NO880084L - OUTPUT MATERIALS FOR PYRIDO PREPARATION (1,4) BENZODIAZEPINES. - Google Patents

Description

The present invention relates to a new process for the production of certain pyrido[1,4]benzodiazepines with antidepressant activity, via new [2-[(nitropyridinyl)-amino]phenyl]arylmethanone precursors and thioxomethy1, ketal or thioketal analogues thereof. Certain of these precursor compounds and derivatives which form part of the invention have anti-depressant activity.

British patent document 907 646 describes the preparation of certain dibenzodiazepines substituted with phenyl radicals on the carbon atom and with alkyl or aminoalkyl radicals on the single bromine nitrogen atom. The production method is via cyclodehydration of ortho-acylaminodiphenylamines. AryImethanones and pyrido compounds are not included.

Japanese patent document 73/54,520 (CA. 80: 133501n) describes the preparation of dibenzodiazepines illustratively from 2-aminobenzophenones and ornithine.

[2- [ (aminopyridin^l) amino] phenyl ] ary Imethanones which are useful as antidepressant "agents" or as intermediates in the preparation of certain pyrido[1,4]benzodiazepines are described in the Preparation method according to this application includes starting with a haloaminopyridine rather than a halonitropyridine as according to the present invention.

The present invention provides a new process for the production of certain pyrido[1,4]benzo-diazepines via new [2-[(nitropyridinyl)amino]phenyl]-arylmethanones and analogues thereof formula:

in which

R is selected from hydrogen or -alk^-Q;

Q is selected from the group consisting of hydrogen, -NR^R^ or halogen;

