KR820002065B1 - Process for the preparation of phenethanol aminos - Google Patents

Abstract

Title compds.(I; R1=H; R2=Me; R3=OH, alkanoyloxy, H2NCO, MeNHCO, alkoxycarbonyl) which are used for redn. in body wt. without a decrease in daily food consumption, were prepd. by reaction of styrene oxide(II) and propylamine(III). Thus, treating 3.6g III(R2=Me; R3=OH) with 2.1g II(R1=H) gave (R,S)-HOCHPhCONHCHMeCH2C6H4OH-4, which was reduced by diborane followed by neutralization with HCI to give IHCI.

Description

Method for producing phenethanol amines

The present invention relates to a novel penethanol amine derivative of the general formula (I) and a pharmaceutically toxic salt thereof, which is effective as a weight control agent in a mammal.

In the above formula,

R ₁ is hydrogen or fluorine;

R ₂ is methyl or ethyl;

R ₃ is hydroxy, C ₁ -C ₄ alkanoyloxy, aminocarbonyl, methylaminocarbonyl or C ₁ -C ₂ alkoxy carbonyl

C _* is an asymmetric carbon with R absolute stereochemical configuration

C _** represents asymmetric carbon with S absolute stereochemical configuration.

Preferred among the above compounds are compounds in which R ₂ is methyl, R ₁ is hydrogen, R ₂ is methyl and R ₃ is hydroxy, methoxy carbonyl, aminocarbonyl or methylaminocarbonyl.

Most preferred compounds of formula (I) are compounds wherein R ₁ is hydrogen, R ₂ is methyl and R ₃ is hydroxy or aminocarbonyl and pharmaceutically nontoxic salts thereof.

Recently, extensive research has been conducted on β-phenylethylamine such as catechol amine. For example, extensive research has been conducted on the natural catecholamine, epinephrine. Epinephrine is a powerful sympathetic stimulant and cardiac stimulant. However, epinephrine is limited in its use due to poor side effects and short shelf life, such as fear, anger, tremor, tension, periodic headaches, increased blood pressure, dizziness, dyspnea, and palpitations.

Drugs that have more than one physiological effect are always very dangerous. For example, bronchial dilation and cardiac stimulation are mediated by a variety of receptors known as β-receptors, so drugs acting on β-receptors not only have bronchodilator action but also act on the heart. In fact, it has been reported that death was caused by ventricular fibrillation due to excessive β-stimulation after bronchodilator use. (See Greenburg and Pines, Br. Med. J. 1,563 (1967).)

The compound according to the invention, named phenethanol amine, is N-substituted-3-phenylpropylamine. Stereochemical coordination of the compounds is defined by R and S nomenclature. For a general description of this nomenclature see Cuhn et al., Experientia, Vol. XII, PP 81-124 (1956). The steric configuration of the carbon atom represented by "C _* " is R and is first shown at the time of naming the compound of the present invention. Asymmetric carbon atoms represented by "C _** " have an absolute Absolute stereochemical configuration. Examples of this nomenclature include compounds of the general formula wherein R ₁ is hydrogen, R ₂ is methyl and R ₃ is aminocarbonyl, R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl It is named 3- (4-aminocarbonyl) phenylpropyl amine.

The compound of the present invention can be prepared by various methods, and a preferred method is a method of reacting optically active styrene oxide with optically active 1-alkyl-3-phenylpropylamine.

The method for preparing the compound of the present invention is as follows.

The styrene oxide of the following general formula (II) is reacted with the propylamine derivative of the following general formula (IV) to prepare a compound of the general formula (I).

In the general formula, R ₁ , R ₂ and R ₃ are the same as in general formula (I). At this time, when styrene oxide is not optically active, that is, not R-styrene oxide, it is divided later.

Optically active amines of formula (IV) are novel materials and are provided by the present invention.

The corresponding ketone of the following formula is reacted with (-)-α-methylbenzylamine in the presence of an acid such as P-toluenesulfonic acid to give the corresponding SN- (α-methylbenzyl) -1- (R ₂ ) -3- ( Prepare 4- (R ₃ ) phenyl) -propylimine.

