NZ227196A - Phenylethanolamine derivatives and their pharmaceutical and veterinary compositions - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £27196 227196 Priority Date(s): Complete Specification Filed: S". Class: C£5?C-?) Publication Date: ?.?. f.Efi . I99J...

P.O. Journal, No: .^jr .

Patents Form No. 5 Class Cont: .. • £ IS. UrK+Sf. S?.; Class Cont: /iby.

NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PHENYLETHANOLAMINES -*s/WE, BOEHRINGER INGELHEIM VETMEDICA GMBH, A Body Corporate organised and existing under the laws of the Federal Republic of Germany, of D-6507 Ingelheim ajn Rhein, FEDERAL REPUBLIC OF GERMANY, hereby declare the invention, for which X/Ve pray that a patent may be granted to AJs/us, and the method by it J.YR ^ / is to be performed, to be particularly described^-n and by°^, i?2' the following statement: j| / i^ ^ ' WAY (followed by Page la. 22 7 1 9 6 1 a- PZ 53 504J Phenylethanolamines This invention relates to new phenylethanolamines, their use as pharmaceuticals and as performance enhancers in animals and processes for their preparation.

Certain new phenylethanolamines have been found to have valuable pharmacological properties, namely an effect on the metabolism, particularly the effect of lowering blood sugar, reducing body fat and increasing energy consumption, and lowering the atherogenic lipoproteins VLDL and LDL.

The new compounds may also be used as performance enhancers in animals, particularly in order to achieve higher daily weight increases and improved food utilisation in animal feeding, especially in the fattening of animals.

Viewed from one aspect therefore, the invention provides compounds of formula I. (wherein A represents a straight-chained or branched alkylene group: B represents a bond, an alkylene group with 1 or 2 carbon atoms, or a carbonyl or hydroxymethylene group; (I) (followed by page 2) 227196 # 4 represents hydrogen, halo or a trifluoromethyl group; R_2 represents hydrogen or an amino group; represents hydrogen, chlorine, bromine or a cyano group; and R4 represents hydrogen, halo or a C^_3 alkyl, hydroxy, carboxy, alkoxy)carbonyl, aminocarbonyl, (ci_3 alkyl)aminocarbonyl or di(C1_3 alkyl) aminocarbonyl group, a C-j^ alkoxy group optionally substituted in the end position by a carboxy, (C]__3 alkoxy)carbonyl, aminocarbonyl, (C^_3 alkyl)aminocarbonyl or di (c^_3 alkyl)aminocarbonyl group, or a ^2-2 alkoxy group substituted in the end position by a hydroxy, c^_3 alkoxy, amino, (c^_3 alkyl) amino, di (C^^alkyl) amino, pyrrolidino, piperidino or hexamethyleneimino group) and the optical isomers, diastereoisomers and acid addition salts thereof.

As examples of the definitions of the substituent groups given hereinbefore: A may represent a methylene, 1-ethylidene, 1-n-propylidene, 1-n-butylidene, ethylene, 1-methyl-ethylene, 2-methyl-ethylene, 1-ethyl-ethylene, 2-ethyl-ethylene, 1,2-dimethyl-ethylene, 1,1-dimethyl-ethylene, l-ethyl-l-methyl-ethylene, 2,2-dimethyl-ethylene, 2-ethyl-2-methyl-ethylene, n-propylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene, 3-ethyl-n-propylene , 1,1-dimethyl-n-pre-pyJ^ene , 2 , 3-dimethyl-n-propylene , 3,3-dimethyl ~ — 227196 n-butylene or n-pentylene group, B may represent a bond or a methylene, ethylene, m l-ethylidene, carbonyl or hydroxymethylene group, may represent hydrogen, fluorine, chlorine, bromine or a trifluoromethyl group, m R2 may represent hydrogen or an amino group, r3 may represent hydrogen, chlorine, bromine or a cyano group and R4 may represent hydrogen, fluorine, chlorine, bromine, a methyl, ethyl, n-propyl, isopropyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, dimethylamino-carbonyl, diethylaminocarbonyl, di-n-propylaminocarbonyl, N-ethyl-methylaminocarbonyl, N-ethyl-isopropylamino-carbonyl, 2-hydroxy-ethoxy, 3-hydroxy-n-propoxy, 2-methoxy-ethoxy, 2-ethoxy-ethoxy, 2-n-propoxy- ethoxy, 3-ethoxy-n-propoxy, 2-amino-ethoxy, 2-methylamino-ethoxy, 2-dimethylamino-ethoxy, 2-isopropylamino-ethoxy, 2-di-n-propylamino-ethoxy, 2-(1-pyrrolidino)-ethoxy, 2-(1-piperidino)ethoxy, 2-(1-hexamethyleneimino)-ethoxy, 3-amino-n-propoxy, 3-diethylamino-n-propoxy, 3-(1-piperidino)-n-propoxy, carboxymethoxy, 2-carboxy-ethoxy, 3-carboxy-n-propoxy, methoxycarbonyl-methoxy, 2-methoxycarbonyl-ethoxy, ethoxycarbonylmethoxy, 2-ethoxycarbonyl-ethoxy, 3-ethoxycarbonyl-n-propoxy, n-propoxycarbonylmethoxy, 2-isopropoxycarbonyl-ethoxy, aminocarbonylmethoxy, 2-aminocarbonyl^ethoxy, me thylami nocar bony lmethoxy, 2-methylaminocarbonyl-ethoxy, dimethylaminocarbonylmethoxy, 2-dimethylajBfS^^^5^K carbonyl-ethoxy, diethylaminocarbonylmethoxy, 2 fy % 22 7 1 9 6 diethylaminocarbonylethoxv, or 2-di-n-propylaminocarbonyl-ethoxy group.

In addition to the compounds mentioned in the Examples hereinafter, the following compounds are further examples of compounds according to the invention: ethyl 4'-[2-[N-(2-(4-amino-3-cyano-5-fluoro-phenyl)-2-hydroxy-ethyl)-amino]propyl]diphenylmethane-2-carboxylate, ethyl 4'-[2-[N-(2-(4-amino-3-cyano-5-fluoro-phenyl)-2-hydroxy-ethyl)-amino]propyl]biphenylyl-4-carboxylate, ethyl 4'-[2-[N-(2-(4-amino-3-cyano-5-fluoro-phenyl)-2-hydroxy-ethyl)-amino]propyl]biphenylyl-4-oxyacetate ethyl 41-[2-[N-(2-(4-amino-3-cyano-5-fluoro-phenyl)-2-hydroxy-ethyl)-amino]propyl]biphenylyl-2-carboxylate, 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]propyl]-biphenylyl-4-oxyacetic acid amide, 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]propyl]-4-[2-(ethoxy)ethoxy]biphenyl, and the optical isomers, diastereoisomers and addition salts thereof, in particular the physiologically acceptable addition salts.

Preferred compounds according to the invention include those of formula I wherein A represents an ethylene group optionally substituted by a C^_2 alkyl group or by two methyl groups, 227196 B represents a bond, or a methylene, ethylene, hydroxymethylene or carbonyl group, represents hydrogen, fluorine, chlorine, bromine or a trifluoromethyl group, R2 represents hydrogen or an amino group, R3 represents hydrogen, chlorine or a cyano group and R4 represents hydrogen, chlorine or a hydroxy, methoxy, methyl, ethyl, carboxy, methoxy-carbonyl, ethoxycarbonyl, carboxymethoxy, 2-hydroxy-ethoxy, methoxycarbonylmethoxy or ethoxycarbonylmethoxy group, and the optical isomers, diastereoisomers and addition salts thereof, particularly the physiologically acceptable addition salts thereof.

Particularly preferred compounds of the present invention include the compounds of formula la (wherein A represents an ethylene or methylethylene group, (la) B represents a bond or a methylene group, R^ represents hydrogen or chlorine, and R^ represents hydrogen or a methyl, ethyl, hydroxy, methoxy, methoxycarbonyl, ethoxycarbonyl, 2-hydroxy-ethoxy, methoxycarbonylmethoxy or ethoxycarbonyl methoxy group in the 2 or 4 position), and the optical isomers, diastereoisomers and addition salts thereof, particularly the physiologically acceptable addition salts thereof.

Viewed from a further aspect, the invention also provides a process for the preparation of the compounds of the invention, said process comprising at least one of the following steps: (II) (III) (wherein A, B, R^, R2, Rg and are as hereinbefore defined, or are protected forms thereof, and one of the groups Z^ and represents a nucleophilic leaving group and the other group Z-^ or Z2 represents an amino group or a protected amino group), and subsequently if required removing any protecting group used; a) reacting a compound of formula II with a compound of formula (III) z2 b) reducing a Schiff base of formula IV optionally formed in the reaction mixture (IV) (wherein R^, R2, and R3 are as hereinbefore defined, or are protected forms thereof, and X represents a group of formula -ch=n-a-t or -n=a*j/ -ch2 wherein A, B and R^ are as hereinbefore defined, or are protected forms thereof, and A' together with the nitrogen atom to which it is attached represents a straight-chained or branched C15 alkyleneimino group or a protected form thereof) and subsequently if required removing any protecting group used; c) reducing a compound of formi^^vT^ptjlonally formed - 1 111 in the reaction mixture 2111 R4 (V) (wherein A, B, R^, R2, R^/ and R^ are as hereinbefore defined, or are protected forms thereof, and V represents a group of formula -CO-CH2-NH- or —CO-CH=N— or a protected form thereof) and subsequently if required removing any protecting group used; d) reacting a compound of formula VI "a ch2 (VI) r4 (wherein Rl' R2' an<^ R3 are as ^ere^nbefore defined or are protected forms thereof) with an amine of formula VII (VII) (Followed by^Sstge»8a) 8a (wherein A, B and R4 are as hereinbefore defined or are protected forms thereof) and subsequently if required removing any protecting group used; e) reducing a compound of formula VIII optionally (followed by page 9) 22719G formed in the reaction mixture R3 (VIII) (wherein B, R^, R2, R3 and R^ are as hereinbefore defined, or are protected forms thereof, and U represents a carbonyl group and W has the meanings given for A hereinbefore or U represents a methylene group and W represents a straight chained or branched alkanone group the carbonyl group whereof is bonded to the amine nitrogen) and subsequently if required removing any protecting group used; f) (to prepare compounds of formula I wherein R^ is hydrogen, chlorine or bromine and R^ is a C2_2 alkoxy group substituted in the end position by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidine, piperidino or hexamethyleneimino group) reducing a compound of formula IX 0-(CH2)n-C0R (IX) (wherein A, B, R, and R_ are as hereinbefq/re^3e i c i or are protected forms thereof, R^' represent hydrogen, chlorine or bromine, / O O 1 •c c /1 n represents the number 1 or 2, and represents a hydroxy, C2.-3 ^^oxy, amino, (c^_3 alkyl) amino, di (C^_g alkyl) amino, pyrrolidino, piperidino, hexamethyleneimino group or protected forms thereof) and subsequently if required removing any protecting group used; g) (to prepare compounds of formula I wherein R4 represents an alkoxycarbonyl, aminocarbonyl, alkylamino-carbonyl or dialkylaminocarbonyl group, or a C^_ 3 alkoxy group substituted in the end position by an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group) reacting a compound of formula X wherein A, B, R^, R2 and R3 are as hereinbefore defined, or are protected forms thereof, and R4' represents a carboxy group or a C1-3 alkoxy group with 1 to 3 carbon atoms substituted in the end position by a carboxy group, or a reactive derivative thereof (such as an activated ester thereof) with a compound of formula XI ^ (XI, (wherein Rg represents a C1-3 alkoxy, amino, (ci_3 alkyl)amino, di(C^_3 alkyl)amino, pyrrolidino, piperidino or hexamethyleneimino group) and subsequently if required removing any protecting group used; 22 7 1 (h) hydrolysing a compound of formula I wherein R4 represents or contains an alkoxycarbonyl or amidocarbonyl group; (i) (to prepare a compound of formula I wherein R4 represents a hydroxy group) effecting ether cleavage on a compound of formula I wherein represents an optionally substituted alkoxy group; (j) separating a compound of formula I into optical isomers or diastereoisomers thereof; and (k) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.

