NO900286L - PROCEDURE FOR PREPARING A PYRIDOBENZODIAZEPINE COMPOUNDS. - Google Patents

Description

The present invention relates to a method for the production of certain known pyrido [~1, 4] benzodiazepines, and therefore new chemical intermediates.

An important feature of the process is the use of a strong non-nucleophilic base such as sodium hydride to effect the condensation of an aminochloropyridine and an aryl(aminophenyl)methanone in admixture with a mobile inert liquid carrier to prepare pyrido Cl,ylbenzodiazepines. Alternatively, condensation can be initiated with titanium tetrachloride and terminated with the non-nucleophilic base, in which case new intermediates are prepared and used.

Aryl-substituted pyrido[/4]benzodiazepines produced by the method according to the invention are described in South African patent 81/7866, and are the subject of a corresponding US CIP application 395218 filed on 6 July 1982. By the production method described in these publications, aminohalopyridines and aminoarylphenones are heated without solvents to form pyrido [J. , 4*3 benzodiazepines.

Publicly Available US Patent Application 431997 filed September 30, 1982 describes the preparation of f2-[(nitropyridinyl)aminoj phenylDarylmethanones useful for the preparation of pyrido(i,43benzodiazepines by heating an undiluted halonitropyridine with an aminoarylphenone.

Heating and reacting such mixtures as described in the preceding publications involves difficult handling of viscous, sticky reactants on reaction products that adhere to the reaction vessel. According to the invention, on the other hand, the diazepine ring is formed by a strong non-nucleophilic base such as sodium hydride in a solvent or liquid carrier which gives high mobility, simple operation and increased yield, and direct formation of the sodium salts of pyridofl,4}benzodiazepines.

Regarding the production of certain chemical intermediates used in the method according to the invention, Yamamoto, M. and Yamamoto, H. describe in Chem. Pharm. Bull.

29 (8), 2135-2156 (1981) reaction of 2-amino-4-chlorobenzo-phenone and an amine in the presence of titanium tetrachloride as represented by the following equation:

wherein R*=alk<y>1, cycloalkyl, phenylalkyl, dialkylaminoalkyl and 4-morpholinoalkyl.

Also with regard to the preparation of certain other intermediates used in the method according to the invention, phase transfer catalyzed N-monoalkylation of 2-aminobenzophenones is described by Mouzin, G. et al, in Synthesis Communications Georg. Thieme Verlag 1981, pp. 448-449 as represented by the following equation: The pyridobenzodiazepine compounds which are produced directly by the new method according to the invention have the formula

wherein R is selected from the group consisting of alkali metal cation (M<+>), hydrogen, -alk -Q where Q is selected from hydrogen, halo, -NR<1>R<2>, -N=CH-0-C2H5or

R 1 and R 2 are selected from the group consisting of

of lower alkyl, -C(0)O-lower alkyl or where R and R together with the adjacent nitrogen atom can form a hetero-

cyclic radical selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl, and 4-substituted-piperazin-1-yl; Ar is selected from the group consisting of 2, 3 and 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted with 1 to 3 radicals selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro, and may be the same or different ; alk"<*>" is a straight or branched hydrocarbon chain containing 1-8 carbon atoms; Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro;

Y is selected from the group consisting of hydrogen or 1-2 radicals selected from lower alkyl, lower alkoxy or hydroxy, and may be the same or different, and acid addition salts thereof except when R=M<+>.

The compounds of formula I can be used as antidepressant pharmaceuticals or as intermediates in the preparation of other compounds of formula I and formula I as described in the following.

In addition, the compounds of formula I wherein R is

used to produce compounds

moieties of formula I wherein R is -alk -R R via new intermediates wherein R is alk -OH and alk^-OSC^W wherein W is as defined below.

In the further definition of symbols in the formulas and otherwise in the present description and claims, the expressions have the following meaning: The straight-chain or branched, connecting hydrocarbon chain marked "alk" containing 1-8 carbon atoms is exemplified by methylene (-Cf^-) / ethylene (- CE^-

1,3-butylene

and such.

The term "lower alkyl" includes straight-chain and branched hydrocarbon radicals of up to eight carbon atoms, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl and the like. The term "halogen" includes chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine.

The term "4-substituted-1-piperazinyl" denotes piperazine substituted in the 4-position with a lower alkyl or alkoxy carbonyl blocking group which can then be removed to form unsubstituted piperazine.

Pharmaceutically acceptable acid addition salts are the salts formed with the pyridobenzodiazepines prepared by the method according to the invention with any acid which is physiologically compatible with warm-blooded animals, such salts being either formed with strong or weak acids. Examples of strong acids are hydrochloric acid, sulfuric acid and phosphoric acid. Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, cyclohexanoic acid and the like.

The 6-aryl-11H-pyridoph2,3-bJ [1,4] benzodiazepines and their 5,6-dihydroderivatives covered by formula I have the formula:

6-aryl-11H-pyrido f3,4-bJ Cl,4]benzodiazepines and the 5,6-dihydroderivatives thereof covered by formula I have the formula: 10-aryl-5H-pyrido£4,3-b]Cl,4]benzodiazepines and the 10,11-dihydroderivatives thereof covered by formula I have the formula: 10-aryl-5H-pyrido[3,2-bJ[l, benzodiazepines and the 10,11-dihydroderivatives thereof covered by formula I have the formula:

In all of the formulas Iw to I^ given above, the symbols R, Ar, Z and Y have the meanings given under formula I.

With the aim of testing the antidepressant activity of the compounds prepared according to the invention, the procedure described by Englehardt, E.L. et al, J. Med. Chem. 11 (2): 325 (1968) which has been a good indication of the applicability of compounds in the treatment of human depression applied as follows: 20 mg/kg of the compound to be tested was administered to five adult female mice (ICR -DUB strain) intra-peritoneally 30 minutes before administration of a ptotic dose (32 mg/kg IP) of tetrabenazine (as methanesulfonate salt). 30 minutes later, the presence or absence of complete eyelid closure (ptosis) was determined in each animal. An ED, -q (mean effective dose) can be determined for each compound tested by blocking tetrabenazine-induced ptosis in mice following the procedure outlined by Litchfield et al, J. Pharmacol. Exp. Therap. 96: 99-113 (1949).

