DE2163641A1 - Benzodiazepine derivatives - Google Patents

Description

Dr, Ing.A. van i'er shipyard

Dr. ίϊϋϊιΖ LviufSf PATENT ADVOCATE!

2 t, Daz, 1971

RAN 4008/182

F. HofFmann-La Roche & Co. Aktiengesellschaft, ¹ Basel / Switzerland Benzodiazepine derivatives

The present invention relates to benzodiazepine derivatives. In particular, it relates to trioyclic ones Benzodiazepines of the general formula

ϊ? ^6th

wherein Λ is a -CHp- or -CG- group, Z -O- or -K- _f

(where R _{r is} hydrogen, lower alkyl or acyl),

nt / ?. 12. 71 209829/1172

R _{1 is} hydrogen or lower alkyl, R _? Hydrogen, lower alkyl, [cyclo-lower-alkyl] -lower alkyl, lower-alkoxy-lower alkyl, lower hydroxyalkyl, lower aminoalkyl, mono-lower-alkylamirion-lower alkyl or di-lower-alkylamino-lower alkyl, R, hydrogen, lower Alkyl or the group COO-lower-alkyl, Y a di- or trimethylene group optionally substituted by R. (where R. stands for lower alkyl or -CHpX, in which X is chlorine, bromine, lower alkoxy, lower-alkoxy-lower alkyl or di -lower-alkylamino denotes) and R_ denotes water or halogen.

The term "lower alkyl" (taken alone or in combinations · such as di-lower-alkylamino) denotes straight-chain or branched hydrocarbon groups with 1-7, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and the like. The term ¹¹ fCyclo-lower-alkyl] -lower alkyl "includes hydrocarbon groups with 4-6 carbon atoms, such as cyclopropyl · - methyl, cyclobutylmethyl, cyclopropylethyl and the like. The term" acyl "denotes an organic radical which is formed by removing a hydroxyl group from one or- W ganic acid, for example an aliphatic acid of 2-7 carbon atoms, derived, such as the propionyl and the like. the term "lower alkoxy" includes by a Säuerstoff function substituted lower alkyl radicals such as methoxy, ethoxy, Propoxy, etc. Unless expressly stated otherwise, halogen is understood to mean all four halogens, ie fluorine, chlorine, bromine and iodine. The term "lower alkano" l "denotes primary, secondary and tertiary saturated aliphatic ^ alcohols such as methanol, ethanol, propanol, isopropanol and the like.

Among the compounds of formula I are those 209829/1172 _B AO omGINAL

-air-

preferred in which Z is -0-.

Particularly preferred are those compounds of the formula I in which Z is -0-, R- is hydrogen or a lower alkyl group having 1-3 carbon atoms, R _{2 is} hydrogen, lower alkyl (especially methyl) or lower hydroxyalkyl (especially /> - hydroxyethyl), Y stands for a di- or trimethylene group, which can be substituted by lower alkyl (especially methyl) or chloromethyl, and R <- hydrogen or halogen (especially fluorine), which preferably adopts the ortho division on the phenyl ring, means g

Those compounds of the above formula I in which Z is -0-, R- is methyl, R _{2 is} hydrogen, methyl or β-hydroxyethyl, Y is a dimethylene group optionally substituted by methyl or chloromethyl and R ^ are very particularly preferred Means hydrogen or halogen in ortho division.

Another specific aspect of the present invention relates to compounds of formula I above, wherein Z is X, where Rg has the above meaning.

Another specific aspect of the present invention relates to compounds of the above formula I, in which A is a -CTL group * -

C.

Another specific aspect of the present invention relates to compounds of the above formula I in which A is the K group, Z is oxygen and R _{2 is} lower hydroxyalkyl and Y, R-,, R, and Rj- have the above meaning, or in which A is the ΐ group , Z is oxygen and Y is a _{di- or trimethylene group substituted by -CH 2} X, where X is chlorine, bromine, lower-alkoxy-lower. Alkyl or di-lower-alkyl-

209 8 29/1172; _; Bathroom original

is amino, and H ₁ ,

"R" and R [- have the above meaning.

. The benzodiazepine derivatives of the above formula I can be prepared according to the invention by a) a compound of the general formula

N- "A-CH-NH-Y-Z-H

II

wherein R ₁ , R ₂ , R-, R ₁ -, A, Y and Z have the above meaning

own,
cyclized or
b) a compound of the general formula

III

"where R- ,, R _?, R-, Rp., A, Y and Z have the above meaning and R" and R _Q, either alone or together, mean any group which can be easily removed by suitable hydrolysis processes,

209829/1172

βΑΟ ORIGINAL

hydrolyzed or.

c) for the preparation of compounds of the formula I in which R _? is different from hydrogen, a compound of the general formula

