DE1445888A1 - Process for the preparation of benzodiazepine derivatives - Google Patents

Description

Process for the preparation of benzodiazepine derivatives

The invention relates to a method for producing Benzodiazepine derivatives of the general formula

(D

where R _{x is} hydrogen, alkyl, alkenyl, alkynyl or one of the groups -C Hp-halogen or ~ ^σ _η Ι% _η ^Ν _Ν *

Re R _{2 is} hydrogen or alkyl, R _{3 is} hydrogen, halogen, trifluoromethyl or nitro, R _{4 is} hydrogen, halogen, trifluoromethyl, nitro or alkylthio, R _{8 is} hydrogen, alkyl, alkenyl, alkynyl or one of the groups -CH-halo or -C HpN _N , but at least • Ines of the symbols R ₁ and Rb one of the groups

zü / Ru 809813/1302

Coll.Zü

-CH ₀ -halogen or -CH ₀ IiC _D , B. _c hydrogen η άτι - η du Ra ο

or SHSammea with B- an additional CH bond, R ₇ and Rg each an · alkyl group or together with the. Nitrogen atom denotes a monoheterocycle with a maximum of one further oxygen or nitrogen heteroatom and η is an integer from 2-7,

and salts of these compounds,

The term alkyl ,, alkenyl or "alkinyl in this specification refers to straight and branched lower alkyl, lower alkenyl or" lower alkynyl radicals having a maximum of 7 carbon atoms "such as methyl, ethyl, propyl ₉ isopropyl, allyl, propargyl, and the like" The G group -GH ₂ = - refers to straight and branched-chain lower alkylene groups ₉ which contain 2 = 7 carbon atoms between the nitrogen atoms or "the nitrogen and halogen atom" which they connect, such as ZoBo ethylene ₉ propylene and the like., Der MonoheterocycluSj , which can be present after this alkylene group, is derived from 5- or 6-membered heterocycles »which contain one or two nitrogen atoms or one nitrogen and one oxygen atom ^ and can be substituted» examples of such monoheterocycles are pyrrolidino ^ piperazines-} Piperidino, horpholino radicals and substituted derivatives thereof »Suitable substituents are alkyl groups, such as methyl or ethyl _{p alkene} nyloxyalkyl _t \ as Vinyloxyaethyl, hydroxyalkyl, such as hydroxyethyl and alkoxy

09813/1302

alkyl groups, such as ethoxyethyl. If the heterocycle contains an additional nitrogen atom, the substituent is preferably located on this nitrogen atom.

Preferred heterocyclic groups are as follows: N-alkyl-piperazinyl, N-hydroxyalkyl-piperazinyl, N-alkyloxyalkyl-piperazinyl, N-alkenyloxyalkyl-piperazinyl, pyrrolidinyl, Piperazinyl, Morpholinyl and Piperidinyl »

The term halogen includes all four halogens.

The method according to the present invention is thereby characterized in that one is a compound of the general formula

CH-R.

(II),

wherein

and

Hydrogen, alkyl, alkenyl or

Alkynyl or the group -GnH2n ^ dp7, R-. _Q water

substance or with R, .. taken together denote an additional CN bond, in which case the nitrogen atom in the 4-position can protrude an oxygen atom +, and in which at least one Jer symbols and R _{11 is} hydrogen and Rp,

8 0 9 8 13/1302 ■ -

R ,, R ₇ and Rg have the meaning given above,

with a compound of the general formula

where X and Z are identical or different halogen atoms, ZoBo are chlorine, bromine or iodine and η has the meaning given above,

implements, wished * all the received connection with one secondary amine of the general formula

wherein R ₇ and Rg have the meaning given above,

; converts, if necessary1 splits off the oxygen atom in the Φ-position and, if desired, the product obtained in eia. Salt transferred »In a preferred embodiment means X bromine and Z chlorine ».

If a substitution is desired in the 1-position _ΰ converts there is conveniently the corresponding 5-phenyl-3H-l ₉ 4-ben2iodiazepin ° "2 (lH) -one ₉ wherein the nitrogen atom is laasubstituiert in l ^ position, which means a hydrogen atom carries , first in the l-liatrium Berivat tarn, Z ₀ B _o diarch. Treatment

8038 13/130 2

with sodium methoxide, sodium hydride or the like, before the compound is reacted with a dihalide of the formula XC _n H _2n -Z g. -

You reaction of the starting material of the formula II with a Dihalide of the formula III is useful rice · in an inert organic solvents using one or more of the following solvents: methanol, Ethanol, dimethylformamide, benzene, toluene, nltromethane, N-methylpyrrolidone or similar. The temperatures and pressures to be used are not critical; the reaction can take place at room temperature or elevated temperature, at normal pressure or elevated pressure be performed.

