DE1668964B2 - 1- (2,3,5-TRIMETHYL-4-HYDROXYPHENOXY) -3-AMINO-2-PROPANOL DERIVATIVES AND METHOD FOR THE PREPARATION - Google Patents

Description

in which X is a hydrogen atom or the residue of an aliphatic or aromatic monocarboxylic acid having 2 to 18 carbon atoms and R is a hydrogen atom or an alkyl or aralkyl radical with 1 to 13 carbon atoms, and their salts with inorganic or organic acids.

2.1 - (2,3,5-tri-trimethyl-4-hydroxyphenoxy) -3-amino-2-propanol and its hydrochloride.

3. 1 - (2,3,5-Trimethyl-4-hydroxyphenoxy) -3-methyl-amino-2-propanol and its hydrochloride.

4.1 - (2,3,5-Trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanol and its hydrogen oxalate.

5.1 - (2,3,5-trimethyl-4-acetoxyphenoxy) -3-phenyltert-butylamino-2-propanol, its hydrogen tartrate and oxalate.

6.1 - (2,3,5-trimethyl-4-hydroxyphenoxy) -3-isopropylamino-2-propanol, its hydrochloride, hydrobromide and fumarate.

7. 1 - (2,3,5-Trimethyl-4-acetoxyphenoxy) -3- (2-tridecylamino) -2-propanol.

8. 1 - (2,3,5-Trimethyl-4-benzoyloxy phenoxy) -3-isopropylamino-2-propanol and its hydrochloride.

9.1 - (2,3,5-Trimethyl-4-palmitoyloxyphenoxy) -3-isopropylamino-2-propanol.

10. Process for the preparation of l- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-aminopropanol derivative th of the general formula I, characterized in that a compound of the general Formula II

CH-,

(H)

H ₃ C- \

OCH ₂ CHCH ₂ -Z

in which X is the same as in formula I, Y is a hydroxyl group and Z is a halogen atom, or Y and Z taken together represent an oxide bridge with an amino compound of the general Formula III

RNH ₂ (III)

in which R is the same as in formula I, or in the event that in the general formula I R represents a hydrogen atom, with a derivative of the amine III, which is capable of through

IO subsequent hydrolysis to provide a compound of the general formula I, where either the trimethylhydroquinone derivative of the formula I obtained is then hydrolytically deacylated or the amine-masking group is split off, or from the outset by the action of excess amine of the formula III at elevated temperature on a compound of the general formula II at the same time introduces and deacylates the amino group -NHR, and optionally converts the amine obtained in each case into a salt of an inorganic or organic acid

The invention relates to the subjects defined in the claims.

The compounds according to the invention have valuable pharmacodynamic properties. Some of they block the beta-adrenergic receptors to a remarkable extent, so they act as so-called beta-lytica. According to previous experience, such substances can be used to treat cardiac arrhythmias and some other disturbances of the heart, which cause the adrenergic system involved, such as the

known 1 - (1 -N aphthoxy) -3-isopropylamino-2-propanol (Propranolol). This compound has been used as the standard in the pharmacological study of 1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanol uses that as one of the most significant

substances according to the invention was found. The results of the individual pharmacological studies of l- (23.5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-piropanol are given below: Acute toxicity (LD50) after intravenous administration to mice 48 mg / kg, after oral administration 350 mg / kg and on rats 51 mg / kg iv and 2300 mg / kg po. The LD50 of propanolol in mice is 40 mg / kg iv and 350 mg / kg p. o _M in rats 25 mg / kg i.p. v, 440 mg / kg po

This shows that 1 - (2,3,5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanol, especially in rats, is less toxic than propranolol. Because the molecular weight is almost the same for both compounds (309.4 and 295.8, respectively), this difference is significant Chronic toxicity tests in dogs and rats after administration of l- (2,3,5-trim ethyl-4-acetoxy-phenoxy) -3-isopropylamino-2-propanol no pathological changes in biochem see values in the blood serum, the blood count as well as the internal organs.

