CA1199324A - Phenyl substituted pyrido¬1,4|benzodiazepines and intermediates therefor - Google Patents

Abstract

ABSTRACT OF THE INVENTION

PHENYL SUBSTITUTED PYRIDO[1,4]BENZODIAZEPINES
AND INTERMEDIATES THEREFOR

Pyrido[1,4]benzodiazepines having antidepressant activity of the formula

Description

AHR-~95 3f~ ~k PEI:@~YL 5UBSTITUI'ED PYRIDO~ BENZODI~æEPl~NES
AND I~TERMEDIATES TEIEREFOR

B~CKGROU~iD OF TXE INVENTIO~
1. Field o~ Invention.
The present invention relates to certain novel pyrido~l,4]benzodiazepines, pharmaceutical methods and compositions for treating depression in humans.

2. Description of tlle Prior Art.
Wander~ A., in British Patent go7,646 di~closes preparation of certain dibenzodiazepines ~ubstituted with phenyl radicals on carbon and with alkyl or aminoalkyl radicals on the bridging nitrogen a~om between ~h~ phenyl rings.
Greig, M. E., et al., J~ Med. Chem. 14 ~o. 2, pag~ 153 (1971), disclose dibenzodia epines similar to ~he foregoing wander di~clo ure useful against an~phylactic shock.
Japanese Patent 73/43,520 (C~Ao 80: 133501n di~closes 6-phenyl~2,3,4~4a-tetrahydro~ pyrido[233-b~
[l~4~benzodiazepines having an~iconvulsant a~tivi~y which are illustratively prepared rom 2-aminobenzophenones and ornithine.
SUMM~RY OF THE lNV~Nl~ION
The novel pyrido~l,4~benæodiazepines o the present invention have the ormula Ar ( )n ( H ) n ~, R Formula I

wherein;
R is selected from the group consisting of hydroyen, loweralkyl, -alk -halo, -alk -NR R2 or -alk -N=CH~OC2H5;
R1 and R2 are selected from the group consistiny of hydrogen, loweralkyl, -C(O)O-loweralkyl, or Rl and ~2 ~aken together with the adjacen-t nitrogen atom may form a hetero-cyclic residue selected from the group consisting of l-pip-eridinyl, l-phthalimido, l-pyrrolidinyl, 4-morpholino, l-pip-erazino, and 4-substituted piperazin-l-yl;
Ar is selected from the group consisting of 2, 3 and 4-pyridinyl, 2 or 3~thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same or different;
Alkl is a straight or branched hydrocarbon chain containing 1 - 8 carbon atoms;
Z is selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro and tri.fluoro-methyl;

Y is selected from the group consisting of hydrogen or 1-2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different;
n is 0 or ] and when n is zero the dotted line is a double bond~ and the acid addition salts thereof.
The compounds of :Eormul.a I have u-tillty as an-ti-depressants for treating depression or as intermediates in the preparation of other compounds of formula I.

- 2a -The novel [2-[(amino-pyridinyl)amino]phenyl]aryl-methanone intermediates (or precursors) which form in the reaction mixture prior to cyclization to diazepines and which have additional utility as antidepressants for treating depression are represented by the formula ~595 r~

C-- Ar ~ ~ IN-' ~ Y
H Formula II

wherein Ar, Z3 and Y are as defined above an~ the pharma ceutically acceptable acid addition salts thereo.
In ~he further definition of ~ymbols in the formulas hereof and where they app~3ar lsew~er~ throughout this ~pecification and claims, ~he terms have ~he following ignif icance .
~5 The "~lk1" ~traight or branched connecting hydrocarbon ch~in containi~g 1-8 carbons i~ ~xemplified by methylene (-C~2~ thylene (-CH2 -CH2~)y propylene (-CH2CH2CH~
ethylidene C-CH-~, 1,2 propylen~ c-c~ 2 - or -OEl~-C~
C~3 CH3 CH3 c~3 isopropylidine t-C- ], or 133 butylene ~-CH~CH2-CH2-~3 and C~ 3 the like.
The term "low ralXyl" includes straight and branched chain hydrocarbon radicals of up to eight carbon atoms inclusivP and is exemplified by such groups as methyl, ethyl, propylg isopropyl~ butyl, isobutyl~ tertiary butylg ~mylg isoamyl3 h2xyl, h~ptylJ octyl3 and the like.
The t0xm "halog~n" includes chlorine, bromine, :Eluorine, and iodine, preferably chlorine, bromine and f luor ine .
~50 The t~rm "al~substituted-piperazin~l-yl" refers ko piperazine substituted in ~he 4-pc>sition by loweraïkyl or a:Lkyl-carbonyl blocking yroup which may subsequently be removed to give the unsubstituted piperazine.
P~armaceukically acceptab:Le acid addition ~lts are tho~e 5alt5 :~ormed by the pyridobenzodiazepine~; oE ~his invention with any acid which i~ physiologically compatible in waxm blooded animals, ~uch 8iillt~( being fonned ei.ther by ~95 Il strong or weak ~cids. Repre~enta~ive of ~trong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acids are fumari~, maleic, ~uccinic, Dxalic~ cyclo-hexamic and the like.
The 6~aryl-llH-pyrido~2,~-b~[1,4~benzodiazepi~es and the 5,6 dihydro derivatives thereof encompa~sed by Formula I
have the formula N~(H)n ~_y ~ Iw ~he 6-aryl-llH-pyrido[3,4-b]C1,4]benzodiazepines and the 5,o dihydro derivative thereof encompassed ky Formula I
have the formula ~ N~
Z ~ 1 ~ d,'~

R Ix The 10-aryl-5H-pyrido~4~3-b]~1~4~benzodiazepines and the 10,11 dihydro derivatives thereof encompassed by Formula I have the formula ,(H)n ~-N
~H~

?~ Iy I~he 10-aryl-5H-pyrido~3,2 b]~l~4~benzodiazepines and the 10,11 dihydro derivatives thereof ~ncompa~ed by Formul~ I have the formula

3~

Z Y
Iz In all the formulas Iw to Iz, the symbols R, Arg z 10 and Y have t21e definition given hereinabove.
For the purpose of testing antidepressant activity of the present invention compound~, the procedure given by Englehardt, E. L., et al., J. Med. Chem. 11(2): 325 (1968) which has been indicative in the past OI use:Eulness of 15 compounds for treating human depression was us~d as follows~
20 mg/kg of the compound to be tested was administered to five adult f~male mice ( IC~-DUB strain~, intraperitoneally 30 minutes prior to the administration of a ptotic do~e ~32 mg/kg IP) of tetraben~zine (as the methane sulfonate 20 salt). Thirty minutes later, the presence or absence of complete eyelid closure (ptosis) Wa9 assessed in each animal. An ED50 (Median Effective Dose) may be established for each tested compound in bloc}cing tetrabenazirle induced depression in mice following the proc~dure given by 25 Litchfield et al., J. Pharmacol. Exp. Therap. ~ : 99 ( 1949) -Compound~ of the invention ~ncompa~sed by Formula I
which have antidepressant activity in the oregoing procedure have the Fonnula Ip ~0 A N,(~)n Z~~'Y
~5 E~ Ip where in, ~t~

R ls selected from -the group consis-tiny of hydro-gen loweralkyl or -alkl-N-RlR ;
Rl and R2 are selected from the group consisting of hydrogen, loweralkyl or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue sel-ected from the group consis-ting of l-pyrrolidinyl, 4-morpho-linyl, l-piperidinyl or 4-loweralkyl--piperazin-1-yl;
Ar is selected from the group consisting of 2, 3 or

4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, lowera]koxy, trifluoromethyl or nitro and may be the same or different;
Alkl is a straight or branched hydrocarbon chain containing 1-8 carbon atoms;
Z is selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro;
Y is selected from the group consisting of hydrogen, or 1-2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different;
n is 0 or 1 and when n is zero the dotted line is a double bond, and the pharmaceutically acceptable acid addition salts thereof.
The compounds of Formula Ip wherein R is -alkl-NRlR2 and Rl and R2 are loweralkyl or hydrogen ha~e been shown to have low incidence of antihistaminic, anticholiner-gic and cardiotoxic side effects when tested in animals.
The preferred pyridobenzodia~epines useful in the method of treating depression are as follows:

