CS209898B2 - Method of making the new substituted 1-piperaziyl-4h-s-triazolo/ 3,4c/ thieno /2,3e/ -1,4-diazepines - Google Patents

Description

The present invention provides novel substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] -1,4 diazepines of formula I

in which

R ¹ represents a hydrogen atom, a straight or branched (C 1 -C 3) alkyl group, a (C 1 -C 2) haloalkyl, a (C 1 -C 3) hydroxyalkyl or a further C 1 -C 2 -alkylaminoalkyl group a methyl, methoxy, nitro- or halogen-substituted phenyl group, a pyridyl or pyrimidinyl group, or a radical of formula R ⁴ -CO-,

R ² represents a fluorine, chlorine or bromine,

R @ 1 represents a chlorine atom, a bromine atom or an alkyl group having 1 or 2 carbon atoms and

R ⁴ is hydrogen, C 1 -C 17 alkyl, C 1 -C 2 alkoxy, phenyl, halophenyl or pyridyl, processes for their preparation and their use as a catalyst ^; substances in pharmaceuticals.

Of the straight or branched alkyl groups having 1 to 17 carbon atoms, R ^{@ 4} is preferred, the corresponding groups having 1 to 6 carbon atoms are preferred.

The term "halogen" refers to fluorine, chlorine, bromine and iodine atoms.

By Dalkylaminoalkyl radical is meant dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylanomethyl.

The substituent on the phenyl ring may occupy the position o-, m- or p-.

The pyridyl residue may be attached to the nitrogen atom of the piperazine core by the 2, 3 or 4 position.

In accordance with the invention, the above-mentioned novel compounds can be prepared by hehydrogenating compounds of formula

II

in which

R ^1, R ² and R ³ are as defined above.

The dehydrogenation of the compounds of formula (II) is carried out using suitable dehydrogenating agents, such as halogens or compounds containing chromium or manganese in a higher oxidation stage, for example cromobromates, dibromites or maugau.

J ko suitable reaction for reacting with hacg · sulfopropyl are chlorinated ^{uh'ovodíky,:} ň'0 cbJoi Ionophores or mcthylonchlorid. ·Χιά. ·; The above chromium or manganese compounds are carried out in solvents such as acetone, tetrahydrofuran or dioxane. Depending on the oxidizing agent used; the reaction temperature is generally between 0 ° C and the boiling point of the solvent used.

As PK ^{1 is an} alkyl group as defined above, the corresponding compound of formula (I) in which R ¹ is a hydrogen atom may be alkylated in a conventional manner. Suitable alkylating agents are preferably the corresponding alkyl thiogonides, dialkylsulfates or toluenesulfonic acid esters. As solvents in this case, for example, tetrahydrofuran, dimethylformamide or lower alcohols are used, but the alkylation can also be carried out in the absence of a solvent.

In the case of introduction of a hydroxyalkyl radical, reaction with the corresponding alkylene oxidein is recommended.

The resulting products of formula (I) wherein R @ ¹ is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl as defined above, form stable water-soluble salts. For the preparation of salts, all acids forming physiologically compatible acid addition salts, such as hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, cyclohexylsulphamic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, formic acid, saicic acid, acid are suitable. inethanesulfone or toluenesulfone.

For example, the following end products, optionally in the form of physiologically acceptable acid addition salts, can be prepared as described above:

8-bromo-6- (o-chlorophenyl) -1- [N- (p-chlorophenyl) piperazinyl] -4H-s-triazolo] 3,4cthieno [2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N-phenylpiperazinyl) -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine,

8-Bromo-6- (o-chlorophenyl) -1- [N- (o-tolyl) piperazinyl] -4H-s-triazolo | 3,4c] thieno [2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- [N- (o-chlorophenyl) piperazinyl] -4H-s-triazoio [3,4c] thieno [2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- [N- (2-methoxyphenyl) piperazinyl] -4H-s-triazolo] 3,4c] thieno [2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- [N- (p-fluorophenyl) piperazinyl] -411-s-confirza-3,4c] thieno (2,3e) -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- [N- (hydroxyethyl) piperazinyl] -4H-S-triazolo [4,3-c] thienof2,3o] -1,4-diazepine;

