DE2011024B - S-Carbalkoxy-ö ^ -dimethoxy-1-thiaisochroman-l, l-dioxide - Google Patents

Description

in which R ^{1 is} a hydrogen atom or a methyl group and R ^{2 is} a straight-chain or branched C _r C ₆ -alkyl radical, a / 3-chloroethyl, tetrahydrofurfuryl, benzyl, allyl or cyclohexyl radical.

The invention relates to 3-carbalkoxy-6,7-dimethoxy-1-thiaisochroman-1,1-dioxides the general formula

H, CO

H, C0

30th

in which R ^{1 is} a hydrogen atom or a methyl radical and R ^{2 is} a straight-chain or branched C ₁ -C ₆ -alkyl radical, a / i-chloroethyl, tetrahydrofurfuryl, benzyl, allyl or cyclohexyl radical.

Of compounds of this ring system, which can also be referred to as ^ -Sultones of 2 - (/? - Hydroxyalkyl) -benzenesulfonic acids, only a few representatives have been produced so far. Thus, GR C 1 em o and JH T ur η bu 11 (J. former Soc. [London] 1947, pp. 124 to 127) obtained the sultones of the 4th generation by treatment of O-methyleugenol or O-acetyleugenol with concentrated sulfuric acid , 5-Dimethoxy -2- {ß- hydroxy- η - propyl) - benzenesulfonic acid or 4 - methoxy - 5 - hydroxy - 2 - (β - hydroxyn - propyl) - benzenesulfonic acid in yields of less than 10% of theory. The aforementioned compounds could be obtained in significantly better yields by sulfonating ^ -bromodihydroeugenol methyl ether or O-AcetyU / i-bromodihydroeugenol and then heating the sulfuric acid sulfonic acid solutions diluted with water.

The compounds obtainable according to the invention can be used as medicaments. they show in animal experiments pronounced pharmacodynamic effects on the central nervous system. In addition to anticonvulsant effects compared to cardiazole or Strychnine effects are particularly central dampening properties in rats in the form of a »taming« - To highlight the effect.

The new 3-carbalkoxy-6,7-dimethoxy-1-thiaisochroman-1,1 -Dioxide of the general formula I can be prepared by either

40

⁴⁵

a) Compounds of the general formula
H ₃ CO _v

H ₃ CO

O COOH

in which R ^{1 has} the meaning given above, esterified or in a manner known per se with an alcohol of the formula R ² OH, in which R ^{2 has the meaning given above}
b) Compounds of the general formula II, in which R ^{1 has} the abovementioned meaning, with inorganic acid halides, such as thionyl chloride, to give carboxylic acid halides of the general formula

H, CO

O CO · shark

H ₃ CO _{/ Λ}

O O

in which R ^{1 has} the abovementioned meaning and Hal denotes a halogen atom, and reacts or reacts the compounds of the general formula II with an alcohol of the general formula R ² OH in which R ^{2 has the abovementioned meaning}

c) compounds of the general formula

H ₃ CO

H ₃ CO

Shark

SO ₃ ^S NH ₄ ®

* in which R ¹ and R ^{2 have} the abovementioned meaning, heated to melt or under normal pressure or in vacuo

d) compounds of the general formula

R ¹
CH ₂ -C-COOR ²

OH V

in which the radicals R ¹ and R ^{2 have} the abovementioned meaning, treated with concentrated sulfuric acid, expediently at room temperature.

The esterification by process a) can be carried out either without a catalyst or in the presence a catalyst, such as B. mineral acids or acid salts of these, chlorosulfonic acid, boron trifluoride, Thionyl chloride, acetyl chloride or chloroformic acid ester can be carried out.

The reaction is conveniently carried out with heating, e.g. B. at the boiling point of the alcohol in question. When using relatively high-boiling alcohols and reaction temperatures between 90 and 12O ⁰ C suffice When using catalysts such as thionyl chloride or Chlorameisensliuröester, the esterification can be carried out at room temperature, but much longer reaction times are required.

The reaction mixtures obtained by process a) are either the precipitated ones Carboxylic acid esters of the general formula I sucked off or the excess alcohol is distilled off and the Crude carboxylic acid ester obtained as a residue for separating off unreacted carboxylic acid treated with aqueous sodium hydrogen carbonate solution. The then washed with water Raw products are made according to customary methods, e.g. B. by Umkrislallisalion from organic solvents or corresponding solvent mixtures, finely cleaned.

In process b), after the reaction of the compounds of general formula II with inorganic acid halides to form compounds of the general formula III initially the excess Acid halide, expediently by distillation, separated off before the reaction of the compounds of the general formula III with the alcohols to give compounds of the general formula I. the Compounds of general formula I obtained by process b) are either already included in the Heat or not infrequently in pure form during the cooling of the reaction mixture.

The obtained and powdered according to the procedure) Raw products are cleaned by washing with water and alcohol, and if necessary recrystallized from organic solvents.

