DE1770135A1 - Process for the preparation of 2,4-benzdiazepines - Google Patents

Description

New, complete for printing the disclosure & sclr-rift beatim nfce registration documents file number: P 17 70 135.8-44

Our reference: 21 294-BR / H - Case SU 498/1 + 2 / E

Applicant: Λ π Π r ι or

CIBA AKTIEiNGESELLSCHAFT ₁ BASEL (SWITZERLAND)

Case SU 498 / I + 2 / E
Germany

Process for the preparation of 2., 4-benzdiazepines.

The present invention relates to the preparation M of 4,5-dihydro-1H-2,4-benzdiazepines of the formula '

—N,

Ph CR ₂ (I)

R ₄

New documents (Art. 7 31 from ₈ .2 No. 1 sau 3 of the amendment ··. & £ a. W ^r 109839/1802

wherein Ph represents an optionally substituted 1,2-phenylene radical, each of the groups R ₁ and R ₂ . for 2 hydrogen atoms or 2 aliphatic radicals or for a hydrogen atom together with an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical of aromatic character or a heterocyclic-aliphatic radical in which the heterocyclic part has aromatic character, R ^ a Hydrogen atom, a hydroxyl group, a mercapto group, an optionally substituted amino group, an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical of aromatic character or a heterocyclic aliphatic radical in which the heterocyclic part has aromatic character, and R means a Hydrogen atom, an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical of aromatic character, a heterocyclic-aliphatic radical in which the heterocyclic part has aromatic character, or the acyl radical of a carboxylic acid as well as N-oxides, quaternary derivatives or salts of such compounds.

An optionally substituted 1,2-phenylene group may contain one or more identical or different substituents, these being any of those for substitution can take suitable positions. Such substituents are e.g. lower alkyl groups, free, ethereal

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te or esterified hydroxyl or mercapto groups, such as lower alkoxy, Lower alkylenedioxy or lower alkyl mercapto groups or halogen atoms, trifluoromethyl groups, nitro groups or amino, such as di-lower alkylamino groups. Preferred radicals Ph are 1,2-phenylene-, (lower alkyl) -l, 2-phenylene-, (Lower alkoxy) -1,2-phenylene-, (lower alkylmercapto) -1,2-phenylene-, (Halogen) -1,2-phenylene-, (trifluoromethyl) -1,2-phenylene-, (Nitro) -l, 2-phenylene or (di-lower alkyl-amino) -1,2-phenylene groups.

An aliphatic radical representing the groups R ₁ , R ₃ , R and / or R 1 is an optionally substituted aliphatic hydrocarbon radical, such as lower alkyl or lower alkenyl radical. These radicals are preferably unsubstituted, but can, for example, be substituted by free or esterified hydroxyl groups such as halogen atoms and represent, for example, hydroxy-lower alkyl or halo-lower alkyl groups, or by heteroatoms, preferably an oxygen, sulfur and / or nitrogen atom, be interrupted and, for example, a lower alkoxy-lower alkyl or a corresponding lower alkyl mercapto-lower alkyl group, as well as a mono- or di-lower alkylamino-lower alkyl or a lower alkylenamino-lower alkyl, an oxa- or thia-lower alkylenamino-lower alkyl or an aza, Niederalkylaza- or a Phenylaza-lower alkylenamino-lower alkyl group, in which a Niederalkylenaminorest preferably 4 to 6 ring

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contains carbon atoms, mean, with heteroatoms through at least 2 carbon atoms are separated.

An aromatic radical representing the groups FL, Rp, FU and / or R ₂ is an optionally substituted phenyl group, an aromatic heterocyclic radical. Character, for example, an optionally substituted pyridyl, thienyl, furyl, pyrryl, pyrazolyl or imidazolyl group. The above radicals can have one or more substituents, such as, for example, those of the radical Ph; preferred aromatic radicals are phenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, (lower alkylmercapto) phenyl, (halogen) phenyl, (trifluoromethyl) phenyl, (nitro) phenyl or ( Di-lower alkylamino) phenyl groups.

One of the groups R., Rp, R, and / or R ^ The araliphatic radical is preferably a monocyclic one Aryl-lower alkyl or aryl-lower alkenyl radical; one heterocyclic-aliphatic group, in which the heterocyclic

see remainder has aromatic character, is e.g. a furfuryl or thenyl residue. These residues can optionally, as for the group Ph has been shown to be substituted.

An optionally substituted amino group Rp contains, for example, an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical of aromatic character or a heterocyclic-aliphatic radical, in which the heterocyclic

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BATH ORIGINAL.

see group has aromatic character. An amino group R _p is preferably a tertiary and a secondary amino group, for example a di-lower alkylamino and a mono-lower alkylamino group, a lower alkyleneamino or a monoaza, monooxa or monothia-lower alkyleneamino group.

An acyl group JU of a carboxylic acid is, for example Lower alkanoyl radical.

The term “lower”, above and below, in connection with organic groups, radicals or compounds mentioned, means that these substituents, radicals and compounds, unless otherwise stated, contain up to 7 », preferably up to 4 carbon atoms.

Lower alkyl groups are, for example, methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl groups; the remainders R, R _? Lower alkyl groups representing R 1 and / or R 1 can also be straight-chain or branched pentyl, hexyl or heptyl radicals linked to any carbon atom. Lower alkenyl radicals are, for example, allyl, methallyl or 3-butenyl groups.

Lower alkoxy groups are e.g. methoxy, ethoxy, ri-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy groups, Lower alkyl mercapto groups, e.g. methyl mercapto or ethyl mercapto groups. Are lower alkylenedioxy radicals e.g. methylenedioxy, 1,1-ethylenedioxy or 1,2-ethylenedioxy groups.

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Halogen atoms are e.g. fluorine, chlorine or bromine atoms.

A hydroxy-lower alkyl radical is e.g. a 2-hydroxyethyl group, while a halo-lower alkyl radical is, for example, a chloromethyl or 2-chloroethyl radical.

A lower alkoxy-lower alkyl radical is, for example, methoxymethyl, ethoxymethyl, n-propyloxymethyl, 1- or 2-methoxyethyl, 1- or 2-ethoxyethyl, 1- or 2-isopropyloxyethyl, 1-, 2- or 3-methoxypropyl-, 1,2- or 3-ethoxypropyl-, 1-, 2- or 3-n-propyloxyethyl or 4-tert-butyloxybutyl group; a lower alkylmercapto-lower alkyl radical corresponds to the above-mentioned oxygen radicals.

