DK145041B - METHOD OF ANALOGUE FOR PREPARING A BENZOPHENO DERIVATIVE OR ACID ADDITION SALTS THEREOF - Google Patents

Description

(or then) DENMARK \ Μ.

| J | (12) PUBLICATION <N> 145041 B

DIRECTORATE OF PATENT AND TRADEMARKET

(21) Application No. 2027/76 (51) intCI * C 07 C 97/10 (22) Filing date 11 · Jun. 1976 (24) Race day 1 1. June 1976 (41) Aim. available 21. December 1976 (44) Posted 9 Aug. 1982 (86) International application no.

(86) International filing day (85) Continuation day (62) Stock application no.

(30) Priority Jun 20 1975 * 26407/75 * GB

(71) Applicant MAY & BAKER LIMITED, Dagenham, GB.

(72) Inventor Berkeley Basil, GB: Kenneth Robert Harry Wooldridge, GB.

(74) Associate Engineering Company Budde, Schou & Co.

(54) Analogous procedure for the release of a benzophenone derivative or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel therapeutically useful benzophenone derivatives or acid addition salts thereof.

It is known, e.g. from British Patent Nos. 994,918, 995,800, 1,021,522, 1,023,214, 1,046,001, 1,047,927, 1,058,822, 1,066,613, Q 1,069,341, 1,069,342, 1,069,345, 1,079,989, 1,089,769, 1,123,258, 1,127,469, 1,128,052, 1,129,072, 1,206,420, 1,231,783, 1,247,384, ^ 1,269,776, 1,327,707, and 1,362,228 that many l-amino -3-aryloxy-2-pro-> panol derivatives possess β-adrenergic blocking properties - and are therefore valuable in the treatment or prophylaxis of heart disease.

judgments such as angina pectoris and cardiac arrhythmias and in the treatment j of hypertension and phaeochromocytoma in humans. It is also known that even small differences in the structure between these derivatives often cause relatively large differences in their pharmacological properties.

It is an object of the present invention to provide a narrow type of novel 1-amino-3-aryloxy-2-propanol derivatives having in the ortho position of the aryloxy (especially phenoxy) ring a benzoyl group, i.e. benzophenone compounds that have particularly valuable pharmacological properties.

Thus, the present invention relates to an analogous process for preparing a benzophenone derivative of the formula

OH

I! 0-CH2-CH-CH2 -NHir I 11 I | (IN)

CH3 0 W

(R% 1.2 where R is isopropyl, t-butyl or 2-phenylethyl, R is methyl or a chlorine atom, n is 1 or 2, and i is 0, 1 or 2, where R2 where m is 2 can be be the same or different, or non-toxic acid addition salts thereof, which is characterized by an epoxy compound of the formula

ISLAND

O-CE2 -CH-CH2 iCH3'n-f II (II> CH3 o 2 where R, m and n have the above meanings are reacted with an amine of formula R1NH2 (III) where R · Has the meaning given above.

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The compounds of formula I occur in stereoisomeric forms, and the present invention comprises the preparation of all such forms and mixtures thereof, including racemic forms, as well as non-toxic acid addition salts.

The reaction of the epoxy compound of formula II and the amine of formula III may be carried out in an organic solvent such as dimethylformamide or an alkanol of 1-4 carbon atoms, e.g. methanol, at a temperature between 0 and 100 ° C.

The epoxides of formula II used as starting materials can be prepared by methods known in the art for preparing epoxides, e.g. by reaction of epichlorohydrin with a phenol of the formula

OH

(CVN-4 ^ lT

.Ti-Λ IV

CH3 0 Who! (R% 2 where R, m and n have the meanings given above. The reaction may be carried out in an aqueous or inert organic solvent such as dimethylformamide or an alkanol having from 1 to 4 carbon atoms, for example methanol, in the presence of a basic condensing agent such as potassium carbonate, sodium hydroxide or sodium methoxide at a temperature between 0 and 100 ° C.

The phenols of formula IV may be prepared by methods known per se or by analogous methods for the preparation of o-hydroxybenzophenones.

The benzophenone derivatives of formula I can be converted by methods known per se to acid addition salts. Thus, the acid addition salts can be obtained by the action of an acid on the benzophenone derivatives in a suitable solvent such as diethyl ether. The acid addition salt which is formed precipitates, if necessary after concentration of its solution, and is separated by filtration or decantation.

