CH615918A5 - Process for the preparation of novel acid amides - Google Patents

Abstract

Novel acid amides of the formula I <IMAGE> in which R1 to R3, which are identical or different, denote hydrogen or alkyl having 1 to 3 carbon atoms, are prepared, starting from the corresponding carboxylic acids or their functional derivatives, by reaction with appropriately substituted amines or ureas. The novel compounds are distinguished by useful pharmacological properties, in particular by muscle relaxant, sedative, antiarrhythmic and anticonvulsive actions.

Description

615918

2nd

PATENT CLAIMS 1. Process for the preparation of new acid amides of the formula I

CH - CO

N,

/ \

K,

R.

10th

Alkoxy, aryloxy, alkylthio, arylthio, acyloxy or optionally substituted amino means.

3. The method according to claim 1 or 2, characterized in that one carries out the reaction in a solvent.

4. The method according to claim 1 or 2, characterized in that the reaction in the presence of a dehydrating agent, e.g. Dicyclohexylcarbodiimide, thionyl chloride or phosphorus oxychloride.

5. The method according to claim 1 or 2, characterized in that one carries out the reaction at temperatures from -50 to + 250 ° C.

(I), 15 The invention relates to a process for the preparation of new acid amides of the formula I.

wherein

R 1 to R 3, which are the same or different, denote hydrogen or alkyl having 1 to 3 carbon atoms, characterized in that a compound of the formula II

20th

25th

CO - N.

/ R2

\

R.

(I),

CH - COA

ai),

wherein A represents a reactive radical with a compound of formula III

H-N

'R,

(III)

30 in which

Rt to R3, which are the same or different, are hydrogen or alkyl having 1 to 3 carbon atoms.

The most similar previously known compound, namely a-35 homophthalimidopropionamide, is described in CA. 64 (1966) 19480 g. This compound has an antidepressant effect. In contrast, the new compounds obtainable according to the invention, which differ from the compound described in the above-mentioned literature by the two methyl groups in the 4-position, are distinguished by muscle-relaxing, sedating, antiarrhythmic and anticonvulsive activity.

The compounds of formula I are prepared according to the invention by using a compound of formula II

45

or, if A is a hydroxy group, with a compound of formula III

H-N

/ R2

(III)

R.

or with a urea of the formula IV

55

- COA

(II),

p pj in which A is a reaction, optionally formed in situ,

2 capable radical, for example a halogen atom, a 1-imide

l \ f —H —J \ [/ jy) 60 azole or an alkoxy, aryloxy, alkylthio, arylthio,

II acyloxy or optionally substituted amino group,

R 7 means with a compound of formula III

-R.

3 0 3

implements. 65 H-tf

2. The method according to claim 1, characterized- ^ '

characterized in that one of a compound of formula II, R ~ r wherein A is a halogen atom, a 1-imidazole radical or a

3rd

615918

implements.

The reaction is optionally carried out in a solvent, e.g. in methanol, ether, tetrahydrofuran, dimethylformamide or benzene, and expediently, depending on the reactivity of the radical A, at temperatures between -50 and + 250 ° C. For example, if A is the hydroxyl group, the reaction is preferably carried out in the melt at temperatures between 200 and 250 ° C or in the presence of a dehydrating agent, e.g. in the presence of cyclohexylcarbodiimide, thionyl chloride or phosphorus oxychloride, and in a solvent at temperatures between -50 and + 100 ° C.

If A in the compound of the formula II denotes a hydroxy group, the compound of the formula II can, in addition to a compound of the formula III, also with a urea of the formula IV

be implemented. The reaction is conveniently carried out at elevated temperature, e.g. in the melt.

Most of the compounds of the formulas II, III and IV which serve as starting materials are known from the literature or can be prepared by processes known from the literature (see examples).

As already mentioned, the new compounds of the formula I have valuable pharmacological properties with long-lasting activity. They are particularly characterized by muscle relaxant, sedative, antiarrhythmic and anticonvulsant effects.

