CS229100B1 - Method of preparing 6-aryl-8-chloro-1-piperazinomethyl-4h-s-triazolo/4,3-a/-1,4-benzodiazepines and salts thereof with fumaric acid - Google Patents

Description

The invention relates to a process for the preparation of 6-eryl-8-chloro-1- (piperazinomethyl) -4H-8-trlezolo (4,3-a) -1,4-benzodiazepines of the general formula I,

2 wherein R is methyl or the radical R -X- (CH ₂ ) _n -, wherein R is methyl, ethyl or phenyl,

X is an oxygen or sulfur atom, β is 2 or 3, and R * represents a hydrogen atom or a chlorine atom, and their salts and fumaric acid.

The compounds of formula I and their fumarates are characterized by neurotrophic and psychotropic efficacy which make them useful in neurology and psychiatry. They have centrally depressant and anticonvulsant efficacy, which can be demonstrated in animal tests, which is hereinafter referred to for two typical substances of the invention.

8-Chloro-6- (2-chloro-phenyl) -1- (4-methyl-piperazino) -tetyl-4H-triazolo (4,3-a) -1,4-benzodiazepine was pharmacologically tested as a sesquifumarate. It was administered orally. Its acute toxicity in mice is low, LDjq = 635 mg / kg. It is highly effective centrally depressant in evaluating the inhibition of mouse locomotor activity by the beam method) a dose of 10 mg / kg attenuates locomotor activity to approximately 30% of the control value. Its discoordination effect is relatively mild; in the rotating rod test, the mean effective dose ED50 = 25.9 mg / kg. The substance is highly potent anticonvulsant in the maximum electro-eye test in mice; the mean protective dose in this test is ΡΏ ^ θ = 1.23 mg / kg. At a dose of 1 mg / kg, it significantly reduces the lethal dose of pentetrazole in mice.

8-chloro-6- (2-chlorophenyl) -1- [4- (2-methoxyethyl) piperazino] methyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine was also tested as sesquifumarate s was also administered orally. Acute toxicity in mice, LD ^ q = 721 mg / kg. Antispasmodic efficacy in the electroshock test in mice; PD ₅₀ is approximately 1 mg / kg.

Most of the compounds of formula I are novel. Specifically (ie in terms of preparation method and physical and pharmacologic properties) a single substance has been described, ie 8-chloro-6-phenyl-1- (4-methylpiperazino) methyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine. It was obtained by substitution reactions of 1-methylpiperazine with 6-phenyl-8-chloro-1-chloromethyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine (Hester JB Jr. et al., J. Med Chem 23, 392,

1980). on the one hand, with 1-tarommethyl-6-phenyl-8-chloro-4H-s-triazolo [4,3-e] -1,4-benzodiazepine (NSR Publication 2,559,242; Chem. Abstr. 78, 72,239, 1973) . the starting 6-phenyl-1-halomethyl-8-chloro-4H-s-triazolo (4,3-a) -1,4-benzodiazepines had to be prepared in several steps from the known 5-phenyl-7-chloro-1, 3-dihydro-1,4-benzodiezepin-2-thione.

It has now been found that compounds of formula I can be prepared in a single step by reacting 5-aryl-7-chloro-1,3-dihydro-1,4-benzodlazepin-2-thiones of formula II,

wherein r 'denotes the same as in formula I, with the piperezinoacethydrazides of formula III,

R — l £ £ ^ ^{CHCH CONCONH} ~ ^NH 2 _(iii) wherein R is also the same as in Formula I.

The reaction is carried out by heating compounds II and III to temperatures of 00 to 170 ° C in suitable solvents which do not enter into the reaction with the reaction components. Suitable are, for example, aliphatic alcohols having 4 to 7 carbon atoms or pyridine bases having a m.p. Preferably boiling 1-butanol can be used as the medium as described in the examples. The starting thiones of formula II are known (Archer GA, Sternbach LH, J. Org. Chem. 22, 231, 1964; Hester, JB et al., J. Med. Chem. JI, 1078, 1971; Vejdělek Z. et al., Collect. Czeeh. Chem. Commun. 48, 123 (1983).

Of the hydrazides of formula III, only a substance with R = CH3, i.e. 2- (methylpiperazino) acethydrazide, is known (Massarani E. et al., J. Med. Chem. 14, 633, 1971: Switzerland, p. 47, 3,826; Chem 72, 21 712, 19701. The others are novel and the methods for their preparation are described in the examples, and a new and technically advantageous process for the preparation of the compounds of formula I is the object of the present invention.

