FI56837C - REFERENCE TO A PHARMACOLOGICAL PROPERTIES OF 6-STATIONARY SUBSTITUTES 4,6-DIHYDRO-5H-S-TRIAZOLO- / 4,3-A / - / 1,5 / -BENODIAZEPIN-5-ONER - Google Patents

Description

Γηΐ / m ADVERTISEMENT „49α U (1) UTLÄGGNINGSSKRIFT 56837 C (45) Patent uyonnetty 13 11 1933 Patent aeddelat T (51) Kv.ik. * / Int.a. · C O? D 487/0 ^ FINLAND · —FINLAND (21) PtMnttlhakemu »- Pitentansöknlng 1070 / T ^

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IW * och ΜΚΏΚΪΪΤΧΐ 31.12.79 (32) (33) (31) Privilege claimed — Begird prlorltet 13 · 04.7 3

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 23l8673.lt (71) C.H. Boehringer Sohn, D-6507 Ingelheim am Rhein, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Adolf Bauer, Ingelheim / Rhein, Karl-Heinz Weber, Gau-Algesheim,

Peter Danneberg, Ockenheim, Franz Josef Kuhn, Bingen / Rhein,

Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (7 * 0 Leitzinger Oy (51 *) Method for pharmacologically valuable 6-position-substituted U, 6-dihydro-5H-s-triazolo- [lt, 3-a / - / l, 5 / for the preparation of benzodiazepin-5-ones - For the preparation of pharmacologically active compounds of the 6-substituted substituents U, 6-dihydro-5H-s-triazolo [1,3 ', 3 - a - [1,5] -benzodiazepin-5-one

The present invention relates to a process for the preparation of pharmacologically valuable 6,6-dihydro-5H-s-triazolo [4,3-a] [1,5] -benzodiazepin-5-ones of the formula I which are substituted in the 6-position.

R, -3 N

Wherein R 1 is hydrogen, alkyl of 1 to 4 carbon atoms, cyclohexyl, hydroxymethyl or phenyl, R 2 is phenyl optionally substituted by fluorine, chlorine, trifluoromethyl or nitro, and R 3 is chlorine, bromine, trifluoromethyl or nitro, and their acid addition salts.

2 56837

The process according to the invention is characterized in that the compound of general formula II

X

N == / Π r2 wherein R2 and Rg are as defined above and X is a halogen tower or a lower alkoxy group, is condensed with a monoacyl hydrazide of formula III

f ^ N -NH-C-Rj III

where

R 1 is as defined above, in which case, in the case where X is an alkoxy group, the condensation is carried out by adding an acid catalyst, e.g. a Lew 1 acid such as aluminum chloride, zinc chloride or boron trifluoride or trifluoroacetic acid.

In this case, intermediate 0 is first formed

R 1 - C - NH

1 I

NH

N-k IV

K2 (R1 »R2 ^ 3 are as defined above) which can be cyclized to the final product without prior isolation; this can possibly be converted into a physiologically acceptable acid addition salt by conventional methods.

In this method, a compound of formula II is best reacted with a 2-7-fold excess of acid hydrazide. 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; in some cases it can also be operated without solvent.

3,56837

If X represents a lower alkoxy group, a Lewis acid, for example aluminum chloride, zinc chloride, boron trifluoride or trifluoroacetic acid, optionally also gaseous hydrochloric acid, is suitably added to the reaction mixture; operates best at elevated temperatures of 100 ° C and refluxing the reaction mixture.

If X represents a halogen atom, the addition of said acid catalysts is omitted: the compound of formula II (X - halogen) is reacted with the acyl hydrazide of formula III best in situ and at lower temperatures, approximately between -10 and + 50 ° C.

If desired, the final product of the general formula I can be converted into its physiologically acceptable acid addition salts in the customary manner. Suitable acids for salt formation are, for example, hydrohalic acids, sulfuric acid, phosphoric acid, cyclohexylsulfamic acid or methane or toluene sulfonic acid.

The starting materials of the general formula II can be obtained, for example, a) in the case where X is halogen, by reacting a compound of the general formula V H / O N- in an inert anhydrous organic solvent such as dioxane at low temperatures (approximately -50 to + 50 ° C); b) In the case where X is alkoxy, by reacting a compound of general formula V with a trialkyloxonium fluoroborate according to the information in Belgian Patent Publication 774,873.

As is known from several publications, the incorporation of a triazolo heterocycle into 1,4-benzodiazepine reinforces the sedative effect of this class of compounds. Surprisingly, it has been shown that targeting this measure to the ring system of 1,5-benzodiazepine strongly alters the effect profile.

