NO165229B - DEVICE FOR EMPTYING A FLEXIBLE TRANSPORT CONTAINER. - Google Patents

Description

Analogous process for the preparation of substituted succinimides suitable for the treatment of epilepsy.

This invention relates to a method for the production of new compounds which are suitable for the treatment of epilepsy.

The compound α-ethyl-α-methyl-succinimide has previously been shown to be effective against the "Petit Mal" form of epilepsy, but it is far less effective against the "Grand Mal" form, and its effective dose approaches then the toxic level.

It has now been found that certain derivatives of α-ethyl-α-methyl-succinimide and related compounds, which are more precisely defined in the following, are considerably more physiologically tolerable and possess a very favorable ratio of anticonvulsant activity to unwanted side effects.

The compounds produced by the method according to the invention have the general formula

12 3

where R , R and R mean hydrogen atoms, or the same or different alkyl groups with 1 to 5 carbon atoms, with at least one

12 3

and no more than two of the substituents R, R and R are different

5 4

from hydrogen; R means a hydrogen or halogen atom, and R means a hydrogen atom, or a lower alkyl or hydroxy-lower alkyl group.

These new compounds possess particularly good pharmacological properties, including strong anti-convulsant activity and particularly good tolerability, and are useful for the treatment of epilepsy. They also exhibit diuretic activity due to the presence of a sulfonamido group.

1 2

Preferably, the substituents are R and R respectively

a methyl and an ethyl group, and R <3.> a hydrogen atom.

The new compounds form salts with bases, e.g. alkali metal salts, such as sodium salts, or salts with ammonia or amines.

The compound N-(α-ethyl-α-methyl-N-succinimido)-4-sulfonamido-benzene has been shown to have particularly favorable properties in pharmacological tests, as its peroral LD^0 is in the order of magnitude 4000 mg/kg or more in mice, compared to α-ethyl-α-methyl-succinimide which has an oral LD^q in mice of

about. 1500 mg/kg. In the electroshock test, which is a measure of activity against "Grand Mal" epilepsy, its oral ED^0 in mice was as low as 5 mg/kg, while the corresponding value in albino

rats was 25 mg/kg. In the same tests, α-ethyl-α-methyl-succinimide showed an ED50 of 500 mg/kg. In the "Cardiazol" shock test, which is a measure of efficacy, against "Petit Mal" epilepsy, the oral ED,-0 for N-(α-ethyl-α-methyl-succinimido)-4-sulfonamido-benzene was shown to be 600 mg/kg, compared

with 200 - 300 mg/kg for α-ethyl-α-methyl-succinimide, but it should be noted that the ratio for ED50/LD^Q is significantly better for the new compound produced by the method according to the invention. This compound showed no anesthetic effect up to 200 mg/kg. Other compounds of formula I have similar properties.

One or more of the compounds of formula I can be formed into pharmaceutical preparations together with one or more pharmaceutical carriers or diluents.

Thus, e.g. the preparations be in the form of tablets, dragées, capsules, caramels, suppositories, ampoules for injection, solutions, etc.

The carriers or diluents in such preparations can e.g. be those usually used for such forms, and may include starch, lactose, magnesium stearate, talc, gelatin, sterile water or suspending, emulsifying, dispersing, thickening or flavoring agents.

Unit dosage forms such as tablets, capsules, suppositories and ampoules are preferred, and conveniently each unit contains 10 to 1000 mg of active ingredient, preferably 100 to 300 mg.

The preparations preferably contain the active compound in a concentration of between 0.10 and 80.0% by weight.

In German patent 1,041,047, substituted succinimides with anti-epileptic activity are described, and an LD50 of 5000 mg/kg and an ED5Q of 700 mg/kg are stated, which gives a therapeutic ratio (LDgQ:ED^0) of 7 ,14.

In Österrtek patent 242,132 which also relates to substituted succinimides, the test results for two compounds are given as follows:

LD,^:1900 mg/kg, EDC^:195 mg/kg, which gives a

50 DO

therapeutic ratio of 9.74; and LD50:2000 mg/kg, ED5Q:47 mg/kg, giving a therapeutic ratio of 42.55.

