DE1929910A1 - Benzodiazepine derivatives - Google Patents

Description

Dr. kg. λ wi * r WeA Or. Froaz lederer

[S2.SEP.i969

P 19 29 910.6 RAN4008 / 152 K.

F. Hoffinann-La Roche & Co. Aktiengesellschaft ,! Basel, Switzerland · Benzodjazepln derivatives

The present invention relates to benzodiazep-in derivatives. In particular, the invention relates

on 5- {2-Pyrimia3.nyl) -1, 4-benzodiazepines and on their production - - - ■ * -. ■ -

The benzodiazepine derivatives according to the present invention correspond to the general formula

098S1 / 1708

in which B is a -C-, -CH ₀ - or -C- group R _a

d. a

and R. independently of one another each hydrogen, halogen, nitro, amino, lower alkylamino, di (lower), alkylamino, trifluoromethyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, lower alkanoyl, lower cycloalkyl, lower Cycloalkyl (lower) alkyl, lower haloalkyl, lower Aminoalkyl, lower monoalkylaminoalkyl, lower dialkylaminoalkyl, lower hydroxyalkyl or -)

) COR, (where η is an integer from 0-5 and R, hydroxy, lower alkoxy or -ϊζ ^ 2, where R ₀ and R., each for hydrogen or ^ lower alkyl or together with the nitrogen atom for a 5- or 6-membered saturated heterocyclic ring) and R, denote hydrogen, lower alkyl, lower acyloxy, lower alkoxycarbonyl, hydroxy, lower alkoxy or lower alkoxy (lower) alkyl.

909881/17 0 8

The invention also encompasses acid addition salts of the compounds of the above formula I.

The term "lower alkyl" refers to straight-chain or branched, saturated "hydrocarbon groups with 1-7, preferably 1-4 carbon atoms, such as methyl, ethyl, propyl and isopropyl. Lower lower cycloalkyl groups are hydrocarbon groups with 3-6 Carbon atoms are to be understood as »Β. Cyclopropyl, cyclobutyl and cyclopentyl. The term" lower alkanoyl "includes radicals such as the acetyl, propionyl and hexanoyl group. DER term "iiiederes alkoxy" includes ^"!. Residues ⁵ as the Ä'ethoxy-, Methöxy-'and Pröpoxygruppe Unless specified otherwise · '" - are unter'Halogen "to understand all four halogens, d, h .- 'Fluorine ·, OfOu, chlorine and bromine. ..- ■■ ·.-.-. ..-.-.. · -.... - .. ·.;: -..- -. -: .-.,

A preferred "Spe'kt- the" present invention relates to those compounds d'er "" Formula T above, in which B denotes C = O ", ie compounds of the" general formula

909881/1708

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

CL LJ O "~ U

and their acid addition salts.

Those compounds are particularly preferred Formula II, in which R is halogen, in particular chlorine, R, hydrogen and R and R, each hydrogen or lower alkyl,

- CQ. . ^v

in particular mean methyl. Examples of these particularly preferred compounds are:

r 7-chloro-1,3-dihydro-5- (2-pyrimidinyl) -2H-1,4-benzo-

diazepin-2-one ■,

7-chloro-1,3-dihydro-1,3-dimethyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one and

7-chloro-1,3-dihydro-1-methyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one .

^; Another Aspelct ^the: present invention relates to compounds The ones-of the formula "!, wherein B is -Clip-, i.e., ^'-'. '

Compounds of the general formula ^: - · ^: ■ "" · ■ '"''-"

909881/1708

where R, R.> R and R, have the above meaning,

ä D C Cl

and their acid addition salts.

Particularly preferred compounds of the formula III are those in which R is hydrogen, halogen (in particular

et

Chlorine), amino or nitro, R, hydrogen, R hydrogen or lower alkyl (especially methyl) and R, denote hydrogen. Examples of these particularly preferred compounds are:

2,3-Dihydro-7-nitro-5- (2-pyrimidinyl) -lH-1,4-benzodiazepine,

2,3-Dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) -IH-1,4-benzodiazepine,

7-chloro-2, j5-dihydro-1-methyl-5- (2-pyrimidinyl) -IH-1,4-benzodiazepine,

2,3-Dihydro-5- (2-pyrimidinyl) -IH-1,4-benzodiazepine and 7-amino-2,3-dihydro-1-methyl-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine.

The benzodiazepine derivatives of the above formula I can be prepared according to the invention by a) for the preparation of compounds of the formula I in which B is a carbonyl group means a compound of the general formula

909881/1708

JüLJL

IV

wherein R, R., R and R. have the above meanings

and X stands for a leaving group, cyclized in the presence of ammonia or

b) for the preparation of compounds of the formula I in which B is a methylene group and R _n and R are each hydrogen,

C CX

a compound of the general formula

where R and R, have the above meaning,

cL D

reacts with ethylenediamine or

c) for the preparation of compounds of the formula I in which B is a carbonyl group and R and R, each alkyl or sub-

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substituted alkyl mean a corresponding compound, where R and R each hydrogen, in the 1- and J-position dialkylated or substituted by a substituted alkyl radical or

d) for the preparation of compounds of the formula I in which R has a meaning other than hydrogen, a

Compound of the formula I in which R. is hydrogen, in

1-position correspondingly substituted or

e) for the preparation of compounds of the formula I in which B is a thione group, a compound of the formula I in which B is a carbonyl group; treated with .a protective agent or ■ · ...-,. - _; ,

... f.); for the production v _; on amino-substituted compounds of the formula I, a corresponding: Nit.ro-substituted compound reduced or -, ■ '-. , _; . - ..-.- ■ ·

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

R and / or R, hydrogen or halogen are enta D

speaking compound, in which R and / ödör R / mean amino,

subject to a Sandmeyer reaction or

h) for the preparation of compounds of the formula I, which are substituted by alkylamino or dialkylamino, a corresponding, amino-substituted compound of Formula I alkylated, for example by means of an alkyl halide or a dialkyl sulfate or

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

B is a carbonyl group, R and R are any of the

a D

& 09881/1708

ÖAD

Have the above meanings except for amino or lower alkyl mercapto, R any of the above meanings except has lower hydroxyalkyl and R has any one of the above meanings besides hydroxy, a compound of the formula

where R, R ,, R and R, which have the meaning just mentioned under i), B is a carbonyl or methylene group means and A for the structural element

C = N '

or

NH

stands,

where A then stands for the structural element CH

IiH stand

must, if B is a carbonyl group, oxidized or

j) in the 5-position of a suitably substituted 1,4-benzodiazepine introduces a HpN-C = NH group and then builds a pyrimidinyl ring from this or

k) for the production of acid addition salts of the

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bonds of the formula I, a corresponding free base with converts an acid.

According to one aspect of the present invention compounds of the formula II are thus obtained by cyclizing a compound of the above formula IV in the presence of ammonia. Suitable leaving groups are, for example, halogen atoms, such as chlorine, bromine or iodine, in particular bromine, or an alkyl, Aryl or alkaryl sulfonyloxy group, such as mesyloxy or Tosyloxy, or a quaternary ammonium group such as trimethylammonium.

The cyclisation of compounds of formula IV with ammonia is conveniently carried out at temperatures between about -55 and +100 ⁰ C ,. in particular between about -35 and +35 ⁰ C. The reaction can be carried out in the presence of an inert organic solvent, for example in the presence of a lower alkanol such as methanol or ethanol, an ether such as diethyl ether, tetrahydrofuran or ethylene glycol dimethyl ether, or a chlorinated hydrocarbon, like methylene chloride.

According to another aspect of the present invention, a compound of formula III is obtained by using a Reacts compound of the above formula V with ethylenediamine.

