NO150159B - ANALOGY PROCEDURE FOR THE PREPARATION OF NEW PHARMACOLOGICAL ACTIVITIES 1,3,4,14B-TETRAHYDRO-2H, 10H-PYRAZINO (1,2A) -PYRROLO (2,1-C) (1,4) BENZODIAZEPINE - Google Patents

Description

The invention relates to an analogous process for the production of new 1,3,4,14b-tetrahydro-2H,10H-pyrazino-t1,2-a/pyrrolo/"2,1-c7/"1,47 benzodiazepines with the general formula I

in which means hydrogen, lower alkyl, halogen or trifluoromethyl, R2 means alkyl, lower alkenyl, lower alkynyl or (cyclopropyl, hydroxy, lower carboxy or phenyl)-lower alkyl, alkanoyl-oxylower alkyl or adamantoyl-oxy lower alkyl, C2H2nmeans the lower alkyl which separates the two nitrogen atoms by 2 or 3 carbon atoms, and R., and R.sup. means hydrogen or lower alkyl,

as well as 2-N-oxides, 2-lower alkyl quaternary ammonium derivatives of compounds in which R2 is different from hydrogen, as well as their salts.

A lower alkenyl or lower alkynyl group

R2 is preferably one such, in which the bond is several times separated from the nitrogen atom by at least two carbon atoms, e.g. allyl, 2- or 3-butenyl or 3-methyl-2-butenyl, propargyl, 2- or 3-butynyl.

A (hydroxy or carbaloxy)-lower alkyl group R2 is preferably one in which the heteroatom (0) is separated from the ring nitrogen atom by at least 2 carbon atoms, e.g. 2-(hydroxy, carbomethoxy or carbethoxy)-ethyl, or -propyl, 3-hydroxy-propyl or (carbomethoxy or carbethoxy)-methyl.

The symbol R-2 preferably means hydrogen or

e.g. methyl or ethyl, fluorine, chlorine, bromine or trifluoromethyl.

A lower alkylene group cnH2ner specially ethylene,

but also 1,2- or 1,3-propylene.

The said acyl derivatives of compound of formula

I is derived from those in which R2 is (hydroxy)-lower alkyl. These derivatives are thus esters which are derived from lower or higher aliphatic acids, e.g. acetic, propionic, butyric, pivalic, decanoic, palmitic, or adamantyl carboxylic acid.

The N-oxides or lower alkyl quaternary derivatives are derived from compounds of formula I, in which R2 is not hydrogen,

and in which only the nitrogen atom is functionalized in the 2-position. The anions or quaternary compounds and acid addition salts are preferably approx. therapeutically usable acids, e.g. of the acids mentioned below.

The term "lower" defined in the above or following mentioned organic residues or compounds, are those with a maximum of 7, preferably up to 1 4, primarily with 1

or 2 carbon atoms. The term "higher" defines residues or compounds with 8 to 20, preferably 8 to 16, carbon atoms.

The compounds according to the invention show valuable pharmacological properties, primarily antidepressant effects. This can be demonstrated in animal experiments, preferably on mammals, such as mice, rats, guinea pigs and monkeys as test subjects. The new compounds can be administered enterally or parenterally, preferably orally, subcutaneously intravenously or intraperitoneally, e.g. by means of gelatin capsules, or in the form of starch-containing suspensions or aqueous solutions. The dose used may range from about 0.01 to 100 mg/kg/day, preferably about 0.05 to 5 mg/kg/day, especially about 0.1 to 0.5 mg/kg/day. The antidepressant properties can be demonstrated in mice by the reversal of clonidine analgesia. In this test system, compounds prepared according to the invention are administered as aqueous solutions orally or intraperitoneally to groups of at least 10 male mice and 30 minutes later are incubated on the 0.1 mg/kg clonidine. After 20 minutes, the animals are injected with 3.75 mg/kg of phenyl-p-benzoquinone intraperitoneally,

and 5-15 minutes after the injection, the number of animals that recover is determined. Each animal that moves is designated as positive, and the Ed,, ^ value is determined for the combination of the tested active substance and clonidine by Berkson's Logit method from the number of positively responding animals.

The compounds produced according to the invention can therefore be used as antidepressants, e.g. in the treatment or management of mental depression. They can also be used as intermediates for the production of other valuable products, especially pharmacologically active preparations.

Of particular note are the compounds of the general formula II

wherein R,, means hydrogen, lower alkyl, lower alkenyl, lower alkynyl, hydroxy-lower alkyl or cycloalkyl-lower alkyl with 3 to 7 ring members and Rg means hydrogen, halogen, or trifluoromethyl, as well as their therapeutically useful acid addition salts.

Particularly preferred are the compounds of the general formula II, in which R 1 - means alkyl, alkenyl, alkynyl or hydroxyalkyl with each time up to 4 carbon atoms or cyclopropylmethyl, and R 6 means fluorine or chlorine, preferably in the 7-position, as well as their therapeutically applicable acid addition alters.

The compounds produced according to the invention can be produced according to methods known per se in that a compound of the general formula III in which X means lower alkylene, mono- or dioxo-lower alkylene, which separates the two nitrogen atoms by 2 or 3 carbon atoms,

and in which oxo is bound to the carbon atom r adjacent to the nitrogen atom and Y means oxo or two hydrogen atoms, with the precaution that at least one oxo group is present in X or Y, is reduced and, if desired, a compound of formula I is converted into another compound according to the invention.

The reduction of the aforementioned lactams of formula III is preferably carried out with simple hydrides or complex light metal hydrides, such as boranes or alane, primarily with alkali metal aluminum hydrides or alkali metal avereal oxyhydrides,

e.g. lithium aluminum hydride, sodium tri-t-butoxy aluminum hydride or sodium bis-(2-methoxyethoxy) aluminum hydride.

The starting materials can be prepared according to the methods mentioned for their known analogues or as shown in the examples.

Thus, the starting materials can be prepared by reaction of a corresponding compound with formula III in which X means two hydrogen atoms, each of which is bound to another nitrogen atom with reactive derivatives of corresponding glycols, glycolic acid or dicarboxylic acids, such as their lower alkyl esters, halides or anhydrides, or with reactive esters of the said glycols or glycolic acid derivatives, e.g. esters of hydrohalic acid or aromatic carboxylic acids such as 1,2-dibromoethane or propane, bromoacetic acid ethyl esters or propyl ester, tosyloxyacetic acid ethyl ester, oxalic acid diethyl ester or malonic acid diethyl ester, oxalic acid hemi-ethyl ester chloride, oxalyl bichloride or malonic anhydride. The aforementioned advantages of formula III corresponding to the starting substances can be obtained analogously to II Farmaco ED. Sc, 24, Phase. 3, page 276 or as shown in the examples.

