AU617353B2 - Pyridylethanolamines - Google Patents

Abstract

Pyridylethanolamines of the formula <IMAGE> in which R denotes a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-hydroxyethoxy group, their optical isomers, their diastereomers and their acid addition salts. The novel compounds of the above formula I, their optical isomers and their diastereomers and also their acid addition salts, in particular their physiologically tolerable acid addition salts with inorganic or organic acids, have useful pharmacological properties, namely an effect on the metabolism, preferably a hypoglycaemic and body fat-reducing effect, and also a lowering effect on the atherogenic beta -lipoproteins VLDL and LDL. The novel compounds of the above formula I can be prepared by processes which are known per se.

Description

71-i 2 AUSTRAL? A PATENTS ACT 1952 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: 617353 Application Number: Lodged: Complete Specification Lodged:

S

Priority: oo Related Art: 6. Name of Applicant: 'Address of Applicant: Actual Inventors: Address for Service: Acceptea: Lapsed: Published: TO BE COMPLETED BY APP.lCANT DR KARL THOMAE GmbH D-7950 Biberach an der Riss, Federal Republic of Germany.

MANFRED REIFFEN, WOLFGANG GRELL, ROBERT SAUTER, RUDOLF HURNAUS, ECKHARD RUPPRECHT and MICHAEL MARK CALLINANS, Patent Attorneys, of 48-50 Bridge Road, Richmond 3121, Victoria, Australia.

Complete Specification for the invention entitled: 'PYRIDYLETHANOLAMINES The following statement is a full description of this invention, including the best method of performing it known to us:-

U*

]a PB 53 165 Pyridylethanolamines The present invention relates to new pyridylethanolamines, processes for their preparation and pharmaceutical compositions containing them.

We have found that certain novel pyridylethanolamines exhibit valuable pharmacological properties, particularly an effect on metabolism, especially an effect of reducing blood sugar and body fat, and the effect of reducing levels of the atherogenic lipoproteins 10 VLDL and LDL. Some of the compounds mentioned e also have an anabolic activity.

s Thus according to one aspect the present invention provides compounds of formula I OH H CH 3 (I) Cl N CH-CH 2

-N-CH-CH

2

R

(wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-hydroxyethoxy group), and the optical isomers, diastereoisomers and acid addition salts thereof.

The compounds of formula I may form salts, e.g.

with inorganic or organic acids, the particularly preferred salts being those which are physiologically acceptable.

I :I 2 According to a further aspect, the present invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of the following steps: reacting a compound of formula II

H

Y N Y (II) (wherein one of the moieties Y represents a hydrogen atom and the other represents a group of formula 9 9 .9 S0 9

CH

CH CH 2 R wherein R is as hereinbefore defined) with a compound of formula III

Z

1 U (III) (wherein U represents a group of formula -CH2-CH 2O ov

CH

-CH-CH

2 wherein R is as hereinbefore defined, and

Z

1 and V together represent a bond, or 1. 1 it -3 z 1 I represents a nucleophilic leaving group suc h as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a suiphonyloxy group, e.g. a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group and V represents a hydrogen atom); reductively aminating a carbonyl compound of formula IV @6O*

S

S.

S

*.S

S

SOOSO

S

*5 0 S S 55 S S

OS

S.

5 0

OS

S S SS S

S

0 CH 3 -CO-0H 2

R

(IV)

(wherein R is as hereinbefore defined) with an amine of formula V OH H

CH-CH

2 -N reducing a compound of formula VI H CH CO-CH 2

-N-CH-CH

2 -C

(VI)

ii i 4 (wherein R is as hereinbefore defined); reacting a compound of formula VII OH H CH CI/i N CH-CH -N-CH-CH 2 H (vOH

C

1 N 2 2 V I I with a compound of formula VIII 5 Z R (VIII) 2 1 (wherein

R

1 represents a carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-hydroxy-ethyl group, and

Z

2 represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, e.g.

Sa chlorine, bromine or iodine atom or a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group, or

Z

2 together with a B-hydrogen atom of the group

SR

1 represents an oxygen atom); hydrolysing a resulting compound of formula I wherein R represents a methoxycarbonylmethoxy or ethoxycarbonylmethoxy group to yield a corresponding compound of formula I wherein R represents a carboxymethoxy group; converting a compound of formula I into an acid addition salt thereof, or an acid addition ,ne i I ii' i I I ii 5 salt of a compound of formula I into the free base; and resolving a resulting compound of formula I or a salt thereof into its diastereomers or enantiomers.