Ι-Λ

where R ,, R ,, R ^, A, Y and Z have the above meaning,

N-substituted or

d) zur'Herstellung of compounds of the general formula

I-B

wherein R ,, R ₂ , IU, R, - and Λ have the above meaning and R 'denotes hydrogen, lower alkyl or CHpX, where X has the above meaning, a 4,5-unsaturated 1,4-benzodiazepine of the general formula

209829/1172

ORIGINAL INSPECTED

^, R ₁ . and A above meaning beworin R ₁ , Rp

sit,

in the presence of an acidic agent with a JBpoxide der general formula

CH,

-CH R ¹

wherein R ¹ . has the above meaning, causes or

e) for the preparation of compounds of the formula I, in which

R '
Z '6 denotes, where R', - lower alkyl is lower acyl, a compound of the general formula

209829/1172

ORIGINAL INSPECTED

where R

IU,

j-, A and Y meaning above be

sit,
alkylated or acylated.

According to a first process aspect of the present invention, the compounds of formula I are thus thereby obtained by cyclizing a compound of formula II. In this process aspect as starting products Compounds of the formula II used can conveniently be prepared so that one corresponding 2-aminophenyl ketone of the general formula

fa Tj '

KA-CH-X ¹

where R ^, Rp, R ^, Rc "and A have the above meaning and X ^{1 is} chlorine, bromine or iodine,

with a diamine or an aminoalkanol of the general formula

VII

where Y and Z have the above meaning, implements.

The implementation between the compounds of the formula Vi and VII takes place in a reaction medium which contains a base and an inert organic solvent, and in a temperature between about 25 C and the reflux temperature

"" • 209829/1172

the reaction medium, preferably at about the reflux temperature. Suitable bases for this are inorganic bases, such as sodium acetate, and organic bases such as tertiary amines (for example trialkylamines), triethylamine and pyridine being preferred are. Suitable solvents are, for example, lower alkanols, such as methanol, ethanol, propanol and the like., where ethanol is preferred; aromatic hydrocarbons such as benzene, toluene, xylene and the like; high-boiling ethers, like Tetrahydrofuran and dioxane; as well as amides such as dimethylformamide, diethylformamide and the like. If in the compounds of the formula VI the symbol X 'stands for chlorine or bromine, the reaction mixture can also contain sodium iodide to remove the chlorine or bromine. To replace the bromine atom with the more reactive iodine atom. Suitable compounds of the formula VIl are, for example 2-aminoethanol, ethylenediamine, 3-aminopropanol and the like.

The resulting intermediate product of the general formula II does not have to be isolated from the reaction mixture, since it cyclizes to the desired compound of the formula I under the reaction conditions used. Used However, if less energy-rich reaction conditions are used, then the intermediate of the formula II can be isolated and then cyclize to the desired product. In a but the preferred embodiment is the intermediate product not isolated, but in the same reaction medium in which it was produced, brought to cyclization.

According to another process aspect of the present invention, compounds of the formula I are obtained by hydrolysis of a compound of the above formula III. In Formula III, R ₇ and R _R , either alone or together, represent any group which can be readily removed by suitable hydrolysis processes. Preferably R ₁ and R 0 each denote lower alkyl or together a -CHpCH ₂ - or -CIIpCHpCH ^ group. 13s, however, it should be noted that the character of the groups R "and R"

209829/1172
COPY

for the successful implementation of diosos ancestral monoaspokts is not critical as long as these groups can be easily hydrolyzed. Particularly preferred for the purpose of vorliogondon Invention is dio grouping, in wolchor IU and Rg together denote a -CIU-CHp group, i.e. the 1,3-dioxolan-2-yl group.

The conversion of the compounds of formula III in the corresponding compounds of formula I can be carried out at a pH below 7 with any suitable Hydrolysis process has been accomplished. In one preferred tone The hydrolysis is carried out in a simple manner Dissolution in an aqueous mineral acid, preferably in a 3 η to 12 η acid, such as nitric acid, hydrochloric acid, aqueous hydrobromic or sulfuric acid. Temperature and pressure are not critical for this aspect of the process but it is preferable to react in a temperature range between about -10 and about 100, preferably at about 10 to 30 °, with room temperature being most advantageous is.

According to another procedural aspect of the present one Invention can be converted into a compound of the above formula I-A a lower alkyl group, a lower hydroxyalkyl group, a lower-alkoxy-lower alkyl group, a lower aminoolkyl group, n1.no mono-nioclor-alkylamitio-niodere Al> yü group, a Dl-nicder-nlkylamino-niodore alkyl group or a rCycXo-lower-alkylj-lower alkyl group by adding one dionc pre-binding with a suitable alkylation agent umnotsil. ί) ο one can compounds of the formula I in which R_ is different from Vianoorstoff, obtained by daoo one jsunüchot the 1-sodium dorivative of a pre-binding of the Obisson Formula I-A and this 1-sodium derivative - without isolate eo au - reacts with a geoignotonic alkylating agent, Beinpielnwoirae with niodoron alkyl halides ^ fCyclo-

209829/1172
■ .V BAD ORIGINAL ■ '-;

lower alkyl] lower alkyl halides, lower haloalkanols, Halo-dl-niodoroalkyl ethers and lower aminoalkyl halides dor formula

X ¹ -C

10

where m is an integer from 2-7 and Hq and R _{10 are} each hydrogen or lower alkyl and X 'has the above meaning.