The implementation of a benzodiazepine derivative of the formula II with a dihalide of formula III provides a compound of the following general formula

wherein fi _L 2 ^and * ^B i4 are hydrogen, alkyl, alkenyl, alkynyl or one of the groups -C _n H _2n -halogen or "- ^ο _η ^Η 2 _η ^Ν \ Γ ♦

809813/1302

however at least one of the symbols B32 and B14 is a group -CH ₂ -halogen, Rj * hydrogen or with R ^. taken together represent an additional C-Nr bond and E ₂ , B. »R ₄ , R ™ and R _{Q denote} the above

have given meaning,.

The reaction of a compound of the formula V with a secondary amine of the formula IV can be carried out in an inert organic solvent using one or more of the following solvents? Acetone, methyl-ethyl-ketone, methanol, ethanol, dimethylformamide, benzene, Nxtromethane, N-methyl-pyrrolidone or the like. Even with this conversion, the temperatures and pressures to be used are not critical. The reaction can be carried out at room temperature or elevated temperature, at normal pressure or elevated pressure. It would be found that the presence of an alkali halide, such as sodium iodide, in the reaction mixture is advantageous . "■■ ,.". ''"'-

If a compound is obtained which has ^{an oxygen atom in the 4- s} "t-'position, this oxygen atom must be split off, e.g. by hydrogenation in the presence of a suitable hydrogenation catalyst, such as Raney nickel, or by treatment with a reducing agent , e.g. a phosphorus trihalide such as phosphorus trichloride,

8098 1 3/1302

U45888

Compounds with a double bond in a 4.5 division, but without an oxygen atom in the 4-position can be on one any stage of the process according to the invention with hydrogen in the presence of a hydrogenation catalyst, such as platinum oxide, are hydrogenated to the corresponding 4 »5-dihydro compound. .

Compounds in 1-position or 4-position unsubsti- ^ can be converted into the corresponding connections are substituted with an alkyl, alkenyl or alkynyl radical in these positions by using them with an alkyl, alkenyl or alkynyl halide. Here, too, in the case of a desired substitution in 1 position initially a conversion into the corresponding 1-sodium derivative useful.

Also can be introduced into the heterocycle later a similar substituent. For example, an -NH group in the heterocyclic ring can be substituted with an alkyl, alkenyloxyalkyl, hydroxyalkyl or alkoxyalkyl substituent by reaction with a suitable halide.

The starting material of the formula II can already be a

R ₇
basic side chain -Οη ^ η ¹ ^ «have. Such Verbin can fertilize from the corresponding unsubstituted compounds by reaction with a halide of the formula

809813/1302

in the above for the main reaction: specified manner.

Compounds of the above formula I form acid addition salts with one or more pick acids (depending on the number of basic nitrogen atoms present), for example with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, tartaric acid, salicylic acid, toluenesulfonic acid, ascorbic acid , Maleic acid, succinic acid, formic acid, acetic acid and the like. ^ - -

Compounds of the above formula I and their pharmaceutically acceptable acid addition salts have anticon = - vulsive, analgesic, sedative and muscle relaxing properties. "-" '-.

80 98 13/1302

They can be used as remedies, e.g. in pharmaceutical preparations, which contain them or their salts in a mixture with one suitable for enteral or parenteral application pharmaceutical, organic or inorganic inert carrier material, such as water, gelatin, lactose, starch, Magnesium stearate, talc, vegetable oils, rubber, polyalkylene « contain glycols, petroleum jelly, etc. For pharmaceutical preparations can be in solid form, »e.g. as tablets, Bragöes, Suppositories, capsules, or in liquid form, e.g. as solutions, Suspensions © of the emulsions are present. If necessary are they sterilized and / or contain auxiliary substances such as preservatives, stabilizers, lubricants or emulsifiers, Salts to change the osmotic pressure or buffers. she can also contain other therapeutically valuable substances.