The reaction of step may conveniently be carried out in a solvent or mixture of solvents such as methanol, ethanol, acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxan or in an excess of the compound of formula III used. Optionally the reaction is effected in the presence of an acid binding agent, 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, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine, N,N-diisopropylethylamine or pyridine, where the latter may also be simultaneously used as solvent, or in the presence of a reaction accelerator such as potassium iodide. The reaction is conveniently effected at temperatures between 0 and 150 0 C, depending on the reactivity of the nucleophilically exchangeable group, preferably at a temperature between and 120 0 C, e.g. at the boiling temperature of the solvent used, The reaction may, however, also be carried out without a solvent. It is particularly advantageous to carry out the reaction with a corresponding epoxide of formula III without the addition of an acid binding agent.

The reductive amination of step may be carried out in a solvent such as methanol, ethanol, tetra-

C

6 hydrofuran, dioxan or acetonitrile in the presence of a reducing agent such as a complex metal hydride, but preferably in the presence of sodium cyanoborohydride at a pH of from 5 to 7, and conveniently at temperatures of between 0 and 50 0 C, but preferably at ambient temperature.

The reduction of step may preferably be 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 and conveniently at temperatures .between 0 and 40 0 C, but preferably at ambient temper- 1, 5 ature.

*pe When the reduction of step is carried out with S*a complex metal hydride such as lithium aluminium hydride, diborane or borane/dimethylsulphide, a carbonyl function present in the group R may be reduced at the same time to yield a methylene group.

The reaction of step may conveniently be carried out in a solvent such as diethylether, tetrahydrofuran, dioxan, methanol, ethanol or dimethylformamide and preferably in the presence of an acid-binding agent such as sodium hydroxide or potassium tert.butoxide, but preferably in the presence of potassium carbonate or sodium hydride or pyridine, whilst an organic base such as pyridine may also be used as solvent, or, in order to prepare 2-hydroxy-ethoxy compounds of formula I, with ethylene oxide. The reaction conveniently is effected at temperatures of between 0 and 100 0 C, preferably at temperatures of between 20 and 80 0

C.

A

7 In the reactions of steps to described above, reactive groups may be protected during the reaction with conventional protecting groups which are then split off again by conventional methods after the reaction.

Examples of suitable protective groups for a carboxy group include benzyl, tert.butyl, tetrahydropyranyl, trimethylsilyl, benzylo-ymethyl, 2-chloroethyl and methoxymethyl groups and a phenacyl group, e.g. a benzoylmethyl group, suitable protecting groups for an amino or alkylamino group include acetyl, benzoyl, tert.butoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl and benzyl groups and suitable protecting groups for a hydroxy group include, for example, trityl, fluorenylmethyloxycarbonyl, benzyloxycarbonyl and benzyl groups.

The optional subsequent splitting off of any protecting group used is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/ water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric or •o sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, conveniently at temperatures of between 0 and 100 0 C, preferably at the boiling temperature of the reaction mixture. A benzyl or benzyloxycarbonyl group, however, is preferably removed by ydrogenolysis, 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, conveniently at temperatures of between 0 and 50 0 C, but preferably at ambient temperature, under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

i 8 The hydrolysis of step is carried out either in the presence of an acid such as hydrochloric, sulp'uric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, methanol, ethanol, ethanol/water, water/isopropanol or water/dioxan, conveniently at temperatures of between -10 0 C and 120 0 C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.

The compounds of formula I obtained may be converted into the acid addition salts thereof, more particularly "o for pharirr-eutical use the physiologically acceptable salts with inorganic or organic acids. Suitable acids for salt formation include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic acid.

As already mentioned hereinbefore, the compounds of formula I may occur in the form of the enantiomers, enantiomer mixtures or racemates thereof or in 0 the form of pairs of diastereoisomers or mixtures of pairs of diastereoisomers.

Thus, the compounds of formula I obtained may be separated into their diastereoisomers on the basis of their physical/chemical differences by methods known per se, e.g. by chromatography and/or fractional crystallisation. A pair of enantiomers thus obtained may then be separated into the optical antipodes thereof by methods known per se (see Allinger N.L.

and Eliel E.L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), e.g. by recrystallisation from an optically active solvent or by reaction with an optically active substance which 9 forms salts with the racemic compound, particularly an acid, and separation of the salt mixture obtained in this way, e.g. on the basis of differences in solubility, into the diastereomeric salts, from which the free antipodes can be liberated by the action of suitable agents. Optically active acids which are particularly useful include the D and L forms of tartaric acid, di-o-toluene tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid and quinic acid.