Compounds prepared by the process according to the invention or from the intermediates thereof which have antidepressant activity by the above-mentioned antidepressant test procedure have the formula I

wherein R is selected from the group consisting of hydrogen, lower

1 1 2 1 2

alkyl or -alk -N-R R ; R and R are selected from the group consisting of hydrogen, lower alkyl or where R and R together with the adjacent nitrogen atom can form a hydrocyclic residue selected from the group consisting of 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl or 4-lower alkyl-1-piperazinyl; Ar is selected from the group consisting of 2,3 or 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted with 1 to 3 radicals selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro, and may be the same or different ; alk<1>is a straight or branched hydrocarbon chain containing 1-8 carbon atoms; Z is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or nitro; Y is selected from the group consisting of hydrogen or 1-2 radicals selected from lower alkyl, lower alkoxy or hydroxy, and may be the same or different, and pharmaceutically acceptable acid addition salts. 1 1 2 The compound of formula I wherein R is -alk~-NR R and 12 P

R and R are lower alkyl or hydrogen have shown little evidence of antihistamine, anticholinergic and cardiotoxic side effects when tested in animals.

In preferred pyridobenzodiazepines in the treatment of depression are as follows: compound as active ingredient (free base) N,N-dimethyl — 6-phenyl-llH-pyridof2,3-b] fl,4} benzodiazepine-ll-propanamine.

6-(4-fluorophenyl)-N,N-dimethyl-11H-pyridoC2,3-b]Cl,4]benzodiazepine-11-propanamine.

6-phenyl-1H-pyrido[2,3-fcJ[1,4]benzodiazepine-11-propanamine. N-methyl-6-phenyl-IIH-pyridoph2,3-bJ fl,4]benzodiazepine-II-

propanamine.

6-(2-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b}[1,4]benzodiazepine-11-propanamine.

6-(2-fluorophenyl)-N,N-dimethyl-11H-pyrido f2,3-b3 Cl, 4]benzodiazepine-11-propanamine.

The generalized schematic equation for the production of the pyridobenzodiazepines according to the method according to the invention is indicated in reaction core I

<*>R = hydrogen, lower alkyl, -alk<1->NR<1>R<2>, -alk<1->N=CH-OC2H5or

1 2

and R and R are as defined under formula I.

X=chlorine, bromine, fluorine or iodine.

<**>R<3>= alkali metal ion, lower alkyl, -alk<1->NR<1>R<2>, -alk -N=

CH-OC„H cells

1 2

and R and R are as defined under formula I.

<***>Q=hydrogen, halogen, -alk<1->N=CH-OC2H5, alk1-NR1R2 or

1 2

and R and R are as defined under formula I.

<****>Add dimethylformamide to the reaction mixture when Q is

hydrogen, halogen -alk<1>N=CH-OC2H5.

Compounds of formula I a , I, b and ^ I c are covered by formula I.

Additional procedures for conversion of compounds

of formula I a or I, b wherein Q is

which has been separated from the reaction mixture (or which has been prepared by reacting isolated compounds in which R<3> is H with sodium hydride and reagent for useful antidepressants (formula VIII) is illustrated in the schematic reaction equation given in reaction scheme II

1 2

*R and R are as defined in formula I + hydrogen. Compounds of formula I and VI are covered by formula I and formula VII is covered by formula I p . Compounds of formula I e' , V and' VII are new.

New intermediates useful in the preparation of the pyridobenzodiazepines of formula I have the formula wherein Ar, Y and Z are as defined under formula I; X=halogen 4€1, Br, F, I) and R is selected from the group consisting of hydrogen, lower alkyl, -alk<1->NR<1>R<2>, -alk1-N=CH-OC2H5 or

11 2

wherein alk , R and R are as defined under formula I, and acid addition salts thereof.

All positions on the pyridinyl nitrogen covered by formula II are illustrated as follows:

Compounds of formula II are new compounds prepared by the following generalized reaction mixture:

X=halo,

1 2 R=H or -aD^-Q, wherein Q=H or -NR R

Compounds of formula. II are new. Compounds of formula IV are available commercially or can be readily prepared by known methods.

Compounds of formula III in which R is H and corresponding to formula Illa i

are available commercially or can be prepared by known methods. New compounds of formula III in which R is -alk^-Q and 1 2 Q is H or -NR R are prepared according to the following generalized schematic reaction equation from compounds of formula Illa in which X is halogen, R is selected from -alk^NR-R- , alk, -N= N=CH-OC2H5 or

1 2

and Ar, Z and R R are

as defined under formula I, and acid addition salts thereof.

An aim of the present invention is thus to provide a new process for the production of aryl-IIH-pyrido[1,43] benzodiazepines which are either antidepressant pharmaceutical agents or which are applicable in the preparation of other aryl-IIH-pyrido[4]benzodiazepines which have antidepressant activity utilizing a strong nucleophilic base in the condensation of (aminophenyl)arylmethanones and amino-chloropyridine or partially condensed intermediates from these reactants, all in a stirrable mixture with an inert liquid carrier.

Another aim is to provide new chemical intermediate products and methods therefore, since such intermediate products are applicable in the production of arylpyridobenzodiazepines, which intermediate products are generally stated to be phenylamines chained to the amine function via a phenyl-substituted iminomethylene bridge to halopyridine, and a method therefore.

A further aim is to provide certain new (aminophenyl)arylmethanones which are useful as intermediates in the process according to the invention.

The new method according to the invention for producing compounds of formula I comprises the following four steps 1 to 4 with an optional preliminary step A. Step 1, reaction of a compound of formula

or a mixture of compounds of formula in which Ar, Y and Z are as defined under formula I, X is halogen (chloro, bromine, fluorine or iodine), R is hydrogen or alk^-Q in which alk1 is as defined above and Q is selected from hydrogen, -NR<1>R<2>, -N=CH-OC2H5 or

1 2

and R and R are selected from lower alkyl,

-in

-C(0)O-lower alkyl or where R and R together with the adjacent nitrogen atom can form a heterocyclic residue selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl together with at least a stoichiometric amount of

a strong non-nucleophilic alkali metal base in a stirrable mixture with an inert liquid carrier, forming a compound of

formula

in a stirrable mixture with an inert liquid carrier, in which Ar, Y and Z are as defined above and R 3 is an alkali metal ion selected from sodium, potassium or lithium or -alk -Q in which alk is as defined above and Q is the same as in the starting the bond. Step 2, optionally if desired, reaction of a compound as prepared in step 1 in mixture with indicated liquid carrier where R 3 is an alkali metal ion, with a proton source to form a compound of formula in mixture with inert liquid carrier, in which Ar, Z and Y is as previously defined. Step 3, if desired, reacting a compound as prepared in admixture with liquid carrier in step 1 wherein R 3 is an alkali metal ion, with a reagent of formula wherein Q is selected from hydrogen, -NR 1 R 2 , -N=CH-0- C2H5or