Reduction of this imine with raninickel yields compounds of the general formula

The amine is purified by making a salt with an acid such as HCl and repeating recrystallization in a suitable organic solvent. The optically active S, SN- (α-methylbenzyl) -1- (R ₂ ) -3- (4- (R ₃ ) -phenyl) propylaluminium salts obtained were α-methylbenzyl on pd / c catalyst. The group is removed and liberated from the salt state into the amine form of formula (IV).

Styrene oxides, such as, for example, R-Otto-fluorostyrene oxide, may be used in combination with phenylpropylamines, such as S-1-methyl-3- (4-methylaminocarbonylphenyl) propylamine, which have an animal amount of optical activity. By reacting corresponding optically active penethanolamines of the invention, ie R, SN- [2- (2-fluorophenyl) -2-hydroxyethyl] -1-methyl-3- (4-aminocarbo Produces Nylphenyl) propylamine. Condensation reactions of this type are carried out in non-reactive polar organic solvents such as ethanol, dioxane, toluene or dimethylformamide, usually from 20 to 120 ° C., preferably from 50 to 110 ° C. Under these conditions, the general condensation reaction is practically completed after 6 to 10 hours and the product phenethanolamine is liberated by simply removing the reaction solvent, for example by evaporation under reduced pressure. The product thus formed may be further purified by methods such as chromatography, crystallization and salt formation if necessary.

The preparation of the compounds of general formula (I) mentioned above can be carried out using starting materials which are not separated from C _* and are obtained as diastereo mixtures of S, N-phenylpropylphenethanolamine. Separation of diastereomers is carried out in a conventional manner when necessary. On the other hand, the R-optical isomers of the penethanol moieties of the compounds having the general formula (ie, C _* ) are necessary because of the useful biological action, and the corresponding S-isomers (ie, C _* ) are mixed with such R-isomers. It is not a big drawback. This is because S-isomers are virtually inoperative and do not cause unnecessary side effects when used in therapeutic amounts in organisms. However, it should be understood that the present invention includes only compounds of general formula (I) in which the asymmetric carbon designated C _** has an absolute S-stereoisomer structure. This is because R-optical isomers (C _** asymmetric carbons) are potent cardiac contractors and cannot be used to treat obesity without affecting the heart. It is particularly desirable to use non-isolated materials if they are used to improve the quality of meat by removing excess fat tissue from cattle, such as cattle, pigs, sheep, or by inhibiting formation. The compounds of the present invention are of great value in improving pork for fat. When used for such purposes, it is appropriate to mix 5 to 250 mg / kg daily in animal feed.

Formula (I), wherein R ₃ is an aminocarbonyl group, is prepared directly by reacting appropriate phenylpropylamine with styrene oxide, or a compound wherein R ₃ is C ₁ -C ₂ alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl. Derived from For example, R-mandelic acid is reacted with S-1-methyl-3- (4-methoxycarbonylphenyl) propylamine and the amidecarbonyl group is reduced to correspond to the corresponding amines of the present invention R, SN- (2-phenyl 2-hydroxyethyl) -1-methyl-3- (4-methoxycarbonylphenyl) propylamine is prepared. The amine is reacted with hydrazine at about 50 to 100 ° C. for about 2 to 40 hours to convert the alkoxy carbonyl group to a hydrazinocarbonyl group. The latter compound is converted to the corresponding aminocarbonyl derivative by hydrogenation using a commercial hydrogenation catalyst such as Raney Nickel.

Compounds of formula (I) wherein R ₃ is a methylaminocarbonyl group are readily prepared by reacting styrene oxide with 3- (4-methylaminocarbonylphenyl) propylamine. The starting material, phenylpropylamine, can be readily prepared by reacting methylamine with a suitable benzoylchloride derivative. For example, reacting S-1-ethyl-3- (4-chlorocarbonylphenyl) propylammonium chloride with methylamine results in S-1-ethyl-3- (4-methylamino carbonyl phenyl) propylamine. . When the latter compound is reacted with styrene oxide, the compound of the present invention is obtained.