This substance as well as other trimethylhydro quinone derivatives of the general formula I block di < adrenergic ß-receptors, what by blocking de Isopropylnoradrenalin effect on heart rate Blood pressure or trachea of the test animals can be detected. These substances also have a pronounced antiarrhythmic effectiveness. The effectiveness of 1 - (2,3,5-trimethyl-4-acetoxy-phenoxy) -3 isopropylamino-2-propanol and of 1- (2,3,5-trimethyl 4-hydroxyphenoxy) -3-isopropylamino-2-propanol is superior to that of propranolol.

The 1 - (2,3,5-trimethyl 4-hydroxyphenoxy) -3-imino-propanol derivatives of all

common formula I in the usual way so that a compound of the general formula II

OX

HjC- CH ₁ —Z H ₃ C- I.
OCH , CHCH ₁
"I. I.
γ J \ Y

(H)

in which X is the same as in formula I, Y is a hydroxyl group and Z is a halogen atom, or Y and Z together represent an oxide bridge with an amino compound of the general formula III

RMl. (Uli

in which R is the same as in formula I, or in the event that R in general formula I Represents hydrogen atom, with a derivative of the amine III, which is capable of subsequent Hydrolysis to provide a compound of the general formula I, optionally either the trimethylhydroquinone derivative of the formula I obtained is then hydrolytically deacylated or the amine splitting off masking group or from the outset by the action of excess amine Formula III at elevated temperature to a compound of general formula II at the same time the amino group -NHR introduces and deacylated, and optionally the amine obtained in each case in a salt of a transferred inorganic or organic acid.

The reaction of the compound of general formula II, in which X, Y and Z are the same as in formula I, with the amino compound of general formula III, in which R is the same as in formula I, used in an equivalent or excess amount, can be carried out in water, an aqueous or an anhydrous alkenol having 1-3 carbon atoms at temperatures of 0-80 ⁰ C, preferably at temperatures of 20-70 ⁰ C, perform.

The reaction of the compound of the general formula II in which X is the same as in formula I. and Y and Z linked together form an oxide bridge, with phthalimide or succinimide one can in carry out an alkanol with 1-3 carbon atoms at the boiling point of the reaction mixture.

Finally, one can use the compound of the general formula II, wherein X is a hydroxyl group and Z is a Halogen atom mean with phthalimide potassium at 170-200 ° C, advantageously at 180 ° C, to react.

The compounds of general formula II, d. H. the corresponding glycidyl ethers or halohydrins, which are also new, can be removed by condensation of epichlorohydrin with trimethyl-hydroquinone or its 1-monoacetyl derivative either in the presence an equivalent amount of an alkaline compound or, advantageously, below the catalytic compound Establish the effect of an amine, for example piperidine.

The possible conversion of the halohydrin (formula II, Y = hydroxyl, Z = halogen) into the glycidyl ether (Formula II, Y and Z form an oxide bridge - O -), or vice versa, the conversion of the glycidyl ether into the halohydrin, can also be carried out in a known manner, ± h. in the first case by the action of alkali metal hydroxides on the halohydrin or, in the second case, by action of hydrohalic acids on the glycidic ether.

When converting the compound of the general formula II, it does not matter whether it is in the form of the halohydrin, glycid ether or a mixture of these derivatives, the amino compound of the general formula III is used, as already mentioned, either in an equivalent amount or in excess, which can have certain advantages in terms of quality and yield of the end product. Examples of possible amino compounds of the general formula III are ammonia, methylamine, isopropylamine, butylamine, 6-methyl-2-aminoheptane, 1- or 2-aminotridecane, phenylaminopropane or phenyl-tert-butylamine.
If the reaction is carried out at an elevated temperature, for example at 60-80 ⁰ C and with excess amine, or if the amine used has a more basic character, depending on the reaction conditions, the hydrolysis of the acyloxy group in the compound of the general formula II can also be carried out at the same time take place (X = an acyl radical with 2-18 carbon atoms). This hydrolysis of the end product of general formula I can also, if desired, be carried out as an independent operation, in a manner known per se by the action of alkaline or acidic agents, for example by boiling with alcoholic alkali metal hydroxide solution.

