 0140922A1
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EP
European Patent Office
Prior art keywords
formula
compound
hydrogen
pharmaceutically acceptable
amide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19840901385
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German (de)
French (fr)
Inventor
Barrie Christian Charles Cantello
Richard Mark Hindley
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Beecham Group PLC
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Beecham Group PLC
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Publication date
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Publication of EP0140922A1 publication Critical patent/EP0140922A1/en
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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)

Abstract

Composés de formule (I) ou son amide, son ester ou son sel pharmaceutiquement acceptable, où R1 représente un hydrogène, un halogène ou un trifluorométhyle, R2 représente un hydrogène ou un méthyle, X représente -O(CH2)xCO2H ou -O(CH2)yM, où x est un nombre entier de 1 à 6, Y est un nombre entier de 2 à 7 et M représente un hydroxy, un alkoxy contenant de 1 à 6 atomes de C ou (II), où R3 et R4 représente chacun un hydrogène ou un alcoyle comportant de 1 à 6 atomes de carbone, ou (III) forment ensemble un cycle à 5 ou 6 éléments; ce composé est utile pour le traitement de l'obésité ou de l'hyperglycémie.Compounds of formula (I) or its amide, its ester or its pharmaceutically acceptable salt, where R1 represents a hydrogen, a halogen or a trifluoromethyl, R2 represents a hydrogen or a methyl, X represents -O (CH2) xCO2H or -O ( CH2) yM, where x is an integer from 1 to 6, Y is an integer from 2 to 7 and M represents hydroxy, an alkoxy containing from 1 to 6 atoms of C or (II), where R3 and R4 represents each hydrogen or alkyl having 1 to 6 carbon atoms, or (III) together form a 5 or 6 element ring; this compound is useful for the treatment of obesity or hyperglycemia.