The following compounds were examined for their biological effect:

A = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] -acetamide,

B = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid-methylamide,

C = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] -propionamide,

D = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid-ethylamide,

E = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] -acetic acid-propylamide,

F = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid-isopropylamide, and

G = 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid-dimethylamide.

1. Muscle relaxant and sedative effects in mice:

This was determined according to the method of Young and Lewis [Science 105, (1947) 368] on female NMRI mice of their own breeding with a body weight between 20 and 26 g by means of slowly rotating wire cylinders inclined at 30 ° to the vertical (length: 43 cm ; Diameter: 22 cm; mesh size of the wire mesh: 0.6 cm) examined. After oral administration of the substance to be tested in 1% tylose suspension to groups of 10 mice / dose, its holding capacity in the slowly rotating cylinders (2 rotations / minute) was checked against a control group. The dose (ED50) at which 50% of the animals had dropped out after the different times was determined graphically:

substance

30-60

EDso mg / kg p.o. 120-150 210-240

270-300 minutes

A

40

34

52

32

B

48

71

100

-

D

70

110

-

-

E

95

140

-

-

F

75

110

-

-

G

34

67

71

© o

2. Anticonvulsant effect in mice:

The anticonvulsant effect was used as a protective effect against the maximum electroshock spasm in male NMRI mice of their own breeding with a body weight between 20 and 26 g, following the method of Swinyard, Brown and Goodman [J. Pharmacol. exp. Therapist 106 (1952) 319]. The animals were exposed to an alternating current of 50 Hz and 50 mA with a stimulus duration of 0.2 seconds, the occurrence of the tonic stretching spasm being rated as positive. After oral administration of the substances to be tested in 1% tylose suspension, the dose (ED50) was determined graphically, at which 50% of the animals were protected against the tonic extensor component of the hind extremities during the spasms after various times:

substance

30th

ED5o mg / kg p.o. 150

300 minutes

A

21st

21st

23

B

22

25th

28

C.

36

32

39

D

31

69

-

F

26

42

-

G

25th

52

-

3. Antiarrhythmic effects on guinea pigs:

The antiarrhythmic effect was determined as antagonism against digitalis-related arrhythmias:

A catheter for the infusion of digoxin and injection of substance A was integrated into the upper vena cava of 11 anesthetized guinea pigs (1.5 g / kg i.p. urethane) weighing 335 to 385 g. Digoxin was at 20 y / min. infused intravenously until ventricular arrhythmias occurred. After the infusion had ended, 40 mg / kg of substance A (2% in 40% polydiol) were administered intravenously to 5 animals within 1 to 2 minutes.

Result:

In the control group (6 animals), the glycoside-related arrhythmias continued for a further 13 to 20 minutes after the digoxin in-fusion had ended, while in the substance group (5 animals) these were eliminated immediately after the injection of substance A.

The compounds of the formula I also have a low acute toxicity, for example the LD50 for compound A on the mouse is 1136 mg / kg po.o. (Observation time: 14 days).

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For pharmaceutical use, the compounds of the formula I can be incorporated into the customary pharmaceutical preparations. The single dose is 50 to 300 mg, but preferably 50 to 200 mg.

The following examples are intended to explain the invention in more detail:

example 1

2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2) J - acetamide a) 95 g 3,4-dihydro-4,4-dimethyl- 1H-isochroman dione - (1,3) and 37.5 g glycine are melted together with stirring, the bath temperature being slowly increased to 180 ° C. The water of reaction formed is distilled off. After a reaction time of 7 hours, the mixture is cooled, taken up warm with glacial acetic acid and, after cooling, the precipitated 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-di-oxo-isoquinolyl- (2)] -sucked off acetic acid.

Melting point: 152-154 ° C, yield: 92.7 g (75% of theory).

b) 5 g of the 2- [l, 2,3,4-tetrahy-dro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] -acetic acid described above are distilled for one hour with 50 ml The thionyl chloride is heated under reflux, the excess thionyl chloride is removed in vacuo, the remaining residue is dissolved in 100 ml of ether and this solution is saturated with ammonia with stirring and cooling. After standing overnight, water is added, the mixture is shaken with chloroform, the organic phases are combined, dried and, after removal of the solvent, the residue is recrystallized from methanol.