alk"<*>" is a straight or branched hydrocarbon chain containing 1-8 carbon atoms; ;B is selected from the group consisting of carbonyl, thioxomethyl, ketal or thioketal; ;R 1 and R 2 are selected from the group consisting of hydrogen, lower alkyl, -C (0)-O-lower alkyl1, or R 1 and R<2>can together with the adjacent nitrogen atom form a heterocyclic residue selected from 1 -phthalimido, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-1-piperazinyl; ;Ar is selected from the group consisting of 2 or 3 thienyl, 2,;3 or 4-pyridinyl, phenyl or phenyl substituted with 1 to;3 radicals selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro, which may be equally or different ; ;Y is selected from the group consisting of hydrogen or 1-2 radicals selected from lower alkyl, hydroxy or lower alkoxy, and which may be the same or different; ;Z is selected from the group consisting of hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy or nitro; ;and acid addition salts thereof.;In the process for the preparation of pyrido-[1,4]benzodiazepine, compounds of formula I are reduced to [2-[(aminopyridinyl)amino]phenyl]arylmethanones and their thioxomethyl, ketal or thioketal analogues of general formula II: ; wherein Ar, B, Y, Z and R have the previously stated meanings. The compounds of formula II wherein B is carbonyl or thioxomethyl have antidepressant activity except when Q is phthalimido, chlorine or when Q is NR R where either R or R is ;-C (O)-O-lower alkyl.; The compounds of formula I and their pharmaceutically acceptable acid addition salts where B is carbonyl or thioxomethyl generally have antidepressant activity except when R is equal to H or when Q is 1-phthalimido, chlorine or when ;12 ]o;Q is NR R where either R or R is -C(O)-O-lower alkyl. Compounds represented by these exceptions are chemical intermediates of the process. The compounds of formula II are described as antidepressants or chemical intermediates in the previously cited patent application. ;The compounds of formula I and II, except in which one 1 2 ;or both of R and R is hydrogen, are generally chemical intermediates in the preparation of pyrido[1,4]benzo-diazepines of general formula: ; ; in which Ar, Y, Z, alk<1> and Q have the meanings given for formula I. In the process according to the invention, [2-[(nitropyridinyl)amino]phenyl]aryImethanones and analogues substituted on the single bronitrogen with a ;1 10;alkyl (alkylation) or an -alk NR R radical (aminoalkylation) in which R and R are as defined above, except for hydrogen, and the nitro radical is reduced to amino. The resulting [2-[(aminopyridinyl)amino]phenyl]arylmethanone is cyclized to the pyrido[1,4]benzodiazepine of formula X. As will be seen, compounds of formula I wherein one or both of R 1 and R 2 are hydrogen , not intermediates in the preparation of pyrido[1,4]benzodiazepines of formula X, but they can be prepared for use as antidepressants by suitable conversions of other intermediates as indicated below. It should further be understood ;1 2 ;that compounds of formula X in which R and R are either individually or both hydrogen, can be prepared by similar techniques. ;As indicated by the preceding formula X, the location of the pyridonitrogen is variable, as illustrated in formulas Xa, Xb, Xc and Xd, all of which are encompassed by formula X. ;6-aryl-11H-pyrido[2,3-b] [1,4]benzodiazepines covered by formula X have formula ; 6-aryl-11H-pyrido[3,4-b][1,4]benzodiazepines comprised of formula X have formula 10-aryl-5H-pyrido[4,3-b][1,4]benzodiazepines comprised of formula X has formula 10-aryl-5H-pyrido[3,2-b][1,4]benzodiazepines comprised by formula X has formula ; As will be further understood by the undetermined position of the pyridonitrogen in formula I, [2-[(nitro and aminopyridinyl)amino]phenyl]aryImethanones and their analogues are encompassed thereby and which are useful as antidepressants or in the preparation of the corresponding compounds of formula Xa, Xb, Xc and Xd varying by pyridonitrogen. The following variations: Iw, lx, ly and Iz covered by formula I cover all positions of the pyridonitrogen within the scope of the invention in relation to other substituents as follows: ; wherein R, B, Z and A are as defined for formula I.; In the further definition of symbols, the term "lower alkyl" includes straight chain or branched radicals containing 1-8 carbon atoms, such as e.g. methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl and n-octyl radicals and the like. The "lower alkoxy" radical has the formula "-O-lower alkyl". ;The straight-chain or branched linking hydrocarbon chain "alk<1>" containing 1-8 carbon atoms is exemplified by methylene (-CH2~), ethylene (-CH2CH2-) / propylene (-CH2CH2CH2), ethylidene f-CH-~i ;_ CH3j;1,2-propylidene -CH-CH2~ or -CH2-0 ,;_CH3 CH3_;CH o;isopropylidene -C- or 1,3-butylene -CH-CH2-CH3-;_CH3 )_CH3X;and the like. The term halogen includes chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine. The term "4-substituted-1-piperazinyl" denotes the piperazine radical substituted in the 4-position with lower alkyl or alkoxycarbonyl or any blocking group which can then be removed to form the substituted piperazine radical. By "acid addition salts" is meant salts formed with the compounds of formula I or X which can be prepared by the method according to the invention, or during the course of the reaction in the process or with the purpose of facilitating the isolation or purification of any compound in which any pharmaceutical preparation. Examples of acid addition salts of strong acids are those formed with hydrochloric acid, sulfuric acid and phosphoric acids and the like. Examples of addition salts with weak acids are those formed with fumaric acid, maleic acid and oxalic acids. The pharmaceutically acceptable acid addition salts are those formed with acids suitable for human administration. Salts of compounds of formula I, II and X can be converted to the free base by partitioning these between a solvent such as methylene chloride and an aqueous base such as sodium hydroxide and evaporating the solvent layer in vacuo. For the purpose of determining antidepressant activity of the compounds of formula I, II and X, the procedure described by Engelhardt, E. L. et al, J. Med. Chem. 11 (2):325 ;(1968) followed. The compound in an amount of 20 mg/kg was administered to five adult mice (ICR-DUB strain) intra-peritoneally for 30 minutes before administration of a ptotic dose (32 mg/kg, IP) of tetrabenazine (as the methanesulfonate salt). 30 minutes later, the presence or absence of complete eyelid closure (ptosis) was determined in each animal. An ED50 (intermediate effective dose) could be determined for any given compound by blocking tetrabenazine-induced ptosis in mice following the procedure described by Litchfield, et al., J. Pharmacol. Ex. Therapy. 96: 99-113 (1949). It is an aim of the present invention to provide a new process for the production of pyrido-[1,4]benzodiazepines substituted with alkyl and aminoalkyl radicals on the lone bronitrogen. Another aim of the invention is to provide new [2-[(nitropyridinyl)amino]phenyl]arylmethanones and analogues of formula I, methods for their preparation and use as antidepressants or as intermediates in the preparation of [2-[(aminopyridinyl)amino ]phenyl]arylmethanones and analogues thereof and pyrido[1,4]benzodiazepines, both of which have antidepressant activity. Further aims and advantages of the invention will be apparent from the following description of the best way of carrying out the invention. The present invention comprises a process for the production of pyrido[1,4]benzodiazepines (Formula X), [2-[(nitropyridinyl)amino]phenyl]arylmethanones and analogues (Formula I) as such and their use as antidepressants as well as any part of the process regarding the preparation of the intermediate products (Formula I and II). ;The new process according to the invention for the production of pyrido[1,4]benzodiazepines comprises the steps: Step 1) reaction of a 2-aminophenyl-arylmethanone or analogue of the formula; with a halo-nitropyridine of the formula: to form [2-[(nitropyridinyl)amino]phenyl]arylmethanone or analog of the formula: ; wherein R is selected from the group hydrogen, methyl or ethyl; and Ar, B, Y and Z are as above defined; ;Step 2) reaction of a compound obtained in step 1 in which R is hydrogen with a reagent of formula: ; forming a compound of formula wherein R is -alk^-Q and Ar, B, Y, Z, alk1 and Q are as defined 1 2 under formula I, except that neither R nor R is hydrogen; Step 3) reducing the nitro group of a compound prepared in steps 1 and 2, forming a compound selected from the formula: ; where Ar, B, Y, Z, R, alk<1> and Q are as defined under;1 2 ;formula I, with the exception that neither R nor R is hydrogen; Step 4) cyclization of a compound obtained in step 3 to form a compound of the formula: ; ; in which Ar, Y, Z and R are as defined under formula I, with the exception of neither R nor R is hydrogen. corresponding [2-[(aminopyridinyl)-amino]phenyl]arylmethanones (formula II) and the pyrido[1,4]-benzodiazepines are indicated in Reaction Schemes I to V. Preparation of [2-[(nitropyridinyl)amino]phenyl]aryl- methanones and analogs. In general, a mixture of halonitropyridine and aminobenzophenone (or analog) (R = H, CH 3 or C 2 H 5 ) is heated together to temperatures of 110 to 160° C; for a period necessary to effect reaction, usually 1/2 hour to 4 hours. The methanones (and analogues) are isolated by cooling the melt and adding a suitable solvent and partitioning between the solvent and an aqueous base, followed by washing and drying the solvent layer and evaporation and recrystallization from a suitable solvent. Compounds of formula I in which -alk-^-Q is a methyl or ethyl radical are completed at this step. Compounds of formula I in which R is H are further reacted with a reagent of formula Q-alk -halo as defined in Reaction Core I, preferably by heating in a mixture with an aqueous alkali metal base, suitably sodium hydroxide; an organic solvent, suitably methylene chloride; and a phase transfer catalyst, suitably tricaprylyl ammonium chloride, for a time sufficient to give a good reaction as indicated by mass spectroscopy data. The impure product can be obtained by careful adjustment of the pH from strongly basic to weakly basic and subsequent extraction with a suitable solvent, such as methylene chloride and evaporation of the solvent. ;Preparation of [2-[(aminopyridinyl)amino]phenyl]arylmethanones and analogues. The nitro compounds are reduced by any of several methods, for example with ;a) palladium/C and hydrogen;b) iron powder and acetic acid;c) zinc powder and base.;These intermediate products are difficult to isolate from the reaction mixture and are more appropriately utilized by that they are directly allowed to cyclize to pyrido[1,4]benzodiazepine without isolation, and this is therefore a preferred procedure. ;1 2 ;The primary amines of formula I in which R and R are both hydrogen are prepared from the compounds of formulas I and II in which the bromine nitrogen is substituted by -alk<1->(1-phthalimido) as shown in Reaction Core II, or by reaction with hydrazine hydrate using the method described by Org. Sight. Coll. Vol. III, pp. 151 - 153. After sufficient boiling under reflux cooling, aqueous acid is generally added and the mixture is filtered. The primary -alk^-amines are isolated from suitable solvents which can be chosen on the basis of experience. Hydrochlorides are preferred salts in the isolation step. The Alk 4 -monoalkylamines of formula I, e.g. R<1>= methyl, R 2= hydrogen, can be prepared as shown in Reaction Scheme II by reacting the primary -alk^-NI^ derivatives with refluxing triethylorthoformate for a period of time sufficient to form methanimidic acid esters which are then reacted with sodium borohydride. The unreacted borohydride is split with water and the product is isolated with a suitable solvent such as ethyl acetate, and can be purified by column chromatography and partitioning with solvent and aqueous base. Hydrochlorides are preferred salts in the isolation step. ;-Alk"'"-monomethylamines of formula I can also be prepared by reaction of the primary amine with ethyl chloroformate and then reduction with lithium aluminum hydride, as exemplified in Reaction Core II. Alternative reductions when B is varied are often shown in Reaction Core II. A further generalized alternative for the introduction of -alk^-monolower alkylamine radicals is via hydrolysis ;0 ;of the radical -alk 1 -N-C"-O-lower alkyl. See Reaction scheme ;l<i>averealkyl ;I and IV.;An alternative method for preparing compounds of formula I in which Q is -NR^-R^ is illustrated in reaction iron III. Compounds of formula I in which the -NR 1 R 2 part is unsubstituted 1-piperazinyl are obtained by hydrolysis of ;1 2 compounds of formula I wherein -NR R is piperazino substituted in the 4-position with an alkylcarbonyl such as t-butoxycarbonyl. R eaction nucleus I ; Q is selected from the group consisting of hydrogen, halo, -N-(lower alkyl) 2 i 1-pyrrolidiny 1, 1-piperidiny 1, 4-substituted piperazin-1-yl, 4-morpholinyl, 1-phthalimido or ; R eaction core II R eaction scheme III ; Reaction§J<iema_jy R eaks Ionian iron V ; B<X*>is -C(0)- or -C(S)-

Q xx is -NR 1R 2 when R 1 and R 2 are as defined above.

The production of the new [2-[(nitropyridinyl)amino]-phenyl]arylmethanones and [2-[(aminopyridinyl)amino]phenyl]-arylmethanones which can be prepared therefrom is illustrated in the following examples and shown structurally in Table 1. Cyclization to Pyrido[1,4]benzodiazepines are also illustrated in the following examples and products thereof are shown structurally in Table 2.

Example 1

[2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone

A mixture of 56.0 g (0.28 mol) of 2-aminobenzophenone and 49.6 g (0.31 mol) of 2-chloro-3-nitropyridine was heated by means of an oil bath with stirring to 150°C for 45 minutes (development of hydrogen chloride gas stopped). The product was partitioned between 130 ml of methylene chloride and 250 ml of aqueous bicarbonate solution. The aqueous layer was extracted three times with 50 ml<1>s portions of methylene chloride. All methylene chloride solutions were combined and dried over sodium sulfate and filtered. Methylene chloride was evaporated on a vacuum rotary evaporator to give a dark brown viscous oil. The product was purified by column chromatography and eluted with methylene chloride on silica gel. On evaporation of the methylene chloride, an orange oil was obtained which crystallized slowly. The crystals were triturated in 105 ml of 1:1 tertiary butyl alcohol/petroleum ether (30+60). 50.5 g (58%) of a crystalline yellow solid was obtained by centrifugation and drying, m.p. 85° C.

