DE2306543A1 - ANTI-CONVULSIVE MEDIUM - Google Patents

Description

Our sign; O. Z. 29 699 D / UB 6700 Ludwigshafen, February 8, 1973

The invention relates to a new anticonvulsant agent, anhydro-2-meroapto-4-methyl-5-phenyl-1,3,4-thiadiazolium hydroxide and / or anhydro-2-mercapto-4-niethyl-5- (p-chlorophenyl) Contains 1,3,4-thiadiazolium hydroxide as an active ingredient »

The compounds are described by KT Potts and C Sapino in Chemical Communications 1968, page 672, those unsubstituted in the phenyl radical also by R. G-rashey, M _n Baumann and W.-D. Lubos in the Tetrahedron Letters, 1968, pages 5881 ff, described their anticonvulsant effectiveness is, however, completely unexpected.

Pur the isomeric anhydro-2-mercapto-4-phenyl-5-methyl-1,3,4-thiadiazolium hydroxide are only bacteriostatic in the Journal of Pharmaceutical Sciences 1967, vol. 56, p. 165 or bactericidal properties against microorganisms and low hypotensive properties are described. Will continue stated in this work that the 5-alkyl compounds at Rats produce convulsions at higher doses.

The compound anhydro-2-mercapto-4-methyl-5-pheny1-1,3,4-thiadiazolium hydroxide and the derivative substituted by chlorine in the phenyl ring in the p-position are distinguished by an excellent anticonvulsant effect. This effect is particularly advantageous, since other neuropharmacological effects, for example sedation, prolongation of the hexobarbital sleep time, only occur at very high doses, so that the therapeutic index in animal experiments is extremely high. The LD ₁ -Q in the mouse is above 2,000 mg / kg po ", while the ED | - ₀ , which protects against the minimum and maximum pentetrazole shock, is only 7.5 and 8 mg / kg, respectively. This results in a protective index that is · greater than 135 or 125 * Only for diazepam

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this protective index reaches a similar level in pentetrazole shock, namely 114. With the comparison substances phenobarbital and trimethadione, the protective index for minimum and maximum pentetrazole shock is below 5. The protection index denotes the ratio of neurotoxic ED to ED ₁ - _n

50 50 "

trying to convulsively.

It should be pointed out that with anhydro-2-mercapto-4-methyl-5-phenyl-1, 3,4-th.iadiazolium hydroxide, an exact determination of the neurotoxic ED ™ according to the method described by Swinyard et al. in J. Pharm. exper. Ther. Method described 106, 319 (1952) is not possible, as in mice up to a dose of I ₀ OOO mg / kg po no signs yet of. neurotoxic effects can be found.

The same result as with pentetrazole shock can also be found with the minimum and maximum electric shock of the mouse. In the case of maximum electric shock, the protective index for anhydro-2-mercapto-4-methyl-5-phenyl-1,3,4-thiadiazoiium hyaroxide is even higher than for pentetrazole convulsions, namely greater than 250, while it is only 9.5 for diazepam , is for phenobarbital 6.4 and trimethadione 2; 5.

Another advantage over the cited comparative substances is that the active ingredients according to the invention only very slight central dampening effects can be observed. Hexobarbital anesthesia is used in mice (at 64 mg / kg i.v.) 'only slightly influenced by lower gifts and only through' approx. 250 mg / kg p.o. doubled. In the comparative experiment, the hexobarbital narcosis doubles under the same conditions a dose of 1.36 mg / kg diazepam and a dose of 50.0 mg / kg trimethadione.

The table below shows experimental results obtained on the mouse with anhydro-2-mercapto-4-methyl-5-phenyl-1,3,4-thiadiazolium hydroxide and known, commonly used anticonvulsants as comparison substances.

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Anticonvulsant effect of anhydro ^ -mercapto ^ -methyl-S-phenyl-l.S ^ -thiadiazolium hydroxide (designated as substance 1 in the table) on the mouse at p.o. application compared to diazepam, phenobarbital and trimethadione and phenytoin

CD OO Ca)

^LD 50
mg / kg NeurotoxtED _5n
(after Swinyard
et al., 1952,
^s · ^TBXtl mg / k _gj MES *
^ED 50
mg / kg Protection index ** min. pent
trazol shock
^ED 50
mg / kg _,,. , Λλλ
Protection index max.
trazol shock
^ED 50
mg / kg XXXX
Protection index Substance 1
Diazepam
Phenobaric
bital
Trimetha
dion
Phenytoin > 20DD
650
320
> 1000 > 1000
57
7D
1150
Θ4 ⁺ 4.0
6.0
11.0
450
8.0 > 250
9.5
6.4
2.5
10.5 7.5
0.5
30, ü
240 > 135
114
2.3
4.6 8.0
0.5
21.5
260 > 125
114
3.3
4.4

XX XXX XXXX

maximum electric shock

Neurotox. ED ₅₀ J MES ED50

Neurotox. ED50: min pentetrazole shock ED ₅₀

Neurotox. ED50: max pentetrazole shock ED50

(after Swinyard et al., J. Pharm. exp. Ther. jL51 »369, 19663

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The rat can also be used for pentetrazole convulsions, for example the same superior properties of the compound to be used according to the invention compared to the specified comparison substances to be shown.