Is a trimethylhydroquinone derivative of the general formula I with an unsubstituted amino group (R = H) if desired, such a connection can be passed through, except by the method already described above Reaction of the compound of the general formula II in any form with a dicarboximide, such as Phthalimide or succinimide, and hydrolysis or solvolysis of the condensation product formed with known agents such as hydrazine or acids. The same result can also be achieved with the Use of a metal salt of dicarboximide, for example phthalimide potassium, which one In can expediently react with the compound of the general formula II in the form of the halohydrin an analogous way is used with hexamethylenetetramine. In both cases the ones obtained are hydrolyzed Condensation products using any of the known methods.

The end products of the general formula I are converted into addition salts either with, if desired inorganic acids, for example hydrochloric, hydrobromic, phosphoric or sulfuric acid, or with organic acids, for example acetic, oxalic, tartaric, fumaric, maleic or camphorsulphonic acid. These salts are usually very soluble in water and are suitable for the production of pharmaceutical preparations.

Examples
example 1

1- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-amino-2-propanol hydrochloride

To a mixture of 7.8 g (0.031 mol) of 3- (2,3,5-trimethyl-4-acetoxyphenoxy) -1,2-perylene oxide and 6.6 g

(0.045 mol) of phthalimide in 70 ml of ethanol are added to 3 drops of pyridine and heated to boiling for 6 hours. To the product which has crystallized out is filtered off with suction after cooling

away. This gives 8.1 g of the phthalimide derivative which melts after recrystallization from ethanol at 155 to 156 ° C, taking place between 120 to 130 ⁰ C tine change in the crystal form is boiled for 30 minutes by the phthalimide derivative 43 g of 50% hydrazine hydrate in 25 ml Ethanol. Then add 60 ml of an ethanolic hydrogen chloride solution and boil for 1 hour. After cooling, the product which has crystallized out, which is a mixture of the desired substance in the form of the hydrochloride with phthalylhydrazide, is filtered off with suction, washed with ethanol and suspended in 110 ml of water. The suspension is heated to 50 ° C., and after cooling, the undissolved phthalylhydrazide is filtered off with suction and washed with water. The aqueous filtrate is combined with the ethanolic fractions, obtained after the hydrochloride-phthalylhydrazide mixture has been filtered off with suction, and it is evaporated i. Vac. under nitrogen at 40 to 5O ⁰ C (bath temperature) from. After concentration to about 30 ml, the residue is allowed to crystallize at 0 to 5 ° C., the precipitated product is filtered off with suction, washed with acetone and dried over sodium hydroxide. Yield 4 g of l- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-amino-2-propanol hydrochloride with a melting point of 236 to 238 ° C. (in vacuo; after recrystallization from water with the addition of concentrated hydrochloric acid) .
Analysis (%) Ci ₂ H ₂₀ CINO ₃ (261.7):

Calculated: C 55.06, H 7.70, N 5.35. Cl 13.55;

Found: C 54.81, H 7.81, N 5.55, Cl 13.57.

Example 2

1- (2,3,5-trimethyl-4-hydroxyphenoxy) -3-methylamino-2-propanol hydrochloride

Heating a mixture of 82 g (0.42 mol) of 2,3,5-trimethyl-4-acetoxy-phenol (mp. 105 to 107 ⁰ C), 125 g (1.35 mol) of epichlorohydrin and 0.9 ml of piperidine to 95 to 100 ^° C. for 6 hours. Thereafter, the excess epichlorohydrin is distilled off at 100 ^° C. (bath temperature). 129 g of a distillation residue are obtained, which consists of a crude mixture of halogetihydrin (Formula II, X = - COCH ₃ , Y - OH ₁ Z - Cl) and glycidyl ether (Formula II, X --COCH ₃ , Y and Z form an oxide bridge —O This mixture is dissolved in 700 ml of absolute benzene and 63 g of powdered sodium hydroxide are added with stirring, the temperature of the reaction mixture being kept at 30 ^° C. by cooling. After 30 minutes of stirring, a further 63 g of powdered sodium hydroxide are added and stirring is continued 40 minutes at room temperature. The reaction mixture is then poured into 100 ml of a Wapser-ice mixture, the benzene layer is separated off and the aqueous layer is shaken out with benzene. The combined benzene extracts are washed neutral with water and dried over anhydrous magnesium sulfate and evaporated under reduced pressure, finally on a boiling water bath. 80 g of crude glycidyl ether are obtained, which are purified by vacuum distillation. Bp 0.05 117 to 120 ° C, mp 94 to 97 ° C (from ethanol).