1 2

and R and R are selected from the group consisting of

of lower alkyl, -C(0)0 — lower alkyl

1 2

or where R and R

together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of 1-piperidinyl,

1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-piperazin-1-yl, forming a compound of formula

in mixture with liquid carrier, in which Q has the same value as in the starting reagent and Ar, Y, Z and alk<1> are as defined above. Step 4, separation of a compound prepared in step 1 other than a compound in which R 3 is an alkali metal cation, and in steps 2 and 3 in a conventional manner from the support and the reaction mixture, forming a compound of formula

wherein Ar, Y, Z and R are as defined above, except that R is not an alkali metal cation, and acid addition salts thereof.

In another new variant of the method, compounds of formula II are prepared as used in step 1, see reaction scheme 1, by a preliminary step A as follows: Step A, reaction of a mixture of a compound of formula in which Ar, Z and R is as defined in step 1 and a compound of formula

wherein X is halogen and Y is as defined under formula I, together with titanium tetrachloride and an excess of a tertiary organic amine in an inert liquid carrier, and separating the product from the reaction mixture.

Of course, step A can also serve as a single process step for the preparation of compounds of formula II, see reaction core I, which, as indicated above, are new chemical intermediates. The following description applies to the preceding process:

In step 1, suitable liquid carriers must be non-reactive with the strong non-nucleophilic base, e.g. sodium hydride^ and other reactants free from moisture and stable enough to counteract the evolution of alkali metal hydroxides, which lead to impurities which are difficult to remove. Carriers generally classified as strictly protic are not suitable. Suitable liquid carriers may or may not solubilize the reactants or products, but some dissolution of organic reactants and products in the carrier is usually desirable. Examples of aprotic aromatic non-polar solvents suitable as carriers are toluene, xylene and benzene. Examples of aprotic non-polar ether solvents which are suitable carriers are tetrahydrafuran, dioxane and ethylene glycol dimethyl ether. Examples of aprotic polar solvents which are suitable as carriers are dimethylformamide, morpholinoformamide, alkyl-2-pyrrolidinones, pyridine and dimethylsulfoxide. A preferred carrier is toluene. The use of mixtures of these carriers has been found to be advantageous, and such advantage will depend on the specific reactants or products involved, particularly when solubility is a factor. Such a preferred mixture comprises toluene and tetrahydrofuran. Another preferred combination is toluene and dimethylformamide which in the case when radicals -alk^-O-

is involved. The amount of carrier can vary widely from as little as five parts per 100 parts by weight of the reactants to as much as 100 parts or more per 100 parts by weight of the reactants. In general, the minimum amount of carrier that can be used is the amount of carrier that will provide sufficient mobility for the reaction mixture to be stirred and which gives the mixture flowability. When toluene is used, 8-12 parts by weight of carrier in relation to the reaction mixture is a preferred range. A wide range of temperatures can be used in step 1, suitably from 20 to 150°C, with 40 to 120°C being preferred. The more specifically preferred temperature is that obtained with boiling tetrahydrofuran and boiling toluene, ie 65 to 110°C. Although it is possible to carry out the reaction using a stoichiometric amount of sodium hydride, a more complete reaction is obtained using at least one molar excess of base. Two molar equivalents of strong alkali metal, non-nucleophilic base, e.g. sodium hydride is therefore preferred. A preferred way of carrying out the reaction in step 1 is to slurry or dissolve the aminohalopyridine in a suitable aprotic carrier, preferably toluene, and simultaneously add a slurry of the non-nucleophilic alkali metal base in the same carrier and a solution of aminobenzophenone in a suitable aprotic non- polar solvent, preferably tetrahydrofuran or dioxane, at a temperature such that the tetrahydrofurans boil off during the addition after which the aminobenzophenone is reacted. As indicated above, sodium, potassium or lithium hydrides are suitable strong non-nucleophilic bases which facilitate the reaction, which enable the use of the solvent carriers, and which are preferred, with sodium hydride being particularly preferred. Other strong, non-nucleophilic bases that can be used are potassium tertiary butoxide, sodium triphenylmethane, sodium dimethylsulfoxide and alkali metal amides.

The following reaction core illustrates the balanced equation involved in step 1 for each type of reactant when the strong, non-nucleophilic alkali metal base is sodium hydride.

In each case it is preferred to use an excess of sodium hydride.

In step 2, an alkali metal salt of compounds as prepared in step 1 and still in the liquid carrier is converted to

compounds by reaction with any re-

agent capable of providing a proton source. Examples of suitable agents are water, weak or strong acids, and aqueous buffer salts. The latter agent is preferred, and the preferred buffer salt is ammonium chloride. A blue-green color of the solution initially present in this step is an indication of the sodium salt of pyridobenzodiazepine, and after the proton source is added, such as aqueous ammonium chloride solution, a golden-yellow solid material is precipitated.

In step 3, the halo-alk^-Q reagent is added in a suitable organic solvent to the reaction mixture containing a metal salt, i.e. R 3=alkali metal ion, and the reaction mixture is heated until the reaction is complete. Solvents used to dissolve the reagent are generally the same as used for supports in step 1, except when Q is pyranoyloxy =

halo or -N^H-OC^H,-used dimethyl-

formamide. The reaction mixture is filtered to remove the halogen byproduct salt.

In step 4, the products can be isolated, a) by extraction, preferably by partitioning between water and methylene chloride; b) by chromatographic separation; c) by conversion to acid addition salts and recrystallization from suitable solvent or solvent combinations; d) by dissolving the strong acid salts such as hydrochloride in water and extracting contaminants with a solvent such as toluene.

In preliminary stage A, compounds of formula II are separated from the liquid carrier in a conventional manner, such as evaporation of solvents and distribution between water and organic solvent, filtration to remove titanium oxide, washing, drying and evaporation of the solvent layer, forming the product as a residue that can be used directly in step 1. The product can be further purified by chromatography or recrystallization from organic solvents.