8-bromo-H- (o-chlorophenyl) 1- [N- (o-n-triphenyl) piperazinyl] -41 (::

-triazolo {3,4c J thieno [2,3e J -1,4-diazepine,

8- (b) 6- (o-bromo-uy1 H- [N- (2-pyridyl) piperazinyl] -41 is irradiated | 3,4cthieno (2,3e | -1,4-diazepine, 'Noorn-6- (o broinfeny 1JJ -1N ·· 2 -pyrides J) Pipe IJ-411- s -1 riazole cοί 3,4c J thieno (2,3o) -1,4-diazepine, bromo- 6 (o-chlorophenyl) -1- [N - (3-pyridyl) piperazinyl] -4,45-trisizolo [3,4c] thieno] 2,3-1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- [N- (4-pyridyl) piperazinyl] -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine,

8-bromo-6- (o-fluorophenyl) piperazines 1-4H-S-triazolo] 3,4cJ thieno [2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N-ethylpiperazinyl) -4H-s-triazolo (3,4c) thieno] 2,3e] -1,4-diazepine,

8-broin-6- (o-chlorophenyl) -1- (N-ethylpiperazinyl) -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N-isopropylpiperazinyl) -4H-s-triazolo [3,4c] thieno] 2,3e] -1,4-diazepine,

8-bromo-6- (o-bromophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno] 2,3e] -1,4 diazepine,

-! N- (p-yloxyisopropyl) piperazinyl] -4H-s-fryazo [3,4-d] pyrido [2,3-c] -1,4-diazeptine,

8-bromo (o-chlorophenyl) -1- [N- (6'-fluorophenyl) piperazinyl] -4H-s-1: 1, 4 ' 3,4c J Ibienoi 2,3e | -3, 4-diazepine,

8-brcm 41- (trans-ethyl) -1-piperazin-4-s-thiiazolo [3,4] thienof 2,3e] -1,4 <i | > i 11,

- br (η 11 - η - (o · c 111; irenyl) -1 - [N - (β-dimethylaminoethyl) piperazinyl] -4H-s-triazolo | 3,4c] thieno [2, 3e] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N- (imethylamino) ethyl) piperazinyl-4H-5-ol; tliieno (2,3e) 1,4-diazepine

S-bromo (3-o (chlorophenyl) -1-N-formylpiperazino-4H-s-triazolo ´ 3.4c iiCcmd 2,3c | -1,4-diazepine, ii- f M -methy 'pi pcrezi no) -say by! - i - - (chlorothenyl) -41-1-s-lriazolo; 3,4c 1, 2, 3c, 4, 4-diazepine, i- (Na.cei yl piperazo) 8-tertiary (4-fluorophenyl) -4H-s-triazolo 3,4c, 2,3c | 1,4-Diazepine, 1- (N-acetylpiperazin) -bromo-6- (o-tertiophenyl) -4H-s-triazolo [eta] &lt; 3 &gt; 2,3c) 1,4-diazepine, N, N -cyclyl, n-thio-8-biphenyl-10-bromo-phenyl-4H-k-triazolo; 3,4c-iidicide 2,3c-1,4-diazepine;

(I- (o-Ciderophenyl) -1- (N - (yydroxypropyl) piperazinyl) -4H-S-iriazol., 3,4-thieno [2,3e] -1,4-diazepine ,

- bi Oi 11 - (i - (o - o 111 or phiyl) -4- (N-starylpiperazino) -4H-s-triazolo | 3.4c Itliicno! 2,3e] -1,4-diazepine,

8-br-om-1- (N-dipropylpiperazino) -6- (o-cb torphenyl) -41-l-sulfazolo [3,4-c] thieno [2,3-c] -1,4-diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N-benzoylpiperazino) -4H-s-triazole | 3,4c! thieno (2,3e) 1,4-diazepine,

- trans-6- (o-trans-phenyl) -1- (N- (p-fluorobenzoyl) piperazino) -H-s-triazolo-3,4c] thieno [2,3e] -1,4-diazepine,

8-bromo-1- (o-chlorophenyl) -1-1-N- (4-chlorophenyl) piperazino | -411-a-1-triazole (.alpha., 3,4c) | -1,4-diazepine, δΗ., Πιηι.ίί'Ιθί'ΐ) ΐ4ΐ4Κ'ηγΐ1 '· ι- f N - nicotine (iy 1 pip of 1 no) - 4 H - st and a zo 1 o | 3,4c í Inciinj 2,3c-1,4 diazepine,

8-bromo-6- (o-chlorophenyl) -1- (N-pizolinoylpiperazino) -1H-s-triazolo [3,4c] thieno (2,3e) -1,4-diazepine, 1- (N-ethoxycarbonylpiperazino) 8-Bromo-6- (o-chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine.