Analysis: Calculated for C^<gH>^<N>^<O->^<:>

C 56.71% H 4.10% N 13.16%

Found: C 67.34% H 4.07% N 13.12%

Example 2

[ 2-[( 3- nitro- 2- pyridinyl) amino] phenyl] phenylmethanone hydrochloride

A mixture of 56.0 g (0.28 mol) of 2-aminobenzophenone and 49.6 g (0.21 mol) of 2-chloro-3-nitropyridine was heated on an ethanol oil bath with stirring at 150° C. for 45 minutes. After cooling, an 8.7 g portion of the product was dissolved in 45 ml of methylene chloride, hydrogen chloride gas was added over 15 min. and 100 ml of hexane was added. After stirring for 20 minutes, the solid was collected and washed twice with a 1:3 mixture of methylene chloride/hexanes. After drying in air, 8.2 g (81.6%) of product was obtained.

Example 3a

3- chlorophenyl[ 2-[( 3- nitro- 2- pyridinyl) amino] pheny1] methanone

To a stirred melt of 10.0 g (0.043 mol) of 2-amino-3<1->chlorobenzophenone under nitrogen gas was added at 115 - 120° C in two portions at 20 minute intervals, 6.3 g (0.040 mol) 2 -chloro-3-nitropyridine. The reaction mixture was heated to 125° C. for 4 hours and then poured into 250 ml of hot 3N hydrochloric acid with vigorous stirring. The mixture was cooled, the aqueous part was decanted and the residue was dissolved in 150 ml of methylene chloride. The methylene chloride solution was washed successively five times with 30 ml<1>s portions of 3N hydrochloric acid, once with 30 ml -% aqueous sodium hydroxide, once with 30 ml of saturated aqueous sodium chloride solution. The washed methylene chloride solution was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropyl ether to give 4.23 g (28%) of a dark yellow solid, m.p. 124 - 125° C.

Analysis: Calculated for C^gH^^C^Cl:

C 61.11 H 3.42 N 11.88

Found : C 60.88 H 3.40 N 11.75

Example 3b and c

By proceeding as described in Example 3a but replacing 2-amino-3'-chlorobenzophenone with equal molar amounts of 2-amino-5-methylbenzophenone and

2-amino-4-methoxy-4'-chlorobenzophenone,

was obtained

3b) [2-[(3-nitro-2-pyridinyl)amino]-5-methylphenyl]-phenylmethanone and

3c) 4-chlorophenyl-[4-methoxy-2-[(3-nitro-2-pyridinyl)-amino]phenyl]methanone.

Example 4a to 4e

By proceeding as described in Example 1 but replacing 2-chloro-3-nitropyridine with equal molar amounts of 2-chloro-5-methoxy-3-nitropyridine,

3-chloro-4-nitropyridine,

5-chloro-2-methoxy-4-nitropyridine,

4-chloro-3-nitropyridine and

3-chloro-2-nitropyridine

was obtained

a) [2-[(5-methoxy-3-nitro-2-pyridinyl)amino]phenyl]-phenylmethanone, b) [ 2-[(4-nitro-3-pyridinyl)amino]phenyl]phenylmethanone, c) [ 2-[(6-methoxy-4-nitro-3-pyridinyl)amino]phenyl]-phenylmethanone, d) [2- [ (3-nitro-4-pyridinyl)amino]phenyl]phenylmethanone and e) [2-[ (2-nitro-3-pyridinyl)amino]phenyl]phenylmethanone.

Example 5a to e

By proceeding as described in Example 1 but replacing 2-aminobenzophenone with

2-aminophenyl-2-thienylmethanone,

2-aminophenyl-3-thienylmethanone,

2-aminopheny1-2-pyridinylmethanone,

2-aminopheny1-3-pyridinylmethanone and

2-aminopheny1-4-pyridinylmethanone,

was obtained

a) [2-[(3-nitro-2-pyridinyl)amino]phenyl]-2-thienyl-methanone, b) [2-[(3-nitro-2-pyridinyl)amino]phenyl]-3-thienyl- methanone, c) [2-[3-nitro-2-pyridinyl)amino]phenyl]-2-pyridinyl-methanone, d) [2-[3-nitro-2-pyridinyl)amino]phenyl]-3-pyridinyl- methanone and e) [2-[3-nitro-2-pyridinyl)amino]phenyl]-4-pyridinyl-methanone.

Example 6a and b

By proceeding as described in Example 1 but replacing 2-aminobenzophenone with equal molar amounts of 2-amino-5-methylbenzophenone and

2-amino-4'-chlorobenzophenone,

and equal molar amounts of 3-chloro-4-nitropyridine instead of 2-chloro-3-nitropyridine, it was obtained a) [5-methyl-2-[(4-nitro-3-pyridinyl)amino]phenyl]- phenylmethanone and b) (4-chlorophenyl)-[2-[(4-nitro-3-pyridinyl)amino]-phenyl]methanone.

Example 7a to c

By proceeding as described in Example 1 and replacing 2-aminobenzophenone with equal molar amounts of (2-aminophenyl)phenylmethanethion,

2-(2-phenyl-1,3-dioxolan-2-yl)benzenamine and

2-(2-phenyl-1,3-dithiolan-2-yl)benzenamine,

was obtained

a) [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenyl-methane-thione, b) 3-nitro-N 2-[2-(2-phenyl-1,3-dioxolan-2- yl)phenyl]-2-pyridinamine and c) 3-nitro-N<2->[2-(2-phenyl-1,3-ditholan-2-yl)phenyl]-2-pyridinamine.

Example 8a

[ 2-[[ 3-( dimethylamino) propyl]( 3- nitro- 2- pyridiny1) amino]-phenyl] phenylmethanone

A mixture of 2 g (0.006 mol) [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone, 3 g (0.019 mol) 3-dimethylaminopropyl chloride hydrochloride, 10 ml 50% aqueous sodium hydroxide, 5 drops of tricaprylylmethylammonium chloride (phase transfer catalyst) and 15 ml of methylene chloride were stirred and maintained at the reflux temperature for 18

hours. Chemical ionization mass spectral analysis indicated only a trace of the methanol parent compound was present with good conversion to the title compound. The reaction mixture was partially neutralized with 10% hydrochloric acid. The dilute but still basic mixture was extracted with methylene chloride and the methylene chloride layer was evaporated to give 1.1 g of a brown residue, predominantly the title compound. Example 8b

3- chlorophenyl-[ 2-[[ 3-( dimethylamino) propy1] ( 3- nitro- 2- pyridinyl) ■ amino] phenyl] methanone

By proceeding as described in Example 8a but using equal molar amounts of 3-chlorophenyl-[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone instead of [2-[ (3-nitro-2 -pyridinyl)amino]phenyl]phenylmethanone, the title compound was prepared.

Example 8c

[ 2-[[ 3-( dimethylamino) propy1]( 3- nitro- 2- pyridiny1) amino]-phenyl] phenylmethanone

A mixture of 3.6 g (0.01 mol) [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone hydrochloride, 4.7 g (0.03 mol) 3-dimethylaminopropyl chloride, 0, 1 g of tricaprylyl ammonium chloride, 16 g (0.20 mol) of 50% aqueous sodium hydroxide, 25 ml of methylene chloride and 5 ml of water were refluxed for 27 hours. Chemical ionization mass spectroscopy analysis indicated that the product was predominantly the title compound. The mixture was cooled and diluted with the methylene chloride-water mixture. The aqueous layer was extracted twice with methylene chloride. The combined methylene chloride layers were washed with aqueous sodium chloride solution, dried, treated with bone char, filtered and evaporated to give 3.3 g of a black material (81.5%) which was predominantly the title compound as indicated by thin layer chromatography and chemical ionization mass spectroscopy analysis of the chromatographed material, i.e. m/e = 40 5.