Mono-lower alkylamino-leather alkyl and di-lower alkyl-amino-lower alkyl groups are e.g. dimethylaminomethyl, 2-methylamino-ethyl, 2-dimethylamino-ethyl, 2-diethylamino-ethyl, 3-dimethylamino-propyl- or 3-diethyl- aminopropyl groups. Lower alkylenamino-lower alkyl groups are e.g. 2-pyrrolidino-ethyl, piperidino-methyl or 3-piperidino-propyl groups, while optionally N-lower alkyl or N-phenyl-substituted aza-lower alkylene-amino groups e.g. 2-piperazino-ethyl-, 2- (4 ^ ethyl-piperazino) -ethyl-, 3- (4-ethyl-piperazino) propyl or 2- (4-phenylpiperazino) ethyl groups are. Oxa-lower alkylene-amino-lower alkyl and thia-lower alkylene-amino-lower alkyl groups are e.g. 2-morpholino-ethyl or 3-thiomorpholinopropyieste.

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Di-lower alkyl amino groups, which radicals are aromatic Substituting characters are e.g. dimethylamino or diethylamino groups. ~

The mono- and di-lower alkylamino groups representing the group R _p are, for example, methylamino, dimethylamine, ethylamino, diethylamino, n-propylamino or di-n-propylamino groups; Lower alkyleneamino groups are, for example, ethyleneamino, pyrrolidino, piperidino, 1,4-pentylenamino, 2,5-hexylenamino, 1,6-hexylenamino or 2,6-heptylenamino groups; Monoaza-lower alkylene-amino groups are, for example, piperazino or 4-lower alkyl-piperazino groups, and monooxa and monothia-lower alkylene-amino groups are, for example, morpholino or thiomorpholino groups.

Aryl-lower alkyl radicals are e.g. benzyl, 1-phenyl- ethyl or 2-phenylethyl groups and aryl-lower alkenyl radicals e.g. cinnamyl groups.

Lower alkanoyl radicals are, for example, acetyl, propionyl, butyryl or pivalyl groups.

Quaternary derivatives are in particular lower alkyl or aryl-lower alkyl quaternary derivatives in which at least a tertiary nitrogen atom is quaternized.

The compounds of the present invention show valuable pharmacological properties. Except coccidiostatis and certain central stimulating effects, they primarily increase the contractility of the

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Heart (positive inotopic effect of the myocardium) and the blood flow in the coronary vessels, which can be demonstrated as test animals using animal experiments, for example using mammals and birds such as mice, dogs and chickens. The coccidiostatic effect can be demonstrated, for example, by the survival of chickens infected with Eimeria tenella which are reared on feed containing from about $ 0.01 to about $ 0.1, preferably about $ 0.05, of the active ingredient. Central stimulating effects can be demonstrated, for example, in the shivering cage of mice to which the active ingredient has been administered in subcutaneous doses of from about 0.005 to about 0.1 g / kg / day, preferably from about 0.01 to about 0.05 g / kg / day . The increase in the contractility of the myocardium can be detected, for example, in dogs by means of strain gauges in oral doses of about 0.001 to about 0.05 g / kg / day, preferably from about 0.005 to about 0.025 g / kg / day. The compounds of the present invention can therefore be used as pharmacologically, in particular as cardiovascularly active agents, for example in the treatment of heart failure; they can also be used as coccidiostats or central stimulants. In addition to pharmacological use, the compounds of the present invention can also be used as valuable intermediates in the preparation of other valuable, in particular pharmacologically active, compounds.

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The compounds of the formula I in which the group Ph is 1,2-phenylene-, (lower alkyl) -l, 2-phenylene-, (lower alkoxy) -1,2-phenylene, are particularly valuable with regard to their pharmacological, in particular cardiovascular, effects -, (Lower alkylmercapto) -l, 2-phenylene-, (halogen) -1,2-phenylene-, (trifluoromethyl) -l, 2-phenylene-, (nitro) -1,2-phenylene- or (di-lower alkyl-amino ) -l, 2-phenylene radical, each of the groups R, and R ₂ , two hydrogen atoms or one hydrogen atom together with a lower alkyl radical,

a R -Lower alkyl radical or the radical R, where a a

R is a phenyl, (lower alkyl) phenyl, (lower alkoxy) -

phenyl-, (Niederalkylmercapto) -phenyl-, (halogen) -phenyl-, (trifluoromethyl) -phenyl-, (nitro) -phenyl- or (di-lower-alkyl-amino-) -phenylre st represents, Rp for a hydrogen atom, a hydroxy , a mercapto-, an amino-, a di-lower alkyl -amino-, and a mono-lower alkyl-amino-, a lower alkylene-amino-, a monoaza-, monooxa- or monothia-lower alkylene-amino-, a lower alkyl, a Lower alkoxy-lower-alkyl, a halo-lower-alkyl, a di-lower-alkyl-amino-lower-alkyl, a lower-alkylene-amino-lower-alkyl, or a monoaza, monooxa or monothian-lower alkylene-amino-nlederalkyl group, with two heteroatoms having at least 2 carbon atoms in heterocyclic radicals are separated, an R -lower alkyl- or an R _a group: is, and R ^. a hydrogen atom, a _{lower alkyl, a R e} lower alkyl or a lower alkanoyl group

el

109839/1802 ^

- ίο -

represents, as well as their N-oxides, lower alkyl quaternary Derivatives and acid addition salts thereof.

Particularly valuable in terms of their pharmacological, especially cardiovascular, properties are the compounds of the formula

(Ia)

where Rl stands for a hydroxy, mercapto, amino, methylamino, Dimethylamine-, methyl-, methoxymethyl-, chlorinethyl-, dimethylamino-methyl-, Piperidinomethyl-, benzyl-, phenyl-, 4-methoxyphenyl-, 4-chlorophenyl-, 4-tri fluorine thyl-phenyl-, 3-NitrophenyI- or 4-Nitro-phenyl group, and their pharmaceutically acceptable, non-toxic acid addition salts, which when administered in doses of about 0.005 to about 0.025 g / kg / day in one coil of the small intestine of an unanesthetized dog, a notable increase in Effect the contractility of the heart (measured in 30 minutes Intervals with the help of a cardiac strain gauge, one hour before the drug administration to the left Ventricle is sutured).

Of particular interest are compounds of the formula Ia in which R * is methyl-, ^ ethylamino- or piperidinomethyl group, and their pharmaceutically usable

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bare acid addition salts; they are extremely active as agents which increase the contractility of the heart.

The compounds of the present invention are prepared by methods known per se, for example by one compound of the formula

^R l

Ph "(II)

with a reactive, functional derivative of a Reacts acid of the formula Rp-COOH, and, if desired, a compound obtained · into another, the formula I having Connection transferred.

