DE2119717C3 - 05/14/70 Japan 41499-70 1-alkoxyalkyl-5- (o-tolyl) -7-chloro-1,3-dihydro-2H-1 ^ -benzodiazepine compounds, their salts, processes for their preparation and these compounds - Google Patents

Description

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The invention relates to 1-alkoxyalkyl-5- (o-toryI) -7-chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one compounds of the general formula 1

in which R denotes the methyl or ethyl group and η denotes the number 1 or 2, and their salts.

2. 1 - (β - Methoxyethyl) - 5 - (o - tolyl) - 7 - chloro-1,3-dihydro-2 H-1 ^ -benzodiazepin ^ -one.

3. 1 - methoxymethyl - 5 - (o - tolyl) - 7 - chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one.

4. Process for the preparation of the compounds according to claim 1, characterized in that either 5- (o-tolyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one is used in a manner known per se of formula II

CH ₃

H //

N-C

CH ₂ (II)

Cl

C = N

in which R denotes the methyl or ethyl group and η denotes the number 1 or 2, and their salts.

The invention also relates to a process for the preparation of the benzodiazepines of the general formula I, which is characterized in that the 5- (o-tolyl) -7-chlorl, 3-dihydro-2H-1,4-benzodiazepin-2-one is used in a manner known per se the formula

with a reactive ester of an alcohol of the general formula III

H Il
NC

RO-C _n H _2n -OH

(III)

in which R and r have the aforementioned meaning, condensed or a compound of the general formula IV

R.
O

C ₁₁ H _2n

Cl

CH,

(H)

C = N

with a reactive ester of an alcohol of the general formula UI

N - COCH ₂ - NZ

RO-C _n H _2n -OH

(III)

(IV)

in which R and η have the abovementioned meaning in which R and η have the abovementioned meaning, condensed and, if appropriate, the compound of the general formula I obtained is converted into the salt by reaction with an inorganic or organic acid.

Examples of reactive esters of the alcohol of the general formula III are the esters of hydrohalic acids, like the chlorides, bromides and iodides, as well as the sulfonic acid esters, like the methane

sulfonate, p-toluenesulfonate, ^ '- naphthalene sulfonate and Trichloromethanesulfonate.

The reaction can be carried out in the presence or absence of a base. One can also the connection of the forms! II with a basic metal compound to form the metal salt bring to implementation and then this with the reactive ester of the alcohol of the general Condense Formula III. Examples of bases or basic metal salts are alkali hydrides, such as Sodium or lithium hydride, alkali hydroxides such as potassium hydroxide, alkali amides such as sodium, potassium or Lithium amide, alkali alkyls such as butyllithium, alkali metal phenyl compounds such as phenyllithium, or Alkali alcohols, such as sodium methylate, sodium ethylate and potassium tert-butoxide. The implementation is generally in an organic solvent such as benzene, toluene, xylene, dimethylformamide, Dimethylacetamide, diphenyl ether, ethylene glycol dimethyl ether, dimethyl sulfoxide, methyl ethyl ketone and N-methylpyrrolidone, or mixtures thereof, at temperatures carried out from about room temperature to the boiling point of the solvent used. According to another embodiment of the method of the invention is known per se Way a compound of the general formula IV

R.
O

a solvent such as methanol, ethanol, isopropanol or water, or mixtures thereof, at temperatures from about room temperature to Carried out boiling point of the solvent used.

If the group Z is a carbobenzoxy group and a hydrogen atom, cleavage takes place with a hydrogen halide such as hydrogen bromide or hydrogen chloride. Hydrogen bromide is preferred.

"o The hydrogen halide can be in the form of hydrohalic acid, such as bromic or hydrochloric acid, can be used. The implementation is in one Solvents such as methanol, ethanol, acetic acid or water or mixtures thereof at temperatures

carried out from about room temperature to the boiling point of the solvent used. The reaction can either directly to the benzodiazepines of the general formula 1 or via a Intermediate of the general formula V

20th R. O

C _n H _2n

i

N-CO-CH ₁ -NH ₂

(V)

Cl

C-O

Cl

C ₁₁ H ₂ ,,

N - CO - CH ₂

C = O

- N Z

CH ₃

(IV)

40

in which R and »1 have the aforementioned meaning and Z denotes a nitrogen protective group which has at least contains an easily removable group, condensed intramolecularly with elimination of the group Z. Examples of the protective group Z are the phthaloyl group, lower alkylide radicals, such as the isopylidene group, the benzal group or the carbobenzoxy group and a hydrogen atom. In the latter Case owns the group

the formula

—N Z

N-COO-CH ₂ - /

55 in which R and »1 have the aforementioned meaning. The intermediate of the general formula V can be isolated in the form of the hydrohalide when working under mild reaction conditions, such as suitable reaction temperatures and reaction times. The ring closure reaction of the compound of general formula V to give the compounds of general formula 1 can be carried out on standing at room temperature or at elevated temperature in a suitable solvent, such as acetic acid, methanol, ethanol, pyridine or dimethyl sulfoxide; optionally in the presence of a base.