~ 63~

Example Compound active ingredient (free base) No.
9 N,N-dimethyl-6-phenyl-llH-pyrido[2,3-b][1,4]
benzodiazepine-ll-propanamine.
23 6-(4-fluorophenyl)-N,N-~imethyl-ll.H-pyrido[2,3-b]
[1,4]benzodiazepine-ll-propanamine.
6~phenyl-llH-pyrido[2,3-bJ[1,4]benzodiazepine-11-propanamlne.
28 N-methyl-6-phenyl-llH-pyrido[2,3-b][1,4]benzodiaze-pine-ll-propanamine.
52b 6-(2 chlorophenyl)-N,N-dime-thyl-llH-pyrido[2,3-b;
[1,4]benzodiazepine~11-propanamine.
52a 6 (2-fluorophenyl)-N,N-dimethyl-llH-pyrido[2,3-b]
[1,4]benzodiazepine-ll-propanamine~

, 6a -q~3t~

Certain of the compounds of formula I wherein the R moiety carries a phthalimido, chloro, carbamoyl or imidate component are intermediates rather than antidepressant ayents.
The present inven-tion also provides a process for producin~ a pyrido[l,4]benzodiazepine of ~he formula I or an acid addition salt thereof, which comprlses the steps of:
(1) heating a mixture of halo-amino pyridine having the formula H2N ~

~ IV
halo and an (aminophenyl)arylmethanone having the Eormula O ~
C - Ar ~ NH2 III

or a reaction product thereof having the formula ~C - Ar ~ 2 ~ II

wherein Y, Z and Ar are as defined above, for a period of time and under condidions to remove wa-ter of reaction to cyclize to pyrido~l,4]benzodiazepine having the Eormula Ar ~ ~-N
~ ~~

Z ~ \ N ~ ~ Ia - 7a -wherein Ar, Y and Z are as defined above;
~ 2) optionally reducing the double bond in the compound prepared in step 1 to a compound havi.ng the formula Ar / 1-1 >~ N

~ N ~ ~ ~ Ia wherein Ar, Y and Z are as defined above;
~ 3) reacting a product of either step 1 or step 2 with a halo-lower alkyl or a halo-alk~Q reagent wherein Q is selected from the group consisting of -N-(loweralkyl)2, 1-pyrrolidinyl, l-piperidinyl, 4-substituted-piperazin l-yl, o LO 4-morpholino, l-phthalimido, -N-C-C-loweralkyl or halo, and loweralkyl when n is O optionally reducing the double bond in the reaction product to give a compound selected ~rom those having the formula Ar (H) )n ~c ~ Ib alkl Q

(4) when Q is l-phthalimido, reduce the produc~ oE
step (3) to the amino yroup, and when n is 0, optionally reduc-ing the double bond of the amino compound to give a compound having the formula - 7b -~N
(H)n\ ~ Ic alkl-NH2

(5) optionally reacting a compound produced in step 4 with triethyl ortho formate for a period of time su:ffic-ient to form the meth~n;m;dic ester haviny the formula Ar (H)n Z ~ N ~ ~ ~ y Id alkl-N=CH-OC2H5 and thereafter reducing the methanimidic ester with sodium borohydride, and when n is 0, optionally reducing the double bond to give a compound having the formula Ar; ~ (H)n Ie H
alk N-CH3

(6) optionally reacting a cornpound produced in step 4 with ethyl chloroformate in the presence of tri.ethyl-amine, followed by reduction with lithium aluminum hydride to give a compound of the formula , '~

~ 7c --I e- 1 alk -N-CH3

(7) optiona:Lly hydrolyzing a compound produced in step 3 wherein Q is -~-C-O-loweralkyl ko g.ive a compound having loweralkyl the formula Ar _~ ~ ~ Ie-5 llk -NH-loweralkyl wherein Ar t Y Z, alkl and n are as given above, or (8~ alternately, when Q is chloro in a compound prepared in step 3~ reacting with dialkyl amine to give a compound having the formula Ar ~ (H)n ~ ~ ~ Ib-3 alkl-N-(loweralkyl)2 Another aspect of the invention provides a process for producing a novel intermediate of the formula II, comprising the step of heatiny a mixture of halo-aminopyridine haviny the formula ,, ~ ,, 93~'~
- 7d -~ ; ~ IV
halo wherein Y is as defined above, and an (aminophenyl)arylmethanone having the formula O
\\C _A.r 2 ~ ~ III

whereln Z and Ar are as defined above for a shorter time than that re~uired for cycliza-tion -to the pyridobenzodiazepine at 170 - 200C. optionally separatiny and isolating the resulting ~2-[(aminopyridinyl)amino]phenyl]arylmethanone usiny solvents to separate it from starting materials and some cyclized pyridobenzodiazepine.
DETAILED DESCRIPTION OF THE INVENTION
The present invention encompasses the novel pyrido-benzodiazepines and methanone in-termediates as set forth herein i.n formulas I and II as compositions of matter and utilization of these compounds as antidepressants or as intermediates in the preparation of other antidepressants.
Description of Compound Preparation. Reaction sequence by equation for the preparation of the compounds of the invention is given in Chart 1. Alternate procedures for prepar-ation of certain compounds of formula I are given by equation in Charts 2, 3 and 4.

Methanones~ Formula II, See Chart 1. The methanone intermediates are prepared by heatiny a mixture of the halo-- 7e -amino pyridine and an aminobenzophenone for a shorter period of time than that required for cyclization to the pyridobenzod-iazepine as indicated by chemical ionization mass spec. analysis.
For the [2-[(3-amino-2-pyrldinyl)amino phenylmethanones, the conditions required are about 1 to ,.,, -, j 1.5 hr at 170-200 C. The methanones may be i~olated as the predominant product5 if desired, by cooling and ~dding a suitable organic solvent ~uch as, for example, methylene chloride which will dissolve unreacted starting materials and some cyclized compound ~Ia) followed by usual methods of isolating such as par~itioning betwPen the ~olvent and aqueous base or methanolic a~ueous base followed by washing, drying, evaporating the solvent layer and recrys~alliæing from a suitable ~olvent.
Unsubstituted Pyridobenzodiazepines, Formulas Ia and Ia-l (R=H), S~e Chart 1. The purified II compounds or crude II compounds may be further heated in an aprotic solvent to cyclize to compounds of Formula Ia, removing water from the reaction mixture hy conventional means' for example, under reflux using a Dean-Stark water trap.
However~ it is not necessary to stop heating at the inter-mediate stage; generally, it i5 sufficient to continue heating of the original reaction mixture; i.e., III f IV, for a longer period of time during which ~ycliza~ion to Ia occurs. In the cyclization stage, whichever alternative is u~ed, the temperature time relationship will vary to some extent depending on the reactants used, it being only neces~ary to heat fox a time suffici~nt to produce the product desirea as indicated by chemical ionizati~n mass spec. The unsubstituted pyridobenzodiazepines are purified by partitioning between a suitable solvent such as methylene ~hloride and aqueous base, washing and drying the solvent layer$ evaporating and chromatographing in a sui~able s~lvent system such as acetone-benzene. The corresponding dihydro-diazepine may b~ prepared by reduction with sodium boro-cyanohydrin.
Substituted Pyridobenzodiazepines. F~rmul~s Ib and Ib ( R=loweralkyl ), See Chart 1. Compounds o~ Formu.la la (or I~-l) wherein R i~ hydrogen are alkylaminated or ~5 radicals are introduced which will l~ad to al~ylamination by reacting first with sodium hydride and then with an appropriat2 reagent represent~d by halo-alklQ w~erein'~lkl"
has the mPaning as defined above and Q is as de~ined in Chart 1. The compounds suspended in a s~itable solvent such as dLmethyl formamide ar~ added to a ~tirred suspension of sodium hydride in the same solvent. T~e halo-alkl-Q
reagent (alkylaminating agent or agent leading to alkyl-amination) is added at abou~ room temperature and thereaction mixture is stirred for a period of time until reaction is complete as, for example, determinecl by thin layer chromatography. The unr~acted ~odium hydride is d~composed by adding to water and the product i5 extracted with a suitable solvent ~uch a~ methylene chloride followed by aqueous acid extraction of the solvent layer and isolating the product from the aqueous lay~r by neutralization and re-extraction with methylene chloride followed by evaporation and precipitating, preferably as an addition salt such as fumarate, hydrochloridQ, oxalate, malea~e and the like.
Generally, once having obtained and purified an acid addition salt, the free base may be regenerated by partitioning the salt between an aqueous base and a suitable solvent such as methylene chloride and evaporating the methylene chloride layer. The corresponding dihydrodiazepines may be prepared by reduction ~ith sodium borocyanohydrin. Alternat~lyg compounds of Formulas Ib wherein Q is halo may be cQnverted to compounds wherein Q is -N~(loweralkyl)2 by reacting with an appropriate dialkyl~mine as given in the reaction sequenc~ of Chart 2.
The primary amines of Formula Ic; i.e., Rl and R2 are both hydrogen, are prepared from the -alkl-~t(1-phthalimido) derivatives, as shown in Chart 1, by reacting with hydra~ine hydrat~, utilizing the method of Org. Syn. Coll. Vol. III, pp 151-153. Generally, about 2-3 hr reflux time is sufficient after ~ich aqueous acid is added and the mixture is filtered. The primary ~-alkl-amines are isolated rom suitable solvents such as isopropyl alcohol. Flydrochlorides and hydrochloride hydrates are prefexred 3alts in the isolation step. The correspondiny dihydrodiazepines may be obtained by reduction with ~odium borocyanohyclrin.