Examples of such alkylating agents are methyl iodide, 2-bromoethanol, 3-bromopropanol, Chlordiinothyltither, BroradiUthylUthor, Cyolopropylmethylbromid, (2-BroraUthyl) dimethylamine, 5-bromopropylamine, (2-bromoethyl) diethylamine.

The 1-sodium fluoride derivative is a compound of the above formula Ι-Λ can be established by making the connection with a lower sodium alkoxide such as sodium methoxide, or treated with sodium hydride. This reaction takes place appropriately in the presence of an inert organic solvent such as dimethylformamide, aromatic hydrocarbons, e.g., benzene, toluene and the like, with dimethylformamide being the preferred solvent is. You can use temperatures above or below room temperature, works but preferably between about 0 and 10.

According to another method aspect of the present In accordance with the invention, compounds of the above formula I are obtained, in which Z stands for 0 atom and Y stands for a dimethylene group which is optionally substituted by R., i.e. compounds of Formula I-B above, in which a 4,5-unsaturated o 1,4-Bonsodiaaepin dor the above formula IV with an epoxide dor the above Formula V oozes. This Urasotzung takes place in the presence of a « sauron agent, for example an aprotic LJUure, such as

209829/1172
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BATH ORIGINAL

Aluminum chloride, ferric chloride, zinc chloride, titanium tetrachloride, Boron trifluoride, tin tetrachloride and the like, or p-toluenesulfonic acid, Benzenesulfonic acid and the like. Particularly preferred acidic agents for the purposes of the present invention are aluminum chloride and tin tetrachloride. Suitable compounds of the formula V are, for example, ethylene oxide, propylene oxide, l-chloro-2,3-epoxypropane etc.

. The reaction of the compounds of the formula IV and V is conveniently carried out in the presence of an anhydrous inert organic solvent, such as aromatic hydrocarbons such as benzene, toluene, xylene and the like, halogenated hydrocarbons such as ethylene dichloride and the like, ethers such as tetrahydrofuran and diethyl ether, or Carbon disulfide. The Reaktionstemperatair can range between about -10 and Rückflusütemperatur of the reaction medium, preferably between 10 and the reflux temperature scroll, but is not critical and depends of course on the properties of the starting materials, the solvent used as reaction medium and of the acid agent.

It should be noted that does not give the compounds of formula V in the reaction with the compounds of the formula IV just to the formation of the heterocyclic ring in position 4 and 5 of Benzodiazepingerüstes occasion, "but also with the nitrogen atom in position 1 of the compounds of formula IV can react, insofar this nitrogen atom is not protected, that is, when R is _hydrogen?. Thus, in the reaction of a compound of formula IV wherein .rp hydrogen, with a compound of formula V is a G-emic result of two compounds , the first constant-1 on the nitrogen atom of which is unsubstituted, but the second is substituted as If, therefore beiapiels _-.? ', _-, a compound of formula IV, wherein R is hydrogen loading

209829/1172

ORIGINAL INSPECTED COPY

indicates, with a compound of the formula V, wherein R '. Means hydrogen, i.e. reacts with ethylene oxide, both the corresponding compound can be obtained from the reaction mixture of the above formula I-B, in which R "denotes hydrogen, as well as the corresponding compound of formula I-B, wherein Rp / P-hydroxyethyl means isolate. By choosing more suitable Reaction conditions can favor the substitution on the 1-position nitrogen atom, depending on the desired end product or suppressed.

When a compound of the formula V, in which R ¹ is different from hydrogen, is reacted with a compound of the formula IV, the carbon atom substituted by R 1 could be bonded in one of two possible positions with respect to the benzodiazepine ring, depending according to where the epoxy ring opens during the reaction. It has now been shown that the epoxy ring tends to open between the oxygen and the unsubstituted carbon atom, so that the through R ¹ . substituted carbon atom in the heterocyclic ring is linked to the oxygen atom. Thus, the above-described reaction between the compounds of Formulas IV and V yields the compounds of Formula IB above.

According to a further process aspect of the present invention, compounds of the formula I in which Z is -NH- i.e. compounds of the above formula I-C, according to customary alkylation or acylation methods in the corresponding compounds of the formula I in which Z is Jj °, where RV is lower alkyl acyl. By the choice of suitable Roaktionsbedingungen one can use the nitrogen Alkylate or acylate Ia tom in the heterocyclic ring without any other reactive points on the Beiiso ™ diazepine scaffold can be affected.