A preferred procedure for carrying out the combination of steps 1 and 3 (ie when step 2 is not included) is to simultaneously add a tetrahydrofuran or dioxane solution of a compound of formula

wherein Ar, R and Z are as defined in step 1, and a slurry of sodium hydride in toluene, to a hot toluene solution of a pyridine compound of formula wherein X and Y are as defined in step 1, at a rate such that the tetrahydrofuran or dioxane is distilled away at the same rate as it is added, after which a toluene solution is added containing a reagent of the formula wherein alk<1>and Q are as defined in step 3, except in the case where Q is in which case the solvent for halo-alk -Q - the reagent is preferably dimethylformamide. A preferred embodiment is the use in step 1 of a mixture of compounds of formula

Another preferred embodiment is the use in step 1 of a mixture of compounds of formula III and IV and a strong base consisting of sodium hydride.

A further preferred embodiment is the use in step 1 of a mixture of compounds of formula III and IV in which R is H.

A further preferred embodiment is the use in step 1 of a mixture of compounds of formula III and IV in which R is H and the strong base is sodium hydride.

Another preferred embodiment is the use in step 1 of a mixture of compounds of formula III and IV consisting of 2-aminobenzophenone and 3-amino-2-chloropyridine and a strong base consisting of sodium hydride in step 1 to form the sodium salt of 6-phenyl -llH-pyrido/,2 , 3-bJ /j., 4j benzodiazepine in step 2.

As an extension of the process illustrated in steps 1-4 with or without the optional step A, the following additional step (see reaction core II) has recently been used to obtain certain compounds of formula I and I pi steps 5 to 8. As will be seen is the generic framework of compounds that can be prepared extended to include R=OH,

-alk<1->OSO--alkyl, alk^-OSO^-phenyl and where one or both of R and R is H. Step 5, reaction of a new compound obtained in step 4 of formula

wherein Ar, Y, Z and alk<1> are as defined under formula I with a strong concentrated acid in a protic solvent, preferably ethanol, forming a new compound of formula

in which Ar, Y, Z and alk<1> are as defined above.

Step 6, reacting a compound prepared in step 5 with thionyl chloride to form a compound of formula

in which Ar, Y, Z and alk<1> are as defined above.

Step 7, reacting a compound prepared in step 5 with a reagent

wso2ci

wherein W is lower alkyl, phenyl or tolyl to form a compound of formula

in which Ar, Y, Z and alk1 are as defined above.

Step 8, reaction of a compound prepared in step 6 or 7, with a secondary or primary amine of formula

1 2 wherein R and R are selected from hydrogen, lower alkyl, and wherein 1 2 -NR R may be a heterocyclic radical as defined under formula I, forming a compound of formula 1 12 12 wherein Ar, Y, Z, alk and R, R and -NR R are as defined above. Primary amines can be prepared by reacting compounds in which -NR R is phthalimido with hydrazine hydrate and acid. Compounds prepared by the process wherein Q is -NHC(0)O-lower alkyl can be reacted with lithium aluminum hydride to form secondary amines of formula

Compounds in which Q is -N=CH-OC2H5 can also be reacted with sodium borohydride to form secondary amines.

The subsequent preparations 1 and 2 illustrate the method for the preparation of aryl-2-amino-substituted-phenyl-methanone of formula III in which R is different from hydrogen (see reaction nucleus II), and must not be regarded as limiting.

Production 1

f 2-£C3-(dimethylamino)propylJaminoJphenylj phenylmethanone~ monohydrochloride

A dry solution of 145.8 g (1 .2 mol) of 3-dimethylaminepropyl chloride in 700 ml of tetrahydrofuran. The mixture was mechanically stirred and maintained at reflux overnight. The tetrahydrofuran solution was decanted from and concentrated. The concentrate was dissolved in toluene. The solid material from which the tetrahydrofuran was decanted was dissolved in water and extracted with toluene solution. The resulting toluene layer was separated and washed twice with water and was then extracted three times with portions of 20% acetic acid totaling 600 ml. The combined acetic acid solution was washed once with toluene and then basified with 50% sodium hydroxide in the presence of toluene. The aqueous layer was separated and extracted once with toluene. The toluene layers were combined and washed with water, dried over sodium sulfate and evaporated to give 112.8 g (100%) of almost pure free base of the title compound. A 20 g sample was dissolved in 75 ml of isopropyl alcohol to which was added 0.076 mol of hydrogen chloride dissolved in 35 ml of isopropyl alcohol. Additional isopropyl alcohol and isopropyl ether (about 1:1) were added to bring the volume to 200 mL. The mixture was stirred overnight. The yellow solid was collected by filtration, washed once with 1:1 isopropyl alcohol/isopropyl ether and twice with isopropyl ether. The weight of the product obtained from the 20 g sample was 16.4 g, melting point 182-183°C.

Analysis: Calculated for C18H23<N>2OCl: C.67.81; H, 7.27;

N,8,79

Found : C,67,68; H, 7.29;

N,8,70 Production 2

By following the procedure described in Preparation 1 but replacing 3-dimethylaminopropyl chloride with the following compounds: 3-(1-pyrrolidinyl)propylamine, 3-(1-piperidinyl)propylamine and 3-(4-morpholinyl)propylamine, it was obtained: [ 2-[[ 3-(1-pyrrolidinyl)propylaminophenyl Jphenylmethanone, C2-CC3-(1-piperidinyl)propylamino Itenyl^phenylmethanone and C2-CC3-(4-morpholinyl)propylaminophenyljphenylmethanone.

The following examples illustrate the invention.

Example 1

N-f(2-aminophenyl)phenylmethylenej-2-chloro-3-pyridinamine

To a stirred suspension of 3.94 g (0.02 mol) 2-aminobenzophenone and 2.58 g (0.02 mol) 3-amino-2-chloropyridine in 20 ml toluene and 6.2 ml (0.048 mol) triethylamine under a nitrogen blanket in an ice bath, a solution of 2.28 g (0.012 mol) titanium tetrachloride in 10 ml toluene was added over a five minute period. After the addition was complete, the ice bath was removed. The mixture turned dark red and a solid material appeared. About. 15 ml of toluene was added followed by 15 ml of methylene chloride. After a total of one hour, TLC showed that starting material and product were present. After a total of three hours, an additional 1.52 g (0.08 mol) of titanium chloride in 4.15 ml (0.032 mol) of triethylamine and methylene chloride was added to the reaction mixture which was then stirred overnight. The mixture was evaporated. The residue was partitioned between water and methylene chloride. Solid precipitate was removed by filtration. The aqueous layer was separated and extracted again with methylene chloride. The methylene chloride layers were combined and backwashed with sodium chloride solution, dried over sodium sulfate and evaporated to give 6.2 g of an orange oil. The chemical ionization mass spectrometer gave a product peak at m/e 308 and starting material peaks at m/e 198 and m/e 129. NMR analysis indicated that the product was composed of 75% of the title compound. The HNMR spectrum of the impure product was obtained in CDCl3 containing 1% tetramethylsilane (TMS). The chemical shifts, multiplicities and what these can be attributed to are given below.

