DE2410030C3 - 8-Bromo-6-phenyl-4H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Description

2. t -Methyl-ö-io-chlorophenyQ-e-bromo ^ H-s-triazolo [3,4-c] thieno [23-e] 1,4-diazepine of the formula

Cl

3. A process for the preparation of compounds of the general formula I according to claim 1, characterized in that a compound of the common a '! is established in a manner known per se Formula Il

NH-NH ₂

30th

OD

in which R ^{1 has} the abovementioned meanings with an acid of the general formula

R-COOH

(III)

in which R represents hydrogen or, if R ^{1 represents} chlorine, also represents methyl, or with a functional derivative of this acid with the formulas

R-qOR ') ₃ (purple) R-Q = NH) -OR ' (HIb) RQ = NH) -NH ₂ (HIc) R-CONH ₂ ("Id) R-CS-NH ₂ ("Ie) R-COOR " ("10 (R-CO) ₂ O ("Ig) R-COCI ("Ih) R-CN (Uli)

in which R 'is a low molecular weight alkyl group and R "denotes the res! Of an aliphatic, araliphatic

or aromatic alcohol means, converts, or, that one is a compound of the general formula

(VI)

to

15th

20th

in which R has the meaning given and X is an HS group, an H ₂ N group or a low molecular weight alkoxy or alkylthio group, with an acid hydrazide of the general formula

R-CO-NH-NH ₂ (VII)

in which R has the meaning given

4. Pharmaceutical compositions containing a compound of claim 1 as active ingredient in combination with customary auxiliaries and / or carriers.

ι 25 The invention relates to e-bromo-e-phenyMH-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepines in general formula

35

40

in which R ¹ denotes fluorine, chlorine or bromine and R denotes hydrogen or, if R ¹ denotes chlorine, also denotes methyl.

The invention also relates to the acid addition salts of the compounds mentioned and processes for their Manufacture and their use as active ingredients in pharmaceuticals.

The compounds of general formula I can be prepared as follows:

a) Implementation of a compound of the general formula

NH-NH ₂

55

60

R ¹

65 wherein R ¹ denotes fluorine, chlorine or bromine, with an acid of the general formula

R-COOH (III)

in which R is hydrogen or, if R 'is chlorine,

also stands for methyl, or with a functional one Derivative of this acid.

The functional derivative of this acid is, for example, an orthoester of the general formula

R-C (OR ') *

an iminoether of the general formula

R-C (= NH) -OR ', an amidine of the general formula

RQ = NH) -NH ₂ , an amide of the general formula

R-CONH ₂ , a thioamide of the general formula

R-CSNH ₂ , an ester of the general formula

R-COOR "

(for example a methyl, ethyl or nitrophenyl ester),

an acid anhydride of the general formula

(R-CO) ₂ O, an acid chloride of the general formula

R-COCI or a nitrite of the general formula

R-CN.

Here, R and R 'have the meaning given above; R 'denotes a low molecular weight alkyl group and R "denotes the radical of an aliphatic, araliphatic or aromatic alcohol. The .minoethers and Amidines are usually in the form of their salts with mineral acids, "z. B. hydrochloride used.

The reaction conditions can be selected depending on the acid derivative used. In general, the reaction can be carried out both with and without solvents (e.g. methanol, ethanol, chloroform, tetrahydrofuran, benzene, toluene) or mixtures of these solvents without or in the presence of an acidic catalyst (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, Polyphosphoric acid, acetic acid, propionic acid, benzenesulfonic acid or toluenesulfonic acid) are carried out ¹ .. The presence of a base, e.g. B. 2-methylimidazole as a catalyst is useful. The reaction temperature is between 0 and 300 ° C, preferably between 20 and 180 ° C.

Special variants of method a) are the following:

Method I. In this case the acid derivative is an orthoester

R-C (OR ') 3

(R 'has the meanings given above). The reaction usually proceeds in the presence of a Excess of orthoester, which then also serves as a solvent, at temperatures between 90 and 100 ° C or in an abovementioned solvent, optionally in the presence of one of the above called catalysts, at temperatures between room temperature and reflux temperature of the reaction mixture.