The compounds used as starting materials which may, obviously, also be used in their optically pure forms, may be obtained by methods known from .1 s the literature (see "Thiazole and its Derivatives" in Heterocyclic Compounds, Vol. 34, and Advances in Heterocyclic Chemistry, Vol 17, page 100ff (1974)) i or are known from the literature. In some cases these compounds are only present in the reaction mixture and therefore cannot be isolated.

S. An intermediate compound of formula II, V, VI or VII may be obtained by corresponding alkylation of a suitable amine, as discussed in EP-A-239815.

An intermediate compound of formula III wherein

Z

1 represents a nucleophilic leaving group maybe obtained by reduction of a corresponding acetyl compound, e.g. with a complex metal hydride, or by conversion of a corresponding hydroxy compound into a reactive derivative thereof.

An epoxide of an intermediate compound of formula III may be obtained for example by reacting a suitable bromo- or tosylethanol with aqueous potassium or sodium hydroxide solution.

;I V 10 As already mentioned hereinbefore, the compounds of formula I, the enantiomers, mixtures of enantiomers or racemates thereof or, if they contain at least 2 asymmetric carbon atoms, the diastereoisomers or mixtures of diastereoisomers, and the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable acid addition salts thereof, have valuable pharmacological properties, including, in addition to the effect of inhibiting platelet aggregation, an effect on the metabolism, especially an effect of lowering blood sugar and reducing body fat, and the effect of reducing the atherogenic 8-lipoproteins VLDL and LDL. Moreover, some of the compounds mentioned above also have an anabolic activity.

The biological properties of the new compounds were investigated as follows: 1. Antidiabetic activity The antidiabetic activity of the compounds according to the invention can be measured as a blood sugarreducing effect in experimental animals. The test substances were suspended in 1.5% methyl cellulose and administered to laboratory-bred female mice by oesophageal tube. 30 minutes later, 1 g of glucose per kg of body weight was dissolved in water and administered subcutaneously. After another 30 minutes, blood was taken from the retroorbital plexus venosus.

The level of glucose in the serum was determined by the hexokinase method using an analytical photometer.

In the Table which follows, the reductions in blood sugar observed in this experimental arrangement are shown as the percentage of a parallel control group.

Statistical evaluation was carried out by the Students t test taking p=0.05 as the limit of significance.

e _I *1

K

K

I; ii i I 11 Compound (Example No.) Change from the level of the control group dosage [mg/kg] 1 0.3 1 0. .0 1 -66 2 -64 5A -66

K

i i 4 *o* s 4 *S 44 2. Anti-adipose activity The anti-adipose activity of the compounds according to the invention was demonstrated by two experimental arrangements: a) In the first experiment the increase in lipolysis was measured by the increase in glycerol in the serum.

The experimental procedure is identical to the experimental arrangement described above for testing the reduction in blood sugar. The glycerol level was determined in a combined enzymatic/colorimetric test using an analytical photometer. The results are shown in the following Table as the percentage of a parallel control group.

Compound Change from the level of (Example No.) the control group dosage [mg/kg] 0.1 0.3 1 +882 2 +454 3 +309 4A +891 +878

MC;

T'

I--

I -12 b) In the second experimental arrangement for determining the anti-adipose effect of the compounds according to the invention, the reduction in fatty tissue was measured on the fatty tissue of the ovary by way of example. For this purpose, the compounds were administered to mice once a day by oesophageal tube in a methylcellulose suspension. On the fifth day the fatty tissue of the ovary was dissected out and weighed. The following Table shows the results as a percentage of a parallel control group.

S

S.

S S S

*SS

55.

S,,

Compound Change from the level of the con- (Example No.) trol group Dosage: 0.3 [mg/kg] 5A -54 3. Cardiac side effects The compounds of the invention have been shown to have no undesirable side effects on the heart in the therapeutic dosage range which has an effect on the metabolism. The evidence for this was provided by the measurement of heart rate in mice during the tests for the blood sugar reducing effect (see above). One hour after oral administration of the compounds heart rate was determined by means of an ECG-triggered tachograph.

The Table which follows shows the change in heart rate as a percentage of the control group.

