DE2163642A1 - Benzodiazepine derivatives - Google Patents

Description

fr-J * A.wn <hrWbit

2 Dec. 1, 1971 2183642

RAN 4008/179

F. HofFmann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

Benzodiazepine Derivates

The present invention relates to benaodiazepine derivatives of the general formula

where R, R and If "are hydrogen or lower alkyl, lc is hydrogen or halogen, R and R are hydrogen or, in addition, an additional

209829/1173

ORIGI _NAL

G-N bond mean in which latter case the nitrogen atom in position 4 is an oxygen

6 7

atom can carry; and R and R either alone or together mean a residue that can be removed by hydrolysis,

and pharmaceutically acceptable acid addition salts of basic compounds of the formula I.

The term "lower alkyl" as used in this specification refers to straight and branched chain hydrocarbon radicals with 1-7, preferably 1-4 »carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl and the like. The The term "halogen" includes the four halogens chlorine, bromine, iodine and fluorine, unless otherwise stated. The phrase "down Alkanoyl "refers to the acyl radical of a lower alkane • carboxylic acid. In the alkyl-CO radical contains the lower alkyl group preferably 1-6, very particularly preferably 1-3 carbon atoms. The acyl radical of formic acid should, however, also be recorded will. So it is residues such as Eormyl, Acetyl, Propionyl, butyryl, valeroyl and the like.

• 2

In a preferred embodiment, R denotes

Hydrogen. Compounds in which R is hydrogen and R 1 is hydrogen, chlorine or fluorine, particularly preferably fluorine, are particularly preferred. Compounds in which R is hydrogen or methyl and R is methyl are also preferred. R ^. and R preferably denote lower alkyl or together a -CH ₂ CH ₂ - or a - ₂₂₂ group. Particularly preferred for the present invention

6 7

are compounds in which R and R together denote -CH ₂ CH ₂ -, ie the 1,3-dioxolan-2-yl radical. Very particularly preferred compounds are accordingly those in which R is methyl,

2 Ί

R is hydrogen and R is hydrogen, chlorine or fluorine, whole

1 6

particularly preferably fluorine, R hydrogen or methyl and R

and R together represent a -CH «(^ - grouping.

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BATH ORIGINAL

Compounds of the formula I and pharmaceutically usable acid addition salts of basic compounds of the formula I can be produced according to the invention by the fact that

a) for the preparation of compounds of the formula I in which R and

5
R together denote an additional CN bond, a compound of the general formula

- HEL

II

-ι ρ "X C. ¹ J

wherein R, R, R, R, R and R have the above meaning

to have,

cyclized, or

b) for the preparation of compounds of the formula I in which R and R is hydrogen, a compound of the general formula

Yes

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SAO ORIGINAL

T O ** ζ fci 7

where R _f R, R, R, R and R 'have the above meaning,
reduced, or

c) for the preparation of compounds of the formula I in which R and

5
R together denote an additional CN bond and the nitrogen atom in the 4-position carries an oxygen atom, a compound of the formula Ia is oxidized, or

d) for the preparation of compounds of the formula I in which R is lower alkyl, a compound of the general formula

Ib

p ^ r / T r »

wherein R ₉ R, R, R and R 'have the above meanings, or a corresponding 4-N-oxide thereof is alkylated in the 1-position and that β), if desired, a basic compound obtained is converted into a pharmaceutically acceptable acid addition salt.

A compound of the formula II can spontaneously form a compound of either in crude or somewhat purified form Formula I, wherein R ^ and R ^ together form an additional C-N bond mean, are cyclized by a compound of formula II in an inert organic solvent, such as a lower alkanol, e.g. methanol, ethanol and the like. Dissolves and the resulting solution leaves to stand. The cyclization can accelerated by heating.

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SAD

Compounds of the formula Ia can be converted catalytically with the aid of a suitable reduction system to the corresponding Tetralydro derivatives of the formula

CH-R

Ic

1 P ^? f \ ■ 7

where R, R, R , R, R and R 'have the above meaning ,

be reduced, for example by hydrogenation in the presence of platinum, Raney nickel and the like * This reaction is in a known manner in an inert organic solvent such as an alkanol, sB ethanol, methanol and the like. Or an ether such as diethyl ether, tetrahydrofuran and the like. Performed.

Compounds of the formula

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CH-R

X 2 "Ί ß 7 in which H, R, R, H, R and R have the above meaning

to have,

can be prepared from the corresponding compounds of the formula Ia by adding a compound of the formula Ia treated in an inert organic solvent with an oxidation system, which converts this compound to the F-oxide. Suitable organic solvents are halogenated hydrocarbons such as methylene chloride. As an oxidizing agent Weak peracids such as chloroperbenzoic acid, peracetic acid and the like can serve

Compounds of the formula Ib can be converted into the corresponding in the 1-position lower alkylated compounds by suitable Proceedings are transferred. For example, compounds of the formula Ib can be mixed with an alkali hydride, e.g. sodium hydride, or potassium tert-butoxide and the like to the corresponding 1-alkali metal salt are implemented. This alkali metal salt can then old an alkylating agent, such as a Methyl halide, e.g. methyl iodide, ethyl iodide, propyl iodide and the like, or a di-lower alkyl sulfate such as dimethyl sulfate or diethyl sulfate can be converted into the corresponding N-lower alkyl derivative,

Fe basic · form compounds of formula I.

with inorganic and. organic, pharmaceutically applicable Acids, such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, acetic acid and the like. Pharmaceutically acceptable acid addition salts.