The present examples illustrate the method according to the invention. All temperatures are given in degrees Celsius and the melting points are corrected «, ■■"' {(

Example 1

0.1 moles of 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one are dissolved in 250 ml of anhydrous dimethylformamide and converted into the sodium salt by adding 0.11 briquette of solid sodium methoxide Convicted. The reaction mixture is stirred and 15 minutes heated on a steam bath. Then in the course of ■

809813/1302

- - -LU - -

Carefully add a solution of iron 0.11 MQlen 2-bromo-ethyl chloride in 200 ml of anhydrous foluene to the heated reaction mixture for 30 minutes. Stir and heat further on a steam bath
l £ hours and then concentrated in vacuo at 50-60 °. The concentrated solution obtained is slowly poured into a mixture of ice and water, whereby a precipitate of crude reaction product is formed. This is dissolved in benzene and purified by chromatography on aluminum oxide
Evaporation of the eluate is obtained from a residue
Mixture of acetone and hexane recrystallized ₉ whereby one
7-chloro-1- (2-chloro-ethyl) -5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one with a melting point of 168-169 ° is obtained.

Example 2

6.7 g of 7-chloro-5-phenyl-3E-1,4-benzodiazepin-2 (1H) -one become dissolved in 40 ml of anhydrous dimethylformamide and added of 6 ml of a 25 # strength methanolic sodium methoxide solution in transferred to the sodium salt. The reaction mix is 30 minutes under protection against atmospheric: - Moisture stirred and on heated in a steam bath. The mixture is then cooled to 30 ° and treated with 2.66 ml (0.0275 mol) of 1-bromo-3-chloro-propane, stirring at 20 ° for 66 hours. The reaction mixture is then evaporated in vacuo and with 100 ml of methylene chloride extracted. The washed and dried methylene chloride extract is evaporated in vacuo to an oil =. This becomes from a

9813/1302

- li -

Mixture of 50 ml of hexane and 10 ml of ether crystallized, with one 7-chloro-1- (5-chloro-propyl) -5-phenyl-3H-1,4-benzodiazepin-2 (IH) -one obtained from the melting point 87-90 °.

10 g of 7-chloro-1- (3-chloro-propyl) -5-phenyl-3H-l _f 4-benzodiazepin-2 (lH) -one are dissolved in 50 ml of methyl ethyl ketone and 4.37 g Sodium iodide and 0.0576 moles of diethylamine. The reaction mixture is stirred and refluxed for 18 hours and then evaporated in vacuo. The residue is extracted with 100 ail ™ methylene chloride and washed with water and then extracted again twice with 60 ml of O, 3N hydrochloric acid each time. The aqueous acidic layer is made alkaline with 4N sodium hydroxide solution, whereupon the precipitate obtained is extracted with methylene chloride, washed and dried. 7-chloro-1- (3-diethylamino-propyl) -5-phenyl-3H-1,4-benzodiazepin-2 (IH) -one with a melting point of 89 ° -91 ° is obtained.

The compound obtained forms a water-soluble maleate, * which can be obtained by dissolving the compound in methanol and adding a methanolic solution of. Maleic acid in the calculated amount. 4-benzodiazepin-2 one obtains the monomaleate of 7-chloro-l- (3-diethylamino-propyl) -5-phenyl-3H-l (lH) -one _s which is recrystallized from methanol.

809813/1302

Example 3

10 g of 7-chloro-1- (3-chloro-propyl) -5-phenyl-3H-1,4-benäGO-diazepin-2 (1H) -one are given 0.0576 moles of H. -Methyl-piperasine reacted, with crude 7-chloro-1- [3- (4-methyl-piperazinyl- [l]) - propylJ-5-phenyl-3H-l _f 4-benzodiazepin-2 (lH) -one in the form of a gel «. This is prepared by dissolving in ethanol and adding a Acetonlö'sung of maleic acid in the calculated amount in the dimaleate converted, which melts NaOH Uakristallisieren from methanol at 180-182 ^Q.

Example 4

10 g (0.0288 moles) of 7-chloro-1- (3-chloro-propyl) -S-phenyl ^ H-1,4-b <Bnzodiazepin-2 (1H) ~ one are according to the information in Example 2 all; 0.0576 moles of N- (2-hydroxy-ätfa.yl) -piperazine reacted. The raw seaction product obtained in lOra of an oil is according to the information in Example 3 in the siaaleate convicted. Recrystallization from acetone gives 7-chloro-1- [3- (4-C2-hydroxy-ethyl] -piperazinyl- [1]) -propyl] -5-phenyl-3H-1,4-benzodiazepia-2 (IH) -one dimaleate vom Melting ~ point 121-123 °.