Compound Change from the level Dosage (Example No.) of the control group 3 +35 10 mg/kg 2 0.3 mg/kg 0.3 mg/kg 13 The figures in brackets are not significant (p greater than 0.05) Furthermore, in the tests on the substances according to the inventior described above, no toxic side effects were observed at the dosages used. The substances are therefore well tolerated.

In view of their pharmacological properties, the compounds of formula I and the physiologically acceptable acid addition salts thereof are therefore suitable for the treatment both of diabetes mellitus and also obesity, particularly for treating obese 0000 o diabetics. Moreover, the new compounds may be 0*SS used for the prophylaxis and treatment of atherosclerotic changes in the blood vessels, which occur particularly in diabetics and obese people. The dosage required can be matched entirely to the metabolic physiological requirements of the individual patients since the substances are free from any effect on the heart or circulation over a wide dosage range. In adults, therefore, the daily dose may be between 1 and 3000 mg, but preferably 1 to 1000 mg, divided up into 1 to 4 doses per 0* e day. For this purpose, the above-mentioned compounds may be incorporated in conventional galenic preparations such as powders, tablets, coated tablets, capsules, suppositories or suspensions, optionally in conjunction with other active substances.

Thus, in another aspect, the invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient. It will be understood that the "pharmaceutical compositions" 14 of the invention include within their scope compositions suitable for administration to non-human animals, i.e. veterinary compositions.

In a still further aspect, the invention provides a method of treatment of the human or non-human body to combat diabetes mellitus, obesity and atherosclerosis comprising administering to said body a compound of formula I or a physiologically acceptable salt thereof.

In a yet further aspect, the invention provides the use of a compound of formula I or a physiologically acceptable salt thereof for the preparation of a therepeutic agent for use in the treatment of diabetes mellitus, obesity and artherosclerosis.

The compounds of the invention may thus also be used to treat overweight animals such as dogs and, as a consequence of their body fat-reducing (lipolytic) 00 -"2b effect, and they may be used to reduce undesirable fat deposits in the fattening of animals, i.e.

in order to improve the quality of meat of fattened animals such as pigs, cattle, sheep and poultry.

In animals, the above-mentioned compounds may be administered by oral or non-oral routes, e.g. as a feed additive or by injection or by means of implanted minipumps. The daily dose is between 0.01 and 100 mg/kg, preferably between 0.1 and mg/kg of body weight.

In a still further aspect the invention thus also provides an animal feed comprising a compound of formula I or a physiologically acceptable salt thereof together with a feedstuff.

J

15 The Examples which follow are provided to illustrate the invention without restricting its scope in any way.

Unless otherwise stated all percentages, parts and ratios referred to herein are by weight.

15 .go 0o 3 g 'I J; o

I

16 Example 1 N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]- 2-hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hydrochloride 0.23 g (0.00133 mol) of 2-hydroxy-2-(6-chloro-pyridin- 2-yl)ethanamine and 0.3 g (0.00133 mol) of 1-(4carbomethoxymethoxyphenyl)propan-2-one are dissolved in 15 ml of absolute methanol, 0.08 g (0.00133 mol) of glacial acetic acid and 0.084 g (0.00133 mol) of sodium cyanoborohydride are added and the mixture is stirred for 16 hours at ambient temperature.

It is then poured onto ice and acidified with hydrochloric acid. After 5 minutes it is made alkaline with ammonia at 0 to 5 0 C and extracted with methylene chloride. The extract is dried over sodium sulphate and concentrated by evaporation and purified over a silica gel column using ethyl acetate/methanol as eluant. The base is converted into the hydrochloride using ethereal hydrochloric acid.

Yield: 0.276 g (46% of theory), Melting point: from 70 0 C (decomposition).

40 Calculated: C 54.94 H 5.82 N 6.74 Cl 17.07 Found: 54.60 6.00 7.00 17.40 1 According to H-NMR spectrum (400 MHz, DMSO/CD3OD) an approximately 1:1 mixture of the pairs of diastereoisomers is present.

delta 1.17 ppm CH-CH 3 delta 1.20 ppm (d,>CH-C) delta 1.20 ppm >CH-CH 3 (113 17 Example 2 N-[2-(4-(2-Hydroxyethoxy)phenyl)-l-methylethvl]-2hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine-hydrochloride Prepared analogously to Example 1 by reacting 2hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine with l-(4-(2-hydroxyethoxy)phenyl)propan-2-one and sodium cyanoborohydride and subsequently purifying the product over a silica gel column using ethyl acetate/methanol as eluant. The base is converted into the hydrochloride using ethereal hydrochloric acid.