In process steps (b) to (e) above, the reagents of formulae IV, V, VI and VIII can optionally be prepared in situ, i.e they may be reacted in process steps (b) to (e) without first being isolated.

Examples of nucleophilic leaving groups for the reagents of formulae II and III include halogen atoms or sulphonyloxy groups, e.g. chlorine, bromine and iodine atoms, and methanesulphonyloxy, p-toluenesulphonyloxy and ethoxysulphonyloxy groups.

The reaction of step (a) is conveniently carried out in a solvent or mixture of solvents (such as acetone, diethylether, acetonitrile, dimethylformamide, dimethylsulphoxide, methylene chloride, chloroform, tetrahydrofuran, dioxan) or an excess of the compounds of formulae II and/or III used and optionally in the presence of an acid-binding agent (e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, a tertiary organic base such as triethylamine, 22 7 1 N,N-diisopropylethylamine or pyridine, whilst the latter may simultaneously also serve as solvent) or a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophilically exchangeable group, conveniently at temperatures of between 0 and 150°C, preferably at temperatures of between 20 and 100°C, e.g. at the boiling temperature of the solvent used. The reaction of step (a) may, however, also be carried out without a solvent.

It is particularly advantageous, however, to perform the reaction in the presence of a tertiary organic base or an excess of the amine of formula II or III used.

The reduction of step (b) is conveniently carried out in a solvent such as methanol, ethanol, diethylether, tetrahydrofuran, dioxan, ethyl acetate or ethanol/ethyl acetate with hydrogen in the presence of a hydrogenation catalyst such as platinum, palladium/charcoal or Raney nickel under a hydrogen pressure of 1 to 5 bar or with a metal hydride such as lithium aluminium hydride, diborane, sodium cyanoborohydride or borane/di-methylsulphide, but preferably with sodium borohydride or sodium cyanoborohydride at temperatures of between 0 and 50°C, preferably at ambient temperature.

In the reduction with a complex metal hydride such as lithium aluminium hydride, diborane or borane/dimethyl-sulphide, any carbonyl or nitrile function present may also be reduced. 22 7 196 The reduction of step (c) is preferably carried out in a solvent such as methanol, ethanol, diethylether or tetrahydrofuran, in the presence of a metal hydride such as sodium borohydride, lithium aluminium hydride, diborane, borane/dimethylsulphide or sodium cyanoborohydride, but preferably with sodium borohydride in methanol or ethanol, at between 0 and 40°C, but preferably at ambient temperature.

In the reduction with a complex metal hydride such as sodium borohydride, lithium aluminium hydride, diborane or borane/dimethylsulphide, any carbonyl or nitrile function present may also be reduced.

The reaction of step (d) is preferably carried out in a solvent such as ethanol, isopropanol, tetrahydrofuran, dioxan, dimethylformamide, dimethyl-sulphoxide or acetonitrile/ethanol, conveniently at temperatures of between 50 and 100°C. However, the reaction may also be carried out without a solvent.

The reduction of step (e) is conveniently carried out in a solvent such as diethylether or tetrahydrofuran, with a reducing agent such as a metal hydride, e.g. with lithium aluminium hydride, diborane or diborane/dimethylsulphide, but preferably with sodium borohydride in the presence of glacial acetic acid or trifluoroacetic acid, at temperatures of between 0 and 100°C, preferably at temperatures of between 10 and 50°C. In the reduction any carbonyl or nitrile function present is simultaneously also 22 7 1 9 6 reduced.

The reduction of step (f) is conveniently carried out in a solvent such as diethylether or tetrahydrofuran with a reducing agent such as a metal hydride, e.g. with lithium aluminium hydride, diborane, diborane/dimethylsulphide or with sodium borohydride in the presence of glacial acetic acid or trifluoroacetic acid, at temperatures of between 0 and 100°C, but preferably at temperatures of between 10 and 50°C.

In the reaction a carbonyl group contained in the moiety B may simultaneously also be reduced.

The esterification or amidation of step (g) is conveniently carried out in a solvent such as methylene chloride, chloroform, ether, tetrahydrofuran, dioxan, toluene or dimethylformamide, but particularly advantageously in an excess of the compound of formula XI used, e.g. in methanol, ethanol, n-propanol, isopropanol, ammonia, methylamine, ethylamine, dimethylamine, diethylamine or piperidine, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionylchloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole.or N,N1-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of between -25°C and 150°C, but preferably at temperatures of between -10°C and the boiling temperature of the solvent used.

In process steps (a) to (g), any reactive groups present such as imino, amino, alkylamino, hydroxy 22 7 1 9 6 and/or carboxy groups may be protected during the reaction if necessary. Suitable protecting groups for imino, amino or alkylamino groups include acetyl, benzoyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, trityl and fluorenylmethyloxycarbonyl groups; suitable protecting groups for hydroxy groups include acetyl, benzoyl, benzyl, trimethylsilyl and trityl groups; and suitable protecing groups for carboxy groups include benzyl and tert.butyl groups.

Any splitting off of a protecting group which may be necessary after the reaction step is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water, dioxan/water or glacial acetic acid, in the presence of an acid such as hydrochloric, sulphuric or hydrobromic acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 150°C, preferably at the boiling temperature of the reaction mixture. If a benzyl or benzyloxycarbonyl group is split off, however, this is preferably done hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

The hydrolysis of step (h) may be carried out in the presence of an acid (such as hydrochloric, sulphuric or trifluoroacetic) acid or in the presence of a base (such as sodium hydroxide or potassium hydroxide), conveniently in a solvent such as water, methanol, ethanol, ethanol/water, water/isopropanol or water/dioxan, e.g. at temperatures of between -10°C and 120°C, for example at temperatures of between ambient temperature and the boiling temperature of the reaction mixture. 22 7 1 9 The ether cleavage of step (i) may be carried out in the presence of an acid (such as hydrochloric, hydrobromic, sulphuric acid or boron tribromide) conveniently in a solvent such as methanol, ethanol, water/isopropanol,methylene chloride, chloroform or carbon tetrachloride, e.g at temperatures of between -30°C and the boiling temperature of the reaction mixture . Where the ether is a benzylether, the cleavage is preferably effected with hydrogen in the presence of a hydrogenation catalyst.

As already mentioned hereinbefore, the compounds of formula I may occur in the form of their enantiomers or mixtures of enantiomers or, if they contain at least two asymmetric carbon atoms, they may also occur in the form of their diastereoisomers or mixtures of diastereoisomers.

Thus, the compounds of formula I obtained which contain only one optically active centre may be separated into their optical antipodes by known methods (see Allinger N. L. and ElielJEs_JU.—in "Topics in Stereocfiemistry"^ Vol.^6, Wiley Interscience, 1971), e.g. by recrystallisation from an optically active solvent or by reaction with an optically active substance (e.g an acid) which forms salts with the racemic compound, and separating the salt mixture thus obtained, e.g. on the basis of different solubilities, into the diastereoisomeric salts from which the free antipodes can be liberated by reaction with suitable agents. Particularly common optically active acids include, for example, the D and L forms of tartaric acid, di-O-benzoyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutaminic acid, aspartic acid and quinic acid.

Furthermore, the compounds of formula I obtained which have at least two asymmetric carbon atoms may be separated into their diastereoisomers on the basis of their physical-chemical differences 22 7 1 by known methods e.g. by chromatography and/or fractional crystallisation. A pair of enantiomers thus obtained may then be separated into its optical antipodes as described above. If for example a compound of formula I contains two optically active carbon atoms, the corresponding (R R', S S') and (R S1, S R') forms are obtained.

Moreover, the compounds of formula I obtained may be converted into the addition salts thereof, more particularly, for pharmaceutical use, the physiologically acceptable salts thereof with inorganic or organic acids. Examples of acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, oxalic, malonic, fumaric, maleic, succinic, ascorbic, malic, tartaric, lactic, citric, benzoic, methanesulphonic, toluenesulphonic, phthalic, naphthalene-sulphonic, nicotinic, palmitic and embonic acid.

The compounds of formulae II to XI used as starting materials may be obtained by methods known from the literature or are known from the literature themselves.

Thus, for example, a starting compound of formula II may be obtained by Friedel-Crafts acetylation of a corresponding compound, subseauent bromination and if necessary subsequent reaction with urotropine followed by hydrolysis. A ketone thus obtained is subsequently reduced.

A starting compound of formula IV may be obtained by reaction a corresponding carbonyl compound with a corresponding amine.

A starting compound of formula V may be obtained by reacting a corresponding haloacetyl or glyoxal 22 7 1 9 6 compound with a corresponding amine.

A starting compound of formula VIII may be obtained by reacting a corresponding carboxylic acid with a corresponding amine in the presence of an acid-activating agent.

Starting compounds of formulae IX and X may be obtained by reacting a suitable alpha-halo alcohol with a corresponding amine.

As already mentioned above, the new compounds of formula I, the enantiomers or mixtures of enantiomers or, provided that they contain at least two asymmetric carbon atoms, the diastereoisomers or mixtures of diastereoisomers thereof and the acid addition salts thereof, particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof, have valuable pharmacological properties, particularly an effect on the metabolism, especially an effect of lowering blood sugar, reducing body fat and increasing energy consumption, as well as reducing the atherogenic lipoproteins VLDL and LDL.

Thus for example, the following compounds were investigated as described below for their biological properties: A = ethyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]biphenylyl-4-carboxylate, B = methyl 41 -[2-[N-(2-hydroxy-2-phenyl-ethyl)amino]-propyl]biphenylyl-4-oxyacetate, C = methyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]biphenylyl-4-oxyacetate, 22 7 1 96 D = 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-4-(2-hydroxy-ethoxy)biphenyl, E = 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-4-ethyl-biphenyl, F = 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]diphenylmethane, G = ethyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy- ethyl) amino]ethyl]diphenylmethane-2-carboxylate, and H = ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy- ethyl)amino]propyl]diphenylmethane-2-carboxylate.

Antidiabetic activity The antidiabetic activity of the compounds according to the invention can be measured as a blood sugar-reducing effect in experimental animals. The substances to be tested were suspended in 1.5% methyl cellulose and administered by means of oesophageal tube to female mice reared by ourselves. 30 minutes later 1 g of glucose per kg of bodyweight, dissolved in water, was administered subcutaneously. Another 30 minutes later blood was taken from the retroorbital venosus plexus. From the serum, the glucose level was determined by the hexokinase method using an analytical photometer.

