FI57942B - FOERFARANDE FOER FRAMSTAELLNING AV NYA 2-PHENYLHYDRAZINOTIAZOLINER ELLER -TIAZINER FOER ANVAENDNING SAOSOM HYPNOTIC ELLER NARCOTIC MEDICINE - Google Patents

Description

GSF ^ l [B] (11) INVITATION PUBLICATION c 7 Q Λ 0 LJ 'UTLÄGGNINGSSKRIFT 0 (7 ^ 1 fltSsSew C Patent granted 10 11 1930 “Patent raeddelnt (S1) K» .ik.Va.3 o 07 D 277/18 , 279/06

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Patent · och registerstyrelsen 7 Amektn uthfd och utUkrHt · * »pubiictnd 31.07.80 (32) (33) (31) Requested« tueikeu »—B« | tN prtortm 0H.12.73

Hungary-Hungary (HU) GO-1255 ^ (71) EGYT Gyogyszervegyeszeti Gyar, 30, Kereszturi ut, Budapest X,

Hungary-Hungary (HU) (72) Läjos Toldy, Budapest, Istvan T6th, Budapest, B # la Rezessy, Budapest, Jözsef Borsi, Budapest, Jözsef Szikely, Budapest, IldikS Mankher nee Kiräly, Budapest, Istvan Polgäri, Budapest, Istvan Elekes , Budapest,

Hungary-Hungary (HU) (7¾) Oy Kolster Ab (5¾) Process for the preparation of new 2-phenylhydrazine thiazolines or thiazines for use as hypnotics and anesthetics -For the preparation of new 2-phenylhydrazinothiazolines or anthiazines This invention relates to a process for the preparation of novel 2-phenylhydrazine thiazolines or thiazines for use as hypnotic and narcotic enhancers.

The 2-phenylhydrazine thiazolines or thiazines prepared according to the invention correspond to the general formula:

Ru ___. N- (OH) / T 1 I 2 n (/ -NH - KH - C b H-R (I) H 3 R 2 in which R is a hydrogen atom or a methyl group) n is 1 or 2; R 1 are hydrogen or halogen atoms or nitro, trifluoromethyl or methyl groups, provided that when n is 1, R is a methyl group and R 2 is a hydrogen atom or a methyl group, R 1 and R 2 cannot be hydrogen atoms.

2 57942

The invention also includes acid addition salts of the above compounds.

Only a very limited number of compounds of similar structure have been described in the literature. G. Avenarius (Ber. 2k f 269-270 (10090)) has described 2-ortho- and 2-para-tolylhydrazine-5-methyl-2-thiazines. According to the reference, these compounds were prepared by cyclization with the appropriate 1- phenyl-U-allyylitiosemi-carbazides. However, no data on the potential physiological effects of these compounds can be found in the literature.

U.S. Patent 3,165,605 describes the preparation of 2-aniline-2-thiazoline from 3- (N-phenyl-thiocarbamoyl) -2-oxazolidinone.

U.S. Patent No. 3,328 Ul6 discloses the preparation of 2,2- (disubstituted hydrazine) -2-thiazolines by reacting substituted hydrazines with 2-chloroethyl isothiocyanate. U.S. Patent No. 3,651,053 discloses 2-aniline-thiazine and 2-aniline-thiazoline having nerve pain relieving and muscle tension triggering properties.

Trav. Soc. Pharm. Montpellier 20 (i960) 2 ^ 5-2 ^ 8 (CA 56 (1962) 13 510i) deals with the local anesthetic effect of 2-benzamidothiazoline and 2-benzylamino-thiazoline.

The published French patent application 2,039 7 ^ 8 (CA 75, 112867t) deals with e.g. 2-hydrazine thiazine. This known compound can be used as a narcotic agent in the transport of fish and other aquatic animals.

The chemical structure of these known compounds differs from the structure of the novel compounds prepared by the process of the invention. Moreover, these known compounds have no hypnotic or narcotic-enhancing effect. Therefore, the excellent pharmacological properties of the novel compounds of the invention will be surprising to a person skilled in the art.