However, the products according to the following examples 1, 5 and 6 have LDgQ values of 4200-5000 respectively,

4800 and 5000 mg/kg and ED5Q values of 25, lo-25 and 25-50 mg/kg respectively, giving therapeutic ratios of 168-200, 192-480 and 100-200 respectively.

According to the invention, the new compounds of formula I are prepared as indicated above, by

a) an amine with the formula

4 5 where R and R are as indicated above, is reacted with an acid with the formula

12 3

where R , R and R are as above, or with a reactive derivative thereof, to form the desired succinimido derivative, or

b) an amine of the formula

where R 5 is as indicated above, is reacted with an acid of formula (III) indicated above or a reactive derivative thereof, and to introduce a sulfonamido group into the thus formed product,

the product is then reacted with a sulfonyl halide, and the resulting compound is reacted with ammonia or an amine with

4 4

the formula I^NR , where R is as indicated above, or

c) an amine of the formula

5

where R is as stated above, is reacted with an acid of formula (III) as stated above or a reactive derivative thereof, and to introduce a sulfonamido group into the product thus formed, the nitro group is reduced to an amino group, and then the product is diazotized and reacted with sulfur dioxide and a copper (I) halide, and the compound obtained containing a

halosulfonyl group is reacted with ammonia or an amine with

4 4

the formula f^NR / where R is as stated above,

in that the reaction with the acid of formula (III) can be carried out in a single step or in two steps.

When the reaction with the acid is carried out in two steps, the first product will be a hemisuccinyl derivative and can optionally be isolated before final ring closure. usually the final condensation requires a reaction temperature of the order of 200°C,

and for single-step reactions, the reaction should be carried out at a temperature of this order of magnitude. The half-condensation of the succinic acid of formula III usually takes place in the range 80 - 100°C.

The first condensation to form the hemisuccinyl derivative is likewise carried out by simple heating in an inert solvent, e.g. a hydrocarbon, nitrohydrocarbon, chlorohydrocarbon, ether or cyclic ether. The second step for generating circularity can e.g. is carried out in the presence of a dehydrating agent such as an anhydrous salt, e.g. sodium acetate or sulfuric acid, phosphoric acid or polyphosphoric acid or phosphorous pentoxide or simply by heating to approx. 200°C in the absence of solvent with or without vacuum.

The reaction time for the reaction with the free acid is preferably 1-5 hours, suitably approx. 2 hours. The effect step reaction with the anhydride is preferably carried out at approx. 200°C

in a short time.

The following examples shall serve to further illustrate the invention.

Example 1

1- N-(a- ethyl- g- methyl- succinimido)- 4- sulfonamido- benzene 17.2 g of sulfanilamide (1 mol) are heated for 30 minutes at

160°C incl

16.0 g α-ethyl-α-methyl-succinic acid (1 mol).

The resulting oil is dissolved in ethyl acetate, cooled

and filtered with suction to give

16.7 g white crystals, m.p. 164 - 166°C. Yield 56%.

The product was recrystallized from ethyl acetate for analysis.

Analysis:

Example 2

(a) 1-N-(g-ethyl-g-methyl- succinimido)-benzene

27.9 g of aniline and 48.0 g of α-ethyl-α-methyl-succinic acid are heated together at 170°C and held at this temperature for 15 minutes. The resulting oil is taken up in ethyl acetate, washed with aqueous NaOH and evaporated in vacuo. Petroleum ether is added to the residue, and the resulting crystals

is filtered to give ,

45.0 g of white crystals with a m.p. 57 - 58°C. Yield: 70%.

(b) 1-N-(g-ethyl-g-methyl-succinimido)-4-chlorosulfonyl-benzene 40.0 g of 1-N-(a-ethyl-a-methyl-succinimido)-benzene is added to 120 ml of chlorosulfonic acid and heated with stirring at 130°C.

After being held at this temperature for 5 minutes, the mixture is poured into ice water, the precipitate is filtered with suction and taken up in chloroform, petroleum ether is added, and the mixture is cooled and filtered

again to give

30.0 g of white crystals with a m.p. 115 - 118°C. Yield: 51%.

