DE2318673A1 - NEW SUBSTITUTED TRIAZOLO-1,5BENZODIAZEPINE - Google Patents

Description

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CH. BOEHRINGER SOHN, Ingelheim am Rhein

== ssss3s = sssa = s = sss3s ==: 3sssa = a »s8iassr

New substituted triazolo-l, 5-benzodiazepines

The invention relates to new substituted s-triazolo-1,5-benzodiazepines the general formula

N.

R.
^R 3

R ₂

as well as their acid addition salts.

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In the formula:

R _{1 is} hydrogen, a straight or branched alkyl radical with 1-4 carbon atoms, a hydroxyalkyl radical with 1-2 carbon atoms, an alkenyl radical with 2 -? Carbon atoms, a cycloalkyl radical with 3-6 carbon atoms or the phenyl or piperidyl radical,

Rp is a phenyl radical, which is optionally in the o-position a fluorine, chlorine or bromine atom or the trifluoromethyl or nitro group can be substituted or one a-pyridyl radical and

R, hydrogen, a fluorine, chlorine or bromine atom or the trifluoromethyl, nitro, methyl, methoxy, cyano or Hydroxyl group.

The invention also relates to the preparation of the new compounds of general formula I by reacting Compounds of the general formula

II

wherein Rp and R, have the abovementioned meaning and X is Means halogen atom or a lower alkoxy group, with a monoacylhydrazld of the general formula

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NH - C - R ₁ III

wherein R _{1 has} the meaning given above. The intermediate product is created first

IV

(R ₁ , R_ and R- have the meanings given above), which can be cyclized to the end product without prior isolation; this is optionally converted into a physiologically acceptable acid addition salt by customary methods.

In the process indicated, a compound of the formula II is preferably used with a 2-7-fold excess of the Acid hydrazide reacted. The use of an inert organic solvent, for example dioxane, toluene, benzene, xylene, acetonitrile, dimethylformamide or mixtures of these solvents depends on the benzodiazepine of the formula II used in each case; under certain circumstances it is also possible to work without a solvent will.

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If X is a lower alkoxy group, a Lewis acid, for. B. aluminum chloride, zinc chloride, boron trifluoride or trifluoroacetic acid, optionally also gaseous hydrochloric acid, are added; it is preferred to work at higher temperatures, between IOP '
mixed lying.

between about 100 ° C and the reflux temperature of the reaction

If X is a halogen atom, there is no need to add the acidic catalysts mentioned; are preferably added to the compound of formula II (X = halogen) in situ, and at low temperatures, such as between minus 10 and plus 50 ⁰ C, with the acyl hydrazide of the formula III.

If desired, the end products of the general formula I can be converted into their physiologically acceptable form in the customary manner Acid addition salts are transferred. Acids suitable for salt formation are, for example, hydrohalic acids, sulfuric acid, Phosphoric acid, cyclohexylsulfamic acid or methane or toluenesulfonic acid.

The starting materials of the general formula II can, for example can be obtained

a) if X = halogen, by reacting a compound the general formula

where FU and R ^ have the meaning given above, with an inorganic acid halide, preferably v / eu ^; cia-yi phosphorus pentahalide, in an anhydrous inert organic solvent such as Bioxan at low temperatures (approximately between -50 and + 5O ⁰ C);

b) in the case X = alkoxy by reacting a compound of general formula V with a trialkyloxonium norborate as indicated in Belgian patent specification no. 774 873.

By the method described above, for example, the following end products, optionally in the form their physiologically compatible acid addition2 ζü, will be obtained:

6-Phenyl-8-trifluoromethyl-4,6-dihydro-5H-s ~ triaaoLo · « (4,3-a) (l, 5) -benzodiazepin-5-one,

8-chloro-6-phenyl-4,6-dihydro-5H-s-triazolo- (4,3 - a) (1, *?) - ■ benzodiazepin-5-one,

8-bromo-6-phenyl-4,6-dihydro-5H-s ~ -triazole- (4,3 -. \ ) (1 _s 5) -benzodiazepin-5-one,

8-Nitro-6-phenyl-4,6-dihydro-5H-s-triazolo- (4,3-a) (1,5) ■■ benzodiazepin-5-one,