~95 ~3~3 The -alk -~-monoalkylamines (Formula Ie); eOg., Rl=methyl~ R2=hydrogen, may be prepared as 6hown in Chart l by reacting the primary -alk~ derivatives Ic or Ic-l with refluxing triethyl orthoformate for a period of time ~ufficient to form the methanimidic acid ester (I d) which is then reacted with sodium borohydride. I~e unreacted borohydride is decomposed with water and the product extracted out with a sui~able solvent ~uch as ethyl acetate and may be purified by column chromatography and partitioning with basic solvent. ~ydrochlorides are preferred salts in the isolation step. The method is more fully exemplified in Examples 27 and 28. The corresponding dihydrob~nzodiaz~pines may then ~e prepared by reduc~ ion with sodium-borocyanohyd~ in .
-Alk~ monomethylamines may also be pr~pared by reaction of the primary amine with ethyl chloroformate as in Example 29J and thereafter reducing with lithium aluminum hydride as exemplified in Chart 3.
A further more generalized alternative for introduction of -alkl ~-monoloweralkyl amine radicals is via the radical:

~r.. ~ -alkl-N-c~o~loweralkyl- See chart ~.
loweralkyl All formulas Ia, Ia-l, Ib, Ib-l, Ib-2, Ib-~, Ib-49 Ic, Ic-l, Ic-2, Id, Ie, Ie-l are encompassed by Formula Io Compounds of Formula I wherein the ~NRlR2 moiety is unsubstituted l~piperazinyl are obtained by hydrolyzing a compound of Formula I wherein -NRlR2 is piperazino substi-tuted in the 4-positicn by an alkyl carbonyl such as t-butoxycarbonyl.

:~95 CH~RT

C Ar ~ NH2 halo ~ Short Period~ /

Heat \ II H
Ar H longer \ / Additional _ ~ ~ A d z ~ ~ h ating 0 Ia-l I NaH ~ ~olvent, halo-alkl-Q
Ar ~ r f(H~

Z ~ ~ N ~ ~ BH CN ~ ~ Ib alkl-Q* alkl-Q ~
Ib-l ~
when Q is (1-A H phthalimido~
N alcoholic hydrazine H ~ when n = 0 ~ ~ h~ydrdte, ~ ~ NaBH3CN, ~ N~ n alkl-NE2 A~ ~ ~ Ic Ar H alk1-~H~
N
H ~ ~ H-C(OC2E5~9 ~ ~r (~
25Ie-l alkl-N~fEl9 ~D~
r ~H) NaBH9cN, 2 ~ N ~ Y
n Acld Id alkl-M=cH-oc2~d5 aBH4 alk1-~-CH9 le s ~ r~J5 ~

Q i3 ~elected ~rorn the group consi~ting of/-N-tlower~lkyl~2 pyrrolidinyl, l-pip~ridinyl, 4-~Obstitutsd-pipera~in-l-yl, pholin~, l-phthalimido~ _~ c_o_lOweralky~ ~r halo-lo~eralkyl C~RT 2 Ar (H~n ( lc>wera lkyl ~ 2 Ib-2 alk l-halo ~1 )~
lC) Ib-3 alkl-~-( loweralXy:L)2 CHP~ RT 3 Ar /(H)n alk Ic Solvent + \ Ar ~ C2 Hs ) ~
E tOC ( O ) C 1 ,/~~ H~n alk~ C~O~-OC2E5 Ic-2 ~`~ /L 1 A lII
A r E~ /

Z ~ y Ie-l alk 1 -~I-CH3 CH~RT 4 ~ N~( ~n ~ ~ ~

~lkl-N-C-O~loweralkyl Ib~4 loweralkyl ~0 Hydrolyze aq. Acid or bas~

Ar (~)n Z~
alkl- N~-loweralkyl Ie-l The preparation of the novel C(amino-pyridinyl)amino-phenyl ryl~methanones which are intermediates in the prepar~
ation of the phenyl substi~u~ed-pyrido~1,4]benzodiazepines are illustrated more ~ully in the following Intenmediates 1 to 16. 5tructures of the intermediates are illustrated in Table 1.