Melting point: 182-184 ° C, yield: 3.8 g (77% of theory).

Example 2

2- [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2) J - acetamide

3.4 gl, 2,3,4-tetrahydro-4,4-dimethyl-isoquinolinedione - (1,3) are dissolved in 50 ml of absolute dimethylformamide, in portions with 1.0 g of sodium hydride (80% suspension in Oil) was added and the mixture was stirred at room temperature for half an hour. 5.3 g of bromoacetic ester are added dropwise and the mixture is stirred for a further 6 hours at room temperature. The solution is poured onto ice water, acidified and extracted with ethyl acetate. The ethyl acetate phase is washed with water and evaporated, the crude ethyl ethyl 2- [1,3,4,4-tetrahydro-4,4-dimethyl-1,3-isoquinolyl- (2)] being left behind as an oil. 1.4 g of this ester are dissolved in 15 ml of saturated methanolic ammonia and heated in an autoclave at 150 ° C. for 2 hours. The solution is then evaporated and the residue is recrystallized from isopropanol.

Melting point: 182-184 ° C.

Example 3

2- [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] ~ -acetamide

1.25 g of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid are mixed with a mixture of 10 ml of chloroform and 5 ml Thionyl chloride heated 2x /% hours at reflux. The chloride of the above acid remaining after evaporation is taken up in 10 ml of benzene. 5 ml of this solution are added dropwise to a suspension of 0.33 g of potassium phenolate in 15 ml of tetrahydrofuran and then left to stand at room temperature for 2 hours. Now it is mixed with 20 ml of ethyl acetate and washed with sodium carbonate solution, water, dilute hydrochloric acid and again with water and evaporated, the crude 2- [1,2,3,4-tetrahydro-4,4-di-methyl-1,3 -dioxo-isoquinolyl- (2)] -acetic acid phenyl ester remains as an oil. The ester is taken up in 100 ml of benzene, 25 ml of saturated methanolic ammonia are added and the mixture is left to stand at room temperature for 2 hours. The solution is then evaporated and the residue is recrystallized from isopropanol.

Melting point: 182-184 ° C.

Example 4

2- [1,2,3,4-T etrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetamide

5 ml of a benzene solution of 2- [l, 2,3,4-tetrahy-dro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] - acetic acid chloride become a solution of 0.27 g Drop thiophenol and 0.3 g triethylamine in 10 ml benzene. After standing for two hours at room temperature, a further 10 ml of benzene are added and the solution is washed successively with dilute hydrochloric acid, dilute soda solution and water and dried.

This benzene solution of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] -acetic acid-thiophenyl-ester is immediately further processed by using it 40 ml of saturated methanolic ammonia are added and the mixture is left to stand at room temperature for 2 hours. The solution is then evaporated and the residue obtained is recrystallized from isopropanol.

Melting point: 182-184 ° C.

Example 5

2- [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetamide

0.31 g of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid are refluxed for 2 hours with 2 ml of thionyl chloride in 6 ml Benzene converted to the chloride. After evaporation, the acid chloride remaining is taken up in 3 ml of tetrahydrofuran and added dropwise to a solution of 0.18 g of imidazole in 5 ml of tetrahydrofuran. After 15 minutes, the precipitated imidazole hydrochloride is filtered off. The solution of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] - acetic acid imidazolide thus obtained is immediately further processed by being saturated with 10 ml added methanolic ammonia and left for one hour at room temperature. After evaporation, the mixture is taken up in ethyl acetate, washed with dilute hydrochloric acid and water. The organic phase is then evaporated and the residue is recrystallized from isopropanol.

Melting point: 182-184 ° C.

Example 6

2- [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetamide

0.06 g of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid are dissolved in 5 ml of tetrahydrofuran and mixed with 0.04 g of triethylamine are added. 0.05 g of isovaleric acid chloride is now added with stirring and the mixture is left to stand for 5 minutes. The precipitated triethylamine hydrochloride is filtered off. The mixed anhydride of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl - l, 3-dioxo-isoquinolyl- (2)] - acetic acid and isovaleric acid, which is in the mother liquor, is not isolated, but rather the 0.4 ml of saturated methanolic ammonia are added to the solution while cooling with ice. After standing at 0 ° C. for two hours, the mixture is evaporated, the residue is taken up in ethyl acetate and this is saturated with

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ter bicarbonate solution. After evaporation of the ethyl acetate phase, the product is recrystallized from isopropanol.