It has now been found that the novel compounds of general formula (i) and their salts have valuable biological properties and can be used mainly as hypnotics.

Some of the compounds of general formula (i) produce a dose-dependent anesthetic effect when administered intravenously in a number of animal species, the duration and depth of which can be adjusted within relatively wide limits. Thus, a significant advantage of the compounds of the present invention over currently used intravenous anesthetics is that there is only slight prenarcotic tension prior to surgical anesthesia and that the post-anesthetic neurological depression lasts much shorter than with known intravenous hypnotics. The anesthesia range of the compounds of the invention is also preferred, resulting in low respiratory and cardiotoxicity. These compounds can be used in therapy primarily as intravenous hypnotic agents in the form of injectable preparations for short-term surgical anesthesia.

Some of the compounds of the invention have a hypnotic and anesthetic-enhancing effect which is evident in various animal species when administered orally. As shown by electroencephalographic experiments, these compounds inhibit the activity of the stanal awakening system (formatio reticularis) and, unlike barbiturates, do not cause other branches in the spasm potential. Experimental animals can be aroused by an external stimulus during anesthesia because the hypnotic activity induced by these compounds in many respects resembles physiological sleep. These compounds have a low toxicity, a good absorption capacity, a rapid development of hypnotic activity and no decrease in long-term treatment, and thus have almost no tendency to become accustomed. Due to their beneficial properties, these compounds can be used in the treatment of oral hypnotics, mainly for the symptomatic treatment of neuropathic insomnia. These compounds can be administered, for example, in the form of tablets or capsules, preferably in a daily dose of 0.1 to 2.0 g. The actual dose depends on the age, pathological conditions and individual sensitivity of the patient to be treated.

Tables 1-3 show the results of pharmacological experiments performed with the novel compounds of the invention. These tables give the acute toxicity, hypnotic activities, and anesthetic-enhancing effects of the various compounds. The methods used in pharmacological experiments are described in the following references:

Litchfield and Wilcoxon: J. Fharm. Exp. Ther. 96, 99 (19-8);

Borsi: Arch. Int. Pharmacodyn, 126, 1 + 26 (1969) j

Dement and KLeitman: EEG Clin, Neurophysiol. 9, 673, (1957);

Faulconer and Bickford: Electroencephalography in Anesthesiology (Ch. Thomas Pubi., Springfield, III, i960).

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It can be seen from the above tables that of the compounds shown, 2- (2,6-dichlorophenyl) -hydrazine-5-methyl-2-thiazoline hydrochloride can be used primarily as an intravenous anesthetic, while 2- (2,6-dimethyl-phenyl) -hydrazine-2 -thiazoline hydrochloride can be used as an oral hypnotic agent with favorable absorption properties.

The novel compounds of general formula (i) can be used very advantageously in therapy in the form of their pharmaceutically acceptable, non-toxic acid addition salts. Of the salts, mention may be made, for example, of hydrochlorides, fumarates and tartrates.

The novel compounds can be processed into pharmaceutical preparations, e.g. tablets, coated tablets, pills, capsules, syrups, elixirs or injectables in known ways by mixing them with customary pharmaceutical carriers, diluents and / or excipients.

"If necessary, the pharmaceutical preparations can be sterilized.

The novel compounds of lava (I) can be prepared according to the invention as follows: a) According to general formula (II)

Ru / X -NH-NH-C-NH-R. (il) R 3 R 2 is a thiocarbazide in which R 8, R 1 and R 2 are as defined above and is a 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or allyl group, is cyclized optionally in the presence of a strong acid, or b ) an R * / P 2 -NH-NH-C-NH 9 (III) R 3 r 23 thiosemicarbazide of the general formula (IIIi) in which R 8, R 2 and R 2 are as defined above is reacted with a Y 1 of the general formula (IV) -CH- (CH2) n-NH2-HY (IV) f

R

with a compound in which R and n have the same meaning as above and Y is β 57942 halogen atom ·

If desired, any of the free bases of formula (i) may be converted into their pharmaceutically acceptable acid addition salts, or bases may be liberated from their acid addition salts if necessary.

