FI63578B - ANALOGIFICATION OF THE PHARMACOLOGICAL PROPERTIES OF FRAMSTAELLNING AV NYA 1,3,4,14B-TETRAHYDRO-2H, 10H-PYRAZINO (1,2-A) PYRROLO (2,1-C) (1,4) BENZODIAZEPINE - Google Patents

Description

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MmM- I »raklttarilwllltu. , «, **« ^ ***** «», ^ _ och r * giat * rttyr «lMn Araekan utltfd oeh utl. * Krlft * n publicarad 31.03.83 (32) (33) (31) • tuolkau * —Ι · | «Η pHoritat 05.10.77 USA (US) 839696 (71) Ciba-Geigy AG, CH-i + 002 Basel, Switzerland-Switzerland (CH) (72) Jan WF Wasley, Chatham, New Jersey, USA (US) (7 ^) Oy Jalo Ant-Wuorinen Ab (5U) Analogue method for the development of new pharmacologically active 1,3,14,14b-tetrahydro-2H, 10H-pyrazino (1,2-a ) for the preparation of pyrrolo (2,1-c) (1,1U) benzodiazepines - Analogifarfarande för framställning av nya, pharmacologically active 1,3,1+, 11b-tetrahydro-2H, 10H-pyrazinoyl, 2-a) pyrrolo ( 2,1-c) (1,1) Benzodi azepiner

The invention relates to an analogous process for the preparation of new 1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-ajpyrrolo (2,1-c) - (1,4) benzodiazepines of the general formula I R4 7R3> -Nv • ex

N-C

c / 2n-R2 wherein hydrogen, lower alkyl, halogen or trifluoromethyl, R2 represents hydrogen, lower alkyl, higher alkyl, lower alkenyl, lower alkynyl or (cycloalkyl, hydroxy, lower carbalkoxy or phenyl) lower alkyl, wherein 7 ring members, CnH2n denotes lower alkylene / L '63578 which separates both nitrogen atoms by two or three carbon atoms, and R3 and denotes hydrogen or lower alkyl; for the preparation of lower alkanoyl, higher alkanoyl or adamantoyl derivatives and 2-N-oxides, 2-lower alkyl quaternary ammonium derivatives of hydroxy-containing compounds from compounds in which R 1 is other than hydrogen, and their salts, wherein the phrase "lower "means residues of up to 7 carbon atoms and the phrase" higher "means residues of 8-20 carbon atoms.

The lower alkyl group R 1, R 2, R 1 and R 2 is primarily methyl, but also ethyl, n- or iso- (propyl, butyl, pentyl, hexyl or heptyl), e.g. 2-methylpropyl or 3-methylbutyl. The higher alkyl group R2 is, for example, n- (octyl, decyl, dodecyl, hexadecyl or octadecyl).

The lower alkenyl or lower alkynyl group R 2 is preferably one in which the multiple bond is at least two carbon atoms away from the nitrogen atom, e.g. allyl, 2- or 3-butenyl or 3-methyl-2-butenyl; propargyl, 2- or 3-butynyl.

In the cycloalkyl-lower alkyl group containing 3 to 7 ring members, R 2 is preferably cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

The (hydroxy or carbalkoxy) lower alkyl group R 1 is preferably one in which the heteroatom (O) is at least two carbon atoms away from the ring nitrogen atom, e.g. 2- (hydroxy, carbomethoxy or carbethoxy) ethyl or propyl, 3-hydroxypropyl or (carbomethoxy or carbethoxy) methyl.

The symbol R 1 preferably represents hydrogen or e.g. methyl or ethyl; fluorine, chlorine, bromine or trifluoromethyl.

The lower alkylene group CnH2n is especially ethylene, but also 1,2- or 1,3-propylene.

Said acyl derivatives of the compounds of formula I are derived from those in which R 2 represents (hydroxy) lower alkyl. These derivatives are thus esters derived from lower or higher aliphatic acids, e.g. acetic, propionic, butyric, pivalic, decanoic, palmitic or adamantyl carboxylic acids.

The N-oxides or lower alkyl quaternary derivatives are derived from compounds of formula I in which R 2 is not hydrogen and 363578 in which only the nitrogen atom in the 2-position is functionalized. The anions or quaternary compounds and acid addition salts are preferably those derived from therapeutically useful acids, e.g. the acids mentioned below.

Above and below, "lower" organic residues or compounds means organic residues or compounds having up to 7, preferably up to 4, preferably one or two carbon atoms. "Higher" residues or compounds contain 8-20, preferably 8-16 carbon atoms.

The compounds of the invention have valuable pharmacological properties, primarily antidepressant effects. These can be demonstrated in animal experiments, preferably using mammals such as mice, rats, guinea pigs and monkeys as experimental animals. The novel compounds can be administered enterally or parenterally, preferably orally, subcutaneously, intravenously or intraperitoneally, e.g. in gelatin capsules or in the form of aqueous solutions of starch-containing suspensions. The dose used may vary between 0.1 and 100 mg / kg / day, and is preferably about 0.05 to 5 mg / kg / day, especially about 0.1 to 0.5 mg / kg / day. Antidepressant properties can be demonstrated in mice by reversing clonidine analgesia. In this experimental setup, the compounds of the invention are administered as aqueous solutions orally or intraperitoneally to groups of at least 10 male mice. Thirty minutes later, they are intubated with 0.1 mg / kg clonidine. Twenty minutes later, the animals are injected with 3.75 mg / kg phenyl-p-benzoquinone intraperitoneally, and 5-15 minutes after the injection, the number of self-shaking animals is observed. Each convulsive animal is positive and the ED 2 value for the combination of active substance tested and clonidine is determined by the Berkson Logit method from the number of positively reacting animals.

Comparative Experimental Report Reversal of Clonidine Analgesia Imipramine hydrochloride is used as a reference substance in this experiment. The test method is described above. This method is based on antagonism of clonidine blockade induced by phenylquinone in mice.

