WO1984004091A1

WO1984004091A1 - Pharmaceutically active 2-phenylethylamine derivatives

Info

Publication number: WO1984004091A1
Application number: PCT/GB1984/000101
Authority: WO
Inventors: Barrie Christian Char Cantello; Richard Mark Hindley
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1983-04-19
Filing date: 1984-03-27
Publication date: 1984-10-25
Anticipated expiration: 1986-09-27
Also published as: EP0140922A1; GB8310556D0

Abstract

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 (II) in which R3 and R4 are each hydrogen or C1-6 alkyl or (III) together from a five or six membered ring is useful in treating obesity or hyperglycaemia.

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 , C_{1 -6} alkoxy or

in which

R³ and R⁴ are each hydrogen or C_1-6 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 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(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(CH_2)YM

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

R³ and R⁴ are each hydrogen or C_1-6 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 C_1-6 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.