According to a particularly preferred embodiment of process variant a), the thiosemicarbazide of the general formula (II) is boiled in an aqueous solution of a mineral acid. As the mineral acid, hydrochloric acid can be used primarily, but other acids can be used as well. The acid can also be added as an aqueous-alcoholic solution. If necessary, the reaction mixture is concentrated and the final product is isolated by basifying the mixture as such or by concentration. The compounds of general formula (I) are separated either as crystalline solids or as oily substances. In the latter case, the products can be isolated by extraction and possibly purified by crystallization.

Process variant b) of the invention is preferably carried out by reacting sonicarbazides of general formula (IIi) with compounds of general formula (IV) in dimethylformamide in a water bath at a temperature of about 100 ° C. The reaction mixture is concentrated, if necessary, and the mixture is taken as such or concentrated to isolate the product basic.

The starting materials of general formula (II) can be prepared by known methods. The method of preparation depends on the nature of the group. For example, in the preparation of a compound of general formula (II) having an allyl group, the appropriate arylhydrazine is reacted with an allyl isothiocyanate (see Beilstein's Handbuch Uth ed., Vol. XV, p. 295; Verlag Springer, Berlin, 1932 ).

Compounds of general formula (II) in which R 1 is a hydroxy-alkyl group may be prepared by reacting the appropriate thiocarbazyl chloride or methyldithiocarbate (prepared from the appropriate aryl hydride) with an amino alcohol.

The thiosemicarbazides of the general formula (II) used as starting materials can also be prepared by reacting the salts of the corresponding arylhydrazines with rhodanides (Liebigs Annalen der Chem. 212, 32k / 1882]). Haloalkylamines of general formula (IV) can also be prepared by known methods (Org. Synth. Coll. Vol. II, p. 91).

The invention is illustrated in detail by the following examples.

Example 1 2- (2,6-Dichlorophenyl) -hydrazine-5-methyl-2-thiazoline hydrochloride

A mixture of 1 g of 1- (2,6-dichlorophenyl) -1+ -allylthiosemicarbazide, 270 ml of concentrated hydrochloric acid and 800 ml of ethanol is boiled for 2 hours. The solution is concentrated in vacuo to a volume of 300 ml, the concentrated solution is cooled, diluted with 200 ml of ice water and basified with concentrated ammonia.

9 57942 This gives off a syrupy substance which gradually solidifies. The substance is dissolved in chloroform, the chloroform solution is washed with water, dried over sodium sulfate, and the solvent is evaporated in vacuo. 39 g of crude 2- (2,6-dichlorophenyl) hydrate, 5-methyl-2-methyl-2-thiazoline are obtained; mp. 105-107 ° C. The product melts at III + -166 ° C after first treatment with acetone.

The crude base obtained is dissolved in 370 ml of benzene, and a chlorohydric acid / ethanol solution is added to the solution under cooling. 35 g of crude hydrochloride are obtained * m.p. 2k2-2k3 ° C. The hydrochloride melts at a temperature of 21 + 3-2l + 1 + uC from a mixture of ethanol and ether (1: 1) ten times.

Analysis:

Calculated for C1QH11N3SC12-HCl (312.35): C 38.1 + 7%, H 3.81+% tn 13.1 + 5% 3 S 10.21+%, Cl 31 +, 05% Found: C 38.62%, H 1 +, 01%, N 13.39%, S 10.33%, Cl 3h vol%

In a similar manner the following salts are prepared: 2- (2,6-dichlorophenyl) -hydrazine-5-methyl-2-thiol sol-fumarate; mp. 180-118 ° C (recrystallized from ethanol).