The starting materials of the above general formula are prepared by reacting the compounds of general formula III

in which

R ² and R ³ have the abovementioned meaning and Hal represents halogen breaks, are reacted with a derivative of formula IV piporazinu

in which

Rf is as defined above, after which the oxygen atom in the ring is then replaced with a nitrogen atom, as described, for example, in German Patent No. 2,531,678.

The resulting compounds of formula (I) have valuable therapeutic properties and can be used as anxiolytics, tranquilizers, sedatives and neuroleptics.

The main effect may vary from substance to substance, so some of these compounds are used predominantly as a neuroleptic, others as predominantly as a sleep agent, and the like.

Thus, for example, compounds in which R @ ¹ is C1 -C3 alkyl have particularly anxiolytic effects. These compounds may form water-soluble salts.

Compounds having a hydroxyalkyl group as defined above for R ¹ which are in salt form. also water-soluble, have a beneficial effect on sleep and wake in cats, extending the SWS phase (slow wave phase - deep sleep). They shorten the active and relaxed waking state and slightly prolong or do not change the REM phase (rapid eye movement) ).

In addition to the explicitly tranquilizing and anxiolytic components of the action, derivatives having an acyl or heteroaryl radical as defined above, R ¹ , also have a good effect in a rat test in which animals actively avoid unpleasant stimuli, both of which have shifting maxima. First it shows neuroleptic effect and only later anxiolytic effect. The neuroleptic properties of acylpiperazinyl derivatives can also be deduced from biochemical assays.

The novel compounds are therefore particularly suitable for the elimination of psychomotor conditions of arousal and anxiety, such as occur, for example, in schizophrenia, and for the treatment of pain conditions and sleep disorders of various origins.

In addition, the compounds of the invention in which R @ ¹ is hydrogen, alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl groups can be converted into stable water-soluble acid addition salts, allowing their parenteral administration and hence their use as short-lived or ultra-short-lived. of narcotics.

Especially effective are those products of formula (I) in which R @ ¹ is hydrogen, C1 -C3 alkyl or C1 -C3 hydroxyalkyl, phenyl or pyridyl or the radical R ^{@ 4} --CO--. R ² represents a chlorine atom, R ³ represents a bromine atom and R ⁴ represents a hydrogen atom or a methyl group.

The anticonvulsant efficacy, tractilization efficacy and toxicity of the compounds of the invention were tested by the following methods.

1. Antagonizing the effect of pentetrazole fM. I. Gluckmann, Curr. Ther. Res. 7, 721 (1965)].

The mean effective dose (ED 50) of the test compound, which abolishes the lethal effect of the 125 mg / kg pentylentetrazole dose on the test substance, antagonizes the effect of pentetrazole (mouse) mg / kg% of the test animals. Pentylentetrazole is administered intraperitoneally 1 hour after administration of the test compound.

2. Inhibition of Passive Avoidance Test [j. Geller, Arch. Int. Pharmacodyn. 149, 243 (1964)].

3. Discrimimative Active Avoidance (P. B. Dobrili, Arch. Int. Pharmacodyn. 178, 351-356 (1969)).

This test demonstrates the possible neuroleptic efficacy of the test compounds.

The rats are trained to press the button after the warning signal. If they do not press the button, they will get a brief painful electric shock to their paws. After a certain neuroleptic dose. The animals do not feel the need to press the button even though they know that a painful stimulus will follow.

The following table shows the dose of the test compound in mg / kg after which the button press rate is reduced by 50 percent.

