Benzudiazepine compound

SWEDEN

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PATENTS AND REGISTRATION OFFICE

PUBLISHING WRITING No. 337 033 int c. C 07 d 53/06 κι. 12 p 10/01

Patent Application. No 16452/67 Received on 29 X1 1967 Validity Day on 29 VIII 1962

Ans. generally available on 1 γΐχ · -j 968

Ans. published and the pamphlet published on the 26 th of 1971

Priority requested from 29 VIII 1961 ooh

III 1962 (USA, 154,569,177,174)

AMERICAN HOME PRODUCTS CORPORATION, NEW YORK, NY USA

Inventor »SC Bell

Ombuds PU PU

Process for Preparation of 3- (Hydroxy or Alkoxy) Substituted 1,4-Benzodiazepine * 2-ones

T '*.

Γ

The invention relates to the preparation of hitherto unknown 3-hydroxy-2H-1,4-benzodiazepin-2-ones having valuable effects on the central nervous system.

. The compounds obtained by the method according to the invention can be thundered by the formula

<img file="SE337033B_D0002.tif" />

wherein Ϊ is hydrogen, chlorine, bromine, nitro, trifluoromethyl or methylsalphonyl, R is lower alkyl, R ^ hydroxy or lower alkoxy and Ar is phenyl, thienyl or phenyl substituted with chlorine, fluorine or trifluoromethyl.

Preferably, R is methyl, R 2 hydroxy, Ar phenyl or chlorophenyl and a chloro substituent at the 7-position.

The compound of general formula I has valuable anticonvulsant and anti-masking effects. Some of them have sedative effects and some have tranquilizing effects without being sedative. Some of them have valuable drug-inhibiting effects and raise libido.

IN ^r The compounds of general formula I can be prepared by a method characterized essentially by reacting an N-alkylating agent containing a lower alkyl group with a benzodiazepine of the general formula

K.

^c L

-&lt;_C/^hrsR¹

II where R¹, Y and Ar are as defined above to form a 1-lower alkyl compound.

Generally, the compound of formula II is treated with an alkaline substance (e.g., sodium or potassium hydroxide) and then with, for example, dimethyl sulfate, diethyl sulfate or methyl iodide.

The starting materials of general formula II, which contain a hydrogen atom at the 1-position, can be prepared by hydrolyzing or alcoholizing a compound of the general formula

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III o

where Y and Ar represent the same as above and R represents an acyloxy radical or a halogen atom. The compounds of general formula 2

III, where R is a halogen atom, can be prepared by producing a 5- &amp; aryl-1,3-dihydro-2H-1,4-benzodiazepin-2-one-h-oxide of the general formula

hrs

IN

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IV where Y and Ar represent the same as above, reacting with an alkyl haloformate (cf. Patent 323 O8) the compounds of general formula III wherein R is a carboxylic acyloxy radical can be prepared by acylating a compound of general formula IV a carboxylic acid halide or anhydride (cf. patent 322 22?).

The products of the invention may be administered parenterally or orally, and may, as desired, be combined with pharmaceutically acceptable diluents, solvents, suspending agents, carriers, fillers, excipients, binders, dyes and flavors, etc. to produce suitable dosage forms.

The following examples illustrate the invention.

Example 1

A mixture of 3.4 g of 7-chloro-3-hydroxy-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 4 ml of 4-N sodium hydroxide and 1.4 ml dimethyl sulfate in 200 ml of 50% alcohol was stirred for 2 hours and then evaporated in vacuo to dryness. Water and ether were added and the ether layer separated. The solvent was removed and the residue was recrystallized from cyclohexane to give 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one. Mp: 119121 ° C.

Example 2

7-Chloro-5- (o-chlorophenyl) -1,3-dihydro-3-hydroxy-1-methyl-2H-1,4-benzodiazepin-2-one was prepared from 7 “chloro-5- (o-chlorophenyl) -1,3-dihydrp-3-hydroxy-2H-1,4-benzodiazepin-2-one according to the procedure described in Example 1. mp .; 192-194- ° C.

^C16^hrs12^C12^N2°2^{S Estimated! c} 57.33 H 3.61 N 8.36 Cl $ 21.15

Found; C 57.4-2 H 3.44 N 8.69 Cl $ 21.25

Example 3 1-Cyclopropylmethyl-7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepine “2” One at m.p. 3 'dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one according to the procedure described in Example 1, but using a cyclopropylmethyl bromide.

Example 4X-methyl-7-chloro-1,3 'dihydro-3-methoxy-5-phenyl-2H-1,4-benzodiazepin-2-one, m.p. chloro-1,3 'dihydro-3-methoxy-5-phenyl-2H-1,4-benzodiazepin-2-one according to the procedure described in Example 1.

Example 5

1-methyl-7-chloro, 3-dihydro-3-methoxy-5- (o-chloro or enyl) -2H-1,4-benzodiazepin-2-one, m.p. 4- ° C can be prepared from 7-chloro-1,3-dihydro-3'-methoxy-5- (o-chlorophenyl) -2H-1,4-benzodiazepin-2-one according to the procedure described in Example 1.