909881/1708

1929S10

Compounds of formulas II and III, wherein R of

Hydrogen is different, can also from the corresponding Compounds in which R is hydrogen can be prepared by methods known per se. For example, the 1-position can be alkylated in the usual way. For example, a compound of formula II or III in which R is hydrogen means, converted into the 1-sodium salt by treatment with sodium hydride and this then with a treat lower alkyl halide (such as methyl iodide) to obtain the corresponding 1-methyl derivative. In an analogous way can also use the other substituents denoted by the symbol R be introduced in 1 position.

It should be noted that the hydrogen atom in 3-position of the compounds of formula II acidic properties and can thus also be replaced by an alkyl group by the process just mentioned. So if you can treats such a compound with an alkali metal hydride and then adds an alkyl halide, so one can except <the product alkylated in the 1-position also that in the I, j5-position obtained dialkylated product of the structure indicated by formula II.

According to a further aspect of the present invention, compounds of formula II (i.e. compounds which have a carbonyl function in the 2-position) on per se

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known manner by treatment with a sulphurizing agent, such as phosphorus pentasulphide, in the appropriately substituted Compounds, polygamy in the 2-position have a thione group, be transferred.

According to a further aspect of the present invention, benzodiazepine derivatives of the formula are obtained

wherein R 'and R' are each hydrogen, halogen, nitro

el D

or trifluoromethyl, R 'is hydrogen, lower alkyl, lower haloalkyl or di (lower) alkylamino (lower) alkyl and R 'are hydrogen or / alkyl, by making a compound, the formula

where R 'R \, R' and R 'have the above meaning, a * b ■ cd

909881/1708

B denotes a carbonyl or methylene group, and A denotes the structural element v “ -: -, ■ -. } .- .. - _; :

or "CH NH, 'Where A then "'''

for the structure element CH r—- NH- .must stand-, · ν- 'i -

when B is a carbonyl group, oxidized by means of ruthenium tetroxide.

Oxidation by means of ruthenium tetroxide leads to the desired product in a smooth and easy manner. According to a preferred The ruthenium tetroxide is carried out in molar Excess brought into the reaction zone. The reaction is preferably carried out below room temperature, for example in a temperature range between approximately -20 and approximately + 15 °, in particular between approximately 0 ° and approximately + 10 °.

The reaction is carried out with advantage in the presence of a inert organic solvents, and among the many suitable solvents are halogenated aliphatic solvents Hydrocarbons such as chloroform and dichloromethane mentioned.

After letting the reaction go for so long until the desired goal is reached, any excess ruthenium tetroxide present in the reaction mixture becomes

■ 9098 8 1/1708 "

advantageously destroyed by adding a suitable reagent; for this purpose a lower alkanol is preferably used,

such as 2-propanol.

If the production of the starting products is not already known, it can easily be carried out according to the in the following reaction schemes. Examples are given. Of course, these schemes can be used for the purpose of introduction other substituents can be modified.

909 ^ 01/1708

Close

: -CN

air

Jy.

ENT ₃

Cl

O ₂ 3

HAc

H ₂

Ni

Ac ₂ O

NH:

0 pyr

CrO ₅

O ₂ N.
4th

H ₂

= 0 Pyr

IX

NH ₈

Pyr

10

909981/170 8

POCl ₅ ,

CrO ₃

Cl /

HO

Mr

Ir

NaÖ-ΗΓ '* i "-

9 0 9 8 81/1 7 0 8 ORIGINAL

It is also possible, in the 5-position of a suitably substituted 1,4-benzodiazepine, to supply an H ₂ NC = ICi group-a, <-, and from this in an analogy to reactions 12, t- * -; 1j3 - "- t.15 r ->. 2 to build up the JRyrimidinyl ring; the, oxidation by means of -, Chroro-r, -, -trlpxyd, can in this case (ie, if the Ben.zodl; azepins _; ystem ^ • is already preformed) of course not applicable.% · _; - 'v;

_t i ι \ '■' ..;

It is also possible for those present in the compounds according to the present invention. To change substituents according to methods known per se. For example, eine_ ₄ nitro group reduz by hydrogenation to an amino group: ated ...:.: Be. _{The amino group can be r} . Or by means of an alkyl halide. of a dialkyl sulfate / are / are mono- or dialkylated .. In addition, the amino group can be replaced by a Sandmeyer reaction by _r .. ,, halogen or hydrogen. : ^ ν

_: As already mentioned above, can the connections -the _r formulas I, _r XI and III in the form of acid addition salts, ER hold _u, are, especially in the form of their pharmaceutically yer _r - .. reversible acid addition salts. Examples. Of inorganic
and organic acids which are pharmaceutically acceptable
Forming salts are hydrogen chloride, hydrogen bromide, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid and p-rtoluenesulfonic acid. These salts can be made from
the free bases of the compounds of the formulas I, II and III. be produced by well-known methods. Besides that

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the pharmaceutically unsuitable acid addition salts of the above compounds are useful as intermediates for the preparation of the pharmaceutically acceptable acid addition salts, which can be obtained, for example, by salination or by releasing the base and subsequent salt formation by means of a pharmaceutically acceptable acid according to known methods Methods is done.

The compounds according to the present invention can to be used as a remedy. They are characterized by anticonvulsant, sedative and muscle relaxing properties; in addition, certain of these compounds show antipyretic properties. The compounds can be used in the usual pharmaceutical Preparations are processed, for example by mixing with common inert, for parenteral or enteral administration suitable carrier materials, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic and the like, polyalkylene glycols or petroleum jelly. They can be administered in the form of conventional pharmaceutical preparations, for example in solid form Form (e.g. as tablets, dragees, capsules or suppositories) or in liquid form (e.g. as solutions, suspensions or emulsions). In addition, the pharmaceutical preparations, which contain the compounds according to the present invention, common pharmaceutical processes (such as, for example, sterilization) can be subjected to common pharmaceuticals

909881/170 8

Contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic vision Pressure or buffer. The preparations can also contain other therapeutically valuable substances.

A suitable pharmaceutical dosage unit may about 1 to 500 mg of a compound according to the present invention

contain. Suitable daily doses for oral administration to mammals range from about 0.1 rag / kg to about 300 mg / kg. For parenteral administration to mammals, a suitable daily dose is about 0.1 mg / kg to about 10 mg / kg. However, the specific dosage should be used in each individual case according to the professional judgment of the person administering the administration of said connection performs or monitors, the individual Needs to be adjusted. It should be noted that the doses given above are purely by way of examples are to be understood.

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

example 1

A solution of 1.1 g of 2-bromo-4-chloro-2 ^{t l} - added to 200-300 ml of liquid ammonia (2-pyrimidinylcarbonyl) acetanilide in 100 ml of tetrahydrofuran v / lrd dropwise. One leaves

909881/1708

the mixture for 4 hours 'reflux and' let i 'thereto ^·'; "evaporate the ammonia. Then water is added in order to dissolve the organic salts, and the solvent is evaporated off under reduced pressure. The residue is partitioned between methylene chloride and water; the organic phase is dried over sodium sulphate and concentrated Evaporated to dryness. The "residue is recrystallized from ethanol, 0.3 g of {J> 6% Y * ■ T-chloro-ljJ-dihydro-S- (2-pyrimidinyl) -2H-1,4-ben ' zodiazepin-2-one "with a melting point of 241-242 °. Crystallization from a" mixture "of ¹ chloroform and hexane gives colorless rods which have the same melting point. IR (KBr) 1690 (Amid-CO), 1565 cm" ¹ , - "■■■ - ■

The starting product can be produced as follows:

(A) To a solution of 5 ^ 4 g (0, ^ 6 mol), ο-chloro phenylacetonitrile in 900 ml of dry tetrahydrofuran is added 17 * 2 g of 50% sodium hydride in mineral oil (0.16 mol) and heated reflux the mixture for 30 minutes. Then will a solution of 4-1.1 g (0.36 mol) 2-chloropyrimidine in 200 ml dry tetrahydrofuran within 10 minutes to the

boiling

4MM * MMh «A solution is added and the mixture is heated for a further 3 hours. After cooling, 100 ml of water are added and the tetrahydrofuran is removed by distillation under reduced pressure. The remaining aqueous phase with _t Methylenehlorid is extracted, washed with water, dried over -

909881/1708 '

■■■■ "■ - 20 -

Sodium sulfate and evaporated to dryness. 9 Λ S of an oil are removed by extracting the residue with twice 375 ml of hot hexane. The residue slowly crystallizes from a mixture of benzene and hexane and gives 23 g of 2- (2-chlorophenyl) -2- (2-pyrimidinyl) acetonitrile. Crystallization of a sample from hexane gives colorless rhombuses with a melting point of 81-82 °; IR (CHCIv) 2250 (CN) cm " ¹ .