Reactive functional acid derivatives that are together with the starting material of the formula II for the formation of a 4,5-dihydro-1H ^ -2,4-benzodiazepine compound, are, for example, orthoesters of aliphatic, araliphatic or aromatic carboxylic acids, of heterocyclic carboxylic acids aromatic character or heterocyclischaliphatic carboxylic acids, in which the heterocyclic part has aromatic character, such as orthoesters of the formula R -C (OR) - ,, where Rp is a hydrogen atom or a the organic radical representing the group Rp, and R ° an organic radical, especially an alkyl, such as Nie-

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deralkylrest, means imino or imiothioal groups of aliphatic, araliphatic or aromatic carboxylic acids, of heterocyclic carboxylic acids of aromatic character or heterocyclic-aliphatic carboxylic acids in which the heterocyclic part has aromatic character, such as an imino ether of the formula R ₂ -C (= NR, ^a ) - OR ° or an iminothioether of the formula R ₂ ^b -C (= NR ^a ) -SR °, in which R _g ^{b has} the same meaning as R ₂ ^a and also represents a group of

Formula -NHR, where R ^a denotes a hydrogen atom or an organic radical which is different from an acyl group and represents the group R, amidines of aliphatic, araliphatic or aromatic carboxylic acids, of heterocyclic carboxylic acids of aromatic character or heterocyclic-aliphatic carboxylic acids, in which the heterocyclic Part has aromatic character, for example an amidine of the formula R ₂ ^a -C (= NR ^a ) -NHR ^a , or nitriles of aliphatic, araliphatic or aromatic carboxylic acids, of heterocyclic carboxylic acids of aromatic character or heterocyclic-aliphatic carboxylic acids, in which the heterocyclic part is aromatic Has character, such as a nitrile of the formula R ₂ -C ^ N, and reactive derivatives of amides of carboxylic acids of the formula R ₂ -COOH, such as thioamides, acetals or thioacetals of N, N-disubstituted amides, addition products of Ν, Ν-disubstituted Amides with Lewis acids, such as boron trifluoride, or salt-like halogen ends derivatives of Ν, Ν-disubstituted amides, or phosgene

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or diimidazolylcarbonyl, as well as the corresponding sulfur analogues, i.e. thiophosgene or diimidazolyl-thiocarbonyl.

The compounds of the present invention can also be obtained by using a compound of formula

^R l

ir c — χ

Ph (III)

ο-γ

Il

^E 4

wherein one of the groups X and Y represents an amino group and the other is an imino (Rp) methyl (R,) amino group, ring closes, and, if desired, one obtained Compound converted into another compound having the formula I.

An imino (Rp) methyl (R,) amino group in the starting material of the formula III is, for example, a group which is formed by condensation of a compound of the form!

^R l

11 ^X

σ - x ¹

Ph (Ilia)

σ — γ »

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wherein one of the groups X ¹ and Y ¹ represents an amino group and the other one can be converted into an amino radical, for example a nitro, azo or acylamino group, means one of the above-described reactive, func tional derivatives of an acid of formula R ₂ -COOH can form. In such a condensation product , the potential amino group can be converted into an amino group, for example by hydrogenation and hydrolysis, preferably in an acidic medium. The ring closure of a starting material of the formula III is preferably carried out with the free compound or in the presence of a basic agent, in particular under pyro lytic conditions.

Compounds obtainable by the above processes can be converted into one another in a manner known per se. For example, connections in which R _? represents a hydroxyl or mercapto group, for example using reactive esters of alcohols, such as Nieder alVvihs "! ogeniden, or reactive acid derivatives, such as Th '-) ny: ^v alogeniden or phosphorus oxyhalides, etherified or esterified. Compounds obtained with ester, ß ■ ♦ ■ hey! "-" - or Halogenalkylgruppierungen in position 3 can with- AMRN ^ nick or amines to form 3-Aminp- or 7 · -.. ^ß Tino alkyl compounds are converted compounds with carbonyl received - or know halophenyl groups ^! r. with catalytically activated or nascent water o ::: ί c ei with complex light metal hydrides, such as lithium

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aluminum hydride or sodium borohydride, corresponding compounds with methylene or dehalogenated phenyl groups are obtained. links with primary, secondary or tertiary amino groups can e.g. by treatment with reactive esters of alcohols, preferably lower alkanols, and e.g. hydrohalic or sulfonic acids, such as hydrochloric, hydrobromic, Methanesulphonic, ethanesulphonic or ρ-toluenesulphonic acid, in compounds with tertiary or quaternary amino groups be transferred. N-oxides are obtained, for example, by treating the free compounds with hydrogen peroxide or a peracid such as peracetic, perbenzoic and monoperphthalic acids.

The above reactions are carried out according to standard methods, e.g., in the presence or absence of diluents, especially those that look to the reactants behave inertly and be able to dissolve them, from catalysts and / or condensation agents, if necessary, carried out in an inert gas atmosphere, with cooling or heating and / or elevated pressure.

The new compounds become in free form depending on the conditions under which they are formed or obtained in the form of their salts; the latter also form an object of the present invention. Obtained salts can in a manner known per se, e.g. by treating with

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an alkaline agent or an ion exchanger, are converted into the free compounds. Got free Compounds can, for example, by treatment with inorganic or organic acids, especially those that are Formation of pharmaceutically acceptable, non-toxic salts are suitable, into which salts are converted, such drinking are e.g. hydrohalic acids such as hydrochloric and hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, or aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, Glycol, milk, apple, wine, lemon, maleic, hydroxymalein, Pyruvic, phenyl acetic, benzoin, aminobenzoe, anthranil, hydroxybenzoic, salicylic, aminosalicylic, embon, Nicotine, methanesulfone, ethanesulfone, hydroxyethanesulfone, Ethylenesulfone, halo-benzene sulfone, toluene sulfone, naphthalene sulf on-, sulfanil- or cyclohexylsulfamic acid, as well as methionine, tryptophan, lysine, arginine or ascorbic acid. These or other salts, such as the picrates, can also be used to purify the free compounds obtained will; these are converted into the salts, the salts are separated off and the free compounds from the Salts released. In view of the close relationship between free compounds and corresponding salts can under a free compound or a salt meaningfully and appropriately also a salt or the free compound

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will stand.

The invention also relates to those modifications of the above-mentioned method in which a intermediate product obtainable at any stage of the process is used as the starting material and remaining reaction steps are carried out, or the process on any stage is interrupted, or after which starting materials formed under the reaction conditions or the Reaction components in the form of derivatives, such as salts, can be used. This is preferred in the above procedures those starting materials are used which lead to the formation of the compounds mentioned above as being particularly valuable.

The starting materials to be used are known or, if new, can be prepared by methods known per se will. Thus, starting materials of the formula II are obtained e.g. by reducing the corresponding amides, nitriles or Anhydrides and / or amination of the corresponding reactive alcohol derivatives, such as hydrohalic acid or Sulfonic acid ester. The making of connector that Formula III was mentioned above.