Compounds prepared in the present invention are amines and natural bases. Thus, they readily react with organic or inorganic acids to form acid addition salts. In the end, the present invention contains pharmacologically acceptable salts of N-phenylpropyleneethanol amines of the above general formula. The acid forming the salt in the present invention is not particularly limited, and the amine and hydrochloric acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, formic acid, acetic acid, butyric acid, citric acid, maleic acid, tartaric acid, hydroxide, fumaric acid of the present invention are not particularly limited. And acid such as butyric acid, methanesulfonic acid, P-toluenesulfonic acid, and the like.

Since pharmacologically acceptable acid addition salts formed by reacting the amine of the present invention with one of the acids listed above are usually present in a high crystalline solid, solvents such as methanol, ethanol and ethyl acetate need to be recrystallized and purified. There is. In addition, such salts are readily prepared in medicinal form, especially orally, and used for the treatment of obesity. If desired, such acid addition salts can be converted to commercially available freeamine bases by reaction with a suitable base compound such as sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, sodium bicarbonate. The compounds listed below are the compounds exemplified by the present invention. The listed tables are not intended to limit the scope of the present invention, but merely to list preferred compounds.

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propyl amine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-aminocarbonylphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-ethyl-3- (4-hydroxyphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-ethyl-3- (4-aminocarbonylphenyl) propyl amine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-methylaminocarbonylphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-acetoxyphenyl) propylamine;

R, S-N- [2- (2-fluorophenyl) -2-hydroxyethyl] -1-methyl-3- (4-ethoxycarbonylphenyl) propylamine;

R, S-N- [2- (2-fluorophenyl-2-hydroxyethyl] -1-ethyl-3- (4-methoxycarbonylphenyl) propylamine,

R-N- (2-phenyl-2-hydroxyethyl) -3- (4-methylaminocarbonyl) phenylpropylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-isobutyroxyphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-ethyl-3- (4-methylaminocarbonylphenyl) propylamine;

R-N- [2- (2-fluorophenyl) -2-hydroxyethyl] -3- (4-ethoxycarbonylphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-ethoxycarbonylphenyl) propylamine;

R-N- (2-phenyl-2-hydroxyethyl) -3- (4-aminocarbonylphenyl) propylamine;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propyl ammonium chloride,

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-methylaminocarbonylphenyl) propylamiminibromide;

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propylammonium acetate,

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propyl aminimumitrate,

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl3- (4-aminocarbonylphenyl) propylaminiumsuccinate,

Obesity is one of the most serious diseases in recent years because no practical treatment is known. A detailed description of nutritional diseases and obesity can be found in Albrink's Textbook of Medicine 12th Edition 1969, W.B. Saunders Cpmpany Philadelphia 1164-1174 page and Salans (current) Current Therapy, 1977, W.B. Saunders Company, pages 455-460. The compounds provided by the present invention are effective in actually losing weight, especially when administered to mature obese animals. Such weight loss is performed without reducing food intake. When the compound of the present invention was administered to immature obese animals, the rate of weight gain was significantly lower than that of the compound of the present invention. The anti-obesity activity of the compounds of the invention has been confirmed by many biological experiments using mice, rats, and dogs. Biological experiments have shown that the main action of the compounds of the present invention is the transfer of fatty acids from the skin tissue fat layer. In order to confirm the movement of the fat, the compound of the present invention was administered to eight rats of Charles River strain, each weighing about 180 to 200 g. Prior to administration of the test compound, each of the eight animals was experienced and used as a control sample. Each animal is then subcutaneously injected at 10 mg / kg body weight. 30, 60, 90, 120 minutes after administration, a blood sample is taken and the concentration of serum free fatty acids is measured. Table I shows the results for the two compounds of the present invention. As shown in the results, a significant increase in serum free fatty acids is based on the compounds of the present invention.

TABLE I

Viable yellow hereditary obesity mice were used as samples to show actual weight loss by the compounds of the present invention. All animals were 6.5 months old at the beginning of the experiment. Animals were fed Purina Laboratory Chow and water during the test. 10 mg subcutaneous injection of R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propylamine twice daily for five randomly selected obese animals / kg and placebo for the other five. The animals are weighed one day before the first injection. Table II shows the results of that study. Values are the mean weights of the test compounds administered and the control. The figures are indicated by g in column I below each date in the table. Column II shows the average daily food intake of the test and control groups.

The results in Table II show that the compounds of the present invention can reduce actual weight without reducing food intake.