These salts can be prepared by leaving the acid in the absence of moisture (to undergo hydrolysis the ketal group to avoid) a solution of the compound of Formula I added in an anhydrous inert solvent. Any inert anhydrous solvent in which the compounds of formula I soluble and in which the formed

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Acid addition salts -insoluble, are, is for the present Suitable for the purpose of salt formation. Representative representatives of such solvents are ethers, suitable aliphatic and aromatic hydrocarbons, tetrahydrofuran and the like.

A process for the preparation of compounds of Formula II is shown in the following formula scheme. In

In this equation, the substituents R, R, R, R have

7th
and R has the meaning given above and X stands for a group which can be converted into an amino group, for example an azido or a phthalimido group or instead a leaving group, for example halogen, such as chlorine, bromine or iodine, alkyl or arylsulfonyloxy groups, for example mesyloxy , Benzenesulfonyloxy and tosyloxy.

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III

VII

CR _n CN

IV

VI

CH-R

ΙΙα

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Ib

Compounds of IOrmel II can be prepared as described in Gisvold et al., .J, Pharm. Sei, % X, 784 (1968).

In the first process stage of the formula scheme, a compound of the formula III is combined with a compound of the formula IV converted to a compound of formula V. This reaction is preferred in the presence of an inert organic solvent carried out. Representative representatives of such solvents are alcohols, e.g. lower alkanols such as ethanol and methanol, dimethyl sulfoxide and dimethyl formamide. Lower alkanols, especially methanol, are preferred. It is It is essential that a base be present in this reaction, and any suitable base can be used. With advantage however, alkali hydroxides such as sodium hydroxide are used. Temperatures are preferably used for this first stage of the process between about room temperature and about 100 °, particularly preferably between about room temperature and about 60 The resulting product of the formula V does not necessarily need to be converted into a compound of the formula VI to be isolated; however, such isolation is preferred

The second process stage of the equation relates to the conversion of a compound of the formula V into a compound of the formula VI by catalytic hydrogenation · Catalysts suitable for this purpose are palladium Carbon, platinum, nickel and cobalt, with palladium on carbon being particularly preferred. This catalytic hydrogenation is used carried out in the presence of a suitable inert organic solvent. Suitable solvents for this purpose are tetrahydrofuran, dimethylformamide, lower alkanols, such as methyl alcohol, ethyl alcohol and the like · During the conversion a compound of the formula V into a compound of the formula VI, the reaction is terminated preferably when the theoretical

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Amount of hydrogen has been absorbed, since secondary reactions can occur with larger amounts of hydrogen, which worsen the yields.

A compound of the formula VI can be converted into the corresponding compound by a large number of preparative methods the formula Ib can be converted.

For example, a compound of formula VI with a

Compound of the formula Halo-COGHY, in which R is as defined above and T is halogen, lower alkylsulfonyloxy or aryl-bulfonyloxy means, or with an anhydride of the formula

Γ f

(Halo-CH-CO) ₀ O or the formula (lower alkylsulfonyl-CH-CO) _O 0

² R ²

or the formula (arylsulfonyl-CH-C0) ₂ 0 are implemented. Examples of such anhydrides are chloroacetic anhydride, mesyloxyacetic anhydride, tosyloxyacetic anhydride and benzenesulfonyl acetic anhydride.

Suitable halogen-lower-alkanoyl halides, i.e. compounds of the above formula, in which Y is halogen, are chloroacetyl chloride, bromoacetyl chloride and bromopropionyl chloride and the like. It follows that the halogen functions of the above-mentioned halogen-lower alkanoyl halides or the The anhydrides mentioned above are preferably chlorine or bromine. This reaction step is preferred in the presence of a Acid acceptor, such as an inorganic or organic one Base. So bases with a Hydroxy lion such as alkali hydroxides, as.B. Sodium hydroxide, potassium hydroxide, ▼ can be used. Other possible bases are sodium carbonate, Triethylamine, pyridine and the like,

f representatives for compounds of the formula Y-CH-CG-halogen,

where Y is lower alkylBUlfönyloxy or arylsulfonyloxy,

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- II -

are mesyloxyacetyl chloride and tosyloxyacetyl chloride,

This process aspect, namely the production of a Compound of the formula VII in which X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy "is preferred in the presence an inert organic solvent such as benzene, ether, Methylene chloride and the like. Performed. Temperature and pressure are not critical, however temperatures will be below Room temperature, e.g., between about 0 and 20 °, is preferred.

When performing this reaction step should

consider that the group _Ώ «/ ^""^ with moisture f

^R "? ^N 0-R7

or alcohols tend to convert to a lower alkanoyl group under acidic conditions. Therefore should water and Acids are avoided in this reaction step.