The identity of all the novel compounds described in the invention, i.e. the end products of formula I as well as the intermediate product, was ensured by means of β-spectrum analyzes. The following examples are intended to illustrate the possibilities of the invention, but the invention is not limited thereto.

Example 1

6-Phenyl-8-chloro-1- (4-methylpiperazino) methyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine

A mixture of 2.9 g of 5-phenyl-7-chloro-1,3-dihydro-1,4-benzodiazepin-2-thione, 1.7 g of 2- (4-methylpiperazino) acethydrazide and 50 ml of 1-butanol is stirred and Boil under reflux for 4 hours.

After standing overnight, butanol is evaporated under reduced pressure, the crystalline residue is dissolved in 30 ml of ethanol. The β solution is filtered with carboraffin. The filtrate is again evaporated and the residue is crystallized by dissolving in 15 ml of ethanol with the addition of 15 ml of cyclohexane. After suctioning off the precipitated product, the mother liquor is worked up by evaporation in vacuo and crystallization of the residue from a mixture of 5 ml of cyclohexene and 1 ml of benzene. In total, 3.1 g (72%) of the desired glass melting point of m.p. 201 DEG-205 DEG C. is obtained. (References cited from 203 to 208 ° C). Neutralization of the base with fumaric acid in ethanol and addition of ether gives a crystalline fumarate melting at 144-149 ° C (ethanol).

Example 2

8-Chloro-6- (2-chlorophenyl) -1- (4-methylpiperazino) ipetyl-4H-s-triezolo (4,3-a) -1,4-benzodiazepine

A mixture of 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-thione, 3.45 g of 2- (4-methylpiperazino) acethydrazide and 80 ml of 1- of butanol was stirred and refluxed for 8 hours. After standing overnight, the mixture was warmed with carboraffin, filtered and the butanol was evaporated in vacuo. The residue is dissolved in 50 ml of benzene, filtered through a column of 40 g of neutral alumina (activity II), which is washed with 160 ml of benzene.

Evaporation of the filtrate gave 8.2 g of a crude oil which slowly crystallized from solution in 20 ml of benzene by addition of 10 ml of hexane. After standing in the refrigerator for 2 days, the precipitated product is filtered, washed with hexane and dried. 5.0 g (57%), mp 175-176 ° C (benzene-hexane). Neutralization with fumaric acid in aqueous ethanol yields a crystalline sesquifumaret, melting at 220-225 ° C with decomposition. Similarly, neutralization with oxalic acid in aqueous ethanol yields an oxel which crystallizes as a sesquihydrate and melts at 207 DEG-209 DEG C. with decomposition.

Example 3

8-chloro-6- (2-chlorophenyl) -1- [4- (2-methoxyethyl) piperazino] methyl-4H-s-triezolo (4,3-a) -1,4-benzodiazepine

A mixture of 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-thione, 4.5 g of 2- / 4- (2-methoxyethyl) piperazino / acethydrazide 8 70 ml of 1-butanol are stirred and refluxed for 5 hours. The residue obtained by evaporation in vacuo is dissolved in a small amount of chloroform and chromatographed on a 150 g silica gel column (Lachema 100/160). Elution with chloroform alone yields 0.5 g of the starting thion.

Elution with chloroform containing 2 X methanol gave 5.4 g (57 X) of a homogeneous desired product. Neutralization without fumaric acid in ethanol and addition of ether gives a crystalline sesquifumaret which melts at 213-216 ° C (aqueous ethanol) in the pure state. Similarly, by neutralizing the base with oxalic acid in aqueous ethanol, crystalline dioxallate monohydrate is obtained, melting at 207-210 ° C.

The starting 2- [4- (2-methoxyethyl) piperazino / ethyl acetide] is a novel compound which can be prepared as described above in two steps from 1- (ethoxycarbonylmethyl) piperazine (Braker W.

229,00

Christiansen W.O., J. Amer. Pharm. Assoc. 22, 950, 1933: Barrett P.A. et al., J, Chem.

Soe. 1961. 2,404} Brit. U.S. Pat. 921,315) and 2-methoxyethyl bromide (Falomea, H., Kenetti A.,

Ber. Deut. Chem. Ges. (79., 1231) ·

A mixture of 25.8 g of 1- (ethoxycarbonylmethyl) piperazine, 150 ml of acetone, 23.5 g of 2-methoxyethyl bromide and 20.6 g of potassium carbonate is heated to reflux with stirring and refluxed for 6 hours. After standing the next day, the precipitated inorganic salts are removed by suction, the filtrate is evaporated, the residue is diluted with 100 ml of benzene and the solution is washed with water. After drying over magnesium sulphate and filtration with carboraffin, the solution is evaporated and the residue is distilled under reduced pressure.