Analysis:

Calculated for c 10 H 11 N 3 SCVCl + H 1 + 01 + (391.90): C 1 + 2.87%, H 3.82 f, N 10.72%, S 8, ΐβ!, Cl 18.09% Found: C 1 +3.03% t H 3.95%, N 10.52%, S 8.1 + 0%, Cl 18.72% 2- (2,6-dichlorophenyl) -hydrazine-5-methyl- 2-thiazoline tartrate m.p. 135 ~ 137 ° C (recrystallized from ethanol).

Analysis:

Calculated for C 10 H 11 N 3 SCl 2 * CitH 6 O 6 (1 + 25.90): C 39.1 + 1 *%, H 3.99%, N 9.86 *, S 7.51 *, Cl 16.65% Found: C 39 , 37% t H 1 +, 05 N 9.81+% ys 7.61%, Cl 16.70%.

The starting material, 1- (2,6-dichlorophenyl) -N + -allylthiosemicarbazide, is prepared as follows: 71 +, 1 + g of 2,6-dichlorophenylhydrazine are dissolved in 500 ml of chloroform, and the solution is added with stirring and cooling over 0.5 hours in small portions. in portions a solution containing 1 + 3.5 g of allyl isothiocyanate in 200 ml of chloroform. The mixture is stirred at room temperature for several hours and then boiled for 30 minutes. The mixture is cooled with ice water and the separated product is filtered off. 88.8 g of crude 1- (2,6-dichlorophenyl) -N + -allylthiosemicarbazide are obtained; mp. 175-176 ° C.

The product, melted from anhydrous ethanol, melts at a temperature of 178-180 ° C.

10 5 79 4 2

Example 2 2- (2,6-Dichlorophenyl) -hydrazine-2-thiazoline hydrochloride

A mixture of 7.2 g of 2,6-dichlorophenylthiosemicarbazide, 7.5 g of 2-aminoethyl bromide hydrobromide and 60 ml of dimethylformamide is stirred for 6.5 hours on a steam bath (100 ° C). The solvent is evaporated off under vacuum, 50 ml of water are added to the residue and the aqueous mixture is basified with aqueous ammonia while cooling the mixture. The separated base is dissolved in chloroform, the chloroform solution is dried over sodium sulfate, and the solvent is evaporated in vacuo. The obtained 1), 6 g of 2- (2,6-dichlorophenyl) -hydrazine-2-thiazoline are dissolved in 25 ml of benzene, the hydrochloride is mixed under cooling with an ethanolic solution of hydrochloric acid. * (8.8 g of 2- (2,6-dichlorophenyl) -hydrazine-2-thiazoline hydrochloride are obtained; mp 2k-2k2 ° C (with decomposition). Recrystallized from a mixture of ethanol and ether (1: 1), the product melts with decomposition 2i At a temperature of + 2-2U3 ° C.

Analysis:

Calculated for C 12 H 18 Cl 2 O 2 HCl (298.35) C 36.19%, H 3.36% t N lit, 07% t S 10.73%, Cl 35.65% Found: C 36.1 * 2%, H 3.61%, N lit, 17%, S 10.71%, Cl 35.28%

By operating as described above, but using 2-aminoisopropyl bromide hydrochloride as a reagent, 2- (substituted phenyl) -hydrazine-5-methyl-thiazoline derivatives such as 2- (2,6-dichlorophenyl) -hydrazine-5- methyl-2-thiazoline, m.p. 11-116 ° C, yield 60% hydrochloride, m.p. 2lt3-2ltlt ° C; fumarate, m.p. L80-L8L ° C; tartrate, m.p. 135 ~ 137 ° C.

The starting material, 2,6-dichlorophenylthiosemicarbazide, is prepared as follows:

A mixture of 21 .mu.g of 2,6-dichlorophenylhydrazine hydrochloride, 7.7 g of ammonium rhodanide and 260 ml of absolute ethanol is stirred and refluxed for 6 hours, and then the mixture is cooled to room temperature. The separated product is filtered off, 150 ml of water are added and the mixture is boiled. 18 g of 2,6-dichlorophenylthio emicarbazide are obtained, m.p. 222-223 ° C.