After the synthesis of a compound of the formula VII in which X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy means,. said compound is treated with ammonia and the resulting compound of the formula Ha cyclized to the corresponding 1,4-benzodiazepin-2-one of the formula Ib.

The compound of the formula Ha needs before |

Cyclization to a compound of the formula Ib does not give rise to being isolated. The reaction does not need to be interrupted either before a compound of formula Ib is obtained.

So you can, for example, a haloacylamido, a Tosyloxyacylamido or a mesyloxyacylamido derivative of Formula VII to a solution of ammonia in a lower alkanol, such as ethanolic ammonia or methanolic Ammonia, give and receive after several hours, e.g. about Night, the corresponding 1,4-benzodiazepin-2-one V foundation of formula Ib (e.g. a 7- (2-R-l, 3-dioxolan-2-yl) benzo-

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ß V diazepin-2-one obtained if R and R together are an ethylene group mean).

In another aspect of the process, one does not work with methanolic ammonia, but dissolves a compound of the formula VII in which X is halogen, lower alkylsulfonyloxy or arylsulfonyloxy, in an inert organic Solvents, 'such as methylene chloride, carbon tetrachloride, ethers such as tetrahydrofuran, dioxane and ethyl ether, dimethyl sulfoxide, Dimethylformamide and the like. And treats the resulting solution with liquid ammonia to form a compound the formula Ha is given. The thus obtained, crude or somewhat purified compound of the formula Ha can become a inert organic solvents, such as a lower alkanol, e.g. methanol, ethanol and the like. Are added, whereby through Allowing the solution obtained to stand and / or heating cyclization to the corresponding compound of formula Ib occurs.

In a further aspect of the process, compounds of the formula VII in which X is a halogen atom other than iodine or bromine or lower alkylsulfonyloxy or arylsulfonyloxy can be converted into the corresponding compounds of the formula VII ₁ in which X is iodine. This is particularly useful when X is a halogen atom other than iodine or bromine. This is conveniently achieved by treating a compound of the formula VII »in which X is a halogen atom other than iodine or bromine or lower alkylsulfonyloxy or arylsulfonyloxy with an alkali iodide in an inert organic solvent. Although sodium iodide is preferably used for this purpose, it is clear that other iodinating agents customary to those skilled in the art can also be used. The iodine compound thus obtained is then preferably reacted with ammonia in the manner described above to give a compound of the formula Ib.

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Compounds of the formula VII can in dor above

for the compounds of formula Ib described manner N-nieoleralkyliert and according to the method given for the corresponding 'an-substituted compounds in the corresponding Compounds of formula I are converted.

In a further aspect of the process, compounds of the formula VII in which X is a phthalimide group can thereby can be obtained that a compound of the formula VI with a compound of the general formula

R ² I.

^X N— CHCOX ·

2
where R has the above meaning and X ¹

Halogen, preferably chlorine or bromine, is reacted in the presence of an alkaline halogen acid binder. The condensation is carried out in a suitable inert solvent such as a halogenated hydrocarbon, for example chloroform or methylene chloride, pyridine and the like. This reaction is preferably carried out at room temperature d.

A compound of formula VII wherein X is a phthalimide group means can also be obtained by adding a corresponding compound of the formula VII in which X is halogen, means lower alkylsulfonyloxy or arylsulfonyloxy, preferably with an alkali metal salt of phthalimide (potassium phthalimide) implements.

A compound of the formula VIZ thus obtained, wherein.X is a Phthalimide group can be converted into the corresponding compound of the formula Ha by treatment with hydrazine hydrate

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GAD ORIGINAL

- '14 -

will. This process is preferably carried out in an inert organic solvent carried out. Preferred works one in the presence of one or more moles of equivalents of hydrazine hydrate. Temperature and pressure are not critical to one successful implementation of this procedural aspect, one works but preferably at elevated temperatures. In order to obtain good yields, the reaction is carried out in an inert organic solvents such as a lower alkanol, e.g. ethanol. A compound of the formula Ha thus obtained can be converted directly, i.e. without isolation or interruption of the reaction, into the corresponding compound of the formula Ib will.

In a further aspect of the method, a compound of the formula VII, wherein X is halogen, lower alkylsulfonyloxy or Arylsulfonyloxy means treated with an azide group-donating reagent. Examples of such azide groups provide Reagents are alkali azides, such as sodium azide, Ealiuinazide, Lithium azide, alkaline earth azides such as Ealziumazid, Ammoniumazid and the like. Sodium azide is preferably used. In this process step, a compound of formula VII is used in one suitable organic solvents such as an alkanol such as methanol, an ether such as dioxane, tetrahydrofuran and the like. solved. This solution is then gently warmed to obtain the azide compound. The compound thus obtained is then by catalytic hydrogenation in the presence of a common catalyst, such as Raney nickel, a noble metal catalyst, such as palladium, platinum and the like. Selectively reduced, the corresponding compound of the formula Ha receives. The catalytic hydrogenation is preferred in the presence of an inert organic solvent, such as ether, e.g., tetrahydrofuran. The compound thus obtained the formula Ha is preferably without isolation from the reaction mixture in which it must be prepared, in one suitable inert organic solvents such as ethanol, Methanol and the like. Dissolved and then as described above

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BATH ORIGINAL

cyclized to the corresponding compound of formula Ib.