(B) To a solution of 3 g (13 mmol) of 2- (2-chlorophenyi) -2- (2-pyrimldinyl) acetonitrile 0.78 g of sodium hydride ($ 50, in mineral oil) are added to 250 ml of dry tetrahydrofuran. The mixture is refluxed for 2 hours with stirring / then cooled to room temperature and left for 16 Blow dry air through for hours in a strong current. Then 30 ml of 33 # aqueous methanol and then carefully about 200 ml of water are added. “The tetrahydrofuran is removed through Distillation under reduced pressure and isolate the solid formed by filtration, 1.7 g of crude 2- (2-chlorobenzoyl) pyrimidine has a melting point of 124-127 °;

IR (CHCl ₃ ) 1695 (CO) cm " ^1....

(C) A solution of 11.9 g (55 mmol) of 2- (2-ChTorbenzoyl) pyrimidine is cooled in 60 ml of concentrated sulfuric acid to 0 ° and are then dropwise within one hour Mixture of 3.1 ml 90 # iga> Nitric acid and 7.7 ml more concentrated Sulfuric acid too. The mixture is stirred for one hour at 0 ° and

909881/1708

then for a further hour at room temperature. The reaction mixture is poured onto ice and made alkaline by adding dilute aqueous ammonia. The pest body formed is removed by filtration, giving 13.8 g of (95 #) crude 2- (2-chloro-5-nitrobenzoyl) pyrimidine, melting point 143-146 °. Crystallization from benzene gives pale yellowish rhombuses with a melting point of 147-Ι49 ^σ ; IR (CHCl3,) 1705 (CO), 1535, 1370 cm " ¹ .

(D) A mixture of 25 g (0.095 mol) of 2- (2-chloro-5-nitrobenzoyl) pyrimidine in 600 ml of dioxane and 600 ml of concentrated aqueous ammonia is heated to 100 ° for 5 hours in an autoclave, the initial pressure being one Atmosphere. The reaction mixture is concentrated under reduced pressure to remove the dioxane. The pest body formed is removed by filtration, suspended in a mixture of 50 ml of 3N hydrochloric acid and 500 ml of ethanol and left to rest overnight at room temperature. The yellow pest body formed is removed by filtration and dried; Yield 14.2 g (62Ji), melting point 239-240 °. Crystallization from ethanol or acetonitrile gives yellow needles of 2- (2-amino-5-nitrobenzoyl) pyrimidine with a melting point of 267-268 ° ι IR (KBr) 3450, 3330 (NH ₂ ), 1640 (CO), 1550, 1302 cm " ¹ .

(E) A mixture of 1 g (4 mmol) of 2- (2-amino-5-nitrobenzoyl) pyrimidine and 50 ml of acetic anhydride is added for 2 hours

909881/1706

heated to reflux and then evaporated to dryness under reduced pressure. The residue is triturated with water, filtered and dried, 0.9 g ($ 86) of a crude product having a melting point of 200-206 ° being obtained. Upon extraction with benzene, a small amount of an insoluble material remains. Repeated crystallization of the benzene-soluble material from ethanol gives fine needles of 2- (2-acetamido-5-nitrobenzoyl) pyrimidine with a melting point of 221-222 °; IR (CHCl ₃ ) 1710 (CO), 1660 (Amid-CO), I563, I5II, 1504, 1350 cm " ¹ .

(P) A solution of 2.86 g (10 mmol) of 2- (2-acetamido-5-nitrobenzoyl) pyrimidine in 250 ml of dimethylformamide containing about 10-20 g of Raney nickel is hydrogenated at atmospheric pressure and room temperature, with about 40 mmol of hydrogen are absorbed. The catalyst is removed by filtration, the piltrate is evaporated to dryness under reduced pressure and the residue is crystallized from ethanol, 0.9 g (35 #) of white prisms of 4'-amino-2 ^l - (a-hydroxy-2 pyrimidinylmethyl) acetanilide with a melting point of 192-194 °; IR (KBr) 5350 (NH), 3250 (OH), 1685 (Amid-CO), 1520 (broad), 1375 cm "" ¹ .

(G) A solution of 6.0 g (2> mmol) 4 ^l -amino-2 '- (a-hydroxy-2-pyrimidinylmethyl) acetanilide in 48 ml> -N hydrochloric acid is cooled to -10 ° and, with stirring, dropwise a solution of 1.76 g (25.5 mmol) of sodium nitrite in 8 ml of water is added. The mixture is stirred for a further 5 minutes at -10 ° and then gives

909881/1708

the cold reaction mixture, while cooling to -10 °, dropwise within 30 minutes to a suspension of 5) 1 g of cuprous chloride in 32 ml of 9N hydrochloric acid. The reaction mixture is then allowed to come to room temperature, diluted with 90 ml of water and the temperature is increased to 55 ° for 2 hours. The reaction mixture is made alkaline by adding concentrated aqueous ammonia and extracted with methylene chloride; the organic phase is washed with water, dried over sodium sulfate and evaporated to dryness.,. The residue crystallizes from a mixture of benzene and hexane, 3.6 g (66%) of 4'-chloro-2 '- (oc-hydroxy-2-pyrimidinylmethyl) acetanilide being obtained in the form of colorless prisms with a melting point of 144-146 ° . Further crystallization does not change the melting point. IR (CHCl,) 3 ^ 50 (OH), 3300 (NH), 1690 (Amid-CO), I567 (Amid'II> cm " ¹ .

(H) To a solution of 0.5 g (1.8 mmol) of V- (α-hydroxy-2-pyrimidinylmethyl) acetanilide In 10 ml of glacial acetic acid, a solution of oil, lo g (1.8 mmol) of chromic acid in 1 ml is added Water, with a brown body of plague almost immediately ruled out. The reaction mixture is heated to 50-55 ° for one hour while stirring, then cooled to room temperature and for the purpose of destroying any excess chromic acid mixed with a few drops of ethanol. The cooled down The reaction mixture is made slightly basic by adding aqueous ammonia and ex-

90 9 881/1708

trahlerti The: organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue crystallizes from a mixture of benzene and hexane, giving 0.3 g of (60 #) 4'-chloro '- (2-pyrimidinylcarbonyl) acetahilide with a melting point of 151-155 °. Crystallization ³ "from ethanol gives pale yellowish rods with the same melting point ι IR (CHC1-) 5350 (NH), 16 £ 5 ( AmId-CO)", 1660 (CO), 1563 (Amide II) cm

-1

(I) A solution of 1 g (36 mmol) of 4 * -Chlort * - (2-pyrimidinylcarbonyl) acetanilide in a mixture of 50 ml of 6N hydrochloric acid and 50 ml of ethanol is refluxed for 15 minutes. Most of the ethanol is removed by concentration under reduced pressure. Ice is added to the acidic residue and it is made alkaline by adding concentrated aqueous ammonia. The reaction mixture is extracted with methylene chloride, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up in ether and filtered through magnesium silicate gel. Concentration of the ethereal solution and crystallization from a mixture of benzene and hexane gives 0.1 g of (12%) 2- (2-amino-5-chlorobenzoyl) pyrimidine of melting point 129-131 °; washing out the gel with ethyl acetate gives a further 0.2 g portion. Further crystallization of the product from cyclohexane gives yellow prisms with a melting point of I29-130 ⁰ ; IR (CHCl ₃ ) 3510, 3350 (NH ₂ ), 1640 (CO) cm " ¹ .