The obtained compounds according to the invention can

if desired or necessary according to methods known in and of themselves are transferred into each other. Thus allows e.g. formed compounds of formula I in which R 2 means hydrogen or their alkali metal salts, e.g. sodium salts by reaction with reactive esters of unsubstituted or correspondingly substituted aliphatic or araliphatic alcohols with methanol, ethanol, allyl alcohol, propargyl alcohol or benzyl alcohol, depending on the molar amount of alkylating agent used are transferred in the corresponding N-substituted compounds resp. to the quaternary ammonium derivatives. Reactive esters are obtained by esterification of the alcohols with strong inorganic or organic acids, primarily with a hydrohalic acid, e.g. hydrogen chloride, hydrobromic or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or m-bromobenzenesulfonic acid.

Conversely, N-alkylated compounds formed can re-

are formed in N-substituted compounds, e.g. by catalytic hydrogenolysis of N-ben.zylf orcompounds. One reacts N-lower alkyl, N-lower alkenyl or N-(CF^-phenyl) derivatives with halogen-formic acid lower alkyl esters, e.g. chloroformic acid ethyl ester, so

N-acyl derivatives are obtained. The latter can be transferred to N-unsubstituted compounds in which R2 is hydrogen, e.g. with aqueous bases,

e.g. with alkali metal hydroxide solutions. Esters can be prepared by reacting the compound of formula I in which R2 is hydroxy-lower alkyl with corresponding acid derivatives, e.g. halides. Formed esters can be hydrolysed in the same way as discussed for the N-acyl derivatives. Unsaturated compounds formed

e.g. wherein R 2 means lower alkenyl or lower alkynyl, can be hydrogenated as discussed above with catalytically activated hydrogen. Formed esters can, by reduction with complex light metal hydrides, e.g. lithium aluminum hydride is converted to the corresponding alcohols.

Formed compounds of formula I in which R4 is hydrogen can be converted into the corresponding lower alkyl derivatives by metallization with reactive organic metal compounds, e.g. n-butyllithium or lithium diisopropylamide and reaction with reactive ester of lower alkanols.

Formed tertiary nitrogen compounds in which R ?

does not mean hydrogen, can be transferred in their N-oxides, e.g.

with hydrogen peroxide or with organic peracids, such as lower peralkanoic acids or perbenzoic acid, e.g. peracetic acid or m-chloro-perbenzoic acid, preferably at or below room temperature with the latter, or at temperatures up to 100°C with dilute hydrogen peroxide solution in the presence of lower alkanoic acids, e.g. acetic acid. Care must then be taken, especially with the aforementioned peracids, to avoid overoxidation due to excessively long reaction times.

Finally, the compounds according to the invention can be obtained

in the form of free bases or as salts. A formed free base can be transferred to the corresponding acid addition salts, preferably with acids which give therapeutically useful acid addition salts or with anion exchangers. Formed salts can be converted into the corresponding free bases. e.g. by treatment with a stronger base, such as a metal hydroxide or ammonium hydroxide, basic salt or a cation exchanger, e.g. with an alkali metal hydroxide or carbonate. Acids that give therapeutically useful acid addition salts are e.g. inorganic acids such as hydrohalic acid, e.g. hydrochloric acid or hydrobromic acid, or sulfuric acid, phosphoric acid, salpotersylic or perchloric acid, or organic acids such as aliphatic or aromatic carboxylic or sulphonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, pamoic acid, nicotinic acid , methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylsulfamic acid, or ascorbic acid. These or other salts e.g. picrates, can also be used in the purification of free base. The bases are transferred into their salts and the salts are separated and the bases are released from the salts.

Due to the close relationship between the new compounds in free form and in the form of their salts, in the foregoing and the following, free compounds and salts are also possibly

to understand the corresponding salts resp. free connections.

Formed isomeric mixtures of compounds, e.g. those with formula I to III, can be separated by methods known per se, e.g. by fractional distillation, crystallization and/or chromatography in the individual isomers. Racemic products can be divided into the optical antipodes, e.g. aqueous separation of their diastereomeric salts, e.g. fractional crystallization of d- or 1-tartrates.

The above-mentioned reactions are carried out according to and

known methods in the presence or absence of diluents, preferably in those that are inert to the reagents, and dissolve these catalysts, condensation or other above-mentioned agents, and/or in an inert atmosphere under cooling at room temperature or at elevated temperatures, preferably at boiling point of the solvent used at normal or

high pressure.

The invention also relates to modifications of preventive methods according to which an intermediate product formed in one or another step of the method is used as starting material and the remaining method step is carried out or according to which a starting material is formed during the reaction conditions or in which a starting material is used in the form of a salt or optically pure antipodes.

In the methods according to the invention, such starting substances are preferably used which belong to the above particularly valuable compounds mentioned, especially those with the formula

II.

The pharmacologically usable compounds according to the invention can be used for the preparation of pharmaceutical preparations containing an effective amount of the active substance, together or in admixture with carriers, which are suitable for enteral or parenteral administration.

The invention shall be explained in more detail by means of

some examples. The temperatures are indicated in degrees Celsius, and indications above parts relate to parts by weight. If nothing else is specified, evaporation of the solvent is carried out under reduced pressure, e.g. between about 15 and 100 mm Hg.

Example 1

A suspension of 12.8 g of 2-methyl-3,4-dioxo-l,3,4,14b-tetrahydro-2H,lOH-pyrazino^/1,2-a/pyrrolo/~2 ,l-c7benzodiazepine in 46 0 ml of tetrahydrofuran is mixed with 200 ml of 1-molar diborane in tetrahydrofuran while stirring and cooling with ice. The mixture is boiled for 1 hour under reflux, cooled again and mixed with 25 ml of acetic acid. The reaction mixture is evaporated, the residue is taken up in 50 ml of a 30% aqueous sodium hydroxide solution and the mixture is extracted with methylene chloride. The extract is dried, evaporated, the residue is dissolved in diethyl ether, the solution is filtered and the filtrate is evaporated. 2-methyl-1,3,4,14b-tetrahydro-2H10H-pyrazino[1,2-a7pyrrolo^2,1-c7/1,4-7benzodiazepine is obtained.