There are obtained 15.0 g of (44 R) 2- / 4- (2-methoxyethyl) piperazino / oetene ethyl acetate, m.p. 120-130 ° C / 0.36 kPe. For characterization, a crystalline dimaleinate can be prepared by neutralization with maleic acid in ethanol, which crystallizes from ethanol and melts at 144-145 ° C.

A solution of 13.2 g of the preceding ester in 13 ml of ethanol was added dropwise to a solution of 3.25 g of 100® hydrazine hydrate in 15 ml of ethanol, and the mixture was refluxed for 8 hours.

After standing the next day, a small amount of the by-product precipitated is aspirated and the filtrate is baked under reduced pressure. The residue was diluted with 100 mL of benzene. The solution was washed with water, dried over magnesium sulfate and worked up by distillation.

10.0 g (80%) of the desired 2- / 4- (2-methoxyethyl) piperezino / acethydrazide, b.p. 160-163 ° C / 0.27 kPa, are obtained. The distillate solidifies to a low melting crystalline mass. For characterization, a crystalline trimalein ether melting at 136-127 ° C (methanol) can be prepared by neutralization with maleic acid in ethanol.

He attaches

8-chloro-6- (2-chlorophenyl) -1- [4- (3-methoxypropyl) piperezino] methyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine

As in the previous example ae, 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-13-benzodiazepin-2-thione 8 carried out 5.8 g of 2- / 4- (3- methoxypropyl) piperezino / acethydrazide in 70 ml boiling 1-butanol (9 h. boiling). A similarly isolated crude product is chromatographed on a 60 g silica gel column (Merck 60) and eluted with chloroform containing 2 ® methanol to give 9.6 g (96 ®) of a homogeneous oily desired base. Neutralization with fumaric acid in aqueous ethanol yields a crystalline sesquifumaret which melts with decomposition at 233-236 ° C.

The starting 2- / 4- (3-methoxypropyl) piperazino / acethydrazide used is a novel compound which can be prepared as described above in four steps from, -ethoxycarbonylpiperazine and 3-methoxypropyl bromide (Smith LI, Sprung JA, J. Amer. Soc. (276, 1943).

A mixture of 110 g of 1-ethoxycarbonylpiperezine, 96.1 g of potassium carbonate, 400 ml of dloxane and 106.4 g of 3-oetoxypropyl bromide is stirred at 90 ° C for 5.5 hours. After standing overnight, the precipitated enorgenic salts were filtered off and washed with dioxane. The filtrate was evaporated under reduced pressure, the residue was made alkaline with aqueous ammonia and extracted with dichloromethane. The extract was dried over potassium carbonate, evaporated and the residue distilled. 118.5 g of (74 ®) 1-ethoxycarbonyl-4- (3-methoxypropyl) piperezine are obtained, m.p. 99-111 ° C / 27 Pa. For characterization, crystalline hydrochloride can be prepared by neutralizing hydrogen chloride in a mixture of ethanol and ether, which crystallizes from a mixture of chloroform and ether at 144.5-145 ° C.

A mixture of 124.5 g of the previous base, 52 g of potassium hydroxide and 150 ml of ethanol was stirred and heated under reflux for 4 hours at 95 ° C (bath of 1.0 ° C). After partial cooling, the mixture is diluted with 300 ml of water, the ethanol is evaporated off under reduced pressure and the residue is extracted with chloroform. Working up the extract yielded 66.8 g of (78 ®) 1- (3-methoxypropyl) piperazine boiling at 94-98 ° C / 50 mbar. For characterization, a dihydrochloride can be prepared which crystallizes from a mixture of acetone and ethanol and melts at 210-212 ° C.

To a solution of 20.0 g of the previous base in 80 ml of ethanol was added 12.2 g of ethyl chloroacetate and 19 g of sodium bicarbonate, and the mixture was refluxed for 16 hours with stirring. The ethanol is evaporated off under reduced pressure, the residue is diluted with 50 ml of water and extracted with chloroform. The extract was washed with water, dried (MgSO4) and distilled. 20.0 g (82%) of 2- [4- (3-methoxypropyl) piperezino] ethyl acetate are obtained, boiling at 124-126 [deg.] C./20 mbar.