4,50837

The triazolo-benzodiazepines of the invention can thus be classified as highly effective anticonvulsants, while the minor sedative effect is completely in the background. The anticonvulsant effect was determined by the pentetrazole-reverse effect; with the new compounds it is of the order of magnitude of the anticonvulsant property of diazepam and is much better than that of phenobarbital.

In contrast, the side effects of the new compounds are substantially lower than with both of the above-mentioned reference substances. Even after high doses, there is no significant restriction of movement coordination; nor can sedative psychopharmacological effects be hardly demonstrated with the new compounds. Thus, for example, the movement of mice is not inhibited in the Open-Field test, and in the condition test applied to the sedation zone in rats (Passive Avoidance), virtually no effect can be demonstrated.

A significant advantage of the new substances is still their very low toxicity, which allows the safe use of the compounds over a wide range of applications.

New neuropsychological studies in cats show that this is a novel anticonvulsant mechanism of action that differs from conventionally used antiepileptic agents. It follows that the compounds according to the invention do not show any effect in electroshock tests, which are generally used for testing anticonvulsants.

The following table gives the results of comparative experiments in which the compounds are given a so-called EDgQ value, which means the dose level of the compound in mg / kg at which said effect is detectable in 50% of the experimental animals. In only one case, the compound Bau 426, is given an LD10 value (10% of the animals died). The value of LD, -0 could thus not be measured. In the lime experiments, except in the amygdalae kii treatment trial in cats, where the test compounds were administered intravenously, the route of administration is oral.

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6 56837

Maximum electric shock: The ED&0 value is the dose after which the maximum tetanus induced by ocular electrodes and a given current can be observed in 50% of the experimental animals. (E.A. Swinyard et al., J. Pharmacol. Exptl. Therap. 106, p. 319 (1952)).

Pentetrazole antagonist smi: The ED50 value is the dose at which seizure and subsequent death can be prevented in 50% of the experimental animals at a dose of 1.25 mg / kg pentylenetetrazole. (M.I. Gluckmann, Current Therapeutic Research _7, s · 721 (1965)).

Oxotremorine-antagonism:

Mice were administered 2.5 mg / kg oxotremorine subcutaneously. The ED50 value is the dose of the test compound, expressed in mg / kg, which prevents the tremor produced in 50% of the experimental animals. (G.M. Everett, Science 124, p. 79 (1956)).

Lateral position: The EDgg value is the dose after which 50% of the experimental animals are unable to rise from the lateral position.

LD50:

The mean lethal dose was determined by Litchfield & Wilcoxon, J. Pharmacol. Exptl. Therap. 96, p. 99 (1949).

Audiogenic seizures:

An audio generator was installed on the mice. The ED50 value is the dose (mg / kg) of test compound that prevents seizures in 50% of the test animals.

Strykniinikouristus:

Mice used as experimental animals were given different doses of the test compound, and after one hour a normal lethal dose of strychnine. The ED 2 value is a dose that prevents seizures in 50% of the experimental animals.

(T. L. Kerley et al., J. Pharmacol. Exptl. Therap. 132, 360 (1961)).

: * / '56837 7

Amygdalae-kiihoitus:

The cat's tonsils, to which the electrodes were attached, were irritated after administration of the experimental association every hour until convulsion. The ED5Q value is the dose (mg / kg) at which no seizures could be observed in 50% of the experimental animals for 2-7 hours.

The following examples illustrate the invention without limiting it:

Example 1 6-Phenyl-8-trifluoromethyl-4,6-dihydro-5H-s-triazolo- (4,3-a) (1,5) -benzodiazepin-5-one 3 g of 2-ethoxy-5- phenyl-7-trifluoromethyl-4H-3,5-dihydro-1,5-benzodiazepin-4-one and 1.8 g of formic acid hydrazide are heated for 60 minutes in an oil bath at 200 ° C. It is then allowed to cool to room temperature and the solidified melt is mixed with 100 ml of semi-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. The organic phase is dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized by adding isopropyl ether and recrystallized from acetone.

Yield: 2.7 g (= 91% of theory); melting point 261-263 ° C.