9.7 g of the latter compound are dissolved in a minimal amount of isopropanol and the solution is acidified with a concentrated solution of 4.45 g of maleic acid in isopropanol. The precipitate formed is separated and recrystallized from methanol diethyl ether. The corresponding mono-maleate is obtained, which melts at 176-178°C.

You can also reduce 2.35 g of the above-mentioned dioxo starting material in 50 ml of methylene chloride with 20 ml of 1-molar alane in triethylamine and then evaporate the mixture. The residue is triturated with acetic acid ethyl ester-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1:9). The eluate is evaporated and the residue acidified as mentioned above. You get the somewhat purer maleate, which melts at 180-182°C.

The starting material is prepared as follows: A mixture of 54 g of potassium phthalimide, 50 g of o-nitrobenzyl chloride and 120 ml of dimethylformamide is boiled for 3 hours under reflux and poured with stirring into 900 ml of ice water. After 30 minutes it is filtered and the residue is washed with water. N-o-nitrobenzyl-phthalimide is obtained which melts at 190-209°C.

A mixture of 70 g of the latter compound, 14.6 g of hydrazine hydrate and 600 ml of ethanol is boiled for 4 hours under reflux and mixed with 50 ml of conc. hydrochloric acid. After 30 minutes, the reaction mixture is cooled to room temperature, filtered and the residue is washed with water. The filtrate is concentrated, the aqueous concentrate is filtered and the filtrate is made basic with 3-normal aqueous sodium hydroxide solution. The mixture is extracted with diethyl ether, the extract is dried and evaporated. One gets o-nitro-benzylamine.

A solution of 7.6 of the latter compound

in 25 ml of glacial acetic acid is mixed with 6.6 g of 2,5-dimethoxy-tetrahydrofuran and the mixture is boiled for one hour under reflux. The reaction mixture is evaporated, the residue is poured into ice water and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. The residue is taken up in diethyl ether, the solution is decoloured with activated carbon, filtered and evaporated. 1-(o-nitrobenzyl)-pyrrole is obtained.

A mixture of 13.4 2 g of the latter compound

140 ml of diethyl ether and 6.85 g of chloroacetonitrile are cooled in an ice-salt bath and saturated with chlorine hydrogen gas while stirring. The saturated mixture is stirred at room temperature overnight, filtered and the residue suspended in 100 ml of water. The suspension is extracted three times with 100 ml of acetic acid ethyl ester, the combined extracts are heated with stirring on a steam bath to dissolve the separated material. The solution is dried and evaporated. One obtains 1-o-nitrobenzyl-2-chloroacetyl-pyrrole.

A solution of 16.2 g of the latter compound in 450 ml of ethanol is mixed with 14.1 g of N-methyl-benzylamine, and the mixture is refluxed for 3 hours. The reaction mixture is evaporated, the residue is taken up in methylene chloride, the solution is washed with saturated aqueous sodium carbonate solution, dried, filtered and evaporated. The residue is triturated with diethyl ether. 1-(o-nitrobenzyl)-2-(N-methyl-N-benzylaminoacetyl)-pyrrole is obtained.

A solution of 3 g of the latter compound in 30 ml of acetic acid is hydrogenated until absorption of the theoretical amount of hydrogen over 100 mg of platinum oxide at 2.7 atmospheres and room temperature. The mixture is filtered, the filtrate is evaporated, the residue is taken up in methylene chloride-diethyl ether and the solution is washed with saturated aqueous sodium bicarbonate solution. The solution is dried, evaporated and the residue is chromatographed on 30 g of silica gel and eluted with methanol-chloroform (1:9). One obtains 11-(N-methyl-N-benzylamino-methyl)-10,11-dihydro-5H-pyrrolo^~2,1-c/ £~ 1,4/benzodiazepine, which melts at 147-149°C.

A solution of 500 mg of the latter compound in 35 ml of ethanol and 5 ml of glacial acetic acid is hydrogenated over 250 mg of a 5% palladium-on-charcoal catalyst for 7 hours at 40°C and 2.7 atmospheres. The mixture is filtered, the filtrate is evaporated and the residue is taken up in methylene chloride. The solution is washed with saturated aqueous sodium carbonate solution, the aqueous phase is extracted with methylene chloride and the combined organic solutions are dried and evaporated. 11-(N-methylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c7Z<_>1'17benzodiazepine is obtained.

A mixture of 300 mg of the latter compound and

232 mg of oxalic acid diethyl ester are heated slowly, during 45 minutes to 140°C and during 15 minutes to 180°C. The mixture is kept. 30 minutes at the latter temperature, then cooled, diluted with benzene, chromatographed on silica gel and eluted with methanol-chloroform (1:9). One obtains 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a7pyrrolo/2,l- c/ £ 1,^benzodiazepine, which melts at 178-179°C.

Example 2

A suspension of 315 ml of 7-chloro-2-methyl-3,4-dioxo-1,3,4,14brtetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo/~2,1-g7Z~l /i/ Benzodiazepine in 20 ml of tetrahydrofuran is mixed with 6 ml of 1-molar diborane in tetrahydrofuran while stirring and ice-cooling. The mixture is boiled for 2 hours under reflux, cooled again and

mixed with 1 ml of 6-normal hydrochloric acid. The reaction mixture is evaporated, the residue is taken up in 5 ml of a 30% aqueous sodium hydroxide solution and the mixture is extracted with methylene chloride. The extract is dried, evaporated, the residue is dissolved in diethyl ether and the solution is mixed with 97 mg of maleic acid in a minimal amount of acetone. The formed precipitate is separated. 7-Chloro-2-methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/"1,2-a7pyrrolo/~2,1- c/ C1,V benzodiazepine mono-maleate is obtained, which melts at 200-202°C.

The starting material is prepared as follows: A mixture

of 9.4 g of potassium phthalimide, 31.35 g of p-chloro-o-nitro-benzyl chloride and 75 ml of dimethylformamide are boiled for 3 hours under reflux and poured

in 180 ml of ice water while stirring. After 30 minutes, the mixture is filtered and the residue is washed with water. N-p-chloro-o-nitrobenzyl-phthalimide is obtained, which melts at 190-194°C.