Method II

In this case the acid derivative is an imino ether general formula

(R and R 'have the meanings given above). The reaction is conveniently in one the aforementioned solvents at a temperature between room temperature and The reflux temperature of the reaction mixture carried out

Method III

In this case the acid derivative is an amidine of the general formula

RQ = NH) -NH ₂ .

The reaction is then conveniently carried out in the presence of a basic catalyst such as 2-methylimidazoI elevated temperature, e.g. between 150 and 250 ° C, carried out. If the temperature is lower, e.g. B. the Reaction is carried out at room temperature, First an intermediate product is formed with the following formula

NH-N =

NH ₂

(IV)

in which R and R ^{1 have} the meanings given above. This intermediate IV can be isolated and subjected to a subsequent ring closure reaction by heating to 150 to 250.degree. However, isolation is not required in any way.

Method IV

In this case, the acid derivative is an amide or Thioamide of the general formula

R-CONH ₂

respectively.

P-CSNH ₂ .

The reaction can be carried out with or without solvents and take place with or without a catalyst at temperatures between 0 and 300 ° C.

Method v Here the ester is used as an acid derivative

R-COOR ", the anhydride (RCO) ₂ O, the acid chloride R-COCI

or the nitrile
R-CN

used (R "has the meanings given above). An intermediate of the general formula V is initially formed

NH-NH-C-R

R ¹

in which R and R ^{1 have} the meaning given, which can be isolated beforehand when carrying out the reaction under moderate conditions (for example at room temperature). , The product V subjected to a ring closure reaction then subsequently "grjjen ^ i _n this one it to temperatures between 100 and 250 ⁰ C without solvent or in the presence of an acid catalyst, as mentioned above, heats the prior isolation, however, is not required.

b) The product of the general formula V can also be obtained by reacting a compound of the general Formula VI

in which R ^{1 has} the meaning given above and X is an HS-T) group, an H ₂ N group or a low molecular weight alkoxy or alkyl mercapto group, with an acid hydrazide of the general formula

R-CO-NH-NH ₂

(VII)

in which R has the meaning given, the reaction being equal to the product of general formula I can be continued. If desired, the reaction can be carried out in a solvent of the type mentioned above and in the presence of an acidic catalyst as mentioned above be performed.

If desired, the products of the general formula 1 can be converted into their physiological harmless acid addition salts are transferred. Acids suitable for salt formation are, for example Hydrohalic acids, sulfuric acid, phosphoric acid, cyclohexylsulfamic acid or methane or Toluenesulfic acid.

The starting materials of the general formulas II, IV, V and VI are new. During the making of the Intermediates of the general formulas IV and V have already been described above, the Preparation of the intermediates of the general formulas II and VI are explained in more detail below:

The hydrazine derivatives of the general formula II can be prepared by adding compounds of the general formula Vl reacts with hydrazine, This can be in one of the above-mentioned solvents take place, if desired one of the aforementioned acidic catalysts can be present. The temperature is expediently between room temperature and the reflux temperature of the reaction mixture,

The compounds of the general formula VI (dip can either be reacted directly with a hydrazide of the general formula VII to give products of the formula I or can also be reacted using hydrazine to give compounds of the formula II) are expediently prepared on the basis of those known from the literature (see DE-OS 22 17 157) Compounds of the general formula VIII

in which R ^{1 has} the abovementioned meaning by brominating it in the customary manner and the resulting compounds of the general formula IX

in which R 'has the meaning given above, is reacted in a solvent such as pyridine, dimethyiiormamid or tetrahydrofuran or mixtures thereof. The temperatures used can be between room temperature and the reflux temperature of the reaction mixture.
This gives the compounds of the general formula VI in which X denotes an HS group. It consists in tautomeric equilibrium with the corresponding thionocompounds according to the following equation:

(Via)

(VIb)

in which R ^{1 has} the meaning given above. These compounds can, after they have reacted in a solvent with the aid of a metalating agent such as sodium methylate or sodium amide, to give the corresponding salts, without prior separation in the customary manner with alkylating agents, e.g. B. methyl or alkyl iodide, are converted to compounds of the general formula VI in which X is a low molecular weight thioalkyl group.