TABLE II

Similar experiments were conducted using genetically obese mice, or mice. When the compound of the present invention was administered to adult obese rats at 6 months of age, there was a marked weight loss. When administered to immature obese rats aged 2 to 5 months of age, they were more effective in inhibiting body weight and gain than those administered without the compound of the present invention. Table III shows R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-hydroxyphenyl) propylamine administered 10 mg / kg twice a day to test animals. Results are shown. All animals were allowed to eat all food and water as they wished. The intake of food did not show a significant difference between the administration of the compound of the present invention and placebo. Body weights shown in the table are average weights for each of the five experimental groups.

TABLE III

The anti-obesity effect of the compounds of the present invention was tested for their effects on obese dogs. As the test animals, 4 to 9 year old Pino-Ack-type obesity, which is 15.4 to 29.0 kg in weight, was selected as breeder beagle. Dogs maintained obesity by feeding Eucanuba containing 16% fat for six months prior to testing. In the experiment, dogs were injected subcutaneously with 3.2 mg / kg twice daily of R, S-N- (2-phenyl-2-hydroxyethyl) -1-3- (4-hydroxyphenyl) propyl ammonium chloride. The effect of this drug was determined by measuring body weight in kg. There was no decrease in food intake. The five week results are summarized in Table IV.

Table IV

In a similar manner, mature obese beaglehounds were used to feed standard dog food and R, SN- (2-phenyl-2-hydroxyethyl-1-methyl-3- (4-aminocarbonylphenyl) propylaminium chloride It is administered orally twice a day for 27 days The effect of the medicine on weight is determined by the measured body weight (kg) and the torso (inch) The control group is fed food and water for two dogs but not the medicine. Table V shows the test results, as shown in the table, the control group showed no significant change in body weight or torso size, whereas the administration of the compound of the present invention reduced body weight by 1.8 to 2.9 kg in 27 days. Body size was reduced by 2 inches over the same period.

TABLE V

As noted above, the only physiological effect of the compounds of the present invention is a potent anti-obesity effect while being physiologically resistant to cardiovascular action. This unique specificity can be achieved by correctly selecting stereoisomers. The only physiological action of the R, S-isomers of the present invention was compared to the R, R-isomers (potent heart contractants) using dogs. The test compound was injected into a dog equipped with a cardiovascular transducer in the left ventricle of which cardiac contractility is known. The amount was injected to increase the cardiac contractility by 25%. The amount needed to increase that amount of shrinkage was investigated in ED VI with ED ₂₅ (mcg / kg). The results showed that the R and R-isomers with deep contraction were only needed to increase the contractile force by 25%, but the corresponding R and S-isomers were required to be significantly larger in order to achieve the same effect.

Table VI

Since the compounds of the present invention have a significantly lower cardiac contractile effect, the compounds of the present invention can be used in amounts sufficient to release fatty acids from the subcutaneous tissue without increasing the heart rate. Because of this unique biological action, the compounds of the present invention can be used to control the weight of obese animals. As used herein, the term "weight control of obese animals" refers to the effect of reducing the compound of the present invention when used in mature obese animals, and to inhibit the rapid increase in weight when administered to immature animals. As used herein, "maturation" and "maturity" are generally distinctions according to age and growth. "Obesity" is also used here as is commonly understood. An additional aspect of the invention is a method of weight control in obese animals. The amount of the compound of the present invention used for the treatment of obesity depends on the drug used and the condition to be treated, and usually 1.0 to 25 mg / kg body weight. The compounds of the present invention are easily prepared for oral use and are used 1 to 5 mg / kg 1 to 4 times a day. If desired, it may be administered in tablets, capsules or sustained release formulations. The compound of the present invention defined by the general formula can achieve weight loss without reducing daily food intake. The compounds of the present invention can be increased in dose if necessary until the desired weight is reduced. Compounds of the present invention can be administered to mature obese animals to reduce body weight without reducing daily food intake. Once immature obese animals mature, weight loss can be achieved until normal weight.