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BATH ORIGINAL

The compounds used as starting materials for the above processes can be prepared by various synthetic methods getting produced.

For example, compounds of the formula IV in which A is a carbonyl group and Rp is hydrogen can be prepared in the manner shown in the reaction scheme below. In this reaction scheme, X ¹ , R _{1, R 1} , R ₅ , R ₇ and Rg have the above meanings and X denotes halogen, lower alkylsulfonyloxy or arylsulfonyloxy.

2098 2 9/1172

Reaction sciiema

(c)

XIII

• R

XII

e.g. X'-CO-CH-X

(d) e.g. φ NaJ © KH-; @ ITatriumazid @ H ₂ / Pd

-CO-CH

NH ₂

= 0 e.g. ethanol

XIV

209829/1172

-Rr

IV-A

The compounds of the formula IX which are used as starting materials in the process according to the reaction scheme can be referred to by G-isvold et al., J. Pharm. Sci., 57 » 784 (1968) can be obtained.

In process stage (a) takes place according to the reaction scheme the reaction preferably in the presence of an inert organic solvent such as alcohols (e.g. ethanol and methanol), dimethyl sulfoxide and dimethylformamide. It is essential that one base be present during this reaction, each appropriate base can be used; however, the use of an alkali metal hydroxide, such as sodium hydroxide, is preferred. For this reaction it is preferred that the temperature is in a range between about room temperature and about 100% moved, preferably between about room temperature and about 60

In process stage (b) a compound of the formula XI is catalytically hydrogenated. The catalysts ^ welejae suitable for this include palladium on carbon, platinum, nickel and cobalt, with palladium on carbon being preferred. the catalytic hydrogenation is carried out in the presence of any suitable one inert organic solvents such as tetrahydrofuran, dimethylformamide and alcohols such as methanol, ethanol and the like

The compounds of the formula XII can be converted into the compounds of the formula XV in analogy to known processes as indicated in aspects c, d and e of the Reaction Scheme.

The compounds of the formula XV can then be converted into the desired starting materials of the formula IV-A as indicated in aspect f of the reaction s chema. This conversion can be carried out by any suitable, at a pH

209823/1172

bath

The hydrolysis method carried out below 7 can be achieved as described above for the hydrolysis of the compounds of the Formula III is described. It should be noted that the hydrolysis of the group ^ V * ^? although preferably

- ^R 8 is carried out after cyclization of the compound of the formula XIV but can also take place at earlier stages of the synthesis. For example, the compounds of the formulas XII, XIII and XIV can be hydrolyzed in the manner described above, giving the corresponding compounds which have the R ^ -CO group.

Starting products of the formula IV, in which R “lower Means alkyl can also be prepared by using compounds of the formula

XVI

XVII

209829/1 1 72

in which Rp, R "and R ₁ - have the above meaning, reacts with a lower alkyllithium.

This reaction is conveniently carried out in the presence of an inert solvent such as hexainethylphosphoric acid amide, Ethers, e.g., tetrahydrofuran, dioxane and the like. Temperature and pressure are admittedly for this process aspect not critical but it is preferred to carry out the reaction at temperatures below room temperature, e.g. at temperatures between about -70 and 20.

Upon treatment of a compound of formula XVI or XVII with a lower alkyllithium, this is obtained Crude product, which contains a complex salt, subjected to hydrolysis conditions, using any conventional methods an appropriate hydrolysis agent used. Used preferably a dilute mineral acid, e.g. dilute hydrobromic acid or dilute sulfuric acid, is used as the hydrolysis agent and the like, or an aqueous organic acid such as aqueous acetic acid, or a base such as an alkali metal hydroxide.

Lower alky! Lithium compounds which are used include methyllithium, ethyllithium, propyllithium and the like

The compounds of the above formula IV, wherein Rp is hydrogen, lower alkyl, CCyclo-lower-alkylJ-lower alkyl, lower hydroxyalkyl, lower aminoalkyl, mono-lower-alkylamino-nicderes Alkyl or di-lower-alkylamino-lower alkyl means can easily be prepared by methods known per se. For those compounds in which the substituent Rp is different from hydrogen, this substituent can be converted into the Compound of the formula IV or any of these

209829/1172

Compounds leading intermediates are introduced. Compounds of the formula IV in which EU is lower-alkoxy-lower Means alkyl can be prepared by adding a compound of the formula IV in which Rp is hydrogen, and converts a halo-di-lower-alkyl ether.

The compounds of the formula VI can be prepared in analogy to the processes shown in the above reaction scheme will. An intermediate of the formula is thus obtained based on this process

-A-CH-X '

XIX

wherein R ^, R ^, R ₁ -, R ", R _ß , A and X ^{1 have the} above meaning.