iYield: 65% of theory, Melting point: 68 0 C (decomposition) Calculated: C 55.81 H 6.24 N 7.23 Cl 18.30 S. Found: 55.60 6.46 7.09 18.47 According to H-NMR spectrum (400 MHz, d6-DMSO/CD30D) an approximately 1:1 mixture of the pairs of diastereoisomers is present.

delta 1.121 ppm CH-CH) e-3 delta 1.136 ppm (d,)CH-CH 3 Example 3 N-[2-(4-Carboxymethoxyphenyl)-l-methylethyll-2hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine 3.6 g (0.0095 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin- 2-yl)ethanamine are dissolved in 20 ml of methanol and 50 ml (0.05 mol) of IN sodium hydroxide solution are added. The solution is stirred for 30 minutes at ambient temperature and then neutralised with ml of IN hydrochloric acid (0.05 mol). The solvent is distilled off in vacuo and the residue r

A

lt 2 18 is stirred with 20 ml of water and 20 ml of methanol for 16 hours, suction filtered and washed with a little methanol.

Yield: 1.8 g (52% of theory), Melting point: 218 0 C (decomposition).

Calculated: C 59.25 H 5.80 N 7.68 Found: 59.47 5.83 7.55 According to IH-NMR spectrum (400 MHz, D6-DMSO/CD3OD) there is an approximately 3:2 mixture of the pairs of diastereoisomers.

delta 4.92 ppm CH-CH 3 delta 4.98 ppm (d,)CH-CH 3 l00 Example 4 .e N-[2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine Pair of diastereoisomers A: 9.3 g of a 3:2 mixture of the pairs of diastereoisomers A and B obtained as described in Example 3 are dissolved hot in a mixture of 600 ml of methanol o. S and 900 ml of water and crystallised by cooling in an ice bath. This crystallisation process is repeated three times with 360 ml of methanol 450 ml of water and 250 ml of methanol 380 ml of water. The pair of diastereoisomers A are then obtained in a degree of purity of about 96%.

Yield: 1 g (17.2% of theory), Melting point: 234 0

C

Calculated: C 59.26 H 5.80 N 7.67 Cl 9.71 Found: 59.07 5.69 7.66 9.97 H-NMR spectrum (400 MHz, CD30D/D 6

-DMSO)

delta 4.949 ppm (dd,>CH-OH) :L I I 19 Example N-f2-(4-Carboxymethoxyphenyl)-1-methylethyl]-2-hydroxy-2 -(6-chloro-pyridin-2-yl)ethanamine-hydrochloride Pair of diastereoisomers A 3.6 g (0.0095 mol) of a 1:1 mixture of the pairs of diastereoisomers A and B of N-[2-(4-carbomethoxyphenyl)-l-methylethyl]-2-hydroxy-2-(6-chloropyridin-2-yl)ethanamine obtained as described in Example 1, are stirreu in 20 ml of methanol and 50 ml (0.05 mol) of IN sodium hydroxide solution at ambient temperature for 45 minutes. The solution is mixed with 50 ml of IN hydrochloric acid and brought to dryness. The residue S• is stirred overnight with 20 ml of methanol and 20 ml of water and the solid product precipitated is suction filtered. The mother liquor is concentrated by evaporation and the residue is triturated wi.th 25 ml of water, then twice wi*h 50 ml and 30 ml, respectively, of acetone and suction filtered. The pair of diastereoisomers B is then present in the form of the hydro- S.chloride with a degree of purity of Yield: 1 g (56% of theory), Melting point: about 80°C (decomposition) Calculated: C 53.87 H 5.52 N 6.97 Cl 17.66 Found: 53.82 5.66 6.86 17.50 H-NMR spectrum (400 MHz, CD 3 OD/D -DMSO) delta 4.907 ppm CH-OH) fv'' 20 Example 6 N-[2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl}]-2-hydroxy-2- (6-chloro-pyridin-2-yl)ethanamine Pair of diastereoisomers A: 48.6 g of a 1:1 mixture of the pairs of diastereoisomer of N- [2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2-hydroxy-2-(6chloro-pyridin-2-yl)ethanamine (Example 2) are dissolved in 500 ml of hot acetone and brought to crystallization by cooling in an ice bath, whereby an approximately 8:2 mixture of pairs of diastereoisomers B and A is obtained (Yield: 15.5 g, Melting point: 134 0 The volume of mother liquor is reduced to 200 ml and this is cooled overnight in a refrigerator. The product precipitated is suction filtered, dissolved in 150 ml of hot acetone and crystallised by cooling in an ice bath. This procedure is repeated with 100 ml of O acetone and with 70 ml of acetone, yielding 6 g of a product with a melting point of 108 0 C. These 6 g were recrystallised twice more from 60 ml and 40 ml, respectively, of acetone, to give the pure pair of diastereoisomers A.