8Q 98 1 3/130 2

Example 5 / ,,, -;

10 g of 7-chloro-1- (3-chloro-propyl) -5-phenyl-3H-l _t 4 = benzodiazepin-2 (lH) -one are reacted with 0.0576 moles of piperazine as described in Example 2. The crude reaction product obtained as an oil is correspondingly transferred to the procedures of Example 3 in das.Dimaleat _s By recrystallization from acetone, 7-chloro ~ l- [3-pipera-

- ■ ■ * '■

zinyl- (1) -propyl} -5-phenyl-3H-1,4-b enasodiazepine-2 (IH) -one dimaleate with a melting point of 120-122 °.

Example 6

7jll g (45 * 2 mmol) of 1-bromo-3-chloro-propane are added in portions at 0 ° to a stirred solution of 34 mols of 7-chloro-5- (2-fluoro-phenyl-3H) -l _s 4 ^ta benzodiazepin-2 (lH) -one in 50 ml of dimethylformamide added »Han allows the reaction mixture to warm to room temperature, stirs for one hour and then poured into one liter of water. The reaction product is extracted with methylene chloride (3x 100 ml) Organic layers are combined, washed, dried and filtered through 50 g of aluminum oxide. After removal of the solvent, the reaction product is recrystallized from a mixture of ether and petroleum ether (boiling range 30-60) , 7-chloro-1- (3-chloro- propyl) -5- (2-fluorophenyl) -3H-l, 4-

8 0 9 813/130 2

- 1.4.- - "" ■■■ / '-

on from ,; Melting point, 86- ^ 9 _<; Λ, .---., " - _r . , .. _{t ¥}

EiSe Mfstciaingvon 5 # S g ^: Co ^

y r .. -M-. ■ *

Piperäziöö -21- g (0.14- mole) - \ r ;; '.-.,

Sodium iodide and 500 ml of meth ^ l-ethyl ketone are stirred χώ &", ■ 'heated to reflux for 17 hours <, the solvents are removed under reduced pressure and the residue is distributed between.Methylenchlorid.und Vassero The methylene chloride layer is : with. Water washed and .the reaction product -with 3n-SaJLzsäure © £ xtrahierit Ό ie acid-.Schichten are combined with _p; immoniak- aibkalisch · gestelXt and, with; Ethylene chloride extracted: _o , The combined en. · J & eth ^^ are washed jnv, ge, - , ^

ü röekne% "country: narrowed ^ Pas preserved., Αβ, Ι " $ '5%. g) billion _; in/. Methanol is converted into "Hyäröafelörid" and precipitated with ether. * Mß ^ _; Recrystallization from a mixture of methanol and ether gives 7-chloro-1- (3-piperazino-4prop3ri) ^ 542-fluoro = phenyl) -3H ^ ls.; 4 ^ henz: o4iaze! pin-2 (lH) -qn-hydrochloride of melting point 235-255 °, CZers <,);.,; ..,: ...,: ,, _, ^ ' ,, ^;,; ^ ,,, _r _ _P , ....

Example 8

line, mixture, from. -11 * 8 .g, (3? ^ 5 ^^^ mmol) ^ - Chlo ^ l-

flμpr ^ phenyl ·) -3H-1 _R 4 "h.enzpdiazepi 4» 85 g

Μ ~ Άβ ethyl piperazine, "4.9 g" (3.2 _?, 5 mMple) sodium iodide and 200 ml methyl ethyl ketone is used according to the information

80 98 1

1 »Example 7 implemented and worked up. To obtain a oil, which is dissolved in 100 si methanol and treated with a solution of 4.5 β maleic acid in 100 al methanol "Bas sais is filtered off and umkristalliiiert from methanol. 7-Chloro-1- [3- (4-ethyl-piperaeino5-propyl] -5- (2-fluorophenTl) -3H-1 _P 4-benzodiazepine-2 (1H) -on-diaalate with a melting point of 185 is obtained -187 °.

Example 9

A mixture of 10 ₉ 26 g (28.2 mmol} 7-ChlQr ~ 1- (3-chloropropyl) -5- (2-fluoro-phenyl) -3H-1 _s 4-beneodiaiepin-2 (1H) = on _p 7-5 g (64 mmoles) of N- (β-Hydrojgr-ethyl) piperazine, 4.2 g (28.2 mmoles) - *. Sodium iodide and 100 ml of methyl-ethyl-ketone are used accordingly the information in Example 7 implemented and worked up. Man

, r,. ^ 3- { 2-fluoro-phenyA

stop 7-Ohlor-l- (3- [4- (2-hydroxy-ethyl) -piper * 85ino] -propyl> -3H- · * '' lp4-beneodlazepin-2 (lH) -on-diaaleate with a melting point of 120-123 °.