Isomeric mixtures of starting materials cv ^ar final products can known methods in ^ '"ri slnen isomers are separated ^ Sc can Verfai :; tr." According ^ζ; - "^ it one or more JLsyir ^ etrisnhen Kcrlerstoffatr " ■ '-. For von Racematgenis? He - ..; ^P ■■ ·: · :: .. "-. Rz ~ -: v Ant: ^T .:> Odsr \. ' ^ - On the basis of pbvsi> ■ -T.si.v. .- ■: -, - : ..; "· " rr3r ~. ". :: R · -

The mixture components can be separated into the pure racemates , for example by chromatography and / or fractional crystallization, racemate mixtures . Racemic products can be split into the optical antipodes, for example by treating with optically active acids, separating the diastereoisomeric salts and releasing the free antipodes from these salts .

The compounds of the present invention can be used, for example, for the production of pharmaceutical preparations which contain them together with inorganic or organic, solid or liquid pharmaceutical carriers and which are suitable for enteral, such as oral, or parenteral administration. Suitable carriers are compounds which do not react with the compounds of the present invention, such as, for example, water, gelatin, sugars such as lactose, glucose or sucrose, starches such as wheat, corn, rice and arrowroot starch, stearic acid and salts thereof , such as magnesium or calcium stearate, talc, vegetable fats or oils, rubber compounds, alginic acid, Benayiaikohoie, glycols and other known fillers. The preparations can be in solid form, for example as tablets, coated tablets, capsules or suppositories, or in liquid form, for example as solutions, suspensions, or emulsions. You kör.iie be sterilized and / or adjuvants such as Konservler-, stabilizers, wetting or emulsifying agents, Lösungsver ^r i ■;.. ■■ -'.- · - "· ■ ,, '· ■ τ · _ir regulation of the osmotic pressure and / or

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Buffer, included. The pharmaceutical preparations are produced by conventional methods and contain from about 0.1 to about 75, preferably from about 1% to about 50% of the active ingredient. If desired, further pharmacologically valuable substances can be added.

The following examples illustrate the invention; Temperatures are given in degrees Celsius.

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Example 1:

A solution of 2 g of 1,2-bis-aminomethyl-benzene in 40 ml of ethanol is mixed with 1.78 g of acetimino-ethyl ether hydrochloride offset; the mixture is refluxed for 16 hours, then to about 2/3 of the original volume evaporated. After standing for 2 hours at room temperature, the precipitate obtained is filtered off with ether washed and dried. 3-methyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride the formula

HCl

melts at 283 (with decomposition).

The starting material can be produced as follows:

A solution of 4 g of 1,2-bis-aminomethyl-benzene dihydrochloride in 10 ml of water the pH is adjusted to 12 with aqueous sodium hydroxide solution. The mixture is made 2 times with portions extracted from each 75 ml of chloroform, the combined extracts washed with 10 ml of water, dried and evaporated.

Example 2:

A solution of 4 g of 1,2-bis-aminomethyl-benzene in 100 ml of ethanol is mixed with 5> 6 g of phenyl-acetimino-ethyl ether *

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hydrochloric! offset; the mixture is for 16 hours boiled under reflux, then concentrated to a volume of about 25 ml and left for 2 hours at room temperature calmly. The precipitate is filtered off, washed with ether and dried; the obtained 3-benzyl-4,5-dihydrolH-2,4-benzodiazepine hydrochloride the formula

CH

0— CH

HCl

melts at 256-259 ° (decomposes).

Example 3 »

A solution of 5 * 0 g of 1,2-bis-aminomethyl-benzene in 125 ml of ethanol is mixed with 8jl g of 4-chloro-benzimino-ethyl ether hydrochloride; the mixture is refluxed for ΐβ hours, then cooled. The precipitate obtained is filtered off, washed with ether and recrystallized from ethanol; the obtained 3 - (^ ^- -Chlorophenyl) -4,5-dihydro-1H-2,4-benzodiazepine hydrochloride of the formula

HCl

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melts at 266-267 °.

Using the appropriate starting materials, one obtains in the same way:

3_ (4-nitrophenyl) -4,5-dihydro-lH-2,4-benzodiazepine, monohydrochloride which melts after recrystallization from ethanol at 278-28O ^0;

3- (3-nitrophenyl) -4,5-dihydro-lH-2,4-benzodiazepine, monohydrochloride which melts after recrystallization from ethanol at 26O ^0; and

3- (4-trifluoromethyl-phenyl) -4,5-dihydro-IH-2,4-benzodiazepine, whose monohydrochloride melts over 300 ° after recrystallization from ethanol.

Example 4;

A mixture of 2 g of 1,2-bis-aminomethyl-benzene, 5.6 g of methoxyacetimino-ethylether-hydrochloriä and 25 ml Aethanoj. is refluxed for 16 hours. To 1000 ml of ether are added to cooling with stirring, and the precipitate formed is filtered off. Do the recrystallization 3-methoxymethyl-4,5-aihyaro ~ 1H-2,4-benzodiazepine hydrochloride melts from n-butanol the formula

C-CH ₂ -O-CH ₅ . HCl

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Sk,

- 23 at 175-I78 ⁰ .

Example 5?

A solution of 6 g of 1,2-bis-aminomethyl-benzene in 150 ml of tetrahydrofuran is slowly stirred and Ice cooling with a solution of 7 * 5 g diimidazolylcarbonyl added in 100 ml of tetrahydrofuran. The mixture is left to stand for 16 hours at room temperature; the precipitate obtained is filtered off and, after washing with tetrahydrofuran, gives 3-hydroxy-4,5-dihydrolH-2,4-benzodiazepine the formula

CH

which melts over 3OO. In the infrared spectrum, the compound shows absorption bands at 3115 * 1595 * 1485 * 1390, 1340, 1265 and 1195 cm " ^1, among other things.

Example 6;

A solution of 2 g of 1,2-bis-aminomethyl-benzene in 25 ml of methanol is mixed with a total of 2.3 g of chloroacetimino-ethyl ether hydrochloride offset; the reaction mixture is left to stand for hours and then dropwise with stirring

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given too much ether. The precipitate obtained is filtered off; it provides 3-chloromethyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride the formula

HCl

which melts at 263-264 °.

A solution of 10 g of this salt in a minimal The amount of water is adjusted to a pH of about 9 with sodium hydroxide. The precipitate obtained is filtered off, washed with water, dried and recrystallized from ethyl acetate; the 3-chloromethyl-4,5-dihydro-1H-2,4-benzodiazepine thus obtained melts at 235-240 °.