4,63578

Compound Number of reacting animals from the example Dose Method of administration (in group 10,15,20 or 30) 1 10 i.p. 23/30 1 20 i.p. 8/20, 10 i.p. 1/10 30 i.p. 2/10 ^ 10 i.p. 3/10 J 30 i.p. 6/10. 10 i.p. 8/10 4 30 i.p. 12/15. 10 i.p. 4/10 4a 30 i.p. 7/10. 10 i.p. 4/10 40 30 i.p. 5/10 and 10 i.p. 10/10 5 30 i.p. 10/10 c: / 1 10 i.p. 7/10 0/1 30 i.p. 6/10 f./0 10 i.p. 0/10 Ö / Z 30 i.p. 2/10 9 10 i.p. 8/10 14/1 10 i.p. 10/10 14/2 10 i.p. 9/10 14/3 10 i.p. 9/10 14/5 10 i.p. 7/10

Imipramine hydrochloride 30 i.p. 0/10

The comparison results show that the compounds according to the invention have a superior antidepressant effect over imipramine.

The compounds of the invention may thus be used as antidepressants, e.g. for the treatment or control of mental depression. They can also be used as intermediates in the production of other valuable products, especially pharmacologically effective preparations.

Particularly noteworthy are the compounds of the general formula II which are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, hydroxy-lower alkyl or cycloalkyl-lower alkyl having 3 to 7 ring members. means hydrogen, halogen or trifluoromethyl, and their therapeutically useful acid addition salts.

Particularly preferred are compounds of general formula II, in which Rg represents alkyl, alkenyl, alkynyl or hydroxyalkyl, in each case having up to 4 carbon atoms or cyclopropylmethyl and Rg represents fluorine or chlorine, preferably in the 7-position, and their therapeutically useful The acid addition salts.

The compounds of the invention can be prepared by methods known per se by reducing a compound of general formula III

ι-ζχ4, iS

--S

x-, N_p.2 where X represents lower alkylene, mono- or dioxo-lower alkylene which separates both nitrogen atoms by two or three carbon atoms and in which oxo is attached to the carbon atom adjacent to the nitrogen atom, and Y represents oxo or two hydrogen atoms, provided that at least one oxo group is in the group X or Y, and if desired, the compound of formula I obtained is converted into another compound of the invention.

The reduction of said lactams of formula III is preferably carried out with simple hydrides or a complex 63578 light metal hydride such as boranes or alanine, preferably alkali metal aluminum hydrides or alkali metal lower alkoxide-sodium butoxy-sodium trioxide (e.g. lithium aluminum trihydride, e.g. methoxyethoxy) -alumiinihydri-hydride.

The starting materials can be prepared in the same way as the starting materials of known analogous materials or as described in the examples.

Thus, the starting materials can be prepared by reacting the corresponding compounds of formula III, wherein X represents two hydrogen atoms, each attached to the other nitrogen atom, with the corresponding glycols, glycolic acids or reactive derivatives of dicarboxylic acids, such as their lower alkyl esters, halides or halides. with reactive esters of glycols or glycolic acid derivatives, e.g. hydrohalic acids or aromatic sulfonic acids, such as 1,2-dibromoethane or propane, bromoacetic acid ethyl ester or propyl ester, tosyloxyacetic acid ethyl ester, oxyacetic acid ethyl ester, with malonic acid diethyl ester, oxalic acid hemeethyl ether tertiary chloride, oxalyl bischloride or malonic anhydride. Said starting precursors of formula III can be obtained analogously to II Farmaco, Ed.Sc. 2Λ, Fasc. 3, p. 276 or as described in the examples.

The compounds according to the invention obtained can, if desired or, if necessary, be converted into one another by methods known per se. Thus, the resulting compounds of formula I wherein R 2 represents hydrogen, or their alkali metal, e.g. sodium salts, can be converted by reaction with unsubstituted or correspondingly substituted aliphatic or araliphatic alcohols, such as methanol, ethanol, allyl alcohol, propargyl alcohol or benzyl alcohol, benzyl alcohol according to the molar amount of the alkylating agent used to the corresponding N-substituted compounds, i.e. quaternary ammonium derivatives. Reactive esters are obtained by esterification of alcohols with strong inorganic or organic acids, primarily with hydrohalic acid, e.g. hydrogen chloride, hydrobromic or hydroiodic acid, sulfuric acid or aromatic sulfonic acid, e.g. p-toluenesulfonic acid or m-bromobenzoic acid. Conversely, the resulting N-alkylated compounds can be converted to N-unsubstituted compounds, e.g., by catalytic hydrogenolysis of N-benzyl compounds. If N-lower-7,63578 alkyl, N-lower alkenyl or N- (CH 2 -phenyl) derivatives are reacted with lower alkyl esters of halogen formic acid, e.g. chloroformic acid ethyl ester, N-acyl derivatives are obtained. The latter can be converted to N-unsubstituted compounds in which R 2 is hydrogen, e.g. with aqueous bases, e.g. with alkali metal hydroxide solutions. Esters can be prepared by reacting compounds of formula I wherein R 2 represents (hydroxy) lower alkyl with the corresponding acid derivatives, e.g. halides. The resulting esters can be hydrolyzed in the same manner as described for N-acyl derivatives. The resulting unsaturated compounds, e.g., wherein R 2 represents lower alkenyl or lower alkynyl, can be hydrogenated, as described above, with catalytically activated hydrogen. The resulting esters can be converted to the corresponding alcohols by reduction with complex light metal hydrides, e.g. lithium aluminum hydride.

The resulting compounds of formula I wherein R 1 represents hydrogen can be converted to the corresponding lower alkyl derivatives by metallization with reactive organometallic compounds, e.g. n-butyllithium or lithium diisopropylamide, and reaction with reactive esters of lower alkanols. The resulting tertiary nitrogen compounds in which R 2 is not hydrogen can be converted to their N-oxides, e.g. with hydrogen peroxide or organic peracids such as lower peralkanoic acids or perbenzoic acids, e.g. peracetic acid or m-chloro-perbenzoic acid, at lower temperatures, preferably at room temperature, preferably at room temperature. or at a temperature of up to 100 ° C with a dilute hydrogen peroxide solution in the presence of lower alkanoic acids, e.g. acetic acid. In this case, care must be taken, in particular for said peracids, for excessively long reaction times in order to avoid overoxidations.

Finally, the compounds of the invention can be obtained in the form of free bases or salts. The resulting free base can be converted to the corresponding acid addition salt, preferably with acids that produce therapeutically useful acid addition salts or with anion exchangers. The resulting salts can be converted to the corresponding free bases, e.g. by treatment with a stronger base such as a metal hydroxide or ammonium hydroxide, a basic salt or cation exchangers, e.g. alkali metal hydroxide or carbonate.