(c) 1- N-(a- ethyl- g- methyl- succinimido)- 4- sulfonamido- benzene

The crude sulfonyl chloride thus obtained is then taken up in chloroform and added dropwise with stirring to concentrated ammonia. After heating to 30-40°C with stirring, the solution is evaporated to dryness in vacuo and the residue recrystallized from ethyl acetate to give colorless crystals with a m.p. 164 - 166°C.

The product does not reduce the melting point with the product from example 1.

(d)

1- N-(a-ethyl-a-methyl- succinimido)- 4-( N- ethyl- sulfonamido)-benzene 5.0 g of the sulfonyl chloride from (b) above is added to 5 ml of aqueous ethylamine and heated under reflux

for 1/2 hour. The precipitate is filtered with suction. The residue is dissolved in ethyl acetate and evaporated to dryness. The residue, a clear oil, is triturated with ether and filtered to give 3.2 g of white crystals melting at 122-128°C. Yield: 62%.

After recrystallization from alcohol, white crystals are obtained which melt at 133-134°C.

Analysis:

(e) 1- N-( a- ethyl- a- methyl- succinimido)- 4-( N- a- hydroxyethyl)- sulfonamido- benzene

Dissolve 5.0 g of the product from (b) above in 20 ml of chloroform, and

1.94 g of ethanolamine i

20 ml of chloroform are added with stirring and heated under reflux for 1 hour. An oil precipitates, some water is added, and the chloroform layer is separated and evaporated. The residue is dissolved in ethyl acetate, washed with water and evaporated. Ether is added to the residue which is triturated well and filtered with suction to give: 3.5 g of white crystals melting at 105 - 110°C.

Yield: 64%.

After recrystallization from ethyl acetate/petroleum ether, white crystals are obtained which melt at 110 - 112°C.

Analysis:

(f) 1-N-(a-ethyl-a-methyl-succinimido)-4-(N-methyl)-sulfanilamido-benzene Dissolve 5.0 g of the product from (b) above in 100 ml of chloroform, and 15 ml aqueous methylamine is added with stirring at 35°C.

After stirring for a further 15 minutes, the product is washed with chloroform and water and evaporated in vacuo. The residue is rubbed well with ether, and the crystals in

steamed with suction to give

3.5 g of white crystals with one m.p. 122 - 125°C.

Yield: 71%.

Analysis:

Example 3

N-(g-ethyl-a-methyl-hemisuccinyl)-aniline

9.3 g of aniline are dissolved in

50 ml ether, and

14.2 g of α-ethyl-α-methyl-succinic anhydride i

50 ml of ether is added.

After the addition of these ingredients, the solution becomes warm and a white precipitate separates.

After filtering with suction, you get

18.7 g of white crystals with m.p. 160 - 163°C. After recrystallization from ethyl acetate/petroleum ether, white crystals with m.p. 169 - 170°C.

Analysis:

g- methyl- a- ethyl- N- fienyl succinimide

2 g of N-(α-ethyl-α-methyl-hemisuccinyl)-aniline is heated for 1 hour to 180 - 200°C. After the reaction, the crude product is taken up in ethyl acetate. The ethyl acetate solution is washed with dilute caustic soda and with water, dried over sodium sulfate and evaporated. The ethyl acetate residue is dissolved again in ethyl acetate and petroleum ether is added. The succinimide is precipitated.

Yield: 0.5 g.

The compound is in terms of melting point, mixture melting point and IR spectrum identical to 1-N-(α-ethyl-α-methyl-succinimido)-benzene prepared according to example 2a and is converted into the p-sulfonamido derivative as described in example 2.

Example 4

N-(g-ethyl-g-methyl-hemisuccinyl)-4- sulfonamido-aniline

8.6 g of sulfanilamide and

7.1 g of g<->ethyl-g<->methyl-succinic anhydride are heated together at 100°C and then dissolved in ethyl acetate and the NaHCO^-NaHCO^ solution is acidified with HCl, and the precipitate is filtered with suction and dried. You get

9.2 g of white crystals with m.p. 165 - 168°C, which after recrystallization from ethyl acetate/petroleum ether gives 7.5 g of white crystals with m.p. 173 - 174°C.