The compounds of the present invention may be prepared in a convenient formulation by any convenient method. The compounds of the present invention are conveniently prepared for oral use. Pharmaceutical formulations that are convenient for weight control in obese animals are part of the present invention. Such pharmaceutical compositions may be formulated with pharmaceutically acceptable carriers, diluents and inert isomers as indicated herein if one or more of the compounds of the present invention are required as the active ingredient. Usually carriers and diluents are such as gelatin, starch, dextrose, sucrose, lactose, cellulose derivatives, stearates, polyvinylpyrate, lollidine, glycerin, ethyl lactate, sorbitol, mannitol, and the like. Suitable pharmaceutical compositions may additionally be used, such as commonly used preservatives, stabilizers, antioxidants, copulation agents. It contains 1 to 50% of the pharmaceutically common active ingredient of the compound according to the invention for use in the treatment of obesity. The remainder of the pharmaceutical composition is a suitable carrier and diluent, if necessary an inert optical isomer. Pharmaceutical compositions containing one or more compounds of the present invention as an active ingredient may be formulated into tablets, filled into gelatin capsules, and prepared into solutions or suspensions. Such pharmaceutical compositions may be administered for the treatment of obesity through various routes including oral or injection. As an example of a preferred formulation, 250 mg of R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-aminocarbonylphenyl) propylaminium chloride are mixed with a suitable carrier and oral administration is carried out. To make tablets, one to four tablets a day are used to effectively control the weight of an obese person. In order to explain in more detail each aspect of the present invention, the following preparation shows how to prepare the starting material used in the present invention, the following example shows the preparation of the final product of formula (I). The examples are merely representative and are not intended to limit the invention.

[Manufacture 1]

Preparation of R-Styrene Oxide

A stirred cooling solution of 300 g of R-mandelic acid dissolved in 2000 ml of tetrahydrofutan was added dropwise to 3000 ml of a 1 mole solution of diborane dissolved in tetrahydrofuran for 2 hours. After the addition, the reaction mixture is stirred at 25 ° C. for 12 hours and cooled to 0 ° C. on an ice bath. 600 ml of methanol was added to the cooled solution, and the reaction mixture was stirred for another 3 hours. Evaporation of the solvent under reduced pressure yields 260 g of solid. Recrystallization of the solid from diethyl ether results in R-2-phenyl-2-hydroxyethanol.

A solution of 256.7 g of R-2-phenyl-2-hydroxyethanol dissolved in 1000 ml of toluene containing 50 ml of pyridine was stirred at 0 ° C. and a solution of 372.1 g of p-toluenesulfonyl chloride in 400 ml of toluene was added dropwise for 2 hours. do. The reaction mixture is stirred at 0 ° C. for 48 hours and filtered to give pyridine hydrochloride. The precipitate is evaporated to dryness under reduced pressure to give an oily material. The oily material is dissolved in satoluene, washed with dilute hydrochloric acid and water and dried. The solvent is evaporated under reduced pressure and crystallized with diethyl ether and hexane to give 435 g of R-2-phenyl-2-hydroxy-1-p-toluenesulfonyl oxyethane. The product formed is dissolved in 1000 ml of dimethylsulfoxide containing 418 ml of 5N-sodium hydroxide. The alkaline solution is stirred at 0 ° C. for 12 hours and poured into ice water. The product is extracted with 50% diethyl ether-pentane and the organic layer is separated, washed with water and dried. The solvent is evaporated and distilled to give R-styrene oxide.

b.p. 55 to 56 ℃ 0.6torr

[α] _D -23.7 ° (chloroform)

[Manufacture 2]

Preparation of R-ortho-fluorostyrene oxide

103 g of dl-0-fluoromandelic acid is reacted with (+)-α-methylbenzylamine to transform into a salt, and the salt is crystallized from ethanol and ethyl acetate to optically active α-methylbenzyl aminirium 2- ( 2-fluorophenyl-2-hydroxy) acetate, mp155-157 ° C., [α] _D −43.1 ° (MeOH). The salt is hydrolyzed to the free acid to R-ortho-fluoromandelic acid, mp88-90 ° C., [α] _D -138 ° (MeOH). The acid is converted to R-ortho-fluorostyrene oxide in the order of Preparation 1. bp5 to 61 ° C. (3torr) [α] _D -32.7 ° (chloroform)

Example 1

R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-methylaminocarbonylphenyl) propylamine