The compounds of the general formulas VIII and IX can also be prepared by the methods of DE-OS 21 07 356 and DE-OS 21 44 105 win by adding compounds of the general formula X. Compound of the general formula XIII against (odaus. The halogen compound obtained is then reacted with ammonia in dioxane or tetrahydrofuran. An amino compound of the general formula XIV is formed as an intermediate

OR '

NH-C-CH ₂ -NH ₂

(X)

(XIV)

in which R 'and R ^{1 have} the meanings given above, but which are converted directly into a compound of the general formula VIc

21

OR '

in which R ^{1 has} the meaning given above, is subjected to an intramolecular condensation. A particularly advantageous variant of this reaction is that the cyclization is carried out by boiling in toluene on a water separator using silica gel as the dehydrating agent. This results in much higher yields and purer products.

Compounds of the general formula VI in which X is a lower alkoxy group can be win by using an aminoketone of the general formula Xl

(Vk)

R ¹

NH ₂

(XO

35

40 in which R 'and R ^{1 have} the meaning given above, passes over.

The preparation of compounds of the general formula VI. where X is the amino group, can be carried out in such a way that the obtained by halogenation of compounds of the general formula VIII Can react substances of the general formula IX with ammonia. The reaction is convenient in one Solvent such as tetrahydrofuran in the presence of a Lewis acid, e.g. B. TiCI performed.

These compounds are also subject to a tautomerism according to the following equation:

NH,

in which R ^{1 has} the abovementioned meaning with a haloacetic acid orthoester of the general formula XII

(RRO) ₃ C-CH ₂ HaI

(XII)

in which R 'has the meaning given above and Hal is chlorine, bromine or iodine, to one Compound of the general formula XIII

OR '

50

CH ₂ HaI

(ΧΙΠ)

in which R ', R ¹ and Hai have the meanings given above, converts. If Hai means chlorine, it is expedient to first exchange the aliphatically bonded chlorine atom in the by means of a Finkelstein reaction (ie by reaction with NaI in acetone)

(VId)

NH

(VIe)

60 where R ^{1 has} the meaning given above.

The compounds of general formula I or their acid addition salts have valuable therapeutic properties Properties on. You have learned to use various pharmacological test methods as anxiolytic, tension-relieving and muscle-relaxing Proven to be effective and, moreover, an intensive one

ίο

shown anticonvulsant effects. They also have the property of significantly increasing feed intake in mammals to reinforce. Also noteworthy is their antagonistic effect on adrenaline as well their extremely low toxicity. They are known thieno-l, 4-diazepincn without additional Triazole ring, as they are known for example from DE-OS 403 and 22 21623, in particular due to their strong anticonvulsant effect consider, while the DE-OS 22 29 845

Pharmacological test results

known 8-alkyl-6-aryl-thieno [2,3-e] 4 H-s-triazolo [3,4c] 1,4-diazepines are similar in efficiency, but with regard to the anticonvulsant effect, as can be demonstrated in different tests and on different animal species to a Are superior to powers of ten. 1-methyl-6-o-chlorophenyl-8-bromo-4 H-s-triazolo [3,4-c] thieno [2,3-e] 1,4-diazepine and its acid addition salts have a pronounced sleep-inducing effect.

link Pentetrazole Pentetrazole conflict Battle mouse LD ₅₀ Therap. index antagonism antagonism situation read LD50: ED50 mouse Rough rat mouse PTZ F.D50 mg / k; ED50 mg / kg DTio mg / kg ED _M mg / kg mg / kg Mouse p.o. M (I) pole) p. 0. (2) P- 0. (3) p.o. (4) A. 0.07 0.7 4.9 0.2 > 35OO 50,000 B. ö, 7 7.4 i.5 1.6 ^ Λ IQC. C. 1.0 2.4 6.7 1.9 > 23OO 2,300 D. 1.2 7.5 18th 1.5 990 825