To a solution of 7.1 g (0.028 mol) of the glycid ether obtained above in 70 ml of ethanol is added 68 ml of an ethanolic methylamine solution (content 0.25 g of methylamine in 1 ml; 68 ml of the solution correspond to 0.547 mol of methylamine) and heated in closed vessel at 70 ^° C. for 3 hours. Then ethanol and excess methylamine are evaporated i. Vac. from, finally on a boiling water bath; the residue (8.6 g) is dissolved in 30 ml of ethanol and the solution is saturated in the cold with dry hydrogen chloride gas. After cooling to 0 ^° C., the precipitated product is filtered off with suction and washed with 6 ml each of ethanol and ether. 6.5 g of l- (2,3,5-trimethyl-4-hydroxyphenoxy-3-methyiamino-2-propanol hydrochloride with a melting point of 225 to 229 ° C. are obtained, melting point 228 to 23 ° C. (from methanol Ethyl acetate).
Analysis (%) C, ₃ H ₂ 4C1NO ₃ (275.8):

Calculated: C 56.62, H 8.04, N 5.08, Cl 12.86;

Found: C 56.32, H 8.16, N 5.25, Cl 12.85.

Example 3

1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanol

A solution of 6 g (0.024 mol) of glycidyl ether from Example 2 and 6.5 g (0.11 mol) of isopropylamine in 25 ml Ethanol is heated to 70 ° C. for 3 hours. Thereafter, ethanol is distilled from the reaction mixture and excess isopropylamine i. Vac. away. The oily residue (7.6 g) is dissolved in 50 ml of 1 M hydrochloric acid Add 50 ml of water and shake out with ether. The aqueous layer is made alkaline with ammonia and takes up the precipitated base in benzene. the

2 $ benzene solution is washed with water, dried over anhydrous magnesium sulfate and evaporated i. Vac. at 80 ⁰ C (bath temperature). The crystalline solidified residue (6 g) provides the crude 1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3-isopropylamino-2-propanoI with a melting point of 97

to 107 ^° C. This product can be purified either by suspension in ether and suction (melting point 104 to 107 ^° C.) or by recrystallization from cyclohexane (melting point 105 to 107 ^° C.). The hydrogen oxalate melts at 160 to 162 ° C (from ethanol-ether).

Analysis (o / o) Ci ₇ H ₂ 7N0 ₃ (309.4):

Calculated: C 65.99, H 8.80, N 4.53;
Found: C 66.23, H 8.93, N 4.55.

Example 4

1- (2,3,5-Trimethyl-4-acetoxyphenoxy) -3-phenyl-tert-butylamino-2-propanol

To a solution of 6.25 g (0.025 mol) of glycidic ether

from Example 2 in 25 ml of ethanol are added 15 g (0.1 mol) phenyl-tert-butylamine and heated 3.5 hours at 7O ⁰ C. Afterwards, the volatile fractions distilled to i. Vac. at 10 Torr, last at 150 ⁰ C bath temperature. The distillation residue (10 g) is dissolved in 50 ml

Ethanol and the still warm solution is mixed with a solution of 1.4 g of oxalic acid in 15 ml of ethanol. After cooling, the precipitated oxalate is filtered off with suction, washed with ethanol, suspended in 30 ml of water and 100 ml of ether and made alkaline with 25 ml of IM NaOH. The mixture is then shaken until the suspension is completely dissolved, the ethereal layer is separated off and the aqueous layer is shaken out with ether. The combined ether extracts are washed with water; after drying, the ether is distilled off. 8 g of 1 - (23,5-trimethyl-4-acetoxyphenoxy) -3-phenyl-tert-butylamino-2-propanol are obtained in the form of a yellowish viscous oil which solidifies to a waxy mass after some time. The crude product may be obtained by vacuum distillation at 181 to 183 ° C / clean 10- ³ Torr.
Analysis (%) C ₂₄ H ₃₃ NO ₄ (399.5):
Calculated: C 72.15, H 8.33, N 3.51;
Found: C 72.41, H 8.53, N 3.65.