~95 Preparation of Me~hanone Intermediates Intermediate 1 r2-~3-Amino-2-pyridinyl)aminolphenyl]phenylmethanone.
A stirred mixture of 39.4 9 (0.20 mole) of 2-amino-benzophenone and 28.3 y (0.22 mol~) of 3-amino~2-chloro-pyridine was heated at 180C. under nitrogen atmosphere for 1.5 hr~ The mixture was allowed to cool somewhat and 200 ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature) 40.1 g of solid was ~iltered off and recrystallized twice ~rom methanol-isopropyl e~her giving 4.3 g~ presumably the hydrochloride 10salt; m.p. 187-90C. This solid was dissolved in a mixture of water-methanol, basified with 3~ sodium hydroxide and extracted with methylene chlorideu The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressuxe. The residue wa~ recrystal lized from isopropyl ether (charcoal) ta give 2.1 g of product; m.p. 91-~ C. Drying prior to analysis wa~ over-night at room temperature/0.02 mm Hg.
Analysis: Calculated for Cl8Hl5~30~ C~74.72, ~,5.23; N,14.52 Fou~d : C~74.94, H,5.23, N,14.69 20Intermediate 2 ~2-[(~-~mino 2-pyridinyl~aminol-4-chlorophenyl]phen methanone.
A stirred mixture of 23.2 g (0.1 mole) of 2-amino-4'-chlorob~n~ophenone and 14.2 g (0.11 mole) of 3-amino-2-chloropyridine ~as heated at 180C. under nitrogen atmosphere for 2.5 hr. The mixture solidified upon cooling to room temperature and was brok~n up with a sp~tula. The solid was susp~nded in 100 ml o~ methylen~ chloride and collec~ed by filtration. The filter caXe was dissolved in a mixture of water-methanol, basified with 3~ sodium hydroxide and extracted twice wilth methylene chloride. The combined methyl~n~ chloride extracts were dried ov~r magnesium sulfat~
and evaporated under r~duced pressure~ ~he residue which had cryst~llized was ~riturated in i~opropyl ether and ~he solid (16.7 g~ collected by fil~ration. A 3 g sample was recrystallized from isopropyl ether to give 1.6 g product;
m.p. 153-155 C0 Analysis. Calcul~ted or Cl8Hl~ClN30: Cg66.77; H,4.~6;
~,12.98 Found : C,67.06; H,4.36;
N,1~.17 Inte~nediate ~
~2-[(3-Amino-2-(pyridinyl~amino)phenyl1(4-methylphenyl)-methanone.
A stirred mixture of 20.0 g (0.095 mole) of 2-amino-4 7 -methylbenzophenone and 13.95 g (0.104 mole) of ~-amino-2-chloropyridine (96~) was heated under a nitrogen atmosphere at 180~C. for 2.0 hr. The mi~ture cooled to a glassy solid which was broken up, triturated in methylene chloride and the mixture stirred overnight. ~he s~lid was collected by filtration and dis~olved in wa~n methanol.
The solution was basified with 3~ sodiurn hydroxide3 diluted with 500 ml of water and extracted 3 times with 250 ml of methylene chloride. The combined methylen~ chloride extracts were dried over magnesium ~ulfate and evaporated under reduced pressure ~ The res idue which crystallized on standing was recrystallized twic~ from benz~n~ ooctane to give 4.2 g product, m.p. 126-127.5C.
Analysis: calculated for Cl9Hl7N30- Cg75.2~, H,5.65;
~ .85 Found : C,75.81, H,5.69, ~,13.96 Inte~nediate 4 ~2-[(~-Amino-2-pyridinyl~amino~-5-chlorophPnyl~-(2-ehlorophenyl)methanone.
3 A stirred mixture of 20.0 g ~00156 mole) of 3-amino-2-chloropyridirle and ~7. ~ g (OY14 mole) of 2-amino-2 ',5-dichlorobenzophenone was heated at 190C. under nitrogen atmo~phere for 5.5 hr. ~hin layer chromatograph~ (5~
methyl alcohol~benzene on ~;ilica gel) indicated xeaction 35 had not substantially occurred . The rnixture was stirred overnight at 190C., cooled ~omewhat, and 100 rnl m ~hylene chloride was added cautiously. Th~ ~u6pension was stirred 3~5 for two hr and the blaek solid which ~ormed was separated by filtration. The solid was suspended in 500 ml ~f methylene chloride and 300 ml of dilute ~odium hydroxide was added.
An emulsion formed and the mixture was filtered which allowed separation of layers. The methylene chloride layer was washed with two 250 ml portions of water by extraction, dried over magnesium sulfate arld evaporated under reduced pressure.
The residue was dissolv ~ in benzene and filtered through a ~00 g column of florisil to remove low Rf material. All fractions were combined and evaporated under reduced pressure. Thin layer chromatography showed presence of two major compcnents with lower R~ spot predominating. The residue was dissolved in benzene and chromatographed on a 600 g column of florisil packed in benzene. The higher Rf ma~erial was eluted with 1~ acetone-benzene. On evaporation, the residue was triturated in benzene and xecrystallized from benzene-isooctane to give 207 g product, m.p. 162-4C.
Analysi~: calculated or ClBHl3C12N3O~ C,60.35; H,3.66;
~ 3 11 73 Found : C,60.67; H,3.67;
N~11077 Intexmedi~tes 5a to 5u Following the procedures of Int~rmediate 3 and substitutlng equal molar amount~ of ~he following for 2-amino-4'-meth~lbenzophenone:
2-amino-4'-ethylbenzophenone, 2-amino~4'-isopropylbenzophenioni-, 2-amino-4'-bromobenzophenone, 2-amino-3'-fluorobenzophenone, 2-amino-4'-ethoxybenzophenone, 2-amino~4'-nitrobenzophenone~
2-amino-4'-trifluoromethylbenzophenone, 2-amino-3'-methylbenzophenone, 2-amino~3'-ethylbenzophenone, 2-amino-~'-methoxybenzophenone, ~amino-~'-ethoxybenzophenone, 2-amino-2'-nitrobenzophenon~, 2-amino~ trifluoromethylb~nzophenone, 2-a~in~-2'-methylbenzophenone, 2-amino-2'-ethylbenzophenone, 2-amino-2'-methoxybenzophenon~, 2-amino-2' J 4 I dichlorobenzophenone, 2~amino-~' 7 4'~5'-trimethoxyb nzop~enone~
2-amino-2'-fluorobenzophenone, 2-amino-2' chlorobenzophenone, and 2-amino-2'-bromobenzophenone, there are obtained:
a) E2-~ (3-amino-2-pyridinyl)amino~phenyl]-(4-ethylphenyl~
methanone, b) ~2-~(3-amino-2-pyridinyl)amino~phenyll-(4-isopropyl-phenyl)methanone, c) ~2-~(3-amino-2-pyridinyl)amino]phenyl]~(4-bromophenyl) methanone, d) [2-[(3-amino-2-pyridinyl)amino~phenyl~-(3-fluorophenyl) methanone, e) ~2-~(3-amino-2-pyridinyl)amino]phenyl]-(4-ethoxyphenyl) methanoneg f) ~2-[(3-amin~-2-pyridinyl)amino]phenyl]-(4-nitroph~n methanone, g) ~2-~(3-amino-2-pyridinyl)amino~phenyl]-(1l-trifluoro-methylphenyl)methanone, h) [2-[(3-amino-2-pyridinyl)amino~phenyl]-(3-methylphenyl) methanone, i) ~2-~-amino--2-pyridinyl)amino~phenyl~ ethylphenyl) methanone, j) ~2-~(3-amino~2-pyridinyl)amino~ph~nyl~ methoxyphenyl) ~ethanone, k) L2-~ amino-2-pyridinyl)amino3phenyl~-(3-~thoxyphenyl) methanone, 1) ~2-t(3-amino-2-pyridinyl)amino~phenyl~-(2-nitrophenyl) methanone, m) t2-r(3-amino-2-pyridinyl)amino~phenyl]-~3-trifluoro-methylphenyl)m~thanone~
n) ~2-t(~-amino-2~pyridinyl)amino]phenyl]-(2-me~hylphenyl) me thanonP 7 ~95 o) ~2-[(3-amino-2-pyridinyl)amino~phenyll-(2-ethylphenyl) methanone, p) ~2-[(3-amino-2-pyridinyl)amino~phenyl~-(2-methoxy-phenyl)methanone, q) t2-~(3-amino-2-pyridinyl)amino~phenyl~-(2,4-dichloro-phenyl)methanone, r) ~2-~(3-amino-2-pyridinyl)amino~phenyl~-(3~475-tri-methoxyphenyl)methanone, s~ ~2-~(3-amino 2-pyridinyl)amino]phenyl~-(2-fluorophenyl) methanone, t) ~2-~(~-amino-2~pyridinyl)amino]phenyl~-(2-chlorophenyl) methanoneg and u) [2-~(~-amino-2-pyridinyl)amino~phenyl~-(2-bromophenyl) methanone.
Intermediates 6a to 60 Following the procedure of Intermediate 2 and substi-tuting equal molar amounts of the following for 2-amino-4-chlorobenzophenone:
2-amino-5-~hlorobenzophenone, 2-amino-6-chlorobenzophenone, 2-amino 4-fluorobenzophenone, 2-amino-4-bromobenzophenone 3 2-amino-4-trifluoromethylben~ophenone, 2-amino-4-methylbenzophenoneg 2-amino-5-methylben~ophenone J
2-amino-6-methylbenzo~henone, 2 amino-4-ethylbe:nzophenoIIe 9 2-amino-4-methoxybenzophenone, 2-amino-4-ethoxyben20phenon~9 30 2-amino-4-nitrobenzophenone, 2-amino-5-nitrobenzophenone, 2 ~am ino-3-me thylbenzophenone, and 2 -amino-~-chlorobenzop~lenone, there are obtained:
a ) ~ 2 - ~ ( 3 am ino -2 -pyr i d inyl ) am i no ] -5 ch 1 oroph e nyl ~ ph e nyl -methanone, b) t2-t(3-amino-~-pyridinyl)amino~-6~chlorophenyl~phenyl-~et~anone, ~g5 c) ~2-[(3-amino~-pyridinyl~amino~ fluorophenyl]phenyl-methanone, d) e2-[(3~amino-2-pyridinyl)amino]-4-bromophenyl]phenyl-methanone, e) [2-[(3-amino-2-pyridinyl)amino]-4-tri1uoxomethyl-phenyl]phenylmethanone, f) ~2-[(3-amino-2~pyridinyl)amino~-4-methylphenyl]phenyl-methanone 3 g) ~2-[(3-amino 2-pyridinyl)amino~-5-methylphenyl]phenyl-methanone, h) ~2-~(3-amino-2-pyridinyl)amino]-6-methylp~enyl~phenyl-methanone, i) C2-C(~-amino-2-pyridinyl)amino] 4-ethylphenyl]phenyl-methanone, j) r2~[(3-amino-2-pyridinyl~amino~4-methoxyphenyl~phenyl-methanone, k) ~2-t~3-amino-2-pyridinyl)amino]-4-ethoxyphenyl]phenyl-methanone, 1) [2-~ amino-2-pyridinyl)amino]-4-nitrophenyl~phenyl-methanone, m) ~2-t(3-amino-2 pyridinyl)amino]-5 nitrophenyl]phenyl-methanone, n) ~2-~(3~amino-2-pyridinyl)amino~-3-methylphenyl]phenyl-methanone, and ) ~2-[(3-amino-2-pyridinyl)amino]-3-chlorophenyl~phen methanone.
Intermediates 7a to 7c Following the procedur~ of preparation 1 and substi-tuting equal molar amounts of the follswing for 3-amino~2-3 chloropyridine:
4 -amino-3-chloropyridirle, ~-amino-4-chloropyridin~, and 2 -amino-~-chloropyridine, there are obta ined ~
35 a ) ~2-~ amino-3-pyridlnyl ) amino ~phenyl ~phenylmethanone 3 b) ~2-~(3-~mino 4-pyridinyl)amino]phenyl~phenylme~hanoneg and c) ~2-[(2-amino~-pyridinyl)amino~phenyl~Jphenylmethanone.