Description

Pharmaceutically active 2-phenylethylamine derivatives
The present invention relates to derivatives of 2-ρhenylethylamine which have anti-obesity and/or anti-hyperglycaemic activity, to processes for their production and to their use in medicine.
According to the present invention there is provided a compound of formula (I):
or a pharmaceutically acceptable salt, ester or amide thereof, in which
R1 is hydrogen, halogen or trifluoromethyl
R2 is hydrogen or methyl
X is -O(CH2)xCO2H or -O(CH2)YM in which x is an integer from 1 to 6, y is an integer from 2 to 7, and
M is hydroxy , C1 -6 alkoxy or in which
R3 and R4 are each hydrogen or C1-6 alkyl ,
or together form a five or six membered ring.
Preferably, R1 is halogen, preferably in the metaposition.
Preferably x is 1 and y is 2.
Particularly preferred compounds are those wherein R2 is methyl.
When M is one of R3 and R4 is preferably hydrogen and the other is C1- 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 C1-6 alkyl esters of the compounds wherein X is -O(CH2)xCO2H. 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(CH2)xCONR3R4, where R3 and R4 are as defined in formula (I).
When R2 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 absolute configuration of any compound of formula (I) may be determined by conventional X-ray crystallographic techniques.
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):
wherein
R1 and R2 are as defined in relation to formula
(I)
R5 is a group X as defined in relation to formula
(I) or a group reducible to the group X
R6 is hydrogen or together with R7 forms a bond
R7 is hydrogen or benzyl or together with R6 or
R8 forms a bond;
R8 is hydrogen or together with R7 forms a bond
and optionally thereafter forming a salt of the a (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I).
Where there are two reducible functional groups in the compound of formula (II) these may be reduced separately in any order or simultaneously.
The aforementioned reductions may be effected by conventional chemical methods or by catalytic methods. Suitably, 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 R7 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):
or reducing a compound of formula (IIB):
or reducing a compound of formula (IIC)
wherein R1, R2 and X are as defined in relation to formula (I), and R5 is as defined in relation to formula (II). =^~~-
The present invention also provides a further process for producing a compound of formula (I), which comprises reacting an amine of formula (III):
A - NH2 (III)
in which A represents:
in which R1, R2 and X are as defined in relation to formula (I),
with a compound of formula (IV): in which B represents :
in which R1, R2 and X are as defined in relation to formula (I),
and Z represents a leaving group, preferably halogen or a tosyloxy group,
with the proviso that A and B are simultaneously different, and optionally thereafter forming a salt of the compound of formula (I) so formed and/or converting the compound of formula (I) so formed into a further compound of formula (I).
The 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.
The salts of compounds of formula (I) may be produced by treating the compound of formula (I) with the appropriate acid.
Compounds of formula (I) and salts thereof, produced by the above processes, may be recovered by conventional methods. Compounds of formula (II) may themselves be produced by reacting an amine of formula (III) as hereinbefore defined, with a compound of formula (V)
or its hydrate or hemi-acetal of a lower alkanol;
or a compound of formula (VI)
wherein R1, R2 and X are as defined in relation to formula (I)
Conventional conditions compatible with the particular compound of formula (V) or (VI) may be used for this ^reaction. Thus, the 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.
Alternatively, 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 (hereinafter 'the drug') 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.
Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, ester or amide thereof with a pharmaceutically acceptable carrier therefor.
As used herein the terms 'pharmaceutical composition' and 'pharmaceutically acceptable' 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.
Particularly suitable 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.
In accordance with conventional pharmaceutical practice 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.
Most suitably the composition will be provided in unit dose form. Such 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.
Conveniently, the drug may be administered as a pharmaceutical composition as hereinbefore defined, and this forms a particular aspect of the present invention.
In treating hyperglycaemic or obese humans 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.
In treating hyperglycaemic or obese animals, especially dogs, 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.
The invention will now be illustrated with reference to the following Examples.
In the Examples, the substituents in formula (I) are as shown in the following Table:
EXAMPLE 1
Methyl 4-[2-(2-(3-Chlorophenyl) ethylamino)propyl]phenoxyacetate hydrochloride
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).
1H nmr δ((CD3)2SO):
1.15 (3H,d); 2.5-3.55 (7H, complex); 3.7 (3H,s), 4.75 (2H,s); 6.85 (2H,d); 7.05-7.45 (6H, complex), 9.2-9.8 (2H, broad s, exchangeable).
EXAMPLE 4
N-Methyl 4-[2-(2-(3-chlorophenyl) ethylamino) propyl]phenoxyacetamide hydrochloride monohydrate
A mixture of methyl 4-[2-(2-(3-chlorophenyl) ethylamino)¬propyl]phenoxyacetate (6.7g) in a 33% solution of methylamine in ethanol was heated under reflux for 3 hours and the solvent was removed under reduced pressure. Chromatography on silica gel in 5% methanol-dichloromethane gave an oil which was treated with a solution of hydrogen chloride in ether to give the title compound m.p. 188-189°C (methanol-ethyl acetate).
1H nmr δ((CD3)2SO) + D2O
1.15 (3H,d); 2.45-3.50 (10H, complex); 4.45 (2H,s); 6.85 (2H,d); 7.05-7.5 (6H, complex).
EXAMPLE 3
N-Methyl 4-[2-(2-(3-Chlorophenyl)ethylamino)propyl]phenoxyethanamine dihydrochloride
To a cooled solution of N-methyl 4-[2-(2-(3-chlorophenyl) ethylamino)propyl] phenoxyacetamide (3.5g) in tetrahydrofuran under nitrogen was added borane/methyl sulphide complex (2ml) dropwise with stirring. After stirring at room temperature for 2 hours the mixture was boiled under reflux for 2 hours, cooled to room temperature and methanol (2ml) was added dropwise. The mixture was allowed to stand at room temperature overnight, cooled in ice and hydrogen chloride was bubbled through the solution for thirty minutes. After boiling under reflux for thirty minutes ether was added and the mixture was filtered to give the title compound m.p. 232-6 ºC (methanol-ethyl acetate).
1H nmr δ((CD3)2SO) :
1.15 (3H,d); 2.40-3.50 (12H, complex); 4.20 (2H,t),
6.65-7.30 (8H, complex), 9.10-9.70 (4H, broad s, exchangeable).
Methyl 4-[2-(2-phenylethylamino)propyl]phenoxyacetate hydrochloride
Methyl 4-(2-oxopropyl)phenoxyacetate (2.22g) and 2-phenylethylamine (1.21g) were reacted together by a similar procedure to that described in Example 1 to give an oil. After chromatography on silica-gel in 2% methanol-dichloromethane, treatment of a solution of this oil in ether with a solution of hydrogen chloride in ether gave the title compound, ra.p. 127-8°C (methanol-ether).
1H nmr S(CD3) 2SO:
1.15 (3H,d); 2.5-3.45 (7H, complex); 3.7 (3H,s); 4.7 (2H,s); 6.85 (2H,d), 7.05-7.45 (7H, complex), 9.25-9.8
(2H, broad s, exchangeable).
DEMONSTRATION OF EFFECTIVENESS OF COMPOUNDS
a) Anti-hyperglycaemic activity
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.
Compounds that produced a significant (P<0.05) reduction of blood glucose, compared with control mice given water, at any time interval, were considered active. The area under the blood glucose curve over the 2 hour period after the administration of the glucose was calculated for each compound and compared with the value for control animals.
Compounds of Dose % Reduction in area under
Example No. (μmol/Kg) Blood Glucose Curve
1 10 .0 45
2 25.0 47
3 12.5 20
(b) Effect on Energy Expenditure
The effect of the compounds on the energy expenditure of mice was demonstrated by means of the following procedure: 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).
Compounds of Dose Mean Energy Expenditure
Example No. mg/kg po (0-3 h)
1 19.9 144
2 20.8 117
4 18.2 147