The starting material can be produced as follows:

A mixture of 500 g. 1,2-bis-bromomethyl-benzene, 1000 g of phthalimide potassium and 3780 ml of dimethylformamide refluxed with stirring for 16 hours, then cooled to about 100 and with an equal volume Water diluted. The precipitate obtained is filtered off and washed with water, ethanol and ether. 1,2-bis-phthaiimjdomethyl-benzene melts at 275 °.

A mixture of 200 g of 1,2-bis-phthalimidomethyl :; ensoJ and TOGO nü n-butanol is mixed with ^ 8.5 ml of hydrazine hydrate

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BATH ORIGINAL

offset; the mixture is refluxed with stirring for 16 hours. After adding 100 ml more concentrated Hydrochloric acid, the reaction mixture is refluxed for a further 24 hours, then under reduced pressure constricted about half of its volume. The precipitate obtained is filtered off and triturated with 500 ml of water. The aqueous solution is evaporated under reduced pressure and the residue is triturated with methanol; the 1,2-bis-aminomethyl-benzene dihydrochloride thus obtained after recrystallization from aqueous ethanol melts above 300 °.

Example 7;

50 ml of a saturated solution of dimethylamine in methanol is mixed with 4.5 g of 3-01ι1οΓπιβ ^ 1-4,5-α11 ^ 3Γο-1Η-2,4-benzodiazepine; the mixture is boiled for half an hour at reflux, then cooled and acidified with ethanolic hydrogen chloride. "The resulting precipitate is filtered off and the 3-DimethyIaminomethyl-4,5-dihydro-lH-2 _i 4-benzodiazepine, dihydrochloride gives the formula

• Ν

CKCH ₂ -N (OH,) ₂ . 2 KGI,

which at 239-241 ° Schmi:

1CS833 / 1802

Example 8:

A mixture of 7.5 g of 3-hydroxy-4,5-dihydro-lH-2,4-benzodiazepine and 30 ^m l of phosphorus oxy chloride id is heated under stirring for 3 hours on a steam bath, then evaporated under reduced pressure. The residue is triturated with ethyl acetate, the solid material is filtered off and added in portions to 200 ml of liquid ammonia. The mixture is stirred and evaporated within about 3 hours at room temperature. The residue is taken up in water, the solution is made strongly basic with saturated aqueous potassium hydroxide solution and extracted with chloroform. The organic extract is dried, filtered and evaporated. The residue is taken up in ethanol, the solution is acidified with ethanolic hydrogen chloride, the precipitate obtained is filtered off and recrystallized from a mixture of ethanol and methanol. The 3-amino-4,5-dlhydro-1H-2,4-benzodiazepine hydrochloride of the formula obtained in this way

C-NH ₂ . HCl

melts at 279-281 °.

If you replace the ammonia with dimethylarain and carry out the reaction as described above, you get that

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3-Diraethylamίno-4,5-dihydro-lH-2 _a 4-benzodiazepine _ί whose monohydrochloride melts after recrystallization from ethanol at 253-255 °. .

Example 9i

After filtering a mixture of 20 g. Imidazo!., 350 ml of tetrahydrofuran and a solution of 8.6 g Thiophosgene in 50 ml · tetrahydrofuran solution obtained dropwise with a solution of 10 g of 1,2-bis-aminomethylbenzene added in 50 ml of tetrahydrofuran with stirring. The reaction mixture is refluxed for 16 hours, then cooled and filtered; the solid residue is washed with tetrahydrofuran and gives 3-mercapto-4,5-dihydro-1H-2,4-benzodia3epine the formula

which melts at 283-284.

Example 10:

A solution of 25 lb. piperidine in 20 ml of methanol

is charged with 10 g of 3-chloromethyl-4 _J 5-dihydro-lH-2 _J ⁱ i-.benzodiazepin treated; the mixture is stirred for 16 hours then

diluted with toluene and evaporated under reduced pressure. The residue is dissolved in aqueous ethanol, the solution is made basic with aqueous sodium hydroxide ^- and extracted with chloroform. The organic extract is dried, filtered and evaporated. The residue is dissolved in ethanol, the solution is acidified with ethanolic hydrogen chloride and the precipitate obtained is filtered off and washed with ether. The 3-piperidinomethyl-4,5-dihydrolH-2,4-benzodiazepine dihydrochloride of the formula

. 2 HOl

melts at 288-289 °.

Example 11:

A mixture of 1 g of 3- (4-chlorophenyl) -4,5-dihydrolH-2,4-benzodiazepine hydrochloride, 100 ml of anhydrous ethanol and 0.2 g of a 5 # palladium-on-carbon catalyst is hydrogenated for 3 hours at a pressure of about 1.8 atmospheres and at room temperature. The reaction mixture is filtered, the Piltrat diluted with ether and the precipitate obtained is filtered off. The 3-phenyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride the formula

109839/1802

^ 29 -

CH

. HCl

melts at 232-23.4 °.

Example 12:

A solution of 5 g of 1,2-bis-aminomethyl-benzene in 125 ml ^ ethanol is hydrochloric with 7.9 g of 4-methoxy-benziminoethyl ether! offset; the mixture is refluxed for 16 hours and then kept at about 4 ° (refrigerator) for 6 hours. The precipitate is filtered off, washed with ether and recrystallized from ethanol j, the thus obtained 3- (4-methoxyphenyl) -4., 5-dihydrolH-2 _J 4-benzodiazepine hydrochloride of the formula

CH

OCH,. HCl

melts at 262-263 °.

109839/1802

Example 13:

A solution of 2 g of 3-phenyl-4,5-dihydro-IH-2,4-benzodiazepine hydrochloride in a minimal amount of water is made basic with aqueous potassium hydroxide and extracted with chloroform. The organic extract is dried, filtered and evaporated. The residue is taken up in ethanol, the solution is slightly acidified with ethanolic maleic acid and the precipitate obtained is filtered off and recrystallized from ethanol; the 3-phenyl-4,5-dihydro-1H-2,4-benzodiazepine maleate melts at 191-193 °.

Example l4;

A mixture of 7.5 g of 3-hydroxy-4,5-dihydro-1H-2,4-benzodiazepine and 30 ml of phosphorus oxychloride is heated on the steam bath with stirring for about 3 hours and then evaporated under reduced pressure. The residue is treated with a solution of 10 ml of methylamine in 100 ml of tetrahydrofuran, the mixture is stirred for 16 hours at room temperature, then evaporated under reduced pressure and the residue is taken up in water. The aqueous mixture is made alkaline with aqueous potassium hydroxide solution and extracted with chloroform; the organic extract is dried, filtered and evaporated. The residue is taken up in ethanol, the solution is acidified with ethanolic hydrogen chloride and the precipitate is filtered off and

109839/1802

recrystallized from ethanol; the so obtained 3-methylamino ^^ - dihydro-lH ^^ - benzodiazepine hydrochloride the formula

HOl

melts at 210-211 °.