A mixture of 29.6 g of the latter compound,

5.5 g of hydrazine hydrate and 300 ml of ethanol are boiled for 4 hours under reflux and then mixed with 21 ml of conc. hydrogen chloride

acid. After 30 minutes, the mixture is cooled to room temperature, filtered and the residue is washed with water. The filtrate is concentrated,

the aqueous concentrate is filtered and the filtrate is made basic with 3-normal aqueous sodium hydroxide solution. It is extracted with diethyl ether, the extract is dried and evaporated. One obtains p-chloro-o-nitro-benzylamine.

A solution of 42.8 g of the latter compound

in 400 ml of glacial acetic acid is mixed with 30.4 g of 2,5-dimethoxy-tetrahydrofuran and the mixture is boiled for one hour under reflux. The mixture is evaporated, the residue is poured into ice water and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated. The residue is taken up in diethyl ether, the solution is decoloured with activated carbon, filtered and evaporated. 1-(p-chloro-o-nitro-benzyl)-pyrrole is obtained.

A mixture of 4.26 g of the latter compound,

20 ml of diethyl ether and 1.46 g of chloroacetonitrile are cooled in an ice-salt bath and saturated with chlorine hydrogen gas while stirring. The saturated mixture is stirred at room temperature overnight, filtered and the residue suspended in 50 ml of water. The suspension is extracted three times with 50 ml of ethyl acetate. The extract is dried and evaporated. 1-(p-chloro-o-nitrobenzyl)-2-chloroacetyl-pyrrole is obtained.

A suspension of 56.5 g of the latter compound

in 960 ml of ethanol is mixed with 21.8 g of N-methyl-benzylamine and 18.2 g of triethylamine and the mixture is boiled for 6 hours under reflux. The reaction mixture is evaporated, the residue is taken up in chloroform, the solution is washed with saturated aqueous sodium carbonate solution, dried, filtered and evaporated. The residue is dissolved in diethyl ether, the solution is filtered, the filtrate is evaporated and the residue is triturated with methanol. 1-(p-chloro-o-nitrobenzyl)-2-(N-methyl-N-benzylamino-acetyl)-pyrrole is obtained, which melts at 90-93°C.

A solution of 1 g of the latter compound i

30 ml of benzene are mixed with 0.545 g of chloroformic acid ethyl ester and the mixture is boiled for 4 hours under reflux. The reaction mixture is diluted with diethyl ether, washed with 1-N hydrochloric acid and saturated aqueous sodium chloride solution, dried and evaporated.

1-(p-chloro-o-nitrobenzyl)-2-(N-methyl-N-carbethoxyamino-acetyl)-pyrrole is obtained.

A solution of 1.43 g of the latter compound i

20 ml of tetrahydrofuran are mixed dropwise with 15 ml of titanium trichloride and the mixture is stirred overnight at room temperature.

The reaction mixture is made basic with 60 ml of a 10% aqueous ammonia solution, filtered and the residue washed with methylene chloride. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried and evaporated. One obtains 8-chloro-1-(N-methyl-N-carbethoxyaminomethyl-5H-pyrrolo-/2,1- c/l 1ȣ7 benzodiazepine).

A solution of 430 mg of the latter compound

1 10 ml of ethanol are mixed with 760 mg of sodium hydride and the mixture is stirred overnight at room temperature. The reaction mixture is acidified with 6-normal hydrochloric acid, diluted with methylene chloride, washed with water and saturated aqueous sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel and eluted with acetic acid ethyl ester-methylene chloride (1:19). 8-Chloro-11-(N-methyl-N-carbethoxyamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c7/1,4-7 benzodiazepine is obtained.

A mixture of 200 mg of the latter compound,

10 ml of ethanol and 3 ml of 20% aqueous sodium hydroxide solution are boiled for 3 days under reflux and evaporated. The residue is taken up in water, the mixture is extracted with methylene chloride, the extract is dried and evaporated. 8-chloro-11-(N-methylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c7/_1,4_7benzodiazepine is obtained.

A mixture of 960 mg of the latter compound

and 600 mg of oxalic acid diethyl ester are slowly heated over 45 minutes to 140°C and over 15 minutes to 180°C. The reaction mixture is kept at the latter temperature for 30 minutes, cooled, evaporated, the residue is washed with diethyl ether and triturated with acetic acid ethyl ester. One obtains 7-chloro-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino /~1,2-α7pyrrolo/~2,1-g7/-1, A /benzodiazepine, which melts at 203°C.

Example 3

A solution of 1.9 g of 2-methyl-1,3,4,14b-tetrahydro-2H-10H-pyrazino^~1,2-α7pyrrolo/~2,1-c7Z<_>1'i/benzodiazepine in 50 ml of benzene is mixed with 2.14 g of chloroformate ethyl ester and the mixture is boiled for 3 days under reflux. The reaction mixture is diluted with diethyl ether, washed with 1-normal hydrochloric acid and with a saturated aqueous solution of sodium chloride and sodium bicarbonate, dried and evaporated. One obtains 2-carbethoxy-1,3,4,14b-tetrahydro-2H-10H-pyrazino(/~1,2-α7pyrrolo/2,1-c//_1,4_7benzodiazepine, which in the NMR spectrum gives a band at 8.55 (t), 6.60 (m), 5.65 (q) and 3.90 (d)ppm and in the mass spectrum a molecular ion of 311.

Example 4

A solution of 4.8 g of 1,3,4,14b-tetrahydro-2H-10H-pyrazino/~l,2-a7pyrrolo/~2,l-c7/~l/4/benzodiazepine in 20 ml of dimethylformamide and 2.44g triethylamine is mixed with 2.91 g of allyl bromide with stirring, dropwise. After one hour, the reaction mixture is diluted with diethyl ether, washed with water and saturated aqueous sodium chloride solution and the aqueous phase is extracted with diethyl ether. The combined organic solutions are washed with saturated aqueous sodium bicarbonate solution, dried and the residue triturated with diethyl ether» 2-allyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a7pyrrolo/ 2,1- g7/~l r^benzodiazepine, which melts at 130-132°C.