Yield: 4 g (16.5% of theory), Melting point: 109-110 0

C

Calculated: C 61.62 H 6.60 N 7.98 Cl 10.10 Found: 61.55 6.64 7.86 10.30 1H-NMR spectrum (400 MHz, CDCL 3 delta 4.620 ppm (dd -CH-OH Pair of diastereoisomers B: 15.5 g of a mixture of pairs of diastereolsomers Hydroxyethoxy) phenyl) -'-methylethyL] -2-hydroxy-2- (6-chioropyridin-2-yl)ethanamine (Examnple 2) (B:A about 8:2) were I recrystallised four times from 600 ml, 500 ml, 400 ml and 350 ml, respectively, of acetone. The pair of diastereoisomers B is obtained with a degree of purity of 96 to 98%..

S S 21 Yield: 7 g (56.5% of theory), Melting point: 142-143°C Calculated: C 61.62 H 7.98 N 7.98 Cl 10.10 Found: 61.45 8.01 7.68 9.98 H-NMR spectrum (400 MHz, CDCl 3 delta 4.666 ppm (dd, CH-OH) Example I ]0 Coated tablet containing 10 mg of N-[2-(4-(2-hydroxyethoxy)phenyl)-l-methylethyl]-2-hydroxy-2-(6-chloropyridin-2-yl)ethanamine I Composition 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 Preparation Components and are mixed together and moistened with component in an aqueous solution. The moist mass is passed through a screen with a mesh size of 1.6 mm and dried at 45 0 C in a circulating air dryer. The dry granules are passed through a screen with a mesh size of 1 mm and mixed with component The finished mixture is compressed to form tablet cores.

Weight of core: 120 mg Diameter: 7.0 mm Radius of curvature: 6.0 mm 1 I I 22 The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. This coating may also contain dye extracts. The finished coated tablets are polished with wax.

Weight of coated tablet: 180.0 mg Example II Coated tablet containing 50 mg of N-[2-(4-(2-hvdroxyethoxy)phenyl)-1-methylethyll-2-hydroxy-2-(6-chloropyridin-2-yl)ethanamine 9 9 *9 9 9.

.9 Composition: 1 coated tablet contains: Active substance Lactose Corn starch Polyvinylpyrrolidone Magnesium stearate Preparation: The tablets are prepared analogously Weight of core: Diameter: Radius of curvature: Weight of coated tablet: 50.0 mg 110.8 mg 50.0 mg 8. mg 1.2 mg 220.0 mg to Example I.

220.0 mg 9.0 mm 8.0 mm 300.0 mg 9 9 Example III Tablets containing 150 mq of N-[2-(4-(2-hydroxyethoxy)phenyl)-l-methylethyl]-2-hydroxy-2-(6-chloro-pyridin- 2-yl)ethanamine 23 Composition: 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 320.0 mg Preparation: Components and are mixed together and moistened with water. The moist mass is passed tt "ough a screen with a mesh size of 1.6 mm and dred at 45 0 C. The dried granules are passed through the same screen again and mixed with component Tablets are compressed from the finished mixture.

1 Weight of tablet: 320.0 mg Diameter: 10.0 mm The tablets are provided with a dividing notch to make it easier to break them in half.

Example IV Hard gelatin capsules containing 100 mg of N-[2- (4-(2-hydroxyethyl)phenyl)-l-methylethyl]-2-hydroxy- 2-(6-chloro-pyridin-2-yl)ethanamine Composition: 1 capsule comprises: Capsule casing: hard gelatin capsules, size 3 I I I, i i PLI~~ 7 I j 24 Capsule contents: Active substance Lactose x 1H 2 0 Dried corn starch Magnesium stearate Weight of capsule filling: Distilled water q.s.