909881/1708

(J) To a solution of 0.5. 0.45 g (2.2 mmol) of bromoacetyl bromide are added to g (2 mmol) of 2- (2-amino-5-chlorobenzoyl) pyrimidine in 10 ml of glacial acetic acid and the mixture is left to stand overnight at room temperature, the oil which has precipitated shortly after mixing crystallized. It is filtered and 0.9 g of 2-bromo - ^ '- chloro-2' - (2-pyrimidinylcarbonyl) aoetanilide with a melting point of 200-202 ° (decomp.) J IR (CHCl,) 3280 (NH), 1692 ( Amid-CO), 1667 (CO), 1580, 1563 cm " ¹ .

The 2- (2-chlorobenzoyl) pyrimidine can also be prepared as follows:

(A ¹ ) A suspension of 89.0 g (1.65 mol) of sodium methylate in 900 ml of anhydrous methanol is mixed with 110.5 g (0.5 mol) of solid a- (2- Chlorophenyl) -a-hydroxyacetamidine-hydro-

Chloride added. 80.0 g (0.5 mol) are then added dropwise Freshly distilled diethyl malonate is added and the mixture is stirred for a further 24 hours at room temperature. That The resulting sodium salt of the product is separated off by filtration and one after the other with 125 nil cold methanol, 500 ml Methanol-ether (1: 4) and finally washed with ether. This salt is suspended in about 600-700 ml of water and stirred while cooling in an ice bath and mixed with concentrated hydrochloric acid until a strongly acidic reaction (for which about 100 ml will). After thorough cooling, the 2- (2-chloro-a-hydroxybenzyl ^^ b-dihydroxypyrlmldln filtered off and up to almost

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neutral reaction with ice water and then with petroleum ether Washed (boiling point 40-60 °), 63 * 5 g ($ 50) colorless Crystals with a melting point of 223-225 ° (decomp.) Are obtained. Crystallization from water gives pale yellowish crystals with the same melting point.

(B ¹ ) A suspension of 25.3 S (0.1 mol) 2- (2-chloro-ahydroxybenzyl) -4, ö-dihydroxypyrimidine in 250 ml glacial acetic acid is added dropwise within one hour with a solution of 10.0 g ( 0.1 mol) of chromic anhydride in 15 ml of water, where d% e color quickly turns into its green black and most of the material goes into solution. The mixture is stirred overnight, then 5 ml of methanol are added to destroy the excess oxidizing agent, the mixture is stirred for 2 hours and then evaporated in vacuo at a temperature below 30 °. The residue is triturated with water; the semi-solid crude product is washed thoroughly with water

and dried at 80 ° in vacuo, removing 3 g (73 #) "2- )

(2-chlorobenzoyl) -4,6-dihydroxypyrimidine in the form of a greenish yellow Solid body with a melting point of approx. 233 °. Crystallization from water gives pale yellow prisms with a melting point 239-241 °.

(C ¹ ) A suspension of 12.00 g (48.2 mmol) of 2- (2-chlorobenzoyl) -4,6-dihydroxypyrimidine in 100 ml of distilled phosphoryl chloride is added for 3 hours with exclusion of moisture

90988171706

heated to reflux in an oil bath. The equipment is concentrated under reduced pressure; the residue is suspended in methylene chloride and slowly added to a well-stirred mixture of ice and water. 40% (weight / volume) aqueous sodium hydroxide solution is then added until the reaction is strongly alkaline, and the mixture is filtered to remove an insoluble precipitate. Careful evaporation of the methylene chloride layer of the piltrate gives the desired product in the form of 6.60 g (40%) of a brownish, viscous oil. Distillation in a bulb tube at 115-205 ° / θ.3 mm gives 4.02 g of 4,6-dichloro-2- (2-chlorobenzoyl) pyrimidine in the form of yellow crystals; repeated distillation at 100-135 ° / 0.1 mm gives the product in the form of colorless crystals with a melting point of 95-98 °.

(D ') To 0.99 g (3.44 mmol) of 4,6 -dichloro-2- (2-chlorobenzoyl) pyrimidine in 20 ml of ethanol are added 100 mg of a lOJ & Lgen (weight / weight) palladium-carbon catalyst, which has been thoroughly wetted with 10.0 ml (10 mmoles) of aqueous N sodium hydroxide solution. The mixture is hydrogenated at room temperature and normal pressure, the hydrogen uptake (1.65 mol) coming to a standstill after 22 hours. The catalyst is separated off by filtration through a filter medium and washed with ethanol. The combined filtrates are diluted with 100 ml of water, acidified with dilute hydrochloric acid and concentrated under reduced pressure. The residual aqueous solution becomes one time

909881/1708

Washed with ether and then made alkaline with dilute sodium hydroxide solution. The precipitated 2- (2-chlorobenzoyl) -pyrimidln is isolated by extraction with ether $ obtained 0.39 g (52 #) of a pale yellow viscous ÖIS. On the basis of a comparison of the infrared spectra and the migration rates in thin-layer chromatography in two solvent systems, this material is found to be identical to an authentic sample of 2- (2-chlorobenzoyl) pyrimidine.

Example 2

To a solution of 1.7 g (6 mmol) of 7-chloro-1,3-dihydro-5- (2-pyrimldinyl) -2H-1 _J 4-benzqdiazepin-2-one in 25 ml of anhydrous dimethylformamide is added 0.46 g (10 mmoles) of 52.5% sodium hydride in mineral oil. Man. The mixture is stirred for 15 minutes at room temperature and then 1.42 g (10 mmol) of methyl iodide are added, the temperature rising slightly. The mixture is stirred for a further 45 minutes. Room temperature, then gives. 5 ml of water are carefully added and the solvent is removed by distillation under reduced pressure. The firm one. The residue is partitioned between methylene chloride and water. The organic phase is dried over sodium sulfate and then evaporated to dryness under reduced pressure. A solution of the residue in ethyl acetate is filtered through magnesium silicate gel, the solvent is removed from the piltrate and crystallized from a mixture of benzene and hexane, 0.2 g of 7-chloro

9 0 9881/170 8

l, 5-dihydro-l, 3-dimethyl-5- (2-pyriinidinyl) -2H-l _J , 4-benzodiazepin-2-one in the form of colorless crystals with a melting point of 187-Ι9θ ^σ . Another portion (0.2 g) with a melting point of 185-107 ° is obtained from the mother liquor (total yield $ 22). Crystallization from ethyl acetate gives a product with a melting point of 198-200 °. IR (KBr) 1692 (Amid-CO), 1563 cm " ¹ * nmr (DMSO) S 1.58 (d, 3, J = 6.5H _Z , CH ₅ ), 3-35 (8.3, NCH ₅ ), 3 -85 (q.-l, J = 6.5H _Z

CH ^p ).