3-Dimethylamino-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride can be obtained in an analogous manner, using equivalent amounts of the necessary starting materials used; it melts at 252-256.

Example 15:

A solution of 9 g of N- (2-aminomethyl-benzyl) -acetamidine in 100 ml. Ethanol is for 24 hours on Boiled to reflux, then cooled, acidified with ethanolic hydrogen chloride and evaporated under reduced pressure. The residue is triturated with ether and recrystallized from ethanol and gives 3-methyl-4,5-dihydrolH ^^ - benzodiazepine hydrochloride, P. 283 (decompose); the product is identical to that according to the procedure of Example 1 obtained connection identical.

The starting material can be obtained as follows:

109839/1802

A mixture of 500 g of 1,2-bis-bromomethyl-benzene and 500 g of phthalimide potassium in 3780 ml of dimethylformamide refluxed with stirring for 10 hours and then concentrated under reduced pressure. The one after The precipitate obtained after cooling is filtered off and recrystallized from aqueous ethanol to give 2-phthalimidomethyl-benzyl bromide.

A solution of 100 g of 2-phthalimidomethyl-benzyl bromide 57 g of sodium nitrite are added in portions to 100 ml of dimethyl sulfoxide; the mixture is during 10 Stirred at 50 hours, then diluted with water. The precipitate obtained is filtered off, with water, ethanol and ether washed and recrystallized from a mixture of ethanol and dimethylformamide. 1-Nitromethyl-2-phthalimidomethyl-benzene is obtained in this way.

A mixture of 20 g of 1-nitromethyl-2-phthalimidomethyl-benzene and 100 ml of concentrated hydrochloric acid is heated in a sealed tube at 175 for 3 hours, then cooled and filtered. The filter residue is washed with water and the filtrate with aqueous sodium hydroxide made basic and extracted with chloroform. The organic extract is evaporated under reduced pressure and the residue, recrystallized from aqueous ethanol, gives 2-nitromethylbenzylamine.

A solution of 10 g of 2-nitromethyl-benzylamine in 50 ml of ethanol is mixed with 7 * 5 g of acetimino-ethyl ether-hydro-

109839/1802

Chloride treated; the mixture is for 3 hours on Boiled to reflux, then concentrated under reduced pressure. The precipitate obtained is filtered off, in a minimal amount of water and the aqueous solution made basic with aqueous potassium hydroxide and with chloroform extracted. The organic extract is dried, filtered and evaporated under reduced pressure to give the N- (2-nitromethyl-benzyl) -acetamidine.

A mixture of 12 g of N- (2-nitromethyl-benzyl) -acetamidine in 100 ml of ethanol is hydrogenated in the presence of 1 g of platinum oxide at room temperature and under an initial pressure of about 3Y4 atmospheres. After the recording the theoretical amount of hydrogen, the reaction mixture is filtered and evaporated under reduced pressure and gives the N- (2-aminomethyl-benzyl) -acetamidine, which without further cleaning is processed.

Example 16;

Tablets containing 0.1 g of the active ingredient are prepared as follows (10 for ¹ OOO tablets):

Components:

3-Amino-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride 1000 g

Milk sugar 2535 g

Talc (powder) 150 g

Magnesium stearate 40 g

109839/1802

Corn starch 125 g ~

Polyethylene glycol 6000 150 g

purified water q.s.

The powdery ingredients are passed through a sieve (Sieve openings: 0.6 mm) driven. 3-Amino-4,5-dihydrolH-2,4-benzodiazepine hydrochloride, the milk sugar, the talc, the magnesium stearate and half of the corn starch are mixed in a suitable mixer. The other half of the corn starch is suspended in 50 ml of water and added to a hot solution of polyethylene glycol in 180 ml of water. The paste obtained becomes Granulation of the powder mixture used, further amounts of water being added if necessary. The granules is dried for 16 hours at 35, driven through a sieve (sieve openings: 1.2 mm) and processed into tablets. concave punches with a diameter of 10.3 mm are used, the upper ones being suitable for forming a breaking groove. .

Similarly, tablets containing from 0.05 to 0.15 g of any of those shown in Examples 1-12 can be used Connections are made.

Example 17:

Tablets, each containing 0.05 g of the active ingredient can be produced as follows (for 10,000 tablets):

109839/1802

Components:

3-methylamino-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride 500 g

Milk sugar I706 g

Corn starch 90 g

Polyethylene glycol 600 90 g

Talc (powder) 90 g

Magnesium stearate '24 g

purified water q.s.

The granulate is produced according to the method of example l6, dried for 16 hours at 35 °, driven through a sieve (sieve openings: 1.2 mm) and using a concave Punches with a diameter of 7.1 mm processed into tablets with a score line.

Analog tablets can be made using 3-methyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride or 3-piperidinomethyl-4,5-dihydro-1H-2,4-benzodiazepine hydrochloride of examples 1 resp. 10 are produced as active ingredients.

109839/1802

Claims (1)

