DE2064926A1 - New benzodiazepine derivatives. Excretion from. 2056174 - Google Patents

Description

PATENT LAWYERS D) L-INO. FROM KREISLEK DR.-ING. SCHDNWALD DR.-ING. TH. MEYI * DR. FUES DIPL-CHEM. ALEK VON KREISLER DIPL-CHEM. CAROLA KELLER DR.-ING. KLÖPSCH COLOGNE 1, DEICHMANNHAUS

Cologne, March 9, 1971 Kl / En

Takeda Chemical Industries, Ltd.,

27, Doshomachi 2-chome, Higashi-ku, Osaka (Japan)

New benzodiazegine derivatives. Removal from patent (patent application P 20 56

The invention relates to compounds of the general formula

H-NH-C-NHR ¹

in which the rings A and / or B! »! are substituted or with halogen atoms, nitro groups, trifluoromethyl radicals, alkyl radicals or Älfcoxyresfcef * are substituted, R a hydrogen or a lower alkyl stress, X an oxygen atom or sulfur atom and R ¹ a hydrocarbon radical int and a Gauerntoffatom is bound to the nitrogen atom in the ^ position c ^^ - ^ enpnfal, and a pharmaceutically acceptable salt? diGE *; r connections,

109830/2109 _{0R (G | NAL}

2064326

These compounds can be produced by the following reaction «

NH-NH

R ¹ NCX
(II)

/ NH-NHC-NHR '

(in)

Here the rings A and B, R and X have the meaning given above. R 'is a hydrocarbon radical, and is attached to the nitrogen atom An oxygen atom can be bonded in the 4-position of the formulas (I) and (III).

As hydrocarbon residues, for di © R * in general Formulas (II) and (III) come in general.Alkyl radicals (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl, cyclohexyl and cctyl), Aryl groups (e.g. phenyl and naphthyl) and aralkyl groups (e.g. benzyl and phenylethyl) in question. The aronstiechen Rings of these aryl and aralkyl radicals can have substituents contain that do not interfere with the respective reaction,

A compound (I) is with the isocyanic acid ester or Tsothiocynnsäurftcnhpr <? <■ »? »General formula (II) implemented. In general, the reaction is advantageous in the presence of an incident solvent at or below room temperature durchse'ickt from room temperature. As a solution! Vr? R ,, ifctel. E.g. aromatic hydrocarbons ferric, ryridine,. Tetrahydrofuran, chloroform, dimethylformamide and alcohols (e.g. methanol and n; l ethanol). If necessary, the

., ..! 09030/2103

BATH

Reaction can also be carried out with heating. The compound (II) is used usually in an amount of from 1 to 1.5 molar equivalents per part of the compound (I). The obtained 2- (4-subst. Semicarbnzido) - or 2-O- sub st. Wiiosemicarbazido) -1 _i 4-bensodiar.epine derivative (III) can be obtained in the desired unit by methods known per se (e.g. by distilling off a solvent and recrystallization).

The compounds according to the invention (III) have remarkable pharmacological effects on the central nervous system, for example rauskelentspannende, anticonvulsant, sedative and hypnotic effects, and "skins valuable%

Medications, e.g. muscle relaxants, anticonvulsants, Tranquilizers and sleeping pills. The compounds (III) and their salts with acids can be used orally or parenterally as such or optionally in a mixture with pharmaceutically acceptable carriers in the form of pharmaceutical preparations such as powders, granules, tablets and injection solutions. The amount administered depends on the nature of the compounds, the clinical picture and the like and is generally about 1 to 30 mg / day in the adult when administered orally.

_; In the following examples, parts are understood to be parts by weight, unless otherwise stated. Parts by weight are related to parts of volume as grams are to cubic centimeters.

The for the method according to the invention as materials used 2-hydrazine ~ 1,4-benzodiazepine derivatives or their 4N-oxides can be easily prepared. For example becomes 7-chloro-2-hydrazine-5-phenyl-3H-1, 'i} - benzodiazepine, which is used as a starting material in the example 1 ^ 4- and 5 described experiments is used on the below under "Experiment 1", "Experiment 2" and "Experiment 3" described way. The other au ^ gan Lines can be manufactured in a similar way.

109830/2109

Attempt 1

1.25 parts of 80% hydrazine hydrate are added to a suspension of 3.4 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine dihydrochloride in 60 parts by volume of methanol. The mixture is stirred for 40 minutes. After adding ^ asee, the equipment is extracted with methylene chloride. The methylene chloride layer is washed with water and dried over anhydrous sodium sulfate, whereupon the solvent is distilled off. Recrystallization of the residue from methylene chloride-benzene 7-chloro-2-hydraziri-5-phenyl-3H-1,4-benzodiazepine is in the form of colorless prisms obtained which have a melting point of about 170 ⁰ C (browning) and 202- 204 ° C (dec.).