Similarly to the previous example, 17.7 g of the separated ester are reacted with 4.1 g of 100% hydrazine hydrate in 37 ml of boiling ethanol. 15.9 g of crystalline 2- [4- (3-methoxypropyl) piperazino] acethydrazide melting at 68 DEG-70 DEG C. (benzene-petroleum ether) is obtained. For characterization it is possible to treat triaaleinet, which crystallizes from ethanol β melts at 108 to 110 ° G.

Example 5

1- / 4- (2-ethoxyethyl) piperazino / methyl-8-chloro-6- (2-chlorophenyl) -4H-s-triezolo (4,3-a) -1,4-benzodiezepine

As in the previous example, 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-thione are reacted with 5.8 g of 2- [4 - ( 2-ethoxyethyl) piperazino / acethydrazide in 70 ml boiling 1-butanol (boiling 5 h). Similar work-up and chromatography of the crude product on 50 g of silica gel yielded 7.4 g (74%) of a homogeneous oily desired base. Neutralization with fumaric acid in ethanol and addition of ether gives a sesquifumarate which crystallizes from aqueous ethanol and melts with decomposition at 194 to 15 ° C.

The starting 2- / 4- (2-ethoxyethyl) piperezino / acethydrazide used is a novel compound which can be prepared as described above in two steps from 1- (ethoxycarbonylmethyl) piperazine and 2-ethoxyethyl bromide (Harrison GC, Diehl H., Org. Syn. Coll., Vol. J, 370 (1955).

Similar to Example 3 described for an analogous case, a reaction of 38 g was carried out

1- (ethoxycarbonyloethyl) piperazine with 38.2 g of 2-ethoxyethyl bromide in 200 ml of boiling acetone in the presence of 30 g of potassium carbonate. Analogous work-up gave 24.5 g (46%).

2- (4- (2-ethoxyethyl) piperazino) ethyl acetate boiling at 120-122 ° C / 0.27 kPa.

Similar to the previous examples, 24.0 g of the preceding ester are reacted with 5.7 g of 100% hydrazine hydrate in 50 ml of boiling ethanol (8 hours boiling). Working up gave 10.2 g (45%) of the required 2- [4- (2-ethoxyethyl) piperazino] acethydrazide, m.p. 140-147 [deg.] C / 0.27 kPa, which solidified on standing with a low melting crystalline solid. For characterization, trimaleineth can be prepared which crystallizes from ethanol and melts at 120-123 ° C.

Example6

8-chloro-6- (2-chlorophenyl) -1- [4- (2-methylthioethyl) piperazino] methyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine

As in the previous examples, 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-thione are reacted with 5.8 g of 2- / 4- ( 2-methylthioethyl) piperezino / acethydrazide in 70 ml of boiling 1-butanol (boiling for 10 h). Analogous work-up and chromatography of the crude product on silica gel gave 9.6 g (96%) of the desired base which crystallized from ethanol and melted at 158-160 ° C. Neutralization with fumeric acid in aqueous ethanol yields a crystalline sesquifumarate which melts with decomposition at 218-222 ° C.

The starting 2- / 4- (2-methylthioethyl) piperazino / acetic hydrazide used is a novel compound which can be prepared as follows in two steps from the known 1- (2-methylthioethyl) pipe 229100 razin (Steck EA, Org. Prep. Proced. Int.) 2 (1), 1975, Chem. Abetr., 83, 131,547, w ·

To a solution of 10.0 g of 1- (2-methylthioethyl) piperezine in 40 ml of ethanol was added 6.1 g of ethyl chloroacetate and 10 g of sodium bicarbonate and the mixture was refluxed for 16 h. After standing to the next day, the inorganic salts are filtered off, the filtrate is evaporated under reduced pressure, the residue is diluted with 40 ml of water and extracted with chloroform. The extract was worked up to give 7.4 g (60 µl) of 2- [4- (2-methylthioethyl) piperazine / ethyl acetate], m.p. 130-132 ° C / 0.27 kPa.

Similarly to the above examples, 7.4 g of the resolved ester are reacted with 1.7 g of 100% sodium hydrate in 15 l of boiling ethanol (8 hours boiling). Analogous work-up yielded 6.4 g of (91%) 2- [4- (2-methyltloethyl) piperazino] -etethrezide which crystallized from ethanol and melted at 79-81 ° C. Neutralization with maleic acid in ethanol yields a treleelein which is also at 119 to 121 ° C and is suitable for characterization of the substance.