8-chloro-1-methyl-6-phenyl-4,6 - dihydro-5H-s ~ triazole- (4 »? - a) (l, 5) -benzodiazepin-5-one,

1-Methyl-6-phenyl-8-trifluoromethyl-4,6-dihydro- '> Ks-tiiazolc »(4,3-a) (1,5) -benzodiazepin-5 ~ one _see

l-methyl-8-nitro-6-phenyl-4,6-dihydro-5H-s-tr.1 πζοχο (/ 'i _s ja.) (1,5) -benzodiazepin-5-one,

l-methyl-6-phenyl-4,6-dihydro-5H ~ s-triazolo ~ (4,> -a) (l _t ö) ■ benzodiazepin-5-one,

l-ethyl-8-chloro-6-phenyl-4,6-dihydro-5H-s-triazole ->. 4th _v 3 ~ a} (1,5) -benzodiazepin-5-one,
ln-3utyl-8-nitro-6-phenyl-4,6- (1,5) -benzodiazepin-5-one,

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l-Allyl ~ 6-phenyl-8 ~ trifluoromethyl-4,6-dihydro-5H-8-triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one,

8-chloro-l-cyclohexyl-5-phenyl-4,6-dihyd.ro ~ 5H-s-tria2: olo- (4,3-a) (l, 5) -benzodiazepin-5-one,

l-hydroxymethyl-8-nitro-6-phenyl-4,6-dihydro-5H-s-triazoio- (4,3-a) (l, 5) -benzodiazepin-5-one,

S-chloro-l-hydroxymethyl-e-phenyl ^^ - dihydro-SH-s-triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one,

1-hydroxymethyl-6-phenyl-8-trifluoromethyl-4,6-dihydro-5H ~ s «· triazolo- (4,3) (l, 5) -benzodiazepin-5-one, 1,6-diphenyl-8-trifluoromethyl-4,6-dihydro ~ 5H-s ~ triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one,

8-chloro-6- (o-trifluoromethylphenyl) -4,6-dihydro-5H ~ s-triazolo- (4,3-a) (1,5) -benzodiazepin-5 ~ one,

6_ (o-chlorophenyl) -8-nitro-4,6-dihydro-5H-s-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one,

8-chloro-e- (o-chlorophenyl) -4,6-dihydro-5H-s-triazole- (4,3-a) (l, 5) -benzodiazepin-5-one,

8-chloro-6- (o-fluorophenyl) -4,6-dihydro-5H-s-triazolo- (4 _i 3 '&) (l, 5) -benzodiazepin-5-one,

δ-ΟιΙοΓ-β- (o-nitrophenyl) -4,6-dihydro-5H-s-triazolo- {4,3-a) (1,5) -benzodiazepin-5-one,

8-chloro-6- (o-chlorophenyl) -l-methyl-4, e-dihydro-SH-s-tri (4,3-a) (l, 5) -benzodiazepin-5-one,

8-bromo-6- (a-pyridyl) -4,6-dihydro-5H »s-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one.

As is known from numerous publications, the annulation of the triazolo heterocycle to 1,4-benzodiazepliia leads to an increase in the tranquilizer effect of this class of substances. Surprisingly, it has been found that the transfer of this measure to the 1,5-benzodiazepme ring system causes a strong differentiation of the impact profile ,

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Thus, the triazolo-benzod! Azepines according to the invention classify as highly effective anticonvulsants, while the minor tranquilizer effect takes a back seat. The anticonvulsant effect was determined with the help of pentetrazole antagonism; it lies "with the new connections on the order of the anticonvulsant property of the Diazepam and surpasses that of the phenobarbital far.

The side effects of the new compounds, on the other hand, are much lower than in the case of the two comparison substances mentioned above. Even after high doses, there is no significant restriction in motor coordination; -vucli sedating psychopharmacological effects are with the hardly detectable new substances. For example, the locomotion of mice is not inhibited in the open field test, and in a conditioning experiment on rats (passive avoidance) used for tranquilizers there is practically none To prove the effect.