Example 5

1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3-pheny! -
tert-butylamino-2-propanol hydrogen tartrate

The hydrogen tartrate of the base obtained according to Example 4 is prepared by adding a solution of 0.3 g (0.002 mol) of tartaric acid in 100 ml of ether with a solution of 0.4 g (0.001 mol) of base in 200 ml of ether. Immediately after the two solutions are poured together, crystals of the salt separate out in the form of a hemihydrate. You suction off and wash with ether. Mp. 75 to 100 ⁰ C (with decomposition). The oxalate prepared in an analogous manner melts with decomposition at 225 to 230 ° C (from ethanol).
Analysis (0 / O) C ₂₈ H ₃₉ NO ₁₀ · 1/2 H ₂ O (558.6):

Calculated: C 60.20, H 7.22, N 2.51;

Found: C 60.21, H 7.33, N 2.50.

Oxalate:

At ₃ IySe ( ⁰ Zo) C ₅₀ H ₆₈ N ₂ O ₁₂ · C ₂ H ₅ OH (935.2):
Calculated: C 66.79, H 7.97, N 2.99;
Found: C 66.61, H 7.78, N 3.14.

Example 6

1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3- (2-tridecyl-amino) -2-propanol

A solution of 5 g (0.02 mol) Glycidäther from Example 2 and 7.7 g (0.039 mole) of 2-Aminotridecan in 20 ml ethanol is heated for 3 hours at 7O ⁰ C. Afterwards, the volatile fractions distilled to i. Vac. from, last at 150 ⁰ C bath temperature and 0.1 Torr. In a yield of 8.6 g, crude 1- (2,3,5-trimethyl-4-acetoxyphenoxy) -3- (2-tridecylamino) -2-propanol is obtained, which is obtained by chromatography on aluminum oxide (activity II) Can clean with the help of an ether-methanol mixture (8: 2) as an eluent or by crystallization from petroleum ether. The pure substance melts at 55 to 57 ° C.
Analysis (%) C ₂₇ H ₄₇ NO ₄ (449.7):

Calculated: C 72.12, H 10 », N 3.19;

Found: C 71.82, H 10.82, N 3.20.

Example 7

1 - (23,5-trimethyl-4-hydroxyphenoxy) -3-isopropylamino-2-propanol hydrochloride

A solution of 2 g (0.0065 mol) of 1- (23,5-trimethyl-4-acetoxyphenoxy) -3-tsopropylamino-2-propanol in 13 ml of methanolic 1 M KOH solution is heated to the boil for 45 minutes under nitrogen. The methanol is then evaporated off under reduced pressure, the distillation residue is diluted with 20 ml of water and neutralized with carbon dioxide. The precipitated product is taken up in 150 ml ether at, the ethereal solution is washed with saturated NaCl solution and dried over sodium sulphate After Abdestillie- ren ether, last L in vacuo, dissolve the residue to distillation (1.8 g) in 15 ml of ethyl acetate acidify the solution with 1.5 ml of an ethereal HQ solution and allow it to crystallize at 0 to 5 ° C. After the product which has crystallized out with suction and washing with ethyl acetate, 1.9 g of 1- (233-trimethyl-4-hydroxyphenoxy) -3-isopropylamino-2-propanol hydrochloride with a melting point of 194 to 19WC are obtained : 5) the pure substance melts at 194 to 195.5 ⁰ G The fumarate melts with decomposition

at 232-236 ° C (from ethanol), the hydrobromide at 158-160 ⁰ C (from methanol-ethyl acetate).
Analysis (o / o) C, 5H ₂₆ ClN03. (303.8):

Calculated: C 59.30, H 8.63, N 4.60, Cl 11.67;

Found: C 59.36, H 8.45, N 4.88, ClIl, 48.