The compounds of the general compounds required as starting materials according to procedures a) and b) Formula II is obtained z. B. either by treating compounds of the general formula

H, CO

H ₃ CO

in which R ^{1 has} the abovementioned meaning and R ^{3 is} a carboxyl, carbalkoxyl, carbamoyl or carbonitrile group and Hai is a halogen atom, initially with concentrated sulfuric acid, expediently at room temperature, and then heating the sulfuric acid solutions diluted with water to about 70 to 90 ⁰ C or by saponification of compounds of the general formula

H ₃ CO

H ₃ CO

O CONH ₂

The compounds of the general formula IV used as starting materials according to process c) can be prepared by treating compounds of the general formula

R '
CH ₂ -CR ⁴

Shark VIII

in which R ¹ and Hal have the meaning given above

and R ⁴ denotes a carbonitrile or a carbamoyl group, with concentrated sulfuric acid at room temperature, subsequent brief heating of the mixture diluted with water and subsequent esterification of the isolated 2 - (// - halo - ß - carboxyethyl) - 4,5 - dialkoxy - benzene ammonium sulfonate derivatives by heating in the corresponding alcohol.

B e i s ρ i e 1 1

2.9 g of S-carboxy-oJ-dimethoxy-1-thia-isochroman-1,1-dioxide and 50 ml of methanol are in the presence of 1 to 2 drops of concentrated sulfuric acid Heated to the boil for 6 hours. The cooled reaction mixture is filtered off with suction and the crude 3-carbomethoxy-6,7-dimethoxy-1 thia-isochroman-1,1-dioxide (3 g) from a mixture of methanol and acetone recrystallized (mp 211-214 ° C). Yield:

2.8 g = 92.7% of theory.

Analysis for C ₁₂ H ₁₄ O ₇ S. Molecular weight: 302.3.
Calculated ... C 47.68, H 4.67, S 10.61;
found .... C 47.71, H 4.58, S 10.73.

Example 2

A mixture of 2.9 g of S-carboxy-oJ-dimethoxy-1-thia-isochroman-1,1-dioxide and 10 g of thionyl chloride is refluxed for 8 hours with the aid of a water bath. After the excess thionyl chloride has been distilled off, the crude 3-chlorocarbonyl-6,7-dimethoxy-1-thia-isochroman-1,1-dioxide is mixed with 60 ml of methanol and the mixture is heated to the boil for 1 to 2 hours. The 3-carbomethoxy-oj-dimethoxy-1-thia-isochroman-1,1-dioxide which has precipitated is filtered off with suction after the reaction mixture has cooled, washed with methanol and dried (mp 211-214 ° C.). Yield: 2.8 g = 92.7% of theory.

Example 3

in which R ^{1 has} the meaning given above, with dilute mineral acids.

2.9 g of S-carboxy-oJ-dimethoxy-1-thia-isochroman-1,1-dioxide are heated to boiling with 130 ml of absolute ethanol for 20 hours. The excess ethanol is then distilled off from the reaction mixture, the residue is extracted with aqueous sodium hydrogen carbonate solution and washed with water. The dried crude 3-carbethoxy-6,7-dimethoxy-l-thia-isochroman-1,1-dioxide is prepared from a mixture of ethanol and acetone recrystallized (F. 208 to 21O ⁰ C). Yield 2.5 g === 78.7% of theory.

Analysis for Ci ₃ H ₁₆ O ₇ S. Molar weight: 316.3,
Calculated ... C49.37, H 5.10, S 10.14;
rounded .... C 49.57, H 5.20, S 10.24.

0.2 g of unconverted S-carboxy-oJ-dimethoxy-l-thiaisochroman-l, l-dioxide covered by acidifying the sodium bicarbonate wlißrigen with dilute sulfuric acid, melting at 274 to 276 ⁰ C from.

Example 4

A mixture of 2.9 g of S-carboxy-oJ-dimethoxy-1-thia-isochroman-1,1-dioxide, 30 ml of absolute ethanol and 0.3 g of thionyl chloride is stirred for 64 hours at room temperature. Subsequently, the crude S-carbethoxy-oJ-dimethoxy-1 -thia-isochroman-1,1-dioxide filtered off with suction, treated with aqueous sodium bicarbonate solution, washed with water and recrystallized from acetone (mp 208-210 ⁰ C). Yield: 2.4 g = 76% of theory.

Example 5

A mixture of 2.9 g of 3-carboxy-6,7-dimethoxy-1-thia-isochroman-1,1-dioxide, 30 ml of absolute ethanol and 0.3 g of ethyl chloroformate is heated to the boil for 3 hours with stirring. After cooling the reaction mixture to room temperature, the crude ethyl ester is filtered off, washed with ethanol, treated with aqueous sodium bicarbonate solution, then washed with water and dried (m.p. 208 to 21O ⁰ C). Yield: 2.9 g = 91.7% of theory.

Example 6

0.9 g of 2 - (/ i-chloro - ^ - carbäthoxyäthyl) -4,5-dimeth oxy-5-benzolammoniumsulfonat be (12 mm Hg) to melt in vacuo at a temperature of 200 to 21O ⁰ C a few minutes. The cooled melt is crushed in a mortar, washed out with water and ethanol and dried.