To a reflux solution in which 3.6 g of S-1-methyl-3- (4-methylaminocarbonylphenyl) propylamine was dissolved in 50 ml of ethanol, 2.1 g of R-styrene oxide dissolved in 20 ml of ethanol was added dropwise over 10 minutes. After all of the styrene oxide was added, the reaction mixture was refluxed for 4 hours, cooled to 25 ° C, and stirred for 12 hours. The solvent is removed by evaporation under reduced pressure to give an oil which is crystallized with diethyl ether to give 3.5 g of solid target product. The solid was recrystallized from ethyl acetate and diethyl ether to obtain 1.7 g of R, S-N- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-methylaminocarbonylphenyl) propylamine. Melting point 158 to 160 ° C. is reacted with hydrochloric acid dissolved in diethyl ether to make hydrochloride, crystallized with ethanol and ethyl acetate, R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- ( 4-Methyl-amino carbonylphenyl) propylaminium chloride (melting point 179-182 ° C.) is obtained.

Analysis of C ₂₀ H ₂₇ ClN ₂ O ₂

Theoretic value: C 66.19; H 7.50; N 7.72

Found: C 66.40; H 7.82; N 7.49

Example 2

R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-aminocarbonylphenyl) propylammonium chloride in 600 ml of ethanol and 200 ml of methanol was added to S-1-methyl-3- ( A solution of 109.6 g of 4-aminocarbonylphenyl) propylamine was refluxed and a solution of 68.4 g of R-styrene oxide in 100 ml of ethanol was added dropwise thereto for 14 hours. After all of the styrene oxide was added, the reaction mixture was refluxed for 3 hours, cooled to room temperature, and the solvent was evaporated under reduced pressure. The reaction mixture is diluted with 200 ml of diethyl ether and filtered. The precipitate is triturated with water, dried and recrystallized with acetonitrile to give 72.6 g of organic amine in the form of a solid. The amine formed is reacted with hydrochloric acid dissolved in diethyl ether to form hydrochloride to form R, SN- (2-phenyl-2-hydroxyethyl) -1-methyl-3- (4-aminocarbonylphenyl) propyl aminium 64.0 g of chloride are obtained.

Melting point 229-231 ° C, [α] _D -52.1 ° (MeOH)

Theoretic value: C 65.41; H 7.22; N 8.03

Found: C 65.17; H 7.10; N 8.03

Example 3

Preparation of 250 mg tablets.

The active ingredient, corn starch, lactose and dicalcium phosphate are mixed uniformly. Corn starch paste prepared as a 10% aqueous paste is added to the mixture and mixed uniformly. The mixture is mixed with calcium stearate and compressed into tablets. These tablets can be administered 1 to 4 tablets per day or as needed to treat obesity.

Example 4

[Manufacture of suppositories]

The ingredients are mixed uniformly at about 60 ° C. and made into long chunks with cooling. Each suppository weighs about 2 grams and is used once or twice a day to reduce the weight of mature animals or to suppress the gain of immature animals.

Example 5

Preparation of Oral Suspension

Sorbitol solution was added to 40 ml of distilled water, and R, SN- [2- (2-fluorophenyl) -2-hydroxyethyl] -1-methyl-3- (4-hydroxyphenyl) propylammonium acetate was added thereto. Dissolve. Lactose, sodium benzoate and fragrance are added and dissolved. The total amount of the solution was added to distilled water and adjusted to 100 ml. Each ml of syrup contains 50 mg of active ingredient. Five to 20 ml of syrup is administered daily to reduce the weight of mature obese mammals.

Claims (1)

Characterized in that the styrene oxide of formula (II) is reacted with the propylamine derivative of formula (IV) and R, S- and S of formula (I) produced to obtain only R, S-enantiomer, Separation of S-enantiomer mixture to prepare an optically active compound of formula (I).

In the above formula R ₁ is hydrogen or fluorine R ₂ is methyl or ethyl R ₃ is hydroxy, alkanoyloxy having 1 to 4 carbon atoms, aminocarbonyl, methylaminocarbonyl, or alkoxycarbonyl having 1 to 2 carbon atoms C _* is an asymmetric carbon atom with absolute stereochemical configuration of R C _** represents an asymmetric carbon atom with S absolute stereochemical configuration.