Patent claims: 1. Process for the preparation of 4,5-dihydro-1H-2,4-benzodiazepines the formula Ph GR ₂ (I) I \ R ₄ ^R 3 where Ph is an optionally substituted 1,2-phenylene radical stands, each of the groups R. and R ^. 2 hydrogen atoms or 2 aliphatic radicals or one hydrogen atom together with an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical aromatic Character or a heterocyclic-aliphatic radical, in which the heterocyclic part has aromatic character has, represents, Rp represents a hydrogen atom, a Hydroxy group, a mercapto group, an optionally substituted amino group, an aliphatic group, an araliphatic group, an aromatic group, a heterocyclic group A radical of aromatic character or a heterocyclic-aliphatic radical, in which the heterocyclic part Has aromatic character, and R, a hydrogen atom, an aliphatic radical, an araliphatic Residue, an aromatic residue, a heterocyclic residue New documents (Art. 7 51 Para. 2 No. 1 109839/1802 aromatic character, a heterocyclic-aliphatic Radical in which the heterocyclic part has aromatic character, or is the acyl radical of a carboxylic acid, N-oxides, quaternary derivatives or salts thereof, characterized in that a compound of the formula Ph (II) ^R 4 condensed with a reactive functional derivative of an acid of the formula Rp-COOH, or a compound of the formula _Ώ Ph (III) ^R 4 wherein one of the groups X and Y represents an amino group and the other is an imino (Rp) methyl (R,) amino group, closes the ring, and, if desired, converts a compound obtained into another compound of the formula I, and / or, if desired, converting a compound obtained into a salt, an N-oxide or a quaternary compound, and / or, if desired, converting a salt obtained into the free compound, and / or, if desired, a obtained salt Isomer mixture separates into the individual isomers. 109839/1802 2. The method according to claim 1, characterized in that a starting material of the formula II with a functional derivative of an acid of the formula Rp-COOH, which forms together with the starting material of a 4,5-dihydro-1H-2,4-benzodiazepine is suitable. 3. The method according to claim 1, characterized in that that the reactive functional derivative of an acid of the formula Rp-COOH is an orthoester, an imino ether, an iminothioether, an amidine or a nitrile of an aliphatic, araliphatic or aromatic carboxylic acid, or a heterocyclic carboxylic acid of aromatic character or a heterocyclic-aliphatic Carboxylic acid, in which the heterocyclic part has aromatic character, phosgene or diimidazolylcarbonyl is used . 4. The method according to any one of claims 1-3 *, characterized in that the reactive functional derivative of an acid of the formula Rp-COOH is an orthoester of the formula Rp ^a -C (0R °) ,, wherein R ^{a is} a hydrogen atom or a die Group Rp represents an organic radical, and R represents an organic radical, in particular an alkyl, such as lower alkyl radical, an imino ether of the formula R ₂ -C (= NR, ^a ) -0-R ° or an iminothioether of the formula R ₂ ^b -C (= NR ^a ) -SR °, where R ₂ ^{b has} the same meaning as Rg * 109839/1802 has and also represents the group of the formula -NHR, and R ^{a represents} a hydrogen atom or an organic radical which is different from an acyl radical and which represents the group R, is an amidine of the formula R ₂ ^a -C (= NR ^a ) -NHR ^a , a nitrile of the formula R ₂ -C = N, a reactive derivative of an amide of the acid of the formula Rp-COOH, phosgene, diimidazolylcarbonyl, thiophosgene or diimidazolylthiocarbonyl are used. 5. The method according to claim 1, characterized in that the imino (Rp) methyl (R.,) Amino group in the starting material of the formula III represents a group which can be formed by reacting a compound of the formula Ph (HIa) ^R 4
in which one of the groups X ¹ and Y ^{1 is} an amino group and the other is a radical which can be converted into an amino group, such as a nitro, azo or acylamino group, formed with a reactive functional derivative of an acid of the formula Rp-COOH will. 6. The method according to claim 5 * characterized by «Net that one as a reactive, functional derivative an acid of the formula R ₂ -COOH one of the claims 109839/1802 mentioned derivatives used. 7. The method according to claim 5 *, characterized in that that one is a reactive, functional derivative an acid of the formula Rp-COOH one of those mentioned in claim 4 Derivatives used » 8. The method according to any one of claims 1 and 5-7 » characterized in that the ring closure is carried out with a free compound of the formula III or in the presence of a basic agent, preferably under pyrolytic conditions. 9. The method according to any one of claims 1-8, characterized in that in a compound obtained wherein R _? represents a hydroxyl group or a mercapto group, the group R_ etherified or esterified using reactive esters of alcohols or reactive functional acid derivatives. 10. The method according to any one of claims 1-9, characterized in that compounds obtained with ester, Ether or haloalkyl groups in the 3-position with the formation of 3-amino or 3-aminoalkyl compounds with Converts ammonia or amines. 10983 9/1802 11. The method according to any one of claims 1-10, characterized in that compounds obtained with carbonyl or halophenyl groups with formation of the corresponding compounds with methylene or dehalogenated phenyl groups treated with catalytically activated or nascent hydrogen or with complex light metal hydrides. 12. The method according to any one of claims 1-11, characterized characterized in that an intermediate product obtainable at any stage of the process A is used as starting material and remaining process steps are carried out, or the process is terminated at any stage. 13 · The method according to any one of claims 1-12, characterized in that the starting materials under the reaction conditions forms, or the reactants are used in the form of derivatives such as salts. 14. The method according to any one of claims 1-13, characterized in that compounds of the formula I according to Claim 1, N-oxides, lower alkyl quaternary derivatives or acid addition salts thereof, wherein Ph is a 1,2-phenylene, (Nlederalkyl) -l, 2-phenylene-, (lower alkoxy) -1,2-phenylene-, (Lower alkyl-mercapto) -l, 2-phenylene-, (halogen) - ' 1,2-phenylene-, (trifluoromethyl) -l, 2-phenylene-, (nitro) -1,2-phenylene- or (di-lower alkyl-amino) -l, 2-phenylene radical, 109839/1802 each of the groups R, and R ^ 2 hydrogen atoms or one hydrogen atom together with a lower alkyl group, R -Nie- 3, deralkylgruppe or R, where R_ is a phenyl, el ä (Lower alkyl) -phenyl-, (lower alkoxy) -phenyl-, (lower alkylmercapto) -phenyl-, (Halogen) -phenyl-, (trifluoromethyl) -phenyl-, (nitro) -phenyl- or (di-lower-alkyl-amino) -phenyl radical Rp represents a hydrogen atom, a hydroxyl group, a Mercapto group, an amino group, a mono-lower alkylamino group, a di-lower alkyl amino group, a lower alkylene amino group, a monoaza, monooxa or monothia-lower alkyleneamino group, a lower alkyl group, a lower alkoxy-lower alkyl group, a halo-lower alkyl group, a di-lower alkyl-amino-lower alkyl group, a lower alkyleneamino-lower alkyl group, a monoaza, monooxa or monothia-lower alkylene-amino-lower alkyl group, where in heterocyclic radicals 2 heteroatoms are separated from one another by at least 2 carbon atoms, an R-lower alkyl group or an R group, and R, for a water a ρ substance atom, a lower alkyl group, an R -lower alkyl group el or a lower alkanoyl group. 