Mixture

The ratio between the integrations at 7.50 ppm and those at 7.35 ppm is roughly calculated as 3:1, so that the product is approx. 75% A.

Example 2

N-f(2-aminophenyl)phenylmethylenej2-chloro-3-pyridinamine

To a stirred suspension of 7.88 g (0.04 mol) of 2-aminobenzophenone and 5.14 (0.04 mol) of 3-amino-2-chloropyridine in 100 ml of methylene chloride and 27.2 ml (0.2 mol) triethylamine under a blanket of nitrogen was added to a solution of 5.28 ml of titanium tetrachloride in 20 ml of methylene chloride dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 22 hours. Water was slowly added to the reaction mixture until a thick suspension was formed. The suspension was poured into 150 ml of water and the resulting mixture was stirred for 15 minutes. The mixture was filtered to remove titanium dioxide. The filter cake was rinsed with methylene chloride. The organic layer of the filtrate was separated. The aqueous layer was extracted once with methylene chloride. The methylene chloride layers were combined, washed with dilute sodium bicarbonate solution, dried and evaporated to give 12.6 g of brown syrup. NMR analysis indicated that the product was composed mainly of the title compound and with approx. 15% 3-amino-2-chloropyridine starting material. The HNMR spectrum of the crude product was obtained in CDCl 2 containing 1% tetramethylsilane (TMS). The chemical shifts, multiplicities and what these can be attributed to are indicated in what follows.

Mixture

The ratio between the integrations at 7.70 ppm and those at 7.55 ppm is roughly calculated as 13:2, so that the product is 85% A.

Example 3

By following the procedure described in Example 2, but replacing 3-amino-2-chloropyridine with the following compounds: 4-amino-3-chloropyridine, 3-amino-4-chloropyridine and 2-amino-5-chloropyridine, it was obtained

a) N-f(2-aminophenyl)phenylmethylene]-3-chloro-4-pyridinamine,, b) N-C(2-aminophenyl)phenylmethylene]-4-chloro-3-pyridinamine and c) N-C(2-aminophenyl )phenylmethylenej-3-chloro-2-pyridinamine.

Example 4

By following the procedure described in Example 2 but replacing 2-aminobenzophenone with the following compounds: 2-amino-4-chlorobenzophenone,

2-amino-4-methylbenzophenone,

2-amino-4-methoxybenzophenone,

2-amino-4-hydroxybenzophenone,

2-amino-4-nitrobenzophenone,

2-amino-5-chlorobenzophenone,

2-amino-4'-chlorobenzophenone and

2-amino-41-methylbenzophenone, it was obtained:

a) N-f(2-amino-4-chlorophenyl)phenylmethylene]-2-chloro-3-pyridinamine, b) N-£(2-amino-4-methylphenyl)phenylmethylene]-2-chloro-3-pyridinamine, c) N-f(2-amino-4-methoxyphenyl)phenylmethylene]-2-chloro-3-pyridinamine, d) N-C(2-amino-4-hydroxyphenyl)phenylmethylene]-2-chloro-3-pyridinamine, e) N-f(2-amino-4-nitrophenyl)phenylmethylene]-2-chloro-3-pyridinamine, f) N-f(2-amino-5-chlorophenyl)phenylmethylene3-2-chloropyridinamine, g) N-£(2 -aminophenyl)-4-chlorophenylmethylene]-2-chloro-3-pyridine-' amine and h) N-[(2-aminophenyl)-4-methylphenylmethylene]-2-chloro-3-pyr dynamite. Example 5 N'-f2-f(2-chloro-3-pyridinylimino)phenylmethyl]phenyl-N,N-dimethyl-1,3-propanediamine To a mixture 2.82 g (0.01 mol) C2-f f3- (dimethylamino) propyl] amino"] phenyl] phenylmethanone and 1.29 g (0.01 mol) 3-amino-2-chloropyridine, 6.2 ml (0.048 mol) triethylamine and 20 ml methylene chloride stirred in an ice bath and under nitrogen atmosphere, 2.28 g (0.012 mol) of titanium tetrachloride in 10 ml of methylene chloride was added over five minutes.The mixture was then stirred at room temperature for two days during which time the mass spectrum-CI showed little change in relative intensity for M.W.129 (starting pyridine ) and M.W. 393 (title product). Water was added to the reaction mixture and stirring was continued for 1.5 hours. The mixture was filtered to remove solids and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of the layers. Methylene chloride- layer was washed once with more sodium chloride solution, the aqueous layer having a pH of 6 was basified to pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloride solution. All methylene chloride extracts were combined, dried and evaporated to give 4.8 g of a semi-solid product. TLC of the product showed that it contained very little starting 3-amino-2-chloropyridine. Mass spectrophotometric analysis showed the presence of compounds with molecular weights corresponding to the title product (393), 3-amino-2-chloropyridine (129) and triethylamine (102) but no C2-CT3-(dimethylamino)propyl]amino]phenyl] phenylmethanone. The HNMR spectrum in CDCl containing 1% TMS indicated that the product consisted primarily of the title compound and some triethylamine. No 3-amino-2-chloropyridine was observed. The chemical shifts, multiplicities and what these can be attributed to are indicated in what follows. A mixture of

Example 6

N'-f 2- L ( 2- chloro- 3- pyridineylimino) phenylmethyllphenylj-N, N- dimethyl- 1, 3- propanediamine

To a mixture of 6.37 g (0.02 mol) L2-Cf3-(dimethylamino)propylJamino]phenyl]phenylmethanone and 2.57 g (0.02 mol) 3-amino-2-chloropyridine, 16.8 ml ( 0.12 mol) of triethylamine in 80 ml of methylene chloride, stirred in an ice bath and under a nitrogen atmosphere, was added dropwise 2.64 ml (0.024 mol) of titanium tetrachloride in 20 ml of methylene chloride over 10 minutes. The mixture was allowed to cool to room temperature with continuous stirring. The next day, chemical ionization mass spectrometry showed that the reaction was essentially complete with no methanone starting compound present. TLC showed that little of the starting pyridine was present. The mixture was stirred over the weekend. Water was added to the reaction mixture and stirring was continued for 1.5 hours. The mixture was filtered to remove solids and the filter cake was rinsed with methylene chloride. Saturated sodium bicarbonate solution was added to facilitate separation of the layers. The methylene chloride layer was washed once with more bicarbonate solution.