Fumarate:

Analysis (° / o) C ₃₄ H ₅₄ Oi ₀ (650.8):

Calculated: C 62.75, H 8.36, N 4.30;
Found: C 62.52, H 8.42, N 4.10.

Hydrobromide:

Analysis (%) C ₅ H ₂₆ BrNO ₃ (348.3):

Calculated: C 51.73, H 7.52, N 4.02, Br 22.95;
Found: C 51.55, H 7.68, N 3.94, Br 23.21.

Example 8

1- (2,3,5-trimethyl-4-benzoyloxyphenoxy) -3-isopropylamino-2-propanol hydrochloride

A mixture of 6.2 g (0.0198 mol) of glycidyl ether (formula II, X = -COC ₆ H ₅ ) with a melting point of 130 to 138 ° C (the pure substance melts at 145 to 146 ° C), 4 g ( 0.068 mol) of isopropylamine and 20 ml of ethanol are heated to 70 ° C. for 3 hours. The volatile components are then distilled i. Vac. and dissolves the residue (7.4 g) in 150 ml of benzene. It is filtered, quenched with dry hydrogen chloride gas and allowed to crystallize at 0 to 5 ° C. The precipitated product is suctioned off, washed with ether and dried. Yield 5.2 g of 1- (2,3,5-trimethyl-4-benzoyloxyphenoxy) -3-isopropylamino-2-propanol hydrochloride with a melting point of 183 ° to 189 ° C. After recrystallization from methanol-ethyl acetate, the pure melts Fabric at 189 to 191 ⁰ C.
Analysis (%) C ₂₂ H ₃₀ ClNO ₄ (407.9):

Calculated: C 64.77, H 7.41, N 3.43, Cl 8.69;

found: C 64.53, H 7.53, N 3.39, C! 8.81.

Example 9

A mixture of 3.7 g (0.02 mol) of phthalimide potassium and 6.5 g (0.0196 mol) of the compound of the formula II in the form of the bromohydrin (X = -COCH ₃ , Y = OH, Z = Br; prepared by the action of 35% hydrobromic acid on the corresponding glycidic ether at room temperature), the mixture is heated to 180 ° C. for 1.5 hours. The cooled melt is dissolved in 150 ml of benzene, washed neutral with water, dried over magnesium sulfate and evaporated, finally L. VaIc. The residue (7 g) is dissolved in 25 ml of ethanol and allowed to crystallize. The product obtained (2.7 g) is purified by further recrystallization from ethanol; it then melts at 152 to 157 ° C and is identical to the phthalimide derivative prepared according to Example 1. Its hydrolysis to the amino derivative of the general formula I (X = H, R = H) is carried out as in the example given.

Example 10

1 - (WiS-Trimethyl ^ palmitoyloxyphenoxy) -3-isopropylamino-2-propanol

A solution of 2 g (0.006 mol) of 1- (234-trimethyl-4-palmitoyloxyphenoxy) -23-epoxypropane (melting point 62 to 65 ° C.) and 2 g (0.034 mol) of isopropylanine in 15 ml of ethanol is heated for 3 hours to 50 ⁰ C thereafter

«509528/495

is distilled ethanol and excess isopropylamine under reduced pressure, finally at 9O ⁰ C (bath temperature). The residue (2.6 g) represents crude 1 - (2,3,5-trimethyl-4-palmitoyloxyphenoxy) -3-isopropylamino-2-propanol, which after cooling

ίο

crystalline solidified and melts at 80 to 83 ° C, r · recrystallization from methanol. Analysis (%) C ₃ | H ₅₅ NO ₄ (505.8):

Calculated: C 73.61, H 10.96, N 2.77;

Found: C 73.32, H 10.85, N 2.69.

Claims (1)

Patent claims: 1.1 - {23,5-Trimethyl-4-hydroxyphenoxy) -3-aminopropanol derivatives of the general formula 1 (D H, C OCH ₂ CHCH ₂ NHR OH