Example 10

A mixture of 20 g (48 «moles) of 7-chloro-1- (3-piperasinopropyl) -5- (2-fluorophenyl J-3H-1,4-b« nEodia »« pin-2 (IH) - en, 8.2 g (96 mmol) ß-chloro-ethyl-vinyl-ether, 6.63 g (48 mmol) potassium carbonate and 100 ml toluene is stirred and refluxed for 19 hours »A solution of this reaction mixture in 100 ml Methanol is treated with a solution of 4.5 g of maleic acid in 100 ml of methanol. 7-chloro-1- (3 = [4 = (2 ~ vinyloxy-

809813/1302

diazeplii-2 (iH) -O3i ^ 'dinialea1; · from "an: acetone solution ¹ and'crystallized from acetone to" yellow prisms with a melting point of 115-122 ° ο are obtained

^; ■ ■ ^: - Example "11

A mixture of 20 g (48 mmol) of 7-chloro-1 ^ (3-piperazinopropyl j -5 - <- (2-ίluorophenylJ-JH-I _p 4-benzodiazepin-2 (IH) -one, 8 "46 g (96 mmol) 2-01ι1θΓ ^% 1-Μ ^ 1 ^ ΐ] ιβΓ ₉ 6 ₉ 63 g (48 mmol) of potassium carbonate and 40 ml of toluene are reacted according to the information in Example 10 and worked up 7-Chlbr ^ -l- .C3- [4- (2-ethoxy-ethyl piperazinyl J ~ (1)] propyl) -5- (2 ^ f luor-phenyl) -3H-l _s, 4-benzodiazepin-2 (lH) - on-trimaleate is isolated from acetone and melted at 125-133 ° »

Example 12 . .

A solution of; 3p "85g l- (2 = Biäthylajnino-ethyl)> 7 = clear». 5-phenyl-3H-l _1> 4 <r = l ^: > enzodiazepin-2 (lH), - on '=' 4 »Qxyd In 30 ml of methanol is hydrogenated at room temperature and atmospheric pressure in the presence of about 2 g of wet Raney-Niekel. After absorption of the calculated amount of hydrogen, the solution is filtered and the Piltra't evaporated in vacuo." The residue is extracted with benzene ',' the hexane solution is concentrated in vacuo and the residue is recrystallized from a mixture of ether and pentane »

(manufactured according to the information in example 2)

8 0 9813/1 302. ·.

being colorless Prismea ve & T-Cy 5-phenyl-3H-l _? 4-benssediaz, epin-2 (1H) -on from the point of view 79-81 °.

Example 15

A suspension of 1.5 g of platinum oxide in 150 ml of glacial acetic acid is hydrogenated. The reduced catalyst are employed, a solution of 2 · £, 4 g 7-0hlor-l-C2-diethylamino ethyl ~) «5-C2 ~ fluorophenyl) -3H-1, 4-benzodiazepin-2 (IH) -one (prepared in accordance with the information in Example 2) in 150 ml of glacial acetic acid and hydrogenated the reaction mixture exhaustively. The catalyst is removed by filtration and the acetic acid evaporated under reduced pressure. The residue is taken up in 50 ml of methylene chloride and washed twice with 20 ml of a JO ^ igen sodium carbonate solution each time. The solution obtained is washed free of alkali, dried and concentrated. Recrystallization from a mixture of ether and petroleum ether (boiling range 30 = .60 °) gives 7-chloro-1- (2-diethylamino-ethyl) -5-C2-fluorophenyl) -4s, 5 "-cLihydro-3H-lp4 -benzodiazepin-2 (lH) -one with a melting point of 98-99 °

The dihydrochloride is obtained by introducing hydrogen chloride into a methanolic solution of the pure base Addition of ether precipitates from the solution. By recrystallization colorless rods with a melting point of 175-190 ° (decomp.) are obtained from a mixture of methanol and ether.