The starting compounds of the general formula IV can, for. B. by implementing a benzophenone of the general formula VI

R.
O

C _n H ₂₁ ,

The protective group is split off by methods known per se. If z. B. the remainder Z. means a phthaloyl group, this is obtained by reaction with hydrazine equivalents, such as hydrazine hydrate or phenylhydrazine, split off This produces the benzodiazepine of the general formula The reaction is preferably carried out in the presence of Cl

Ν —Η

C = O

(Vl)

in which »1 and R have the aforementioned meaning, with

a carboxylic acid of the general formula VII

ZN -CH ₃ -COOH

(VIl)

in which Z has the aforementioned meaning, or its reactive derivative, e.g. B. the Sä.irechlorid or mixed anhydride, or by oxidation of one of the general formula VIII

CH,

(VIII)

of ten male albino mice with a body weight of 22 ± 2 g are such animals used can be kept on the rotating rod 'The ED _a0 -W'ert, which is the dose at which 50% of animals no longer on the can hold rotating rod is calculated by probit analysis.

3. Acute toxicity

The acute toxicity is determined in groups of ten mice with a body weight of 20 ± 2 g in three different doses. The LD _5U value is the dose at which 50% of the animals examined die 10 days after oral administration of the compound to be examined.

The results are summarized in the following table:

in which Z, 11 and R have the aforementioned meaning, with an oxidizing agent such as chromic acid or Ozone.

To prepare the salts, the free bases with inorganic or organic acids, such as chlorine or Hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, maleic acid, fumaric acid, Tartaric acid, succinic acid, citric acid, capersulfonic acid, ethanesulfonic acid, ascorbic acid or lactic acid.

The benzodiazepines of the general formula I according to the invention and their salts are valuable tranquillizers. This can be seen from the following experiments, in which the l-methoxymethyl-5- (o-tolyl) -7-chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one (compound A) and the 1 - (ß - Methoxyethyl) - 5 (o-tolyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (compound B) with the known 1-methyl-5-phenyl - 7 - chlorine -1,3 - dihydro - 2 H -1,4 - benzodiazepin-2-one (diazepam) is compared:

1. Antipentamethylene tetrazole test

This test is a measure of the central nervous system depressant effect of benzodiazepines. The suppression of the convulsions induced by pentamethylenetetrazole is carried out on groups of ten male mice with a body weight of 20 ± 2 g in seven different doses according to the method of EA Swinyard, J. Am. Pharm. Assoc. (Sci. Ed.), Vol. 38 (1949), p. 201. Thirty minutes after the oral administration of the test compound, the mice are administered intravenously 65 mg / kg of pentamethylenetetrazole. The ED ₅₀ value is calculated by probit analysis, taking into account both suppression of convulsions and deaths.

2. Torsion bar test

This test is a measure of the muscle-relaxing effect and the influence on coordination.

A device is used that has a horizontally supported rod with a diameter of 3 cm rotating at a speed of 5 rpm. Every experimental group passes

, _n Tcst- Anlipenfa- Turn Acute Sicberbeiis- connection methylcn- slab test Toxi / ital index rotary tctra / ol- tl>, " LD ₅₁ , staff member ED _M Tcsl. ED ₅₁ , Antipentious methylcn- telr; i7ol-lcsl. (mg / kg) (mg kg (mg kg 1 EGG),,, pole Ver 3.5 60 > 3000 17.14 bond A 3 ° Ver 5.8 100 > 3000 17.24 binding B Diazepam 0.96 2.7 > 680 2.81

In the torsion bar test, the muscle-relaxing effect and the activity on motor coordination the connection to be examined checked. In general, a compound used in the torsion bar test shows a potent effect, can be used as a muscle relaxant. Such connections however, inhibit the coordination movement due to their muscle relaxing effect, which z. B. leads to speech and walking disorders. A compound with a strong muscle relaxing effect is therefore not an ideal tranquilizer.