~ 2 Intermediate 8 ~ 2-[(3-Amino-2-p~ridinyl)amino~phenyl~(3-chlorophenyl) methanone.
A stirred mixture of 35 g (0.152 mole~ of ~-arnino-3'-chlorobenzophenone and 23.4 g (0.182 mole~ of 3-amino-2-chloropyridine was heated at 180C. for 2 hr, The hot meltwas allowed to cool to 110C., after which 100 ml of hot toluene was added dropwise with vigorous stirring. ~he mixture was allowed to cool while stirring to 30C. and 50 ml of methylene chloride was added. After stirring for an additional 1 ~ hour~ the mixture was filtered and the filter cake suspended in methylene chloride with stirring for 1/2 hr and methylene chloride was separated by filtration.
llhe filter cake containing the product (2504 g~ was partially dissolved in hot methanol ~total volume 150 ml) and 50~ a~u~ous sodium hydroxide was added untll the mixture was basic. Ice water was added and the solution was extract~d with methylene chloride. ~his methylene chloridP
extract was washed with water and dried over magnesium sulfate and evaporated to dryness~ The re~idue was dissolved in isopropyl alcohol and boiled with charcoal. The mixture wa~ filtered, reduced in volume to give a first crop of crystals weighing 16 g (33~ portion of the crystals was recrystallized from isopropyl alcohol to give a brick red solid melting 119-120C.
Analysis: calculated for : C,66.77; H~4.~6;
~J 12.98 Found ~ C,66.78; H,4.42;
~,12.
Intermediate 9 r2-~(3-Amino-2-pyridinyl)amin~phenyll(4-fluorop~lenyl) methanone.
A stirred mixture of ~5 g (0.163 mole) of 2-amino-4'-fluorobenzophenone and 27 g (0,21 mole) of 3-amino-2-chloro-pyridine was heated at 175-180C. ~or 2.5 hr. The mixture wa~ allowed to cool to llO~C., after which 100 ml of hot ~5 toluene Wa5 added. On ~ooli.ng to 50 C., 50 ml of methylene ch~oride was added. The solvent layer wa~ dec~nted, leaving ~ ~~ 9 ~

a black solid mass which was dissolved in hot methanol. The solution volume was reduced by one half and allowed to stand overnight at room temperature. The mixture was filtexed and the filter cake washed twice by suspending in methylene ~hloride. The weight of crude ~ol id produced was 22.5 g. The solid was dissolved in methanol and basified with 50~ aqueous sodium hydroxide. ~he mixture was extracted with methylene chloride and the extract dried and concentrated. The residue was twice crystalliæed from isopropyl alcohol,decolorizing by boiling with charcoal the second time,to give 14 g (28~) solid which was red-orange ih color; m.p. 121.5-122.5C.
Analysis. calculated for Cl8Hl4N3OF: C,70.35, H~4.59;
N,13.67 Found ~ C~70.23; H,4.59 N,13.64 Intermediate 10 ~2~ Amino-2-pyridinyl~amino~phenyl~(2-thienyl~
methanone .
In accordance with the procedur~ of Intermediate 9, (2-aminophenyl)(2-thienyl)methanone, prepared by the method of Steinkopf & G~nther~Ann. ~ , 28-34 (1936), is xeacted with 3-amino-2-chloropyridine to qive the ti~le compound.
Intermediate 11 r2-r(3-Amino-2~pyridinyl)aminolphenyll(3-thienyl~
methanone.
In accordance with the procedure o~ Intermediate 9, (2-aminophenyl)(~-thienyl)meth~none is reacted with 3-amino-2-chloropyridine to give the title compound.
Intermediate 12 ~2-[(3-Amino-2-pyridinyl)amino~phenyl~(2-pyridinyl~
methanone.
~ he title compound is prepared by reacting (2-amino-phenyl~(2-pyridinyl)methanone, as prepared by Scho~ield, K.
J. Chem. Soc. ~ , 2408-12, with ~-amino-2-chloropyridine.

Intermediate 13 [2-[(3-Amino-2-pyridinyl~aminolphenyl](3-pyrldinyl) methanone.
The title compound is prepared by reacting (2-amino-phenyl)(~-pyridinyl)methanone as prepared by Abramovitch R. A. & Tertzakidn, G., Tetrahedron Letters, 196~, 1511-15 and Abramovitch, R. A. et al., Carl. J. Chem. 4~, 725- 51 (1965) with 3-amino-2-chloropyridine.
Intermediate 14 r2-r(~-Amino-2-pyxidinyl)amino~phenyl](4-pyridinyl) methanone.
The title compound is prepared by reacting (2 amino-phenyl)(4-pyridinyl)methanone as prepared by ~ann, A. J.
and Schofield, K., J. Chem. Soc. ~ , 58~-9 with ~-amino-2-chloropyridine.
Intermediates 15a to 15g Following the procedure of preparation 1 and substi-tuting equal molar amounts of the following for 3-amino-2-chloropyridine:
~-amino-2-chloro-4-methylpyridineg ~-amino-2-chloro 5-methylpyridine, ~-amino-2-chloro-6-methylpyridine, 3-amino-2-chloro-5,6-dimethylpyridine, 3-amino-2-chloro-6-methoxypyridine, 3-amino-1~-chloro-2-methylpyridine, and 3-amino~2-chloro-5-methoxypy:ridine, there are obtained:
a) r2-~(3-amino-4~methyl-2-pyridinyl)amino]phenyl~phen methanone, b) ~2-C ( 3-amino-5-methyl-2-pyridirlyl ) amino]pherlyl ]phenyl-methanone, c) ~2~ -amino-6-methyl-2-pyridinyl)amino~phenyl]phen methanoneg d) ~2-~(3-amino-5,6-dimethyl-2-pyridinyl)amino~ph~nyl~
phenylmethanon~, e) ~2-~(3-amino-6-methoxy-2-pyridinyl~amino]phenyl]
p~enylmethanone, ~95 ~ 3 ~ ~

f) [2-[(3-amino-2-rnethyl-4-pyridinyl~amino]phenyl]phenyl-methanone, and g) [2 ~r( 3-amino-5-methoxy-2-pyridinyl)amino]phenyl~phenyl~
methanone.
Intermediates 16a to 16f Following the pxocedure of preparation 1 and ~ubsti-tuting e~ual molar amounts o~ the following for 3~amino-2-chloropyridine:
2-amino-3-chloro-5-methylpyridine, 2-amino-3-chloro-4,6-dimethylpyridine, 2-amino-3-chloro-5-ethylpyridine, 4 amino-3-chloro-5-methylpyridine, 4-amino-3-chloro-2l6-dimethylpyridine, and 4-amino 3-chloro~2~methylpyridine, thPre are obtained:
a) ~2-~(2-amino-5-methyl-~-pyridinyl)amino]phenyl]ph2nyl-methanone, b) [2-~(2-amino-4,6-dimethyl-3-pyridinyl)amino]phenyl]
phenylmethanone J
c) ~2-[(2-amino-5-ethyl~3-pyridinyl)amino]phenyl]phenyl-methanone, d) ~2-t(4-amino 5-me~hyl-3-pyridinyl)amino]phenyl~phenyl-methanone~
e) [2-t(4-amino-6-methyl-3-pyridinyl)amino]phenyl~phen methanone, and :E) [2-~(4-amino-2-methyl-3-pyridinyl~amino~phenyl~phenyl-methanone.