Example 9a to 9i

By proceeding as described in Example 8a, [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenyl]methanone hydrochloride was prepared with equal molar amounts of [2-[(3-nitro-2-pyridinyl)amino] ]-5-methylpheny1]phenylmethanone, 4-chloropheny1[4-methoxy-2-[(3-nitro-2-pyridiny1)amino]-phenylmethanone,

[2-[(5-methoxy-3-nitro-2-pyridinyl)aminophenyl]phenylmethanone, [2-[(4-nitro-3-pyridinyl)amino]phenyl]phenyl]methanone, [5-methyl-2-[(4 -nitro-3-pyridinyl)amino]phenyl]phenylmethanone, (4-chlorophenyl([2-[(4-nitro-3-pyridinyl)amino]phenyl]methanone, [2-[(6-methoxy-4-nitro- 3-pyridinyl)amino]phenyl]phenylmethanone, [2-[(3-nitro-4-pyridinyl)amino]phenyl]phenylmethanone, and [2-[(2-nitro-3-pyridinyl)amino]phenyl]phenylmethanone,

was obtained:

a) [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridiny1)amino]-5-methylphenyl]phenylmethanone, b) [2-[[3-(dimethylamino)propyl](3-nitro -2-pyridiny1)amino]-4-methoxyphenyl](4-chlorophenyl)methanone, c) [2-[[3-(dimethylamino)propyl](5-methoxy-3-nitro-2-pyridinyl)amino]phenyl] phenylmethanone, d) [2-[[3-(dimethylamino)propyl](4-nitro-3-pyridinyl)amino]-phenyl]phenylmethanone, e) [2-[[3-(dimethylamino)propyl](4-nitro -3-pyridinyl]amino]-5-methylphenyl]phenylmethanone, f) (4-chlorophenyl) [2-[[3-(dimethylamino)propyl] (4-nitro-3-pyridinyl)amino]phenyl]methanone, g) [ 2-[[ 3-(dimethylamino)propyl](6-methoxy-4-nitro-3-pyridinyl)amino]phenyl]phenylmethanone, h) [2-[[3-(dimethylamino)propyl](3-nitro- 4-pyridinyl)amino]-phenyl]phenylmethanone, and

i) [2-[[3-(dimethylamino)propyl](2-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone.

Example 10

2-[3-[(2-benzoylphenyl)(3-nitro-2-pyridinyl)aminopropyl]-1H-isoindole-1,3-(2H)dione

By proceeding as described in Example 8a, but using N-(3-bromopropyl)phthalimide hydrochloride instead of 3-dimethylaminopropyl chloride hydrochloride, the title compound was obtained.

Example 11

[ 3- [ ( 2- benzoylphenyl) ( 3- nitro- 2- pyridinyl) ] aminopropyl]- methylcarbamic acid- 1, 1- dimethyl ethyl ester

The title compound was prepared by reacting [2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone and (3-chloropropyl)methylcarbamic acid tertiary butyl ester.

Example 12

[ 2-[( 3- chloropropyl)( 3- nitro- 2- pyridinyl) amino] phenyl] phenylmethanone

By following the procedure described in Example 8a

but using equal molar amounts of 1,3-dichloropropane instead of 3-dimethylaminopropyl chloride hydrochloride, the title compound was obtained.

Example 13

[ 2-[[ 3-( dimethylamino) propyl]( 3- nitro- 2- pyridinyl) amino]-phenyl] phenylmethanone

The title compound was prepared by reaction of [2-[[3-chloropropyl)(3-nitro-2-pyridinyl)amino]phenylmethanone and dimethylamine.

Example 14a and 14b

By proceeding as described in Example 8a but replacing 3-dimethylaminopropyl chloride hydrochloride with equal molar amounts of

2-dimethylaminoethyl chloride and

4-dimethylaminobutyl chloride,

was obtained

a) [2-[[2-(dimethylamino)ethyl](3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone and b) [2-[[4-(dimethylamino)butyl](3-nitro-2 -pyridinyl)amino]-phenyl Imethanone.

Example 15 a to d

By proceeding as described in Example 8a but replacing 3-dimethylaminopropyl chloride hydrochloride with 4-(3-chloropropyl)-morpholine hydrochloride,

N-(3-chloropropyl)-piperidine hydrochloride,

N-(3-chloropropyl)-pyrrolidine hydrochloride and N-(3-chloropropyl)-4-methyl-1-piperazinyl hydrochloride,

was obtained

a) [2- [ [ 3-(4-morpholinyl) propyl] (3-nitro-2-pyridinyl) amino] - phenyl] phenylmethanone, b) [2- [ [3-(1-piperidinyl)propyl] ( 3-nitro-2-pyridiny1)amino]-phenyl]phenylmethanone, c) [2-[[3-(1-pyrrolidinyl)propyl](3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone, and d) [2-[[3-(4-methylpiperazin-1-yl-propyl)](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone.

Example 16a to e

By proceeding as described in Example 8a but replacing [ 2-[(3-nitro-2-pyridiny1)amino]phenyl]phenylmethanone with

[2-[(3-nitro-2-pyridinyl)amino]phenyl-2-thienyl-methanone, [2-[(3-nitro-2-pyridinyl]amino]phenyl-3-thienyl-methanone, [2-[ 3-nitro-2-pyridinyl)amino]phenyl]-2-pyridiny1-methanone, [2-[3-nitro-2-pyridinyl)amino]phenyl-3-pyridinyl-methanone,

[2-[3-nitro-2-pyridinyl)amino]phenyl-4-pyridinyl-methanone, it was obtained

a) [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-2-thienylmethanone, b) [2-[[3-(dimethylamino)propyl](3- nitro-2-pyridiny1)amino]-phenyl]-3-thienylmethanone, c) [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-2-pyridinylmethanone, d ) [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-2-pyridinyImethanone, and e) [2-[[3-(dimethylamino)propyl](3- nitro-2-pyridinyl)amino]-phenyl]-4-pyridinyImethanone.

Example 17

[ 2-[( 3- aminopropyl)( 3- nitro- 2- pyridiny1) amino] phenyl]-phenylmethanone

[2-[(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone was reacted with a) sodium hydride in solvent followed by N-(3-bromopropyl)phthalimide. The product from a) was reacted with alcoholic hydrazine hydrate and acid to form the title compound.

Alternatively, the product from Example 10, 2-[3-[ (2-benzoylphenyl) (3-nitro-2-pyridinyl)amino]propyl]-1H-isoindole-1,3-(2H)dione is reacted with alcoholic hydrazine hydrate and acid under formation of the title compound.

Example 18

[ 2-[[ 3-( dimethylamino) propyl]( 3- nitro- 2- pyridiny1) amino]-phenyl] phenylmethanone

[3-[(2-Benzoylphenyl)(3-nitro-2-pyridinyl)amino]-propyl]methyl-carbamic acid-1,1-dimethylethyl ester was hydrolyzed in an aqueous solution of hydrochloric acid to form the title compound.

Example 19a and b

By following the procedure described in Example 1 but replacing 2-aminobenzophenone with

N-methyl-aminobenzophenone and

N-ethyl-1-aminobenzophenone,

was obtained

[2-[N-methylamino-(3-nitro-2-pyridinyl)]phenyl]phenylmethanone and

[2-[N-ethylamino-(3-nitro-2-pyridinyl)]phenyl]phenylmethanone.