The aqueous layer was washed with methylene chloride and all of the methylene chloride extracts were combined, dried and evaporated to give 7.35 g (93%) of a brown oil. The chemical ionization mass spectrum gave a signal corresponding to a molecular weight of the title compound at m/e 393.5, and showed traces of compound at m/e 282 (starting methanone - free base) and some compound at m/e 102 (triethylamine) and some compound at m/e 129.5 (amino-chloropyridine starting compound). The HNMR spectrum of the product was obtained in CDCl containing 1% tetramethylsilane (TMS) and was consistent with the proposed structure and with methylene chloride as a minor impurity. No signal from the starting materials was detected. The chemical shifts , multiplicities and what these can be attributed to are stated in what follows.

Example 7

6- phenyl- llH- pyridoC2, 3- b] Cl, 4lbenzodiazepine- ll- pyra-

noyloxypropyl

To a solution of 10.82 g (0.04 mol) of 6-phenyl-11H-pyrido£2,3-b]f 1,4]benzodiazepine in 60 ml of dimethylformamide was added 3.2 g (0.08 mol) sodium hydride as a 60% suspension in mineral oil, followed by 13.2 ml (0.08 mol) of 1-chloro-3-pyranoyloxypropane. The course of the reaction was monitored via TLC, and an additional 0.7 g of 60% sodium hydride was added. After the reaction mixture had been stirred for three days, traces of pyridobenzodiazepine starting material were detected. The reaction mixture was treated with aqueous ammonium chloride and was extracted three times with toluene. The toluene layer was backwashed with water, dried, treated with activated carbon and filtered. The filtrate was evaporated to give 22.8 g of a black oil. The oil was passed through a short column of 45 g silica gel, and was first eluted with toluene and then with toluene-ethyl acetate. Fraction A was concentrated to give 16.3 gave a mixture consisting of 85% of title product and 15% 1-chloro-3-pyranoyloxypropane + mineral oil + toluene. Fraction B was concentrated to give 2.4 g of residue. Mass spectrum of fraction A showed the following: m/e 179 which is the 1-chloro-3-pyranoyloxypropane starting compound used in excess, m/e 330 which is a fragment from the product, and m/e 414 which is the title product.

The HNMR spectrum of the crude product was obtained and was consistent with the proposed structure and with toluene and 1-chloro-3-pyranoyloxypropane. The chemical shifts, multiplicities and what these can be attributed to are indicated in what follows.

Example 8

6- phenyl- llH- pyridof2, 3- b] [ l , 4] benzodiazepine- ll- hydroxypropyl

A mixture of 3.6 g (0.0088 mol) of 6-phenyl-11H-pyrido C2,3-b]T1,4}benzodiazepine-11-pyranoyloxypropyl, 3.6 ml of 37% aqueous hydrochloric acid and 15 ml of 95 % ethanol was stirred overnight. 1.7 g of sodium hydroxide pellets were added and the mixture was stirred until the pellets were dissolved. The solvent was evaporated and the residue was partitioned between methylene chloride and water. The aqueous layer was extracted once more with methylene chloride. The combined methylene chloride layers were washed with water, dried and evaporated to give 2.93 g of a brown oil which crystallized. The crystals were separated by filtration and washed with isopropyl ether-petroleum ether. After drying, the yellow crystals weighed 1.91 g, melting point 131-134°C. Mass spectrum of the product showed the following: m/e 103 which is isopropyl ether which was used as crystallising agent, m/e 414 which is starting material, trace amount, and m/e 33 0 which is the title product. The HNMR spectrum of the crystalline product was obtained and was consistent with the proposed structure

The chemical shifts, multiplicities and what these can be attributed to are indicated in what follows.

Example 9

N'- C2- chloro- 6- C( 3- chloro- 4- pyridineylimino) phenylmethyl] phenylJ- N, N- dimethyl- 1, 3- propanediamine

By following a procedure described in Example 6 using E2-CT3-(dimethylamino)propylamino-6-chloro-phenyl]phenylmethanone, the title compound was prepared.

Example 10

6- phenyl- llH- pyrido f2 , 3- bJ Cl , 47benzodiazepine sodium salt (impure mixture)

To a solution of 516 g (4 mol) 3-amino-2-chloropyridine in 3.8 1 toluene was simultaneously added in batches a solution of 830 g (4.2 mol) 2-amino-benzophenone in 2.2 1 pyridine , and a slurry of 290 g (12 mol) (as 60% in mineral oil) of sodium hydride slurried in 500 ml of toluene over two hours under reflux conditions. The reflux was continued for a further three hours. The development of hydrogen was powerful. After stirring overnight at ambient temperature, the mixture was heated to remove a 3.8 L volume of distillate which NMR showed to be 65% toluene and 35% pyridine.

Example 11

6- phenyl- 11H- pyrido C2, 3] fl, 4] benzodiazepine

A solution of 440 g (8 mol) of ammonium chloride in 700 ml of water was carefully added to the residual mixture according to example 10 (great foaming). The mixture was heated to remove 1.5 L of distillate composed of water, pyridine and toluene. To the residual solution was added 500 ml of toluene, and the mixture was heated a second time to remove 900 ml of distillate. A further 500 ml of toluene was added to the residual solution and the mixture was again heated to remove 500 ml of distillate. The orange colored residual slurry was diluted with 7.2 L of tetrahydrofuran. The mixture was filtered, the filter cake was washed by slurrying in 3 L of hot tetrahydrofuran and the slurry was filtered. The filtrates were combined and passed through a silica gel column. The eluent was concentrated and the residue slurried in isopropyl ether-toluene (3:1). A brown-orange solid was collected by filtration. The filtrate was concentrated and azeotropically distilled with toluene to remove pyridine. The residual solution was diluted with isopropyl ether-toluene (1:1) and the solution was cooled to form yellow crystals. The combined yield of the title compound was 813 g (75%) based on starting materials of Example 10.

