DE2037668A1 - New 1 ^ Benzodiazepines - Google Patents

Description

DR. ING. F. AVUESTHOFF • DIPI * ING. G. PtTLS DR.E.Y.PECHMANN DR. ING. D. BEURENS

PXTENTANMTiI ₁ TE

8 MUNICH 9O

SCHWEIGERSTRASSE

TILXTOI 33 09 31

PIOTIOTUTIHT

U - 38 344

Description ₂ u of the patent application

Aktieselskabet Grindstedvaerket 53, Jens Baggesens vej, Srhus, Denmark

concerning

New 1,4-benzodiazepines

The invention relates to new 1,4-benzodiazepines, useful as sedatives, muscle relaxants, anticonvulsants, and tranquilizers. It affects 1,4-benzodiazepines of the general formula I.

(D

009887/2247

COPY

in which R is a hydrogen or halogen atom, a lower one

ο alkyl group or alkoxy group or a nitro group and R means a lower alkyl group, as well as intermediates, which arise in the preparation of compounds of the formula I, and a process for the preparation of these compounds .and the intermediate products

The term "lower alkyl or alkoxy group" is to be understood to include groups with a maximum of 6 carbon atoms designated.

The connections of the. Formula I can be used as a drug with sedative and tranquilizer properties, those of the known 1,4-benzodiazepines, e.g. 7-chloro- ' 1,3-dihydro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one (Diazepam) are similar, but differ in that they have no blood pressure lowering effect or with Antihypertensive agents act synergistically.

According to the present invention, the compounds of general formula I are prepared by the corresponding Compounds of the general formula II

(II)

009887/2247

ORIGINAL INSPECTED

in which R and R have the meanings given above, dehydrated.

The dehydration is preferably done with phenyl isocyanate carried out as a dehydrating agent.

The intermediates of general formula II are new chemical compounds that can be prepared according to the following reaction scheme:

(III)

(IV)

or

(II) and ^ hydrolysis

C ₆ H ₅ MgBr

1 2 '

where R and R have the meaning given above «

The compounds of the general formula III are known and are made in accordance with the French patent 1 482 641 manufactured.

The invention will be further illustrated by the following examples explained.

009887/2247

example 1

7-chloro-2-methoxy-3H-1,4-benzodiazepine-4-oxide (IV):

14.7 g (0.07 mol) of 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-4-oxide were suspended in a mixture of 150 ml of methanol and 150 ml of ither. 225 ml (0.113 mol) of a 0.5M ethereal solution of diazomethane was added at 10 ⁰ C under stirring, to the suspension, every 15 minutes, a fraction of 25 ml was added. The. The resulting yellow suspension was stirred at room temperature overnight. The next day the suspension was colorless. An additional 150 ml (0.075 mol) Dikzomethan solution at 10 ⁰ C is added, with every 60 minutes, a fraction of 25 ml was added. After the last addition, the yellow diazomethane parbe no longer disappeared and the methylation appeared to be complete.

The colorless substance was filtered off and washed twice with 10 ml of ether and the filtrate and the ash liquids were evaporated.

The Piltrat and washings from 7-Chlormetbyl-3H-1 ^ -benzodiazipin - ^ - on - ^ - were oxide evaporated on a water bath (5O ⁰ C) -in the vacuum (20 mm / Hg) to dryness and the crystalline residue (12.5 g) was dissolved in 100 ml of acetone at 50 ^° C. The warm solution was filtered and the filtrate was left to stand at 10 ^° C. overnight. The resulting crystals were filtered, washed with cold acetone (10 + 10 ml) and dried at 5O ⁰ C and a pressure of 0.1 mm / Hg. Bulky white needles were obtained. Yield: 3.14 g (20 $ d.3? H.). ? p. 205-207 ⁰ C. flat recrystallization from acetone gave an analytically pure product. Pp 209 -. 21O ⁰ C (2ers.). . Analysis; found: C, 53.4; H 4.1} Cl 15.7; N 12.4

calculated for

C ₁₀ H ₉ ClN ₂ O ₂ (224.6): ^.: 7 ', \'

C 53.5; H 4, Or Cl 15, β; N 12, ^. 00 9887/2247

Example 2

7-chloro-2-methoxy-4-hydroxy-5-phenyl-4,5-dihydro-3H-1,4-benzo-diazepine:

1.68 g (0.0075 mol) of the product obtained according to Example 1 were suspended in a mixture of 60 ml of dry ether and 25 ml of dry tetrahydrofuran and the suspension was heated ^{to 35 ° C. with stirring.} To this was added over 50 minutes a solution of phenyl magnesium bromide, which was added dropwise of 0.3 g (0.0124 mol) of magnesium and 1.88 g (0.012 mol) of bromobenzene was erbalten in 30 ml ether, at about 35 ⁰ C. The resulting orange-colored solution was ^{kept at 40 °} C. for ^{35 minutes, then cooled to 0} ° C. and processed further in the usual way. When the reaction product was crystallized from benzene and then from cyclohexane, 1.57 g ($ 70) of the desired product were obtained in the form of white crystals. Pp. 146 - 147 ⁰ C.