Example 3 2- (2,6-Dichlorophenyl) -hydrazine-2-thiazoline hydrochloride

A mixture of 2 g of 1- (2,6-dichlorophenyl) -U- (2-hydroxyethyl) thio-semicarbazide, 12 ml of concentrated hydrochloric acid and 36 ml of ethanol is boiled for 2.5 hours. The ethanol is evaporated in vacuo, the residue is cooled, diluted with 20 ml of ice water and basified with concentrated ammonia. The separated syrupy product is dissolved in chloroform, the chloroform solution is dried over sodium sulfate and the solvent is evaporated in vacuo. The obtained 1.8 g of crude 2- (2,6-dichlorophenyl) -hydrazine-2-thiol is dissolved in 15 ml of benzene, and the hydrochloride is precipitated with an ethanolic solution of hydrochloric acid under cooling. 0.6 g of 2- (2,6-dichlorophenyl) -hydrazine-2-thiazoline hydrochloride is obtained; mp. 2Ul-2U2 ° C (dec.). Recrystallized from a mixture of 11 57 9 4 2 ethanol and ether (1: 1), the product melts with 2 l + 2-2 l + 3 ° C with decomposition.

The structure and physical properties of the product obtained are the same as those of the product prepared according to Example 2.

The starting material is prepared as follows: a) Methyl ester of 2,6-dichlorophenyldithiocarbazine bap 6.3 g of carbon disulphide are added in small portions over 10 minutes to a mixture of 11 g of 2,6-dichlorophenylhydrazine and 120 ml of ethanol at room temperature. 2,6-Dichlorophenyldithiocarbazine acid is already separated when the reagent is added. A solution of 3.7 g of potassium hydroxide in 8 ml of water is added to the mixture over 5 minutes with stirring at room temperature, then the mixture is stirred at 1 + 0 ° C for 2 hours. The 2,6-dichlorophenyldithiocarbazate thus formed redissolves. 8.8 g of methyl iodide are then added to the mixture over 10 minutes, and the mixture is stirred at room temperature for 1 hour. The separated product is filtered and washed twice with 20 ml of water. 11 + 1. g of methyl 2,6-dichlorophenyldithiocarbazate are obtained; mp. ll-ll + 0 * 2 ° C.

If desired, potassium 2,6-dichlorophenyldithiocarbazate (m.p. 161 + -166 ° C) can be separated from the reaction mixture by diluting the mixture with 150 ml of ether before adding methyl iodide.

b) 1- (2,6-Dichlorophenyl) -1- (2-hydroxyethyl) -thiosemicarbazide A mixture of 1 (.3 g of methyl 2,6-dichlorophenyldithiocarbazate, 10 ml of 2-aminoethanol and 60 ml of ethanol). , reflux for 5.5 hours, cool and pour into 200 ml of water to give a syrupy substance which gradually solidifies to give 1- (2,6-dichlorophenyl) -β- (2-hydroxyethyl) -thiocarbazide filtered, washed twice with 20 ml and triturated with 10 ml of ethanol to give 2.3 g of product, mp 195 DEG-19 DEG C.

Example 1+ 2- (U-Nitrophenyl) -hydrazine-5 * methyl-2-thiazoline

The procedure described in Example 2 is repeated except that 1- (2,6-dichlorophenyl) -U-allylcarbazide is replaced by 1- (1+ -nitrophenyl) -U-allylthiosemicarbazide. The product obtained melts at 128-130 ° C (recrystallized from a mixture of ethanol and petroleum ether (1: 1)).