Analysis:

1- N-(a- ethyl- g- methyl- succinimido)- 4- sulfonamido- benzene 2 g N-(g<->methyl-g<->ethyl-hemisuccinyl)-4-sulfonamido-aniline kept for 1 hour at 180 - 200°C. After cooling, the crude product is dissolved in ethyl acetate and filtered. The clear ethyl acetate solution is then evaporated to approx. half volume and cool to 0 - 5°C. There-wood crystallizes

1.3 g of succinimide.

According to melting point, mixture melting point, thin layer chromatogram and IR spectrum, the compound is identical to 1-N-(g<->ethyl-g<->methyl-succinimido)-4-sulfonamidobenzene prepared according to examples 1 and 2c.

Example 5

1- N-( g, g- dimethyl- succinimido)- 4- sulfonamido- benzene 17.2 g of sulfanilamide and

14.6 g <g>,<g->dimethyl succinic anhydride are heated together for 30

minutes at 180°C. After cooling, the oil is taken up with dioxam, ether is added and the whole is cooled and filtered with suction to give

20.4 g of white crystals with m.p. 213 - 215°C, yield 72%

after recrystallization from dimethylformamide/ether.

Analysis:

Example 6

1- N-(a, g- diethyl- succinimido)- 4- sulfonamido- benzene 17.2 g of sulfanilamide and

17.4 g <g>,<g->dimethyl succinic anhydride are heated together for 20 minutes at 170°C. After cooling, the oil is taken up with ethyl acetate, cooled and filtered with suction. You get

o

23.4 g of a light brown product with m.p. 125 - 132 C,

yield 75%, which after recrystallization from ethyl acetate/petroleum ether gives white crystals with m.p.

129 - 131°C.

Analysis:

Example 7

1-( g- methyl- succinimido)- 4- sulfonamido- benzene

6.6 g methylsuccinic acid and

8.6 g of sulfanilamide are heated together at 180-190°C and held at this temperature for 15 minutes. After cooling, ethyl acetate is added, and the resulting precipitate is filtered with suction to give

10.2 g of white crystals with m.p. 237-239°C, which after recrystallization from acetone gives white crystals with m.p. 238-240°C.

Analysis:

Example 8

1-(g-ethyl-succinimido)-4- sulfonamidobenzene

4.9 g ethyl succinic acid and

5.8 g of sulfanilamide are heated together with 170-180°C. Ethyl acetate

is then added to the reddish-brown solution, and that

precipitated product is filtered by suction.

8.2 g of brown crystals are obtained, and after recrystallization from petroleum ether, white crystals with m.p. 199-200°C.

Analysis;

Example 9

1- (a-n-butyl-succinimide6)-_ 4- sulfonamidobenzene

3.5 g of butyl succinic acid and

3.5 g of sulfanilamide are heated together at 180°C and kept for 20

minutes at this temperature. After cooling, ethyl acetate is added, and after standing overnight, the resulting precipitate is filtered by suction for

to give

4.0 g of beige crystals, from which one recrystallizes

from ethyl acetate gives white flakes with m.p. 203-205°C.

Example 10

1-(a-methyl-fB-n-butyl-succinimido)-4- sulfonamidobenzene 2.0 g g<->methyl-6-n-butyl-succinic acid and

2.0 g of sulfanilamide are heated together at 180°C and held at this temperature for 15 minutes. Ethyl acetate is added after cooling. The resulting precipitate is filtered

by suction, and 1.5 g of light brown crystals are obtained which, after recrystallization from alcohol, give white crystals with m.p. 190-192°C.

Analysis;

Example 11

1-( g- methyl- B- n- propyl- succinimido)- 4- sulfonamidobenzene 2.0 g a-B-propylsuccinic acid and

2.0 g of sulfanilamide are heated together at 180°C and maintained

this temperature for 15 minutes. After the temperature has dropped to 80°C, ethyl acetate is added, whereby a brown product is precipitated. The whole is dissolved in hot ethyl acetate. The ethyl acetate solution is extracted with 2N HCl and 1N NaHCO 3 , dried and evaporated to give

1.5 g of a light brown crystalline product which is dissolved in ethyl acetate, filtered over charcoal and cooled, and the resulting precipitate is filtered with suction. Mon

sheep

0.5 g of white crystals with a m.p. 182-188°C, which after recrystallization for analysis gives white crystals with m.p. 190-192°C.