In an analogous way, a) 2-(3-methyl-2-butenyl)-

b) 2-propargyl-; c) 2-cyclopropylmethyl-; d) 2-carbomethoxymethyl and e) 2-phenylethyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/

pyrroloi/<_>2,l-c7/~1,47benzodiazepine, starting from equivalent amounts of corresponding bromides. The compounds a) to d) according to the invention are transferred in their below-mentioned acid addition salts according to examples 1 and 2 and recrystallized from the indicated solvents. The salts melt as follows a) maleate 152-153°C (after recrystallization from isopropanol); b) fumarate 138-140°C (ethanol); c) maleate, 189-190°C (isopropanol);

d) maleate, 162-164°C (isopropanol-diethyl ether) and the free base

e) melts at 132-134°C after recrystallization from isopropanol.

Example 5

A solution of 780 mg of 2-carbomethoxymethyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~l,2-α7pyrrolo/"2 ,l- c/ l~ l,4_7ben,zodiazepine in 20 ml tetrahydrofuran is mixed with 150 mg of lithium aluminum hydride and the mixture is stirred for 2 days at room temperature.The reaction mixture is then mixed with 0.15 ml of water, 0.15 ml

of a 15% aqueous sodium hydroxide solution and with 0.15 ml of water in this order, filtered and the filtrate evaporated. Mon

gives 2-(2-hydroxy-ethyl)-1,3,4,14b-tetrahydro-2H,10H-pyrazino £~ 1, 2-a/pyrrolol/-2 , l- c/ l~ l, 4_7benzodiazepine, which is converted into its monofumarate. It melts at 187-189°C during decomposition.

Example 6

A solution of 1.16 g of 2-allyl-l,3,4,14b-tetrahydro-2H,lOH-pyrazino/-!,2-a7pyrrolo/~2,l-c// 1,4_7benzodiazepine 1 25 ml of ethanol is hydrogenated over 40 mg platinum oxide 2 \ hours at room temperature and atmospheric pressure. The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up in isopropanol and the solution is acidified with maleic acid. One obtains 2-n-propyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~l,2-a/pyrrolo/ 2 ,l- c//_~ l,4_7benzodiazepine maleate, which melts at 157-159°C.

2-(3-methyl-butyl)-1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a7pyrrolo[2,1-c/fl,47 benzodiazepine- maleate. It melts at 146-147°C.

Example 7

According to the methods shown in examples 1 and 2, 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/1,2-α7pyrroloi/ 1,2-07/ 1,4_7benzodiazepine reduced with diborane to 2,12-dimethyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/_ 1, 2-a/pyrrolo/~2 , l-c7 /~l, ^/benzodiazepine. Its mono-maleate melts at 173-175°C.

The starting material is prepared as follows: A mixture of 170 mg of phosphorus oxychloride and 100 ml of dimethylformamide is stirred at room temperature for 30 minutes and then mixed dropwise

show with a solution of 281 mg of 2-methyl-3,4-dioxo-l,3,4,^pha-te trahydro-2H, 10H-pyrazino,/_l, 2-a7pyrrolo/~2 , l-c7/~ l, ^benzodiazepine in 5 ml of methylene chloride. After 30 minutes, the mixture is boiled for a further 30 minutes under reflux and cooled to room temperature. The reaction mixture is mixed with 1.5 g of sodium acetate in 5 ml of water, stirred for 30 minutes and the organic layer is separated. It is washed with water and with 5% aqueous sodium bicarbonate solution, dried, evaporated and the residue triturated with diethyl ether. One obtains 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-α7pyrrolo/2 ,1-c7/1,4_7benzodiazepine, which melts at 300-302°C.

Example 8

A mixture of 500 mg of 2-methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino/~l, 2-a7pyrrolo(/~2 , l-c7/ 1,4_7benzodiazepine, 10 ml of methylene chloride and 0 .5 ml of methyl iodide is stirred at room temperature for one hour. The reaction mixture is filtered and the residue is washed with methylene chloride. This gives 2,2-dimethyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/ pyrrolo/~2 , l- c/ l~ l, 4_7benzodiazepine iodide, which melts during decomposition at 258-260°C.

Example 9

A solution of 300 mg of 2-methyl-1,3,4,14b-tetrahydro-2H,1OH-pyrazino/1,2-a/pyrrolo/~2,1-c// 1,4/benzodiazepine in 10 ml of methylene chloride and the mixture stirred for 5 hours at room temperature. The reaction mixture is shaken with 5 ml of 10% aqueous sodium sulphite solution, washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. 2-methyl-1,3,4,14b-tetrahydro-2H,10H,pyrazino/~l,2-a/pyrrolo/~2 ,l- c//~l,4_7benzodiazepin-2-N is obtained -oxide, which melts at 143-145°C.

Example 10

A solution of 140 mg of 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo/~2, l- c/ £~ l , 4_7benzodiazepine in 5 ml of tetrahydrofuran is mixed with stirring and cooling with ice with 2 ml of 1-molar diborane in tetrahydrofuran. The reaction mixture is stirred overnight at room temperature and then boiled for 4 hours under reflux. After cooling to room temperature, mix with 0.5 ml of glacial acetic acid, evaporate and make the residue basic with 3-normal aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is taken up in diethyl ether. The solution is filtered and the filtrate is evaporated. 2-methyl-1,3,4,14b-tetrahydro-2H,1OH-pyrazino/-! .

The starting material is prepared as follows: A solution of 16 g of oxalyl chloride in 150 ml of diethyl ether is mixed with stirring and cooling to -50°C (solid carbon dioxide-acetone bath) with a solution of 7.36 g of pyrrole in 30 ml of diethyl ether, so that the internal temperature of the reaction mixture remains at -50°C. After completion of the addition, it is stirred for one hour and then slowly poured into the solution of 27.5 g of sarcosine ethyl ester in

150 ml of diethyl ether. The precipitate formed is filtered, extracted re-

nice with methylene chloride and the extract is evaporated. N-(2-pyrrylglyoxyl)-sarcosine ethyl ester is obtained, which melts at 114°C.

A solution of 5.5 g of the latter compound

in 30 ml of dimethylformamide is mixed with 1.07 g of a 50% sodium hydride suspension in mineral oil and mixed with 20 ml of dimethylformamide. The mixture is heated for one hour at 60-70°C, cooled to room temperature and mixed with a solution of 5 g of o-nitrobenzyl bromide in 20 ml of dimethylformamide. The reaction mixture is stirred for one hour at 45-50°C, cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried, evaporated, and the residue triturated with diethyl ether. N-(1-o-nitrobenzyl-2-pyrrylglyoxyl)-sarcosine ethyl ester is obtained, which melts at 105-108°C.