Example 2 0

[ 2-[( 3- amino- 2- pyridinyl) amino] phenyl] ( 3- chlorophenyl) methanone

A solution of 7.6 g (0.0215 mol) of 3-chlorophenyl-[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone in 200 ml of ethyl acetate-ethanol (95:5) was shaken together with 1 g palladium hydroxide (20% on carbon) in a Parr bottle under 2.7 kg/cm<2>hydrogen for 1 3/4 hours at room temperature. The mixture was filtered through celite. The filter cake was washed by suspension in methylene chloride three times, and was filtered. The methylene chloride extracts were combined with the ethyl acetate-ethanol filtrate and everything was concentrated in vacuo to give 4 g of residue. The residue was dissolved in methyl alcohol and the solution was acidified with 6N hydrochloric acid. After stirring for 16 hours at room temperature, the mixture was basified with 10% sodium hydroxide and the methanol was removed in vacuo. 50 ml of water was added and the mixture was extracted twice with methylene chloride. The combined methylene chloride extract was washed with water, followed by washing with saturated sodium chloride solution, was dried over sodium sulfate and concentrated in vacuo. The residue was recrystallized twice from isopropyl alcohol (bone charcoal added) to give 1.09 g (15.7%) of a bright red solid, m.p. 120 - 121° C (after a phase change at 108 - 110° C).

Analysis: Calculated for C-^gH-^N-^OCl:

C 66.77 H 4.36 N 12.98

Found : C 67.06 H 4.35 N 13.10

Example 21a

[ 2-[[ 3-( dimethylamino) propyl] ( 3- amino- 2- pyridiny1) amino]-phenyl] phenylmethanone

A mixture of (0.05 mol) [2-[ [3-(dimethylamino)-propyl](3-nitro-2-pyridiny1)amino]phenyl]phenylmethanone, 13 g (0.20 mol) zinc dust, 2 g ( 0.05 mol) of sodium hydroxide in 75 ml of ethanol and 25 ml of water was stirred under reflux for 1 hour. The mixture was filtered and evaporated under reduced pressure. The residue was dissolved in methylene chloride and the resulting solution was dried over magnesium sulfate and decolorized with bone charcoal and filtered. The filtrate was evaporated to dryness to give the title compound in a crude mixture.

Example 21b

[ 2-[[ 3-( dimethylamino) propyl]( 3- amino- 2- pyridinyl) amino]-phenyl] phenylmethanone

Impure [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone, 1.1 g obtained in Example 8a, was dissolved in methanol and hydrogenated in the presence of 5% palladium- on-carbon catalyst under 2.1 kg/cm hydrogen for 3 hours. The mixture was filtered and evaporated to a brown

13

residue. C nuclear magnetic resonance determination in the C=X region showed a signal for C=0 and not C=N-. Chemical ionization mass spectroscopy showed that C=0 was not due to the starting material.

Example 22a to 1

By proceeding as described in Example 21a, but replacing [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)-amino]phenyl]phenylmethanone with equal molar amounts of: [2-[[ 3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-5-methylphenyl]phenylmethanone,

[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridiny1]amino]-4- methoxyphenyl]-(4-chlorophenyl)methanone,

[2-[[3-(dimethylamino)propyl](5-methoxy-3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone,

[2-[[3-(dimethylamino)propyl](4-nitro-3-pyridinyl)amino]-phenyl]phenylmethanone,

[ 2-[[ 3-(dimethylamino)propyl](4-nitro-3-pyridinyl)amino]-5-methylphenyl]phenylmethanone,

(4-chlorophenyl) [2-[[3-(dimethylamino)propyl] (4-nitro-3-pyridinyl)amino]phenyl]methanone,

[2-[[3-(dimethylamino)propyl](6-methoxy-4-nitro-3-pyridinyl)amino]phenyl]phenylmethanone,

[2-[[3-(dimethylamino)propyl](3-nitro-4-pyridinyl)amino]-phenyl]phenylmethanone,

f2-[[3-(dimethylamino)propyl](2-nitro-3-pyridinyl]amino]-phenyl ] phenylmethanone,

1,3-dihydro-2-[3-[(2-benzoylphenyl)(3-nitro-2-pyridinyl)-amino]propyl]-1H-isoindole-1,3-dione,

[3-[(2-benzoylphenyl) (3-nitro-2-pyridiny1)]amino]propyl]-methylcarbamic acid 1,1-dimethyl ester, and

3- Chlorophenyl-[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]methanone

was obtained

a) [2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-5-methylphenyl]phenylmethanone, b) [2-[(3-amino-2-pyridinyl)[3- (dimethylamino)propyl]amino]-4- methoxyphenyl](4-chlorophenyl)methanone, c) [2-[(3-amino-5-methoxy-2-pyridinyl)][3-(dimethylamino)-propyl]amino]phenyl ]phenylmethanone, d) [2-[(4-amino-3-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]phenylmethanone, e) [2-[(4-amino-3-pyridinyl)[3 -(dimethylamino)propyl]amino]-5- methylphenyl]phenylmethanone, f) [2-[(4-amino-3-pyridinyl)[3-(dimethylamino)propyl]aminophenyl]-4-chlorophenyl]methanone, g) [2- [(4-amino-6-methoxy-3-pyridinyl)[3-(dimethylamino)-propyl]amino]phenyl]phenylmethanone, h) [2-[(3-amino-4-pyridinyl)[3-(dimethylamino) propyl]amino]-phenyl]phenylmethanone, i) [2-[(2-amino-3-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]phenylmethanone, j) 2-[3-[[3- amino-2-pyridinyl)(2-benzoylphenyl)amino]propyl]-1H-isoindole-1,3-(2H)-dione, k) [3-[(3-amino-2-pyridinyl)(2-benzoylphenyl) ]amino]propyl]-methylcarbamic acid-1,1-dimethylethyl ester, and 1) [3-%(3-amino-2-p yridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-3-chlorophenylmethanone.

Example 2 3a and b

By proceeding as described in Example 21a but replacing [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)-amino]phenyl]phenylmethanone with: [2-[[2-(dimethylamino) ethyl] (3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone, and

[2-[[4-(dimethylamino)butyl] (3-nitro-2-pyridiny1)amino]-phenyl]phenylmethanone,

was obtained:

a) [2-[[2-(dimethylamino)ethyl] (3-amino-2-pyridinyl)amino]-phenyl]phenylmethanone, and b) [2-t[4-(dimethylamino)butyl](3-amino- 2-pyridinyl)amino]-phenyl]phenylmethanone.

Example 24a to d

By proceeding as described in Example 21a but replacing [2-[[3-(dimethylamino)propyl] (3-nitro-2-pyridinyl)-amino]phenyl]phenylmethanone with: [2-[[3-(4- morpholinyl)propyl](3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone,

[2-[[3-(1-piperidinyl)propyl] (3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone,

[2-[[3-(1-pyrrolidinyl)propyl] (3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone, and

[2-[[3-(1-(4-methylpiperazin-1-yl)propyl)] (3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone

was obtained:

a) [2-[[3-(4-morpholiny1)propyl](3-amino-2-pyridinyl)amino]-phenyl]phenylmethanone, b) [2-[[3-(1-piperidinyl)propyl](3 -amino-2-pyridinyl)amino]-phenyl]phenylmethanone, c) [2-[[3-(1-pyrrolidinyl)propyl](3-amino-2-pyridinyl)amino]-phenyl]phenylmethanone, and d) [ 2-[[3-(4-methylpiperazin-1-yl)propyl](3-amino-2-pyridinyl)amino]phenyl]phenylmethanone.

Example 25a to e

By proceeding as described in Example 21a but replacing [2-[[3-(dimethylamino)propyl]-(3-nitro-2-pyridinyl)-amino]phenyl]phenylmethanone with: [2-[[3-(dimethylamino )propyl](3-nitro-2-pyridinyl)amino]-phenyl]-2-thienylmethanone,

[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-3-thienymethanone,

[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-2-pyridinyl Imethanone,

[2-[[3-(dimethylamino)propyl] (3-nitro-2-pyridiny1)amino]-phenyl]-3-pyridinyImethanone, and

[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]-4-pyridinylmethanone,

was obtained:

a) [2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-2-thienylmethanone, b) [2-[(3-amino-2-pyridinyl)[3 -(dimethylamino)propyl]amino]-phenyl]-3-thienylmethanone, c) [2- [ ( 3-amino-2-pyridinyl) ] 3-(dimethylamino) propyl] araino] - phenyl]-2-pyridinyImethanone, d ) [2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-3-pyridinylmethanone, and e) [2-[(3-amino-2-pyridinyl)[3 -(dimethylamino)propyl]amino]-phenyl]-4-pyridinylmethanone.