In a further process aspect, the azide can Compound of the formula VII can be prepared directly from a compound of the formula VI by reacting this compound with a compound of the formula F-CHCOCl (e.g. azidoacetylchlbrid)

at a temperature between about 10 and about 50 ° in the presence an organic solvent such as chloroform.

Compounds of the formula I and pharmaceutically usable acid addition salts of basic compounds of the formula I are muscle-relaxing, sedative and anti-convulsive. f

The new compounds of the formula I and pharmaceutically usable acid addition salts of basic compounds of the formula I can be incorporated into pharmaceutical dosage forms which contain about 0.5 mg to 200 mg of active substance, the dosage of the species to be treated and the individual. Is adapted to requirements. Parenterals Formulations usually become less active as preparations for oral administration included. The new compounds according to this invention can be used alone or in Combination with pharmaceutically applicable carrier materials. can be used in many dosage forms.

For example, you can use solid preparations for oral administration such as tablets, capsules, powders, granules, "Janrulaions, suspensions and the like. Solid preparations can be an inorganic carrier such as talc, or an organic one Contain carrier such as lactose or starch. Additives such as ilagnesium stearate (a lubricant) can also be used will. Liquid preparations such as solutions, suspensions or emulsions - can contain the usual diluents, like Waoser, a suspending agent, win poly-oxy ^ ethylene glycol, vegetable oils and the like. You can also add others Contain ingredients such as preservatives, dilution

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medium or wetting agent.

The following examples illustrate the invention. All temperatures are given in C.

example 1

A mixture of 2.0 g (5.6 mmol) of 2'-benzoyl-2-chloro-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide and 1.68 g (11, 2 iaMol) sodium iodide in 100 ml acetone is refluxed for half an hour. After cooling, the insoluble inorganic salts are filtered off and the filtrate is evaporated to dryness. The residue is then partitioned between methylene chloride and water, the organic phase is separated off, dried and evaporated to dryness. The residue obtained in this way is crystallized from methanol, 2 ^l -benzoyl-2-iodo-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide being obtained as colorless prisms, melting point 117-119 °. The crystals are dissolved in 150 ral tetrahydrofuran and the resulting solution is added to 400 ml of liquid ammonia in a 1000 ml three-necked flask equipped with a stirrer and a dry ice cooler. The reaction mixture is then stirred under reflux for 5 hours, then the excess ammonia is evaporated off overnight and the inorganic salts are filtered off. The tetrahydrofuran is evaporated off under reduced pressure and the remaining oil is dissolved in 200 ml of ethanol and the resulting solution is refluxed for 2 hours. On cooling, 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodia3epin-2-one crystallizes out as colorless prisms, melting point 250- 252 °.

The starting material can be produced as follows:

To a loosening of 330 g (2.0 Mo3) p-NitroacetnphPnor 160.0 g (2.5 mol) of ethylene glycol are added to 2.5 liters of benzene

209829/1173 _{8AD 0R1G} , nal

and 5.0 g of p-toluenesulfonic acid are added. The clear Losing is refluxed for 3 hours with a Dean-Stark trap until no more water is separated out. After cooling, the cloudy benzene solution is decanted off from a small alcoholic layer and dried over anhydrous sodium sulfate. The solution is then concentrated to about 1 liter and poured onto 4 liters of hexane. The colorless flakes of 2-methyl-2- (4-nitrophenyl) -1 _f 3-dioxolane are separated off and washed with hexane, melting point 71-73. By recrystallization from methyl chloride / hexane, analytical material is obtained as colorless flakes with a melting point of 73-74.

To a solution of 100 g (2.5 mol) of sodium hydroxide in 500 ml of methanol are added 58.6 g (0.50 mol) of phenylacetonitrile and then 104 g (0.50 mol) of 2-methyl-2- (4-nitrophenyl) -l, 3-dioxolane added at room temperature, the temperature rising to about 55 in the first half hour. After stirring vigorously for 16 hours, the reaction mixture is filtered and the residue is washed with water and then with small portions of cold methanol, 5- (2r-methyll, 3-dioxolan-2-yl) -3-phenyl-2, l-benzisoxazole obtained as a light yellow powder, melting point 137-138 °.

A solution of 2.81 g (10 mmol) of 5- (2-methyl-1,3-dioxolan-2-yl) -3-phenyl-2,1-benzisoxazole in 35 ml of tetrahydrofuran is in the presence of 200 mg of palladium Hydrogenated coal at atmospheric pressure and room temperature for 2 hours. The catalyst is then filtered off and the filtrate is evaporated to dryness. The remaining oil is crystallized from benzene / hexane, crude3 2-araino-5- (2-metbyl-1 _f 3-dioxolan-2-yl) benzophenone being obtained as pale yellow needles, melting point 97-99. The crude product is further purified by chromatography on 50 g of aluminum oxide (neutral, v / o elm activity I). Obtained by eluting with 2C Diafchyliither / methylene chloride and crystallization from methylene chloride / hexane

209829/1173 «** d original

- Io -

one 2-amino-5- (2-methy 1-1,3-dioxolan-2-yl) bonsoplienone as - ^; yellow prisms, melting point llP-114. '·

A mixture of 14.2 g (50 racol) 2- / unino-5 ~ (2-meth, yll, 3-dioxolan-2-yl) ben3ophenone and 10.4 g (50 nl-Iol) chloroacetic anhydride in 150 nil benzene is left to stand over fold at 5 °. The benzene solution is washed with saturated sodium bicarbonate solution and then with water, dried and evaporated to dryness. Crystallization of the residue from ethanol gives 2 ^f -benzoyl-2-chloro-4 '- (2-methy1-1,3-dioxolan-2-yl) acetanilide as colorless needles, melting point 131-133 °.