4 US041 In medicine, the benzophenone derivatives of formula I are used as they are or in the form of non-toxic addition salts, i.e. salts containing anions that are relatively harmless to the organism when used in pharmacodynamically effective doses so that the beneficial properties of the bases are not destroyed by side effects due to the anions. Suitable non-toxic salts include salts of inorganic acids, e.g. hydrochlorides, hydrobromides, phosphates, sulphates and nitrates, and of organic acids, e.g. oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, succinates, fumarates, maleates, methylene bis-3-hydroxynaphthoates, gentisates and D-di-p-toluoyl tartrates.

The term "methods known per se" as used in the present specification is to be understood as hitherto used methods or methods described in the chemical literature.

The compounds of formula I which are of particular importance are the following: DL-1- (2-benzoyl-3,5-dimethylphenoxy) -2-hydroxy-3-isopropylamino-propane, (A), DL-1- (3 , 5-Dimethyl-2-p-toluoylphenoxy} -2-hydroxy-3-isopropylaminopropane, (B), DL-1- (2-benzoyl-3,5,6-trimethylphenoxy) -2-hydroxy-3- isopropylaminopropane, (C), DL-1- (3,5-dimethyl-2-o-toluoylphenoxy) -2-hydroxy-3-isopropylaminopropane, (D), DL-1- [2- (2, 6-dimethylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy-3-isopropylaminopropane, (E), DL-1- [2- (2,4-dimethylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy -3-isopropylaminopropane, (F), DL-1- (2-benzoyl-3,6-dimethylphenoxy) -2-hydroxy-3-isopropylamino-propane, (G), DL-1- (2-p-chlorobenzoyl) 1- (3,5-Dimethylphenoxy) -2-hydroxy-3-isopropylaminopropane, (H), DL-1t-butylamino-3- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy propane, (I), DL-1- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy-3- (2-phenylethylamino) -propane, (J), U5061 and non-toxic acid addition salts thereof, eg hydrochloride salts Compounds A and B o g Their non-toxic acid addition salts are of particular importance.

The letters A-J are appended to the compounds for further reference later in the description, e.g. in the following tables.

The novel benzophenone derivatives of formula I and their non-toxic acid addition salts possess valuable pharmacodynamic properties. Thus, they have a valuable vascular β-adrenoceptor blocking effect in association with a relatively low car-dial β-adrenoceptor blocking effect of shorter duration. This association of properties indicates their utility in the treatment of disorders where a vascular β-adrenoceptor blocking effect is desired but where a cardiac β-adrenoceptor blocking effect is not beneficial or may be detrimental and therefore unfortunate. In particular, this combination of properties is important for the utility of treating migraine, which is thought to be caused by focal carcinoma of the cerebral cortex, followed by vasodilatation, which presents with symptoms of migraine, and where block of cardiac β-adrenoreceptors is not beneficial but can be harmful and therefore unlucky.

The above properties have been demonstrated by the following laboratory screening methods.

β-Adrenoceptor blocking activity

Sample I. β-Adrenoceptor-blocking effect on anesthetized cat (Intravenous administration).

Cats are anesthetized with a mixture of pentobarbitone (6-12 mg / kg) and chloralose suspension (80 mg / kg) administered intraperitoneally. The heartbeat is recorded with the ECG or from the pulse and blood pressure is measured on the carotid artery. Whole (0.3-0.6 µg) and half (0.15-0.3 µg) doses of isoprenaline are then administered intravenously through the cervical vein alternately at 7 minute intervals over a period of several hours. 210 seconds after a half dose of isoprenaline, one of the compounds being tested is administered intravenously. 210 seconds later, the entire dose of isoprenaline is administered.

The doses of the test compound necessary to reduce (1) the tachycardia and (2) the decrease in diastolic blood pressure induced by the entire dose of isoprenaline to the pressure produced by the half dose are determined. The former mentioned provides a measure of the ability of the test compound to block the β-adrenoceptors in the heart, while the latter provides a measure of the ability of the test compound to block the vasodilatation mediated by the β-adrenoceptors.

The results obtained are shown below in Table I.