63578

Acids which produce therapeutically useful acid addition salts are, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid; or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, fumaric , hydroxymalein, palory, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotine, methanesulfonic, ethanesulfonic, hydroxyethanesulfone -, ethylenesulfonic, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid. These or other salts, e.g. picrates, can also be used to purify the free bases. The bases are converted to their salts, the salts are separated and the bases are liberated from the salts.

Since the novel compounds of the invention in free form and in the form of their salts are very similar, the above and the following free compounds and salts are to be understood simultaneously and expediently as meaning possibly also the corresponding salts or free compounds.

The resulting isomeric mixtures of the compounds, e.g. the isomeric mixtures of the compounds of the formulas I-III, can be separated by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography into individual isomers. Racemic products can be resolved into optical antipodes, e.g., by resolution of their diastereoisomeric sholes, e.g., by fractional crystallization of d- or ε-tartrates.

The above reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in diluents which are inert to the reagent and dissolve these catalysts, condensing agents or other aforementioned substances and / or in an inert atmosphere of 9,63578, while cooling. temperature or elevated temperatures, preferably at the boiling point of the solvent used, at normal pressure or at elevated pressure.

The invention likewise relates to variants of this process in which an intermediate obtained at any stage of the process is used as starting material and the missing process steps are carried out or in which the starting material is formed under reaction conditions or in which the starting material is used in the form of a salt or optically pure antipode.

In the process of the present invention, it is preferred to use starting materials which lead to the compounds described above as being particularly preferred and valuable, in particular to the compounds of the formula II.

The pharmacologically useful compounds of this invention can be used in the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration.

The following examples further illustrate the invention. Temperatures are given in degrees Celsius and ingredients are by weight.

Unless otherwise specified, the evaporation of the solvents is performed under reduced pressure, e.g. 15-100 mmHg.

Example 1; 2-Methyl-1,3,4-14b-tetrahydro-2H, 10H-pyrazino (Ί, 2-a) -pyrrolo (2,1-c] (1,4) benzodiazepine and its monomaleate

To a suspension of 12.8 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-ajpyrrolo (2,1c) (1,4) benzodiazole pine in 460 ml of tetrahydrofuran, while stirring, 200 ml of a 1 molar solution of diborane in tetrahydrofuran are added under ice-cooling, the mixture is refluxed for one hour, cooled again and 25 ml of acetic acid are added, the reaction mixture is evaporated, the residue is dissolved in 50% sodium hydroxide solution The extract is dried, evaporated and the residue is dissolved in diethyl ether, the solution is filtered and the filtrate is evaporated to give 2-methyl-1,3,4,14b-tetrahydro-2H, 10H, pyrazino (1,2-a). ) pyrrolo (2,1-c) (l, 4) benzodiazepine.

Dissolve 9.7 g of the latter compound in a small amount of isopropanol and acidify the solution with 4.45 g of a concentrated isopropanol solution of maleic acid. The resulting precipitate is separated and recrystallized from methanol-diethyl ether. The corresponding mono-maleate is obtained, melting at 176-178 °.

2.35 g of the above-mentioned dioxo starting material in 50 ml of methylene chloride can also be reduced with 20 ml of a 1 molar solution of alanine in diethylamine and then the mixture is evaporated. The residue is triturated with ethyl acetate-diethyl ether, chromatographed on 70 g of silica gel and eluted with methanol-chloroform (1: 9). The eluate is evaporated and the residue is acidified as described above. A purer maleate is obtained which melts at 180-182 °.

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

A mixture of 70 g of the latter compound, 14.6 g of hydrazine hydrate and 600 ml of ethanol is refluxed for 4 hours and 50 ml of concentrated hydrochloric acid are added. 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 basified with 3N aqueous sodium hydroxide solution. The mixture is extracted with diethyl ether, the extract is dried and evaporated. O-Nitrobenzylamide is obtained.

To a solution of 7.6 g of the latter compound in 25 ml of glacial acetic acid is added 6.6 g of 2,5-dimethoxy-tetrahydrofuran and the mixture is refluxed for one hour. 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 hydrogencarbonate solution 63578, dried and evaporated. The residue is dissolved in diethyl ether, decolorized with activated carbon, filtered and evaporated. 1- (o-Nitrobenzyl) pyrrole is obtained.

A mixture of 13.42 g of the latter compound, 140 ml of diethyl ether and 6.85 g of chloroacetonitrile is cooled in an ice-salt bath and saturated with hydrogen chloride while stirring. The saturated mixture is stirred at room temperature overnight, filtered and the residue is suspended in 100 ml of water. The suspension is extracted three times with 100 ml of ethyl acetate, the combined extracts being heated with stirring on a steam bath until the solute no longer dissolves. The solution is dried and evaporated. 1-o-Nitrobenzyl-2-chloroacetylpyrrole is obtained.

To a solution of 16.2 g of the latter compound in 450 ml of ethanol is added 14.1 g of N-methylbenzylamine and the mixture is refluxed for 3 hours. The reaction mixture is evaporated, the residue is dissolved 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 the theoretical amount of hydrogen is dissolved, 100 mg of platinum oxide at 2.7 atmospheres and at room temperature.

The mixture is filtered, the filtrate is evaporated, the residue is dissolved in methylene chloride-diethyl ether and the solution is washed with saturated aqueous sodium hydrogen carbonate solution. The solution is dried, evaporated and the residue is chromatographed on 30 g of silica gel and eluted with methanol-chloroform (1: 9). 11- (N-methyl-N-benzylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 147-149 °.

A solution of 500 mg of the latter compound in 35 ml of ethanol and 5 ml of glacial acetic acid is hydrogenated with 250 mg of 5% palladium-on-carbon catalyst for 7 hours at 40 ° and 2.7 atmospheres.

The mixture is filtered, the filtrate is evaporated and the residue is dissolved 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-methylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained.

A mixture of 300 mg of the latter compound and 232 mg of oxalic acid diethyl ester is slowly heated to 140 DEG C. and 140 DEG C. in 15 minutes. The mixture is kept at the latter temperature for 30 minutes, then cooled, diluted with benzene, chromatographed on silica gel and eluted with methanol-chloroform (1: 9). 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazono (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 178-179 °.