Table I below shows the lowering of blood sugar observed in this test as a percentage of the figures for a control group were determined simultaneously. Statistical evaluation was carried out by Students t-test taking p=0.05 as the limit of significance. 227196 TABLE I Compound % Change from the control level Dosage [mg/kg] 1 3 A - 37 - 49 B - 29 - 34 C - 27 - 44 D - 62 E - 29 - 40 F - 21 - 39 G - 35 - 50 H - 62 Antiadipose activity The antiadipose activity of the compounds according to the invention, which takes the form of an increase in lipolysis, was measured by means of the rise in glycerol in the serum. The test procedure was the same as that described above for testing for a blood sugar reducing effect. Glycerol was determined in a combined enzymatic-colorimetric test using an analytical photometer. The results are shown in Table II below as a percentage of the figures for a control group which were determined simultaneously. ' / 22 7 1 TABLE II Compound % Change 1 from the control level Dosage [mg/kg] 3 A 121 220 B 194 301 C 185 D 378 E 141 165 F 80 182 G 143 364 H 402 In the investigations of the compounds according to the invention described above, at the dosages used, no circulatory effects could be observed nor were there any toxic side effects up to a dosage of 30 mg/kg. The compounds are therefore well tolerated.

In view of their pharmacological properties, therefore, the compounds of formula I and the physiologically acceptable addition salts thereof are suitable for treating both diabetes mellitus and also obesity, and particularly for the treatment of obese diabetics. The dosage required may be adapted to the metabolic/phy siological requirements of the individual patient, since the compounds are free from any effects on the heart or circulation over a wide dosage range. In adults, therefore, the daily doses range from 1 to 300 mq, preferably 1 to 100 mg, distributed over 1 to 4 doses per day. For this purpose, the above-mentioned compounds, optionally in conjunction a5oq- ii'io rr^pinrs o ucnn minu uj. Wi. r Yb r.<iD 227196 with other active substances, may be incorporated into conventional galenic preparations such as powders, tablets, coated tablets, capsules, suppositories and suspensions.

Thus viewed from a further aspect the invention provides a pharmaceutical composition comprising a compjound of formula I or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient.

Viewed from a still further aspect the invention also provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a therapeutic agent for use in combatting diabetes mellitus, obesity or atherosclerotic changes.

Viewed from a still further aspect the invention provides a method of treatment of a _____ non-huWan animal body to combat diabetes mellitus, obesity or atherosclerotic changes, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

Owing to their body fat-reducing (lipolytic) activity, the compounds of the invention may be used to treat obese animals and to reduce or prevent undesirable fatty deposits during the fattening of animals and hence to improve the meat quality of fattened animals. Moreover, the compounds of the invention may be used to achieve higher daily weight increases and improved food utilisation in animal nutrition, especially in the fattening of animals- u 22 7 1 96 The performance-enhancing and fat-reducing activity of the compounds of the invention was tested, by way of example, using compounds A, C and H as follows: 1). 4 groups of 20 (control) and 10 (experimental groups A, C and H) male mice, each animal being kept on its own, were given identical food and water ad libitum. In addition, the experimental groups were given 20 ppm of the compounds mentioned above (A, C or H) in their food. The test period lasted 14 days.

Table III below shows the results found as relative changes compared with a control (control = 100): 2271 9 TABLE III Compound A C H Starting v?eight 101. 2 100.3 99. 3 Weight gain 90.5 183.2 239.

Food uptake 91. 6 106.0 106.

Weight gain/ food intake 99.1 173.0 225. 1 2). 4 groups of 20 (control) and 10 (experimental, groups A, C and H) male mice, each animal being kept separately, were given identical food and water ad libitum. The experimental groups were additionally given 10 mg/kg of bodyweight of the above-mentioned compounds p.o. The test period was 4 days.

Table IV below shows the results found as relative changes compared with a control (control = 100): 22 7 1 9 6 TABLE IV Compounds AC H Weight gain/ 90.5 122.5 54.5 food intake Epididymal fatty 89.6 97.7 74.2 deposits Musculus gastroc- 111.4 103.3 110.7 nemius Musculus soleus 115.1 120.2 108.7 Meat: fat ratio 126.0 112.2 147.0 In view of these properties, the compounds of the invention may be used as performance enhancers for animals in order to promote and accelerate growth, production of milk and wool, to improve feed utilisation, carcass quality and to increase the meat:fat ratio. The compounds of the invention can be used with farmed, cultivated and decorative animals and pets.

Farmed and cultivated animals include mammals such as cattle (e.g. calves, oxen, bulls, heifers and cows), buffalo, pigs, horses, sheep, qoats, rabbits, hares, deer, animals farmed for their skins such as mink and chinchilla, birds such as doves, chickens, geese, ducks, turkeys, guinea-fowl, pheasants and quail, fish such as carp, trout, salmon, eels, tench and pike, and reptiles such as snakes and crocodiles. 22 7 1 96 Examples of decorative animals and pets include mammals such as dogs and cats, birds such as parrots, canaries, and fish such as ornamental and aouarium fish, e.g. goldfish.

The compounds of the invention may be used irrespective of the sex of the animal throughout all growth and performance phases of the animal. Preferably, the compounds are used during the intensive growth and performance phase. The intensive growth and performance phase generally lasts from one month to ten years, depending on the type of animal.

Thus viewed from another aspect the invention provides a method of treatment of a non-human animal body to combat obesity, to improve meat quality or to improve feed utilization, said method comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

The quantity of the compound according to the invention administered to the animals in order to achieve the desired effect may be varied substantially on account of the favourable properties of the active substances. It is preferably around 0.001 to 50 mg/kg, more particularly 0.01 to 10 mg/kg of bodyweight per day. The appropriate quantity of active substance and the appropriate duration of administration depend particularly on the type of animal, its age, sex, state of health and the type of keeping and feeding of the animal and can easily be determined by anyone skilled in the art.

The active substances may be administered to animals by conventional methods. The type of administration depends in particular on the type of animal, its behaviour and its state of health. 22 7 1 The active substances may be administered once.

However, they may also be administered occasionally or continuously throughout some or all of the growth phase. If they are administered continuously, they may for example be given one or more times a day at regular or irregular intervals.

The compounds of the invention may be administered orally or parenterally in suitable formulations or in pure form. Oral formulations may be, for example, in the form of powders, tablets, granules, drenches, boli and feedstuffs, premixes for feedstuffs, and formulations for adding to drinking water.

The oral formulations preferably contain the active substance in concentrations of from 0.01 ppm to 100%, especially preferably from 0.01 ppm to 10%.

Parenteral formulations may for example be in the form of solutions, emulsions and suspensions for injection , as well as implants.

The compounds of the invention may be present in the formulations on their own or mixed with other active substances, mineral salts, trace elements, vitamins, proteins, colourings, fats or flavourings.

The concentration of the active substances administered in feed is normally about 0.01 to 500 ppm, preferably 0.1 to 50 ppm. The active substances may be added to the feed as such or as active substance containing premixes or feed concentrates.

Thus viewed from further aspects the invention also provides an animal performance enhancing composition containing a compound of formula I or a physiologically acceptable salt thereof together with at least 22719 one carrier or excipient, an animal feed composition containing a compound of formula I or a physiologically tolerable salt thereof together with at least one nutrient, and an animal feed premix containing a compound of formula I or a physiologically acceptable salt thereof together with at least one nutrient, vitamin, mineral, diluent, extender or other excipient. Viewed from still further aspects the invention also provides the use of a compound of formula I or a physiologically acceptable salt thereof for the manufacture of a such performance enhancing composition, feed composition or feed premix for non-human animals to improve feed utilisation thereby.

Thus, the feed compositions according to the invention may contain, in addition to the active substance and possibly a conventional vitamin/mineral mixture, conventional feed bases, for example for pig feeds: barley, wheat bran, broad beans, rape extract groats and edible fat, and for broilers: maize, soya bean flour, meatmeal, edible fat and soya oil, and for cattle: shredded sugar beet, maize gluten, malt germs, soya bean flour, wheat and molasses and for lambs: barley, soya bean flour, maize and molasses. To this feed base mixture is added one or more of the compounds of the invention in a concentration of 0.1 to 500 ppm, preferably 0.1 to 50 ppm, the active substance preferably being added in the form of a premix. This premix may contain, for example, 10 mg of active substance per 10 g, preferably lOmg in 9.99 g of corn starch.

The following Examples are provided to illustrate the invention further without in any way restricting its scope. All ratios, parts and percentages are by weight unless otherwise indicated. 22 7 1 9 6 Preparation of the starting compounds Example A Ethyl 4'-acetonyl-biphenylyl-4-carboxylate a) A solution of 10 g (0.044 mol) of ethyl biphenylyl-4-carboxylate in 70 ml of methylene chloride is added dropwise at 0°C to a solution of 25 g (0.187 mol) of aluminium chloride and 9.6 g (0.076 mol) of 2-chloro-propionylchloride in 250 ml of methylene chloride. After standing overnight at ambient temperature it is added to ice water and dilute hydrochloric acid and extracted with methylene chloride. The extracts are dried and, after concentration by evaporation, purified by column chromatography using cyclohexane/ethyl acetate (7:1) as eluant. 6.9 g of ethyl 4'-(2-chloro-propionyl)biphenylyl-4-carboxylate are obtained.

Melting point: 75-78°C b) 6.8 g (0.021 mol) of ethyl 41-(2-chloro-propionyl)bi-phenylyl-4-carboxylate are refluxed for two days in 40 ml of acetone with 3.9 g (0.034 mol) of potassium acetate. Then the precipitate is filtered off, the filtrate is evaporated down and the evaporation residue is purified by column chromatography (eluant: cyclohexane/ethyl acetate (7:1)). 5.5 g of ethyl 41-(2-acetoxy-propionyl)-biphenylyl-4-carboxylate are obtained. c) 5.5 g (0.016 mol) of ethyl 41-(2-acetoxy-propionyl)-biphenylyl-4-carboxylate are dissolved in 160 ml of ethanol and at 5 to 10°C sodium borohydride is added in batches (about 1 g) until no further starting material can be detected in the chromatogram. 22 7 1 96 Then the mixture is evaporated down, decomposed with water and extracted with ethyl acetate. The extracts are concentrated by evaporation and, after the addition of 50 g of polyphosphoric acid, they are stirred in an oil bath at 80°C. The mixture is poured onto ice water and extracted with ethyl acetate. The extracts are dried, concentrated by evaporation and purified by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (3:1)) to yield the title compound.

Yield: 2.8 g (62% of theory) Melting point: 71-73°C.

The following compounds are obtained analogously to the title compound of Example A: 4'-acetonyl-4-methoxy-biphenyl, Melting point: 89-92°C 4'-acetonyl-2-methoxy-biphenyl, Melting point: less than 20°C ethyl 4'-acetonyl-biphenylyl-2-carboxylate, Melting point: less than 20°C ethyl 4'-acetonyl-diphenylmethane-2-carboxylate, 4 *-acetonyl-4-chloro-biphenyl, Melting point: 74-76°C ethyl 4'-acetonyl-1,2-diphenylethane-2-carboxylate. Example B 4'-Acetonyl-4-hydroxy-biphenyl 22 7 1 9 6 4.8 g (20 mmol) of 4'-acetonyl-4-methoxy-biphenyl are dissolved in 50 ml of benzene and, after the addition of 6.14 g (46 mmol) of aluminium chloride, refluxed for 24 hours. The reaction mixture is then poured onto ice and dilute hydrochloric acid, extracted with chloroform and the extracts are purified by silica gel chromatography (eluant: toluene/ethvl acetate (6:1)).