^{In an analogous manner, 2'-benzoyl-2-mesyloxy-4 l} - (2-methyl-1,3-dioxolane) is obtained from 2-amino-5- (2-methyll, 3-dioxolan-2-yl) benzophenone and mesyloxyacetyl chloride -2-yl) acetanilide and also 2-amino-5- (2-methyl-1,3-dioxolan-2-yl) benzophenone and tosyloxyacetyl chloride 2'-benzoyl-2-tosyloxy-4 '- (2-methyl-1 , 3-dioxolan-2-yl) acetanilide.

Example 2

A mixture of 14.0 g (39 mmol) of 2'-benzoyl-2-chloro-4 ^l - (2-methyl-1,3-dioxolan-2-yl) acetanilide and 11.6 g (78 mmol) of sodium iodide in 500 ml of acetone is refluxed for half an hour. After cooling, the reaction mixture is filtered and the solvent is evaporated off under reduced pressure. The residue consisting of crude 2 • -Benzoyl-2-iodo-4 '- (2-methyll, 3-dioxolan-2-yl) aeetanilide is dissolved in 150 ml of tetrahydrofuran and this solution is added to 400 ml of liquid ammonia in a stirred vessel Dry ice cooler. The reaction mixture is then stirred under reflux for 5 hours, the excess ammonia is evaporated off overnight and the inorganic salts are removed by filtration. Thereafter

20 9 8 2 9/1173 "'bad original

the tetrahydrofuran is removed under reduced pressure and receives an oil from crude 2'-benzoyl-2 ~ amino-4 '- (2-methy 1-1,3-dioxolan -? - yl) acetanilide, which is dissolved in 200 ml of ethanol and heated to reflux for 2 hours. When cooling down colorless prisms of 1,3-dihydro-7- (2-methyll, 3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one crystallize off, melting point 250-252. After recrystallization from ethanol, the melting point remains unchanged.

In a manner analogous to that described above, the following compounds can be prepared: 1,3-Dihydro-7- (2-ethyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepine- 2-one; 1 _f 3-dihydro-7- (2-propyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one; 1,3-Dihydro-7- (2-butyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiascpin-2-one.

Example 3

A solution of 3.0 g (9.3 mmol) 1,3-dihydro-7- (2-methy1-1,3-d.ioxolan-2-y 1) -5-pheny1-2H-1,4-benzodiazepin-2-one in 150 ml of tetrahydrofuran is hydrogenated in the presence of 2.0 g of platinum oxide at atmospheric pressure for 8 hours. Thereafter the catalyst is filtered off and washed with tetrahydrofuran. The filtrate is evaporated under reduced pressure and the residue crystallized from acetonitrile, 7- (2-Hethyl-1,3-dioxolan-2-yl) -5-phenyl-1,3,4,5-tetra hydro-2H-1,4-benzodiazepine 2-on Obtained as colorless prisms, melting point 181-182 °.

Example 4

A solution of 6.2 mllol 2-Asido-2 -bonzoyl ^l-4 '- (2-methyl l, 3-dioxolan-2-yl) acetanilide in 125 ml of tetrahydrofuran is at Atmosphiirendruck mg for two hours in the presence of 350 10 ; 5igem palladium on carbon; hydrogenated, using 2 - / «mino-

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⁸ ^ ORIGINAL

2 '-benzoy1-4' - (2-methyl-l, ^ - dioxolan ^ -yl) acetanilide is obtained. After the hydrogenation has ended, the catalyst is overturned filtered off and the filtrate evaporated to dryness. The le.i.cht yellow residue is dissolved in 125 ml of ethanol and the resulting Solution heated to reflux for 2 hours. The solvent is then evaporated off, 1,3-Dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodia3cpin -? - on Obtained as colorless prisms, melting point 250-252 °.

The starting material can be produced as follows:

To a solution of 8.4 mmol of 2-benzoyl-2-chloro-4 '(2-methyl-1,3-dioxolan-2-yl) acetanilide 16.8 mmol of sodium azide are added all at once in 120 ml of methanol. the The reaction mixture is then heated on a steam bath for 15 minutes. The reaction mixture then becomes Evaporated dry and the residue partitioned between water and methylene chloride. The organic phase is separated washed with water, dried and evaporated. Crystallization of the residue from ethanol gives 2-azido-2'-benzoyl-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide.