Analysis:

Calculated for C 12 H 23 N 2 O 2 (252): C 1 + 7.62%, H 1 +, 75%, N 22.23%, S 12.69% Found: C 1 + 7.75%, H 1 +, 81 N 22.08% t S 12.75% · The starting material, 1- (U-nitrophenyl) -β-allylthiosemicarbazide, is prepared as described in Example 1 (see Preparation of starting material) with the difference that 2,6-dichlorophenylhydrazine is replaced by 1 + -nitrophenylhydrazine . The product obtained is boiled in ethanol; the substance obtained melts at a temperature of 192-193 ° C · 57942 12

Example 5 2- (2,6-Dimethylphenyl) -hydrazine-2-thiazoline hydrochloride

The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosemicarbazide is replaced by 2,6-dimethylphenylthiosemicarbazide. The product obtained melts at 234-236 ° C with decomposition (recrystallized from a mixture of ethanol and ether (1: 1)).

Analysis:

Calculated for C 11 H 19 SCl (257.45): C 51.27%, H 6.22% t H 16.32%, S 12.43%, Cl 13.77% Found: C 51.26 %, H 6.11%, H 16.15%, S 12.31%, Cl 13.68% The starting material, 2,6-dimethylphenylthiosemicarbazide, is prepared as described in Example 2 (see Preparation of starting material) with the difference that 2.6- dichlorophenylhydrazine hydrochloride is replaced by 2,6 dimethylphenylhydrazine hydrochloride. The product obtained melts at 186-188 ° C (triturated with ethanol).

Example 6 2- (2,6-Dichlorophenyl) -hydrazine-5-methyl-2-thiazoline hydrochloride

The procedure described in Example 3 is repeated except that 1- (2,6-dichlorophenyl) -4- (2-hydroxyethyl) -thio semi-carbazide is replaced by 1- (2,6-dichlorophenyl) -4- (2-hydroxypropyl) H; iosemikarbatsidilla. The product obtained melts at a temperature of 242-243 ° C (crystallized from a mixture of ethanol and ether (1: 1)) and has the same structure and physical properties as the product prepared according to Example 1.

The starting material, 1- (2,6-dichlorophenyl) -4- (2-hydroxypropyl) -thiosemicarbazide, is prepared as described in Example 3 (see Preparation of starting material) with the difference that 2-aminoethanol is replaced by 1-amino-2-hydroxypropane. After recrystallization from ethanol, the product melts at 178-180 ° C.

Example 7 2- (2,6-Dichlorophenyl) -hydrazine-4H-5,6-dihydro-1,3-thiazine hydrochloride

The procedure described in Example 3 is repeated except that 1- (2,6-dichlorophenyl) -4- (2-hydroxyethyl) -thiosemicarbazide is replaced by 1- (2,6-dichlorophenyl) -4- (3-hydroxypropyl) -tiosemikarbatsidilla. The title compound melts at 229-230 ° C (recrystallized from a mixture of ethanol and ether (1: 1). The petroleum treated with ether gives the free base at 114-115 ° C.

Analysis:

Calculated for C 18 H 18 N 2 O 3 SCl 3 HCl (312.35): C 38.47 J 6, H 3.84% t N 13.45%, S 10.24%, Cl 34.05%.

Found: c 38.58%, H 4.00%, N 13.27%, s 10.4l 36, Cl 34.23% is 5 79 4 2 Starting material, 1- (2,6-dichlorophenyl) -1+ - (3-hydroxypropyl) -thiosemicarbazide, prepared as described in Example 3 (see Preparation of starting material) with the difference that 2-aminoethanol is replaced by 3-aminopropanol. The product obtained after recrystallization from ethanol melts at a temperature of 189 ~ 190 ° C *

Example 8 2- (2,1 +, 6-Trimethylphenyl) -hydrazine-2-thiazoline hydrochloride The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosemicarbazide is replaced by 2, H, 6-trimethylphenylthiosemicarbazide. The product obtained after recrystallization from a mixture of ethanol and ether (1: 1) melts at 222-221 + c '' Cjn with decomposition.