4. Toxicity [Litchfield and Wilcoxon, J. Pharmacol. Exp. Therap. 98 99 (1949)].

The mean lethal dose (LD 50) is determined.

white mice (NMRI 1 weighing 20-25 g or white rats (FW-49) weighing 140-200 g) are used as test animals. The test compound is administered orally in suspension in olive oil using a esophagus probe.

The results of the above-described tests (values determined graphically) are shown in the following table:

Geller (rat) Dobrin (rat) LD 50 (mouse) mg / kg img / kg 'mg / kg

8-bromo-6- (o-chlorophenyl) -1- [N- (2-hydroxyethyl) piperazino] -4H-s-triazolo [3,4c] thienof 2,3e] -1,4-diazepine 8-bromo -6- (o-chlorophenyl) -1- [N- (2-pyridyl) piperazino] -4H-s-triazolo [3,4c] thienof 2,3e] -1,4-diazepine 1- (N-acetyl) 8-Bromo-6- (o-chlorophenyl) -4H-s-thiazolo [3,4c] thieno [2,3-c] -1,4-diazepine

1.5 4.8 17 the substance is only effective after

2.6 24 hours 6

0.5

1280 *)

1623 *)

5.1 <30 1280 *

209898.

Legend:

* This value is approximate because no animal died at the given dose

The unit dose of the compounds of the invention is 0.05 to 50 mg, preferably 0.1 to 25 mg (orally), with a daily dose of from 5 to 150 mg.

The invention is illustrated by the following non-limiting examples.

Example 1 a d 1

8-Bromo-6- (o-chlorophenyl) -1- (N-methylpiperazinyl) -4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine

3.5 g (0.075 mol) of 1,8-dibromo-6- (o chlorophenyl) -4H-s-triazolo [3,4c] thieno [2,3e] -4,1-oxazepine were added with 2 ml of methylpiperazine and 100 ml of xylene was refluxed for 4 hours. The reaction mixture is filtered off with suction, the filtrate is evaporated in vacuo and the residue is taken up in methylene chloride. The solution was washed with water, dried and evaporated and the residue was crystallized with isopropyl ether.

2.9 g (80% of theory) of 8-bromo-6- (o-clorophenyl 1-1- (N-methylpiperazinyl) -4H-s-triazolo [3,4-c] thieno [2,3e] are obtained. -4,1-oxazepine, m.p. 150-153 ° C.

2.4 g (0.005 mol) of the above oxazepine are stirred at room temperature with 20 ml of concentrated hydrobromic acid for 30 minutes. The mixture was poured into 200 ml of ice-water and made alkaline with ammonia under ice-cooling. The product is taken up in methylene chloride, the solution is dried and concentrated to a volume of 30 ml by evaporation.

Thionyl chloride (2.5 ml) was added to the residue, the mixture was stirred at room temperature for 2 hours, then evaporated to dryness and 30 ml of methanol previously saturated with ammonia were added to the residue. The mixture was heated in an autoclave at 60 ^DEG C. for 15 minutes, then the methanol was evaporated, the residue was taken up in methylene chloride and the resulting salts were washed with water. From the methylene chloride phase, a dihydro compound is obtained which is stirred without stirring for 4 hours at room temperature with 100 ml of acetone and 1 g of powdered potassium permanganate. The resulting manganese dioxide is filtered off with suction and 1.2 g (50% of theory) of the title compound of melting point 206 DEG-208 DEG C. are obtained in the filtrate.

Example 2

8-Bromo-6- (o-chlorophenyl) -1- (N-methylpiperazinyl) -4H-s-triazolo [3,4c] thieno, [2,3e] -1,4-diazepine

4.6 g (0.01 mol) of 8-bromo-6- (o-chlorophenyl) -1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepine was dissolved in 200 ml of tetrahydrofuran were stirred at 40-50 ° C for 3 hours with 1.2 ml (0.02 mol) of methyl iodide. Column chromatography gave the title compound (3 g, 63%), m.p. 206 DEG-208 DEG C., from the reaction mixture.

The hydrochloride prepared by treatment with alcoholic hydrogen chloride melts at 210 DEG C. with decomposition.