~95 2~

Table 1 `C--~ r Z~ ~ /~N ~~

Inter-mediate Ar Y Z
C~s~ H H
2 C6H5- H 4-Cl 4 2--Cl-C6H4- H 5-Cl ~ 3 I~-C2H5 -C8H4- H H
b 4-i-C3H7-C6H4- H El c 4 -Br~C 6H4 EI H
d 3-F-ceH4- H H
e 4-oc2H5-c6H4-f 4 ~NO2 -C 8H4 - H H
g~ 4-CF3--CffH4- ~ H
h ) ~-CH3 -C6H4- H H
i ~-CzH5-C6EI~- H
i 3-OCH3-C8H4- H H
k 3-OCz H~; -C6H4 - H H
1 2-~02-Cs~4~ H H
m 3-cF3-c6H4 H
n 2-C~I3-C6H4- H H
o 2-CzHs-C6H4~ H E~
P 2-OCH3 C6H4- ~ H
q) 2~4-cl2-c6EI3- H H
r~ 3,4,5-(OCEI3)3-C~H2- }I H
s ~ 2-F-C6H~- H
t ) 2-Cl-C~H4 H El u ) 2 Br-C~;H4 H H
6 a ? CeHs - ~ 5-Cl b) CsHs~ El 6-Cl c ) C~H5 - ~1 4 -F
d ? C6H5 - H 11 -Br ) Cs~s - ~ 4 -C~3 f ~ C (3~5 - N 4 -Me g? Cs~s~ H 5-~e h CeE~;- H 6-CH3 i (~6Hs - E[ 4-Cz ~15 i C~ H 4-oCH~
k) C~s~ ~ 4-C)C~H5 1 C6E~5- ~ 0~
m C~H5- H 5-~2 n C~H5- El 3-CH3 o CeH5- Fl 3 Cl ~ cor~

~y~

~q3~

Table 1 ( c~nt . ) Inter-mediate Ar Y Z

8 ~i-Cl-C,3H",- H El

9 4-F C~3H~- H H
2-thienyl H E~
11 3~thienyl H H
12 2 -pyr idinyl H H
13 3-pyridinyl H H
14 4-pyridinyl H El 15a CBH5- 4-CH3 H
15b C6H5- 5-C~3 H
15c C6H5- 6-CH3- H
15d C3H5- 5,6-(CH3)2 H
15e C6H5- 6-~CH3 H
15g C6H5- 5-OC:H3 H
o ~C--Ar Z~ Y
H

7a C6Hs~ H H
16d C6H5- 5-CHg II
e C6H5- 6-C~3 H
f ~6Hs~ 2-CH3 H
o ~C ~A r Z ~

7b C6E~5- H H
15~ C6Hs~ 2-CH3 H
o ~C_A r Z ~ ~ Y
H

7c C~H5~ H H
16a I~H5 5-CH3 H
b C6H5- 1~,6(CH3)2 H
C C 6E~[5 - 5--C~ H5 H

~595 The preparation of novel phenyl~subs~.ituted pyrido-[l~4]benzodiazepine compounds of the p:resent invention and the novel process is exemplified more fully by th~ following examples. Structures of the compound~ of the examples are illustrated in Table 2. The ~cope of the invention is not limi~ed thereto, however.
Example 1 6-Phenyl-llH pyrido~2,3-b1rl~41benzodiazepine.
A mixture of 19.7 g (0.1 mole) of 2-aminobenzophenone

10 and 15.0 g (0.12 mole) of ~-amino-2-chloropyridine was heated under nitrogen at~osphere at 190C. ~or 1.75 hr~ The mixture was cooled to room temperature and partitioned between 3 N aqueous sodium hydroxide and methylene chloride.
The combined methylene chloride extrac~s were washed with water, dried over magnesium sulfate and evaporated under reduced p~essure~ The residue; 32.7 g, was dissolved in ben~ene and chromatographed on a column o florisil packed in benzene, eluting with benzene and 1-2~o acetone-benzene mixtures. After evaporation~ the solid was crystallized 20 fro~ enzene to give 7.3 g product, m.p. 106-108 C.
Analysis: Calculated ~or Cl8H13~3. C,79.68, H~4.83, ~,15.49 Found : C,79.70; H,4.81, ~,15O42 Example 2 8-Chloro~6-phenyl~llH-pyrido~2, 3-b]~ 1, 4~benzodiazepine.
A mixture of 15.0 g ~0.0647 mole) of 2-amino-5-chloro-benzophenone and 9.1 g (o.o68 mole) of 3-amino-2~chloro-pyridine was heated at 200C. (in an oil bath) for 0.75 hr under nitrogen atmosp~2re. The mixture was cooled and methylene chloride added. The mixture was stirr~d for 1 hr 30 then allowed ko stand overnight. Brown solid precipita te weighing 8.7 g was separated by iltration. The filkrate was evaporated under r~duced pressur~. ~he residu~ was combined with the brown solid and partitioned with aaueous sodiurn hydroxid~ and methylene chloride and cruda product isolated a~ in ~xample 1, ~xcept the crystallizing solvent was ethanol. Recrystallization rom ethanol and drying over ~ 3 night at 82 C./0.1 mm Hg gave 3.0 ~ product; m.p. 156.5-15~-5~C.
Analysis: calculated for Cl8Hl2ClN3: C,70.71; H,3.96;
N,1~.74 Found : C,70.24; H,4.01;
N,13.76 Example 3 9-Chloro 6-ph~nyl-llH~pyrido~2,3 b~ r 1,4~bPnzodiazepine.
A suspension of 6.6 g (0.02 mole) of ~2~ amino-2-pyridyl)amino~-4-chlorophenyl~-(phenyl)methanone (Inter-mediate 2) in 200 ml of toluene was heated at reflux over night under nitrogen atmosph2re. The xeaction mixture was filtered hot and the filtrate hPated back to ~eflux temperature. The precipitate formed in cooling to room temperature was separated by filtration and recrystallized from benzene and dried 4 hr at 97-98C./0.1 mm Hg and over night at room temperature/0.1 mm Hg to give ~.7 g; m.p.
250.5 to 252C. ~lemental analysis for carbon was high and ~he product was redried at 139C. (xylenes in drying pistol) for 8 hr. Although the carbon analysis remained high, the proton nuclear magnetic resonance spectrum and mass sp~ctrum was consistent with the proposed structure.
Analysis: Calculated for Cl6Hl2ClN3: C,70.71; ~,3.96; ~,13.74 Found ~ C,71.46; H,4.o6, N~13.46 Example 4 8-Chloro-6-(2-chlorophenyl~-5,6-dihydro-llH-pyrido r2,3-b~ r 1,4~benzodiazepine.
Furth2r elution of the 1Orisil column in the preparation of Intermediate 4 with 10~15% acetone in benzene and 5-25%
methanol in benz~ne gave two fractions of the title prod~ct o thi~ example, 6.4 g and 5.7 g, the second being ouite impure. T~e 6.4 y fraction was recrystallized from benæene_ isooctane to give ~.7 g of solid; m.p. 203-6c.(decompositior~
which was id0ntified by chemical ionization mass spec.
analysis, 1~ and 13C NMR as 8-chloro 6-(2-chlorophenyl)-5,6-dihydro-llH-pyridor2,3-b~1,4~benzodiazepine.