7-Chloro-2-methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a-Example 2: pyrrolo (2,1-c) (1,4) benzodiazepine mono- maleate 315 mg 7-chloro-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1, 4) To a suspension of benzodiazepine in 20 ml of tetrahydrofuran is added 6 ml of a 1 molar solution of diborane in tetrahydrofuran with stirring and ice-cooling, the mixture is refluxed for two hours, cooled again and 1 ml of 6N hydrochloric acid is added. is dissolved in 5 ml of 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 97 mg of maleic acid in a minimum amount of acetone are added to the solution, the precipitate obtained is separated to give 7-chloro-2-methyl. -1,3,4,14b-Tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine mono-maleate, melting at 200-202 ° :in.

The starting material is prepared as follows: A mixture of 9.4 g of phthalimid potassium, 31.35 g of p-chloro-o-nitrobenzyl chloride and 75 ml of dimethylformamide is refluxed for 3 hours and poured into 180 ml of ice water with stirring. After 30 minutes, the mixture is filtered and the residue is washed with water. N-p-chloro-o-nitrobenzyl fatalimide is obtained, melting at 190-194 °.

A mixture of 29.6 g of the latter compound, 5.5 g of hydrazine hydrate and 300 ml of ethanol is refluxed for 4 hours and then 21 ml of concentrated hydrochloric acid are added. After 30 minutes, the mixture is cooled to room temperature, filtered and the residue is washed with water. The filtrate is concentrated, the aqueous condensate is filtered and the filtrate is basified with 3N aqueous sodium hydroxide solution. Extract with diethyl ether, dry the extract and evaporate. P-Chloro-r-o-nitrobenzylamine is obtained.

To a solution of 42.8 g of the latter compound in 400 ml of glacial acetic acid is added 30.4 g of 2,5-dimethoxy-tetrahydrofuran and the mixture is refluxed for one hour. 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 dissolved in diethyl ether, decolorized with activated carbon, filtered and evaporated. 1- (p-chloro-o-nitrobenzyl) pyrrole is obtained.

A mixture of 4.26 g of the latter compound, 20 ml of diethyl ether and 1.46 g of chloroacetonitrile is cooled in an ice-salt bath and saturated with hydrogen chloride gas with stirring. The saturated mixture is stirred at room temperature overnight, filtered and the residue is suspended in 50 ml of water. The suspension is extracted three times with 50 ml of acetic acid ethyl ether. The extract is dried and evaporated. 1- (p-chloro-o-nitrobenzyl) -2-chloroacetyl-pyrrole is obtained.

To a suspension of 56.5 g of the latter compound in 960 ml of ethanol are added 21.8 g of N-methylbenzylamine and 18.2 g of triethylamine, and the mixture is refluxed for 6 hours. The reaction mixture is evaporated, the residue is dissolved 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 ethanol. 1- (p-chloro-o-nitrobenzyl) -2- (N-methyl-N-benzylaminoacetyl) pyrrole is obtained, melting at 90-93 °.

To a solution of 1 g of the latter compound in 30 ml of benzene is added 0.545 g of chloroformic acid ethyl ester and the mixture is refluxed for 4 hours. The reaction mixture is diluted with diethyl ether, washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried and evaporated. 1- (p-Chloro-o-nitrobenzyl) -2- (N-methyl-N-carbethoxyaminoacetyl) pyrrole is obtained.

To a solution of 1.43 g of the latter compound in 20 ml of tetrahydrofuran is added dropwise 15 ml of titanium trichloride, and the mixture is stirred overnight at room temperature. The reaction mixture is basified with 60 ml of 10% aqueous ammonia solution, filtered and the residue is washed with methylene chloride. The organic phase is separated, washed with saturated sodium chloride solution, dried and evaporated. 8-Chloro-11- (N-methyl-N-carbethoxyaminomethyl-5H-pyrrolo (2,1-c) (1,4) -benzodiazepine is obtained.

To a solution of 430 mg of the latter compound in 10 ml of ethanol containing 14,63578 is added 760 mg of sodium borohydride, and the mixture is stirred overnight at room temperature. The reaction mixture is acidified with 6N 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, eluting with ethyl acetate-methylene chloride (1:19). 8-Chloro-11- (N-methyl-N-carbethoxyaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) 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 is refluxed for 3 days and evaporated. The residue is dissolved in water, the mixture is extracted with methylene chloride, the extract is dried and evaporated. 8-Chloro-11- (N-methylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained.

A mixture of 960 mg of the latter compound and 600 mg of oxalic acid diethyl ester is slowly heated to 140 ° over 45 minutes and to 180 ° over 15 minutes. 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. 7-Chloro-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) is obtained. benzodiazole. ioka melts at 203 ^.

1,3,4,14b-Tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) - Example 3: Benzodiazepine maleate 1.9 g of 2-methyl- 1,3,4,14b-Tetrahydro-2H, 10H-pyrazina (1,2-a) -pyrrolo (2,1-c) (1,4) benzodiazepine In 50 ml of a solution containing benzene is added 2.14 g of chloroformic acid ethyl ester and the mixture boil for 3 days at reflux. The reaction mixture is diluted with diethyl ether, washed with 1N hydrochloric acid and saturated aqueous sodium chloride and sodium hydrogen carbonate solution, dried and evaporated. 2-Carbethoxy-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, which has lines at 8 in the NMR spectrum. , 55 (t), 6.60 (m), 5.65 (q) and 3.90 (d) ppm and molecular ion 311 in the mass spectrum.

930 mg of 2-carbethoxy-1,3,4,14b-tetrahydro-2H, 10H, pyrazino- (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine, 40 ml of ethanol and 20 ml of a mixture of 20% aqueous potassium hydroxide is refluxed for 2 days. After cooling, the reaction mixture is diluted with ethyl acetate, washed with water, dried and evaporated. The residue is dissolved in diethyl ether and 0.55 g of maleic acid in as little acetone as possible is added to the solution. The resulting precipitate is separated and washed with diethyl ether. 1,3,4,14b-Tetrahydro-2H, 10H-pyrazino (1,2-a) -pyrrolo (2,1-c) (1,4) benzodiazepine maleate is obtained, melting at 173-175 °.

In a similar manner, 7-chloro-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine maleate is also obtained by hydrolysis with 20% aqueous sodium hydroxide solution) melting at 184-186 °.