15. The method according to any one of claims I-I3, characterized characterized in that one compounds of the formula 109839/1802 (Ia) or acid addition salts thereof, where R * represents a hydroxy, mercapto, amino, methylamino, dimethylamine, methyl, methoxymethyl, chloromethyl, dimethylamino-methyl, piperidinomethyl, benzyl, phenyl, 4- Chlorophenyl, 4-tri % fluoromethylphenyl, 3-nitrophenyl, 4-nitrophenyl or 4-methoxyphenyl group. l6. Method according to one of Claims 1-13 * thereby characterized in that compounds of the formula Ia according to claim 15 or acid addition salts thereof are prepared in which R 'represents a methyl, methylamino or piperidinomethyl group. 17 · Method according to one of claims 1-13 »thereby characterized in that 3-methylamino-4,5-dihydro-1H-2,4-benzodiazepine or an acid addition salt thereof is prepared. 10983S / 1802 The procedure described in Examples 1-15. 19. Which is obtained by the method of claims 1-17 borrowed connections. 20. Those obtainable by the procedure of Examples 1-15 Links. ' 4,5-Dlhydro-1H-2,4-benzodiazepines of the formula -N 0-IL (D -N where Ph stands for an optionally substituted 1,2-phenylene radical, each of the groups R ₁ and R ^ 2 hydrogen atoms or 2 aliphatic radicals or a hydrogen atom together with an aliphatic radical, an araliphatic radical, an aromatic radical, a heterocyclic radical of aromatic character or a heterocyclic-aliphatic radical, in which the heterocyclic part has aromatic character, R _{g represents} a hydrogen atom, a hydroxyl group represents a mercapto group, an optionally substituted amino group represents an aliphatic radical, an araliphatic radical, an aromatic radical «a hetero - 109839/1802 cyclic radical of aromatic character or a heterocyclic-aliphatic Radical, in which the heterocyclic part has aromatic character, and R is a hydrogen atom, an aliphatic group, an araliphatic group, an aromatic group, a heterocyclic group aromatic character, a heterocyclic-aliphatic radical, in which the heterocyclic part has aromatic character or represents the acyl radical of a carboxylic acid. 22. Compounds of formula I according to claim 21, wherein Ph is a 1,2-phenylene-, (lower alkyl) -l, 2-phenylene-, (lower alkoxy) -1,2-phenylene-, (lower alkyl-mercapto) -1 , 2-phenylene, (halogen) -1,2-phenylene, C-trifluoromethyl) -1, 2-phenylene, (nitro) -1, 2-phenylene or (di-lower alkyl-amino) -1,2-phenylene radical , each of the groups R, and R ₁ , 2 hydrogen atoms or a hydrogen atom together with a lower alkyl group, R -Lower alkyl group or R, where el et R _a for a phenyl, (lower alkyl) phenyl, (lower alkoxy) phenyl, (lower alkyl mercapto) phenyl, (halogen) phenyl, (trifluoromethyl) phenyl, (nitro) phenyl or (Diniederalkylamino) -phenylre st, Rp "is a hydrogen atom, a hydroxy group, a mercapto group, an araino group, a di-lower alkylamino group, a lower alkylenearaino group, a monoaza, monooxa or monothia-lower alkyleneamino group, a lower alkyl group, a lower alkoxy-lower alkyl group , 109839/1802 a halo-lower alkyl group, a di-lower alkyl-amino-lower alkyl group, a lower alkyleneamino-lower alkyl group, a monoaza, monooxa or monothia-lower alkyleneamino-lower alk * yl group, where in heterocyclic radicals 2 heteroatoms are separated from one another by at least 2 carbon atoms, represents an R lower alkyl group or an R group, a ■ a and R, for a hydrogen atom, a lower alkyl group, a R represents a lower alkyl group or a lower alkanoyl group, a 23 · Compounds of the formula I according to claim 21, in which Ph, R., Rp, R, and R ^ the meaning given in claim 22 have and R "also stands for a mono-lower alkyl-amino group stands. 24. Compounds of the formula (Ia) where R 'is a hydroxy, mercapto, amino, dimethylamino, Methyl, methoxymethyl, chloromethyl, dimethylaminomethyl, Piperidinomethyl, benzyl, phenyl, 4-chlorophenyl, 4-trifluoromethylphenyl, 3-nitrophenyl or 4-nitrophenyl group stands. 109839/1802 25. Compounds of formula Ia according to claim 24, wherein Rp has the meaning given in claim 24 and also represents a methylamino or 4-methoxyphenyl group. 26. Compounds of formula Ia according to claim 24, wherein R «is a methyl, methylamino or piperid inotnethylgruppe represents. 27 • 3-methyl-4,5-dihydro-1H-2,4-benzodiazepine. 28. 3-Benzyl-4,5-dihydro-1H-2,4-benzodiazepine. 29 x 3- (4-chlorophenyl) -4,5-dihydro-1 H-2,4-benzodiazepine. 30. 3- (4-Nitrophenyl) -4,5-dihydro-1H-2,4-benzodiazepine. 31. 3- (3-Nitrophenyl) -4,5-dihydro-1H-2,4-benzodiazepine. 32. 3- (4-Trifluoromethylphenyl) -4,5-dihydro-1H-2,4-benzodiazepln. 33 • 3-methoxymethyl-4,5-dihydro-1H-2,4-benzodiazepine. 34 · 3-Hydroxy-4,5-dihydro -IH -2,4-benzodiazepine. 109839/1802 35 x 3-chloromethyl-4,5-dlhydro-1H-2,4-benzodiazepine. 36. 3-Dimethylamino-methyl-4,5-dihydro-1H-2,4-benzodiazepine. 37. 3-Amino-4,5-dihydΓO-1H-2,4-benzodiazepine. 38. 3-Dimethylamino-4,5-dihydro-1H-2,4-benzodiazepine. 39. 3-Mercapto-4,5-dihydro-1H-2,4-benzodiazepine. 40. 3-piperidinomethyl-4,5-dihydro-1H-2,4-benzodiazepine. 41. 3-Phenyl-4,5-dihydro-1H-2,4-benzodiazepine. 42. 3- (4-Methoxyphenyl) -4 _i 5-dihydro-1 H-2,4-benzodiazepine. 43 • 3-methylamino-4,5-dihydro-1H-2,4-benzodiazepine. 44. The compounds of claims 21, 22, 24 and 27-41 in free form. 45 · The compounds of claims 21, 22, 24 and 27-41 in the form of their acid addition salts. 109839/1802 46. The compounds of claims 21, 22, 24 and
27-41 in the form of their pharmaceutically acceptable acid addition salts. 4γ. The compounds of claims 23, 25, 26 and 42 in free form. 48. The compounds of claims 23, 25, 26 and 42 in the form of their acid addition salts. M. 49. The compounds of claims 23, 25, 26 and 42 in the form of their pharmaceutically acceptable acid addition salts. 50. The compound of claim 43 in free form. 51. The compound of claim 43 in the form of its acid addition salts . 52. The compound of claim 43 in the form of their
pharmaceutically acceptable acid addition salts. 53 · N-oxides of compounds of claims 21 and 22. 54. N-oxides of compounds of claim 23. 10983 9/180 2 55 · Quaternary derivatives of compounds of the claim 21. 56. Lower alkyl quaternary derivatives of compounds of claim 22. 57. Lower alkyl quaternary derivatives of compounds of claim 23. 58. The new compounds described in Examples 1-11. 59. The new compounds described in Examples 12-14. 60. Pharmaceutical preparations, characterized by a content of a compound of claims 21, 22, 24, 27-31, 44, 46, 53, 55 and 56. 61. Pharmaceutical preparations, characterized by a content of a compound of claims 23 * 25 * 26, 42, 47, 49, 54 and 57. 62. Pharmaceutical preparations, characterized by a content of a compound of claims 43, 50 and 52. 109839/1802 63. The pharmaceutical described in Example 16 Preparations. t> 4. The pharmaceutical described in Example 17 Preparations. 109839/1802