Example 26

2-[( 3- amino- 2- pyridiny1)( 3- aminopropyl1) amino] phenyl] phenylmethanone

Following the procedure described in Example 21a, [2-[(3-aminopropyl)(3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone was reduced to form the title compound.

Example 2 7

[ 2-[( 3- amino- 2- pyridinyl)[ 3-( methylamino) propyl] phenyl]-phenylmethanone

By following the procedure described in Example 21a, [2-[[3-(methylamino)propyl](3-nitro-2-pyridinyl)amino]-phenyl]phenylmethanone was reduced to the title compound.

Example 28

N,N- dimethyl- 6- phenyl- llH- pyrido[ 2, 3-b][ 1, 4] benzo- diazepine- 11- propanamine

[2-[[3-(dimethylamino)propyl](3-amino-2-pyridiny1)-amino]phenyl]phenylmethanone from Example 21a was refluxed in excess acetic acid or in toluene solution containing a catalytic amount of p- toluenesulfonic acid, forming a solution of the title compound.

Example 29

N, N- dimethyl1- 6- phenyl- llH- pyrido[ 2, 3- b][ 1, 4] benzo- diazepine- ll-propanamine- fumarate [ 1:1]

Impure [2-[[3-(dimethylamino)propyl] (3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone was prepared as described in Example 8c and dissolved in a 75-25 volume mixture of ethanol and water. Zinc dust and sodium hydroxide were added as in Example 21a, and the mixture was boiled under reflux until thin layer chromatography showed that the reaction was complete. The mixture was filtered and the filtrate evaporated. The residue was added to acetic acid containing a small amount of p-toluenesulfonic acid, and the solution was refluxed until the reaction was complete. The solution was evaporated to dryness and the residue dissolved in hot isopropyl alcohol. The solution was decolorized with bone charcoal and filtered. Fumaric acid was added to the filtrate to form the title product as a precipitate. The melting point after recrystallization from isopropyl alcohol-isopropyl ether is 171 - 173° C.

Example 30a to d

By proceeding as described in Example 28 but replacing [2-[[3-(dimethylamino)propyl](3-amino-2-pyridinyl)-amino]phenyl]phenylmethanone with: [2-[[3-(4- morpholinyl)propyl](3-amino-2-pyridinyl)amino]-phenylmethanone,

[2-[[3-(1-piperidinyl)propyl](3-amino-2-pyridinyl)amino]-phenyl]phenylmethanone,

[2-[[3-(1-pyrrolidinyl)propyl](3-amino-2-pyridinyl)amino]-phenyl]phenylmethanone, and

[2-[[3-(4-methylpiperazin-1-yl-propyl)](3-amino-2-pyridinyl)amino]phenyl]phenylmethanone,

was obtained:

a) 11-[3-(4-morpholinyl)propyl]-6-phenyl-11H-pyrido][2,3-b]-1,4-benzodiazepine, b) 6-phenyl-11-[ 3-( 1-piperidinyl)propyl]-HH-pyrido][2,3-b]- [ 1,4]benzodiazepine, c) 6-phenyl-11-[3-(1-pyrrolidinyl)propyl]-11H-pyrido][2,3-b]-[1,4]benzodiazepine, and d) 6- phenyl-11-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrido-[2,3-b][1,4]benzodiazepine.

Example 31a to e

By proceeding as described in Example 2 8 but replacing [2-[[3-(dimethylamino)propyl](3-amino-2-pyridinyl)-amino]phenyl]phenylmethanone with: [2-[(3-amino- 2-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-2-thienylmethanone,

[2-[(3-amino-2-pyridiny1)[3-(dimethylamino)propyl]amino]-phenyl]-3-thienylmethanone,

[ 2-[(3-amino-2-pyridiny1)[3-(dimethylamino)propyl]amino]-phenyl]-2-pyridinyImethanone,

[2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-3-pyridinylmethanone, and

[ 2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]-4-pyridinylmethanone,

was obtained:

a) 11-[3-(dimethylamino)propyl]-6-(2-thienyl)-11H-pyrido-[2,3-b] [1,4]benzodiazepine, b) 11-[3-(dimethylamino)propyl ]-6-(3-thienyl)-11H-pyrido-[2,3-b] [1,4]benzodiazepine, c) 11-[3-(dimethylamino)propyl]-6-(2-pyridinyl)-11H -pyrido-[2,3-b][1,4]benzodiazepine, 11-[3-(dimethylaminolpropyl]-6-(3-pyridinyl)-11H-pyrido-[2,3-b] [1,4] benzodiazepine, and e) 11-[3-(dimethylamino)propyl]-6-(4-pyridinyl)-11H-pyrido-[2,3-b][1,4]benzodiazepine.

Example 32a to 1

By proceeding as described in Example 2 8 but replacing [2-[[3-(dimethylamino)propyl](3-amino-2-pyridinyl)-amino]phenyl]phenyl]methanone with

[2-[(3-amino-2-pyridiny1)[3-(dimethylamino)propyl]amino]-5-methylphenyl]phenylmethanone,

[2-[(3-amino-2-pyridinyl)[3-(dimethylamino)propyl]amino]-4-methoxyphenyl](4-chlorophenyl)methanone,

[2-[(3-amino-5-methoxy-2-pyridinyl)[3-(dimethylamino)-propyl]amino]phenyl]phenylmethanone,

[2-[(4-amino-3-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]phenylmethanone,

[2-[(4-amino-3-pyridinyl)[3-(dimethylamino)propyl]amino]-5-methylphenyl]phenylmethanone,

[2-[(4-amino-3-pyridinyl)[3-(dimethylamino)propyl]aminophenyl]-4-chlorophenylmethanone,

[2-[(4-amino-2-methoxy-5-pyridinyl)[3-(dimethylamino)-propyl]amino]phenyl]phenylmethanone,

[2-[(3-amino-4-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]phenylmethanone,

[2-[(2-amino-3-pyridinyl)[3-(dimethylamino)propyl]amino]-phenyl]phenylmethanone,

2-[3-[(3-amino-2-pyridinyl)(2-benzoylphenyl)amino]propyl]-1H-isoindole-1,3-(2H)-dione,

[2-[[2-(dimethylamino)ethyl](3-amino-2-pyridiny1)amino]-phenyl]phenylmethanone, and

[2-[[4-(dimethylamino)butyl](3-amino-2-pyridiny1)amino]-phenyl]phenylmethanone,

was obtained:

a) N,N-dimethyl-8-methyl-6-phenyl-11H-pyrido[2 , 3-b] [1,4]-benzodiazepine-11-propanamine, b) 6-(4-chlorophenyl)-N, N-dimethyl-9-methoxy-6-phenyl-11H-pyrido [2,3-b] [1,4]benzodiazepine-11-propanamine, c) N,N-dimethyl-3-methoxy-6-phenyl-11H -pyrido[2,3-b][1,4]-benzodiazepine-ll-propanamine, d) N,N-dimethyl-6-phenyl-llH-pyrido[3,4-b][1,4]benzodiazepine- 11-propanamine, e) N,N-dimethyl-8-methyl-6-phenyl-11H-pyrido[3,4-b][1,4]-benzodiazepine-11-propanamine, f) 6-(4-chlorophenyl )-N,N-dimethyl-11H-pyrido[3,4-b] [1,4]-benzodiazepine-11-propanamine, g) N,N-dimethyl-3-methoxy-6-phenyl-11H-pyrido [3,4-b] [1,4]-benzodiazepine-11-propanamine, h) N,N-dimethyl-11-phenyl-5H-pyrido[4,3-b][1,4]benzodiazepine-5- propanamine, i) N,N-dimethyl-10-phenyl-5H-pyrido[3,2-b][1,4]benzodiazepine-5-propanamine, j) 11,[3-(1,3-dihydro-l ,3-dioxo-2H-isoindol-2-yl)propyl]-6-phenyl-llH-pyrido[2,3-b][1,4]benzodiazepine, k) N,N-dimethyl-6-phenyl-llH -pyrido[2,3-b][1,4]benzodiazepine-11-ethanamine, and 1) N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine- 11 -butanamine.