4 · 2 “allyl-1'3 / 4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) -er. -1- · pyrrolo (2,1-c) (1,4) benzodiazepine 4.8 g of 1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo- (2,1-c) (1,4) benzodiazepine in 20 ml of dimethylformamide and 2.44 2.91 g of allyl libromide are added dropwise to the stirred solution containing triethylamine. After 1 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 solvents are washed with saturated aqueous sodium hydrogen carbonate solution, dried and the residue is triturated with diethyl ether. 2-Allyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 130-132 °. :in.

In a similar manner a) 2- (3-methyl-2-butenyl) - is also prepared; b) 2-propargyl; c) 2-cyclopropylmethyl-? d) 2-carbomethoxymethyl and e) 2-phenylethyl-1,2,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine from equivalent amounts of bromides. The compounds a) to d) according to the invention are converted into their acid addition salts mentioned below, according to Examples 1 and 2, and recrystallized from said solvents. The salts melt as follows a) maleate 152-153 ° (after recrystallization from isopropanol)? b) fumarate, 138-140 ° (ethanol); c) maleate 189-190 ° (isopropanol); d) maleate 162-164 ° (isopropanol-diethyl ether) and free base e) melts at 132-134 ° after recrystallization from isopropanol.

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Example 5: 2- (2-hydroxy-ethyl) -1,3,4,14b-tetrahydro-2H, 10H-pyrazino-1,2 (a) pyrrolo (2,1-c) (1,4) Benzodiazepine and its monofumarate 780 mg of 2-carbomethoxymethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino-1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine 20 ml To a solution of tetrahydrofuran in is added 150 mg of lithium aluminum hydride and the mixture is stirred for 2 days at room temperature. To the reaction mixture are then added 0/15 ml of water, 0.15 ml of 15% aqueous sodium hydroxide solution and 0.15 ml of water in this order, filtered and the filtrate is evaporated. There is obtained 2- (2-hydroxyethyl) -1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) -benzodiazepine, which is converted to the mono -fumaraatikseen. It melts at 187-189 ° with decomposition.

Example 6; 2-n-propyl-1,3,4,14b-tetrahydro-2H-10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4J benzodiazepine maleate 1.16 g of 2- allyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) -pyrrolo (2,1-c) (1,4) benzodiazepine A solution of 25 ml of ethanol is hydrogenated with 40 mg of platinum oxide 2.5 hours at room temperature and atmospheric pressure, the reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in isopropanol and the solution is acidified with maleic acid to give 2-n-propyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2 -a) pyrrolo (2,1-c) (1,4) benzodiazepine maleate melting at 157-159 °.

In an analogous manner, 2- (3-methyl-butyl) -1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) Bent -sodiatsepiinimaleaattia. It melts at 146-147 °.

Example 7: 2,12-Dimethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino- (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine and its mono- maieaatti

According to the methods illustrated in Examples 1 and 2, 12-formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1- c) (1,4) Benzodiazepine with diborane 2,12-dimethyl-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1 , 4) benzodiazepine. Its mono-maleate melts at 173-175 °.

The starting material is prepared as follows: A mixture of 170 mg of phosphorus oxychloride and 100 ml of formaldehyde is stirred at room temperature for 30 minutes and then a solution of 281 mg of 2-methyl-3,4-dioxo-1,3,4,14b- tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine in 5 ml of methylene chloride. After 30 minutes, the mixture is refluxed for a further 30 minutes and cooled to room temperature. To the reaction mixture is added 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 5% aqueous sodium hydrogen carbonate solution, dried and evaporated and the residue is triturated with diethyl ether. 12-Formyl-2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino-1,2 (a) pyrrolo (2,1-c) (1, 4) a benzodiazepine that melts at 300-302 °.

Example 8: 2,2-Dimethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino- (1,2-a) pyrrolo (2,1-c) (Ί,4) benzodiazepinium iodide 500 mg 2- methyl 1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine, containing 10 ml of methylene chloride and 0.5 ml of methyl iodide the mixture is stirred at room temperature for one hour. The reaction mixture is filtered and the residue is washed with ethylene chloride. 2,2-Dimethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (2,1-a) pyrrolo (2,1-c) (1,4j benzodiazepinium iodide is obtained), melting with decomposition 258-260 ° :in.

Example 9; 2-methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine-2-N-oxide 300 mg 2-methyl -1,3,4,14b-Tetrahydro-2H, 10H-pyrazino (1,2-a-pyrrolo (2,1-c) (1,4) benzodiazepine To a solution of 10 ml of methylene chloride is added 290 mg of m-chloroperbenzoic acid. In 100 ml of methylene chloride and the mixture are stirred at room temperature for 5 hours, the reaction mixture is shaken with 5 ml of 10% aqueous sodium sulphite solution, saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give 2-methyl-1,3,4,14b-tetrahydro -2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine-2-N-oxide, melting at 143-145 °.

Example 10: 2-Methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine and its mono-maleate 140 mg of 2-methyl-1,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino-1,2 (a) pyrrolo (2,1-c) (1,4) benzodiazepine 5 To a solution containing 1 ml of a 1 molar solution of diborane in tetrahydrofuran is added to a solution containing 1 ml of tetrahydrofuran under stirring and ice-cooling.

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The reaction mixture is stirred at room temperature overnight and then refluxed for 4 hours. After cooling to room temperature, 0.5 ml of glacial acetic acid are added, the mixture is evaporated and the residue is basified with 3N 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. 2-Methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine, identical to the product of Example 1, is obtained. Its mono-maleate melts at 176-178 °.

The starting material is prepared as follows: To a solution of 16 g of oxalyl chloride in 150 ml of diethyl ether is added, with stirring and cooling to -50 ° (solid carbon dioxide-acetone bath), 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 °. At the end of the addition, it is stirred for one hour and then slowly poured into a solution of 27.5 g of sarcosine ethyl ester in 150 ml of diethyl ether. The precipitate obtained is filtered off, carefully extracted with methylene chloride and the extract is evaporated. N- (2-pyrryl-glyoxyl) sarcosine ethyl ester is obtained, melting at 114 °.

To a solution of 5.5 g of the latter compound in 30 ml of dimethylformamide are added 1.07 g of a 50% mineral oil suspension of sodium hydride and 20 ml of dimethylformamide. The mixture is heated for one hour at 60-70 °, cooled to room temperature and a solution of 5 g of o-nitrobenzyl bromide in 20 ml of dimethylformamide is added. The reaction mixture is stirred for 1 hour at 45-50 °, cooled to room temperature, diluted with water and extracted with ethyl acetate. The extract is dried, evaporated and the residue is triturated with diethyl ether. N- (1-o-nitrobenzyl-2-pyrryl-glyoxyl) -sarcosine ethyl ester is obtained, melting at 105-108 °.