The intermediates of the formula XIX can be converted into the desired compounds of the formula VI, by using hydrolysis methods similar to those described for process aspect f in the reaction scheme, resemble. When compounds of the formula VI in which Rp is hydrogen is different, i.e. compounds wherein Rp is lower alkyl, lower hydroxyalkyl, [cyclo-lower-alkyl] lower Alkyl. lower-alkoxy-lower alkyl, lower aminoalkyl, Mono-lower-alkylamino-lower alkyl or di-lower-alkylamino-lower Means alkyl, you can these compounds by alkylation of the compound of formula XIX or

209829/1 172

Alkylation of the compound of the formula VI in which R _? "Hydrogen" means obtained. Such an alkylation can be carried out by customary methods.

In addition, the intermediate of the formula XIX with the compound of formula VII are reacted to give the tricyclic compound of formula III, which in the the process aspect involving the hydrolysis of this compound is used as the starting material for the corresponding compound will.

The tricyclic benzodiazepine derivatives of Formula I can be used as medicaments; they are characterized by sedative, muscle relaxing and anticonvulsant properties. These compounds can be used in the form of conventional pharmaceutical preparations. For example, they can be mixed with conventional organic or inorganic, inert pharmaceutical carrier materials suitable for parenteral or enteral administration, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petrolatum and the like. They can be administered in the form of conventional pharmaceutical preparations, for example in solid form (for example as tablets, coated tablets, capsules, suppositories and the like) or in liquid form (for example as solutions, suspensions or emulsions). In addition, the pharmaceutical preparations which contain the compounds according to the present invention can be subjected to customary pharmaceutical processes (such as, for example, sterilization) and can contain customary pharmaceutical auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for processing ! «Σ r>Oiiio" t '"i" ^ oVinvi UminVo r \ r \ nv "Pi ι-PP ρ τ» Λ τι ο ο ο vrl am lrnnnon

the preparations also contain other therapeutically valuable substances.

209829/1172

A suitable pharmaceutical dosage unit can contain about 1 to 500 mg of a compound of the above formula I, with doses of about 1 to 100 mg for oral and doses of about 1 to 50 mg are preferred for parenteral administration. Specific dosage should however be used in each individual case according to the professional judgment of the person administering the administration of the said connection carried out or monitored, can be adapted to individual needs. Bs is to be observed that the doses given above are only to be understood as examples and the scope of the invention in in no way intended to limit.

In the following examples, which are intended to illustrate but not limit the invention, they are all Temperatures given in Ceicius degrees.

example 1

A solution of 417 mg (1.5 mmol) 7-cyano-5- (2-fluorophenyl ) ~ l, 3 ~ dihydro-2H-l, 4-benzodiazepin-2-one in 30 ml dry tetrahydrofuran is cooled in powdered dry ice under nitrogen. Through a serum stopper, in a 4 ml (6.0 rmol) portion of a 1.55 M solution of methyllithium injected in ether. The mixture is stirred for 4 hours at the temperature of dry ice and then Poured into 50 ml of 0.1 η hydrochloric acid for decomposition with stirring. After 10 minutes at room temperature, the solution becomes Basic up to about pH 8 with 1 η Hatriunihydroxyd, up front the product through "Brtrolcbionen with Mot.hyl cncb'l orjri i.so.i i c't will. Crystallization from ether gives 7-Aoet, yl - r> (2-fluorophenyl) - 1,3 ~ dihydro ~ 2K - l, 4-boni; odiazepin-2-one in Forin yellowish rriöiuoii vojü oulüut'lüpuuikt 211-213.

To a solution of 2.96 g (0.01 mol) of 7-acotyl ~

5- (2-fluorophenyl) -l, 3-dihydrο -2H-1, 4 ~ beii3ud.iascipj.n-2-one in 50 ml

2 0 9 8 2 9/1172 bad original

_ 21 -

540 mg (0.011 mol) of a dimethylformamide are added. 57 $ igen Disperse sodium hydride in oil and stir the mixture in an ice bath for 15 to 20 minutes "until a clear solution arises. 1.85 g (0.013 mol) of methyl iodide are then added and leaves the reaction geraisch for 15 hours at -5 to -10 stand. The reaction mixture is partitioned between water and benzene, whereupon the organic layer over anhydrous sodium sulfate is dried and evaporated to dryness. The remaining oil crystallizes from methylene chloride / Petroleum ether and provides 7-acetyl-5 ~ (2-fluorophenyl) ~ 1,3-dihydro ~ 1-methyl-2H-1,4-benzodiazepin-2-one of melting point 106-108.5 °.