Example 3

A mixture of 446.2 g (1.70 mol) of 2- (2-chloro-5-nitrobenzoyl) pyrimidine, 510 g (8.5 mol) of ethylenediamine and 1700 ml of anhydrous pyridine is heated on the steam bath with stirring for 5 hours . Most of the solvent is removed by concentration under reduced pressure and subsequent distillation with xylene and toluene. The tar-like residue obtained is smeared with 200 μl of methanol and 2.5 liters of aqueous 3N hydrochloric acid. The solution is left to stand for 2 hours at a room temperature, then cooled and made alkaline with aqueous 5N sodium hydroxide solution. The precipitated crude product is separated off by filtration, washed with water and dried. For purification, 1 kg of neutral aluminum oxide (activity X) is added to a suspension of the product in methanol and the solvent is then removed under reduced pressure. The dried mixture of product

909881/1708

OfHGiNM. INSJ ³ ICTH)

and aluminum oxide is then in a Soxhlet apparatus with hot Methylene chloride extracted continuously until no more product appears in the extract (which takes 4-5 days). Filtration of the The extract gives IJO.7 g of 2,3-dihydro-7-nitro-5- (2-pyrimiainyl) -1H-1,4-benzodiazepine from melting point 222-224 °. Further portions are obtained by evaporating the filtrate; the yield Product with a melting point of 215-231 ° is a total of 195 g of crystallization from ethanol-benzene-hexane and then from methylene chloride-ethanol-hexane gives shiny yellow Rhombuses of the above compound with a melting point of 230-232 ° (decomp.).

Example 4

A solution of 147.7 g (0.55 mol) 2,3-dihydro-7-nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine and 33.0 g (o / 6l mol) sodium methylate in 1300 ml of anhydrous Ν, Ν-Dlmethylformaniid is stirred for one hour at room temperature and then added dropwise within 2 hours with a solution of 77.0 g (0.61 MoX) of dimethyl sulfate in 260 ml of dry «dimethylformamide, the temperature of the Reafctionegettisehas is kept at 0-5® by cooling in an ice bath. The mixture is stirred for a further 24 hours at room temperature \ ma giesßt thereto the mixture into 6 liters Siswssser. Then dry ice is added until the reaction is almost neutral (pH 5-6). Extraction with methylene chloride gives 156.8 g of crude product in the form of a

world-going crystalline solid. One extracts this

909881/170 8

1929 SiG

Material with: cold methylene chloride, removes unchanged starting material by filtration and lets the filtrate flow through 785 g of neutral aluminum oxide (activity: III) for the purpose of further purification. The methylene chloride eluate is evaporated .und = the crystallized; received Huckst and, {9-4 * 0. g.) from benzene-hexane, 71.8 g of 2,3-dihydro-1-methy: L-7-nitro-5- (2-pyrimldinyl) rlH ^ lj4-benzodiazepine having a melting point of 179-101 °. Another portion (10.2 g) with a melting point of 177-179 ° * is obtained from the mother liquors, the yield is 6 * 2.0 g ($ 61, based on the starting material not recovered). Crystallization from methylene chloride-hexane gives the product in the form of yellow rods with a melting point of 181-Ib ¹ ? ⁰ (dec.). '

■. , Example 5

Be in a 500 ml three-necked flask with a magnetic stirrer 9 ^ 4 mg (3.33 mmol) 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) · lH-1,4-benzodiazepine under cooling, drop by drop, within of 30 minutes, with 2bO ml of a 0.058 M solution of ruthenium tetroxide (15 mmol, i.e. 4.5 equivalents) are added. One lets " stir for a further 30 minutes and then add 5 ml of 2-propanol to; the reaction mixture is filtered and evaporated to dryness. The oil obtained is made from methylene chloride-hexane crystallized, l, 3-Dihydro-l-methyl-7-nitro-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one from the melting point

909881/1708

t) RK3JNAL INSPECTH)

194.0-196.5 ° (dec.) - obtained.

Example 6 .

A suspension of 72 g (0/25 mol) of 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine in 1400 ml of methanol is over at room temperature and atmospheric pressure an alcohol-washed Raney nickel catalyst (5 teaspoons, activity about W-2) hydrogenated, the hydrogen uptake (3.2 mol) comes to a standstill after J5 hours. By removing the catalyst and the solvent, the crude 7-amino compound is obtained as a non-crystalline residue. For purification, a solution of this material in methylene chloride is filtered through a column containing 350 g of neutral aluminum oxide (activity III), the filtrates are evaporated and 62.9 g ($ 98) of 7-amino- _2I 3-dihydro-1-methyl are obtained -5 -. (2-pyriinidinyl) -lH-1,4-benzodiazepine in the form of a brown foam, which can be used directly for the next stage.

A solution of 61.35 g (0/2 * 12 moles) 7-Amlrio-2,3-dihydrol-methyl-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine in 483 ml "(1.45 mol) 3-N hydrochloric acid is slowly with -5 to -10 ° a solution of 20.4 g (0.296 mol) of sodium nitrite in 100 ml of water and then with a suspension of 52.0 g (0.534 mol) Cuprous chloride in a mixture of 250 ml of concentrated hydrochloric acid and 125 ml of water are added. The mixture is 500 ml

909881/170 8

Water added »over 1 1/2 hours to 35 ° and then during Heated to 4o ° for 2 hours until the evolution of nitrogen It comes to a standstill and the diazo test using R-SaIz turns out negative. The mixture is made by adding 28 pounds (weight / Volume) aqueous ammonia made alkaline and the product isolated by extraction with methylene chloride. For cleaning a methylene chloride solution of the material obtained is replaced by a solution containing 315 g of neutral aluminum oxide (activity III) Column filtered. When the eluates are evaporated, 23.4 g of 7-chloro-2,3-dihydro-1-methyl-5- (2-pyriroidinyl) -lH-1,4-benzodlazepine are obtained in the form of a yellow-brown crystalline residue, which in the crystallization from benzoil-hexane (1: 2) 22.5 g (34 #) of a product with a melting point of 106-109 °. By Crystallization from methylene chloride petroleum ether (boiling point 40-60 °) gives yellow needles with a melting point of 107-109 °.

. Example 7

A »Oxidation with chromic acid

A solution of 15 g (0.055 mol) of 7-chloro-2,3-dihydro-rl methyl-5- (2-pyrimidinyl) -lH-1,4-benzodiazepine in 240 ml of glacial acetic acid is stirred at 25 ° within 4 37 * 5 ml of Jones reagent (corresponds to 0.1 mol of CrO.) Are added dropwise for 1/2 hour. [For the preparation of Jones reagent, proceed according to C. Djerassi * RR Engle and Ao Bowers * JoOrg.Chem., 9098Ö1 / 1708

21 , 15 ^ 7 (1956) by adding 25 ml of concentrated sulfuric acid to a solution of 26.72 g of chromium trioxide in 60 ml of water and then making up to 100 ml with water). The resulting solution is stirred overnight, then poured into one liter of ice water and made alkaline with 10 N aqueous sodium hydroxide solution. The product is isolated by extraction with methylene chloride, 11 g of a dark colored, rubbery mass being obtained. For purification, a methylene chloride solution of the crude product is filtered through a column containing 110 g of neutral aluminum oxide (activity 1}. Evaporation of the eluates gives 8.5 g of 7-chloro-l, 5-dihydro-l-methyl-5- (2- pyrimidinyl) -2H-1,4-benzodiazepin-2-one as a dark-colored, gummy mass; for further purification, extracted with helssem benzene and chromatographed the extracts on 75 g of neutral aluminum oxide (activity III) in a column 290 mm long and 19 mm in diameter The benzene eluate (1250 ml) is discarded; when the methylene chloride eluate is evaporated, 1.59 g of a yellow, rubbery mass are obtained ) Prisms with a melting point of 155-150 ° are obtained. By further crystallization from the same solvent mixture, an analysis sample in the form of cream-colored prisms with a melting point of 157-159 ° is obtained.