A solution of 3 g of the latter compound in 30 ml of ethyl acetate is hydrogenated with 100 mg of platinum oxide in 3 atmospheres until 3 molar equivalents of hydrogen are dissolved. 1.5 ml of glacial acetic acid are added to the mixture and the hydrogenation is terminated at 3 atmospheres and 40 °. The reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in methylene chloride and purified by chromatography on silica gel. Elute with 10% methanol-methylene chloride to give N- (1,2-1963578 dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepin-2-ylcarbonyl) -sarcosine ethyl ester melting at 147-148 °.

To a suspension of 100 mg of the latter compound in 10 ml of toluene is added 20 mg of sodium methoxide and the mixture is refluxed for 1 hour. The reaction mixture is cooled, filtered and evaporated. 2-Methyl-1,4-dioxo-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 165-167 °.

Example 11: 2- and β-antipodes of 2-methyl-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) -pyrrolo (2,1-cJ (1,4) benzodiazepine) g of 2-methyl-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine (Example 1) in 300 ml of isopropanol A hot solution of 3 g of d-tartaric acid in 50 ml of isopropanol is added to the hot solution containing the mixture, the mixture is cooled overnight to room temperature, the precipitate obtained is filtered and recrystallized from aqueous ethanol until the (three) liberated basic optical rotation is constant, namely when a) p5 = + 344.26 ° (c = 1 in methanol) The solution is converted to its mono-maleate, which melts with decomposition at 190-191 °.

Using Δ-tartaric acid, the corresponding ί, -antipod, (ot) D = 358.89 ° is obtained, the mono-maleate of which melts at 188-189 ° with decomposition.

Example 12: 2-Methyl-1,2,3,4,5,15b-hexahydro-11H- (1,4) diazepino [1,2-a] pyrrolo (2,1-c) (1,4) benzodiazepine and its monofumarate 800 mg 2-methyl-5-oxo-1,2,3,4,5,15b-hexahydro-11H- (1,4) diazepino (1,2-a) pyrrolo (2,1-cj To a solution of (1,4) benzodiazepine in 50 ml of tetrahydrofuran is added 6.2 ml of a 1 molar solution of diborane in tetrahydrofuran, the mixture is refluxed for 2 hours, cooled and stirred overnight at room temperature, and 2 ml of glacial acetic acid are added to the reaction mixture. the residue is basified with 3N aqueous sodium hydroxide solution, the mixture obtained is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in a small amount of methylene chloride The solution is chromatographed on silica gel, eluting with 10% methanol-methylene chloride. 1,2,3,4,5,15b-Hexahydro-11H- (1,4) diazepino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine where R 1 = R 3 = R4 = H, R2 = methyl, and n = 3. The product is converted to its mono-fumarate, which melts at 174-175 °.

The starting material is prepared as follows: 1.5 g of 11- (N-methylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine Example 1) in 7.5 ml of acrylic acid -methyl ester solution is stirred for 24 hours at room temperature and the excess reagent is evaporated. N-methyl-N- (1,2-dihydro-5H-pyrrolo (2,1-c) (1,4) -benzodiazepin-2-ylmethylene) -β-alanine methyl ester is obtained as an oil which is chromatographed on silica gel and eluted with 2% methanol-methyl chloride.

A solution of 1 g of the latter compound in 20 ml of tetrahydrofuran is added to a stirred solution of 475 mg of 2,2,6,6-tetramethylpiperidine (distilled just with calcium hydride) in 10 ml of tetrahydrofuran and then 1.37 ml of n -butyl-lithium 2,45 molar hexane solution at -75 °. The reaction mixture is stirred at this temperature for 30 minutes and then allowed to warm to 0 °. The mixture is diluted with acetic acid-water (2: 1), evaporated, the residue is dissolved in methylene chloride, chromatographed on silica gel and eluted with 5% methanol-methylene chloride. 2-Methyl-5-oxo-1,2,3,4,5,15b-hexahydro-11H- (1,4) diazepino (1,2-a) -pyrrolo (2,1-c) (1 , 4) a benzodiazepine melting at 156-158 °.

Example 13: 2,10-Dimethyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4] benzodiazepine and its mono-maleate 2.5 g of 2-methyl-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine (Example 1) in 25 ml of tetrahydro 4.5 ml of a 2.5 molar solution of n-butyllithium in hexane are added to the solution containing furan at room temperature with stirring, the pale yellow solution rapidly turns Kirsi-red and the temperature rises to about 7 °. 45 minutes and then treated with methyl iodide until the color of the solution disappears, 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, washed successively with water and saturated aqueous sodium chloride solution and evaporated. With 2% methanol-methylene chloride to give 2,10-dimethyl-1,3,4,14b-tetrahydro o-2H, 1OH-pyrazino (1,2-a) -pyrrolo (2,1-c) (1,4) benzodiazepine, which is converted to the mono-maleate, m.p. 157 °. The same product is also obtained according to the methods of Examples 1 and 10 using o-nitro-α-methyl-benzyl chloride or bromide to prepare the starting material.

Example 14: 2- (2-Acetoxyethyl) -1,3,414b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine and its monofumarate 2.5 g 2- (2-hydroxyethyl) -1,3,4,14b-tetrahydro-2H-1OH-pyrazino [1,2-a] pyrrolo (2,1-c) (1,4) benzodiazepine (Example 8) and 935 To a solution of 21 63578 in 72 ml of tetrahydrofuran is added 720 mg of acetyl chloride. The mixture is stirred at room temperature for 2 hours, evaporated and the residue is extracted with methylene chloride. The extract is washed successively with water and saturated aqueous sodium chloride solution, dried, filtered and evaporated. There is obtained 2- (2-acetoxyethyl) -1,3,4,14b-tetrahydro-2H, 10H-pyrazino- (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine, which is converted to its mono-fumarate . Mp 156-158 ° (dec.).