Elemental analysis: , ClN .: C. 43 4th H N , 27 Calculated for Cj ₁ -IL, 63, 27 4th 748 19th , 68 Found: attempt 63, , 60 19th 2

5 parts by volume of hydrazine hydrate are added to a solution of 2 parts of 7-chloro-2-ethyl-mercapto-5-phenyl-3H-1,4-benzodiazepine in 70 parts by volume of methanol. The mixture is left to stand at room temperature for 3 days, after which the solvent is distilled off. The residue is diluted with water, whereby eich ^ -Chlor ^ -hydrazine - ^ - phenyl-3H-1,4-benzodiazepine separates out in the form of crystals. By recrystallization from methylene chloride-benzene colorless prisms are obtained which melt at 175 ° C (softening) and 205 to 207 ⁰ C (dec.).

This product is similar to that prepared according to "Experiment T" Connection identical.

Attempt 3

A mixture of 2.9 parts of 7-chloro-1,3-dihydro-5-phenyl-2H-1v ^ -bensodiazepine-S-thione, 2.5 Rnuratcilen Dimethylsulfcxyd, 100 parts of ethanol and 5 rooms hurry Hydrazine hydrate is left to stand for 1 day * According to E des / ithanols by distillation under reduced pressure

109830/210 «

the concentrate is diluted with water and mixed with methylene: Chloride extracted. The methylene chloride layer is removed and dried over anhydrous sodium sulfate, whereupon the solvent is removed. The treatment the residue with benzene gives 7- ° chloro-2-hydrazine-5-phenyl-3H-1,4-bensodiazepih in the form of crystals. Uncristallization from methylene chloride ~ benzene gives colorless prisms with a melting point of 2O5-2O7 ° C (decomp.).

This product is identical to the products in the "Trials 1 and 2" were obtained. '

example 1

3.5 parts by volume of methyl isocyanate are added dropwise to a solution of 14.2 parts of 7-chloro-2-hydrazine-5-phenyl-3H-1,4-benaodiazepine in 250 parts by volume of tetrahydrofuran, while cooling with ice and stirring. After stirring for 1 hour, the mixture is poured into 2000 parts per volume. The precipitate is filtered off, washed with water and acetone and then dried, 7-chloro-2- (4-methylsemicarbazide) -5-phenyl-3H-1,4-benzodiazepine being obtained in the form of crystals. Recrystallization from Dimethylfornamid-water gave colorless needles melting at 247 ⁰ C (dec.).

Elemental analysis: ₁₆ C1N ₅ O: C. 73 4th H
■ Wed . N Calculated for C ^ nH. 59, 53 4th , 72 20.49 Found J. example 59, , 62 20.80 2

To a solution of 1.4 parts

10'9830 / 210ί

5H-1,4-benzodiazepine in 25 parts by volume of tetrahydrofuran are added 0.6 parts by volume of phenyl isocyanate, while cooling with ice and stirring. After stirring for 1 hour, double the amount of water is added to the mixture. The crystals formed are filtered off, washed with water and acetone and dried, 7-chloro-5-phenyl-5- {4-phenyleeaicarbazide) -3H -1,4-benzodiazepine is obtained in the form of crystals. Recrystallization from dimethylformamide-water gives fine colorless needles melting at 220-221 ⁰ C (dec.).

Elemental analysis: C 5H

Calculated for C ₂₂ H ₁₈ ClN ₅ O: 65.42 4 _S 49 17.34 Found: 65.61 4, ^ 0. 1?, 2S

Example 3

To a solution of 3.1 parts of 7-chloro-2-hydra2in- »5 (paethoxyphenyl) -3H-1,4-benzodiazepine 0 * 7 parts by volume of methyl isocyanate are added dropwise to 40 parts by volume of pyridine, while cooling and stirring with ice. After stirring for about 30 minutes, it will be 100 roughness t / ater given a mixture. The crystals formed are filtered off, ashed with !! ethanol and dried, 7-chloro-5- (p-methoxyphenyl) -2- (4-methyl-semicarfcazid) -3H-1,4-benzodiazepine is obtained in the form of crystals.

Recrystallization from dimethylformamide water gives color loose, fine needles with a melting point of 234-235 ° C (decomp.)