Λ = l-methyl-6- (o chlorophenyl) -fl-bromo-4 H-s-triazolo [3,4-c] thieno [2.3-e] l.4-diazepine

B = 8-ethyl-6- (ochloropnenyl) -l-methyl-4H-s-triazolo [3,4-c] thieno] 2,3-e] 1,4-diazcpin

C = 8-6- (o-chlorophenyl) -1-methyl-4 H-s-triazolo (3.4-c] thieno [thieno [2.3-e] 1,4-diazepine

D = 7-chloro-methyl-5-phenyl-3 H-l.4-benzodiazepin-2 (l H) -one

Albino mice (NMRI) with a body weight of 20 to 25 g or albino rats (FW 49) were used for the tests. from 140 to 200 g body weight used.

The test substances were suspended in olive oil and, in all cases, placed in the stomach by means of a stomach tube brought.

1. Pentetrazole antagonism:

Dose at which the lethal effect of 125 mg / kg pentylenetetrazole, which occurs 1 hour after administration of the Test substance is administered intraperitoneally, in 50% of the animals is canceled (M. I. Gluckmann, Curr. Then Res. 7, 721 [1965]).

2. Conflict situation (inhibition of passive avoidance):
Dose in which the animals in a conflict situation press a button ten times to receive a food pill, although a signal that is switched on at the same time indicates that the food pill is being punished in the form of an electric shock (J. Geller, Arch. Int. Pharmacodyn, 149, 243 [1964]).

3. Combat mouse test (isolation induced fight):

Dose at which the aggressiveness of adults, isolated in the dark for 3 to 4 weeks bucks kept is inhibited in 50% of the animals compared to young bucks (Wirth, Gösswald, Hörlein, Risse and Kreiskott, Arch. InL Pharmacodyn. 115, 1 to 31 [1958]).

4. LD ₅₀ :

Dose survived by 50% of the animals (Lichfield and Wilcoxon, J. Pharmacol. ExpL Therap. 99, 99 [1949]).

The stated values were determined graphically in all tests

The single dose of the substances according to the invention is 0.1 to 50, preferably 03 to 25 mg (orally) and up to 150 mg as a daily dose.

The compounds obtainable according to the invention can be used alone or in combination with others

jo active ingredients according to the invention are used. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, juices, emulsions or dispersible powder. Corresponding tablets can, for example, by mixing the or the

j5 active ingredients with known auxiliaries, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as Corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or agents to achieve the depot effect, such as carboxypolymethylene, carboxymethyl cellulose, Cellulose acetate phthalate, or polyvinyl acetate can be obtained. The tablets can also consist of several layers.

Correspondingly, coated tablets can usually be coated with cores produced analogously to the tablets Agents used in dragee coatings, for example collidon or shellac, gum arabic, Talc, titanium dioxide or sugar.

To achieve a depot effect or to avoid incompatibilities, the core can also consist of consist of several layers. Likewise, the coated tablet shell can also be used to achieve a depot effect consist of several layers, the excipients mentioned above for the tablets being used can.

Juices of the active ingredients or combinations of active ingredients according to the invention can also use a sweetener such as saccharin, cyclamate, or glycerin Sugar and a taste-improving agent, e.g. B. flavorings such as vanillin or orange extract contain. You can also use suspension aids or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols such as ethylene oxide, or protective substances such as p-hydroxybenzoates.

Injection solutions are used in the usual way, for. B. with the addition of preservatives such as p-hydro

xybenzoalcn, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid and prepared in injection bottles or filled into ampoules.

The capsules containing an active ingredient can be produced, for example, by the Active ingredient mixed with inert carriers, such as lactose or sorbitol, and encapsulated in gelatin capsules.