In an analogous manner, 2- (2- (n-hexanoyloxy, n-decanoyloxy, n-hexadecanoyloxy and 1-adamantylcarbonyloxy) ethyl) -1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1 , 2-a) pyrrolo- (2,1-c) (1,4) benzodiazepine monofumarates. These compounds melt at 56-58 °, 59-61 °, 71-73 °, respectively. 47-50 ° C.

Example 15: 2-Methyl-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo - * (2,1-cj (1,4) benzodiazepine and its monomaleate

348 g of 2-methyl-3,4-dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) - (1, 4) benzodiazepine in 4500 ml of tetrahydrofuran and 7410 ml of a 1 molar solution of diborane in tetrahydrofuran on the same ice under cooling to 18 ° and stirring under a nitrogen atmosphere. The mixture is refluxed for 24 hours, cooled to 5 ° and first 1200 ml of glacial acetic acid and then 900 ml of water are added. The solution is refluxed for 24 hours, evaporated and the residue is dissolved in 10500 ml of methanol. The solution is further refluxed for 2 hours, evaporated, the residue is dissolved in 3000 ml of water and the pH of the solution is adjusted to 14 with 1200 ml of 10% aqueous sodium hydroxide solution. The mixture is extracted with diethyl ether, the extract is dried, filtered and evaporated. 2-Methyl-1,3,4,14b-tetrahydro-2H, ΙθΗ-pyrazino [1,2-a] pyrrolo (2,1-c) (1/4) Bent-zodiazepine is obtained, melting at 98-100 °: in.

Dissolve 307 g of the latter compound in 1280 ml of absolute ethanol under reflux, filter the solution, cool the filtrate to 28 ° and then add 140.5 g of maleic acid in 294 ml of ethanol. The precipitate obtained is separated, washed with cold ethanol and recrystallized from ethanol. The corresponding mono-maleate is obtained, melting at 183-185 °. The product is slightly purer than the corresponding product of 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 rapidly added to 10,000 ml of glacial acetic acid with stirring at 86 ° under a nitrogen atmosphere. The mixture is stirred for 1 1/4 hours at 95 °, cooled to 25 ° and 22,000 ml of water are added. The reaction mixture is extracted with ethyl acetate, the extract is washed with 10% aqueous sodium hydroxide solution and 10% aqueous sodium chloride solution, filtered and evaporated. 1- (o-Nitrobenzyl) pyrrole is obtained.

A mixture of 3467 g of the latter compound in 8500 ml of tetrahydrofuran and 1290 g of chloroacetonitrile is saturated with stirring and cooling to 5-35 ° for 3 hours with hydrogen chloride gas. The saturated suspension is stirred for a further hour at 17 °, filtered and the residue is suspended in 1000 ml of tetrahydrofuran and further filtered. 1-o-Nitrobenzyl-2- (1-imino-2-chloroethyl) -pyrrole hydrochloride is obtained, melting with decomposition at 210-212 °.

A suspension of 3469 g of the latter compound in 3500 ml of water is stirred at 80 ° for one hour, then the suspension is cooled to 25 ° and filtered. The residue is washed with water and dried. Dissolve 6000 g of the residue in 60 000 ml of ethanol under boiling and reflux under a nitrogen atmosphere. The solution is filtered hot, concentrated by distilling off 36,000 ml of ethanol and cooled overnight at 25 °. The resulting suspension is filtered and the residue is dried. 1-o-Nitrobenzyl-2-chloroacetylpyrrole is obtained, melting at 112-114 °.

A suspension of 5112 g of the latter compound, 26,400 ml of toluene, 2445 g of n-methylbenzylamine and 2040 g of tritylamine is stirred under a nitrogen atmosphere for 6 hours at 93 ° and overnight at room temperature. 20,000 ml of water are then added to the reaction mixture, the aqueous phase is separated off, 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 2000 ml of ethanol and stirred at room temperature overnight. The crystals obtained are filtered off, washed with ethanol and dried. 1- (o-Nitrobenzyl) -2- (N-methyl-N-benzylaminoacetyl) pyrrole is obtained, melting at 103-105 °.

A solution of 300 g of the latter compound in 3000 ml of ethyl acetate and 250 ml of glacial acetic acid is hydrogenated with 30 g of platinum oxide at room temperature and atmospheric pressure until the theoretical amount of hydrogen has dissolved. The reaction mixture is filtered, the residue is washed with ethyl acetate and the filtrate is evaporated. The residue is dissolved in methylene chloride, the solution is washed with 2.5N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution 2363578, dried and evaporated. The residue is triturated with diethyl ether. 11- (N-methyl-N-benzylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 151-152 °.

To a solution of 142.5 g of the latter compound in 2000 ml of toluene and 45 g of triethylamine is added, with stirring at 10-20 ° for 90 minutes, 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 is separated. It is washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried and evaporated. The residue is recrystallized from methanol. 10-Ethyloxalyl-11- (N-methyl-N-benzylaminomethyl) -10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained, melting at 99-101 °. :in. (Using larger amounts of oxalic acid hemiethyl ester chloride gives the corresponding 3,10-bis-ethyl-oxalyl compound, which melts at 115-116 °. This is less soluble in isopropanol than the previously mentioned compound and can be separated from concentrated solutions. filtration).

6.9 g of said 10-ethyloxalyl compound in 100 ml of ethanol and 27 ml of a solution containing glacial acetic acid are hydrogenated with 1.65 g of 5% palladium-on-carbon catalyst at 2.7 atmospheres and 40 ° for about one hour. I drive. 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-a) (1,4) benzodiazepine is obtained, melting 178 At -179 °.

Example 16:

According to the methods described, the following compounds of formula II are prepared starting from equivalent amounts of the corresponding starting materials: 24 63578

No Rr Salt Sul.p. ° C

_ J__ __ (decomposed) _ 1 H 9-CH3 maleate 185-187 2 CH3 9-CH3 maleate 172-174 3 CH2 = CH-CH2 9 “CH3 maleate 159-161 4 H 8“ ch3 maleate 169-171 5 CH3 8 -CH3 maleate 162-164 6 CH3 7-F maleate 179-181 7 H 7-CF3 maleate 172-174 8 CH3 7-CF3 maleate 189-191 9 (CH2) 3-OH H fumarate 201-203 10 (CH2) j ^ -CH3 H fumarate 144-148

Example 17: 1,3,4,14b-Tetrahydro-2H, 1OH-pyrazino (1,2-a-pyrrolo- (2,1-c) (1,4) benzodiazepine and its mono-maleate

To a solution of 2.8 g of 1,4-dioxo-1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine In 50 ml of tetrahydrofuran, 45 ml of 1 molar diborane in tetrahydrofuran are added under stirring and ice-cooling. The mixture is stirred at room temperature overnight and refluxed for 4 hours. The reaction mixture is cooled to room temperature, 10 ml of glacial acetic acid are added, the mixture is evaporated and the residue is basified with 3N aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in ethyl ether. The solution is filtered and the filtrate is evaporated. 1,3,4,14b-Tetrahydro-2H, 1OH-pyrazino (1,2-a) -pyrrolo (2,1-c) [1,4] benzodiazepine, identical to the product of Example 3, is obtained. Its mono-maleate melts at 173-175 °.