Table I

p / intravenous dose (mg / kg Bond-body weight ratio) - cardiac dose: __cardial_vascular vascular dose AX 1.1 0.023 48 B 2.9 '0.031 93.5 C 4.4 2.3 1.9 D 0.8 0 , 16 5.0 E 3.7 1.8 2.1 F 0.59 0.24 2.5 GX 7.1 4.2 1.7 H * 0.72 0.037 19 I 0.46 0.027 17 JX ca . 2.0 0.068 29

X

hydrochloride salt

Hydrochloride salts of compounds A, G, H and J are dissolved in water and administered as an aqueous solution. Compounds B, C D, E, F and I are each dissolved in dilute aqueous hydrochloric acid solution (0.1N) to give a neutral solution of the hydrochloride salt of the test compound, suitable for administration.

Sample II. β-Adrenoceptor-blocking effect in anesthetized rhesus monkeys and anesthetized dogs (intravenous administration)

Test compound A (the hydrochloride salt) is tested intravenously on anesthetized rhesus monkeys and dogs by proceeding in the same manner as described above in Sample I.

The results are given below in Table II

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Table II

Dose (mg / kg body weight) 210 sec interval after 1 hour interval after dose of test compound sis of test compound

Animals__cardial__va s cow leather__cardial__vascular

Rhesusabe__0 / 1__0 / 0067 ___ 1__0 / 0076_

Dog_ 0.1 0.02__0.13 0.02_

Sample III. β-Adenoceptor-blocking effect in anesthetized dog (oral administration)

Test compound A (the hydrochloride salt) is tested orally on anesthetized dogs by proceeding as described above in Sample I and Sample II. The results are given below in Table III

Table III

Time interval after oral dose (mg / kg body weight) dose of test compound- cardinal__ vascular_ 1 hour 4 0.1 2 hours 3.2 0.08 3 hours 6 0.1

Toxicity

In the above tests I, II and III, the novel compounds do not give rise to any acute side effects.

(i) Mice, orally

Acute toxicity studies in mice show that DL-1- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy-3-isopropylaminopropane (test compound B) has an LD 1000 mg / kg body weight by oral administration.

(ii) Mice, intravenously

The acute intravenous LD5Q counts observed in mice are shown below in Table IV

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Table IV

Test compound AB CDEFH I i.v. LD50 (mg / kg) 40 25-31 23 34 42 24 32-40 24 (iii) Rats, oral

Test compound A is well tolerated by four groups of rats, each of five male rats and five female rats given daily oral doses of 12, 24, 48 or 96 mg / kg body weight over two weeks.

(iv) Dogs, orally

Test compound A is well tolerated by three groups of dog dogs who receive daily doses for two weeks. Two groups, each of two males and two bitches, each receive a daily dose of 10 or 50 mg / kg body weight and one group of a male and a bitch receive a daily dose of 100 mg / kg body weight.

The following examples serve to illustrate the process of the invention.

Example 1

Compound A

A mixture of 35 g of 2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone, 40 ml of isopropylamine and 200 ml of anhydrous methanol is refluxed overnight. The solution is then evaporated in vacuo and the residue is treated with an excess of anhydrous ethereal hydrogen chloride solution. The resulting rubber is separated by decantation and triturated with anhydrous diethyl ether to give 47.6 g of solid, mp 119-121 ° C. The solid dissolves in water. The resulting solution is left at room temperature for one hour and then shaken with ethyl acetate. The aqueous layer is separated, made alkaline by the addition of concentrated sodium hydroxide solution and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo. The oily residue is extracted with light petroleum (boiling point 60-80 ° C) and the extract is treated with anhydrous ethereal hydrogen chloride solution to give 29.4 g of DL-1- (2-benzoyl-3,5-dimethylphenoxy) - 2-hydroxy-3-isopropylaminopropane hydrochloride, mp 138-140 ° C, in the form of a white solid.