Analysis:

Calculated Mica (271.1 + 5): C 53.05% t H 6.63 %% N 15.1 + 7 S 11.79% t Cl 13.06% Found: C 52.96%, H 6, 37%, N $ 15.53, s 11.97%, Cl 12.91+% The starting material, 2.1+, 6-trimethylphenylthiosemicarbazide, is prepared as described in Example 2 (see Preparation of starting material) with the difference that 2.6 -di-chlorophenylhydrazine hydrochloride is replaced by 2,1+, 6-trimethylphenylhydrazine hydrochloride and the mixture is boiled for 12 hours. The product obtained melts at 207-209 ° C with decomposition.

Example 9 2- (3-Trifluoromethylphenyl) -hydrazine-2-thathioline hydrochloride The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosemicarbazide is replaced by 3-trifluoroethylphenylthiosemicarbazide. Recrystallized from a mixture of ethanol and ether. 1: 1) the product obtained melts at 203-20 l at + ° C with decomposition.

Analysis:. Calculated for · HCl (297.1 + 5): C 1 + 0.31 +%, H 3.69%, N 11 +, 12%, S 10.76% t Cl 11.91% t F 19, 16% Found: C 1 + 0.56% t H 3.89%, N 13.96%, S 10.68% t Cl 11.79%, f 18.99% The starting material, 3-trifluoromethylphenylthiocarbazide, is prepared as described in Example 2 (see Preparation of starting material) except that 2,6-dichlorophenylhydrazine hydrochloride is replaced by 3-trifluoromethylphenylhydrazine hydrochloride and the mixture is boiled for 12 hours. The obtained product melts at 199 ~ 200 ° C with decomposition.

Example 10 2- (2,3-Dimethylphenyl) -hydrazine-2-thiazine hydrochloride The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosemicarbazide is replaced by 2,3-dimethylphenylthiosemicarbazide.

11 57942

The product obtained from a mixture of ethanol and ether (1: 3) melted at 225-227 ° C.

Analysis:

Calculated for C 12 H 12 N 2 · HCl (257.81): C 51.30%, H 6.21+% tn 16.30% t S 12.1 + 0%, Cl 13.75% Found: C 51.1 + 8% t H 6.36%, N 16.2U S 12.1 + U% t Cl 13.68% The starting material, 2,3-dimethylphenylthiosemicarbazide, is prepared as described in Example 8 (see Preparation of starting material) with the difference that 2,1 +, 6-trimethylphenylhydrazine hydrochloride is replaced by 2,3-dimethylphenylhydrazine hydrochloride. The product obtained decomposes at a temperature of 168-170 ° C.

Example 11 2- (2,5-Dimethylphenyl) -hydrazine-2-thiol soline hydrochloride The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosicarbazide is replaced by 2,5-dimethylphenylthiosemicarbazide and the residue obtained after evaporation of the chloroform solution dissolved in 200 ml of a mixture of benzene and ether (1: 6); the product obtained decomposes at 222-22U ° C. Analysis:

Calculated for C 18 H 18 S-HOl (257.81): C 51.30%, H 6.2 + +, N 16.30%, S 12.1 + 0%, Cl 13.75% Found: C 51.31% t H 6.29%, N 16.38% t S 12.32%, Cl 13.70% The starting material, 2,5-dimethylphenylthiosemicarbazide, is prepared as described in Example 8 (see Preparation of starting material) with the difference that 2,1 +, 6-trimethylphenylhydrazine hydrochloride is replaced by 2,5-dimethylphenylhydrazine hydrochloride. The obtained product decomposes at 205 ~ 207 ° C.

Example 12 2- (2-Methyl-6-chlorophenyl) -hydrazine-2-thiazoline hydrochloride The procedure described in Example 2 is repeated except that 2,6-dichlorophenylthiosemicarbazide is replaced by 2-methyl-6-chlorophenylthiosemicarbazide. After recrystallization, the product obtained from a mixture of ethanol and ether (1: U) decomposes at a temperature of 2 »+ 5-2i + 70C.