Yield: 2.8 g (62% of theory), Melting point: 151-153°C The following compound is obtained analogously to the title compound of Example B: 4'-acetonyl-2-hydroxy-biphenyl.

Example C Methyl 4'-acetonyl-biphenylyl-2-oxyacetate 4.3 g (19 mmol) of 4'-acetonyl-2-hydroxy-biphenyl are dissolved in 50 ml of acetone and after the addition of 2.63 g (19 mmol) of potassium carbonate and 1.8 ml (19 mmol) of methylbromoacetate the mixture is refluxed for 5 hours. It is then filtered, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel (eluant: toluene/ethyl acetate (10:1)).

Yield: 5.0 g (88.2% of theory), Melting point: less than 20°C.

The following compound is obtained analogously to the title compound of Example C: methyl 4'-acetonyl-biphenylyl-4-oxyacetate Melting point: 81-82°C. 22 7 1 9 6 Example D 4 ' - (2-Amino-propyl)-4-ethyl-biphenyl a) 9.0 g (0.0426 mol) of 4-(2-amino-propyl)biphenyl are dissolved in 50 ml of glycol and after the addition of 6.3 g (0.0426 mol) of phthalic acid anhydride the mixture is stirred for 2 hours at 170°C. It is then diluted with water and the 4- (2-phthalimido-propyl)biphenyl is extracted with ethyl acetate. After concentration of the extracts by evaporation and crystallisation from methanol, 10.4 g (72% of theory) of 4-(2-phthalimido-propyl)-biphenyl are obtained, melting point 143-145 °C. b) 3 g (8.8 mmol) of 4-(2-phthalimido-propyl)biphenyl are placed in 50 ml of carbon disulphide and, after the addition of 4 g (0.03 mol) of aluminium chloride, 0.78 g (0.01 mol) of acetylchloride are added dropwise. After standing overnight, the mixture is poured onto ice water/dilute hydrochloric acid and extracted with chloroform. By concentration of the extracts by evaporation and crystallisation from acetone, 1.58 g (47% of theory) of 4'-(2-phthalimido-propyl) -4-acetyl-biphenyl are obtained, melting point 157-159 °C. c) 1.0 g (2.6 mmol) of 4'-(2-phthalimido-propyl)-4-acetyl-biphenyl are stirred into 25 ml of glycol with 0.5 ml of hydrazine hydrate and 0.9 g (0.016 mol) of potassium hydroxide for 3 hours at 200°C. The mixture is then diluted with water, extracted with ether and the extracts are concentrated by evaporation to yield to title compound. Yield: 0.56 g (90% of theory). 22 7 1 96 The following compound is obtained analogously to the title compound of Example D: 4'-(2-Amino-ethyl)-4-ethyl-biphenyl.

By hydrazinolysis of the corresponding phthalimido compounds, the following compounds are obtained analogously to the title compound of Example D: 4'-(2-amino-ethyl)-4-methoxy-biphenyl and 4'- (2-amino-propyl)-4-methoxy-biphenyl.

Example E Ethyl 4'-(2-amino-propyl)bjphenylyl-4-carboxylate a) 0.9 g (2.3 mmol) of 4'-(2-phthalimido-propyl)-4-acetyl-biphenyl (the product of step (b) of Example D) are suspended in 10 ml of dioxan and 10 ml of water and after the addition of 0.96 g (24 mmol) of powdered sodium hydroxide, with cooling, 1.43 g (9 mmol) of bromine are added dropwise. The mixture is stirred for another hour, acidified with hydrochloric acid and suction filtered to remove the precipitate. 0.8 g (90.3% of theory) of 41-(2-phthalimido-propyl)bi-phenylyl-4-carboxvlic acid are obtained, melting point 280°C. b) 2.0 g (5.2 mmol) of the product of step (a) above are suspended in 50 ml of concentrated hydrochloric acid and shaken in a pressurised vessel at 120°C for 6 hours. Then the suspension is evaporated to dryness, digested with warm acetone and suction filtered to remove the precipitate. The precipitate is dissolved in ethanol and refluxed for 2 hours whilst dry hydrochloric acid gas is piped in. 22 7 1 9 6 The reaction mixture is then evaporated down, made alkaline and extracted with ethyl acetate. After the extracts have been evaporated down, 0.6 g (41% of theory) of ethyl 4(2-amino-propyl)biphenylyl-4-carboxylate are obtained The following compound is obtained analogously to the title compound of Example E: ethyl 4'-(2-amino-ethyl)biphenylyl-4-carboxylate.

Example F 4-(2-Amino-pentyl)biphenyl a) 9.11 g (50 mmol) of biphenylyl-4-aldehyde are mixed with 7.4 ml of butylamine in 100 ml of toluene and boiled for 2 hours using a water separator.

The mixture is then evaporated down, taken up in 100 ml of glacial acetic acid and after the addition of 10 g (0.096 mol) of nitrobutane, the mixture is stirred for 1 hour at 100°C. It is then evaporated down and the nitro-olefin product is recrystallised from isopropanol.

Yield: 85.0% of theory, Melting point: 67-69°C. b) 11.9 g (0.044 mol) of the nitro-olefin product of step (a) above are dissolved in 50 ml of tetrahydrofuran and added dropwise to a boiling suspension of 3.8 g (0.1 mol) of lithium aluminium hydride in 100 ml of tetrahydrofuran. The mixture is stirred for a further hour, then decomposed with 4N sodium hydroxide solution, filtered from the sodium aluminate and the filtrate is evaporated down. The base thus obtained, the title compound, is converted into the hydrochloride by the addition of ethanol/ethanolic 22 7 196 hydrochloric acid.

Yield: 80% of theory.

Melting point: 204-206°C Analogously to Example F, using nitromethane or nitroethane, the following compounds are obtained: 4-(2-amino-ethyl)biphenyl, 4-(2-amino-propyl)biphenyl, 4 1 - (2-amino-ethyl)-4-methoxy-l,2-diphenylethane, 4' — f2-amino-propyl)-4-methoxy-l,2-diphenylethane, 4'-(2-amino-ethyl)-4-methoxy-diphenylmethane, and 4'-(2-amino-ethyl)-4-methoxy-biphenyl.

Example G 4-(2-Amino-ethyl)diphenylmethane The title compound is prepared by Friedel-Crafts acylation of N-acetyl-2-phenyl-ethylamine with benzoylchloride, subsequent hydrolysis to obtain the 4-(2-amino-ethyl)benzophenone and subsequent Wolff-Kishner reduction with hydrazine (see J. _Amer_-jChem. Soc. 76, 5623 (1954)). ■ ■ —— __ __—^ The following compounds are obtained analogously the title compound of Example G: 4'-(2-amino-propyl)-4-methyl-diphenylmethane, 4-(2-amino-propyl)-diphenylmethane, 22 7 1 9 6 41-(2-amino-propyl)-4-chloro-diphenylmethane, 4'-(2-amino-ethyl)-4-methyl-diphenylmethane, 4'-(2-amino-ethyl)-4-chloro-diphenylmethane, ethyl 4(2-amino-ethyl)diphenylmethane-2-carboxylate (by subsequent esterification of 4'-(2-amino-ethyl)di-phenylmethane-2-carboxylic acid), and ethyl 41-(2-amino-ethyl)diphenylmethane-4-carboxylate (by subsequent esterification of 4(2-amino-ethyl)-diphenylmethane-4-carboxylic acid).

Example H Methyl 4'-(2-amino-ethyl)diphenylmethane-2-oxyacetate hydrochloride a) 15.7 q (0.053 mol) of phenyl 4-[2-(ethoxycarbonyl-amino)ethyl]benzoate are dissolved in 80 ml of chlorobenzene and after the addition of 25 g (0.094 mol) of aluminium bromide, stirred for 5 hours at 110°C.

The mixture is then poured onto ice/hydrochloric acid and extracted with methylene chloride. By column chromatography on silica gel using cyclohexane/ethyl acetate (3:1) as eluant, 41-[2-(ethoxycarbonylamino)- ethyl]-2-hydroxybenzophenone is obtained in a 46% yield. b) 6.5 g (0.021 mol) of the product of step (a) above are stirred into 50 ml of glycol for 4 hours at 180°C after the addition of 7.1 g (0.127 mol) of potassium hydroxide and 4.1 g of hydrazine hydrate.

This reaction mixture is then poured onto ice/hydrochloric acid, made alkaline with ammonia, extracted with chloroform and concentrated by evaporation. After silica 22 7 1 9 6 gel chromatography using chloroform/methanol/methanolic ammonium (5:1:0.1) as eluant, 4'-(2-amino-ethyl)-2-hydroxy-diphenylmethane is obtained in a 26% yield. c) 11.5 g (0.05 mol) of the product of step (b) above are placed in 60 ml of dioxan and 60 ml of 2N sodium hydroxide solution and, whilst cooling with ice, 12 g (0.07 mol) of benzyl chloroformate are added dropwise. After standing overnight the mixture is acidified, extracted with chloroform and, after evaporation of the extracts, chromatographed on silica gel (eluant: toluene/ethyl acetate (14:1)). A 55% yield of 4'-[2-(benzyloxycarbonylamino)ethyl]-2-hydroxy-diphenylmethane is obtained. d) 5 g (0.014 mol) of the product of step (c) above are refluxed for 3 hours in acetone with 1.9 g (0.014 mol) of potassium carbonate and 2.1 g (0.014 mol) of methyl bromoacetate. The mixture is then filtered, concentrated by evaporation and chromatographed on silica gel using chloroform as eluant. The methyl 4'-[2-(benzyloxycarbonyl-amino)ethyl]diphenyl-methane-2-oxyacetate thus isolated is then hydrogenated in 40 ml of methanol, at ambient temperature and under a hydrogen pressure of 5 bar, after the addition of 8 ml of saturated methanolic hydrochloric acid and 0.4 g of 10% palladium on charcoal. After the uptake of hydrogen has ceased the catalyst is filtered off and the filtrate is concentrated by evaporation. 1.9 g of methyl 4'-(2-amino-ethyl)-diphenylmethane-2-oxyacetate hydrochloride are obtained.

The following compound is obtained analogously to the title compound of Example H: 22 7 1 9 4'-(2-Amino-ethyl)-2-methoxy-diphenylmethane-hydrochlor ide.