2- (2,3-Epoxypropoxy) -4,6-dimethylbenzophenone used as starting material in the above preparation is prepared as follows:

A solution of 50 g of 2-hydroxy-4,6-dimethylbenzophenone prepared as described by R. Baltzly et al. in J. Amer. Chem. Soc., 77, 1955, 2522, in 450 ml of anhydrous methanol is added to a methanolic solution of sodium methoxide prepared from 5.2 g of sodium and 200 ml of anhydrous methanol and the mixture is heated at reflux for 10 minutes. The solvent is evaporated and the residue is treated with anhydrous diethyl ether. The yellow solid is filtered off, dissolved in 600 ml of anhydrous dimethylformamide and heated on a steam bath with 88 ml of epichlorohydrin for 2 hours. The mixture is evaporated in vacuo and the residue is treated with water. The insoluble oil is extracted with diethyl ether. The extract is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is triturated with light petroleum, boiling point 60-80 ° C to give 40.3 g of 2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone in the form of a whitish solid, m.p. 72-74 ° C, which was clean enough for the next step in the synthesis.

A pure sample of 2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone, mp 74-75 ° C is obtained as a white solid by recrystallization from cyclohexane.

Example 2

Compounds B and D

A mixture of 10.0 g of 2- (2,3-epoxypropoxy) -4,41,6-trimethylbenzophenone, 10 ml of isopropylamine and 50 ml of anhydrous methanol is heated at reflux for 17 hours. The solution is then evaporated in vacuo and the residue dissolved in 100 ml of water containing 10 ml of concentrated hydrochloric acid. The solution is adjusted to pH 6-7 and shaken with ethyl acetate. The aqueous phase is then adjusted to pH 12 by the addition of aqueous sodium hydroxide solution. The precipitated oil is extracted with ethyl acetate and the extract is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in a hot mixture of light petroleum, boiling point 40-60 ° C, 75 ml, and 3 ml cyclohexane and allowed to cool slowly. The solid is filtered off and recrystallized from 25 ml of cyclohexane to give 5.9 g of DL-1- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy-3-isopropylaminopropane, m.p. -91 ° C.

By proceeding in a similar manner but replacing the 2- (2,3-epoxypropoxy) -4,4 ', 6-trimethylbenzophenone used as starting material with 2- (2,3-epoxypropoxy) -2', 4, 6-trimethylbenzophenone is obtained DL-1- (3,5-dimethyl-2-O-toluoylphenoxy) -2-hydroxy-3-isopropylaminopropane, mp 103.5-106 ° C.

10 145041

The 2- (2,3-epoxypropoxy) -4,4 ', 6-trimethylbenzophenone, m.p. 58-60 ° C, and the 2- (2,3-epoxypropoxy) -2', 4,6-trimethylbenzophenone, m.p. 5-87.5 ° C used as starting materials in the above preparations is prepared by proceeding as described in Example 1 in the preparation of 2- (2,3-epoxypropoxy) -4,6-dimethyl-benzophenone, but replacing 2-hydroxy-4,6-dimethylbenzophenone with appropriate amounts of 2-hydroxy-4,4 ', 6-trimethylbenzophenone and 2-hydroxy-2', 4,6-trimethylbenzophenone.

The 2-hydroxy-4,4 ', 6-trimethylbenzophenone used as starting material in the above preparation is obtained as follows: 123 g of anhydrous aluminum chloride is added portionwise over 10 minutes to 1400 ml of nitrobenzene, allowing the temperature to rise 40 ° C. 109 g of 3,5-dimethylphenyl p-toluate are added over 10 minutes and the mixture is heated at 60-65 ° C for 6 hours, then cooled and poured into a mixture of 500 g of ice, 1000 ml of water and 100 ml. concentrated hydrochloric acid. The mi trobenzene is removed by steam distillation and the cooled residue is extracted with 600 ml and 2 x 250 ml diethyl ether. The combined extracts are washed with 3 x 50 ml of water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue which crystallizes on cooling is treated with light petroleum, boiling point 40-60 ° C, filtered, recrystallized from a mixture of light petroleum (boiling point 40-6Q ° C) and diethyl ether and dried in a vacuum desiccator to give 67 g of 2-hydroxy-4,4 ', 6-trimethylbenzophenone in the form of a pale brown solid, mp 102-105 ° C. A pure sample of 2-hydroxy-4,41,6-trimethylbenzophenone, mp 103-105.5 ° C, which is almost colorless, is obtained after two recrystallizations from diethyl ether.