100.0 mg 38.0 mg ?0.0 mg 00.0 mg 200.0 mg *r *.ee

SOSO

9* S Preparation: A small amount of lactose is dissolved to about in distilled water (granulating liquid). The active substance, the remaining lactose and corn starch are mixed together and moistened with the granulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.

Example V Hard gelatin capsules containing 200 mg of N-[2- (4-(2-Thydroxvethoxy)phenyl) methylethyll-2-hydroxy- 2-(6-chloro-pyridin-2-yl)ethanamine Composition: Capsule casing: hard gelatin capsules, size 1 Capsule contents: Active substance Lactose x 1H 2 0 Dried corn starch Magnesium stearate Weight of capsule filling: Distilled water g.s.

200.0 mg 47.0 mg 70.0 mg 3.0 mg 320.0 mg 25 Preparation: A small amount of lactose is dissolved, to about in distilled water (granulating liquid). The active substance, the remaining lactose and corn starch are mixed together and moistened with the Sgranulating liquid. The mass is screened, dried, re-screened and homogeneously mixed with magnesium stearate. The fine granules are packed into capsules in a suitable machine.

*s j4 ]0 5 S* e I S so ooI 2oo*4 S

Claims (8)

1. Compounds of formula I H CH3 t I 0 OSOO 0@ S. 00 0* S S. S *5 S S *5 S 05 5 S (wherein R represents a carboxymethoxy, carbomethoxymethoxy, ethoxycarbonylmethoxy or 2-hydroxyethoxy group) and the optical isomers, diastereoisomers and acid addition salts thereof.

2. A compound as claimed in claim 1 being N- [2-(4-(2-Hydroxyethoxy)phenyl)-1-methylethyl]-2- hydroxy-2-(6-chloro-pyridin-2-yl)ethanamine, or an optical isomer, diastereoisomer or acid addition salt thereof.

3. A compound as claimed in claim 1 or claim 2 being a physiologically acceptable acid addition salt of a compound of formula I.

4. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 or a physiologically acceptable acid addition salt thereof together with at least one pharmaceutical carrier or excipient.

A process for the preparation of compounds as claimed in claim 1, said process comprising at least one of the following steps: *SSS S 55*S 0 S S S. a"> li:rs T.. J"T r -l I 7 27 a) reacting a compound of formula II H Y N Y (II) (wherein one of the moieties Y represents a hydrogen atom and the other represents a group of formula OH CH CI N -C or CH CH 2 R s 2 s 4 o: wherein R is as defined in claim 1) at 0 e e with a compound of formula III Z U (III) z 55 S(wherein U represents a group of formula S-CH3 or _CHC 2 3 -CH 2 -CH N C CHCHR OV Swherein R is as defined in claim 1; and Z 1 and V together form a bond, or Z 1 represents a nucleophilic leaving group and i 28 V represents a hydrogen atom) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter; b) reductively aminating a carbonyl compound of formula IV CH3-CO-CH 2 R IV) (wherein R is defined as in claim 1) with an amine of formula V N, Ci N CH-CH 2 -N H optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter; c) reducing a compound of formula VI H CH- (VI) NCl N CO-CH 2 -N-CH-CH 2 R 29 (wherein R is as defined in claim 1) optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter; d) reacting a compound of formula VII OH H CH /CH-CH -N-CH-CH "OH v N Cl N 2 2 l I: with a compound of formula VIII S- R (VIII) 2 1 (wherein R 1 represents a carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl or 2-hydroxyethyl group, and Do I Z 2 represents a nucleophilic leaving group; or Z 2 together with a beta-hydrogen atom of the group R represents an oxygen atom), optionally with reactive groups being protected during the reaction by a protecting group and with any said protecting groups being removed thereafter; hydrolysing a resulting compound of formula I wherein R represents a methoxycarbonylmethyl or., ethoxycarbonylmethoxy group to yield a corresponding compound of formula I wherein R represents a carboxy- methoxy group; 30 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; and resolving a resulting compound of formula I or a salt thereof into its diastereomers or enant- iomers.

6. An animal feed comprising a compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof together with a feedstuff. 0 S

7. A method of treatment of the human or non- human Sbody to combat diabetes mellitus, obesity and atherosclerosis comprising administering to said body a compound of formula I as defined in claim 1 or a physiologically acceptable salt thereof.

8. Compounds of formula I, as defined in claim 1 and salts thereof substantially as herein disclosed in any one of the Examples. DATED this 15th day of March 1991. By Their Patent Attorneys: CALLINAN LAWRIE i S 1 r