The following are examples of the preparation of compounds of formula I and salts thereof: 22 7 1 96 Example 1 Ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)-aminojpropyl]biphenvlvl-4-carboxylate .6 g (20 mmol) of ethyl 41-acetonyl-biphenylyl-4-carboxylate and 3.4 g (20 mmol) of 2-(3-chloro-phenyl) -2-hydroxv-ethylamine are dissolved in 75 ml of ethanol and after the addition of 1.25 g (20 mmol) of sodium cyanoborohydride and 1.2 ml (20 mmol) of glacial acetic acid, the mixture is stirred for 24 hours at ambient temperature. It is then concentrated by evaporation, added to water and acidified with dilute hydrochloric acid. After 30 minutes' stirring it is made alkaline with sodium hydroxide solution and extracted with ethyl acetate. The extracts are concentrated by evaporation and the evaporation residue is purified by column chromatography on silica gel (eluant: ethyl acetate/methanol (40:1)). It is then recrystallised from acetonitrile. Yield: 4.3 g (49% of theory), Melting point: 104-116°C Calculated: C 71.30 H 6.44 N 3.20 CI 8.10 Found: 71.45 6.30 3.47 8.08 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.56 ppm (dd, 0.5 H), delta = 4.62 ppm (dd, 0.5 H)] The following compounds are prepared analogously to the title compound of Example 1: a) 4'-Hydroxy-4-[2-[N-(2-hydroxy-2-phenyl-ethyl)amino]-propyl]biphenyl-hydrochlor ide Prepared from 2-hydroxy-2-phenyl-ethylamine and 41-acetonyl-4-hydroxy-biphenyl. 22 7 1 Yield: 50% of theory.

Melting point: 154-156°C Calculated: C 71.95 H 6.83 N 3.65 Found: 71.77 6.79 3.61 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers. b) Methyl 41-[2-[N-(2-hydroxy-2-phenyl-ethyl)amino]-propyl]biphenylyl-4-oxyacetate Prepared from 2-hydroxy-2-phenylethylamine and methyl 41-acetonyl-biphenylyl-4-oxyacetate.

Yield: 23% of theory, Melting point: 90-91°C Calculated: C 74.44 H 6.97 N 3.34 Found: 74.31 7.13 3.03 According to "'"H-NMR (400 MHz) there is a 2:3 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.60 ppm (dd, 0.6 H), delta = 4.66 ppm (dd, 0.4 H)] c) 41-[2-[N-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-4-hydroxy-biphenyl Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 4'-acetonyl-4-hydroxy-biphenyl.

Yield: 41% of theory, Melting point: 97-99°C Calculated: C 72.34 H 6.33 N 3.67 Found: 72.17 6.59 3.88 According to "^H-NMR (400 MHz) there is a 5:3 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.60 ppm (dd, 0.62 H), delta = 4.66 ppm (dd, 0.38 H)] d) Methyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]biphenylyl-4-oxyacetate Ill A 9 Prepared from 2-(3-chloro-phenyl)-2-hydroxv-ethylamine and methyl 4'-acetonyl-biphenylyl-4-oxyacetate.

Yield: 25% of theory, Melting point: 106-109°C Calculated: C 68.79 H 6.22 N 3.09 CI 7.81 Found: 68.90 6.06 3.07 7.62 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.55 ppm (dd), delta = 4.615 ppm (dd) ] e) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino] propyl]-4-methoxy-biphenyl Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 41-acetonyl-4-methoxy-biphenyl.

Yield: 20.1% of theory, Melting point: 109-111°C Calculated: C 72.81 H 6.62 N 3.54 CI 8.95 Found: 72.80 6.64 3.57 8.82 According to "^H-NMR (400 MHz) there is a 1:3 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.55 ppm (dd, 0.75 H) , delta = 4.62 ppm (dd, 0.25 H)] f) 41-Chloro-4-[2 - [N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]biphenyl Prepared from 41-acetonyl-4-chloro-biphenyl and 2-(3-chloro-phenyl)-2-hydroxy-ethylamine.

Yield: 26% of theory, Melting point: 115-117°C Calculated: C 69.00 H 5.79 N 3.50 CI 17.71 Found: 69.10 5.74 3.34 17.98 According to ^H-NMR (400 MHz) there is a 3:4 mixture of pairs of diastereoisomers.

[CDCI3: delta = 4.56 ppm (dd, 0.57 H), delta 22 7 1 9 = 4.62 ppm (dd, 0.43 H) ] g) Ethyl 4'-[2-[N-(2-hydroxy-2-phenyl-ethyl) amino]-propyl]-biphenylyl-4-carboxylate Prepared from 2-hydroxy-2-phenyl-ethvlamine and ethyl 4'-acetonyl-biphenylyl-4-carboxylate.

Yield: 62.5% of theory, Melting point: 96-98°C Calculated: C 77.39 H 7.24 N 3.47 Found: 77.20 7.08 3.29 According to ''"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.62 ppm (dd, 0.5 H), delta = 4.67 ppm (dd, 0.5 H)] h) Ethyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]-biphenylyl-2-carboxylate Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and ethyl 4'-acetonyl-biphenylyl-2-carboxylate.

Yield: 39.3% of theory, Melting point: less than 20°C Calculated: C 71.30 H 6.44 N 3.20 Found: 71.55 6.27 3.09 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.50 ppm (dd, 0.5 H), delta = 4.60 ppm (dd, 0.5 H)] i) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-2-methoxy-biphenyl Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 4'-acetonyl-2-methoxy-biphenyl.

Yield: 88.4% of theory, Melting point: less than 20°C 22 7 1 9 6 Calculated: C 72.81 H 6.62 N 3.54 Found: 72.61 6.60 3.62 According to ^H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.61 ppm (dd, 0.5 H), delta = 4.55 ppm (dd, 0.5 H)] 22 7 1 k) Methyl 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]-biphenylyl-2-oxyacetate Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and methyl 4'-acetonyl-biphenvlyl-2-oxyacetate.

Yield: 83% of theory, Melting point: less than 20°C Calculated: C 68.79 H 6.22 N 3.08 Found: 68.80 6.10 2.91 According to "*"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.686 ppm (dd, 0.5 H), delta = 4.62 ppm (dd, 0.5 H)] 1) Ethyl 4*-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) aminojpropyl]-1,2-diphenylethane-2-carboxylate Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and ethyl 41-acetonyl-1,2-diphenylethane-2-carboxylate.

Yield: 67% of theory, Melting point: less than 20°C Calculated: C 72.16 H 7.12 N 3.01 CI 7.61 Found: 72.40 7.18 2.93 7.41 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.54 ppm (dd, 0.5 H), delta = 4.62 ppm (dd, 0.5 H)] m) Ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]diphenylmethane-2-carboxylate Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and ethyl 4'-acetonyl-diphenylmethane-2-carboxylate. Yield: 83% of theory, Melting point: less than 20°C 22 7 1 45 Calculated: C 71.75 H 6.69 N 3.10 CI 7.84 Found: According to 71.45 6.87 2.94 8.03 "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.51 ppm (dd, 0.5 H), delta = 4.59 ppm (dd, 0.5 H) ] Example 2 4'-[2-[N-(2-Hydroxy-2-phenyl-ethyl)amino 3ethyl]-4-methoxy-biphenyl 4 g (20 mmol) of phenacylbromide are dissolved in 20 ml of methylene chloride and added dropwise to a solution of 4.6 g (20 mmol) of 4'-(2-amino- ethyl) -4-methoxy-biphenyl and 3.45 ml (20 mmol) of N,N-diisopropyl-ethylamine and 100 ml of methylene chloride at ambient temperature. After 2 hours, 50 ml of methanol are added and, with slight cooling, 1 g (27 mmol) of sodium borohydride is added in batches. After stirring overnight the mixture is evaporated ijn vacuo, acidified with dilute hydrochloric acid and stirred for 30 minutes. It is then made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform evaporation residue is purified by column chromatography on silica gel (eluant: chloroform/methanol (10:1)). Finally, it is recrystallised from acetonitrile.

Yield: 1.1 g (16% of theory), Melting point: 137-138°C Calculated: C 79.51 K'7.25 N 4.03 Found: 79.62 7.19 3.97 The following compounds are prepared analogously to the title compound of Example 2: a) 41-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)- 22 7 196 . I -n , » amino]ethyl]-4-hydroxy-biphenyl-semihydrate Prepared from 3-chloro-phenacylbromide and 4 ' — f2— amino-ethyl)-4-hydroxy-biphenyl.

Yield: 13% of theory, Melting point: 114-117°C Calculated: C 70.09 H 6.15 N 3.72 Found: 69.90 6.11 3.74 b) 41-T 2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]-4-methoxy-biphenyl Prepared from 3-chloro-phenacylbromide and 4 ' —2— amino-ethyl)-4-methoxy-biphenyl.

Yield: 34% of theory, Melting point: 114-116°C Calculated: C 72.34 H 6.33 N 3.67 Cl 9.28 Found: 72.40 6.17 3.53 9.08 c) Ethyl 4'-[2-[N (2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]ethyl]-biphenylyl-4-carboxylate From 3-chloro-phenacylbromide and ethyl 4'-(2-amino-ethyl) biphenylyl-4-carboxylate.

Yield: 14% of theory, Melting point: 121-122°C Calculated: C 70.83 H 6.18 N 3.30 Cl 8.36 Found: 70.90 6.19 3.35 8.39 d) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]biphenyl Prepared from 3-chloro-phenacylbromide and 4-(2- amino-propyl)biphenyl.

Yield: 23% of theory, Melting point: 95-96°C Calculated: C 75.50 H 6.61 N 3.89 22 7 1 9 6 Found: 75.70 6.69 3.93 According to "'"H-NMR (400 MHz) there is a 1:2 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.57 ppm (dd, 0.66 H), delta =4.63 ppm (dd, 0.33 H)] e) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-4-ethyl-biphenyl Prepared from 4'-(2-amino-propyl)-4-ethyl-biphenyl and 3-chloro-phenacylbromide.

Yield: 26% of theory.

Melting point: 104-114°C Calculated: C 76.22 H 7.16 N 3.56 Cl 9.00 Found: 76.37 7.30 3.53 9.12 According to "'"H-NMR (400 MHz) there is a 2:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.56 ppm (dd, 0.33 H), delta = 4.62 ppm (dd, 0.66 H)] f) Ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]biphenylyl-4-carboxylate Prepared from ethyl 41-(2-amino-propyl)biphenylyl- 4-carboxylate and 3-chloro-phenacylbromide.

Yield: 25% of theory, Melting point: 94-96°C Calculated: C 71.30 H 6.44 N 3.20 Found: 71.45 6.52 3.37 According to "*"H-NMz (400 MHz) there is a 1:2 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.56 ppm (dd, 0.33 H), delta = 4.62 ppm (dd, 0.66 H)] g) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]biphenyl 22 7 1 Prepared from 3-chloro-phenacylbromide and 4 —(2— amino-ethyl)-biphenyl.

Yield: 23% of theory, Melting point: 109-110°C Calculated: C 75.10 H 6.30 N 3.98 Cl 10.07 Found: 74.99 6.30 3.97 10.28 h) 4 ' 2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]-4-ethyl-biphenyl Prepared from 3-chloro-phenacylbromide and 4'-(2-amino-ethyl)-4-ethyl-biphenyl.

Yield: 23% of theory, Melting point: 123-125°C Calculated: C 75.97 H 6.90 N 3.69 Cl 9.33 Found: 75.95 6.78 3.58 9.37 i) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]diphenylmethane Prepared from 4-(2-amino-ethyl)diphenylmethane and 3-chloro-phenacylbromide.

Yield: 49% of theory, Melting point: 86-87°C Calculated: C 75.50 H 6.61 N 3.83 Cl 9.69 Found: 75.74 6.41 3.96 9.53 j) 41-f 2-fN-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]-4-methoxy-diphenylmethane Prepared from 3-chloro-phenacylbromide and 4'-(2-amino-ethyl)-4-methoxy-diphenylmethane.