Corresponding results are also obtained for the p-chlorophenyl compound biological activities.

The invention thus provides an anticonvulsant with a far higher selectivity than known anticonvulsants and provided a very favorable therapeutic index. In terms of the therapeutic range, i.e. the Distance of the doses with neurotoxic side effects, the known anticonvulsants including diazepam are exceeded.

Anhydro-2-iaeroapto-4-niethyl-5-phenyl-1,3,4-thiadiazolium hydroxide or the chlorophenyl derivative can be used for psychomotor cramps, epilepsy, grand mal, petit mal or electric shock can also be used for prophylaxis. ,

With a suitable carrier or diluent and the usual pharmaceutical-technical auxiliaries can in itself Usually a corresponding pharmaceutical preparation is produced in the form of a dosage unit suitable for use will.

A preferred pharmaceutical preparation is a dosage form which is suitable for oral application. Such dosage forms include, for example, tablets, Dragees, capsules which can be produced by the person skilled in the art in a manner known per se.

Ankydro-2-mercapto-4-meth.yl-5-ph.eny 1-1, 3,4-thiadiazolium hydroxide, for which the chemical structural formula is given here,

³ il ⁽⁺⁾ il

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can in practice, for example, according to the following explained processes are produced.

. Sodium dithiobenzoate;

126.6 g (1.0 mol) of benzyl chloride are added dropwise at room temperature to a mixture of 64 g (2 mol) of ground sulfur in 500 ml of absolute methanol and 396 g of 30 folgev sodium methylate solution over the course of 1 hour heated up to boiling temperature »This mixture is then heated to boiling temperature for 16 hours on a reflux condenser. It is then cooled, the sodium chloride formed is filtered off with suction, washed with methanol and the mother liquor is evaporated. 251.9 g of sodium dithiobenzoate are obtained as a red oil.

2. 2-mercapto-S-thiobenzoyl acetic acid;

The sodium dithiobenzoic acid from Example 1 is taken up in 600 ml of water, ^{cooled to 0} ° C. and 116.5 g (1.5 mol) of sodium chloroacetate are added. The temperature should not rise ^{above +5 0 C.} The mixture is stirred for 2 hours in an ice bath and the reaction vessel then for 48 hours at O ⁰ C. The solution is extracted once with 200 ml of ether and then acidified with concentrated aqueous hydrochloric acid. A deep red precipitate separates out, which is filtered off with suction and dried. Yield 117 »2 g (55 ° of theory) of 2-mercapto-S-thiobenzoyl acetic acid with a melting point of 117 ° to 119 °.

3. 1-methyl-i-thiobenzhydrazide:

117.2 g of 2-mercapto-S-thiobenzoylessigsäure from Example 2 are dissolved in 552 ml of 1 Normal sodium hydroxide solution and at ⁰ ° C with 27.6 g (0.6 mole) methyl hydrazine was added dropwise in I50 ml of water. The mixture is stirred for 1 hour and the precipitate which has separated out is filtered off with suction. 86.7 g (95% of theory) of 1-methyl-i-thiobenzhydrazide with a melting point of 86 to 87 ^° C. are obtained

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4. Hydro-2-nieroapto-4-niethyl-5-phenyl-1, 3,4-thiadiazolium hydroxide:

• 25 g of 1-methyl-i-thiobenzhydrazide are dissolved in 200 ml of absolute acetonitrile, an excess of carbon disulfide (about 30 ml) is added and the mixture is heated to boiling temperature on a reflux condenser for 10 hours will. Upon cooling, 26.1 g (83% of theory) fall Anhydro-2-mercapto-4-methyl-5-phenyl-1,3,4-thiadiazolium hydroxide melting point of 219 to 221, ⁰ G from.,

Anhydro-2-mercapto-4-methyl-5- (p-chlorophenyl) -1, 3 _s 4-thiadiazolium hydroxide with a melting point of 201 to 202 G is obtained analogously from 1-methyl- (p-chloro-thiobenz) -hyarazide from Melting point 113 to 116 ⁰ G produced.

The specified exemplary embodiments can also be found in the literature, e.g. German patent specification 1,274,121 for 1., K.A. Jensen et al. Acta Chem. Scand. 15, 1109 (1961) for 2nd and 3rd and for 4th of the literature given on page 1.

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Claims (1)

0.2. 29 699 Claim Ant! "Convulsive agent, the hydro-2-mercapto-4-metn.yl-5-pn.enyl-1 ^, ^ - thiadiazolium hydroxide and / or Anb.ydro-2-mercapto-4-meth.yl-5- (p-clilorphenyl) -1 Contains 3,4-thiadiazolium hydroxide as an active ingredient. Badische Anilin- & Soda-Pabrilc AG 409833/1016