A solution of 1.3 δ (0.00483 mol) tin tetrachloride in 20 ml of dry ethylene dichloride is mixed with 0.5 g (0.00161 mol) of 7-acetyl-5- (2-fluorophenyl) -l, 3-dihydrol under nitrogen -methyl-2H ~ 1,4-benzodiazepin ~ 2-one treated. The mixture is stirred in an ice bath and a solution of 0.44 g (0.01 mol) of ethylene oxide in 3 ml of ethylene dichloride is added dropwise. The reaction mixture is stirred for a further 3 hours at room temperature. Ice is then added, the mixture is made basic with ammonium hydroxide and filtered. The precipitate is washed with dichloromethane; the combined filtrates are washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 10 ml of dichlonaethiin and chroaatographiort on a Florisilnäxile. Elution with benzene and dichloromethane gives 0.1 g of an oil, and elution with ether gives 0.15 g of a gold, "which can be called from a mixture of ether and pebrol ether. By recrystallizing the product from ciner; j Gejni. From dichloromethane and methanol one obtains 10-acet.7l-llb- (2-f.Vjorphenyl) -2,3,5, ll ^ -tetrahyclro-7 ~ methyloxu £: olo ^ 3,? ^> '-ciJ / " l, - ^{/ l} JbcnKodiazcpin- "6 (7H) -on in Forin weicser wi ;; i.hebc; n vom iJchrnols'-Punkt 176-") ΠΙ.

D ORiGSMAL 2 0 9 8 2 9/1172 ^AL

example 2

A solution of 3.9 g (0.015 mol) of tin tetrachloride in 60 ml of dry ethylene dichloride is mixed with 2.0 g (0.00675 mol) of 7-acetyl-5- (2-fluorophenyl) -l, 3-dihydro-2H under nitrogen -l, 4-benzodiazepin-2-one treated. The mixture is stirred in an ice bath and a solution of 2.0 g (0.045 mol) of ethylene oxide in 6 ml of ethylene dichloride is added dropwise. After 18 hours, a further 3.9 g (0.015 mol) of tin tetrachloride and a further 2.0 g (0.045 mol) of ethylene oxide are added. The mixture is stirred for 5 hours at room temperature, then ice is added and the reaction mixture is made basic with ammonium hydroxide. The mixture is filtered and the filtrates are washed with 40 ml of water, dried over anhydrous sodium sulfate and evaporated to dryness 20 ml of benzene dissolved and chromatographed over Florisil.Elution with benzene gives, after evaporation, 0.6 g of an oil.Elution with benzene / 10 ^ ether and then with ether gives 1.4 g of an oil after removal of the solvent crystallized from ether and recrystallized from a mixture of methanol and ether and there is obtained 10-acetyl-LLB (2-fluorophenyl) -2,3, 5, llb-tetrahydro- · oxazoloß, 2-dj [l, 4j benzodiazepine 6 (7il) -one in the form of white prisms with a melting point of 163-168.

209829/1172

Example A. Suppositories

Per suppository zn. 1.5 g

10-acetyl-llb- (2-fluorophenyl) -

2,3,5, llb-tetrahydro-7-methyl-

oxasolo £ 3.2-dJ £ 1.4 / benzbdiazepine-

6 (7H) -one 0.010 g

Cocoa butter, melting point 36-37 ° 1.245 g carnauba wax 0.045 g

Cocoa butter and carnauba wax are melted in a suitable size vessel fitted with a glass or steel insert, mixed thoroughly and cooled to 45 °. Finely powdered 10-acetyl-IIb- (2-fluorophenyl) -2,3,5, IIb-tetrah3 '"dro-7-methyloxazolo / 3, 2 ~ aJ £ ± , Aj benzodiazepin-6 (7H) -one are then added The mixture is poured into molds for suppositories weighing 1.3 g each. After cooling, the suppositories are removed from the molds and individually wrapped in wax paper or foil.

Example B. Capsules

Per capsule

10-Ace Ly1-llb- (2-xluorophenyl) -

2,3,5, llb-t etrahydro-7-raethyl-

oxazolo [5 , 2-d // "l, 4j benzodiazepine-

6 (7H) -one '10 mg

Milk sugar 165 mg

Corn starch '30 mg

Talk _JL_2 £ I

Total weight 210 mg

10-acetyl-llb- (2-fluorophenyl) -2,3,5, llb-tetrahydro-

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bath

V-methyloxasolo jjj , 2-äJ [l, r] benaodiaE-cpin-ö (7H) -one, lactose and corn starch are mixed in a suitable mixer. The mixture is passed through a further decomposition solution. Put the veriüisoat.o powder back into the mixer, add the talc and dilute thoroughly. The mixture is mechanically filled into hard gelatine capsules.