B. Oxidation with ruthenium tetroxide

One suspends 5 ß 55 * 3 ^ iges ruthenium dioxide (Engelhard Industries, i.e. 1.66 g, 12.4 inMol Ru0 ") In 36Ο ml of chloroform,

909881/1708

■■ - "• 35--

which; in order to remove the .Aethanols previously washed with water _; been .is .--. While stirring and cooling in an ice bath, a solution can manvtropfenweise 4b ^1., bg (22 ¹ Jr mmol) NatriummefcaperiXXlat zufHessen in 360 ml of water. One stirs during further. 2, hours and filtered the mixture through a glass frit. The yellow organic phase is separated off, washed immediately three times with ice-cold aqueous sodium metaperiodate solution (5 g in. 250 ml) and then added dropwise to a yellow solution of 2 g (7.33 mmoles) over a period of 2 hours with stirring and with ice cooling. 7-C.hlor-2 _i 3-dihydro-1-methyl-5- (2-pyrimidinyl) -1H-1 _,! 4-'benzodiazepine in 50 ml of chloroform, stir for a further 15 minutes and then add dropwise Add 10 ml of isopropanol to destroy the excess ruthenium tetrahydrofuran. The mixture is filtered to recover the precipitated ruthenium dioxide and washed with methylene chloride. The filtrates are combined and washed with water Sodium sulfate dried and evaporated, leaving 0.2 × g of a greenish-brown, gummy mass. For purification, a methylene chloride solution of this material is filtered through a column containing 2.3 g of neutral aluminum oxide (activity III). The eluates are obtained on evaporation man 0, 14 g (b, 7 $) 7-chloro-1,3-dihydro-1-methyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one as a yellow, rubbery mass, which was rubbed with ether and upon recrystallization from methylene chloride-hexane gives colorless flat prisms with a melting point of 157-159 °; the mixed melting point using a method A

909881/170 8

The sample presented does not show any depression. ■ · ..- ■; - -

Example ü

To a solution of 8.7 ^ g »(^ O mmol) 2- (2-chlorobenzoyl) pyrimidine and 13.3 ml (12.0 g, 200 mmol) ethylenediamine in 100 ml 50% (volume / volume) aqueous dioxane gives 1 g of cuprous bromide. the mixture is heated for 10 hours under reflux to boiling, then cooled and filtered. extrahiert.den residue with 200 mL of aqueous 3 N hydrochloric acid is evaporated, the F PiItrat under reduced pressure and. The extract is washed with ether and then made alkaline with aqueous 5N sodium hydroxide solution; 6.3 g of the product are obtained in the form of a dark red oil by extraction with methylene chloride. This oil is dissolved in 63 ml of anhydrous pyridine, heated for 3 hours to The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate and evaporated to give 4.4 g of a dark red oil which contains some crystalline material. For further purification one filtered a methylene chlorine Id solution of the product through a column containing neutral aluminum oxide (activity III); when the eluates are evaporated, 3 * 5 g of a red, rubbery mass are obtained, which is carefully chromatographed on 70 g of aluminum oxide of the same activity. The mixture is eluted with benzene and 0.13 g (1.4 liters) is obtained. 2,3-Dihydro-5- (2- pyrimidinyl) -1H-1,4-benzodiazepine.

9 0 9 8 81/17 0 8

Crystallization from benzene-hexane gives pale yellow prisms with a melting point of 171-173®

The pharmacological activity of a number of compounds according to the present invention was based on the following, generally used test arrangements:

Fight test

This test is suitable for testing compounds with muscle-relaxing properties and / or anti-anxiety properties (tranquilizers). Two mice are placed under an inverted 1-liter beaker on a grid, through which they are hit on the feet. This puts the animals in a state of excitement, which manifests itself in occasional short duels. Pairs of mice are selected which have fought at least five times during a 2-minute test period, the test substance is administered to them orally and the test is repeated after an hour. Here one uses logarithmically increasing doses of Hiß up to a maximum of XOQ mg / kg. One defines the 100% dose that is the dose which, with three of ~ '& V & i. Mice pairs. prevented a fight.

Test aa den? inclined

this attempt <& emtttelt mm muscle relaxant and / £ 69861/1708

or sedative properties. The test substance is administered in doses of up to a maximum of 500 mg / kg to groups of 6 male mice each, the animals are placed on an inclined plane and observed for at least 4 hours whether they slide off the plane due to symptoms of paralysis. If such an effect is observed, the doses are varied until at least 2 doses are found at which some, but not all, of the animals slide off the plane. This does not take into account doses at which the mice slide off due to toxicity or excitement. The PDe _{0 is} determined graphically, plotting the doses against the percentage of paralyzed mice; the PD ^ ₀ value obtained in this way defines the dose (in mg / kg) at which it can be expected that 50% of the mice slide off the plane.

Try on the awake cat

Treat cats orally and watch for symptoms (usually ataxle). First, use 'on a cat and a dose of 50 a & ag. If it shows an effect, the poafs are varied and up to 3 cats are used per dose. The results «own the minimum effective dose. This experiment only helped me to determine muscle-relaxing properties. .

Hit this attempt enaitfcelfc one anticonvulsant imd / or 909881/1708

sedative properties of compounds. The test substance is administered to groups of 4 mice each in different doses on an oral weighing. After one hour, the animals are given metrazol subeutanely in a previously determined dose (approximately 125 mg / kg) which induces seizures in all test animals, and it is observed whether the animals are now protected from seizures. The number of animals protected from seizures is noted and the dose at which 50% of the animals are protected from seizures is _{defined as ED ^ 0.}

Maximum electric shock

With this experiment, which is carried out on the mouse, connections can be tested for anti-convulsive properties. If the mouse was used for 0.2 seconds by means of corneal electrodes a current surge of 3Q mA (about 6 times the threshold value) is displaced, a maximum tonic-clonic seizure ensues. This maximum seizure in the mouse includes a stretching spasm the hind paw (tonic phase) and a clonic ~ Phase of the trunk. 24 hours before the start of the chief attempt a preliminary test is used to determine whether the animals respond normally. In the main experiment, the substance to be examined is based on oral route in various doses to groups of 4 mice each administered. One hour after administration, the animals receive the mentioned electric shock (30 mA); Criterion for effectiveness the test substance is the absence of the streak-

9 09881/170 8

: ORIGINAL INSPECTED

- 4ü -

.1.02.09 I.

cramp of the hind paw. If the compound is found to be active, it is administered in reduced doses to additional groups of 8 mice each until the spasm recurs. The dose (in mg / kg) which prevents the hind paw stretching _{spasm in two out of four animals is called ED 1} - bezelchhet.

> u

Minimal electric shock - '■■ --- · ■

* This experiment, which is also carried out on mice, is used to "determine anti-convulsive" properties. A "current" applied to the animals' eyes by means of corneal electrodes produces cramps (one gives "one drop of physiological ^ köchsalzlösung ^ ^aT; '· eyes of animals ürtd ^";' 'brings the eye in direct contact with the electrodes) in a preliminary ^Λ added to all the mice a 0.2-second Strömstoss of 6.0 mA;. be in Hauptversucii only those animals are used which have shown a minimal seizure. 24 hours after the preliminary test, the substance to be examined is administered in various doses to groups of four animals. One hour later, the animals are again given an electric shock of 6.0 mA; while the test substance is then referred to as active * if it protects the animals from shock caused by this electric minimal seizure. In determining the ED values _trt of acti ven compounds are used in groups of 8 animals per dose.