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

25 63578

To a solution of 2.56 g of 11-carbethoxy-10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine in 50 ml of methylene chloride is added a solution of 5.8 g of g of sodium hydrogen carbonate in 50 ml of water. The mixture is cooled to 10 ° and a solution of 1.5 g of chloroacetyl chloride in 10 ml of methylene chloride is added dropwise with vigorous stirring. The layers are separated 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 off under reduced pressure. 11-Carbethoxy-10-chloroacetyl-10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine is obtained.

A solution of 10 g of 11-carbethoxy-10-chloroacetyl-10,11-dihydro-5H-pyrrolo (2,1-c) (1,4) benzodiazepine in 400 ml of ethanol is cooled to 10 ° and excess ammonia is introduced for 2 hours. The reaction mixture is then evaporated to dryness and the residue is dissolved in 100 ml of methylene chloride. Insoluble salts are removed from the solution by filtration and evaporated. 1,4-Dioxo-1,3,4,14b-tetrahydro-2H, 10H-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) benzodiazepine is obtained.

Claims (1)

26 63578 Claim: Analogue process for the preparation of new pharmacologically active 1,3,4,14b-tetrahydro-2H, 1OH-pyrazino (1,2-a) pyrrolo (2/1-c) (1/4) benzodiazepines of the general formula I R 1 -CX) = N, N = R 2 wherein represents hydrogen, lower alkyl, halogen or trifluoromethyl, R 1 represents hydrogen, lower alkyl, higher alkyl, lower alkenyl, lower alkynyl or (cycloalkyl, hydroxy, Lower picarbalkoxy or phenyl) -alkylalkyl, lower alkyl -7 ring rings, C 11 H 2n represents lower alkylene which separates both nitrogen atoms by two or three carbon atoms, and R 1 and R 4 represent hydrogen or lower alkyl; for the preparation of lower alkanoyl, higher alkanoyl or adamantoyl derivatives and 2-N-oxides, 2-lower alkyl quaternary ammonium derivatives of hydroxy-containing compounds from compounds in which R2 is other than hydrogen, and for the preparation of their salts, the expression "lower" meaning not more than 7 carbon atoms residues and the phrase "higher" means residues containing 8 to 20 carbon atoms, characterized in that a compound of general formula III r> · xn - r2 is reduced in which X represents lower alkylene, mono- or dioxo-lower alkylene, which separates both nitrogen atoms by two or three carbon atoms and wherein the oxo is attached to the carbon atom adjacent to the nitrogen atom, and Y represents an oxo or two hydrogen atoms, provided that at least one oxo group is in X or Y, and 1. if desired, a compound in which R 1 represents lower alkyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl-lower alkyl, phenyl-lower alkyl alkyl or carbalkoxy-lower alkyl, is coupled to a compound of formula I wherein R 2 represents hydrogen, by reaction of one of said residues with correspondingly reactive esters, and / or 2. if desired, a compound in which R 1 is lower alkyl is reduced to a final product in which R 2 is lower alkyl or lower alkynyl with catalytically activated hydrogen, and / or 3. if desired, the compound in which R 1 represents hydrogen is converted in the final product in which R 2 represents lower alkyl, lower alkenyl or C 1-4 phenyl, these residues by reaction with halogen formic acid-lower alkyl esters , and / or 4. if desired, a compound in which the substituent at the 2-position nitrogen atom is a lower alkanoyloxy-lower alkyl or higher alkanoyloxy-lower alkyl residue is esterified by reaction with a hydroxyalkylalkyl group by reaction with the corresponding acid derivative, and / or 5. if desired a derivative compound, quaternizing the product substituted in the 2-position by reaction with reactive esters of lower alkanols, and / or 6. if desired, N-oxy, N-oxidizing the product in which the nitrogen atom in the 2-position has a substituent, and / or 7. if desired a compound in which R 4 represents lower alkyl, a product in which R 1 is hydrogen, is metallated by reaction with reactive organometallic compounds and then reacted with reactive esters of lower alkanols, and / or, if desired, converted the resulting free compound into a salt or the resulting salt into the free compound or another salt, and / or, if desired, separating the resulting mixture of isomers or racemates into individual isomers or racemates, and / or, if desired, dividing the resulting racemate into optical antipodes, optionally forming the starting material under reaction conditions. 28 63578 Analogs for the preparation of pharmacologically active substances 1,3,4,14b-tetrahydro-2H, 10-pyrazino (1,2-a) pyrrolo (2,1-c) (1,4) -benzodiazepines med den all of the formulas I ri "CX u) · XN- <T c / h ^ -R0 n 2n 2 i vilken betecknar vete, lägalkyl, halogen ell trifluoromethyl, R2 betecknar väte # lägalkyl, högalkyl, lägalkenyl, lägalkynyl eller (cycloalkyl, hydroxy, pendant carbalkoxy or phenyl) -alkyl, colored cycloalkyl having 3 to 7 ring moieties, cyano-2-alkyl or p-alkyl, having a quaternary atom with three or more carbon atoms, and R 2 and R 2 -alkyl having the same or a lower alkyl; or an adamantoyl derivative of a compound of the hydroxyl group, 2-N-oxider, 2-carbon-quaternary ammonium derivative of a compound R2 of the compound which is # # and obtained from the group, the color of the "residue" is limited to 7 columns "rester with 8 to 20 chapters, to be reduced by a reduction of the amount of form III to 4? / Rj ri =. X-N_r2 1 vilken X betecknar ligalkylen, mono- eller dioxo-lägalkylen, som skiljer de tvä kväveatomerna med 2 eller 3 kolatomer och i vilken