Example 7

1- / 4- (2-Phenoxyethyl) piperezino / methyl-8-chloro-6- (2-chlorophenyl) -4H-s-trlezolo (4,3-e) -1,4-benzodlazepine

Similar to the previous examples, 6.4 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiphenyl-2-thione are reacted with 7.0 g of 2- - (2-Phenoxyethyl) piperezino / ethyl hydroside in 70 ml of boiling 1-butanol (6 h of boiling). Analogous workup and chromatography the crude product on silica gel afforded 10.4 g (95 *) without homogeneous oily desirable that neutralization of fumaric acid in ethanol and ether smésl provides crystalline melting at 167 aeskvifumarét EŽ 170 ^e C.

The starting 2- / 4- (2-phenoxyethyl) piperazino / acetic hydrazide used is a novel compound which can be prepared in two steps from 1- (ethoxycarbonylmethyl) plperesin and 2-phenoxyethyl bromide (Nerval CS, Tanenbeum Α »L., Org) Syn., Coll. Vol. 1, 435 (1932). Similar to Example 3 described for an analogous case, 34.4 g of 1- (ethoxycarbonylmethyl) plperazine are reacted with 40.6 g of 2-phenoxyethyl bromide in 200 ml of boiling acetone in the presence of 30 g of anhydrous potassium carbonate. Analogous workup afforded 31 g (53%) of 2- [4- (2-phenoxyethyl) piperazinyl] ethyl acetate, boiling at 160-165 [deg.] C./20 mm Hg.

Similarly to the previous examples, 20.0 g of the separated ester are reacted with 4.0 g of 100% hydrazine hydrate in 35 ml of boiling ethanol (8 h). Analogous work-up gave 10.7 g of (56%) 2- [4- (2-phenoxyethyl) piperazino] -beta-hydrazide, which crystallized from a mixture of benzene and hexane and melted at 83.5-84.5 ° C.

Example

1- [4- (2-Phenylthioethyl) piperazino] methyl-8-chloro-6- (2-chlorophanyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine.

As in the previous examples, ee reacts 5.63 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-thione and 6.2 g of 2- / 4- ( 2-phenyltloethyl) piperazino / acethydrazide in 70 [mu] l of 1-butanol (10 h of boiling). Analogous work-up and chromatography of the crude product on silica gel yielded 2.7 g (27%) of a homogeneous oily desired product which, by neutralizing fumaric acid in ethanol / ether, gave a sesquifumyate crystallizing from aqueous ethanol and melting at 206-208.5 ° C.

The starting 2- / 4- (2-phenylthioethyl) piperazino / acetic anhydride used is a novel material which can be prepared in the following two steps from 1- (ethoxycarbonylmethyl) piperazine.

Ί and 2-phenylthioethyl bromide (Scherlln S. M., Jekubowitsch A. I., J. Prakt. Chem. (N. F.),

LE, 23, 1232).

In analogy to Example 3, 19.0 g of 1- (ethoxycarbonylmethyl) piperazine are reacted with 26 g of 2-phenylthioethyl bromide in 120 ml of boiling acetone in the presence of 16 g of anhydrous potassium carbonate. Analogous work-up gave 13.0 g (38%) of 2- [4- (2-phenylthioethyl) piperazino] ethyl acetate boiling at 170-180 [deg.] C / 0.3-0.4 kPa.

Similarly to the previous examples, 12.0 g of the preceding ester are reacted with 2.5 g of 100% hydrazine hydrate in 25 ml of ethanol (8 hours boiling). Analogous work-up yields 8.0 g of 2- [4- (2-phenylthioethyl) piperazino] acetafaydrazide which is oily but neutralizes with maleic acid in ethanol to give a crystalline dimaleine ether melting at 1118-120 ° C.

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of 6-aryl-8-chloro-1- (piperazinomethyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepines of formula I is methyl, ethyl or phenyl wherein R is methyl or the radical R-X- (CH ₂ ) _n X is an oxygen atom or a sulfur atom, n is 2 or 3 and R 'β of their fumaric acid salts, characterized in that 5-aryl-7-chloro-1 is 3-dihydro-1,4-benzodiezepin-2-thiones of formula II, wherein R '' is hydrogen or chlorine, (II) in which r 'is the same as in formula I, are reacted with formula III, piperezinoacethydrezidy R —NN—CH, CONH —NHj (III) in which R impurities are the same as those in the formula 1-butanol, and the resulting bases of formula I with the talc fumerates. I, at temperatures of 100 to 170 ° C, preferably in the boiling state are converted into fumaric acid by neutralization into a rat.