~95 Example 5 6-(4-Chlorophenyl)-llH-pyrido~2,3-b~[1,4~benzodiazepine.
~ mixture of 23.2 g (0.10 mole) of 2-amino-4'-chloro-benzophenone and 14.7 g (0.11 mole) of ~-amino-2-chloro-pyridine (96~ were heated for 1.5 hr at 180C. under nitrogen atmosphere. The mixture was cooled to room temper-ature and methylene chloride added. After stirring for 30 min.,solids were s~parated by filtration and triturated in hot 190 proof ethanol. I~he remaining insoluble material was collected by filtration and recrystallized rom benzene-isooct~ne to give 2.7 g product, m.p. ~03-204.5 C. Drying conditions prior to analyses were: overnight at 97 98C./
O ol mm Hg.
Analysis: Calculated for C18~1~C1~3 C970.71, H,3.96; H,13.74 Found : CJ70.76; ~I,3.92; N~13-95 Example 6 6-(4-Methylphenyl~-llH-pyrido~2,3-b~ r 1,41ben~odiazepine.
A solution of 3.6 g (0.012 mol~) of ~2-r (3-amino-2-pyridyl)amino]phenyl~(4-methylphenyl)methanone in 100 ml of anhydrous toluene was treated with a catalytic amount of para toluene sulfonic a~id and r~fluxed overnight while separating water with a D~an-~tark trap. The r~action mixture wa~ filtered while hot. The product precipitated a~
the filtrate cooled to room temperature and was collected by filtration. Weight of solid after solv~nt evaporated was 2.5 gJ m.p. 20~.5-205~C. (d~comp.).
Analysis: calculated for ClgHl5N3: C,79.98; H,5.30; ~914.73 Found : C,79.95; H,5.27; N914.76 Example 7 6-(4-Methoxyphenyl)-llH-pyridoC~,3-b~[1,4~henzodiazepine.
3o A stirred mixture of 20.0 g (o.o88 mole~ of 2-amino-4'-methoxybenzophenone and 13.0 g (0.097 mole) of ~~~mino-2-chloropyridine (96~) was heated at 180C. under a nitrogen atmosphere for 2.0 hr. The reaction mixture was cooled to approximately 70 C~ and 100 ml of methylene chloride was ~5 ~dded 610wly~ After the mixture had cooled to room ~emperature9 ~9 another 50 ml of methylene chlorid~ was added and the mixture was stirrPd overnight. The ~uspended ~olid was collected by filtration, air driedJ dissolved in methanol and basified with 3 N sodium hydroxide. The suspension was diluted with 500 ml water and extract d with three 250 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. Analysis by ma.ss ~pectra (EI and CI) indicated the residue was a mixture of [2-[(3-amino-2~
pyridyl)amino]phenyl](4-methoxyphenyl)methanone and the title compound. The residue-mixture was dissolved in 250 ml toluene with a catalytic amount of para toluene sulfonic acid and the solution was refluxed overnight under a nitrogen atmosphere while separating water in a D~an-Stark tr~p. The reaction mixture was filtered while hot. The product pre-cipitated as the filtrate cooled to room t~mperature and was collected ~y filtration~ After recrystallization from benzene the product weighed 1.8 ~, ~.p. 198.5-200-5C. (d).
Analysis: Calculated or ClgH15N30: C,75.73; H,5.02; N~13.94 Found ~ C,75.65; H,4.98; N,14.03 Example 8 8-chloro N,~-dimethyl-6-phenyl-llH-pyridr293-blrl,4 benzodiazepine-11-propanamine oxalate [1:1~.
To a stirred suspension of 1.05 g (0.044 mole) of sodium hydride (in mineral oil) in 50 ml of anhydrous dimethylformamide, under nitrogen atmosphere was added, portionwise, 6.1 g (0.02 mole) of 8-chloro-6-phenyl-llH-pyrido~ 2,~-b]~ benzodiazepine. The reaction mixture was s~irred at room temperature for 1~5 hr~ during which evolution of hydrogen ceased. To the mixture was added, portionwise, 3.5 g (0.022 mole) of 3-dimethylaminopropyl chloride hydrochloride. After stirring overnight at room temperature, the reaction mixture was poured int~ 1600 ml water and the combination extracted with three 250 ml portions of methyl~ne chloride. 'rhe combined methylene chloride extract was wa~hed with two 250 ml portions of ~95 3o water, dried over magnesium ~ul~ate and e~aporated under reduced pressuxe. The residue was dis~olved in ~enæene and chromatographed with ace~one-benzene on a 300 g column of florisil packed in benzene. Starting materialJ 1.6 g., was recovered in the benzene elu~ion and 3.6 g. containing the product as free base was obtained from the acetone-benzene ~lution on evaporation o~ solvent. A portion of the cxude free base, 2.5 g.~ was dissolved in hot isopropyl alcohol and reacted with 0.8 g (o.oo64 mole) of oxalic acid di-hydrateO The oxalate ~alt, which precipitated on cooling,was collected by fil~ration and recrystalli~ed rom ethanol to gi.ve 2.2 g product, m.p. 206-208C. Drying conditions prior tQ analyses were 5 hx at 97-98~./0.02 mm ~gi over ni~ht at room temperature/0.02 mm Hg.
Analysis: Calculated or C~5H25C1~40~: C,62,43i H,5.24;
~,11.65 Found : C,62052; H,5.23, ~,11.76 ~xample ~
N,~-Dimethyl 6-phenyl-llH-pyrido~2,3-b~1,4~benzo-diazepine-ll~propanamine fumarate [1:1].
To a stirred suspension of 1.68 g (0.070 mole) of sodium hydride (in mineral oil) in 25 ml 9f anhydrous dimethylformamid2, under nitro~en atmosphere, was added, portionwise, a ~u~pension of 8.o g (0.029 mole) of 6-phenyl-llH-pyridoC2,3-b][1,4~benzodiazepine in 20 ml of anhydrous dimethylfolmamide. ~he mixture was ~tirred for ~0 min after addition was complete, warmed to 65C. for 15 min and cooled again to room tempPrature. To the mixture was added 5~6 g (0O0~5 mole) of 3-dimethylaminopropyl chloxide hydrochlorid2. After stirring overnight at room emperature, thin-layer chromatoyraphy indicated the r~action was nearly completed. ~he reaction mixture was pou.red into 1500 ml water and extracted with 250 ml of methylene chloride.
The methylene chloride extract was washed with three 250 ml portions of water, dried over magne~ium sulfate and evaporated ~5 under reduced pre~ure. The residue was dissolv~d in ~95 3 ~ ~

methylene chl.oride and extracted wi.th 100 ml and 150 ml portions of 3 N hydrochloxic acid. Unreacted 6-pheny]. 11H-pyrido[2,3-b~134]benzodiazepine starting material precipi-tated from the aqu~ous ~cidic solution and was separated by 5 carefully decanting the liquid rom the solid. ~e aqueous solution was basified with 3 N sodium hydroxide and ext.racted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over rnagnesium sulfate and evaporated under reduced pressure to give 7.7 g residue, the free base o the title compound. A solution of 6.6 ~ of the residue in hot isopropyl alcohol was reacted with 2.15 g of fumaric acid and the mixture heated until dissolution was compl~ted. On standing for 48 hr, the salt which had precipitated was collected by filtration. After 15 recrystallization from isopro~yl alcohol-isopropyl ether, 5.9 g of product was o}:tained, m.p. 171-173C~ Drying conditions prior to analyses were: 4 hr at 90C./0.1 mm Hg;
overnight at room temperature/0.1 mm Hg.
Analysis: Calculated for C27~H404. C,68.6~, H,5.97; N,11.86 Found ~ C~68.37; H,6.o5; H,11.73 Example 10 ~,~ Dimethyl-6-pheny~ H-pyxido~2J3-b~[l~4~b~n diazepin ll-ethanamine fumarate ~1:1~.
To a stirr d su~pension of 1.48 g ~0.062 mole) of sodium hydride ~ in mineral oil) in 35 mï of anhydrous di-methylformamide, under nitrogen atmosph~re, was added, portionwise, 7.0 g (o.026 mole) of 6-ph~nyl-llH-pyrido ~2,3 b~ 4]b~nzodiazepine. After cooling the reac~ion mix-ture to room temperatureJ 4.46 g (0.031 mole) o 2-dimethyl-~50 aminoethyl chloxide hydrochloride was added portionwise and stirring continued overnigh~. The reaction mixture was poured into 1500 ml of water and the resultant mixture extracted with 250 ml of methylene chlc)ride. The methylene chloride extract was washed with three 500 ml portions of water9 dr.ied over magnesium sulfate and ~vaporated under reduced pres~ure to give 8.6 g of an oilg the free base of the title compound.