909881 / 17.08

■ \. ,; ν. .,, = ORUSINAL i.feiSF £ CTSD

Testing for anti-pyretic properties

For this experiment, 30 male rats are used in 6 groups of 4-5 animals. The test substance is administered to the animals orally as a 2% solution or suspension in an aqueous carrier. The control animals receive only 1/100 g of the carrier's body weight. One hour after administration of the test substance, 0 * 1 ml of a 2J & gen suspension of brewer's yeast are injected into the feet of the animals. After a further hour, the temperature of the inflamed foot «of the normal foot and of the recturn by means of a thermocouple» is ^{determined. The results (in 9} C) indicate the deviations from the values determined for the controls.

The results of the experiments described above for are certain compounds according to the present invention in the. Table I below compiled.

1 / 170-8

Table I.

Connection

Aiitlißet.

ED ₁

50

Fight «Inclined

Teat level

(Dose, (dose,

I8g / kg) »g / kg

Electric Shock Max. Min.

Antipyretus.

Guard Rectal Inflammatory. Cat · puss

(Dose)

nitro-5- (2-pyrimidinyl) -lH »1,4-benzodiazepine

93

250

800

20th

yT
(2-pyrimidinyl) -1H-1,4-benzodiazepine

7-chloro-1,3-dihydro-iinethyl-5- (2-pyrimidinyl) 2H-1,4-benzodiazepin-2-one

7-chloro-2,3-dihydro-l-Qiethyl-5- (2-pyrimidinyl) -IH-I, 4 "benzodiazepine

7-chloro-1,3-dihydro-5- (2 »pyrimidinyl) -2H-1,4-benzodiazepin-2-one

68

0.75

1.75

100

100

200

500

800

800

-1.5 ° -1.2 ° (dose (dose 100 mg / 100 mg / kg) kg _t

CD K> CD CD

Example A. ,

Manufacture of suppositories for a suppository ■ ^: · ■ · of ^; 1.3 g ..... ':

y-S- (2-pyrimidinyl) -:, 2H-1,4-benzodiazepin-2-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 glass or steel vessel 1 ^ suitable Grosse, thoroughly · ¹ \ ^· mixed and cooled to 45 °. Then finely add 'powdered T-chloro-1 ^ -dihydro-S- (2-pyrimidinyl) -2H-1,4-ben; zo-v diazepin-2-one' and stir until it is complete and uniform The mixture is poured into suppository molds, and suppositories each weighing 1.3 S are obtained. After cooling, the suppositories are removed from the molds and individually wrapped in wax paper or metal foils.

. - Example B Manufacture of capsules

7-chloro-1,3-dihydro-5- (2-pyrimidinyl) -2H-1,4-benzoaiazepine-2-oen

Lactose

Cornstarch

Talk

Total weight 210 mg

909881/1708

INSPECTED

Per capsule 10 mg 165 mg 30th mg 5 mg

■ .- 44 -

^ - (2-pyrimidinyl) -2H-1,4-benzodlazepin-2-one, Milk sugar and corn starch are first put in a mixer and then in a mixer fitted with sieve knives Crushing machine mixed up. The mixed powder is returned to the mixer, the talc is added and mingled thoroughly. The mixture is machine-packed into hard oelatin capsules bottled.

Example C -, _} Preparation of one solution for injection per ml

7-chloro-1,3-dihydro-5 ~ (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one 5 * 0 mg

Propylene glycol 0.4 ml

Benzyl alcohol (benzaldehyde-free) 0.015 ml

Ethanol (95%). 0.10 ml

Sodium benzoate 48.8 mg

Benzoic acid 1.2 mg

Water for injection 'q.s. ad 1.0 ml

Dissolve to make 10,000 ml solution for injection

50 g of T-chloro-l ^ -dihydro-S- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one in 150 ml of benzyl alcohol and add 4000 ml of propylene glycol and 1000 ml of ethanol. Then 12 g of benzoic acid are dissolved in the above mixture and add 486 g of sodium benzoate, dissolved in JOOO ml Water (for injection) too. The solution is brought to a volume of 10,000 ml by adding water (for injection),

909881/1708

filtered through a filter candle and more suitable in ampoules Large bottled; the remaining volume of the ampoules is filled with nitrogen, the ampoules are melted and sterilized -for 30 minutes in an autoclave at 0.7 atm.

Example D

The following compounds can also be used to produce preparations according to Examples A, B and C will:

7-chloro-2O-dihydro-1-methyl-S- (2-pyrimidinyl) -IH-1, 4-benzodiazepln and

7-chloro-l, 3-dihydro-l-methyl-5- (2-pyrimidinyl) -2H-l, 4-benzodiazepin-2-one .. ·

8 S 1/1 7

Claims (1)