809813/1302

'. ■ ie - 1M5888

A mixture of 6 g (15 ₉ 5 mmoles) 7-chloro ~ 1 ~ (2-diethylamino ethyl) -5- (2-fluorophenyl) -4 ₉ 5-aihydro-3H-1 _f 4-bensodiazepine = 2 ( IH) on and 8.8 g (62 mmol) of methyl iodide in 20 ml of dimethylformamide is stirred for 17 hours at room temperature. The mixture is then poured into 1 liter of water and the reaction product is extracted therefrom with methylene chloride (2 × 55 ml) _{; p} washed are combined, dried and evaporated. The reaction product is recrystallized from a mixture of acetone and ether to give 7-Chl · or-l- (2-diethylamino · · = ethyl) -4-methyl-5- (2- fluorophenyl) -4 _f 5-dihydro-3H-l _s 4 ~ benzodiazepine-2 (lH) -oh-methyl iodide with a melting point of 185-190 °.

In an analogous manner as described in the preceding examples, the following compounds can be prepared:

1- (2-Dimethylamina-ethyl) -7-nitro-5-phenyl-3H- * l "4-b enzodiasepin-2 (IH) -on-dihy (iroehloria5 colorless prisms from a mixture of methanol ₉ ethers and something methanolic hydrogen chloride j melting point 232-255 ° "

1- (2-Dimethylandno = ethyl) «7-nitro ~ 5» phenyl-5H == - l ₁₎ 4 = beiizö - = - diazepin-2 (lH) -one; colorless prisms made from a mixture of ether and petroleum ether, melting point 121-122 ° "

1- (2-dimethylamino-ethyl) -5-phenyl-7 = trifluoromethyl- »3H- = lp4-benzodiazepin-2 (lH) -one dihydrochloride; colorless! blame out a mixture of methanol, ether and a few drops methanolic hydrogen chloride; Melting point 217-221 ° ■ »

809813/1302

7-chloro-1- (2-dimethylamino-ethyl) ^ -phenyl- ^ Hl "4-benzodiazepine-2 (1H) -OHj yellow prisms from ether / hexane; Melting point 96-98 ° _β

7-chloro-l- (3-dimethylamino-propyl) -5-phenyl-3H-l _? 4-benzodiazepin-2 (1H) -one; colorless prisms made of hexane; Melting point 94-96 °

7-chloro-1- (2-diethylamino-ethyl) -5- (2-fluorophenyl) -3H-1,4-benzodiazepine-2 (1H) * - one dihydrochloride; light yellow rods made of methanol / ether5 melting point 190-220 °,

7-chloro-1- (3-diethylamino-propyl) -5-phenyl-3H-1 ^ 4-'benzodiazepin-2 (1H) -one dihydrochloride; Melting point 208-210 ° (recrystallization from ethanol / acetone / ether) «■. \.

7-chloro-1- (2-dimethylamino-1-methyl-ethyl) -5-phenyl-3H-1,4-benzodiazepine-2 (1H) -onj Melting point 134-135 ° (umcrystallization from hexane) "

7-chloro-1- (2-dimethylamino-1-methyl-ethyl) -5-phenyl-3H = -l _P 4-benzodiazepine-2 (1H) ^ one dihydrochloride, melting point 165-168 (recrystallization from a mixture of isopropanol / Aether) ■ "

7-chloro-1- (2-pyrrolidino-ethyl) -5-phenyl-3H-1 _St 4-benzodiazepin-2 (IH) -one; Melting point 106-107 ° (recrystallization from hexane) =

7-Ohlor-l- (2-pyrrolidino-ethyl) -5-phenyl-3H-l, 4 = benzodiazepin-2 (lH) -one monomaleatj melting point 157-159 ° (Umkristallieation from _acetone); , -,.

809813/1302

7-chloro-1- [2- (4-methyl ~ piperazinyi- [l J) -ethyl] -5 = - 1 ρ 4-benzodiazepin-2 (IH) -one j Melting point 159-160 ° (single crystal! Sation from a mixture of acetone / hexane) "

7-Chloro-1- [2- (4-methyl-piperazinyl- [l]) -ethyl] -5-phnyl-3H-1- ₍ , 4- "benzodiazepine-2 (lH) -one-dimeate5 Melting point 156-160 ° (recrystallization from my mixture of methanol / acetone) "

7-chloro-l- (2-piperazino-ethyl) -5-phenyl-3H-l ₉ 4-l 'enzodiazepin-2 (lH) -one dimaleate; Melting point 172-178 ° (recrystallization from a mixture of methanol / acetone) _o

7-chloro-1- (2-morpholino-ethyl) -S-phenyl- ^ H-JLp 4-b enzodiazepine-2 (1H) -QnJ Melting point 144-146 ° (recrystallization from a mixture of acetone / hexane), ο -

