CH621340A5 - Process for the preparation of novel substituted arylalkylamines - Google Patents

Description

The invention relates to a process for the preparation of new substituted arylalkylamines of the formula I as defined in claim 1.

For the alkyl radicals mentioned in the definition of the radicals R 1, R 4 and R 5, the importance of the methyl, ethyl, propyl or isopropyl group is particularly important, and for the alkoxy radicals mentioned in the definition of the radicals R 6 and R 7 in particular that of the methoxy, Ethoxy, propoxy or iso-propoxy group into consideration. The compounds of formula I and their acid addition salts have valuable pharmacological properties, in particular a heart rate-lowering effect.

The compounds of formula I are prepared using the method defined in claim 1.

Particularly preferred starting compounds of the formula II are those in which Z represents a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group.

The reaction is optionally carried out in a solvent, e.g. in methanol, ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethyl sulfoxide or benzene, and expediently, depending on the reactivity of the radical Z, at temperatures between -50 and 250 ° C. The presence of an acid-binding agent, such as e.g. an alcoholate, an alkali metal hydroxide or a tertiary organic base, such as triethylamine or pyridine,

or a reaction accelerator such as potassium iodide.

If a compound of the formula I is obtained in which R4 represents a hydrogen atom, this can be obtained by means of alkylation, e.g. can be lower alkylated by reaction with an appropriate alkyl halide or dialkyl sulfate or methylated by reaction with formaldehyde / formic acid.

The compounds of formula I obtained can be converted into their physiologically tolerable salts using inorganic or organic acids. Examples of suitable acids have been found to be hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid.

The compounds of formulas II and III used as starting materials can be prepared by processes known per se.

As already mentioned at the beginning, the new compounds of formula I and their acid addition salts have valuable ones

3rd

pharmacological properties. In addition to a mild antihypertensive effect, they have a selective lowering of heart rate.

For example, the following compounds were examined for their biological properties: s

A 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethyl methylamino] propyl) phthalimidine hydrochloride; B 5,6-dimethoxy-2- (3- [2- (3,4-dimethoxy) phenylethyl methylamino] propyl) -1, 2-benzisothiazoline-1,1-dioxide hydrochloride; 10th

C 5,6-methylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethyl methylaminol] propyl) phthalimidine hydrochloride; D 5,6-dimethoxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) is phthalimidine hydrochloride; and E 5,6-ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride.

20th

1. Effect on heart rate in anesthetized guinea pigs:

The heart rate of guinea pigs under urethane anesthesia was recorded using an electrocardiogram. The substances to be investigated were used in increasing doses between 0.5 25 and 20 mg / kg IV. given.

The following table shows the changes in heart rate:

Substance dose mg / kg IV

n

Percentage reduction in heating frequency

0.5

3rd

-23.5

1.0

3rd

-36.1

2.0

3rd

-47.2

A 5.0

3rd

-51.6

10.0

3rd

-59.1

20.0

3rd

-67.2

0.5 5

1.0 5

2.0 5

B 5.0 5

10.0 5

20.0 5

45

2. Effect on heart rate on guinea pig atria:

Isolated spontaneously beating auricles of guinea pigs of both sexes with a body weight of 300 to 400 g were examined in an organ bath in Tyrode solution. so the nutrient solution was mixed with carbogen (95% O2 5% CO2)

supplied and kept constant at 30 ° C. The contractions were recorded isometrically using a strain gauge on a grass polygraph. The substances to be examined were added to the organ baths, so that final dilutions of 10 5 g / ml were produced. 5 atria per substance.

The following table shows the percentage decrease in heart rate on average from 5 atria with a substance concentration of IO-5 g / ml. <> 0

substance

Frequency reduction in%

A

-52

c

-60

D

-51

E

-48

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3. Acute toxicity:

The acute toxicity of the substance to be investigated was determined in mice (observation time: 14 days) after oral or intravenous administration. The LD50 was calculated from the percentage of animals that died within the observation period after various doses (see J. Pharma-col. Exp. Therap. 96 (1949) 99):

substance

LD50

A

98 mg / kg IV

A

1,570 mg / kg p.o.