Another significant advantage of the new fabrics is theirs extremely low toxicity, which makes it possible to use the substances safely in a wide dose range.

The new triazolo-benzodiazepines of the general tunnel 1 and their physiologically acceptable acid addition salts are therefore valuable anticonvulsants with extremely low toxicity. Particularly emphasized are those compounds in which

R _{1 is} a hydrogen atom,

Rp an optionally in the o-position by chlorine or

Trifluoromethyl substituted phenyl radical and R_ is a chlorine atom or the nitro or trifluoromethyl radical.

means.

The dose for the use of the new compounds of general formula I is 0.5 to 50, preferably 1 to 25 mg suggested as a single dose and 5-150 mg as a daily dose.

The compounds obtainable according to the invention can alone or in combination with other active ingredients according to the invention, possibly also in combination with other pharmacologically active ingredients such as antispasmodics or psychotropic drugs, come into use. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, Juices, emulsions or dispersible powders. Corresponding tablets can, for example, by mixing the or the 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. The tablets can also consist of several layers.

Correspondingly, coated tablets can be produced by coating cores produced analogously to the tablets with usually coated tablets agents used, for example collidon or shellac, gum arabic, talc, titanium dioxide. or sugar, getting produced. To achieve a depot effect or to avoid incompatibilities, the core can also consist of several layers. Likewise, the coated tablet shell can also be used to achieve a depot effect from several Layers exist, it being possible to use the auxiliaries mentioned above for the tablets.

Juices of the active ingredients or active ingredient combinations according to the invention can also use a sweetener such as saccharin, ' Cyclamate, glycerine or sugar as well as a flavor enhancer Contain agents, e.g. flavorings such as vanillin or orange extract. You can also use suspension aids

4098457: 1 Q2S; ■ c ,, λ -_

or thickeners, such as sodium carboxymethyl cellulose, Wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoates, contain.

Injection solutions are used in the usual way, e.g. under Addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali salts of ethylenediaminetetraacetic acid manufactured and in injection bottles or ampoules bottled.

The capsules containing one or more active ingredients or active ingredient combinations can be produced, for example, by mixing the active ingredients with inert carriers such as lactose or sorbitol and encapsulating them in gelatin capsules.

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

The following examples serve to illustrate the invention without restricting its scope:

example 1

6-Phenyl-8-trifluoromethyl-4 _f 6-dihydro-5H-s-triazolo O "(4,3- a) (1,5) -benzodiazepin-5-one

3 g of 2-ethoxy-5-phenyl-7-trifluoromethyl-4H-3,5-dihydro-1 _f ^{5-benzodiazepin-4-one are heated to 200 °} C. in an oil bath with 1.8 g of formic acid hydrazide. The mixture is then allowed to cool to room temperature and the solidified melt is stirred with 100 ml of half-concentrated hydrochloric acid. The suspension is shaken with ethyl acetate, the aqueous phase is separated off, neutralized with concentrated ammonia and extracted several times with methylene chloride. One dries the organic

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Phase with magnesium sulfate and evaporated in vacuo. The residue crystallizes on addition of isopropyl ether and is recrystallized from acetone.
Yield: 2.7 g (= 91 % of theory); Mp. 261-263 ° C

Example 2

l-Methvl- »8-nitro-6-phenyl-4 _t 6-dihydro-3H ~ s-triazolo ~ (4,3-a) (l _t 5) -benzodiazepin ~ 5-one

8.3 g of 7-nitro-5-phenyl-1H-1,5-benzodiazepine-2,4- / 3H, 5H7-dione in 90 ml are added to a solution of 39.4 g of phosphorus pentachloride in 250 ml of absolute toluene dissolved in absolute dioxane and 15 ml of acetonitrile, added dropwise. It is allowed to ^{react for 30 minutes at 0} ° C. with stirring. The suspension that forms is slowly added to a solution of 70 g of acetyl hydrazide in 200 ml of dimethylformamide so that the temperature does not exceed + 3 ° C. After 15 minutes, it is evaporated in vacuo, the residue is stirred with water, extracted with methylene chloride and then the methylene chloride phase is extracted several times with half-concentrated hydrochloric acid. The further work-up is carried out as described in Example 1; the end product obtained is recrystallized from methylene chloride / isopropyl ether.
Yield: 5.7 g (= 63% of theory); M.p .: 302-3O5 ° C