Claims _:. 1. Process for the preparation of benzodiazepine derivatives of the general formula in which B is a -C-, -CH ₀ - or -C- group, R d. egg and R, independently of one another, are each hydrogen, halogen, nitro, amino, lower alkylamino, di (lower) alkylamino, trifluoromethyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, lower alkanoyl, lower cycloalkyl, lower cycloalkyl (lower) alkyl, lower haloalkyl, lower aminoalkyl, lower monoalkylaminoalkyl, lower dialkylaminoalkyl, lower hydroxyalkyl or - (CHp) COR ₁ (where η is an integer from 0- 5 and R-, hydroxy, "A- lower alkoxy or -N ^, where R _p and R-, ^N R ₃ ^d > each for hydrogen or lower alkyl or together with the «nitrogen atom for a 5- or 6- membered saturated heterocyclic ring) ■■ '■ 903881/1708 and R, hydrogen, lower alkyl, lower acyloxy, lower alkoxycarbonyl, hydroxy, lower alkoxy or mean lower alkoxy (lower) alkyl, "characterized in that a) for the preparation of compounds of the formula I, in which B is a carbonyl group, a compound of the general formula .NCOCHX • IV wherein R, R _H , R and R, have the above meaning et DOU and X stands for a leaving group, cyclized in the presence of ammonia or b) for the preparation of compounds of the formula I in which B is a methylene group and R 'and R are each hydrogen, a compound of the general formula 909881/1708 where R and R, have the above meaning, 8. D. reacts with ethylenediamine or c) for the preparation of compounds of the formula I in which B is a carbonyl group and R and R, each alkyl or substituted Denote alkyl, a corresponding compound in which R and R. each denote hydrogen, in the 1- and ^ -position dialkylated or substituted by a substituted alkyl radical or d) for the preparation of compounds of the formula I, in which R has a meaning other than hydrogen, a Compound of the formula I in which R is hydrogen, correspondingly substituted in the 1-position or e) for the preparation of compounds of the formula I in which B is a thione group, a compound of the formula I, wherein B represents a carbonyl group, treated with a sulfurizing agent or. f) for the production of amino-substituted compounds of formula I, a corresponding nitro-substituted compound reduced or g) for the preparation of compounds of the formula I in which R .. and / or R are hydrogen or halogen, a corresponding compound in which R_ and / or R _{w are} amino, Si D subject to a Sandmeyer reaction boring h) for the preparation of compounds of the formula I which are substituted by alkylamino or dialkylamino, * a corresponding, amino-substituted compound of Formula I alkylated, for example by means of an alkyl halide 909881/1708 or a dialkyl sulfate or i) for the preparation of compounds of the formula I, in which B means a carbony group, R and R, any of the a D Have the above meanings except for amino or lower alkyl mercapto, R any of the above meanings except has lower hydroxyalkyl and R, any of the above Has meanings other than hydroxy, a compound of the formula where R, R., R and R _{d have} the meaning just mentioned under i), B denotes a carbonyl or methylene group and A denotes the structural element ^or stands, where A then stands for the structural element CH NH N <T ^ J must, if B is a carbonyl group, oxidized or j) in the 5-position a suitably substituted 1,4 909881/1708 Benzodiazepines introduces a HpN-C = NH group and from this then builds up a pyrimidinyl ring or k) for the preparation of acid addition salts of the compounds of the formula I, a corresponding free base with converts an acid. 2. The method according to claim 1, characterized in that R is hydrogen, lower alkyl, lower alkanoyl, lower cycloalkyl, lower cycloalkyl (lower) alkyl, lower aminoalkyl, lower monoalkylaminoalkyl, lower dialkylaminoalkyl, lower hydroxyalkyl or - (CHp) COR. where η is an integer from 0 to 5 and R. is hydroxy, lower alkoxy or -N ^ (where R ₀ and R, each water- NR-j ^d -> Substance or lower alkyl or together with the Nitrogen atom is a 5- or 6-membered saturated heterocyclic Form a ring) and that one proceeds according to paragraph a, b, c, d, e, f, g, h, j or k of claim 1. j. Process for the preparation of benzodiazepine derivatives the general formula R ¹ R ¹ 9 0 9 8 81/17 0 8 wherein R ¹ and R 'each hydrogen, halogen, nitro or £ L D Trifluoromethyl, R ¹ hydrogen, lower alkyl, lower haloalkyl or di (lower) alkylamino (lower) lower alkyl and R 'are hydrogen or / alkyl, gekennzelehnet by the fact that one connects the general formula where R ', R /, R' and R 'have the above meaning, t B is a carbonyl or methylene group means and A for the structural element N ^ ^ CH 'NH- "is or where A must then stand for "^ CH --- NH ^" if B means a carbonyl group, oxidized by means of ruthenium tetroxide. 4. The method according to claim 1, characterized in that a compound of the formula I is prepared in which B is a carboxyl group, R _{a is} halogen, R, hydrogen and R and R ^ each 909881/1708 - 52 - '' ■ ■ Mean hydrogen or lower alkyl. 5. The method according to claim 1, characterized in that that a compound of the formula I is prepared in which B is a methylene group, R is hydrogen, halogen, amino or nitro, R. hydrogen, R hydrogen or lower alkyl and R, Mean hydrogen. P 6. The method according to claim 4, characterized in that 7-chloro-l,; 5-dihydro-5- (2-pyrimidinyl-2H-l, 4-benzodiazepin-2-one manufactures. 7. The method according to claim 4, characterized in that that 7-chloro-1,3-dihydro-1,3-dimethyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one manufactures. 8. The method according to claim 4, characterized in that ' that 7-chloro-l, 3-dihydro-l-methyl-5- (2-pyrimidinyl) -2H-1,4-benzodiazepine-2-όη is prepared. 9. The method according to claim 4, characterized in that that one l, 3-dihydro-l-methyl-7-nitro-5- (2-pyrimidinyl) -2H-l, 4-benzodiazepin-2-one manufactures. " 10. The method according to claim 5 »characterized in that that one 2,3> -dihydro-7-nitr0-5- (2-pyrimidinyl) -IH-1,4-benzodiazepine manufactures. 909881/1708 11. The method according to claim 5> characterized in that 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl) -1H-1,4-benzodiazepine manufactures. 12. The method according to claim 5 »characterized in that 7-chloro-2,3-dihydro-l-methyl-5- (2-pyrimidinyl) -lH-1,4-benzodiazepine manufactures. 15. The method according to claim 5 »characterized in that that one 2,> - Dihydro-5- (2-pyrimidinyl) -lH-1,4-benzodiazepine manufactures. 14. The method according to claim 5 *, characterized in that 7-amino-2,3-dihydro-1-methyl-5- (2-pyrimidinyl) -IH-1,4-benzodiazepln manufactures. 15. Process for the manufacture of pharmaceutical Preparations, characterized in that one or more of the compounds of the formula I or defined in claim 1 an acid addition salt thereof as an active ingredient with non-toxic, suitable for therapeutic administration, inert solid or liquid carriers and / or excipients that are customary in such preparations. 909881/1708 l6. A pharmaceutical preparation containing one or more of the compounds of the formula defined in claim 1 I or an acid addition salt thereof and a carrier. 9098 8 1/1708 17. Benzodiazepine derivatives of the general formula in which B is a -C-, -CH ₀ - or -C- group, R _Q c. a and R. independently of each other each hydrogen, Halogen, nitro, amino, lower alkylamino, di (lower) alkylamino, Trifluoromethyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, lower alkanoyl, lower cycloalkyl, lower Cycloalkyl (lower) alkyl, lower haloalkyl, lower Aminoalkyl, lower monoalkylaminoalkyl, lower dialkylaminoalkyl, lower hydroxyalkyl or -I COR ₁ (where η is an integer from 0-5 and R _{1 is} hydroxy, lower alkoxy or -NC, where R ₀ and R, each stand for hydrogen or lower alkyl or together with the nitrogen atom for a 5- or 6-membered saturated heterocyclic ring) and R _{d is} hydrogen, lower alkyl, lower acyloxy, lower alkoxycarbonyl, hydroxy, lower alkoxy or lower alkoxy (lower) alkyl mean, and their acid addition salts. 9 0 9 8 8 1/17 0 8 lower hydroxyalkyl or - (CHo ^ n ^COR i, where η is a Whole number from 0 to 5 1st and R ₁ for hydroxy, lower alkoxy R ₂ ^L or -N ^, (where R _g and R, each hydrogen or mean lower alkyl or together with the nitrogen atom a 5- or 6-membered saturated heterocyclic ring form); 19, benzodiazepine derivatives of the general formula wherein R 'and R' are each hydrogen, halogen, nitro el O ·. or Tr 1 fluorinet hy I, R 'hydrogen, lower alkyl, lower haloalkyl or di (lower) alkylamino (lower) alkyl and Rl is hydrogen or lower alkyl. ? 0. Compounds according to claim 17, wherein B is a Carbonyl group, R _& halogen, R _fe hydrogen and R ₀ and R _d Je 909881/1708. 18. Compounds according to claim 17, wherein R is aqueous. "i substance, lower alkyl, lower alkanoyl, lower cyolo-. j alkyl, lower cycloalkyl (lower) alkyl, lower aminoalkyl,; lower monoalkylaminoalkyl, lower dialkylaminoalkyl, = 57 = Mean hydrogen or lower alkyl. . 21 · Compounds according to claim 17 «wherein B is a methylene group, R is hydrogen, halogen, amino or nitro, R _{b is} hydrogen, R _{Q is} hydrogen or lower alkyl and R _d Mean hydrogen. . 2 * 2. 7-chloro-1,4-dinydro-5- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one. · 23. T-chloro-1,4-dihydro-10-dimethyl-S- (2-pyrimidinyl) -2H-1,4-benzodiazepin-2-one. • 24. 7-Chloro-1,4-benzodiazepin-2-one. j 25. 1,3-Dihydro-1-methyl-7-nitro-5- (2-pyriraidinyl) -2H-, 1,4-benzodiazepin-2-one. ■! 26. ' 2,3-Dihydro-7-nitro-5- (2-pyrimidinyl) -IH-1,4-benzo-J diazepine. ' 27 ^, J-Dihydro-1-methyW-nitro-S- (2-pyrimidinyl) -IH-1,4 -benzodiazepine . 28, 7 chloro-2,3-dihydro-1-methyl-5 »(2-pyrimidinyl) -1H-1,4-b.mzodiazepine. _{90g881 / 1708} ' .29. 2,3-Dihydro-5- (2-pyriraidinyl) -1H- ^1,4: -benzodiazepine. 30. 7-Araino-2,3-dihydro-1-methyl-5- (2-pyriraidinyl) -1H-Λ -benzodiazepine. 909881/1708