By reacting 2 ¹ -benzoyl-2-mesyloxy-4 '- (2-methyl-1,3-dioxolan-2-yl) acetanilide or 2' -benzoyl ^ -tosyloxyM '- (2- methyl-1,3-dioxolan-2-yl) acetanilide with sodium azide 2-azido-2'-ben3oyl-4 '- (2-methyl-1,3-dioxolan -? - yl) acetanilide.

Example 5

A suspension of 1.61 g (5.0 mmol) 1,3-dihydro-7- (2--1,3? -Dioxolan-2-yl) -5-phGixyl-2II-1,4-bon ^ odiai ; epin-2-on

in 10 ml of absolute dimethylformamide is mixed in a Nitrogen atmosphere with 288 mg (ό mmol) of oxygen sodium hydride dispersion in OeI in small portions within 1 minute

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, - ^ =; -. ' BATH ORIGINAL

added, initially developing hydrogen. The reaction mixture solidifies within 10 minutes Gelatin mass. After 15 minutes, 0.5 ml (8 ml-Ioi) of methyl iodide are added at once added, the whole body of the plague dissolving within 10 minutes. After 30 minutes, the reaction mixture is poured into 100 ml of ice-cold water and washed with ether extracted. The ether extracts are washed with water, dried over anhydrous sodium sulfate and reduced to a smaller size Volume constricted. On cooling, 1,3-dihydro-imethyl-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one crystallizes off, m.p. 122-124. Recrystallization from acetone / hexane gives colorless prisms, melting point 122-124 °.

Example 6

To a stirred solution of 9 »65 g (30 mmol) 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepine-2 -on 6.0 g (30 mmol) of 857? m-chloroperbenzoic acid are added to 150 ml of methylene chloride. The reaction mixture is then stirred until a clear solution is obtained, which then stand at room temperature for 24 hours is left. The reaction solution is then concentrated to a smaller volume and the precipitated m-chlorobenzoic acid is filtered off. The filtrate is evaporated to dryness, whereby 1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide is obtained.

Example 7

A solution of 5.0 g (11.4 mmol) of 2 ^l -benzoyl-4 '- (1,3-dioxolan-2-yl) -2-iodoacetanilide in 50 ml of tetrahydrofuran is added to 250 ml of ammonia. The reaction time will be during

Stirred under reflux for 5 hours and the excess ammonia evaporated off overnight, 2-amino-2'-ben3Oyl-4 ^l - (1,3-dioxolan-2-yl) acetanilide being obtained. The tetrahydrofuran

20 & 829/1173

is evaporated under reduced pressure and the residue distributed between methylene chloride and water, the methylene chloride phase separated, dried and evaporated to dryness and the residue dissolved in 25 ml of ethanol. These The solution is then heated to gentle reflux on a steam bath for 15 minutes. When cooling the ethanol Solution crystallizes 1,3-dihydro-7- (1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one as light yellow prisms, melting point 153-154 °.

The starting material can be produced as follows:

To a solution of 44.0 g (1.10 mol) of sodium hydroxide in 200 ml of methanol, 26.0 g (0.22 mol) of benzyl cyanide and 43.0 g (0.22 mol) of p-nitrophenyl-1,3-dioxolane were added. the The reaction mixture is stirred vigorously for 30 minutes, the solution initially takes on a dark red color and then silky yellow needles crystallize out. the Kirstalle are filtered off, washed with water and methanol and recrystallized from methanol, giving 5- (1,3-dioxolan-2-yl) -3-phenyl-2, l-ben2isoxazole obtained as colorless needles, melting point 134-135 °.

A solution of 26.7 g (0.1 mol) of 5- (l, 3-dioxolan-2-yl) -3-phenyl-2 _f l-benziaoxazole in 350 ml of tetrahydrofuran is in the presence of 2.0 g of 10 ^ igem palladium on Koh ^ e hydrogenated at atmospheric pressure and room temperature for 1 ½ hours, then the catalyst is filtered off and the filtrate is evaporated to dryness. The crystalline residue is then recrystallized from benzene / hexane to a constant melting point, 2-amino-5- (1,3-dioxolan-2-yl) benzophenone being obtained as pale yellow flakes, melting point 95 ° -97 °. *

A solution of 2.69 g (10 sMo.1)? -Amino-5- (1,3-dioxolan-2-yl) benzophenone and 2.08 g (10 mmol) of chloroacetic anhydride

209829/1173

BATH ORIGINAL

in 30 ml of benzene is left to stand at 5 overnight. The reaction mixture is then washed with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization of the residue from ethanol yields 2'-3.jnzoyl-2-chloro-4 ^f - (1,3-dio: colan-2-yl) acetanilide as colored needles, melting point 152-153 °.

• A mixture of 5.2 g (15.0 mmol) of 2'-benzoyl-2-chloro-4 '- (1,3-dioxolan-2-yl) acetanilide and 4.45 g (30 ml-Iol) of sodium iodide in 250 ml of acetone is refluxed for 30 minutes. The insoluble inorganic salts are then filtered off and the filtrate is evaporated to dryness. Crystallization of the residue from ethanol to a constant melting point gives 2 • -Bonzoyl-4 ^l - (1,3-dioxolan-2-yl) -2-iodoacetanilide as colorless needles, melting point 110-112 °.