Example 3

8-Bromo-6-phenyl-4,6-dlhydro-5H-s-triazolo- (4 «3-a) (1.5) -benzodiazepin-5-one

6 g of 2-ethoxy-7-bromo-5-phenyl ~ 4H-3,5-dihydro-1,5-benzodiazepin-4-one and 4.8 g of formic acid hydrazide are dissolved in 150 ml of absolute dioxane with gentle warming and with 2 ml of trifluoroacetic acid Heated under reflux for 60 minutes. Afterward

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the solution is evaporated and worked up as in Example 1 further. The end product is recrystallized from methylene chloride / isopropyl ether.
Yield: 5.9 g (= 96 % of theory); Mp 282 -. 284 ⁰ C

The following compounds were prepared analogously to Examples 1-3:

Example-
No.: ^R l CH,
3 R ₂ ^R 3 Fp. - ⁰ C 4th CH ₃ ^C 6 ^H 5 Cl 292 - 295 5 ^C 6 ^H 5 ^C 6 ^H 5 CF ₃ 266 - 268 6th H ^C 6 ^H 5 CP ₃ 238 - 241 7th H ^C 6 ^H 5 Cl 284 - 286 8th H ^C 6 ^H 5 NO ₂ 310 - 313 9 CH ₂ OH 0-Cl-C ₆ H ₄ Cl 280 - 283 10 CH ₂ OH ^C 6 ^H 5 NO ₂ 175 - 180 11 CH ₂ OH ^C 6 ^H 5 Cl 278 - 280 12th C ₂ H ₅ ^C 6 ^H 5 CF 240 - 242 13th H ^C 6 ^H 5 Cl 290 - 292 14th H 0-Cl-C ₆ H ₄ NO ₂ 256 - 258 15th H O-CF ₃ -C ₆ H ₄ Cl 294 - 296 16 Θ 0-FC ₆ H ₄ Cl 211 - 213 17th C.
7 CH ^C 6 ^H 5 Cl 260 - 262 18 ^H 3 ^{C. C} 6 ^H 5 Cl 318 - 320 ^H 3 409845 / 1C

Pharmaceutical application examples

a) Dragees

1 dragee contains:

Active ingredient according to the present application 5 »0 mg Milk sugar 28.5 mg

Corn starch 15.0 mg

Gelatin 1.0 mg

Magnesium stearate 0.5 mg

50.0 mg

Manufacturing:

The mixture of the active substance with lactose and corn starch is granulated with a 10% aqueous gelatin solution through a sieve with 1 mm mesh size, dried at 40 ° C. and driven 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 applied with the aid of an aqueous suspension of sugar, tetanedioxide, talc and gum arabic. The finished coated tablets are polished with beeswax.
Final coated weight: 100 mg

b) tablets

Active ingredient according to the present application 10.0 mg

Milk sugar 50.0 mg

Cornstarch. 35.0 mg

soluble starch 4.0 mg

Magnesium stearate ¹ ^ ^{0 m} K

100.0 mg

5 / 102b

Manufacture;

Active ingredient and magnesium stearate are mixed with an aqueous Granulated solution of the soluble starch, dried the granules and mixed intimately with lactose and corn starch. The mixture is then compressed into tablets weighing 100 mg each containing 10 mg of active ingredient.

c) suppositories

1 suppository contains:

Active ingredient according to the present application 10.0 mg

Suppository mass 1,690.0 mg

Manufacturing:

The finely powdered substance is stirred into the melted suppository mass, which has been cooled ^{to 40 °} C., with the aid of an immersion homogenizer. The mass is poured into slightly pre-cooled molds at 35 ° C.

d) ampoules

Active ingredient according to the present application 2.0 mg sodium chloride 18.0 mg

distilled water to 2.0 ml

Manufacturing:

Active ingredient and sodium chloride are dissolved in water, the solution is filtered free of suspended particles and poured into 2 ecm ampoules filled under aseptic conditions. Last the ampoules are sterilized and sealed.