The following compounds of formula I are also prepared as described above:

Example R ¹ ? R.

number

Rt melting point

PC)

3 4 (HER Ol Br Br 5 Cl Br 6 Cl Br 7 Cl Br 8 Cl Br 9 Cl Br 10 Cl Br 11 Cl Br

ΙΗ · 2 — Clh — OH H 125 to 126 246 to 248 -O N — J 215 to 216 —CO — CH3 247 to 249 CO-O-C-2H5 216 to 218 —COH 205 to 215 \ O> 248 to 249 @ - 241 to 242 ch ₃ <O> - 134 to 135

Cl

.209898 example number 11 1Ž R'2 Rs Ri melting point (° C) 12 Cl Br ocw ₃ 218 to 222 13 Cl Br / = rN 240 to 241 14 Cl Br C / X 262 to 263 15 Dec Cl Br NO _Z 264 16 Br Br 167 to 169 17 F Br H— 240 to 242 18 Cl O2H5 CH3— ch ₃ z 180 to 182 19 Dec Cl Br —Ch ₂ —ch ₂ —n \ CH3 224 to 228 20 May Cl Br Cl — CH2 — CH'2— 216 to 217 21 Cl Cl H 160 to 162 (decomposition) 22nd Cl Br -CH ₂ -CH-CH 3 OH 1 222 to 224 23 Cl Br —CH2 — CH2-CH2 — OH 196 to 197 24 Cl Br O- 294 25 Cl Br Zy ^c ° · 311 to 312 26 Cl Br 247 to 248 27 Mar: Cl C2H5 CH3 — what— 220 to 224 28 Cl Cl CH3 — what— 222 to 225 29 Cl Br CH3 - (CH2) 16 - G - 126 to 128 30 Cl Cl CH3- (CH2) 4-CO- 173 to 175 31 Cl Cl CH3- (CH2) 15-CO- 126 to 128

OBJECT OF THE INVENTION

Claims (3)

i. A process for the preparation of novel substituted 1-piperazinyl-4H-s-triazolo [3,4c] thieno [2,3e] -1,4-diazepines of the general formula I in which: R 1 represents a hydrogen atom, a straight or branched (C 1 -C 3) alkyl group, (C 1 -C 2) haloalkyl, (C 1 -C 3) hydroxyalkyl or (C 1 -C 2) dialkylaminoalkyl group optionally containing 1 to 2 carbon atoms in each alkyl moiety; methyl, methoxy, nitro- or halo-substituted phenyl, pyridyl or pyrimidinyl, or a radical of formula R ⁴ -CO-, R ² represents a fluorine, chlorine or bromine, R ³ represents a chlorine atom, a bromine atom or an alkyl group having 1 or 2 carbon atoms and R ⁴ is hydrogen, C 1 -C 17 alkyl, C 1 or C 2 alkoxy, phenyl, halophenyl or pyridyl, and physiologically tolerable addition salts of those compounds of formula I wherein R ¹ is hydrogen , an alkyl, hydroxyalkyl, haloalkyl or dialkylaminoalkyl group as defined above, with acids, characterized in that the compounds of the general formula II are dehydrogenated in which: R ^1, R ² and R ³ are as defined above, whereupon the resulting product of Formula I in which R ¹ represents a hydrogen voidíku, as defined above, alkyl, hydroxyalkyl, haloalkyl, or dialkylaminoalkyl group, optionally converted into physiologically tolerated addition salts with acids. 2. The process of item 1, for the preparation of compounds of the above general formula I, wherein: R ¹ is hydrogen, straight or branched alkyl group having 1 to 3 carbon atoms, halogenoalkyl having 1 to 2 carbon atoms, a hydroxyalkyl group having 1-3 carbon atoms, dialkylamino radicals in which each alkyl moiety has 1 to 2 carbon atoms, an optionally methyl, methoxy, nitro or halogen substituted phenyl, pyridyl or pyrimidinyl group, and R ² and R ³ are as defined above, characterized in that the compounds of formula (II) are dehydrogenated in which R ² and R ³ are as defined in point 1 and R ¹ is as defined therein. 3. The process of item 1, for producing compounds of formula IA wherein: R ^2, R ³ and R ⁴ are as defined in claim 1, characterized in that the dehydrogenated compounds of the formula IIA in which R ^2, R ³ and R ⁴ tnají meaning as in point 1.