Example 8

A mixture of 1.24 g (4.0 mmol) 1,3-dihydro-7- (1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one and 240 mg (5.0 mmol) of sodium hydride (· ν 50? oil dispersion in OeI) in 10 ml Dimethylformamide is stirred in an ice bath for 5 minutes. Then 660 mg (5.28 mmol) of dimethyl sulfate are added and the mixture was stirred at 0 ° for 15 minutes. The Mixture ™ is then added to 100 ml of Eisvrasser and extracted with ether. The ether extracts are dried and reduced under reduced pressure Pressure evaporated to dryness. Crystallization of the residue from ether / pentane gives 1,3-dihydro-7- (1,3-dioxolan-2-yl) -1-methyl-5-phenyl-2H-1,4-benzodiazepine as yellow prisms, melting point 138-139 °.

Example 9

A solution of 1.0 g of 3-dihydro-7- ( 1,3 _{-dioxolan-P-yl) - 209829/1173 ftAA}

5-phenyl-2H-1,4-bcnzodia3epin-2-one in 10 nil dry tetrahydrofuran is diluted with 50 ml of freezing agent in ether. Danaoli passes dry HCl gas through this solution, at once cream-colored, amorphous l, 3-dihydro-7- (l., 3-dioxolan-2-yl) -5- phenyl-2H-1,4-benzodiazepin-2-one hydrochloride precipitates, which filtered off and vird washed well with anhydrous ether. The melting point of the hydrochloride is indeterminate with gradual Decomposition in the range of 100-145 °.

Any of the following compounds can be used as the active ingredient in any of the following examples:

1,3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-pheny1-2H-1,4-benzod, azepin-2-one;

7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one;

1,3-Dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide.

Example 10

Pills are presented the following composition: Per tablet 25.0 ng Active component 98.0 mg Lactose 61, ö mg Cornstarch 5.0 mg Corn starch as a lozenge paste 4.5 mg Talk 1.5 ng Magnesium stearate 5.0 να / * Corn starch 200.0 mg Total weight

The active ingredient, lactose and corn starch are mixed in a suitable Ilischvorrichtunj and then the starch paste is slowly added up to one thick moist mass obtained, which can be obtained by a coarse üicb conducts, the moist granules are discharged as drying plates

209829/1173

SAD ORiGfNAL

spread and dried at 45. The dry granules are passed through a sieve and then mixed in a suitable mixing device with tall :, n with magnesium stearate and the second portion of corn starch. Mix well and compress to tablets of 200 ng each.

example 11 Capsules are made with the following composition:

Per capsule

Active component Milk sugar 165 mg % Cornstarch

Talk

Total weight 210 mg

The active ingredient, lactose and corn starch are mixed in a suitable mixer. The mixture is then passed through a grinding machine. The mixed powder is returned to the mixer, the talc is added and mixed well again. The mixture obtained is packed in hard gelatin capsules bottled on a capsule filling machine.

Example 12

A parenteral use form is produced according to the following composition:

10 ng 165 mg 30th mg -JL

« Active component Per ml mg Propylene glycol 5.0 ml Benzyl alcohol (benzaldehyde free) 0.4 ml Ethanol 95% 0.015 ml ITatriuiabenzoa fc 0.10 mg 209829/1173 48.8 SAO ORIGINAL

Benzoic acid 1,2

V / ater for Iniektionszwecke q.s. 1.0 ml

The active ingredient is dissolved in 150 ral benzyl alcohol whereupon 4 liters of propylcnf-lycol and 1 liter of ae + hanol clogs. 12 g of benzoic acid are dissolved in this solution whereupon 488 g hatriun benzoate dissolved in 3 liters of water for Injections added. Bring the solution to the final volume of 10 liters of water for injections. The solution is filtered through a candle filter, into suitable Ampoules filled, gassed with nitrogen and sealed. It is then autoclaved at 0.7 atmospheres for 30 minutes,

209829/1173

Claims (25)