The table shows that compounds A and B have an excellent safety index and are therefore superior to diazepam. The benzodiazepines of general formula 1 and their salts can, for. B. parenterally or orally in therapeutic Dosage forms, e.g. B. in solid or liquid form, such as tablets, coated tablets, capsules, Suspensions, solutions or elixirs.

The examples illustrate the invention.

example 1

A solution of 2 g of 5 - (o - tolyl) - 7 - chloro -1,3 - dihydro - 2 H - 1,4 - benzodiazepin - 2 - one in 20 ml of dimethylformamide is mixed with 0.5 g of sodium methylate. The mixture is stirred for 1 hour at 50 to 6O ⁰ C and then cooled. Subsequently, the reaction mixture is below 20 ⁰ C is added dropwise a solution of 1.0 g / i-Methoxyäthylchlorid in 10 ml of anhydrous toluene. The mixture is stirred for 3 hours at 100 ° C., then cooled, poured into ice water and extracted with chloroform. The chloroform extracts are combined,

washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. After that the solvent is distilled off under reduced pressure. The residue is dissolved in benzene, on Kicselgcl chromatographies and with chloroform cluicrl. Evaporation of the eluate gives one syrupy residue which crystallizes after the addition of isopropanol. After recrystallizing from Isopropanol / Isopropyläthcr one obtains the 1 - (// - Mclhoxyäthyl) -5- (o-tolyl) -7-chloro-1,3-dihydro-2 H 1,4-benzodiazepin-2-one as colorless prisms from F. 115 to 116.5 C.

The following benzodiazepines of general formula 1 are produced in a similar manner:

I - (, i-Ethoxyäthylj-S-to-lolylM-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one, F. 141 to 142 C, and

1 -Methoxymethyl-S-lo-tolyO-T-chloro-1,3-dihydro - 2 H -1,4 - benzodiazcpin - 2 - one, m.p. 130 bis 13 IC.

Example 2

A mixture of Ig 2 - (N - phthalimidoacetyl-N - / ι - ethoxyethyl) - amino - 5 - chloro -T- methylbenzophcnon, 15 ml of methylene chloride and 15 ml of ethanol is mixed with a solution of 2 g of hydrazine hydrate in 2 ml of water. The mixture is stirred at room temperature and then concentrated under reduced pressure. The residue is diluted with water, made alkaline with aqueous ammonia and extracted with ether. After drying the ether extracts and evaporation of the solvent, the residue is recrystallized from isopropanol. This gives 1 - (// - ethoxyethyl) -5- (o-tolyl) -7-chlorl, 3-dihydro-2H -1,4-benzodiazepin-2-one as colorless prisms from F. 141 to 142 ' C.

Example 3

A mixture of I g of 2- [N ¹ - (/ i-Äthoxyälhyl) -N 'ίο (N ² -carbobenzoxyglycyl) -amido] -5-chloro-2'-methylbenzophenone and 20 ml of a 30% strength hydrogen bromide solution in acetic acid is stirred at room temperature. The reaction mixture is poured into water, aqueous ammonia is added until it has an alkaline reaction and the mixture is extracted with methylene chloride. The methylene chloride extracts are combined and dried over sodium sulfate. After the solvent has been distilled off, the residue is crystallized and recrystallized from isopropanol. The l - (/ i-Ethoxyethyl) -5- (o-tolyl) -7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one with a melting point of 141 to 142 ° C. is obtained.

According to Examples 2 and 3, the following benzodiazepines of the general formula 1 are prepared:

1 - (/ i - methoxyethyl) - 5 - (o - tolyl) - 7 - chloro -1-3 - dihydro-2H-1,4-benzodiazepin-2-one, m.p. 115 to 116.5 ⁰ C, and

1 - methoxymethyl - 5 - (o - tolyl) - 7 - chloro -1,3 - dihydro - 2 H -1,4 - benzodiazepin - 2 - one, F. 130 bis

609641/149

Claims (1)

Patent claims: 1. 1-Alkoxyalkyl-5- (o-tolyl) -7-chloro-1,3-dihydro-2H -1,4-benzodiazepine-2-one compounds of the general formula I. and Z represents a nitrogen protecting group which contains at least one easily cleavable group, condensed intramolecularly with elimination of the group Z, and optionally the obtained converted free base into the salt by reaction with an anoi ganischen or organic acid. 5. Medicinal preparations consisting of a compoundgeneral Formula I according to claim 1 and customary, pharmacologically acceptable carriers and diluents.