Pro? Η1

10-acetyl-llb »(2-fluorophenyl) -

2,3,5, llj3-tetraliydro-7-methyl-

oxazolo [p, 2-dj £ l, 4j benzodiazepine

6 (7H) -one '5.0 mg

Propylene glycol 0.4 ml

Benzyl alcohol (benzaldehyde-free) 0.015 ml

Ethanol 95% / «0.10 ml

liatrium benzoate 48.8 rag

Benzoic acid 1.2 mg

V / water for injections q.s. 1.0 ml

To prepare 10,000 ml injection solution, 50 g of 10-acetyl-llb- (2-fluorophenyl) -2,3,5, llb-tetrahydro-7-methyloxazolo j [3.2 ~ d7 / "1.47be ⁿ 2odiaaepin-6 (7H) -one in 150 ml of benzyl alcohol. 4000 ml of propylene glycol and 1000 ml of Aetha.no! are then added The solution is brought to the final volume of 10,000 nl by adding water for injection purposes. The solution is filtered through a candle and filled into ampoules of suitable grease, which are flushed with nitrogen, then added to the autoclave for 30 minutes at 0.7 atmospheres

. BATH ORIGINAL

0 9 8 2 9/1172

Example D '

Per tablet 10-acetyl-llb- (2-fluorophenyl) -

, 3.5, y7y

orariolo (3,2-dJ ^ "1,4j benzodiazepin-6 (7H) -one '25.00 mg

Dicalciuin phosphate dihydrate, un-

counted 175.00 rag

Corn starch 24 * 00 mg

Magno s iiua ü te ar at 1.00 : no,

Total weight 225.00 mg

10-Acetyl ~ irij- (2-fluoroph.enyl) -2,3,5, llb-tetrahydro-7-raethylozaaolo {3,2-dJ £ 1,4j benaodiazepin-6 (7H) -one and corn starch are mixed and passed through a shredder. This mixture is mixed with dicalcium phosphate and half of the magnesium stearate, passed through a grinding machine and granulated. Passing the grains through a Zerkleineningsmasohino and gives the Magneciumstearats to Renk. The mixture is mixed and pressed »

Example R

In analogy to those described in examples Λ bio D. This process produces pharmaceutical preparations and uses 10-acetyl-llb- (2-fluorophenyl) -2,3,5,11btotrahydroozazolo as the active ingredient [3,2-dJ [l, 4jbon2odiazepin-6 (7H) -one.

209829/1172 BAD original

Claims (1)

