NO127302B - - Google Patents

Description

Procedure for the production of therapeutically active

1-Substituted 2-oxy-2,3-dihydro-5-aryl-1H-1,4-benzodiazepines.

The present invention relates to a new process for the production of 1-substituted 2-oxy-2,3-dihydro-5-aryl-1H-1,2-benzodiar.epines.

From Chem. Fox. 68 page" 766 . (1968) it is known to reduce 1-

unsubstituted 5-aryl-1H-1,<1>+-benzodiazepine-2-ones to 1-unsubstituted 5-aryl-1H-1^-benzodiazepines or a corresponding tetrahydro derivative.

In contrast, it has now been rather surprisingly found that 5-aryl-1H-1,1f-benzodiazepine-2-ones with a substituent L I position,

can be selectively reduced to the corresponding 2-hydroxy compounds.

The benzodiazepines obtained according to the method are compounds

of the general formula

and pharmaceutical: acceptable -salts thereof, .

where X is -.hydrogen, halogen, -'trifluoromethyl, ni tro,, hydroxyl, lower-alkyl or lower alkoxy,.--^ is lower alkyl poly.yf lubr-lower-alkyl-, phenyl-lower- alkyl r lower cycloalkyT,. layer.e-cyclo.alkyl-lower-.aikyl,

lower alkenyl or amino-lower-alkyl, ie. the amino group can be

substituted, with one or more ...lower alkyl groups, is hydrogen, lower alkyl, -hydroxyl or lower alkanoyloxy, R^ is phenyl, X-substituted phenyl, naphthyl," thienyl, or ..pyrryl,, and VR^ is hydrogen, lower alkyl e L i or..

where r. 6r 0 or i and .R^ and R^ are hydrogen or lower alkyl, and where m is 0 or 1. ..the term "lower alkyl" refers to both straight-chain and branched saturated hydrocarbon radicals with. up to 6 carbon atoms. Preferred lower alkyl groups methyl, ethyl, propyl,' isopyrropyl, n-butyl and i.bu ly i.

In the corresponding sense, "lower alkenyl" denotes straight-chain and

■ branched olefinic hydrocarbon radicals with up to 6 carbon atoms, such as e.g. 1-propenyl, 2-i isopropenyl., 2-butenyl, 3'-butenyl and 2-i. sopentenyl. The figures "lower cycloalkyl" and "lower-cycloalkyl-lower-alkyl" are similarly limited and illustrate, e.g. by eylopentyl, cycl ohexyl. and cyclopropylmethyl.. Similarly, the term "phenyl-lower-alkyl" is illustrated by phen-et hyl and.benzyl. "Lower -Alkoxy" denotes ether radicals in which the la v.-r o a'! kyl group is as defined for "lower alkyl" above, such as V. ek r.;, rnethoxy, ethoxy, propoxy and the like. "Lower alkanoyloxy" they denote. acid rad i.kal is which is derived from alkanoic acids with up to. 6 carbon atoms and thus includes row i kai is such as f o-r myl,

•:/:':;.;/ : , propionyl, but.yry] , ■ valeryi, hexanoyl and the "branched in so-

more of these, the term "halogen" includes all four halogens, although chlorine is preferred. In preferred compounds obtained by the process, X is a 7-chloro-substituted

The term "polyfluoro-lower alkyl" refers to lower alkyl radicals substituted with more than one fluorine atom, and includes radicals such as 2,2,2-trifluoroethnyl, trifluoromethyl, 2,2,3,3,3-pentafluoropropyl and the like. In preferred compounds, the polyfluoro-lower alkyl radical has two α-hydrogen atoms,

and can thus be illustrated by R^CH^ where R^. is polyfluoroalkyl. Most preferably, R 1 is trifluoromethyl, as in the 1-(2,2,2-trifluoroethyl)-substituted compounds.

The pharmaceutically acceptable salts include those formed with both inorganic and organic acids, such as, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like.

In solution, the 2-hydroxy compounds produced by the method according to the invention can best be represented by the structure indicated by formula II, as there is an equilibrium between this 2-hydroxy form and the 2,5-oxy form (III) which contains a bridge.

When the compound is in the solid state, the equilibrium may be shifted in the direction of the 2,5-oxy form. In the following, when reference is made to 2-hydroxy compounds according to the invention, this means compounds which can have either formula II or formula III.

The new process according to the invention for producing compounds of formula I is characterized by a compound of the general formula IV.

where X, , R^ i ^-z °S m is as indicated above, is subjected to reduction of the keto group with a complex metal hydride. The thereby obtained compound of formula I, which has a free hydroxyl group in the 2-position, can then, if desired, be etherified to the corresponding compound of formula I where R^ is lower alkyl or A preferred embodiment of this method involves adding a lithium aluminum hydride in a suitable inert solvent, such as tetrahydrofuran or ether, to the corresponding 2,3-dihydro-2-oxo-5-aryl-1H-1,>+-benzodiazepine at lower temperatures, e.g. at temperatures around 0°C. The reaction can be illustrated by the following reaction equation:

where R1? R 2 , R 1 and X are, as indicated above, R^ is lower alkyl and s has the value 0, 1, 2 or 3.