Suitable suppositories can be prepared, for example, by mixing them with carriers provided, such as Manufacture neutral fats or polyethylene glycol or its derivatives.

example 1

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

a) 11.5 g of 7-bromo-5- (o-chlorophenyl) -3 H [2,3-e] thienol, 4-diazepin-2-one (see DE-OS 22 21 623) according to formula IX with 100 cm ^{3 of} absolute pyridine and 6.5 g

nl · L _ »n _n », «■ .. ·

- riOSptiCrpCriiaSti

heated to 60 ^{0 C.} It is allowed to cool and poured onto 100 cm ^{3 of} saturated ice-cold NaCl solution. The precipitate is filtered off with suction and washed with water, then dissolved in 100 cm ^{3 of} methylene chloride, the solution is dried and evaporated and the residue is worked through with a little methylene chloride. After suction filtration, 6 g of brown crystals with a melting point of 214 ° C. (decomp.) Of 7-bromo-5- (o-chlorophenyl) -3 H [2,3-e] thieno-1,4-diazepine-2 are obtained thion according to formula VIa.

b) 6.0 g of the above compound are suspended in 100 cm ^{3 of} tetrahydrofuran and stirred at room temperature with 1.2 g of hydrazine hydrate for 20 minutes. After concentration to about 10 cm ³ , 20 cm ^{3 of} ether are added and the crystals are suctioned off.

Yield: 5.2 g of 7-bromo-5- (o-chlorophenyl) -2-hydrazino-3 H- [2,3-e] thieno-1,4-diazepine with a melting point of ~ 300 ° C (decomposed) according to formula II.

c) 5.2 g of the above compound are ^{suspended in 50 cm 3 of} triethyl ortho-acetate and heated to 80.degree. After about 30 minutes at this temperature, a clear solution has formed, from which colorless crystals later separate out. It is allowed to cool, the crystals are filtered off with suction and washed with ether.

Yield: 5 g of the title compound of mp 211 bis 213 ° C.

Starting from the end product of stage b), the

7-Bromo-5- (o-chlorophynyl) -2-hydrazino-3 H [2,3-e] thieno-1,4-diazepine is obtained by reacting with orthoformic acid ester analogously to step c) the 6- (o- chlorophenyl) -8-bromo-4 Hs-triazolo [3,4-c] thieno [2,3-e] -1,4-diazepine, melting at 216-218 ⁰ C.

Pharmaceutical compositions

a) Dragees

1 dragee contains:

Active ingredient according to Example 1

present registration

Milk sugar

Cornstarch

gelatin

Magncsium stearate

Manufacturing

1.0 mg

28.5 mg

19.0 mg

1.0 mg

0.5 mg

50.0 mg

rvuiiicii aui JJ The mixture of the active ingredient with milk sugar and corn starch is granulated with a 10% strength aqueous gelatin solution through a sieve with a mesh size of 1 mm, dried at 40 ° C. and forced through a sieve again. The granules obtained in this way are mixed with magnesium stearate and pressed. The cores obtained in this way are coated in the usual way with a shell, which is made with the help of an aqueous suspension of sugar. Titanium dioxide. Talc and gum arabic is applied. The finished coated tablets are polished with beeswax. Final coated weight: 100 mg

Tablets 0.5 mg Active ingredient according to Example I. 50.0 mg present! Sign up 43.5 mg Milk sugar 5.0 mg Cornstarch 1.0 mg Soluble starch 100.0 mg Magnesium stearate Manufacturing

Active ingredient and magnesium stearate are granulated with an aqueous solution of the soluble starch, the Dried granules and intimately mixed with lactose and corn starch. The mixture then becomes too Compressed tablets weighing 100 mg each containing 0.5 mg of active ingredient.

Claims (1)

Patent claims: 1. e-Bromo-e-phenyMH-s-triazolop ^ cltbieno- [23-e] 1,4-diazepines of the general formula 5 (D R ¹ in which R ¹ denotes fluorine, chlorine or bromine and R denotes hydrogen or, if R ¹ denotes chlorine, also denotes methyl and their acid addition salts.