Pat ent an s όγ loan r. Process for the preparation of tricyclic bensodiazepines the general formula where A is a -CH ₂ - or -CG group, Z ~ 0- or -K-, (where R _{fi is} hydrogen, lower alkyl or acyl), R-, hydrogen or lower alkyl, R ₂ hydrogen, lower alkyl, fCyclo-lower-alkylJ-lower alkyl, lower-alkoxy-lower alkyl, lower hydroxyalkyl, lower aminoalkyl, mono-lower-alkylamino-lower alkyl or di-lower-alkylamino-lower alkyl, R-hydrogen, lower alkyl or the group COO-lower-alkyl, Y a di- or trimethylene group optionally substituted by R. (where R. stands for lower alkyl or -CH ₀ X, in which X is chlorine, bromine, lower alkoxy, lower-alkoxy-lower alkyl or di-lower -alkylamino) and R _r denotes hydrogen or halogen, characterized in that one a) a compound of the general formula 209829/1 172 ORIGINAL 163641 _ A— CH-Ϊ \ ^Τ Η — Υ— Ζ — Η wherein R- ,, Rp, R ₇ ,, R ₁ -, A, Y and Z oMge own,
cyc-T ieiert or
b) a compound of the general formula wherein R ₁ , Rp, R ^, R ₁ -, A, Y and Z have the above meanings and R _{1 and R 0,} either alone or together, denote any group which can be easily removed by suitable hydrolysis processes, hydrolyzed or c) 7AiT preparation of compounds of the formula I, wherein W iwt different from Waf.würijkoff ;, a compound of the all- 209823/1172 common formula where R-,, R. ,, Rp-, A, Y and Z have the above meaning, N-substituted or d) 'for the preparation of compounds of the general PomeI I-B where R- ,, R _? , R _7. , R _r and A have the above meaning and R ¹ . Hydrogen, lower alkylene or 4 * CIIpX denotes, where X has the above meaning, a 4,5-unsaturated 1,4-bonsodiaacpin of the general formula: iol 209829/1172 OBiQiNAL IV where H-,, R_, R ", Rj- and Λ have the above meaning, in the presence of a caustic agent with an epoxy aligeme in en Po rme.l -CH R ¹ Ο- in which R 'o? has the same meaning, realifcion or e) for the preparation of compounds of l'Onael I, wherein Ed
Z 'denotes, where R'g is lower alkyl lower acyl, a compound of the general formula I-C 2098? 9/1 172 SAD ORIGINAL where R ,, Hp, R *, R ₁ -, A and Y have the above meaning,
alkylated or arylated. 2. The method according to claim 1, characterized in that dn.es one is a compound of the formula. II cyclized or that a compound of the formula III is hydrolyzed or a compound of the formula I-A is hydrolyzed by lower hydroxyalkyl, lower-alkoxy-lower alkyl, lower aminoalkyl, mono-lower alkylamino-lower Alkyl or di-lower-alkylamino-lower Alkyl N-substituted or that a compound of the formula I · in the presence of an acidic agent with a compound of Formula V converts, or that, a compound of the formula 1-0 alkylated or acylated. 3 * Method according to claim 1 Ovlor.2, characterized in that that a starting material of the formula III is used in which R "and Rg are each lower alkyl or together are a -CHp-GHp- or a -CHp-CHp-GHp grouping mean. 4 »Process according to one of claims 1 to 3> characterized in that a compound of the formula III is hydrolyzed at a pH below 7, 5. The method according to any one of claims 1 to 4 »characterized in that ^ 3s Z -0- means 6. The method according to claim 5, characterized in that R _{1 is} hydrogen or lower alkyl having 1 to 3 carbon atoms, R ~ hydrogen, lower alkyl or hydroxyalkyl and Y is a di- or trimethylene group bo 7. Ancestors according to claim 6, characterized in that _ i-vthvl, R hydrogen, Ilethyl or / '- Ilydroxyäthyl, 209829/1172 _B ad original 1163641 Y denotes a methylene group optionally substituted by methyl or chlorineethyl and R ₁ denotes hydrogen or halogen in ortho division. 8. "The method according to claim 7, characterized in that 10-acetyl-llb- (2-fluorophenyl) -2,3,5, llb-tetrahydro-7-methyloxazolo [5 , 2-dJ [l , A] benzodiazepine -6 (7H) -one produces. 9. The method according to claim 8, characterized in that that 7-acetyl ~ 5- (2-fluorophenyl) ~ 1,3-dihydro-1-methyl ~ 2II-1,4-bensodiazepin-2-one and ethylene oxide used as starting products. 10. The method according to claim 7> characterized in that 10-acetyl-llb- (2-fluorophenyl) -2,3,5, lib-tetrahydrooxazolo £ 5,2-dJ £ l, A] benzodiazepine ™ 6 ( JE) -on manufactures. 11. The method according to claim 10, characterized in that 7-acetyl-5- (2-fluorophenyl) -1,3 ~ dihydro-2H-1,4-benzodiazepin-2-one and ethylene oxide are used as starting materials. 12. Process for the production of pharmaceutical preparations with sedative, muscle relaxant and anticonvulsant Properties, characterized in that a tricyclic eenzodia, zepin as defined in claim 1 is used Formula I as an effective ingredient with therapeutic administration suitable, non-toxic, inert solid or liquid carriers which are customary in such preparations and / or excipients mixed. 15 = preparations with sedative, muscle relaxing and anticonvulsant properties, including a tricyclic BeiiüodiazeyLn of the formula I defined in claim 1 and one Carrier. 209829/1172 14 »Tricyclic benzodiazepines of the general formula where A-a -CHp- or -CG- group, Z -0- or -N-, (where R ^ is V / water, lower alkyl or acyl), R _{1 is} hydrogen or lower alkyl, R _{p is} hydrogen, lower alkyl, fjCyclo-lower-alkylJ-lower alkyl, lower-alkoxy-lower alkyl, lower hydroxyalkjrl, lower aminoalkyl, mono-lower-alkylainino-lower alkyl or di-lower-alkylamino-lower alkyl, R, hydrogen, lower alkyl or the group COO-lower-alkyl, Y a di- or trimethylene group optionally substituted by R. (where R. stands for lower alkyl or -CEpX, in which X is chlorine, bromine, lower alkoxy, lower-alkoxy-lower alkyl or di-lower-alkylamino means) and R _{F means} hydrogen or halogen. 15. Compounds according to claim 14, wherein Z is -0-, 16. Pre-binding according to claim 15, wherein R-, hydrogen or lower alkyl of 1 to 3 carbon atoms, Rp Hydrogen, lower alkyl or lower hydroxyalkyl and Y an · optionally through lower alkyl or chloromethyl ε Substituted i) i or trimethylene group mean. 209 8 29/1 172 BATH 2163SA1 17. Compounds according to claim 16, wherein R-, methyl,; Rp is hydrogen, methyl or ^ -hydroxyethyl, Y is a dimethylene group optionally substituted by methyl or chloromethyl and R _{1 is} hydrogen. or halogen in ortho position. 18. 10-Acetyl-llb- (2-fluorophenyl) -2, 3 , 5, llb-tetrahydro-7-methyloxazolo [3, 2-dJ / "l, ^ j benzodiazepin-6 (7H) -one. 19. 10-Acetyl-IIb- (2-fluorophenyl) -2,3,5, IIb-tetrahydrooxazolo [312-dJ £ l , Q benzodiazepine-6 (7H) -one. ORIGINAL IMSPECTED 209829/1172