Analysis: found:

for

¹ k - L

C. 63 63 , 2; H 5 ,1 i ei 1 2, 1 K 9, 9, 3; OCH 3 10.3 (302, 8th) C. , 5; H 5 , 0 ; Cl 1 1, 7th H 3i OCH, 10 , 29t.

Example 3 '

7-chloro-2-metboxy-5-phenyl-'3H-1,4-benzodiazepine: ■ '".-.' ■

6.2 g (0.025 mol). of the product according to Example 2 were dissolved at 20 ^° C. in a mixture of 60 ml isobutyl acetate and 6 ml 1,4-dimethylpiperazine and the solution was ^{stirred at 25 °} C. for 5 minutes. To this, 4.85 ml (0.0456 mol) of phenyl iooyanoate were added and the solution was refluxed for 15 minutes. The evolution of carbon dioxide

■ - 6 -. 0Q9887 / 2247.

ORIGINAL mSPECTED

- 6 - 203 * 7 B 6 * 8 f ΐ

began at about 4O ⁰ C and stopped when the solution started to boil under reflux. The yellow suspension was ^{cooled to 25 °} C. and 100 ml of methylene chloride were added to this with stirring. The white crystals were filtered off, (30 + 30 ml) washed with methylene chloride and dried at 60 ⁰ C. 4.0 g of carbanilide (92 # d.Tb.) were obtained. Mp. 243 ⁰ C • The filtrate and the washing liquids were combined and under reduced pressure on a water bath (70 ⁰ C) for. Evaporated dry. To. 100 ml of cyclohexane were added to the yellowish-brown residue, most of the residue being dissolved. The mixture was allowed to stand overnight at 5 ⁰ C and the solution decanted from the insoluble oil-like residue. The cyclohexane solution was evaporated under reduced pressure on a water bath (9O ⁰ C) to dryness. The light yellow, highly viscous residue (6.45 g) was obtained in an oil bath - distilled (178 182 ⁰ C). One obtains 5.29 g (919 ^ d.Th.), (Kp _{0 3162-165} ⁰ C) of the desired product.

Analysis; found C, 67.3; Ii 4.7; Cl 12.1

N 9.8; OCH ₅ 10.7

calculated for C ₁₆ H ₁₃ C1N ₂ O (284.7):

C 67.5; N 4.6; Cl 12.5 »9.9; OCH ₅ 10, J.

7-Nitro-2-methoxy-5-phenyl-3H-1,4-benzodiazepine can be prepared analogously. Kp ₀ , 165-175 ⁰ C. ^Λ

-. - Claim

6238 * - 7 -

009887/2247

" ^v * '' ORIGINAL INSPECTEP

Claims (2)

DH. ING. F. "WXTBSTIiOFF DIPUINCCPITtS DR.K.T.PKCHMANN DR. ING. D. BKHREWS ' 8'MUNICH 90 SCHWEIGERS! S3 0β 81 TILIOITU HlSHlMI « mOxcbzn U - 38 344 Claims 1 · 1,4-benzodiazepines of the general formula I N = "C -. OE ² Λ (D in which R is a hydrogen or halogen atom, a lower one 2 alkyl or alkoxy group or a nitro group and E means a lower alkyl group. 2. Process for the preparation of the 1,4-benzodiazepines according to Claim 1, characterized in that paves one is a compound of the general formula B ' 00988772247 ORiGiNAL INSPECTED with a diazo compound of the general formula RN ₂ reacts »the resulting with pbenyl-lithium or with phenyl-magnesium bromide and hydrolyzing the reaction product, being a 1,4-benzodiazepine of the general formula II , 2 (II) arises, where R is a hydrogen or halogen atom or a lower alkyl or alkoxy group or a nitro group, 2
and R is a lower alkyl group and debydrates this compound. 3. The method according to claim 2, characterized in that that the dehydrating agent used is phenyl isocyanate used. 4. In the process according to claim 2, 1,4-benzodiazepines of the general formula II occurring as an intermediate 009887/224 7. (H) where E is a hydrogen or halogen atom, a lower one Alkyl or alkoxy group. or a nitro group and H a means lower alkyl group. 5 · 1 - ^ - benzodiazepines according to claim 1 or 4, characterized in that R is a chlorine atom in the 7-position 2
and R is a methyl group. 6238 009887/2247 - ORfGHNAL INSPECTED