If X denotes a nitro group in the above-mentioned reaction, this group, being the smallest to some extent, will also be attacked during the reduction. Thereby, the yield of the desired compound is reduced.

The corresponding 2-ethers can be easily prepared by reacting the corresponding 2-hydroxy compounds of formula II with the appropriate alcohol (R,OH), Rh being lower alkyl or the group

1 where n, R^ and R^ are as indicated above. The starting materials of the general formula IV are well known and can be prepared e.g. by means of the methods described -in- Austrian Patent Document No. 2-75 • 528 and Belgian Patent Document No.

692,621.

The following examples illustrate the invention.

Example 1

Preparation of 7-chloro-1-(2,2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1,^-benz odiazepine

0.6<!>+ g (0.017 mol) lithium aluminum hydride is added to a stirred solution of 5.6 g (0.016. mol) 7-chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro -2-oxo-5-phenyl-2H-1,If-benzodiazepine in 80 ml of dry tetrahydrofuran cooled to 0°C. After complete addition, the mixture is stirred for a further 5 minutes, after which it is quenched with wet ether. The solution is filtered, filtered over sodium sulphate and concentrated under reduced pressure. The solution is then treated with a small amount of hexane. 3.0 g of the desired compound are obtained in the form of white needles. (m.p.: 1-3.0-131°C).

If in this example 1-(2,2,2-trifluoroethyl)-1,3-dihydro-2-oxo-5-phenyl-2H-1,>+-benzodiazepine is used as starting material, 1-(2, 2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1,3-benzodiazepine. (M.p. 123°-125°C).

Example 2

Preparation of 7-chloro-1-(2,2T2-trifluoroethyl)-2-methoxy-2,3-dihydro-5-phenyl-1H-1T>+- benzodiazepine

2.5 g (0.0071 mol) of 7-chloro-1-(2,2,2-trifluoroethyl)-2-hydroxy-2,3-dihydro-5-phenyl-1H-1/f-benzodiazepine is dissolved in 10 ml of methanebl, and the mixture is allowed to stand at 0°C until crystallization takes place. 2.2 g of the desired compound are obtained. (Sm. p. : 1^5°-l<1>+6<0>).

If ethanol is used instead of ethanol in this example, the corresponding 2-ethoxy compound is obtained, with a melting point of 135°-13l-",<0>C.

Example 3.

Preparation of 7-chloro-1-methyl-2-hydroxy-2t.3-dihydro-5-phenyl. l- lH- 1 , h ~ benzodiazepine

1.2 g (0.032 mol) lithium aluminum hydride" is added to a stirred solution of 7.0 g (0.025 mol) 7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1 ^-benzodiazepine in 150 ml of dry tetrahydrofuran cooled to 0°C. After complete addition, the mixture is stirred for a further 5 minutes. It is then triturated with wet ether. The solution

filtered, dried over sodium sulfate and concentrated under reduced pressure...The mixture is then triturated: with etherpetroleum ether. 2.8 g of the desired product are obtained; connection. Melting point: 125° - 126°C.

Example h

1-(p.ptp-trifluoroethyl)-7-chloro-2-hydro-xv-2. 3- dihydro- 5-( o- fluorophen-nvl)

- 1H- 1 A-. benzodiazepine

To a solution of 0.371 g (0.001 mol).7-chloro-1,3-dihydro-1-(P,p,p-trifluoroethyl)-5-(o-fluorophenyl)-2H-1,1+-benzodiazepine- 2-Mon

in 20 ml of benzene at 5°C was added 0.2 ml. (0.001^ equivalents) of

a 70^-ig benzene solution of latri .in. bis(2-methoxyethoxy)aluminum hydride. After stirring for 10 min., 1.5 ml of water was added and the mixture diluted with benzene. filtered, and dried over MgSO^.' The solution was concentrated and hexane added, whereby 0.15<!>+g of 1-(p,p,p-trifluoroethyl)-7-chloro-2-hydroxy-2,3-dihydro-5-(o -fluorophenyl)-1H-1,^-benzodiazepine, at melting point 119 - 120°C.

Example 5

Preparation of 7-chloro-2,3-dihydro-2-hydroxy-1-(p.p.p-trifluoroethyl)

-5-fe nyl- lH- 1A- benzodiazepine ^-- oxyd

To a solution of 2.0 g (0.005'+ mol) 7-chloro-1,3-dihydro-1-(P,P,p-trifluoro et hy I)-5-phenyl-2H-1 - benzod in azepin-2-one 2-oxide in 50 ml dry tetrahydrofuran was added with stirring 1.65 g (0.0065 mol) 11 thium(tri-t-butoxyaluminum)hydride'. (Li[(CH^)CO]^AlH). The reading was oyeb 1. in yellow. After stirring overnight at room temperature, 2 ml of water was added together with . 25 ml. owns. the precipitate was filtered off and the filtrate dried over MgSO,

The supernatant was filtered and all solvent removed under reduced pressure. The resulting crystals were recrystallized from ether-hexane (bone charcoal).