TLC analysis of the product gave a good comparable result with the known title product.

Example 12

N, N- dimethyl- 6- phenyl- llH- pyrido f2, 3- b] fl, 4] benzodiazepine- ll- propanamine furamate fl: ]]

A mixture of 920 g (3.4 mol) of 6-phenyl-1lH-pyrido-[2,3-b]Cl,4]benzodiazepine prepared as described in Example 11 (and a further smaller experiment) in 2 1 of toluene and 1 .5 1 of tetrahydrofuran, and 84 g (3.5 mol) of sodium hydride (as 60% in mineral oil) were heated to reflux under vigorous evolution of hydrogen. The mixture became dark green in colour. To the mixture was added a solution of 7.6 moles of 3-dimethylaminopropyl in 2 L of toluene, and the reaction mixture was heated to reflux for five hours and then cooled overnight. The dark yellow mixture was filtered with difficulty in removing the sodium chloride. The filtrate was concentrated to remove all but 1.5-2 L of toluene. The residual toluene concentrate was diluted with 2 l of methylene chloride, and the solution was washed with water. The washed solution was concentrated on a rotary evaporator at 80°C bath temperature. The remaining black syrup weighed 1400 g. The syrup was very slowly turned into a hot solution of 394 g (3.4 mol) fumaric acid in 4 1 isopropyl alcohol. The solution was treated with activated carbon and filtered. The filtrate was seeded and refrigerated overnight. The yellow precipitate was collected by filtration and washed with a small amount of isopropyl ether and dried to give 1491 g (93%) of the fumarate salt. The salt was dissolved in 17.2 L of isopropyl alcohol, and the solution was treated with 75 g of carbon heated to reflux for 15 minutes, and was filtered through a column containing 100 g of celite which had been moistened with 200 ml of isopropyl alcohol. The filtrate was then stirred for 20 hours. The precipitate was collected by filtration, the filter cake was washed with cold isopropyl alcohol followed by 3 L of isopropyl ether and was dried to give 1255 g (85%) of crystalline product. The crystals were triturated with 1 L of isopropyl ether-methylene chloride (3:1 by volume), and the mixture was subjected to filtration. The filter cake was vacuum dried at 60°C overnight and under high vacuum, melting point 174-175°C, uncorrected. Analysis: calculated for C27H28<N>4°4<:>C'68'63'H,5.97;

N,11,86

found : C, 68.48; H,6.00;

N,ll,80

Example 13

N, N- dimethyl- 6- phenyl- llH- pyrido[ 2 , 3- b] Cl , 4] benzodiazepine- ll- propanamine fumarate 11:13

Preparation of the impure free base of the title compound

To a solution of 780 g (6 mol) 3-amino-2-chloropyridine in 1 2 1 toluene under reflux conditions was added simultaneously a solution of 1320 g (6.6 mol) 2-aminobenzophenone in 3 1 tetrahydrofuran, and a slurry of 444 .0 g (18.5 mol) of sodium hydride in 1.2 1 of toluene over three hours. (During the addition at reflux conditions, the tetrahydrofuran was distilled from at the same rate as it was added). 12 mol of 3-dimethylaminopropyl chloride in 3.5 1 of toluene were added to the reaction mixture. The mixture was heated to reflux for five hours and then allowed to cool and allowed to stand overnight at ambient temperature. TLC indicated that some 6-phenyl-11H-pyrido 12,3-b]T1,4]benzodiazepine was present so an additional 12 g of sodium hydride was added and the mixture was heated to reflux to complete the reaction. The mixture was allowed to cool slightly and 2 L of saturated ammonium chloride and 3 L of water were added. The aqueous layer was discarded and the toluene layer was washed four times, each time with 2 L of water. The toluene layer was concentrated on a rotary evaporator and finally subjected to high vacuum distillation to remove unreacted 3-dimethylaminopropyl chloride. Yield of impure syrup containing primarily a free base of the title compound was 2680 g.

Conversion of fumarate salt and purification thereof

The impure syrup was mixed with 6 moles of fumaric acid in 10 1 isopropyl alcohol. The precipitate was collected and washed with 3 L of isopropyl alcohol and was recrystallized twice to form 2200 g of yellow crystals. A sample triturated with a mixture of hot isopropyl ether-methylene chloride (3:1 by volume) gave the following analysis: Analysis: calculated for C27<H>2gN4<0>4<:>C, 68.63; H, 5.97;

N,ll,86

found : C,68.23; H, 5.99;

N,11,87

Example 14

N, N- dimethyl- 6- phenyl- llH- pyrido C2, 3- b] Cl, 4] benzodiazepine- ll- propanamine fumarate Cl:1]

Preparation of the impure free base of the title compound

To a solution of 129 g (1 mol) of 3-amino-2-chloropyridine in 350 ml of pure toluene at reflux was added simultaneously a solution of 217 g (1.1 mol) of 2-aminobenzophenone in 500 ml of tetrahydrofuran, and a slurry of 74.5 g (3.1 mol) of sodium hydride in 250 ml of toluene over 1.5 hours. (During the addition at reflux, tetrahydrofuran was distilled from at the same rate as it was added). 2 mol of 3-dimethylaminopropyl chloride in 600 ml of toluene were added to the reaction mixture. The mixture was heated to reflux for five hours.

To the black slurry composed of the free base of the title compound and some unreacted sodium hydride and 3-dimethylaminopropyl chloride in toluene (shown by TLC to be free of 6-phenyl-11H-pyrido[2,3-b]Cl,4Ubenzodiazepine) was added 1 mole ammonium chloride in 800 ml of water. The organic layer was separated and washed with four 500 ml portions of water. The organic layer was concentrated on a rotary evaporator to remove solvent and under high vacuum to remove unreacted 3-dimethylaminopropyl. The yield of the dark brown-yellow syrup composed mainly of the free base of the title compound was 433 g.

Conversion to fumarate salt

The syrup was dissolved in 800 ml isopropyl alcohol, and 1 mol of fumaric acid in 1.5 1 isopropyl alcohol was added to the solution. The salt was crystallized by seeding and was separated by filtration.

Example 15

6-(2-thienyl)-IIH-pyrido C2,3-b]Cl,4]benzodiazepine

By following the procedure described in Examples 10 and 11 but using 2-aminophenyl-(2-thienyl)methanone instead of 2-aminobenzophenone according to Example 10, the title compound was obtained.