Example 33

N, N- dimethy1- 6- pheny1- 11H- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11-propanamine

To a stirred solution of 3.3 g of impure [2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenyl]phenylmethanone obtained in Example 8c) in 20 ml of acetic acid at 65° C was 6.6 g of iron powder added in portions. The reaction was exothermic at the start as the temperature rose to 90° C. Then the temperature was regulated to 85° C for 1 hour. The mixture was filtered through celite and washed with acetic acid and methanol. The filtrate and washings were combined and evaporated, and the residue was dissolved in methanol. The solution was filtered to remove insoluble ferric acetate. The filtrate was evaporated and the residue dissolved in water/methylene chloride and made basic with sodium hydroxide and potassium carbonate. The mixture was mixed with celite and filtered through celite. The aqueous layer of the filtrate was extracted twice with methylene chloride which had been used to wash the filter cake. The combined methylene chloride solution was washed once with NaCl solution, was dried and treated with bone charcoal, was filtered and evaporated to form a black foam weighing 1.63 g (46%). The foam was dissolved in isopropyl alcohol. The solution was treated with bone charcoal and the mixture was filtered into a solution of 0.7 g of fumaric acid in isopropyl alcohol. This solution was re-treated with bone charcoal and filtered. Chemical ionization mass spectral analysis and thin layer chromatography established the presence of the title compound.

Example 34

( 2- chlorophenyl) [ 2-[( 3- nitro- 2- pyridinyl) amino] pheny1] methanone

Under a nitrogen atmosphere, 44.4 g (0.192 mol) of 2-amino-2<1->chlorobenzene was added in four portions at 15 minute intervals to a stirred melt (130 - 135° C) of 33.5 g (0.221 mol) 2 -chloro-3-nitropyridine. The heating continued

for 30 minutes at 130-135° C. and for 45 minutes at 145° C. The reaction mixture was cooled to 110° C. and 200 ml of hot toluene was added. To the cooled mixture (room temperature) 100 ml of 10% aqueous sodium hydroxide was added, and stirring was continued for 15 minutes. The toluene layer was separated and washed three times with 75 ml portions of water, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in 300 ml of methylene chloride and the solution was stirred with 100 g of fluorisil for 30 minutes. The mixture was filtered, the fluorisil filter cake was rinsed several times with methylene chloride. The combined filtrates were treated in the same manner with an additional 100 g of fluorisil. The methylene chloride was separated by filtration and concentrated in vacuo. The residue was crystallized from ethyl acetate-cyclohexane to give 26.0 g of a clear, yellow solid, mp 119°C. Another mass (7.0 g) was obtained from the filtrate and was recrystallized from isopropyl ether with melting point 118-119° C. The total yield was 49% of theory.

Analysis: Calculated for C-^gH-^^<C>^d:

C 61.11 H 3.42 N 11.88

Found : C 61.47 H 3.43 N 11.79

Example 35

( 4- chlorophenyl) [ 2-[ ( 3- nitro- 2- pyridinyl) amino] phenylmethanone Under a nitrogen atmosphere, 50.0 g (0.216 mol) of 2-amino-4<1->chlorobenzophenone was added in four portions at 15 min-

ters intervals to a stirred melt (105 - 110° C) of 35.9 g (0.227 mol) of 2-chloro-3-nitropyridine. The reaction temperature was increased to 120° C. for 3 hours and then to 150° C. for 2 hours. The stirred mixture was cooled to 115°C and 100 ml of hot toluene was added. The cooled mixture (room temperature) was filtered. The filtrate was washed with 75 ml of 5% sodium hydroxide solution, 50 ml of water and 30 ml of saturated sodium chloride solution, was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 43 g (56.4%) of a solid.

x Recrystallization from ethyl acetate-isopropyl ether gave 18.26 g of a clear, yellow solid, m.p. 138 - 140° C.

Analysis: Calculated for C,0Hnn<No0>oCl:

lo ±z jj

C 61.11 H 3.42 N 11.88

Found : C 61.09 H 3.37 N 11.81

An additional 9.6 g of material was obtained from the filtrate. Example 36

( 3- fluorophenyl)[ 2-[( 3- nitro- 2- pyridinyl) amino] pheny1] methanol Under a nitrogen atmosphere, 45.0 g (0.209 mol) of 2-amino-3<1->fluorobenzophenone was added in four portions at 15 minute intervals to a stirred melt (120-125° C.) of 38.2 g (0.241 mol) 2-chloro-3-nitropyridine. The reaction mixture was heated to 120-125°C for 1 hour, and then to 145-150°C for 45 minutes. The mixture was cooled to 130°C and 100 ml of toluene was added. The cooled mixture (room temperature) was diluted with 100 ml of ethyl acetate and extracted with 100 ml of 10% potassium hydroxide. The organic layer was extracted with three 100 ml portions of 3N hydrochloric acid, 100 ml water and 50 ml saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethyl acetate-isopropyl ether to give 35.5 g (50%) of a solid. The solid material was dissolved in 200 ml of methylene chloride and the solution was stirred with 50 g of fluorisil for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo. A 5 g portion of the residue was recrystallized from ethyl acetate-isopropyl ether to give 4.1 g of a yellow-orange solid, m.p. 98 - 101° C.

Analysis: Calculated for C^<gH->^^<O>^F:

C 64.10 H 3.58 N 12.46

Found : C 64.13 H 3.52 N 12.43

Example 3 7

3-(fluorophenyl)[2-[methyl(3-nitro-2-pyridinyl)amino]phenylmethanone

Under a nitrogen atmosphere, a solution of 3.4 g (0.010 mol) of (3-fluorophenyl) [2-[(3-nitro-2-pyridinyl)amino]-phenyl]methanone in 20 ml of dry dimethylformamide was added dropwise to a stirred suspension of 0.6 g (0.013 mol) of sodium hydride (50% in oil) in 20 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes, then at 55-60° C. for 3 hours. The mixture was cooled to 10°C and 2.9 g (0.020 mol) of methyl iodide was added. The mixture was stirred at room temperature for 16 hours in a closed flask and then poured into 200 ml of ice water. The mixture was basified to pH 14 with 10% sodium hydroxide solution and extracted three times with 50 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with four 75 mL portions of water, 25 mL saturated sodium chloride, and were dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in ether and the solution was stirred with 15 g of fluorisil for 1 hour. The mixture was filtered, the fluorisil was rinsed several times with ether. The combined filtrates were concentrated in vacuo and the residue recrystallized twice from isopropyl ether-ethyl acetate to give 1.5 g (43%) of a dark yellow solid, m.p. 117 - 119° C.