Yield: 22.5% of theory, Melting point: 90-92°C Calculated: C 72.81 H 6.62 N 3.54 Cl 8.95 Found: 72.66 6.51 3.53 8.93 22 7 1 k) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]-4-methy1-diphenylmethane Prepared from 3-chloro-phenacylbromide and 41 — (2— amino-ethyl)-4-methvl-dipbenylmethane.

Yield: 25.5% of theory, Melting point: 100-102°C Calculated: C 75.87 H 6.90 N 3.69 Cl 9.33 Found: 75.56 6.94 3.77 9.43 1) Ethyl 42-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]ethyl]diphenylmethane-4-carboxylate Prepared from 3-chloro-phenacylbromide and ethyl 4'-(2-amino-ethyl)-diphenylmethane-4-carboxylate.

Yield: 19% of theory.

Melting point: 97-98°C Calculated: C 70.97 H 6.39 N 3.20 Cl 8.09 Found: 71.14 6.44 3.29 8.14 m) 4'-Chloro-4-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]ethyl]diphenylmethane Prepared from 41-(2-amino-ethyl)-4-chloro-diphenylmethane and 3-chloro-phenacylbromide.

Yield: 16% of theory, Melting point: 86-88°C Calculated: C 69.01 H 5.79 N 3.50 Cl 17.71 Found: 69.11 5.72 3.45 17.66 n) 4-[2-[N-(2-Hydroxy-2-phenyl-ethyl)amino]propyl]-diphenylmethane Prepared from 4-(2-amino-propyl)diphenylmethane and phenacylbromide.

Yield: 17% of theory.

Melting point: 86-88°C 22 7 1 9 6 Calculated: C 83.44 H 7.88 N 4.05 Found: 8 3.35 8.03 4.06 According to "'"H-NMR (400 MHz) there is a 45:55 mixture of pairs of diastereoisomers.

(CDCl-ji delta = 4.57 ppm (dd, 0.45 H) , delta = 4.64 ppm (dd, 0.55 H)] o) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]diphenylmethane Prepared from 4-(2-amino propyl)diphenylmethane and 3-chloro-phenacylbromide.

Yield: 17.9% of theory, Melting point: 92-96°C Calculated: C 75.87 H 6.80 N 3.69 Cl 9.33 Found: 75.70 6.97 3.57 9.46 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.52 pm (dd), delta = 4.58 ppm (dd) ] p) 4'-Chloro-4-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]propyl]diphenylmethane Prepared from 3-chloro-phenacylbromide and 4'—(2— amino-propyl)-4-chloro-diphenylmethane.

Yield: 19.2% of theory.

Melting point: 85-90°C Calculated: C 69.57 H 6.08 N 3.38 Cl 17.11 Found: 69.70 6.01 3.26 17.24 According to "'"H-NMR (400 MHz) there is a 20:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.54 ppm (dd, 0.05 H), delta = 4.61 ppm (dd, 0.95 H)] g) Ethyl 41-[2-[N-(2-hydroxy-2-phenyl-ethyl)amino]ethyl]-benzhydrol-4'-carboxylate 22 7 1 Prepared from phenacvlbromide and ethyl 4'-(2-amino- ethyl) benzophenone-4-carboxylate.

Yield: 14.6% of theory, Melting point: 111-113°C Calculated: C 74.80 H 6.52 N 3.35 Found: 75.00 6.65 3.49 r) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-2-methyl-propyl]biphenyl Prepared from 3-chloro-phenacylbromide and 4 — f2— amino-2-methyl-propyl)biphenyl.

Yield: 13% of theory, Melting point: 80°C Calculated: C 75.87 H 6.90 N 3.69 Cl 9.33 Found: 76.00 6.96 3.68 9.25 s) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-pentyl]biphenyl-hydrochloride Prepared from 3-chloro-phenacylbromide and 4-(2-amino-pentyl)biphenyl-hydrochloride.

Yield: 11.5% of theory, Melting point: 164-167°C Calculated: C 69.77 H 6.79 N 3.25 Cl 16.48 found: 69.74 6.74 3.21 16.45 According to ^"H-NMR (400 MHz) there is a 2:1 mixture of pairs of diastereoisomers.

[CDC13/CD30D: delta = 5.10 ppm (dd, 0.66 H), delta = 5.17 ppm fdd, 0.33 H)] t) 4'-[2-[N-(2-(4-Amino-3-cyano-5-fluoro-phenyl)-2-hydroxy-ethyl)amino]ethyl]-4-methoxy-biphenyl Prepared from 4-amino-3-cyano-5-fluoro-phenacylbromide and 4 '-(2-amino-ethyl)-4-methoxy-biphenyl.

Yield: 22.3% of theory, 22 7 1 Melting point: 150-153°C Calculated: C 71.09 H 5.97 N 10.36 Found: 70.93 5.91 10.24 u) Ethyl 4'-[2-LN-(2-(4-amino-3-cyano-5-fluoro-phenyl) -2-hydroxy-ethyl)amino]ethyl]biphenylyl-4-carboxylate Prepared from 4-amino-3-cyano-5-fluoro-phenacylbromide and ethyl 4'-(2-amino-ethyl)biphenylyl-4-carboxylate.

Yield: 18% of theory.

Melting point: 153-154°C Calculated: C 69.78 H 5.86 N 9.39 Found: 69.59 5.64 9.23 v) Ethyl 4'-[2-[N-(2-(4-amino-3,5-dichloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]biphenylyl-4-carboxylate Prepared from 4-amino-3,5-dichloro-phenacylbromide and ethyl 4'-(2-amino-ethyl)biphenylyl-4-carboxylate. Yield: 17.6% of theory, Melting point: 123-125°C Calculated: C 63.70 H 5.13 N 5.94 Cl 15.04 Found: 63.78 5.24 5.95 15.22 w) 41-[2-[N-(2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]-4-methoxy-biphenyl Prepared from 4-amino-3,5-dichloro-phenacylbromide and 4'-(2-amino-ethyl)-4-methoxy-biphenyl.

Yield: 17% of theory, Melting point: 150-151°C Calculated: C 64.04 H 5.61 N 6.49 Cl 16.44 Found: 64.17 5.78 6.45 16.44 x) 41-[2-IN-(2-(4-Amino-3,5-dichloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]-4-hydroxy-biphenyl 22 7 1 9 Prepared from 4-amino-3,5-dichloro-phenacylbromide and 4'-(2-amino-ethyl)-4-hydroxy-biphenvl.

Yield: 11% of theory, Melting point: 88-90°C Calculated: C 63.32 H 5.31 N 6.71 Cl 16.99 Found: 63.35 5.58 6.81 16.63 y) Ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino]ethyl]diphenylmethane-2-carboxylate Prepared from 3-chloro-phenacylbromide and ethyl 4'-(2-amino-ethyl)-diphenylmethane-2-carboxylate Yield: 30.4% of theory, Melting point: less than 20°C Calculated: C 71.30 H 6.44 N 3.20 Found: 71.36 6.44 3.37 z) 41-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]4-methoxy-l,2-diphenylethane Prepared from 3-chloro-phenacylbromide and 4 * — (2— amino-propyl)-4-methoxy-l,2-diphenylethane.

Yield: 17% of theory, Melting point: 108-110°C Calculated: C 73.65 H 7.13 N 3.30 Cl 8.36 Found: 73.45 7.19 3.50 8.40 According to "4l-NMPv (400 MHz) there is a 4:1 mixture of pairs of diastereoisomers.

[CDC13/CD30D: delta = 4.59 ppm (dd, 0.8 H), delta = 4.52 ppm (dd, 0.2 H)] aa) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino] ethyl]-4-methoxy-l,2-diphenylethane Prepared from 3-chloro-phenacylbromide and 41 —(2— amino-ethyl)-4-methoxy-l,2-diphenylethane.

Yield: 27.8% of theory, 22 7 1 9 Melting point: 112-113°C Calculated: C 73.24 H 6.88 N 3.42 Cl 8.65 Found: 73.45 6.92 3.28 8.60 ab) Methyl 4'-[2-lN-(2-(3-chloro-phenyl)-2-hydroxy-ethyl) amino ] ethyl ]diphenylmethane-2-oxyacetate Prepared from 3-chloro-phenacylbromide and methyl 4'-(2-amino-ethyl)-diphenvlmethane-2-oxyacetate- hydrochloride with the addition of N,N-diisopropyl- ethylamine.

Yield: 14% of theory.

Melting point: 84-86°C Calculated: C 68.80 H 6.22 N 3.09 Cl 7.81 Found: 68.61 6.05 3.07 8.01 ac) 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]-2-methoxy-diphenylmethane Prepared from 3-chloro-phenacylbromide and 4'-(2- amino-ethyl)-2-methoxy-diphenylmethane-hydrochloride with the addition of N,N-diisopropyl-ethylamine.

Yield: 16% of theory.

Melting point: 73-75°C Calculated: C 72.80 H 6.62 N 3.54 Found: 72.53 6.61 3.44 Example 3 Ethyl 4'-[2-[N-(2-hydroxv-2-phenyl-ethyl)amino]ethyl]-biphenylyl-4-carboxylate 1.0 g (3.27 mmol) of ethyl 4(2-amino-ethyl)biphenylyl-4-carboxylate hydrochloride are combined with 367 mg (3.27 mmol) of potassium tert.butoxide in 10 ml of absolute ethanol and heated to reflux temperature under nitrogen. After 5 minutes, 0.37 ml (3.27 mmol) 22 7 1 of styrene oxide dissolved in 10 ml of absolute ethanol are added dropwise. The mixture is then refluxed for a further 3 hours. After coolinq, it is concentrated by evaporation and purified by column chromatography on silica gel using chloroform/me thanol (15:1) as eluant. Finally the title compound is recrystallised from acetonitrile.

Yield: 270 mg (21.3% of theory), Melting point: 116-117°C Calculated: C 77.09 H 6.99 N 3.60 Found: 77.10 6.92 3.57 The following compounds are prepared analogously to the title compound of Example 3: a) 4'-Hydroxy-4-[2-[N-(2-hydroxy-2-phenyl-ethyl)amino] ethyl]biphenyl Prepared from styrene oxide and 4(2-amino-ethyl)- 4-hydroxy-biphenyl.

Yield: 14.2% of theory.

Melting point: 134-136°C Calculated: C 79.25 H 6.95 N 4.20 Found: 79.10 7.06 4.24 b) 4-[2-[N-(2-Hydroxy-2-phenyl-ethyl)amino]propyl]-biphenyl Prepared from styrene oxide and 4-(2-amino-propyl)biphenyl.

Yield: 27% of theory, Melting point: 96-100°C Calculated: C 83.34 H 7.60 N 4.23 Found: 83.30 7.52 4.22 According to "'"H-NMR (400 MHz) there is a 1:6 mixture of pairs of diastereoisomers.

[CDC1-,: delta = 4.61 ppm (dd, 0.85 H) , delta 22 7 1 96 = 4.67 ppm (dd, 0.15 H) ] c) 4-[2-[N-(2-Hydroxy-2-phenyl-ethyl)amino]ethyl]benzo-phenone-hydrochlor ide Prepared from styrene oxide and 4-(2-amino-ethyl)benzo-phenone-hydrochlor ide.