A solution of 3 g of the latter compound i

30 ml of acetic acid ethyl ester are hydrogenated over 100 mg of platinum oxide at 3 atmospheres until absorption of 3 molar equivalents of hydrogen. The mixture is mixed with 1.5 ml of glacial acetic acid and the hydrogenation is terminated at 3 atmospheres and 40°C. The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up in methylene chloride and purified by chromatography on silica gel. One elutes with 10% methanol-methylene chloride and N-(1,2-dihydro-5H-pyrrolol/~2,1-c7/~1,4,7benzo-diazepin-2-yl-carbonyl)-sarcosine is obtained -ethyl ester, which melts at 147-148°C.

A suspension of 100 mg of the latter compound in 10 ml of toluene is mixed with 20 mg of sodium methoxide and the mixture is refluxed for 1 hour. The reaction mixture is cooled, filtered and evaporated. One obtains 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-α7pyrrolo(/~2 ,l-c7/ 1,4_7benzodiazepine, which melts at 165-167°C.

Example 11

A warm solution of 10 g of 2-methyl-1,3,414b-tetrahydro-2H,10H-pyrazino/~1,2-α7pyrrolo/~2 ,1-c7/~1,4_7benzodiazepine (Example 1) in 300 ml of isopropanol mixed with a warm solution of 3 g d-tartaric acid in 50 ml isopropanol. The mixture cools overnight to room temperature. The formed precipitate is filtered off and recrystallized (3 times) from aqueous ethanol until the optical rotation of the liberated base

- -25 o

is constant, namely [_ a/ =+344, 26 (c = 1 in methanol). For-

the bond is converted into mono-maleate which melts during cleavage at 190-191°C.

Using 1-tartaric acid gives the corresponding 1-antipodes, /~a/^<5>= -358.89°C, whose mono-maleate melts at 188-

189°C during decomposition.

Example 12

A solution of 800 mg of 2-methyl-5-oxo-1,2,3,4,515b-hexahydro-llH-/~l, 4/diazepino/~l, 2-a7pyrrolo(/~2, l- c7£~ l, 4/ benzodiazepine in 50 ml of tetrahydrofuran is mixed with 6.2 ml of 1-molar diborane in tetrahydrofuran. The mixture is boiled for 2 hours under reflux, cooled and stirred overnight at room temperature.

trip. The reaction mixture is mixed with 2 ml of glacial acetic acid, evaporated and the residue made basic with 3-normal aqueous sodium hydroxide solution. The resulting mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in a minimal amount of methylene chloride. The solution is chromatographed on silica gel and eluted with 10% methanol-methylene chloride. One obtains 2-methyl-1,2,3,4,5,15b-hexahydro-llH-/-l, 4_7diazepino/~l, 2-a/pyrrolo £~ 2 , l- c/ £ 1, 4_7ben;zodiazepine of formula I, wherein R^=R^=R^=R^=H,

R^= methyl, Ph = 1,2-phenylene and n = 3. The product is converted in

its monofumarate, which melts at 174-175°C.

The starting material is prepared as follows: A solution

of 1.5 g of 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo/~2,1-c7 l~1,47benzodiazepine (Example 1), in 7.5 ml acrylic acid methyl ester is stirred for 24 hours at room temperature and the excess reagent is evaporated. N-methyl-N-(1,2-dihydro-5H-pyrrolo/ 2,1-07/ 1,47benzodiazepine-2-yl-methylene)-g-alanine methyl ester is obtained as an oil, which is chromatographed on silica gel and eluted with 2% methanol-methylene chloride.

A solution of 1 g of the latter compound i

20 ml of tetrahydrofuran is added to a stirred solution of 475 mg of 2,2,6,6-tetramethyl-piperidine (which has been freshly distilled over calcium

hydride) in 10 ml of tetrahydrofuran ag is then mixed with 1.37 ml of 2.45 molar n-butyllithium in hexane, at -75°C. The mixture is stirred at this temperature for 30 minutes, and it is allowed to warm to 0° C. The mixture is diluted with acetic acid-water

(2:1), evaporated, the residue dissolved in methylene chloride, chromatographed on silica gel and eluted with 5% ethanol-methylene chloride. One obtains 2-methyl-5-oxo-1,2,3,4,5,15b-hexahydro-11H-/_ 1, 4_7diazepino/ 1, 2-a/pyrrolo/ 2,1-c// 1, 4_7benzodiazepine , which melts at 156-158°C.

Example 13

A solution of 2.5 g of 2-methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo/2,1-c7/~1,4_7benzodiazepine ( example 1) in 25 ml of tetrahydrofuran is mixed at room temperature with stirring in a nitrogen atmosphere with 4.5 ml of 2.45-molar n-butyl lithium in hexane. The slightly yellow solution quickly turns cherry red and the temperature rises to around 7°C. The mixture is stirred for a further 45 minutes, and then treated with methyl iodide to decolourise the solution. The reaction mixture is stirred for a further 30 minutes, then poured into 100 ml of water, and the product is extracted with diethyl ether. The extract is washed successively with water and saturated aqueous sodium chloride solution and evaporated. The oil formed as a residue is chromatographed on silica gel and eluted with 2% methane-methylene chloride. One obtains 2,10-dimethyl-1,3,4,14b-tetrahydro-2H,1OH-pyrazino/<->!,2-a/pyrrolo/_ 2,1-c/</ 1,4_7benzodiazepine which is converted into mono-maleate,

sm.p. 157°C. The same product can also be obtained according to the method in examples 1 and 10, using o-nitro-a-methyl-benzyl chloride or

- bromide.

Example 14

A solution of 2.5 g of 2-(2-hydroxyethyl)-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~l,2-α7pyrroloj/ 2 ,l-c7/~l,^benzodiazepine ( example 8) and 935 mg of triethylamine in 72 ml of tetrahydrofuran are mixed with 720 mg of acetyl chloride. The mixture is stirred for 2 hours at room temperature, evaporated and the residue extracted with methylene chloride. The extract is washed successively with water and saturated aqueous sodium chloride solution, dried, filtered and evaporated. One obtains 2-(2-acetoxyethyl)-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-α7pyrrolo/~2,1-c7Z~1,47 benzodiazepine, which is converted into its mono - fumarate. Melting point 156-158°C..(under decomposition).