Analysis: Calculated for C-^gH^gN^O^F:

C 64.95 H 4.02 N 11.06

Found : C 64.98 H 3.96 N 11.84

Example 38

By proceeding as described in Example 8a, but replacing 3-chlorophenyl-[2-[(3-nitro-2-pyridinyl)amino]phenyl]-methanone with equal molar amounts of

(2-chlorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]-methanone,

(4-chlorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]-methanone, and

(3-fluorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]-methanone,

was obtained

a) 2-chlorophenyl-[2-[[3-(dimethylamino)propyl](3-nitro-2-pyridinyl)amino]phenylmethanone, b) 4-chlorophenyl-[2-[[3-(dimethylamino)propyl]( 3-nitro-2-pyridinyl)amino]phenylmethanone, and c) 3-fluorophenyl)[2-(3-nitro-2-pyridinyl)amino]phenyl]methanone. Example 39

[ 2-[( 3- amino- 2- pyridiny1) amino] phenyl] ( 4- chlorophenyl) methanone

Under a nitrogen atmosphere, 29 g (0.187 mol) of titanium trichloride was added portionwise (carefully in a fume hood) to 200 g of ice, and the resulting solution was diluted to 250 ml volume with water. This was added, all at once, at 30°C to a stirred solution of 11.0 g (0.0312 mol) (4-chlorophenyl)[ 2-[(3-nitro-2-pyridinyl)amino]pheny 1 ] methanone, 300 ml ethyl acetate:methanol (1:1), 100 ml acetic acid:water (1:1) and 20 ml more solution of titanium trichloride. The reaction mixture was stirred for 20 minutes and was then diluted with one liter of water and filtered. The filter cake was washed with water and then distributed between 200 ml of methylene chloride and 75 ml of 10% aqueous sodium hydroxide solution. The methylene chloride layer was washed with 75 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue (7 g) was recrystallized from ethyl acetate-isopropyl ether to give 6.0 g of a gold-colored solid, m.p. 145-146°C.

Analysis: Calculated for C^gH-^^N^OCl:

C 66.77 H 4.36 N 12.98

Found : C 66.63 H 4.32 N 12.98

Example 40

[ 2- [ ( 3- amino- 2- pyridinyl) amino] phenyl] ( 3- fluorophenyl) methanone

Under a nitrogen atmosphere, 30 g of titanium trichloride was added portionwise (carefully) with stirring to 200 ml of ice. The resulting solution was added all at once to a stirred solution of 10.0 g (0.0297 mol) (3-fluorophenyl) [2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone in 150 ml acetic acid: ethanol (1:1) and 150 ml acetic acid: water (1:1). After stirring for 30 minutes, the reaction mixture was poured into 1 liter of water. The mixture was filtered and the resulting filter cake was suspended in 100 ml of water. The mixture was again filtered and the filter cake (10.0 g) was partially dissolved in 100 ml of hot methanol. The solution was basified with 25 mL of concentrated ammonium hydroxide, stirred for an additional 15 minutes, and then diluted with 500 mL of water. The mixture was extracted three times with 75 mL portions of methylene chloride. The combined methylene chloride extracts were washed with 50 ml of water, dried over sodium sulfate and concentrated in vacuo. The residue (6.9 g) was recrystallized twice from ethyl acetate-isopropyl ether while simultaneously treating once with bone charcoal to give 4.5 g (49%) of a dark gold solid, m.p. 135 - 137° C.

Analysis: Calculated for C-^gH-^N^OF:

C 70.35 H 4.59 N 13.67

Found: C 70.29 H 4.56 N 13.68

Example 41

[ 2-[( 3- amino- 2- pyridinyl) amino] phenyl] ( 2- chloropheyl) methanone

Following the procedure described in Example 39, (2-chlorophenyl)[2-[(3-nitro-2-pyridinyl)amino]phenyl]methanone was reduced to the title compound.

Example 42

6-( 3- Chlorophenyl)- N, N- dimethyl1- llH- pyrido[ 2, 3- b][ 1, 4] benzodiazepine- 11- propanamine

[3-[(3-amino-2-pyridiny1)[3-(dimethylamino)propyl]-amino]phenyl-3-chlorophenylmethanone was refluxed in excess acetic acid or in toluene solution containing a catalytic amount of p-toluenesulfonic acid during formation of the title compound.

Formulation and administration

Effective amounts of the compounds of formula:

wherein R is -alk^-Q,

1 2

Q is hydrogen or -NR R ,

alk<1> is a straight-chain or branched hydrocarbon chain containing 1-8 carbon atoms,

B is carbonyl or thioxomethyl,

12

R and R are selected from the group consisting of hydrogen, lower alkyl or can together with an adjacent nitrogen atom form a heterocyclic residue selected from 1-pyrrolidinyl, 4-morpholinyl, 1-piperidinyl, 1-piperazinyl or 4-lower alkyl-1-piperazinyl,

Ar is selected from the group consisting of 2 or 3-thienyl, 2, 3 or 4-pyridinyl, phenyl or phenyl substituted with 1 to 3 radicals selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro which may be the same or different,

Y is selected from the group consisting of hydrogen or 1-2 radicals selected from lower alkyl, hydroxy or lower alkoxy and may be the same or different,

Z is selected from the group consisting of hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy or nitro, and pharmaceutically acceptable acid addition salts thereof can be used in therapeutic preparations.

For parenteral administration, the carrier or excipient may be a sterile, parenterally acceptable liquid, e.g. water or a parenterally acceptable oil, e.g. arachis oil contained in ampoules.

Although very small amounts of the active ingredients of the invention are effective when light therapy is involved or for administration to patients of relatively light body weight, unit doses are usually from 5 mg or higher and are preferably 25, 50 or 100 mg or even higher , depending on the current situation and the desired result. 5 to 50 mg seems to be optimal per unit dose or wider ranges appear to be 1 to 500 mg per unit dose. Daily doses should preferably vary from 10 mg to 100 mg. The active ingredients can be combined with other pharmacologically active agents as indicated above. It is only necessary that the active ingredient constitutes an effective amount, i.e. so that a suitable effective dose will be obtained in accordance with the dosage form used. It goes without saying that several unit dosage forms can be administered at the same time. The exact individual doses as well as the daily doses will be determined according to standard medical practice under the direction of a physician.

The following formulations are representative of all of the pharmacologically active compounds of formula Ia: Formulations

1. Capsules

Capsules of 5 mg, 10 mg, 25 mg and 50 mg of active ingredient per capsule was produced. With higher amounts of active ingredient, a reduction in the amount of lactose can be made.

Further capsule formulations preferably contain a higher dose of active ingredient and are as follows:

In each case, mix the selected active ingredient with lactose, starch and magnesium stearate and encapsulate the mixture.

2. Tablets

A typical formulation for a tablet containing 5.0 mg of active ingredient per tablet is as follows. The formulation can be used for other strengths of active ingredient by adjusting the weight of dicalcium phosphate.

Mix evenly 1, 2, 4 and 5. Prepare 3 as a 10% paste in water. Granulate the mixture with starch paste and pass the wet mass through an 8 mesh sieve. The wet granulation is dried and sieved through a 12 mesh sieve. The dried granules are mixed with calcium stearate and pressed.

Prepare the solution, make it ready by filtration, fill into ampoules, seal and autoclave.

Claims (1)

Starting materials for the production of therapeutically active pyrido[1,4]benzodiazepines, characterized in that they have the general formula: wherein X is N0„ or NH ,1 R is selected from hydrogen or -alk -Q; Q is selected from the group consisting of hydrogen, -NR 2 -R 2 or halogen; alk <1> is a straight or branched hydrocarbon chain containing 1-8 carbon atoms; B is selected from the group consisting of ketal or thioketal; 1 2 R and R are selected from the group consisting of lower alkyl, -C(0)-O-lower alkyl1, or R 1 and R <2> can together with the adjacent nitrogen atom form a heterocyclic residue selected from 1-phthalimido, 1- pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-1-piperazinyl; Ar is selected from the group consisting of 2 or 3 thienyl, 2, 3 or 4-pyridinyl, phenyl or phenyl substituted with 1 to 3 radicals selected from halogen, lower alkyl, lower alkoxy, trifluoromethyl or nitro, which may be the same or different; Y is selected from the group consisting of hydrogen or 1-2 radicals selected from lower alkyl, hydroxy or lower alkoxy, and which may be the same or different; Z is selected from the group consisting of hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy or nitro; and acid addition salts thereof.