Yield: 17% of theory, Melting point: 169-172°C Calculated: C 72.34 H 6.33 N 3.67 Cl 9.28 Found: 72.50 6.13 3.78 9.57 Example 4 4'-[2-[N-(2-Hydroxy-2-phenvl-ethyl)aminojethyl]-4-methoxy-diphenylmethane 2.82 g (11 mmol) of 4-[4-methoxy-benzylJphenylacetic acid are dissolved in 25 ml of chloroform and after the addition of 2.5 ml of thionylchloride the mixture is stirred for 30 minutes at 50°C. It is then concentrated by evaporation, taken up in 30 ml of chloroform and added dropwise, with cooling, to a solution of 1.37 g (10 mmol) of 2-hydroxy-2-phenyl-ethylamine and 2.1 ml (15 mmol) of triethylamine in 40 ml of chloroform. After 2 hours stirring at ambient temperature, the mixture is washed first with dilute sodium hydroxide solution then with dilute hydrochloric acid. The chloroform extracts are then dried and concentrated by evaporation. The evaporation residue, which consists of N-(2-hydroxy-2-phenyl-ethyl)-4-(4-methoxy-benzyl)phenylacetamide, is dissolved in 20 ml of tetrahydrofuran and added dropwise, under nitrogen, to 1.33 g (35 mmol) of lithium aluminium hydride in 20 ml of tetrahydrofuran.

After 4 hours' refluxing, 2N sodium hydroxide solution is added, the sodium aluminate formed is separated 22 7 1 9 off by suction filtering and the filtrate is evaporated down. The evaporation residue is recrystallised from acetonitrile.

Yield: 890 mg (27% of theory), Melting point: 103-104°C Calculated: C 79.74 H 7.53 N 3.87 Found: 80.03 7.34 3.86 Example 5 4-[2-[N-(2-Hydroxv-2-(3-trifluoromethyl-phenyl)ethyl)-amino3propyl]diphenylmethane 3.8 g (20 mmol) of 3-trifluoromethyl-acetophenone are dissolved in 70 ml of dioxan and 3 ml of water and, after the addition of 2 g of kieselguhr and 2.45 g (22 mmol) of selenium dioxide, the mixture is refluxed for 6 hours. It is then cooled and filtered and 4.5 g (20 mmol) of 4-(2-amino-propyl)diphenylmethane and 2.6 g (20 mmol) of N,N-diisopropyl-ethylamine are added to the filtrate which contains the corresponding glyoxal. After 1 hours' stirring at 35°C the mixture is cooled in an ice bath, 50 ml of ethanol are added and, to reduce the Schiff base obtained, 1 g (26.3 mmol) of sodium borohydride is added. After 5 hours' stirring at ambient temperature the mixture is concentrated by evaporation and the evaporation residue is stirred for 15 minutes with dilute hydrochloric acid. It is then made alkaline and extracted with chloroform. The chloroform extract is evaporated down and the evaporation residue is purified by silica gel chromatography (eluant: chloroform/ethyl acetate/methanol (7:2:1)) Yield: 900 mg (11% of theory), Melting point: 104-107°C Calculated: C 72.62 H 6.34 N 3.39 Found: 72.74 6.49 3.38 2271 According to "'"H-NMR (400 MHz) there is a 7:1 mixture of pairs of diastereoisomers.

ICDCI^: delta = 4.64 ppm (dd, 0.87 H), delta = 4.57 ppm (dd, 0.13 H)] The following compound is prepared analogously to the title compound of Example 5: a) 4-[2-[N-(2-Hydroxy-2-(3-trifluoromethyl-phenyl)-ethyl)amino]propyl]biphenyl-hydrochloride Prepared from 3-trifluoromethyl-acetophenone and 4-(2-amino-propyl)biphenyl.

Yield: 11% of theory, Melting point: 188-192°C Calculated: C 66.12 H 5.78 N 3.21 Cl 8.13 Pound: 65.98 5.66 3.10 8.22 According to ^"H-NMR (400 MHz) there is a 1:5 mixture of pairs of diastereoisomers.

[CDCl^: delta = 1.32 ppm (dd, 2.5 H), delta = 1.38 ppm (dd, 0.5 H)] Example 6 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-propyljbiphenylyl-4-carboxylic acid 0.5 g (1.1 mmol) of ethyl 4'-[2-[N-(2-(3-chloro-phenyl) -2-hydroxy-ethyl)amino]propyl]biphenylyl-4-carboxylate are suspended in 30 ml of ethanol and after the addition of 2 ml of 2N sodium hydroxide solution the mixture is stirred for 5 hours at 50°C. It is then neutralised with 4 ml of IN hydrochloric acid, filtered and the filtrate is diluted with 40 ml of water. After standing overnight, the crystals formed are suction filtered and washed with ethanol/water (1:1). 22 7 1 9 6 Yield: 360 mg (80% of theory), Melting point: 199-201°C Calculated: C 70.32 H 5.90 N 3.42 Cl 8.65 Found: 70.22 5.97 3.38 8.60 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[DMSO-dg/CD^OD: delta = 4.98 ppm (dd), delta = 5.01 ppm (dd)] The following compound is prepared analogously to the title compound of Example 6: 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]biphenylyl-4-oxyacetic acid Prepared from ethyl 4'-[2-[N-(2-(3-chloro-phenyl)- 2-hydroxy-ethyl)-amino]propyl]biphenylyl-4-oxyacetate.

Yield: 95.5% of theory, Melting point: 216-218°C Calculated: C 68.25 H 5.96 N 3.18 Found: 68.37 5.97 3.26 According to ^"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

Example 7 Ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)-amino]ethyl]biphenylyl-4-carboxylate 1.7 g (10 mmol) of 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 3.66 g (11 mmol) of ethyl 41 — (2— bromo-ethyl)biphenylyl-4-carboxylate are dissolved in 50 ml of dimethylformamide and after the addition of 2.8 g (20 mmol) of potassium carbonate the mixture is stirred for 3 hours at 90 to 100°C. It is then filtered, concentrated by evaporation and the evaporation residue is purified by column chromatography on silica gel (eluant: ethyl acetate/methanol (40:1)). 22 7 196 Yield: 1.52 g (36% of theory), Melting point: 120-122°C Calculated: C 70.83 H 6.18 N 3.30 Cl 8.36 Found: 70.76 6.09 3.24 8.46 Tthe following compound is prepared analogously to the title compound of Example 7: a) 4-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)amino]-ethyl]diphenylmethane Prepared from 2-(3-chloro-phenyl)-2-hydroxy-ethylamine and 4-(2-bromo-ethyl)diphenylmethane.

Yield: 37% of theory.

Melting point: 85-87°C Calculated: C 75.50 H 6.61 N 3.83 Cl 9.69 Found: 75.63 6.72 3.69 9.57 Example 8 4'-[2-[N-(2-(3-Chloro-phenyl)-2-hydroxy-ethyl)-amino]propyl]-4-(2-hydroxy-ethoxy)biphenyl A solution of 1.75 g (3.85 mmol) of methyl 4'—[2— [N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]propyl]-biphenylyl-4-oxyacetate in 30 ml of absolute tetrahydrofuran is added dropwise, with stirring, to 1.75 g (46 mmol) of lithium aluminium hydride in 40 ml of absolute tetrahydrofuran. The mixture is then refluxed for 1 hour, decomposed by the dropwise addition of 4N sodium hydroxide solution and filtered to remove the sodium aluminate formed. The filtrate is evaporated down and the residue is recrystallised from acetonitrile.

Yield: 660 mg (40.2% of theory), Melting point: 120-126°C Calculated: C 70.49 H 6.63 N 3.29 22 7 1 9 Found: 70.50 6.76 3.42 According to "'"H-NMR (400 MHz) there is a 1:1 mixture of pairs of diastereoisomers.

[CDCl^: delta = 4.56 ppm (dd, 0.5 H), delta = 4.62 ppm (dd, 0.5 H)].

The following are examples of pharmaceutical compositions, feed compositions, premixes and performance enhancing compositions according to the invention: 22 7 1 96 Example I Coated tablet containing 10 mg of ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]propyl]di-phenylmethane-2-carboxylate 1 coated tablet contains: Active substance 10.0 mg Lactose 69.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 5.0 mg Magnesium stearate 1.0 mg 120.0 mg The active substance, lactose and corn starch are mixed together and moistened with the polyvinylpyrrolidone in an aqueous solution.

The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45°C in a circulating air dryer. The dry granules are passed through a screen with a mesh size of 1 mm and mixed with the magnesium stearate. The finished mixture is compressed to make tablet cores, weighing 120 mg, of diameter 7.0 mm and radius of curvature 6.0mm. The tablet cores are then coated in a conventional known manner with a coating consisting essentially of sugar and talc. This coating may also contain colourings. The finished coated tablets, of weight 180.0 mg, are polished with wax.

Example II Coated tablet containing 50 mg of ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)aminolpropyl]- 22 7 1 9 6 diphenylmethane-2-carboxylate 1 coated tablet contains: Active substance 50.0 mg Lactose 110.8 mg Corn starch 50.0 mg Polyvinylpyrrolidone 8.0 mg Magnesium stearate 1.2 mg 220.0 mg The coated tablets are prepared analogously to the tablets of Example I but have the following weights and dimensions: Weight of core: 220.0 mg Diameter: 9.0 mm Radius of curvature: 8.0 mm Weight of coated tablet: 300.0 mg Example III Tablets containing 150 mg of ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]propyl] -diphenylmethane-2-carboxylate 1 tablet contains: Active substance 150.0 mg Lactose 86.0 mg Corn starch 50.8 mg Microcrystalline cellulose 25.0 mg Polyvinylpyrrolidone 7.0 mg Magnesium stearate 1.2 mg 3 20.0 mg The components, with the exception of the magnesium 22 7 1 9 6 64 - stearate, are mixed together and Tnoistened with water. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45°C.

The dry granules are passed through the same screen once more and mixed with the magnesium stearate. Tablets of weight 320.0 mg and diameter 10.0 mm are compressed from the finished mixture.

The tablets are provided with a dividing notch to make it easier to break them in half.

Example IV Hard gelatine capsules containing 100 mg of ethyl 4'-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino] ■ propyl]-diphenylmethane-2-carboxylate 1 capsule contains: Capsule shell: hard gelatine capsule size 3 Capsule contents: Active substance 100.0 mg Lactose x 1H20 38.0 mg Dried corn starch 60.0 mg Magnesium stearate 2.0 mg Weight of capsule filling: 200.0 mg Distilled water q.s.

A small amount of lactose is dissolved at about 10% in distilled water (granulating liquid). The active substance, the remaining lactose and corn starch are mixed in and moistened with the granulating liquid. The mass is screened, dried and after being screened once more, homogeneously mixed with magnesium stearate. The fine-grained granules are packed into capsules in a suitable machine. 22 7 1 9 6 Example V Hard gelatine capsules containing 200 mg of ethyl 4'—[2—[N—(2-(3-chloro-phenyl)-2-hydroxy-ethyl)-amino3propyl]-diphenylmethane-2-carboxylate 1 Capsule contains: Capsule shell: hard gelatine capsules size 1 Capsule contents: Active substance 200.0 mg Lactose x IHjO 47.0 mg Dried corn starch 70.0 mg Magnesium stearate 3.0 mg Weight of capsule filling: 320.0 mg Distilled water q.s.