Melting point: 182-184 ° C.

Example 7

2- [1,2,3,4-T etrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetamide

0.03 g of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid are mixed with 0.2 g of urea and 2 minutes heated to 220 ° C. After cooling, water is added and the mixture is extracted with ethyl acetate, the precipitates which are insoluble in both phases being filtered off. The ethyl acetate phase is washed with bicarbonate solution and evaporated. The residue is recrystallized from isopropanol.

Melting point: 182 to 184 ° C.

Example 8

2- [1,2,3, '4-T-etrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetamide

0.31 g of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-iso-quinolyl- (2)] - acetic acid are converted into the chloride and this in 5 ml of benzene added. This solution is added dropwise to a solution of 0.08 g of ethyl mercaptan and 0.14 g of triethylamine in 20 ml of benzene. The mixture is left to stand at room temperature for 2 hours and then washed successively with dilute hydrochloric acid, dilute soda solution and water. This benzene solution of 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3 - dioxo-isoquinolyl- (2)] - acetic acid thioethyl ester is used immediately after drying. It is mixed with 20 ml of saturated methanolic ammonia and heated in an autoclave at 100 ° C for 2 hours. It is evaporated, taken up in ethyl acetate and washed with bicarbonate solution. After evaporation of the ethyl acetate phase, the product is recrystallized from isopropanol.

Melting point: 182 to 184 ° C.

Example 9

2- [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] propionamide

Al, 5 g of 3,4-dihydro-4,4-dimethyl-isochroman dione (1,3) and 22.3 g of L-alanine are melted together with stirring, the bath temperature slowly increasing to 180 ° C. and the water of reaction is distilled off over a bridge (reaction time: 5 hours). After cooling, it is dissolved in 100 ml of acetone, mixed with 500 ml of saturated sodium bicarbonate solution and extracted with chloroform.

The aqueous phase is made strongly acidic with 2N hydrochloric acid and the oily product which has precipitated out is extracted several times with chloroform. After drying and removing the

615918

Solvent remains an oil that slowly crystallizes. Recrystallization from toluene gives 31.4 g (48% of theory) of 2- [1,3,4,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] propionic acid as colorless crystals with a melting point of 143-145 ° C.

Analogously to Example 1, the 2 - [1,2,3,4-tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] - propionic acid described above is converted into the amide.

Melting point: 184-186 ° C.

Example 10

2- [1,2,3,4-T etrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetic acid-methylamide

15.5 g of the acid chloride prepared analogously to Example 1 from 2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] - acetic acid and thionyl chloride are mixed in 400 ml ether dissolved and methylamine introduced until saturated. The mixture is then heated under reflux for a further 2 hours, then the solvent is removed and the residue is washed with water.

Melting point: 182-184 ° C (from isopropanol).

Example 11

2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] acetic acid-dimethylamide

Manufactured analogously to Example 10, but using dimethylamine as the amine component.

Melting point: 183-185 ° C (from methanol).

Example 12

2- [l, 2,3,4-tetrahydro-4,4-dimethyl-l, 3-dioxo-isoquinolyl- (2)] acetic acid-ethyl amide

Manufactured analogously to Example 10, but using ethylamine as the amine component.

Melting point: 143-145 ° C (from ethyl acetate).

Example 13

2- [1,2,3,4-Tetrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetic acid propylamide

Prepared analogously to Example 10, but using n-propylamine as the amine component.

Melting point: 116-118 ° C (from ethyl acetate).

Example 14

2- [1,2,3,4-T etrahydro-4,4-dimethyl-1,3-dioxo-isoquinolyl- (2)] acetic acid-isopropylamide

Manufactured analogously to Example 10, but using isopropylamine as the amine component.

Melting point: 125-128 ° C (from ethyl acetate).

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