The 3,5-dimethylphenyl-p-toluate used as a starting material in the above preparation is obtained as follows: 154 g of p-toluoyl chloride is added to a solution over 30 minutes. 122 g of 3,5-dimethylphenol in 200 ml of anhydrous pyridine with stirring. The temperature rises to 80 ° C. The mixture is stirred and heated in a steam bath for 3 hours, then cooled and stirred with 500 ml of diethyl ether and 2000 ml of water. The organic layer is separated and the aqueous layer is further extracted with 3 x 250 ml diethyl ether. The combined ether solutions are washed with N aqueous sodium hydroxide solution to remove unchanged starting material and with 2N hydrochloric acid to remove pyridine and finally with water. The solution is dried over anhydrous sodium sulfate and evaporated in vacuo, and the residue is recrystallized from 11 ml of light petroleum at boiling point 40-60 ° C to give 203 g of 3,5-dimethylphenyl p-toluate, mp 55-57 ° C .

The 2-hydroxy-2 ', 4,6-trimethylbenzophenone used as starting material in the above preparation is obtained as follows: 20 g of anhydrous aluminum chloride are added portionwise over 5 minutes to 36.3 g of 3,5-dimethylphenyl-o toluate and the mixture is heated at 140-150 ° C for three hours. After cooling, 300 ml of water and 25 ml of concentrated hydrochloric acid are added and the mixture is stirred and heated on a steam bath until the hydrolysis is complete. After cooling, the mixture is stirred with 110 ml of diethyl ether and filtered through charcoal and silica. The layers are separated and the aqueous phase is extracted with 2 x 50 ml of diethyl ether. The combined ethereal solutions are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue slowly crystallizes. 50 ml of light petroleum with boiling point 40-60 ° C are added and the solid is filtered off, washed with light petroleum with boiling point 40-60 ° C at 0 ° C and dried in a vacuum desiccator. The solid is recrystallized from methanol to give 15.9 g of 2-hydroxy-2 ', 4,6-trimethylbenzophenone, mp 65-67 ° C.

The 3,5-dimethylphenyl-o-toluate with boiling point 192-192.5 ° C at 10 mm Hg used as starting material in the above preparation is obtained from 3,5-dimethylphenol by proceeding in the manner described above in the preparation of 3,5-dimethylphenyl-p-toluate, but replacing p-toluoyl chloride + v used as starting material with o-toluoyl chloride.

Example 3

Compound C

A mixture of 10.0 g of 2- (2,3-epoxypropoxy) -3,4,6-trimethylbenzophenone, 10 ml of isopropylamine and 100 ml of anhydrous methanol is heated at reflux for 17 hours. The solution is evaporated in vacuo and the residue is dissolved in 100 ml of water containing 6 ml of concentrated hydrochloric acid. The solution is filtered through charcoal and silica, adjusted to pH 11 using 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract is washed three times with water, dried over anhydrous sodium sulfate and evaporated. The residue is recrystallized from cyclohexane to give 6.6 g of DL-1- (2-benzoyl-3,5,6-trimethyl-phenoxy) -2-hydroxy-3-isopropylaminopropane, mp 121-123 ° C.

The 2- (2,3-epoxypropoxy) -3,4,6-trimethylbenzophenone of m.p. 67-69 ° C used as starting material at the above-mentioned position is obtained by proceeding in a similar manner as described in Example 1. in the preparation of 2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone, but replacing the 2-hydroxy-4,6-dimethylbenzophenone with an appropriate amount of 2-hydroxy-3,4,6-trimethylbenzophenone.

The 2-hydroxy-3,4,6-trimethylbenzophenone, m.p. 98-100 ° C, used as starting material in the above preparation of 2- (2,3-epoxypropoxy) -3,4,6-trimethylbenzophenone, is obtained by proceed in a similar manner as described in Example 2 in the preparation of 2-hydroxy-2 ', 4,6-trimethylbenzophenone, but replace the 3,5-dimethylphenyl-o-toluate with an appropriate amount of 2,3,5- trimethylphenylbenzoate, prepared as described by O. Kruber and A. Schmitt, Ber., 64, 1931, 2270.

The 2-Hydroxy-3,4,6-trimethylbenzophenone is also prepared by H. Wexler and B. Arventiev's method described in An. Stiint., Univ. Eel. I. Cuza Iasi, Sect lc, 17, 1971, 67-71.