B

100 mg / kg IV

For pharmaceutical use, the compounds of the formula I and their physiologically tolerable acid addition salts can, if appropriate in combination with other active substances, be incorporated into the customary pharmaceutical preparation forms, such as tablets, dragées, powders, suspensions, solutions or suppositories. The single dose is 20 to 300 mg, preferably 25 to 200 mg. The following examples are intended to explain the invention in more detail.

example 1

2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -3-phenyl-phthalimidine 1.75 g (5.3 mmol) of N- (3-bromopropyl) -3-phenyl- phthalimine-din are refluxed with 2.06 g (10.6 mmol) of 3,4-dimethoxyphenyl-ethyl-N-methylamine in 30 ml of xylene for 10 hours. After cooling, the mixture is concentrated and chromatographed on silica gel (chloroform / methyl alcohol = 19/1). The base is obtained as a viscous oil.

Yield: 1.1 g (48% of theory)

Rf value (chloroform / methanol = 19/1): 0.4.

Example 2

3-phenyl-5-chloro-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -1,2-benzisothiazoline-1,1-dioxide hydrochloride 3 g (9.3 mmol) of N- (3-chloropropyl) -3-phenyl-5-chloro-l, 2-benzisothiazoline-l, l-dioxide together with 3 g of 3,4-dimethoxyphenylethyl-N-methylamine and a spatula tip of potassium iodide in a solution of 30 ml of dimethylformamide and 5 ml of triethylamine heated under reflux for 5 hours. The mixture is then evaporated to dryness, the residue is taken up in chloroform and the organic phase is washed out several times with water. After drying, the mixture is evaporated and the residue is chromatographed on silica gel (chloroform / methanol 40/1). Precipitation with ethereal hydrochloric acid gives the hydrochloride as an amorphous product. Yield: 1.5 g (29.5% of theory)

Rj value (chloroform / methanol = 19/1): 0.5.

Analysis for C27H31CIN2O4S X HCl (551.54):

c

H

N

S

Calculated:

58.8

5.60

5.10

5.80

Found:

58.7

5.75

5.20

5.90

Example 3

5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethyl methylamino] propyl) -1, 2-benzisothiazoline

1,1-dioxide hydrochloride a) 2-methyl-4,5-dimethoxy-benzenesulfochloride To 15.2 g (0.1 mol) of 3,4-dimethoxy-toluene are added

- 9.8 -20.0 -27.4 -37.6 -46.9 -53.9

40

621340

4th

23.2 g (0.2 mol) of chlorosulphonic acid are slowly added dropwise with stirring and cooling at about -10 ° C. After the addition has ended, the mixture is allowed to warm to room temperature and stirring is continued until the evolution of hydrogen chloride has ended. The reaction mixture is poured onto ice and the sulfochloride which separates is extracted with ether. The organic phase is washed successively with sodium bicarbonate solution and water and concentrated to dryness in vacuo. A cloudy oil remains as residue, which solidifies after cooling.

Yield: 18 g (72% of theory)

Rf value (benzene): 0.5.

b) 2-methyl-4,5-dimethoxy-benzenesulfonamide 18 g (0.07 mol) of the compound obtained according to Example 3a are suspended in 200 ml of concentrated ammonia and stirred for 4 hours at room temperature. It is suctioned off, washed again with water and, after drying, the desired sulfonamide is obtained as an amorphous product.

Yield: 17 g (100% of theory)

Rf value (benzene / acetone = 1/1): 0.6.

c) 5,6-Dimethoxy-l, 2-benzisothiazolin-3-one-l, l-dioxide 16 g (0.08 mol) of 2-methyl-4,5-dimethoxy-benzenesulfonamide are dissolved in 500 ml of 5% sodium hydroxide solution dissolved and after the addition of 39.6 g (0.25 mol) of potassium permanganate heated to boiling for 2 hours. After cooling, it is filtered off through Celite and the desired product is precipitated by adding concentrated hydrochloric acid.