Each ampoule contains 2 mg of active ingredient.

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Claims (14)

Claims 1. New substituted triazolo-l, 5-benzodiazepine of ■ ^ general formula wherein FL is hydrogen, a straight or branched alkyl radical with 1-4 carbon atoms, a hydroxyalkyl radical with 1-2 carbon atoms, an alkenyl radical with 2-3 carbon atoms, a cycloalkyl radical with 3-6 carbon atoms, the phenyl or piperidyl radical, R _{2 is} a phenyl radical optionally substituted in the o-position by a fluorine, chlorine or bromine atom or a trifluoromethyl or nitro group or an α-pyridyl radical and R, hydrogen, a fluorine, chlorine or bromine atom or the Trifluoromethyl, nitro, methyl, methoxy, cyano or hydroxyl groups and their acid addition salts. 409845/1025 2. New substituted triazolo-l, 5-benzodiazepines of the general formula wherein R ₁ hydrogen, Rp optionally in the o-position by a chlorine atom or the trifluoromethyl group substituted phenyl radical and
R, a chlorine atom or the trifluoromethyl or nitro group and their acid addition salts. 3. 6-phenyl-8-trifluoromethyl-4,6-dihydro-5H-s-triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one and its acid addition salts. 4. 8-Chloro-6-phenyl-4,6-dihydro-5H-s-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one and its acid addition salts. 5. 8-chloro-S- (o-chlorophenyl) -4,6-dihydro-5H-s-triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one and its acid addition salts. 4098 ^ 5 / 102b 6. 6- (o-Chlorophenyl) -8-nitro-4,6-dihydro-5H-s-tria2olo- (4,3 ~ a) (l, 5) -benzodiazepin-5-one and its acid addition salts. 7. e-chloro-6- (o-trifluorobethylphenyl) -4, S-dihydro-SH-s-triazolo- (4,3-a) (l, 5) -benzodiazepin-5-one and its acid addition salts. 8. Process for the preparation of compounds of the general formula wherein FL is hydrogen, a straight or branched alkyl radical with 1-4 carbon atoms, a hydroxyalkyl radical with 1-2 carbon atoms, an alkenyl radical with 2 - 3 carbon atoms, a cycloalkyl radical with 3-6 carbon atoms, the phenyl or piperidyl radical, Rp an optionally in the o-position by a fluorine, Chlorine or bromine atom or a trifluoromethyl or nitro group or a substituted phenyl radical oc-pyridyl radical and R ₇ . Hydrogen, a fluorine, chlorine or bromine atom or the trifluoromethyl, nitro, methyl, methoxy, cyano or hydroxyl group and their acid addition salts, characterized in that a connection of the 409845/1025 general formula II R ₂ and R-, which have the meanings given above and X denotes a halogen atom or a lower alkoxy group, with a monoacyl hydrazide of the general formula Ii - NH - C - R ₁ R _{1 has} the meaning given above, condenses and that, if appropriate, an end product of general formula I obtained in this way is converted into a physiologically acceptable acid addition salt in the customary manner. 09845/1026 9. The method according to claim 8, characterized in that one the condensation in the case of compounds of the general formula II in which X is an alkoxy group, with the addition of one acid catalyst performs. 10. The method according to claims 8 and 9, characterized in that that the acidic catalyst used is a Lewis acid such as aluminum chloride, zinc chloride or boron trifluoride or Trifluoroacetic acid used. 11. Pharmaceutical preparations containing as active ingredient one or more compounds of the general formula I in Combination with customary auxiliaries and / or carriers. 12. Pharmaceutical preparations containing substances of general formula I in combination with other pharmaceutical Active ingredients and customary auxiliaries and / or carriers. 13. A method for the production of pharmaceutical preparations according to claim 11, characterized in that one or several compounds of the general formula I with customary pharmaceutical auxiliaries and / or carriers to customary processed pharmaceutical application forms. 14. Process for the production of pharmaceutical preparations according to claim 12, characterized in that compounds of general formula I are used in combination with others Active ingredients and customary auxiliaries and / or carriers too usual pharmaceutical application forms processed. 4139845/102 5 ^