Analysis:

Example 12

1- N-( a- ethyl- g- methylsuccinimido)- 4- sulfonamidobenzene (a) 1- N-( q- ethyl- a- methylsuccinimido)- 4- nitrobenzene p-Nitroaniline (13.8g) and a-methyl- α-Ethyl succinic acid (16.Og) is heated together in a flask at 170-180°C for 20 minutes. The mixture is then taken up with ethyl acetate, extracted with HCl and NHCO 3 , washed with water and concentrated. The residue is recrystallized from ethyl acetate/

petroleum ether to give

11.5 g of product with a melting point of 125-127°C.

Analysis:

(b) 1-N-a-ethyl-a-methylsuccinimido)-4-aminobenzene The product from step (a) (6.55g) is dissolved in glacial acetic acid (100 ml) and hydrogenated using platinum oxide as catalyst until the theoretical uptake of hydrogen has been reached. The mixture is then filtered and evaporated to dryness, and the residue is mixed with water. The insoluble residue is washed with more water

and dried to give a crude product which, after recrystallization from ethyl acetate/petroleum ether, gives 5.5 g with a melting point of 132-135°C.

Analysis:

(c) 1- N-( g- ethyl- g- methylsuccinimido)- 4- sulfonamidobenzene The product from step (b) (5.5g) is dissolved in 2N HCl (100 ml) at 0°C and a mixture of NaN02 (l .7g) in water (20 ml) is added dropwise over time. The diazonium solution thus formed is added dropwise at 20°C to a mixture of glacial acetic acid (40 ml) saturated with SO2 and a solution of Cugl^ (3.3g) in water (20 ml) with stirring and continuous introduction of SOj. Nitrogen is evolved, and a brown product is precipitated. This product is filtered off with suction, dissolved in chloroform (50 ml), and concentrated ammonia (50 ml) is added dropwise at 20°C. This mixture is refluxed for 15 minutes and then concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, and the acetyl acetate layer is dried and evaporated to

give

0.3 g raw product. Recrystallization from ethyl acetate/petroleum ether gives white crystals with m.p. 164-166°C (no lowering of the melting point for a sample of the product from Example 1).

Claims (2)

1. Analogy method for the preparation of therapeutically active, substituted succinimides of the general formula 12 3 where R , R and R mean hydrogen atoms or the same or different alkyl groups with 1 to 5 carbon atoms, with at least one 12 3 and no more than two of the substituents R , R and 3 being different straight from hydrogen; R^ means a hydrogen or halogen atom, and R 4 means a hydrogen atom, or a lower alkyl or hydroxy-lower alkyl group, characterized in that a) an amine with the formula 4 5 where R and R are as indicated above, is reacted with an acid with the formula 12 3 where R , R and R are as above, or with a reactive derivative thereof, to form the desired succinimido derivative, or b) an amine of the formula where R 5 is as indicated above, is reacted with an acid of formula (III) indicated above or a reactive derivative thereof, and in order to introduce a sulfonamido group into the thus formed product, the product is then reacted with a sulfonyl halide, and the resulting compound is reacted with ammonia or an amine with 4 4 the formula I^NR , where R is as indicated above, or c) an amine with the formula where R 5 is as stated above, is reacted with an acid of formula (III) as stated above or a reactive derivative thereof, and to introduce a sulfonamido group into the product thus formed, the nitro group is reduced to an amino group, and then the product is diazotized and reacted with sulfur dioxide and a copper (I) halide, and the resulting compound containing a halogensulfonyl group is reacted with ammonia or an amine of the formula 4 4 H 2 NR , where R is as above, in that the reactions with the acid of formula (III) can be carried out in a single step or in two steps. 2. Method as stated in claim 1, characterized in that an acid with the gene-1 2 is used as starting material regular formula III where R and R are respectively a methyl and an ethyl group, and R 3 is a hydrogen atom.