7-chloro-1 = (2-morpholino-ethyl) -5-phenyl-3H-i ₉ 4-l3enzodiazepine-2 (1H) -one monomaleate; colorless acetone prisms; Melting point 156-157 ° o

7-chloro-1- (2-piperidino-ethyl) -5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one; colorless «prisms made of hexane, melting point 90-92 °»

7-chloro-l- (2-piperi'dino-ethyl) -5-phenyl-3H-l, 4-benzodiazepin-2 (lH) -one monoinaieati colorless prisms from acetone? Melting point 172-173 ° "^ '""'["'' ■. ■

7-chloro-l- (2-diethylamino-ethyl) -5- (2-chloro-phenyl) -3H-1 ₉ 4 = benzodiazepin-2 (lH) -one; colorless needles made of hexane; Melting point 68-70 ° o

809 8 1 3/1 302. · . ■

- 9Λ -

7-Chloro-1- [2- (4-methyl-piperazino) -ethyl] -5- (2-fluoro-phenyl) 3H-1,4-benzodiazepine-2 (IH) -on-trihydrochloride j melting point 225-239 ° (recfistallization from a mixture of methanol / Ether).

7-chloro-l- (2-diethylamino-ethyl) -5- (2-fluorophenyl) -4-methyl-4 _r 5-dihy <lro-3H-l _f 4-benzodiajsepia ~ 2 (IH) - on? Melting point 85-85 ° (Umkrißallisation. From petroleum ether).

Example 14

10 g of 7-chloro-1- (3-chloro-propyl) -5- (2-fluorophenyl) -3H-1 _P 4-benzodiazepin-2 (1H) -one are mixed with 165 g of lactose and 30 g of corn starch and passed through a crusher. The mixed powder is then mixed with 5 g of alkali. After thorough mixing, the hard gelatin is filled in capsules, each capsule containing 210 mg of the preparation obtained.

Example 15

10, 2 g of 7-chloro-1- (3-chloro-propyl) -5- (2-fluorophenyl) -3H-l, 4-ben »odiazepin-2 (1H) -one, 109.4 g lactose, 47.9 g corn starch and 10.0 g of prehydrolyzed corn starch are mixed together. The mixture obtained is washed with water mixed into a thick paste and adjusted to a suitable grain size granulated and dried for about 16 hours at 60 °,

8 0 9 813/1302

Claims (1)