Elemental analysis: C. H H Calculated for C-qFLqCII « '3O ₂ : 58.14 4.88 18.84 Found: 57.63 4.74 19.17

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Example 4
A mixture of 2.8 room dividers! 2-Ainino-7 ~ nitro-5-phenyl-

. 3H-1,4-benzodiazepine and 2 parts by volume hydrasine hydrate Stirred for 1 hour at room temperature and then strass in ISi poured. The chloroform layer is washed with water

, and dried over anhydrous sodium sulfate. The solvent is distilled off, with 2 ~ hydrazine-7-nitro-5 ~ phenyl-3H-1,4-benzodiaeepine as a viscous oily substance is obtained.

The 2-hydrazine derivative thus prepared is divided into 20 R&Ds Pyridine dissolved, whereupon 1.1 parts by volume of methyl isocyanate added | while the ice is being used to bruise and stir · After stirring for 1 hour, the mixture is mixed with 80 Siuir.tcilen Water mixed. The precipitate formed in this way is filtered off, washed with acetone and dried, robei

diazepine is obtained in fora from crystals. Ümkristallisation from Dimethylforaiamid-T7asser resulting yellow fine flakes of melting point 239-24O ⁰ C (dec.).

Elemental analysis: 0 H H

Calculated for C ₁₇ H ₁₆ N ₆ O ₅ : 57.95 4 »58 23.85 Found: 57.98 4.47 24.14

Be lapIeI 5

0.7 parts by volume of pyridine are added to a solution of 3 parts of 7-chloro-2-hydrazine-5-phenyl-3H-1 ^ -benzodiazepine-AH-oxide in 60 parts by volume of pyridine, while the mixture is cooled and stirred with ELs. After about 30 minutes, the crystals formed are filtered off, washed with methanol and dried, 7-chloro-2- (4-methylsenicarba? Iid) • ^; 6 ~ phenyl-3H-1,4-bensodiazepine-4lT-oxide is obtained in the form of crystals. Uiacristerilization from dinethylformanide water gives colorless, fine needles, melting point 25 ° C (decomp.).

109830/2109 ORIGINAL BATHROOM

_β a »© ο

Elemental analysis: σ H N

Calculated for C ₁₇ H ₁₆ CIN ₅ O ₂ ! 57.06 4.51 19.58 Found :, / 56 * β6__. ._4

Belaplal 6

"SSueiner Iß" img of 2.85 fur 7-chloro-2-hydra "in-5- : phenyl-3H-1,4-bensodiasepine in 250 parts by volume of iithenol, 1.5 parts of phenyl isothiocyanate are added to the mixture Left to stand for about 3 hours at room temperature. Tue « precipitated crystals are filtered off, whereby 7-chlorine » 5-phenyl-2- (4-phenyl tbloaemiearbazid) - "3H-1,4-bensodias" pin is obtained in the form of crystals from acetone gives pale yellow needles with a sea point of 199-2O5 ° 0 (decomposition).

Elemental analysis: £ H H Calculated for C ₂₂ H ₁₈ OlN ₅ Si 62: .96 4.31 16.6?

Found: _ ^ 62.51 *, 31 16.65

BATH ORIGINAL

109830/2109

Claims (6)

Claims e Compounds of the general formula H
[-NH-C-NHR ¹ in which the rings A and / or B are unaubstituted or with Halogen atoms, nitro groups, trifluoromethyl radicals, alkyl radicals or alkoxy radicals are substituted, S is a hydrogen atom or a lower alkyl radical, X is an oxygen atom or sulfur atom and R * is a hydrocarbon radical and optionally to the nitrogen atom in the 4-position an oxygen atom is bonded, and pharmaceutically acceptable salts of these compounds. 2) 7-chloro-2- (4-methylbeiniearbazid) -5-phenyl-5H-1,4-benzodiazepine y) 7-0hloro-2- (4-phenyleemicarbazide) -5-phenyl-3H-1,4-benzodiaxepine. 4 ) 7-chloro-5- (p- «ethox3rphen7l) -2- (4-aethyleemlcarbazid) -3H-1,4-benzodiazepine 5) 2- (4-methyl8enicarbazide) -7-nitro-5-phenyl-3H-1,4-benzodiatepine. 6) 7-Qhior-2- (4-methylsemioarbaBid) -5-phenyl-3H-1,4-benzo- T) 7-Ohlor-2- (4-phenylthioeemicarbazid) -5-phenjl-3H-1, * - ■ · benzodiaeepin. 109830/2109 bad orwinal