Yield: 7 g (41.5% of theory)

Rf (benzene / acetone = 3/1): 0.2 to 0.4.

d) 5,6-Dimethoxy-l, 2-benzisothiazoline-l, l-dioxide 7 g (288 mmol) of the compound obtained according to Example 3c are refluxed with 3.3 g (865 mmol) of lithium aluminum hydride in 400 ml of tetrahydrofuran for 2 hours heated. After cooling, decompose. the excess lithium aluminum hydride by adding ethyl acetate, diluted with water and then adding 2N hydrochloric acid until the aluminum hydroxide precipitate has dissolved. The reaction solution is extracted with ethyl acetate and the organic phase is washed with water and dried. The mixture is concentrated in vacuo, the residue is digested in ether and the compound is suctioned off.

Yield: 2.4 g (36.4% of theory).

e) N- (3-chloropropyl) -5,6-dimethoxy-l, 2-benzisothiazoline-1,1-dioxide

2.4 g (10.5 mmol) of the compound obtained according to Example 3d are dissolved in a mixture of 15 ml of 2.5% sodium hydroxide solution and 30 ml of ethanol and after the addition of 10 ml of 3-bromo-l-chloropropane for 8 hours heated under reflux. The reaction volume is concentrated to half, diluted with water and extracted with chloroform. After the organic phase has been dried, the mixture is concentrated in vacuo and the desired product is obtained as a viscous oil.

Yield: 2 g (62.5% of theory)

Rf value (chloroform / methanol = 19/1): 0.8.

f) 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethyl-

methylamino] propyl) -l, 2-benzisothiazoline-1,1-dioxide hydrochloride Prepared analogously to Example 2 by reacting N- (3-chloropropyl) -5,6-dimethoxy-l, 2-benzisothiazoline-l, l-dioxide with 3,4-dimethoxyphenylethyl-N-methylamine.

Melting point: 196 to 198 ° C (acetone).

Example 4

5,6-ethylenedioxy-2- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -1, 2-benzisothiazoline-1,1-dioxide hydrochloride Prepared analogously to Example 1 by reacting N - (3-

Chloropropyl) -5,6-ethylenedioxy-l, 2-benzisothiazoline-l, l-dioxide with 3,4-dimethoxy-phenylethyl-N-methylamine.

Rf value (chloroform / methanol = 9/1): 0.6.

Example 6

3-Methyl-5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride Prepared analogously to Example 1 by reacting 3-methyl-5,6-dimethoxy -N- (3-chloropropyl) phthalimidine with 3,4-dimethoxy-phenylethyl-N-methylamine in chlorobenzene in the presence of potassium carbonate.

Melting point: 135 to 136 ° C

C.

H

N

Cl

Calculated:

62.68

7.36

5.85

7.40

Found:

62.31

7.40

5.80

7.12

Example 6

5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride 5 g (12.1 mol) 5,6-dimethoxy-2N- (3rd - [2- (3,4-dimethoxy) -phenylethylamino] propyl-phthalimidine hydrochloride are in a mixture of 1.38 g (30 mmol) of formic acid and 1.5 g (20 mmol) of formalin for one hour at 100 ° C. heated.

After cooling, the reaction solution is made alkaline by adding 2N sodium hydroxide solution, extracted with chloroform and the chloroform phase is washed with water,

dried and concentrated in vacuo. The residue is chromatographed on silica gel (chloroform / methanol = 45/1), the main fractions are concentrated and the base is precipitated from ethereal hydrochloric acid as hydrochloride.

Yield: 3.2 g (57% of theory)

Melting point: 170 to 172 ° C

Example 7

5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethyl-

n-propylamino] propyl) phthalimidine hydrochloride A solution of 2.5 g (5.5 mmol) of 5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylamino] propyl) - After adding 20 ml of 1-bromopropane and 5 g of potassium carbonate, phthalimidine in 100 ml of acetone is heated under reflux for 6 hours. After cooling, the solid substance is filtered off and the filtrate is concentrated. It is taken up in ether, the insoluble matter is filtered off again and, after concentration, the hydrochloride is precipitated from ethereal hydrochloric acid.