The dry granulate is crushed to the appropriate fineness. smaller and. then, mil? 2.5 g of magnesium stearate mixed together. The product obtained is compressed into tablets of 180 mg. Bie tablets can be either flat or biconvex and may have a break line if necessary » > Example, 16 . '.. 0.25 g of 7-chloro-l- (5-chloropropyl) -5- (2-fluorophenyl) -3H-l _? 4-benzodiazepin-2 (lil) -one are dissolved in 15.0 ml of benzyl alcohol, the solution obtained is mixed with 400 ml of propylene glycol and then with 100 ml of ethanol and mixed homogeneously. 50.0 g of sodium benzoate are added in the required amount of water ( for injection purposes). Both solutions are mixed homogeneously and brought to a volume of 1000 ml with water (for injection purposes). The solution obtained is filtered through a candle filter and filled into ampoules of suitable sizes, gassed with nitrogen and sterilized in an autoclave at 0.7 atmospheres for 1 hour. It is preferred dark vials _β Bie solution should be protected during the preparation and storage of light. ' 809813/1302 Pat ent claims ; 1.] Process for the preparation of benzodiazepine derivatives the general formula wherein IL is hydrogen, alkyl, alkenyl, alkynyl or one of the groups -GH ₂ -halogen or ' ^ß 2 V ^{& SBeTB} * ^{ofi or} alkyl, E, Hydrogen, halogen, trifluoromethyl or nitro E. hydrogen, halogen, trifluoromethyl, nitro or alkylthio, IL. Hydrogen, alkyl, alkenyl, alkynyl or one of the groups -CH ₉ -halogen η η dU ¹ w or -0 H CJX in , but at least one of the Symbols IL and IL. one of the groups -CH ₂ -halogen or -CH ₀ NC ", B. _c hydrogen or together η ün" to ο with IL · an additional C-N bond, IL. and one alkyl group each or, together with the nitrogen atom, a monoheterocycle with a maximum another oxygen or nitrogen- 8 0 98 1 3 / .1 30 2 mean heteroatom and η an integer is from 2-7, and salts of these compounds, characterized in that one is a compound of the general formula 9 .0 (II). where Rg and R _{11 are} hydrogen, alkyl _s alkenyl or alkynyl or the group -C _n H ^ _n NcCD? . " R ₁₀ denotes hydrogen or _{, taken together with R 11} , an additional CN bond »in which case the nitrogen atom in the 4-position can carry an oxygen atom, and in which at least one of the symbols R _Q and R _{11 is} hydrogen and R ₅ , R- , R ,, R ₇ and Rg have the meaning given above, with a compound of the general formula - η 2n v-L-ii;, where X and Z are identical or different 8 0 9813/1 302 Mean halogen atoms and η has the meaning given above, converts, if desired, the connection obtained with a secondary AmIn of the general formula where B_ and R _{Q have} the meaning given above, converts, if necessary, the oxygen atom in 4-position splits off and, if desired, the product obtained in a salt transferred. 2. The method according to claim 1, characterized in » that at any stage of the process a compound which has the configuration C = ΪΓ, reduced. 3. The method according to claim 1, characterized. that you get a compound which is in the 1-position or 4-position is unsubstituted, alkylated, alkenylated or alkynylated and / or introduces a substituent into the heterocycle. 4. The method according to claim 1 or 3 »characterized in that for substitution in 1-position first forms a 1-sodium derivative and the latter with a the desired fiadikal in! -position introducing means implemented 809813/1302 5. The method according to claim 1 or 4, characterized in that a 7-halo-5-phenyl-3H-l _f 4-benzodiazepine-2 (lH) -one is reacted with a haloalkyl halide and the T-halogen formed -l-haloalkyl-S-phenyl-JH-1,4-benzodiazepin-2 (IH) -one is reacted with a dialkylamine. 6. The method according to claim 5, characterized in that 7-chloro-5-phenyl-3H-l, 4-benzodiazepine-2 (1H) ⁱ -one is reacted with a haloethyl halide and the 7-chloro-I-haloethyl- Reacts 5-phenyl-3H-l _p 4-benzodiazepin-2 (lH) -one with diethylamine. 7. The method according to claim 5 »characterized in that m, at. 7-chloro-5-phenyl-3H-1,4-benzodiazepin-2 (lH) -one with a Reacts halogen ethyl halide and the 7-chloro-l formed = > ialogenethyl-5-phenyl-3H-1,4-benzodiazepin-2 (1H) -one with Di = converts methylamine » 8 _a method according to claim 1 or 4 _9, characterized in that 7-Uitro-5-phenyl-3H-l _t 4-benzodiazepine-2 (lH) = - ori is reacted with a halogen ethyl halide and the 7-jiitrol-halogen ethyl Reacts 5-phenyl-3H-1,4-benzodiazepin-2 (1H -) - one with dimethylamine. 9 »Process according to claim 1 or 4, characterized in that 7-trifluoromethyl-5-phenyl-3H-l _s 4-benzodiaezepin-2 (lH) -one is reacted with a haloethyl halide and the 7-trifluoromethyl-l- haloethyl-5-phenyl-3H-1,4-benzodiazepin-2 (IH) -one 8 09813/1302 Reacts with dimethylamine. 10. The method according to claim 1 or k _s characterized in that 7-halo-5- (2-fluoro ⁱ -phenyl) -3H'l, 4-benzodiazepin-2 (lH) -one is reacted with a haloalkyl halide and the resulting 7-Halogen ~ 1-haloalkyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepin ~ 2 (1H) -one is reacted with a bialkylamine. 11. The method according to claim 10 _f, characterized in that «7-chloro-5- (2-fluoro-phenyl) -3H-l, 4-benzodiazepine ~ 2 (lH) -one is reacted with a haloethyihalide and the 7-chlorine formed -l-halogenoethyl-5- (2-fluorophenyl) -3H-1,4-benzodiazepin-2 (lH) -one is reacted with diethylamine. 12. The method according to claim 1, characterized in that the product obtained according to claim 11 is reduced with hydrogen in the presence of a hydrogenation catalyst. > Process according to Claim 1, characterized in that 7-chloro-5-phenyl-3H-1,4-benzodiazepine-2 (1H) - one is reacted with a haloalkyl halide. l4. Process according to Claim 13, characterized in that 1,3-dichloropropane or 1-chloro-3-bromopropane is used as the haloalkyl halide. 809813/1302