Example 16

6-(3-thienyl)-HH-pyridoI2,3-b][1,4]benzodiazepine

By following the procedure described in Examples 10 and 11 but using 2-aminophenyl-(3-thienyl)methanone instead of 2-aminobenzophenone according to Example 10, the title compound was obtained.

Example 17

6-(2-pyridinyl)-llH-pyrido Z2,3-bJQ,4]benzodiazepine

By following the procedure described in Examples 10 and 11 but using 2-aminophenyl-(2-pyridinyl)methanone instead of 2-aminobenzophenone according to Example 10, the title compound was obtained.

Example 18

6-(3-pyridinyl)-IIH-pyridof2,3-b]Cl,4]benzodiazepine

By following the procedure described in Examples 10 and 11 but using 2-aminophenyl-(3-pyridinyl)methanone instead of 2-aminobenzophenone according to Example 10, the title compound was obtained.

Example 19

6-(4-pyridinyl)-IIH-pyrido[2,3-b]Cl,4]benzodiazepine

By following the procedure described in Examples 10 and 11 but using 2-aminophenyl-(-pyridinyl)methanone instead of 2-aminobenzophenone according to Example 10, the title compound was obtained.

Example 20

By following the procedure described in Example 12 but replacing 6-phenyl-1H-pyrido C2,3-b][1,4]benzodiazepine with the following compounds: 6-(2-thienyl)-1H-pyrido C2,3-b] Cl,4]benzodiazepine, 6-(3-thienyl)-llH-pyrido C2,3-b]Cl,4]benzodiazepine, 6-(2-pyridinyl)-llH-pyridoC2,3-b]Cl,4]benzodiazepine . ,N-dimethyl-6-(2-thienyl)-11H-pyridoC2,3-b] fl,4]benzodiazepine-11-propanamine f umar at , b) N,N-dimethyl-6-(3-thienyl) - HH-pyridoC2 , 3-cfu Cl, 4]benzodiazepine-11-propanamine f umar at , c) N,N-dimethyl-6-(2-pyridinyl)-llH-pyridof2,3-b] [1,4]benzodiazepine -11-propanamine fumarate, d) N,N-dimethyl-6-(3-pyridinyl)-11H-pyrido C2,3-b]Cl,4]benzodiazepine-11-propanamine fumarate and e) N,N-dimethyl-6- (4-pyridinyl)-11H-pyridoC2,3-b]Cl,4]benzodiazepine-11-propanamine fumarate.

Example 21

By following the procedure described in Example 5, but replacing C2-CC3-(dimethylamino)propyl]amino]phenyl]phenyl-methanone with the following compounds: C2-CC3-(1-pyrrolidinyl)propyl]amino]phenyljphenylmethanone, f 2-TC3 -(1-piperidinyl)propyl]aminoJphenyl]phenylmethanone and C2-CT3-(4-morpholinyl)propyljamino]phenyljphenylmethanone were obtained: N-C2-C(2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl) propanamine, N-C 2 -f(2-chloro-3-pyridinylimino)-3-(1-piperidinyl)propanamine and N-f 2 -f(2-chloro-3-pyridinylamino]-3-(4-morpholinyl)propanamine.

Example 22

N, N- dimethyl- 6- phenyl- llH- pyrido- C2 , 3- b] Cl, 4lbenzodiazepine- ll- propanamine fumarate fl. : 1]

To a solution of 2.5 g (0.00637 mol) of N'-£j2-£(2-chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamine obtained in Example 5 in 20 ml of toluene (the solution was dried by azeotropic distillation using a Dean Stark trap and was cooled) was added 0.62 g (0.0128 mol) of sodium hydride as a 50% mineral oil suspension added to a small amount of toluene. The mixture was heated to reflux for three hours. The water was carefully added. The toluene layer was washed twice with water and was extracted twice with 1 N aqueous hydrochloric acid solution. The aqueous acidic layer was washed with toluene. The aqueous layer was then basified with 50% sodium hydroxide solution in the presence of toluene. The aqueous layer was extracted twice with toluene. The toluene layers were combined, treated with carbon, filtered and evaporated to give 2.03 g of a brown oil, the free base of the title compound (89.5% yield). The oil was dissolved in isopropyl alcohol and 0.7 g of fumaric acid was added while heating. The solution was seeded with the known title compound and allowed to stand for 15 hours at room temperature. Isopropyl ether was added with stirring for 15 minutes. The solid was collected by filtration and washed once with isopropyl alcohol-isopropyl ether mixture and once with isopropyl ether. After air drying, 2.4 was obtained

g (80%) with melting point 168-170°C. The melting point, NMR analysis and mass spectrum analysis were comparable to the known title compound.

Example 23

By following the procedure described in Example 22 but substituting N'-C2-C(2-chloro-3-pyridinylimino)phenylmethyl]phenyl]

-N,N-dimethyl-1,3-propanamine with the following: N-C2-|j[2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl)propanamine, N-f2-fi 2-chloro-3 -pyridinylimino)-3-(1-piperidinyl)propanamine and N-T2-r(2-chloro-3-pyridinylimino)-3-(morpholinyl)propanamine ■ was obtained: 6-phenyl-11-[ 3-(1 -pyrrolidinyl)propyl]-1lH-pyrido £2,3-b] Cl,4]

benzodiazepine fumarate,

6-phenyl-11-[3-(1-piperidinyl)propyl]-11H-pyrido C2,3-b][1,4J

benzodiazepine fumarate and

6-phenyl-11-D-(4-morpholinyl)propyl]-HH-pyridoC2,3-bJD-,4]

benzodiazepine fumarate using ethanol-ethyl acetate recrystallizing solvent in the latter case.

Claims (1)

Process for the production of pyridobenzodiazepine- compounds of formula 1 2 where Ar is phenyl and Q is hydrogen, -NR R or 1 2 in which R and R are C^ -C^ -alkyl, and acid addition salts thereof, characterized in that a compound of formula or a mixture of compounds of formula in which Ar and Q are as defined above, and X is chlorine, bromine, fluorine or iodine, is ring-closed in the presence of at least a stable chiometric amount of a strong non-nucleophilic alkali metal base in a stirrable mixture with an inert liquid carrier, after which the compound obtained with formula Ic is separated in a conventional manner from the indicated carrier and reaction mixture, and, if desired, acid addition salts thereof are prepared.