Yield: 0.8 g (29% of theory)

Melting point: 120 to 122 ° C (acetone / methanol).

The following compounds were prepared analogously to Examples 1 to 7:

2N- (3- [2- (3,4-Dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride Melting point: 146 to 148 ° C.

5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethylamino] -

propyl) phthalimidine hydrochloride

Melting point: 207 to 209 ° C.

5,6-dimethoxy-2N- (3 -2-3,4-dimethoxy) phenylethyl-

n-propylamino] propyl) phthalimidine hydrochloride

Melting point: 120 to 122 ° C (acetone / methanol).

5,6-dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylethyl-

methylamino] ethyl) phthalimidine hydrochloride

Melting point: 149 to 151 ° C.

5,6-methylenedioxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride melting point: 237 to 239 ° C.

s io

IS

20th

25th

30th

35

40

45

50

55

60

65

5,6-ethylenedioxy-2N- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride melting point: 208 to 210 ° C. 5,6-methylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride melting point: 206 to 208 ° C. 5,6-ethylenedioxy-2N- (3- [2- (3,4-methylenedioxy) phenylethylmethylamino] propyl) phthalimidine hydrochloride) Melting point: 180 to 182 ° C.

5,6-dimethoxy-2N- (3- [2- (3,4-methylenedioxy) phenylethyl-

5 621 340

methylamino] propyl) phthalimidine hydrochloride melting point: 235 to 237 ° C. 5,6-ethylenedioxy-2- (3- [2- (3,4-dimethoxy) phenylethylmethylamino] propyl) -1, 2-benzisothiazoline-s 1,1-dioxide hydrochloride Rf value (chloroform / methanol = 9/1): 0.6. 5,6-Dimethoxy-2N- (3- [2- (3,4-dimethoxy) phenylisopropylmethylamino] propyl) phthalimidine hydrochloride, melting point: 183 to 185 ° C.

B

Claims (5)

621340 2. The method according to claim 1, characterized in that one starts from a compound of formula II, wherein Z is a chlorine, bromine or iodine atom or an alkylsulfonyloxy or arylsulfonyloxy group. 2nd PATENT CLAIMS 1. Process for the preparation of new substituted arylalkyl amines of the formula I R, N- (CH2) -N-CH-CH2 FL (I), bliss Ri represents a hydrogen atom, a lower alkyl group or the phenyl group; R2 represents a hydrogen atom, a chlorine atom or the methoxy group; R3 represents a hydrogen atom or the methoxy group or together with R2 the methylenedioxy or ethylenedioxy group; R4 and RS, which may be the same or different, are hydrogen atoms or lower alkyl groups; R6 represents a hydrogen atom or a lower alkoxy group; R7 is a lower alkoxy group or together with R6 the methylenedioxy or ethylenedioxy group; X is the carbonyl or sulfonyl group; and n is the number 2 or 3 mean, as well as their physiologically compatible acid addition salts with inorganic or organic acids, characterized in that a compound of formula II 15 N- (CH2) n-Z (II) wherein Z is a removable group with a substituted phenylethylamine of the formula III R, H-N-CH-CK 5 25th 35 40 45 (HD 55 is implemented and the process products are then optionally converted into their physiologically tolerable acid addition salts with inorganic or organic acids. 3. The method according to claim 1 or 2, characterized in that one carries out the reaction in a solvent and at temperatures in the range from -50 to + 250 ° C. "O 65 4. The method according to claim 1, 2 or 3, characterized in that one carries out the reaction in the presence of an acid-binding agent and / or a reaction accelerator. 5. The method according to claim 1, characterized in that an obtained compound of formula I, wherein R4 is hydrogen, N-alkylated with a lower alkyl donating agent.