In an analogous manner, the mono-fumarates of 2-J2-(n-hexano<y>lox<y>, n-decanoyloxy, n-hexadecano/loxy and 1-adamantylcarbonyloxy)-ethyl/-1,3,4,14b- tetrahydro-2H,10H-pyrazino /~1,2-a/pyrrolo/ 2,1-c// 1,4_7benzodiazepine. These compounds melt at 56-58°C, 59-61°C, 71-73°C resp. 47-50°C.

Example 15

348 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/ pyrrolo/ 2, 1- c / l 1,4/benzodiazepine to 4500 ml of tetrahydrofuran and 7410 ml of 1-molar diborane in tetrahydrofuran while cooling with ice to 18°C and stirring in a nitrogen atmosphere. The mixture is boiled for 24 hours under reflux, cooled to 5°C and mixed first with 1200 ml of glacial acetic acid and then with 900 ml of water. The solution is boiled for 24 hours under reflux, evaporated and the residue taken up in 10,500 ml of methanol. The solution is again boiled for 2 hours under reflux, evaporated, the residue is dissolved in 3000 ml of water and the pH value of the solution is adjusted with 1200 ml of 10% aqueous sodium hydroxide solution of 14. The mixture is extracted with diethyl ether, the extract is dried, filtered and evaporated. One obtains 2-methyl-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo / 2,1-c/ {_ 1,4/benzodiazepine which melts at 98-100 °C.

207 g of the latter compound are dissolved in 1280 ml abs. ethanol under reflux/filter off the solution, cool the filtrate to 28°C and mix it with 140.5 g of maleic acid in 294 ml of ethanol. The formed precipitate is separated, washed with cold ethanol and recrystallized again from ethanol. The corresponding mono-maleate is obtained, which melts at 183-185°C. The product is somewhat cleaner than that which was produced according to example 1.

The starting material is prepared as follows: A mixture of 3078 g of o-nitrobenzylamine and 2670 g of 2,5-dimethoxy-tetrahydrofuran is quickly added to 10,000 ml of glacial acetic acid while stirring at 86°C

in a nitrogen atmosphere.

The mixture is stirred for 1 1/4 hours at 95°C, cooled to 25°C and mixed with 30,000 ml of water. The reaction mixture is extracted with acetic acid ethyl ester, the extract is washed with 10% aqueous sodium hydroxide solution and with 10% aqueous sodium chloride solution, filtered and evaporated. One obtains l-(o-nitrobenzyl)-pyrrole.

A mixture of 3468 g of the latter compound,

8500 ml of tetrahydrofuran and 1290 g of chloroacetonitrile are saturated with stirring and cooling to 5-35°C for three hours with chlorine hydrogen gas. The saturated suspension is stirred for a further hour at 17°C, filtered, the residue is suspended in 1000 ml of tetrahydrofuran and filtered again. 1-o-nitrobenzyl-2-(1-imino-2-chloro-ethyl)-pyrrole hydrochloride is obtained, which melts during cleavage at 210-212°C.

A suspension of 3469 g of the latter compound

in 3500 ml of water is stirred for one hour at 80°C, then cooled to 25°C and filtered. The residue is washed with water and dried. 6,000 g of the residue is dissolved in 60,000 ml of ethanol while boiling and refluxed in a nitrogen atmosphere. The solution is filtered hot, concentrated by distilling off 36,000 ml of ethanol and cooled overnight to 25°C. The resulting suspension is filtered and the residue is dried. 1-o-nitrobenzyl-2-chloroacetyl-pyrrole is obtained, which melts at 112-114°C.

A suspension of 5112 g of the latter compound, 26,400 ml of toluene, 2445 g of N-methyl-benzylamine and 2040 g of triethylamine is stirred in a nitrogen atmosphere for 6 hours at 93°C overnight at room temperature. The reaction mixture is mixed with 20,000 ml of water, the aqueous phase is separated, the organic phase is washed with 10% aqueous sodium chloride solution and evaporated. The residue is dissolved in 20,000 ml of hot ethanol, the solution is concentrated by distilling off 2,000 ml of ethanol and stirred overnight at room temperature. The formed crystals are filtered off, washed with ethanol and dried. 1-(o-nitrobenzyl)-2-(N-methyl-N-ben:2ylamino-acetyl)-pyrrole is obtained, which melts at 103-105°C.

A solution of 300 g of the latter compound

in 3000 ml of acetic acid ethyl ester and 250 ml of glacial acetic acid is hydrogenated over 30 g of platinum oxide at room temperature and atmospheric pressure until the theoretical amount of hydrogen is absorbed. The reaction mixture is filtered, the residue is washed with acetic acid ethyl ester and the filtrate is evaporated. The residue is taken up in methylene chloride, the solution is washed with 2.5 normal aqueous sodium hydroxide solution

ning and with saturated aqueous sodium chloride solution, dried and evaporated. The residue is triturated with diethyl ether. One obtains 11-(N-methyl-N-benzylaminomethyl)-10,11-dihydro-5H-pyrrolo/~2,1-c/1,4/benzodiazepine, which melts at 151-152°C.

A solution of 142.5 g of the latter compound

in 2000 ml of toluene and 45 g of triethylamine are mixed with stirring at 10-20°C during 90 minutes with 61 g of oxalic acid hemiethyl ester chloride in 850 ml of toluene. After 4 hours, the mixture is poured into 750 ml of water, stirred for 20 minutes and the organic layer separated. It is washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried and evaporated. The residue is recrystallized from methanol. One obtains 10-ethyloxalyl-11-(N-methyl-N-benzylaminomethyl)-10,11-dihydro-5H-pyrrolo(/-2 , l-c/ /_ 1, 4/benzodiazepine, which melts at 99-101 °C. (By using larger amounts of oxalic acid hemi-ethyl ester chloride, the corresponding 3,10-bis-ethyloxalyl compound is obtained, which melts at 115-116°C. This is less soluble in isopropanol than the aforementioned compound and can be separated from concentrated solution by filtration).