ίο to give 3-carbethoxy-6,7-dimethoxy-l-ll--thiaisochroman dioxtd mp 208 to 21O ⁰ C. Ausbeule: 0.6 g 78% of theory.

The 2- (f / -Chlor- / J-carbäthoxyäthylH.S-dimethoxy-benzolammonium-

sulfonate was prepared as follows: 12 g of -chloro- β- (3,4-dimethoxyphenyl) propionic acid nitrile and 12 ml of concentrated sulfuric acid are combined at ⁰ ° C. and left to stand overnight at room temperature. Danin is used for sulfuric acid

Solution 40 g of ice and heated to the boil for a few minutes. The 2 - (ß - chlorine - β - carbäthoxyäthyl) 4,5 - dimethoxybenzenammoniumsulfonat which precipitated after cooling the mixture is filtered off with suction (10.8 g) and then with 50 ml of absolute ethanol

Boiled under reflux for 2 hours. After part of the solvent has been distilled off, 7.5 g of 2- (ß- carbethoxyethyl) -4,5-dimethoxy-benzene ammonium sulfonate crystallize out after cooling the ethanolic solution (melting point 204 to 214 ° C; (decomposition).

The following connections were also established:

Surname Molecular formula Melting point
⁰ C 3-Carbo-n-hexyloxy-6,7-dimethoxy-1 -thia-
isochroman-l, l-dioxide Q ₇ H ₂₄ O ₇ S
C ₁₄ H ₁₈ O ₇ S
Q ₆ H ₂₂ O ₇ S
Q ₄ H ₁₇ O ₇ S 94 to 95
176 to 178
108 to 110
154 to 156
165 to 167 S-carbisopropoxy-oJ-dimethoxy-l-thia-isochroman-
1,1-dioxide Q ₃ H ₁₅ O ₇ ClS
Q ₇ H ₂₁ O ₇ S
Q ₅ H ₂₀ O ₇ S
Q ₃ H ₁₆ O ₇ S
C ₁₄ H ₁₈ O ₇ S 130 to 133
170 to 172
136 to 138
99 to 101
115 to 117
90 to 92 S-carbisoamyloxy-oJ-dimethoxy-l-thia-isochroman-
1,1-dioxide S-carballyloxy-öJ-dimethoxy-l-thia-isochroman-
1,1-dioxide S-carbobenzyloxy-oJ-dimethoxy-l-thia-isochroman-
1,1-dioxide S-carbotetrahydrofurfuryloxy-oJ-dimethoxy-l-thia-
isochroman-l, l-dioxide S-Carbo-ß-chloroethoxy-oJ-dimethoxy-l-thia-
isochroman-l, l-dioxide S-carbocyclohexyloxy-oJ-dimethoxy-1 -thia-
isochroman-l, l-dioxide 3-methyl-3-carbisopropoxy-6,7-dimethoxy-1-thia-
isochroman-l, l-dioxide 3-methyl-3-carbomethoxy-6,7-dimethoxy-1-thia-
isochroman-l, l-dioxide S-methyl-S-carbethoxy-oJ-dimethoxy-l-thia-
isochroman-1,1-dioxide

Pharmacological comparison report

(Carbamazepine) a stronger central sedative effect 65 with a better therapeutic index. Besides that As can be seen from the table below, some of the compounds have the general the compounds of general formula I also have a stronger anticonvulsant effect compared to 5 - carbamoyl - 5 H - dibenz [b, f] azepine as carbamazepine.

2 Ol 1

R ¹ R ² i-propyl a b C. d e f 1 33 Compound of formula I. 5-carbamoyl-5 H-dibenz [b, f] aze- ethyl T ¹ Av ι "711 Π t Strychnine Cardiazole Alcohol- battle Therapeutic 1 > 2900 pin (carbamazepine) Allyl 1 UAI £ 1 ld L antagonism antagonism torsion bar test index 1 > 2500 H Benzyl mgAg mg / kg mg / kg 1 > 2OO0 CH ₃ Cyclohexyl 1 > 180C H Tetrahydrofurfuryl 390 1.1 0.03 / 0.40 12.0 50 1 > 250C H > 2000 1.8 0.02 / 0.12 0.7 50 1 > 250C H > 2000 1.1 0.02 / 0.05 0.8 50 H > 2000 1.0 > 2000 1.1 '> 2000 0.8 > 2000 0.8

a = LD ₅₀ mouse in mg / kg ip

b = Multipla of the LD ₁₀₀ strychnine.

c = ml additional consumption of cardiacol solution for cramp / death. d = ED ₅₀ for shortening the holding time.

e = ED ₅₀ for the suspension of the rat's fighting instinct.

f = therapeutic index (alcohol torsion bar: toxicity).

Claims (1)

Claim: 3-carbalkoxy-6,7-dimethoxy-1-thia-isochroman-1,1 -dioxide of the general formula H ₃ CO, IO H ₃ CO