Analysis:

Calculated for c 10 H 12 N 3 SCl, HCl (278.22): C 1 + 3.15 X, HU, 72 X, N 15.11 X, S 11.53% t Cl 25.50% Found: C 1 + 3.13 % t H) +, 90%, N 15.06% t S 11.1 + 5%, Cl 25.37%.

57942 The starting material, 2-methyl-6-chlorophenylthiosemicarbazide, is prepared as described in Example 8 (see Preparation of starting material) with the difference that 2,6-trimethylphenylhydrazine hydrochloride is replaced by 2-methyl-6-chlorophenylhydrazine hydrochloride. The product obtained decomposes at 211 ° C.

Example 13 2- (2,4-Dichlorophenyl) -hydrazine-5-methyl-2-thiazine hydrochloride

The procedure described in Example 1 is repeated except that 1- (2,6-dichlorophenyl) -4-allylsemicarbazide is replaced by 1- (2,4-dichlorophenyl) -4-allylthiosemicarbazide. Recrystallized from a mixture of ethanol and ether (1: 1), the product decomposes at 221-223 ° C.

Analysis:

Calculated for C 21 H 21 SCl 2 O 3 (312.68): C 38.45%, H 3.86%, N 13.42% t S 10.24% t Cl 34.05% Found: C 38, 60%, H 3.99%, N 13.23 l, S 10.18%, Cl 33.96% Starting material, 1- (2,4-dichlorophenyl) -4-allylthiosemicarburide, prepared st et as described in Example 1 (see Preparation of starting material) with the difference that 2,6-dichlorophenylhydrazine is replaced by 2,4-dichlorophenylhydrazine. The product obtained melts at 142 ° C.

Claims (1)

ie 57942 Patents: A process for the preparation of a compound of general formula (I) or a pharmaceutically acceptable acid addition salt thereof for use as a hypnotic and anesthetic enhancer, A 1 V 3 ”~ NH _ NH ~ c CH_fi (d R3 ^" R2 wherein R is a hydrogen atom or a methyl group, n is 1 or 2, and R 2, R 1 and R 2 are hydrogen or halogen atoms, nitro, trifluoromethyl or methyl groups, provided that when n is 1, R 1 is a methyl group and R 1 is a hydrogen atom or a methyl group, R 1 and R 2 cannot be hydrogen atoms, characterized in that a) R 1, / N-NH - NH - C - NH - R (II) S R 3 H 2 thiosemicarbazide of the general formula (II) in which R 2 , R 1 and R 2 are as defined above, and R 1 is a 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl or allyl group, optionally cyclized in the presence of a strong acid, or b) according to the general formula (lii)? - UH - o -> H2 (III) R3 R2 S is a semicarbazide in which R2, R2 and R2 are as defined above, by heating to react with a compound of general formula (IV) 57942 IT Υ - CH - (CH 2) n --NH 2 · HY (IV) R wherein R and n are as defined above and Y is a halogen atom; and, if desired, converting the base of general formula (i) into a pharmaceutically acceptable acid addition salt thereof, or liberating the base of general formula (i) from its salt. ✓ ib 57942 latent kr av: Förfarande för framställning av en förening med den allmänna formuleln (I) fvandning som et hypnotic och narcos-potentierande medel A A ΐ% '"\ v V-NH - NH - C UH-R A < = A A- 'R3 R2 color R is for a hydrogen atom or a methyl group, n is 1 or 2, and R1, R1 and R3 are och and a hydrogen atom, a nitro, trifluoromethyl or methyl group, under the heading 1 or 1, R a starch having a methyl group and an R 2 is a compound or a methyl group, or a starch of the present invention, or a pharmaceutical form having the same name, the subject of the present invention all of the formula (II) Ru // \ -NH - NH - c - NH - R (II) , 2-hydroxypropyl-, 3-hydroxypropyl-, or allyl groups, rings are optionally added to the starch mixture, or b) en thiosemicarbazides with all of the formulas (lii) ΐ \ -NH - NH - C - N HQ (III) A ^ r "s R3 R2 color R ^, R ^ och R