Claims

1) A compound of formula (I):
or a pharmaceutically acceptable salt, ester or amide thereof, in which
R1 is hydrogen, halogen or trifluoromethyl
R2 is hydrogen or methyl
X is -0(CH2)xCO2H or -0(CH2)YM
in which x is an integer from 1 to 6, y is an integer from 2 to 7, and
M is hydroxy, C1-6 alkoxy or
in which
R3 and R4 are each hydrogen or C1-6 alkyl,
or together form a five or six membered ring.
2) A compound according to claim 1, in which R1 is hallogen in the meta-position.
3) A compound according to claim 1 or claim 2, in which x is 1 or y is 2
4) A compound according to any one of claims 1 to 3,
in which, when m is one of R3 and R4 is hydrogen and the other is C1-6 alkyl.
5) A process for producing a compound of formula (I), according to claim 1, 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):
wherein
R1 and R2 are as defined in relation to formula
(I)
R5 is a grpup X as defined in relation to formula
(I) or a group reducible to the group X
R6 is hydrogen or together with R7 forms a bond
R7 is hydrogen or benzyl or together with R6 or
R8 forms a bond;
R8 is hydrogen or together with R7 forms a bond and optionally thereafter forming a salt of the compound of formula (I) so formed, and/or converting the compound of formula (I) so formed into a further compound of formula (I).
6) A process for producing a compound of formula (I), according to claim 1, which comprises reacting an amine of formula (III):
A - NH2 (III)
in which A represents:
in which R1, R2 and X are as defined in relation to formula (I),
with a compound of formula (IV):
B - Z (IV)
in which B represents:
in which R1, R2 and X are as defined in relation to formula (I),
and Z represents a leaving group.
7. A pharmaceutical composition comprising a compound of formula (I), according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester or amide thereof, together with a pharmaceutically acceptable carrier.
8. A composition according to claim 7 in unit dosage form.
9. A method for treating obesity or hyperglycaemia in human or non-human animals, which comprises administering an effective, non-toxic amount of a compound of formula (I), according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester or amide thereof, to an animal.
EP19840901385 1983-04-19 1984-03-27 Pharmaceutically active 2-phenylethylamine derivatives Withdrawn EP0140922A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8310556 1983-04-19
GB838310556A GB8310556D0 (en) 1983-04-19 1983-04-19 Compounds

Publications (1)

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EP0140922A1 true EP0140922A1 (en) 1985-05-15

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EP19840901385 Withdrawn EP0140922A1 (en) 1983-04-19 1984-03-27 Pharmaceutically active 2-phenylethylamine derivatives

Country Status (3)

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EP (1) EP0140922A1 (en)
GB (1) GB8310556D0 (en)
WO (1) WO1984004091A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9124512D0 (en) * 1991-11-19 1992-01-08 Smithkline Beecham Plc Novel compounds
US5563171A (en) * 1993-11-05 1996-10-08 American Cyanamid Company Treatment of glaucoma and ocular hypertension with β3-adrenergic agonists
US5578638A (en) * 1993-11-05 1996-11-26 American Cyanamid Company Treatment of glaucoma and ocular hypertension with β3 -adrenergic agonists

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1604675A (en) * 1978-05-08 1981-12-16 Allen & Hanburys Ltd Aminoalkylbenzenes
SE8003278L (en) * 1979-05-04 1980-11-05 Continental Pharma phenylethylamine
EP0023385B1 (en) * 1979-06-16 1982-12-15 Beecham Group Plc Ethanamine derivatives, their preparation and use in pharmaceutical compositions
EP0052963B1 (en) * 1980-11-20 1985-02-20 Beecham Group Plc Secondary amines
EP0070133B1 (en) * 1981-07-11 1986-05-14 Beecham Group Plc Secondary phenylethanol amines, processes for their preparation and their pharmaceutical application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8404091A1 *

Also Published As

Publication number Publication date
GB8310556D0 (en) 1983-05-25
WO1984004091A1 (en) 1984-10-25

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