The connections obtained by the new fr method beyond one

effect on the central nervous system in mammals, as shown by standard pharmacological testing and are useful as sedatives or as anxiolytics. In addition, they exhibit valuable antispasmodic and muscle-relaxing properties. During the pharmacological testing, significant differences were observed between sedative and muscle relaxant doses and doses that cause neurologic impairment, such as .e.g. ataxia. The therapeutic ratio is usually higher for the compound obtained according to the method than for analogous, known compounds. As a further advantage, it has been shown that the test animals do not develop any tolerance upon repeated treatment during the testing of the anticonvulsant properties.

The compounds according to the new method are more water-soluble than

the corresponding 2-oxo starting materials. They have a more favorable distribution constant between organic and aqueous layers. This factor is important, because it indicates greater absorption in the blood of mammals.

animals by oral administration.

Using standard laboratory test methods, such as "Antagonism of Pentylene Tetrazole", Everett and Richard, J. Pharm, and Exp. Ther.,

Vol. 81, pp. h02 (19'+<*>+) and "Antagoni sm of Maximal Electro-Shock-Induced. aeizures in Mice", Synward, E.A. et al., J. Pharm, and Exp. Ther.,

Vol. 106, p. 319 (1952) for testing the anticonvulsant effect, "Central Nervous System Activity and Acute Toxicity", Irwin, Seiince 136, p. 123 (1962) for testing the muscle relaxant and sedative-hypnotic effects, "Antagonism of Foot-Schock Induced Fighting in Mice", Tedeschi, et al., J.Pharm, and Exp. Ther., Vol. 125, p. 28

(1959) and "Tårning Activity in Monkeys", Randall, Diseasos of the Nervous System, Vol. 21, p. 7 (1960) for testing the anxiolytic effect, it has been found that for the use of the compound as anxiolytic agents the dose about. 0.1-5 mg/kg body weight, per day, in the the compound is preferably administered orally in divided doses. When using the compounds as anticonvulsants, the dose range is approx. 2-30 mg/kg body weight per day, the administration preferably taking place orally in divided doses. When using the compounds as muscle relaxants, the dose range is approx. 0.1-1.5 mg/kg body weight per day, as also in this case administer none preferably occurs orally - in divided doses. When the compounds are to be used as sedative-hypnotic agents, the dose range is approx. 3_10 mg/kg body weight per day, and the administration preferably takes place orally in a single dose.

The compounds according to the new method can be administered alone or together with other drugs. Whether they are used alone or together with other active compounds, a suitable, pharmaceutically acceptable carrier is usually used. - It must not react chemically with the compound to be administered. Preferably, the compounds are administered orally, although parenteral and local administration may also be relevant. The preparations containing the new compounds can take the form of tablets, capsules, syrups, elixirs, suspensions, ointments, creams and the like.

In the farrnazoytic preparations there can be used in pharmazoytic

regarding acceptable diluents, such as e.g. water, gelatin, lactose, starch, magnesium tearate, talc, vegetable oils, gums and petroleum jelly.

Claims (3)

1. Procedure for the preparation of .1,^-benzodiazepines of the general formula I: and pharmacologically acceptable salts thereof, wherein X is hydrogen, halogen, trifluoromethyl, nitro, lower alkyl, hydroxyl or lower alkoxy, R-^ is lower alkyl, polyfluoro-lower-alkyl, phenyl-lower-alkyl, lower cycloalkyl, lower cycloalkyl-lower-alkyl, lower alkenyl or amino-lower-alkyl, the amino group may be substituted with one or several alkyl groups, R^ is hydrogen, lower alkyl, hydroxyl or lower alkanoyloxy,... R^ is phenyl,- X-substituted phenyl, naphthyl, . thienyl or pyrryl, and R^ is hydrogen, lower alkyl or the group : where n is 0 or 1, R^ and R^ are hydrogen or lower alkyl and m is 0 or 1, characterized in that a compound of the general formula (IV): where R-^, R 2 , R-^ j X and m are as indicated above, is reduced at the keto group with a complex metal hydride, and that, if the compound thus obtained is a compound of formula I in which R^ is hydrogen, under one or more of the following steps are discarded: i) etherification of the hydroxyl group in the 2-position, ii) conversion of a compound of formula I to a pharmacologically acceptable salt, iii) conversion of a compound of formula I where m is 0 to its <>>+-oxid. 2. Method according to claim 1, characterized in that the hydride used is a complex alkali aluminum hydride. 3. Method according to claim 2, characterized in that the reduction is carried out using a complex metal hydride of the general formula' where FU is. lower alkyl and s is 0, 1, 2 or 3-h. Method, according to claim 3, characterized in that the reduction is carried out with the help of LiAlH^, in a suitable inert solvent which is added to the 2-keto compound at reduced temperature