A solution of 6.9 g of said 10-ethyloxalyl compound in 100 ml of ethanol and 27 ml of glacial acetic acid is hydrogenated over 1.65 g of a 5% palladium-on-charcoal catalyst at 2.7 atmospheres and 40° C for about an hour. The mixture is filtered and the filtrate is evaporated. 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H-10H-pyrazino/~1,2-a/pyrrolo/2,1-c7/~1,47benzodiazepine is obtained, which melts at 178-179°C.

Example 16

According to the method described in example 15, the following compounds of formula II are prepared, starting from equivalent amounts of corresponding starting substances:

Example 17

A solution of 2.8 g of 1,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo/~2,1-c//<_>l ,^benzodiazepine in 50 ml of tetrahydrofuran is mixed with 4 5 ml of 1-molar diborane in tetrahydrofuran while stirring and ice-cooling. The mixture is stirred overnight at room temperature, and then boiled for 4 hours under reflux. The reaction mixture is cooled to room temperature, mixed with 10 ml of glacial acetic acid, evaporated and the residue made basic with 3-normal aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in diethyl ether. The solution is filtered and the filtrate is evaporated. 1,3,4,14b-tetrahydro-2H,10H-pyrazino/1,2-§/pyrrolo/ 2,1-c?/ 1,^benzodiazepine is obtained which is identical to the product from example 3. Its monomaleate melts at 173- 175°C.

The starting material is prepared as follows: A solution of 3.34 g of 1-(o-aminobenzyl)-pyrrole (produced by catalytic hydrogenation of 1-(o-nitrobenyl)pyrrole with platinum oxide as catalyst) in 50 ml of ethanol, mix with 2.5 g glyoxylic acid ethyl ester and 1 ml glacial acetic acid. The mixture is allowed to stand for 3 hours and is then evaporated under reduced pressure. The residue is treated with isopropanol to obtain 11-carbethoxy-10,11-dihydro-5H-pyrrolo (~2,1-c7) 1,4/benzodiazepine.

A solution of 2.5 6 g of 11-carbethoxy-10,11-dihydro-5H-pyrrolo/~2,1-c// 1,47benzodiazepine in 50 ml of methylene chloride is mixed with a solution of 5.8 g of sodium bicarbonate in 50 ml water. The mixture is cooled to 10°C and mixed dropwise with vigorous stirring with a solution of 1.5 g of chloroacetone acetyl chloride in 10 ml of methylene chloride. The layers separate,

and the aqueous phase is extracted with a further 100 ml of methylene chloride. The combined methylene chloride extracts are dried over sodium sulfate, filtered, and the solvent is evaporated under reduced pressure. One obtains 11-carbethoxy-10-chloroacetyl-10,11-dihydro-5H-pyrrolo/2,1-c//1,47ben.20diazepine.

A solution of 10 g of 11-carbethoxy-10-chloroacetyl-10,11-dihydro-5H-pyrrolo/~2,1-c7/~1,4/benzodiazepine in 400 ml of ethanol is cooled to 10°C, and it is carried out for 2 hours excess ammonia. The reaction mixture is then evaporated to dryness and the residue is dissolved in 100 ml of methylene chloride. The solution is filtered off and insoluble salts are evaporated. One obtains 1,4-dioxo-1,3,4,14b-tetrahydro-2H,10H-pyrazino/~1,2-a/pyrrolo/2,1-c7/1,4_7benzodiazepine.

Comparison test:

Withdrawal of clonidine analgesia

In this test, imipramine hydrochloride is used as a comparison substance. The test method has been discussed previously. This method is based on antagonism of the clonidine blockade of phenylquinone-induced movement in mice.

The comparison tests show that the compounds obtained according to the invention have a superior antidepressant effect compared to imipramine.

Claims (1)

Analogous process for the preparation of new pharmacologically active 1,3,4,14b-tetrahydro-2H,10H-pyrazino-/l,2-a7pyrrolo/2,l-c7/l/47benzodiazepines with the general formula in which R-^ means hydrogen, lower alkyl, halogen or trifluoromethyl, R 2 means hydrogen, alkyl, lower alkenyl, lower alkynyl or (cyclopropyl, hydroxy, lower carboxy or phenyl)-lower alkyl, alkanoyl - oxy lower alkyl or adamantoyl - oxy lower alkyl, C 2 H 2 denotes the lower alkyl which separates the two nitrogen atoms with 2 or 3 carbon atoms, and R^ and R^ mean hydrogen or lower alkyl as well as the 2-N-oxides, 2-lower alkyl quaternary ammonium derivatives of compounds, in which R 2 is different from hydrogen and their salts, characterized by a compound of the general formula III in which X means lower alkylene, mono- or dioxo-lower alkylene, which separates the nitrogen atom by two or three carbon atoms and in which oxo is bonded to the carbon atoms neighboring the nitrogen atom, and Y means oxo or 2 hydrogen atoms with the condition that at least one oxo group is present in X or Y, and R^ R 2 , R^ , R 4 have the above meaning, reduce.s, and 1) when desired, with a compound, in which R 2 means alkyl, lower alkenyl, lower alkynyl, cyclopropyl lower alkyl, phenyl lower alkyl or car carboxy lower alkyl, is introduced into one compound of formula I, in which R2 means hydrogen, one of the aforementioned residues by reaction with corresponding reactive, capable esters, and/or 2) when it is desired with a compound, in which R2 means lower alkyl, an end product is reduced, in which R2 means lower alkenyl or lower alkynyl, with catalytically activated hydrogen, and/or 3) when a compound is desired, in which the substituent at the nitrogen atom in the 2-position is a lower-alkanoyloxy-lower alkyl or a higher alkanoyloxy-lower alkyl residue, a product is esterified with a hydroxyl lower alkyl group by reaction with corresponding acid derivatives and/or 4) when it is desired with a quaternary compound, the product which is substituted in the 2-position is quaternized by reaction with a reactive ester of lower alkanols and/or 5) when it is desired with a N-oxide, N-oxidises a product in which the nitrogen atom in the 2-position has a substituent and/or 6) when it is desired with a compound, in which R^ means lower alk yl, a product, in which R^ is hydrogen, is metallized by reaction with reactive organic metal compounds, and is then reacted with reactive esters of lower alkanols, and/or if desired, a formed free compound is transferred in a salt or (a formed salt in the free compound, or in another salt, and/or if desired, a formed mixture of isomers or racemates is divided into the individual isomers or racemates, and/ or, if desired, the racemates formed are split in the optical antipodes, possibly forming the starting material under the reaction conditions.