Claims /, Process for the preparation of benzodiaepine derivatives of the general formula: el 1 2
wherein R, R and R are hydrogen or lower alkyl, R- ^ hydrogen or halogen, R and R are hydrogen or together an additional CN bond, in which latter case the nitrogen atom in the 4-position is an oxygen fi 7 atom can wear and R and R either alone or together one removable by hydrolysis Rest mean and pharmaceutically usable acid addition salts of basic ones Compounds of the formula I, characterized in that one a) for the preparation of compounds of the formula Ι, ν / orin R and R together represent an additional C-N bond, a compound of the general formula 209829/1173 • R R ¹ OR ² I 11 I. il - C - CH - Wd, T O Ά f \ 7 ■ wherein R, R, R, R, R and Ir have the above meaning to have, cyclized, or b) for the preparation of compounds of the formula I in which R and R denotes hydrogen, a compound of the general formula wherein R, R ¹ , R ² , R ⁵ , R ⁶ and R ^{7 have} the above meaning, reduced, or c) for the preparation of compounds dor formula I, vrorin R ^r and R zuüaniziGn a KUö-'itzliche C-rT bond and put the nitrogenatora in 4-position an oxygenator, a 209829/1173 Compound of the formula Ia is oxidized, or d) z \ w preparation of compounds dor "formula I, vtorin R is lower alkyl, a compound of the general formula Ib 2 "^ f> 7
wherein R, R, R, R and R have the above meaning I or a corresponding 4-N-oxide thereof is alkylated in the 1-position and that e) if desired, a basic compound obtained is converted into a pharmaceutically usable acid addition salt. 2. The method according to claim 1, characterized in that 2 that R is hydrogen. 3. The method according to claim 1 or 2, characterized in that that R is hydrogen, chlorine or fluorine. 4. The method according to claim 1, 2 or 3, characterized in that R is V / hydrogen or I-ethyl. 5. The method according to any one of claims 1-4, characterized in that that R is methyl iat. 6. The method according to any one of claims 1-5, characterized r η indicates that If 'and R together mean a -0H ₂ 0H ₂ ~ group. 209829/1173 bath so - ■ ■ · ^: · 7. The method according to any one of claims 1-6, characterized characterized that nan 1,3 ~ MhydiO-7- (2-HCtI ^ l-1,3-dioxolan-2-yl) -5-phcnyl-2H-1,4-ben: '; odia2; ppin-2- on manufactures. 8. The method according to any one of claims 1-6, characterized in that 7- (2-methyl-l, 3-dioxolane-r; -yl) -5-phenyl-1,3,4 » 5-tetrahydrc-2II-1,4-bonsodiazepin-2-one hers shares. 9. The method according to any one of claims 1-6, characterized in that 1,3-dihydro-l-inethy 1-7- (2-raethy 1-1,3-dioxolan-2-yl) -5-phenyl- 2ii-l, 4 ~ benzodiazepine - ;: ~ one manufactures. 10. The method according to any one of claims 1-6, characterized in that l _t 3-dihydro-7- (2-methyl-1,3-dioxolan-2-yl) -5'-phenyl-2H-1,4 ~ Benzodiazepin-2-one 4-Oxide manufactures. 11, "Method according to one of claims 1-4, and 6, characterized in that l, 3-dihydro-7- (l, 3-dioxolan-2-yl) -5-phenyl-2H-l, 4-'benzodia3epin-2-one manufactures. 12. The method according to any one of claims 1-4 and 6, characterized in that l, 3-dihydro-7- (l, 3-dioxolan-2-yl) -l-methyl-5-phenyl-2H-l, 4-benzodiasepin-2-one produces. 209829/1173 13. Process for the manufacture of preparations with relaxing, sedative and anticonvulsant properties, characterized in that one has a benzodiasepine derivative of the formula I in claim 1 or a pharmaceutical applicable acid addition salt of a basic compound of formula I as an active ingredient for therapeutic use Administration of suitable, non-toxic, inert solid and liquid carriers which are customary in such preparations and / or excipients mixed. 14. Pharmaceutical preparations with muscle laxative, sedative and anticonvulsant properties, thereby marked | draws that it is a benzodiazepine derivative of the formula I in claim 1 or a pharmaceutically acceptable acid addition salt a basic compound of the formula I and a carrier material. 209829/1173 ÖAD ORIGINAL 15. Bzodiazepinaerivabe of the general formula 12 wherein R, R and R are hydrogen or lower Ί 4th Alkyl, R ^ hydrogen or halogen, K * and R denotes hydrogen or together an additional ON bond, in which latter case the nitrogen atom in the 4-position can carry an oxygen atom, and R and R either alone or together denote a radical _{r which can be removed by hydrolysis} * and pharmaceutically acceptable acid addition salts of basic compounds of formula I. 16. Benzodiazepine derivatives of the formula I according to claim 15, 2 where R is hydrogen. 17. Benzodiazepine derivatives of the formula I according to claim 15, wherein R ^{-5 is} hydrogen, chlorine or fluorine. 18. 3enzodiasepine derivatives of the formula I goiaäüß claim 15, wherein R is hydrogen or Ho thyI . 19. Benaodiaaepinderivate of the formula I geraüos claim 15, wherein R is Ilethyl. 209829/1173 - 33 - ■■ ·· ■ · ··· 20. Benzodiazepine derivatives of the formula I according to claim 6 7 15, in which R and R together represent a -CH ₂ OIl2 group, 3. 21. 1,3-T) ihydro-7- (2-rae thyl-1,3-dioxolan-2-yl) ~ 5-pheny 1-2H-1,4-benzodiazepin-2-one. 22. 7- (2-Methyl-1,3-dioxolan-2-yl) -5-phenyl-1,3,4,5-tetrahydro-2H-1,4 "benzodiazepin-2-one. 23.1,3-TH.hydro-1-methyl 1-7- (2-aio-thyl-1,3-dioxolan-2-yl) 5-phenyl-2H-1,4-'benzodiazepin-2-one. 24. l ^ - 2H-1, 4-bcnzodiazepin-2-one, 4-oxide 25.1,3-Dihydro-7- (1,3-dioxolan-2-y1 ) -5-pheny1-2H-1,4 -benzodiazepin-2-one. 2β. 1,3-Dihydro-7- (1,3-dioxolan-2-yl) -1-methyl-5-phenyl 2H-1,4-benzodiazepinr2-one 209829/1173