Example 2 N-Methyl-8-nitro-6-phenyl-4,6-dihydro-5H-s-triazolo (4,3-a) (1,5) -benzodiazepin-5-one

To a solution of 39.4 g of phosphorus pentachloride in 250 ml of absolute toluene is added dropwise 8.3 g of 7-nitro-5-phenyl-1H-1,5-benzodiazepine-2,4- [3H, 5H] -dione, which is dissolved in a mixture of 90 ml of absolute dioxane and 15 ml of acetonitrile. Allow to react for 30 minutes at 0 ° C with stirring. The resulting suspension is slowly added to a solution of 70 g of acetylhydrazide in 200 ml of dimethylformamide so that the temperature does not rise above + 3 ° C. After 15 minutes, evaporate in vacuo, mix the residue with water, shake with methylene chloride and then extract the methylene chloride phase several times with semi-concentrated hydrochloric acid. Further processing is carried out according to Example 1; the final product obtained is recrystallized from methylene chloride / isopropyl ether.

Yield: 5.7 g (= 63% of theory); melting point 302-305 ° C.

8 66837

Example 3 8-Bromo-6-phenyl-4,6-dihydro-5H-s-triazolo- (4,3-a) n, 5) -benzodiazepin-5-one 6 g of 2-ethoxy-7-bromo-5-one -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 heating and refluxed for 60 minutes with 2 ml of trifluoroacetic acid. The solution is then evaporated and worked up as in Example 1. The final product is recrystallized from methylene chloride / isopropyl ether. Yield: 5.9 g (= 96% of theory); melting point: 282-284 ° C,

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

Eg R. R_ R- Sp. ° C

n: o _'_____ 4 CH3 CgH5 Cl 292 - 295 5 CH3 CgHg CF3 266 - 268 6 ceH5 CgHg CF3 238 - 241 7 H CgHg Cl 284 - 286 8 H CgHg NO2 310 - 313 9 H 0-Cl-CgH4 Cl 280 - 283 10 CH 2 OH CgHg NO 2 175 - 180 11 CH 2 OH CgHg Cl 278 - 280 12 CH 2 OH CgHg CF 3 240 - 242 13 C2Hg CgHg Cl 290 - 292 14 H o-Cl-CgH4 NO2 256 - 258 15 H o-CF3-CgH4 Cl 294 - 296 16 H oF-CgH4 Cl 211-213 17 (h) CgHg Cl 260 - 262 HC ---- 18 0 C, Hc Cl 318 - 320 H.JC "" '^ 6 5 19 H C6H4 "NQ2 CF3 302 - 306 20 CgHg Cl 260 - 262 ·· ;! * "56837 9

For example, R-R2 R2-Sp. ° C

n: o_ 21 CH- (CH3) 2 CgH5 Cl 318 - 320 22 CH3 C6H4 "CF3 C1 252" 255 23 n-C4Hg CgH5 NO2 233 - 235 24 CH3 C6H4'Cl C1 278 "280 25 H C6H4" NO2 C1 250 " 252 26 CH3 C6H4'NO2 C1 287 '290

Claims (1)

A process for the preparation of pharmacologically valuable 6-substituted 4,6-dihydro-5H-s-triazolo [4,3-a] -FL, 5/-benzodiazepin-5-ones of the formula I yS 2 \ R1 -3 1 I R 2 is hydrogen, alkyl of 1 to 4 carbon atoms, cyclohexyl, hydroxymethyl or phenyl, R 2 is phenyl optionally substituted by fluorine, chlorine, trifluoromethyl or nitro, and R 1 is chlorine, bromine, trifluoromethyl or nitro, and their acid addition salts, characterized in that the compound of general formula II X 2 XT "S R 3 I \ R 2 in which R 2 and R 1 have the same meaning as above, and X is a halogen atom or a lower alkoxy group, is condensed with a monoacyl hydrazide of formula III H2N - NH - C - III wherein has the same meaning as above, in which case, in the case where X is an alkoxy group, the condensation is carried out by adding an acid catalyst, e.g. a Lewis acid such as aluminum chloride, zinc chloride t boron trifluoride or trifluoroacetic acid, and that the final product of general formula I thus obtained is optionally converted in the usual manner into a physiologically acceptable acid addition salt. 56837 12 For the preparation of pharmacologically active substances, the 6-substituted substituents 4,6-dihydro-5H-s-triazolo [4,3-a] benzodiazepine-5 are substituted by the formula I_ <f / N-1 joc;> <[“N Rp Dar 2 R1 is alkyl of 1-4 cholatomers, cyclohexyl, hydroxymethyl or phenyl, R2 is optionally fluoro, chloro, trifluoromethyl or nitro substituted with phenyl and R3 is chlorine, bromine , trifluoromethyl or nitro, and for the further preparation of a cyanide addition salt, having the same meaning as in formula II X ^ r \ ^ N === <f II R3 f \ där R2 and R3 are defined above, and X is en halogen atom or alkoxy group, condenser with monoacylhydrazide of formula III 0 II H, N - NH - C - R, III