A small amount of lactose is dissolved at about 10% in distilled water (granulating liquid). The active substance, the remaining lactose and corn starch are mixed in and moistened with the granulating liquid. The mass is screened, dried and after being screened once more, homogeneously mixed with magnesium stearate. The fine-grained granules are packed into capsules in a suitable machine.

Example VI Complete feed II for fattening pigs Barley 370 g/kg Wheat bran 200 g/kg Manioc flour 135 g/kg Broad beans 100 g/kg Rape extract groats 100 g/kg 22 7 196 Edible fat 65 g/kg Lysine-rich mineral feed for pigs 20 g/kg Active substance premix 10 g/kg These components in the Quantities specified produce 1 kg of feed when carefully mixed together.

The 10 g of active substance premix contains for example, 10 mg of active substance and 9.99 g of corn starch.

Example VII Fattening feed II for broilers Maize 625 g/kg Soya bean flour 260 g/kg Meat meal 40 g/kg Edible fat g/kg Soya oil 17 g/kg Bicalcium phosphate 12 g/kg Calcium carbonate 6 g/kg Vitamin/mineral mixture g/kg Active substance premix g/kg These components in the quantities specified produce 1 kg of feed when carefully mixed together.

The 10 g of active substance premix contain, for example, 10 mg of active substance and 9.99 g of corn starch.

Example VIII Feed concentrate for cattle Shredded sugar beet 600.0 g/kg 22 Maize gluten 100.0 a/kg Malt germs 50. 0 g/kg Soya bean flour .0 g/kg Wheat 110.0 a/kg Molasses 60.0 g/kg Edible phosphates 12.0 g/kg Calcium carbonate 2.5 g/kg Salt .0 g/kg Minerals .0 g/kg Vitamin premix .5 g/kg Active substance premix .0 g/kg These components in the Quantities specified produce 1 kg of feed when carefully mixed together.

The 10 g of active substance premix contain, for example, 10 mg of active substance and 9.99 g of corn starch.

Example IX Fattening feed for lambs Barley 690 g/kg Soya bean flour 100 g/kg Maize 150 g/kg Molasses 30 g/kg Vitamin/mineral mixture 20 g/kg Active substance premix 10 g/kg These components in the Quantities specified produce 1 kg of feed when carefully mixed together.

The 10 g of active substance premix contain, for example, 10 mg of active substance and 9.99 g of corn starch. 22719

Claims (17)

WHAT WE CLAIM IS: 68

1. Compounds of formula I oh E r ■4 ch-ch2-n-a. (I) "3 (wherein A represents a straight-chained or branched alkylene group; B represents a bond, an alkylene group with 1 or 2 carbon atoms, or a carbonyl or hydroxymethylene group; represents hydrogen, halo or a tri-fluoromethyl group; R2 represents hydrogen or an amino group; R^ represents hydrogen, chlorine, bromine or a cyano group; and R^ represents hydrogen, halo or a alkyl, hydroxy, carboxy, (cj_3 alkoxy)carbonyl, aminocarbonyl, (^-3 alkyl)aminocarbonyl or di (Ci_3 alkyl) aminocarbonyl group, a C-^_3 alkoxy group optionally substituted in the end position by a carboxy, (C^_3 alkoxy)carbonyl, aminocarbonyl, (C-L_3 alkyl) aminocarbonyl or di (C^_3 a^y group, or a C2-3 alkoxy group substituted in the end position by a hydroxy, C^_3 1-3 alkyl)aminocarbonyl 2271 69 alkoxy, amino, (c^_3 alkyl)amino, di(C^_3alkyl)-amino, pyrrolidino, piperidino or hexamethyleneimino group) and the optical isomers, diastereoisomers and acid addition salts thereof.

2. Compounds of formula I as claimed in claim 1, wherein A represents an ethylene group optionally substituted by a alkyl group or by two methyl groups, B represents a bond or a methylene, ethylene, hydroxy-methylene or carbonyl group, represents hydrogen, fluorine, chlorine, bromine or a trifluoromethyl group, R2 represents hydrogen or an amino group, R^ represents hydrogen, chlorine or a cyano group and R^ represents hydrogen, chlorine or a hydroxy, methoxy, methyl, ethyl, carboxy, methoxy-carbonyl, ethoxycarbonyl, carboxymethoxy, 2-hydroxy-ethoxy, methoxycarbonylmethoxy or ethoxycarbonylmethoxy group, and the optical isomers, diastereoisomers. and addition salts thereof. 227196 70

3. Compounds as claimed in claim 1 being compounds of formula la r 1 ch-ch2-n-a oh h (la) (wherein A represents an ethylene or methylethylene group, B represents a bond or a methylene group, R-^ represents hydrogen or chlorine and R^ represents hydrogen or a methyl, ethyl, hydroxy, methoxy, methoxycarbonyl, ethoxycarbonyl, 2-hydroxy-ethoxy, methoxycarbonylmethoxy or ethoxycarbonylmethoxy group in the 2 or 4 position) and the optical isomers, diastereoisomers and addition salts thereof.

4. Compounds as claimed in claim 1 being 41-[2-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)amino]-propyl]-4-(2-hydroxy-ethoxy)biphenyl, and the optical isomers, diastereoisomers and acid addition salts thereof.

5. Compounds as claimed in claim 1 being ethyl 42-[N-(2-(3-chloro-phenyl)-2-hydroxy-ethyl)am- ino]propyl]diphenylmethane-2-carboxylate, and the ~ optical isomers, diastereoisomers and acid salts thereof. II 227196 - 71 -

6. Compounds as claimed in any one of claims 1 to 5 being physiologically acceptable salts of compounds of formula I.

7. A pharmaceutical composition containing a compound of formula I or a physiologically acceptable addition salt thereof as claimed in any one of claims 1 to 6 together with at least one pharmaceutical carrier or excipient.

8. A process for the preparation of compounds of formula I and salts thereof as claimed in claim 1, said process comprising at least one of the following steps: a) reacting a compound of formula II with a compound of formula III 72 1 9 (wherein A, B, R^, R2, R-j and R^ are as defined in any one of claims 1 to 5, or are protected forms thereof, one of the groups Z^ and Z2 represents a nucleophilic leaving group and the other group Z^ or Z2 represents an amino group or a protected amino group), and subsequently if required removing any protecting group used; b) reducing a Schiff base of general formula IV (wherein R^, R2 and R^ are as defined in any one of claims 1 to 5, or are protected forms thereof, and X represents a group of formula R (IV) —CH=N—A - 73 - 227 t ^ wherein A, B and are as defined in any one of claims 1 to 5, or are protected forms thereof, and A' together with the nitrogen atom to which it is attached represents a straight-chained or branched alkyleneimino group or a protected form thereof, and subsequently if required removing any protecting group used; c) reducing a compound of formula V R V - A (V) (wherein A, B, R^, R2, R^ and R^ are as defined in any one of claims 1 to 5, or are protected forms thereof, and V represents a group of formula -CO-CH2~NH- or -CO-CH=N- or a protected form thereof), and subsequently if required removing any protecting group used; d) reacting a compound of formula VI C*. (VI) (wherein R^, R2 and R^ are as defined in any one of claims 1 to 5 or are protected forms thereof) with an amine of formula VII - 74 - , V , , „ (VII) h2n - a B (wherein A, B and are as defined in any one of claims 1 to 5 or are protected forms thereof), and subsequently if required removing any protecting group used; e) reducing a compound of formula VIII (wherein B, R-^, R2# R^ and R^ are as defined in any one of claims 1 to 5, or are protected forms thereof, and U represents a carbonyl group and W has the meanings given for A in any one of claims 1 to 5, or U represents a methylene group and W represents a straight-chained or branched C^_5 alkanone group the carbonyl group whereof is bonded to the amine nitrogen), and subsequently if required removing any protecing group used; f) (to prepare compounds of formula I wherein R^ represents hydrogen, chlorine or bromine -—: and R^ represents a C2-3 al^oxy group substituted in the end position by a hydroxy, alkoxy, ami»e, alkylamino, dialkylamino, pyrrolidino, piperidino - 75 - or hexamethyleneimino group) reducing a compound of formula IX / i 9 6 oh h ' J/ ^ ch-ch2-n-a-// \ o-(cH2)n-coR5 (IX) (wherein A, B, and R2 are as defined in any one of claims 1 to 5, or are protected forms thereof, R^' represents hydrogen, chlorine or bromine, n represents the number 1 or 2, and Rg represents a hydroxy, C^_3 alkoxy, amino, (C-^_3 alkyl)amino, di(C^_3)alkylamino, pyrrolidino, piperidino, hexamethyleneimino group or protected forms thereof), and subsequently if required removing any protecting group used; g) (to prepare compounds of formula I wherein R^ represents an alkoxycarbonyl, aminocarbonyl, alkylamino carbonyl or dialkylaminocarbonyl group, or a C^_ 3 alkoxy group substituted in the end position by an alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl group) reacting a compound of formula X R1 X\—CH-( r H -ch2-n-a (wherein A, B, R^, #2' an^ R3 are as defined in any one 76 Zf 7 j g of claims 1 to 5, or are protected forms thereof, and R4' represents a carboxy group or a C13 alkoxy group substituted in the end position by a carboxy group, or a reactive derivative thereof) with a compound of formula XI (wherein Rg represents a C-j^j alkoxy, amino, (Ci_3 alkyl)amino, di(C1_3 alkyl)amino, pyrrolidino, piperidino or hexamethyleneimino group), and subsequently if required removing any protecting group used; (h) hydrolysing a compound of formula I wherein R^ represents or contains an alkoxycarbonyl or amidocarbonyl group; (i) (to prepare a compound of formula I wherein R^ represents a hydroxy group) effecting ether cleavage on a compound of formula I wherein R^ represents an optionally substituted alkoxy group; (j) separating a compound of formula I into optical isomers or diastereoisomers thereof; and (k) converting a compound of formula I into an acid addition salt thereof or an acid addition salt of a compound of formula I into the free base.

9. An animal performance enhancing composition containing a compound of formula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6 together with at least H R, 6 (XI) one carrier or excipient. 227196 77

10. An animal feed composition containing a compound of formula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6 together with at least one nutrient. 3 1.

An animal feed premix containing a compound of fotmula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claimfe 1 to 6 together with a nutrient, mineral, vitamjln, diluent, extender or excipient.

12. A method of treatment of a non-human animal to cofobat obesity, to improve meat quality or to improve feed utilization, said method comprising administering to said animal a compound of formula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6.

13. A method as claimed in claim 12 wherein said compound or salt is administered to a meat animal during the fattening thereof.

14. A method of treatment of a non- ; human animal body to combat diabetes mellitus, obesity or atherosclerotic changes, said method comprising administering to said animal a compound of fotmula I or a. physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6. 227196 - 78 -

15. Use of a compound of formula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6 for the manufacture of a therapeutic agent for use in combating diabetes mellitus, obesity or atherosclerotic changes.

16. Use of a compound of formula I or a physiologically acceptable acid addition salt thereof as claimed in any one of claims 1 to 6 for the manufacture of a performance enhancing composition, feed composition or feed premix for administration to non-human animals to improve feed utilization thereby.

17. Compounds of formula I as defined in claim 1 and salts and compositions thereof substantially as herein disclosed in any one of the Examples. BOEHRINGER INGELHEIM: VETMEDICA GmbH