Example 4

Compounds G and H

A mixture of 10 g of 2- (2,3-epoxypropoxy) -3,6-dimethylbenzophenone, 10 ml of isopropylamine and 50 ml of dry methanol is heated at reflux overnight. The solid, which is separated by cooling, is dissolved in 100 ml of water containing 5 ml of concentrated hydrochloric acid. The solution is adjusted to pH 8 with 2N aqueous sodium hydroxide solution and extracted with 3 x 25 ml of dichloromethane. The combined extracts are dried over aqueous sodium sulfate and evaporated. The residue is boiled with 50 ml of ethyl acetate and then cooled to give 6.4 g of DL-1- (2-benzoyl-3,6-dimethyl-phenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, m.p. 188-191.5 .

By proceeding in a similar manner, but replacing the crude 2- (2,3-epoxy-propoxy) -3,6-dimethylbenzophenone used as a starting material with crude 4'-chloro-2- (2,3- epoxypropoxy) -4,6-dimethylbezonphenone is obtained DL-1- (2-p-chlorobenzoyl-3,5-dimethylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride, mp 176.5-178.5 ° C .

The above crude 2- (2,3-epoxypropoxy) -3,6-dimethylbenzophenone and the crude 4'-chloro-2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone used as starting materials in the above preparations of DL-1- (2-benzoyl-3,6-dimethylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrochloride and DL-1- (2-p-chlorobenzoyl-3,5-dimethylphenoxy) -2- hydroxy-3-isopropylaminopropane hydrochloride prepared in a similar manner as described in Example 1 for the preparation of 2- (2,3-epoxypropoxy) -4,6-dimethylbenzophenone, but substituting 2-hydroxy-4,6- dimethyl-benzophenone with appropriate amounts of 2-hydroxy-3,6-dimethylbenzophenone, respectively, prepared as described below, and 4'-chloro-2-hydroxy-4,6-dimethylbenzophenone, prepared as described in English U.S. Patent No. 1,302,299.

The 2-hydroxy-3,6-dimethylbenzophenone used as starting material in the preparation of 2- (2,3-epoxypropoxy) -3,6-dimethylbenzophenone is prepared in a similar manner as described in Example 2 for the preparation of 2-hydroxybenzophenone. 2 ', 4,6-trimethylbenzophenone, but the 3,5-dimethylphenyl-o-toluate is replaced by an appropriate amount of 2,5-dimethylbenzoate, prepared as described by CG Reid and P- Kovacic, J. Org. Chem. 34, 1969, 3308. The crude product also contains 4-hydroxy-3,6-dimethylbenzophenone. The two compounds are separated as follows:

The crude mixture is stirred with light petroleum (boiling point 40-60 ° C) and filtered. The insoluble material is 4-hydroxy-3,6-dimethylbenzophenone, mp 165-168 ° C. The filtrate is evaporated and the residue is recrystallized from a small amount of light petroleum (bp 40-60 ° C) and then from a small amount of methanol to give 2-hydroxy-3,6-dimethylbenzophenone, mp 111-114 ° C. This compound has also been prepared in another manner by B. Arventiev, M. Strul, and H. Wexler, Acad. rep. popular Romine, Filiala lasi Studii cercetari Stiint. Chim. 11, 1960, 53.

Example 5

Compounds E and F

A mixture of 60 g of 2- (2,3-epoxypropoxy) -21,4,5,5'-tetramethyl-benzophenone, 60 ml of isopropylamine and 300 ml of dry methanol is heated at reflux overnight. Then, the solution is evaporated in vacuo and the residue recrystallized from cyclohexane to give 60 g of DL-1- [2- (2,6-dimethylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy-3-isopropylaminopropane 102-104 ° C.

Following a similar procedure, but replacing the 2- (2,3-epoxypropoxy) -2 ^ 4,6,61-tetramethylbenzophenone with 2- (2,3-epoxypropoxy) - 2 ', 4,4', 6- tetramethylbenzophenone is obtained DL-1- [2- (2,4-dimethylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy-3-isopropylaminopropane, m.p. 89-91 ° C.

The 2- (2,3-epoxypropoxy) -2 ', 4,6,6'-tetramethylbenzophenone, m.p. 108-110 ° C and 2- (2,3-epoxypropoxy) -2 benzophenone, m.p. 66-68 ° C, used as starting materials in the above preparations of DL-1- [2- (2,6-dimethylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy-3-isopropylaminopropane and DL 1-% 2- (2,4-di-methylbenzoyl) -3,5-dimethylphenoxy] -2-hydroxy-3-isopropylaminopropane is obtained in a similar manner as described in Example 1 for the preparation of 2- (2.3 -epoxypropoxy) -4,6-dimethylbenzophenone, but by replacing the 2-hydroxy-4,6-dimethylbenzophenone with appropriate amounts of 2-hydroxy-2 ', - 4,6,6'-tetramethylbenzophenone and 2-hydroxy-2', 4,4-6-tetramethylbenzene zophenon.

The 2-hydroxy-2 ', 4,6,6'-tetramethylbenzophenone having a melting point of 98-100 ° C and 2-hydroxy-2', 4,6,6'-tetramethylbenzophenone having a melting point of 85-87 ° C used as starting materials in the above preparations of 2- (2,3-epoxypropoxy) -2 ', 4,6,6'-tetramethylbenzophenone and 2- (2,3-epoxypropoxy) -2', 4,4 ', 6-tetramethylbenzophenone, is obtained in a similar manner as described in Example 2 for the preparation of 2-hydroxy-4,4 ', 6-trimethylbenzophenone, but by replacing the 3,5-dimethylphenyl-p-toluate with appropriate amounts of 3,5-dimethylphenyl-2 , 6-dimethylbenzoate and 3,5-dimethylphenyl-2,4-dimethylbenzoate.

The 3,5-dimethylphenyl-2,6-dimethylbenzoate, m.p. 95-97 ° C and 3,5-dimethylphenyl-2,4-dimethylbenzoate, m.p. 34-36 ° C, used as starting materials in the above-mentioned preparations of 2- hydroxy-2 ', 4,6,6'-tetramethylbenzophenone and 2-hydroxy-2', 4,4 ', 6-tetramethylbenzophenone are prepared in a similar manner as described in Example 2 for the preparation of 3,5-dimethylphenyl-β toluate, but by replacing the p-toluoyl chloride with appropriate amounts of 2,6-dimethylbenzoyl chloride and 2,4-dimethylbenzoyl chloride.

Example 6

Compound I

A mixture of 10 g of 2- (2,3-epoxypropoxy) -4,4 ', 6-trimethylbenzo-phenone, 10 ml of t-butylamine and 50 ml of dry methanol is heated at reflux overnight. The mixture is evaporated in vacuo and the residue is recrystallized from cyclohexane to give 7 g of DL-1-t-butylamino-3- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxypropane, mp 116-118 ° C.

The 2- (2,3-epoxypropoxy) -4,4 ', 6-trimethylbenzophenone used as starting material in the above preparation is obtained as described in Example 2.

145041 15

Example 7

Compound J

A mixture of 10 g of 2- (2,3-epoxypropoxy) -4,41,6-trimethylbenzo-phenone, 10 ml of 2-phenylethylamine and 50 ml of dry methanol is heated at reflux overnight and then evaporated in vacuo. The residue is dissolved in 400 ml of ethyl acetate and the solution is washed with 3 x 50 ml of water and dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in ethanol and excess of a solution of hydrogen chloride in diethyl ether is added. The solid which is separated is filtered off and recrystallized from ethanol to give 8 g of DL-1- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy-3- (2-phenylethylamino) ) -propane hydrochloride, mp 209-211 ° C.

The 2- (2,3-epoxypropoxy) -4,4 ', 6-trimethylbenzophenone used as starting material in the above preparation is obtained as described in Example 2.

Example 8

A solution of 0.5 g of DL-1- (3,5-dimethyl-2-p-toluoylphenoxy-2-hydroxy-3-isopropylaminopropane, prepared as described in Example 2) in dry diethyl ether is treated with excess hydrogen chloride solution in diethyl ether.

The resulting gum is grated with diethyl ether to give 0.4 g of DL-1- (3,5-dimethyl-2-p-toluoylphenoxy) -2-hydroxy-3-isopropylaminopropane hydrocyloride as a white solid mp 121-123 ° C.

The benzophenone derivatives of formula I or a non-toxic acid addition salt thereof can be incorporated into pharmaceutical compositions together with a pharmaceutically acceptable carrier or coating material. In clinical practice, the compounds of the invention are usually administered orally or parenterally.