~95 Part of the oil, 6.9 g, was reacted with an equal molar amount of fumaric acid in isopropyl alcohol. Addition of isopropyl ether gave an oily solid. ~he mixture was evaporated under reduced pressure and the residue crystal-lized on standing. The crys~als were tritura~ed withacetone and recrystallized from acetone-isopropyl ether to give 4.~ g of the fumarate salt, m.p. 175-177.5 C.
Analysis: calculated for C2~H26N~4: C,68.11, H~5.72, N,12.22 Found : C,67.88; H,5.72;
~,12.17 Example 11

11 ~3 (4-Morpholinyl)propyl~-6-phenyl-llE~-pyrido~2,3-b]
[1,4]benzodiazepine fumarate ~
To a stirred suspension o 1.10 g (o.o46 mole~ of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen pr~ssure was added, portion-wise, 5.0 g (0.0184 mole~ o 6-phenyl llH-pyrido[2,3 b~
[l~4]benzGdiazepine~ The reaction mixture was stirred at room ~emperature for 15 min9 warmed at 65-70C. for 10 min and allowed to cool to room temperature. To the mixture was added, portionwise, 4.1 g (0.02 mole~ of 4~ chloro-propyl)morpholine hydrochloride. The reaction mixture was stirred at room temperature for 16 hr and then poured into 800 ml of water. ~his mi~turP was extracted twice with 200 ml portions of methylene chloride. The combined methylene chloride extr~cts were extracted with 150 ml and 75 ml portions of 3 ~ hydrochloric acid and the combined aaueous extract~ were ba~ified with 3 N sodium hydxoxide. The r~sulting suspension was extracted with two 150 ml portions ~0 of methylene chloride and these latter two extracts combined, dried over magnesium sulfate and evaporated under reduced pre~sure. The residue, the free base of the title compound~ was reacted with an equal molar amount of fumaric acid in warm isopropyl alcohol and the mixture treated with 35 isopropyl ether. The umaratP ~alt was collectecl by iltration and recrystallized from ekhanol-ethyl acetate to yive 5.6 g, m.p. 154-7C. Drying conditions prior to 3~
analyses w~re: 4 hr at 97-98C./0.1 mm Hg; overnight at room temperature~0.1 mm Hg.
Analysis: Calculated for C29H30N405: C,67.69; H35.88, N,10.88 ~ound O C,67.52; H,5.84;
~,10.90 Example 12 N,N-Diethyl-6-phenyl-llH-pyrido~2,3-bl~1,4~benzo-diazepine-ll-propan~mine oxalat~ 1].
To a stirred suspension of 1.10 g (0.0461 mole) of sodium hydride (in mineral oil~ in 25 ml of anhydrou~
dimethylformamide under nitrogen atmosphere was added, portionwise, 5.0 g (0.0184 mole) of 6-phenyl-llH-pyrido-~2,3-b][1,4~be~zodiazepine. The reaction mixture was stirred at room temperature for 0.5 hr, wa~med to 65 70 C.
and cooled slowly to room temperature. To the mixtur was addedJ portionwi~e3 3.77 g (0~020 mole) of 3-diethylamino-propylchloride hydrochloride and the reaction mixture stirred at room temperature for 16 hr. The mixtur~ was poured into 750 ml of w~ter and extracted with three 150 ml portions of methylene chloride. The combined methyl n~ chloride extracts were extracted with 150 ml and 75 ml portions of 3 ~ hydrochloric acid. The combined aqueous extracts were basiied with 3 N sodium hydroxide and then extracted with three 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pres~ux~ to give 705 g of the free base of the title compoun~. A portion, 506 g, was reacted with an equal molar amount of oxalic acid dihydrate in hot isopropyl alcohol. The oxalate salt was ~0 collected by ~iltration to give 5.5 g product3 m~p~ 196-199 C. Drying conditions prior to analyses were~ 1 hr at 97-g8C /o ~ Ig -AnalysisO Calculated for C27~0N~0~: C,68.~4; ~,6~37; ~,11.81 Found : C,68.~1; EI,6.43, N,11.86 31, Example 13 9-Chloro-N,~-dimethyl-6-phenyl-llH-pyrido~2,3-bl~1,4 ~enzodia~epine-11-propanamine fumarate ~
To a stirred suspension of o.g8 g (0.041 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen ~tmos~here was added, pvrtionwise, 5 .0 g ( 0 .016 mole) of 9-chloro-6-phenyl-llH--pyrido~2,3-b~[1,4]benzodiazepine over a 45 min perlod. The reaction mixture was stirred at room temperature or 1 hrg warmed to '70C. and then cooled slowly to .room temperature.
~o the mixture was added, portionwise, over a 30 min period, 2.84 g (0.018 mole) of 3-dimethylaminopropyl chloride hydrochloride and the reaction mixture stirr~d at room temperature for 17 hr. The mixture was poured into 750 ml water and extracted with 150 ml and two 100 ml por~ions of methylene chloride. The combined methylene chloride extracts were wa~hed with two 100 ml portions of water followed by extraction with 100 ml and 75 ml portions of 3 N hydrochloric acid. The acidic extracts were combined and filter4d to remove precipitate which had formed and the filtrat~ was basifled with 3 ~ sodium hydroxide and e~tracted with thrce 100 ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under r~duced pressure.
The residue was dissolved in methylene chloride and filtered through a 50-60 y bed of florisil in a sinterPd glass funnel.
The bed was washed in succession with 1%, 2~o~ 3% and 5%
methanol-methylene chloride mixtures~ the filtrates combined and evaporated under reduced pressure to give the free base of the title compound. The free ba~e was reacted with an equal molar amount of fumaric acid in hot isopropanol to give 3.3 g :Eumarate, m~p. 199-202C.
Analysis: Calculated for C27H27N~O~Cl C~63.96; H,5.37;
~1.05 Found : C~63.63; ~1,5.36;
N,11.00 ~95 ~5 Example 1 4 6-Phenyl-11 [3~ piperidinyl)propyl~-llH~pyrido ~2,3-b~1,4~benzodiazepine fumarate ~
To a stirred suspen~ion of 1.10 9 (0,0461 mole) of scdium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide under nitrogen atmosphere was ~ddedJ
portionwise, 5.0 g (0.018 mole) of 6-phenyl-llH-pyrido t2,~-b]~1,4]benzodiazepine. The xeaction mixture was stirr~d fQr 30 min, warmed to 70C. and cooled to r~om temperature. To the mixture was added, portionwise, 4.14 ~
(0.0203 mole~ of ~-(3~chloropropyl)pipexidine hydrochloride and the reaction mixture was stirred at room temperature for 16 hr. The mixture was poured into 750 ml of w~ ter, extracted with 150 ml methylene chloride by stirring fvr 15 min. Th~ aqueous layer was extracted with two additional 100 ml portions of methylene chloride. The combined methyl-ene chloride extracts were extracted wi'ch 150 ml and 75 ml portions of 3 ~ hydrochloric acid and the combined acid extract~ ~asified with 3 N sodium hydroxide and then extracted with three 100 ml portions of methylene chloride.
The methylene chloride extracts were combined, dried ovex magnesium sulfate and evaporated under reduced pressureO
The r~sidue was dissolved in a minimum of methylene chloride and filtered through a 100 g bed of florisil in a slntered glass funnel. The bed was washed successively with methylene chloride, 1~, 2%, 3~ and 5~ methanol-methylene chlorid2 mixtures. A11 the iltrates were combinPd and evaporated under reduced pressure. The residue was reacted with 1.3 g fumaric acid in hot isopropanol and isopropyl ether added.
~n amorphous precipitate was formed. The en~ire mixtur4 was ~0 ~vaporated to dryness and th~ residue dissolved in 200 ml o~
~thanol. The solution was warm~d to reflux, filtered and isopropyl ether added to the iltrate. crystals which ~ormed overnight were filt~red ofE to give 4.1 9 fumarate ~alt, m.p. 153~6C. Drying condition~ prior ~o analyses were: 4 hr at 97-98C./0.1 mm Hg.

~5~95 3;~f~

Analysis: calculated for C30H32N4O~: C370.29, H36.29;
N, 10 . 93 Found : C,70.38; H,6.32;
N , 1() . 92 Example 15 6~(4-chlorophenyl) -N,N-dimethyl-llH-pyridor2,;~5-b~1,4 benzodiazepine-ll-propa~amine fumarate ~
To a stirred suspension of 1057 g (0.065 mole) of sodium hydride (in mineral oil) in 25 ml of anhydrous dimethylformamide was added under nitrogen atmosphere, 8.o g 10 (o.026 mole) of 6-(4-chlorophenyl)-llH-pyridot2,~-~][1,4]
benzodiazepine. The r~action mixture was stirred for 1 hr at room temperature, warmed at 80C. for 15 min and cooled to room tempera-tur~ To the mixture ~9a~ added, portionwise, 4.55 g (0.0~9 mole) of ~-dimethylaminopropyl chloride hydrochloride and th~ mixtuxe was stirred overnight at room temperature. The mixture was poured into 750 ml of water and stirred for 30 min with 150 ml of methylene chloride.
Ths aqueous layer was extracted further with three 100 ml portions of methylene chlorid~. Th~ combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure to give th~ free base of the title compound. ~he fre~ base was reacted with an equal molar amount of fum~ric acid in hot isopropanol. On cooling, ~.6 g of the fumarate ~alt precipitated, m.p. 200.5-20~.5 C.
~he product was air dried further prior to analysis.
Analysis: Calculated for C2 7H27ClN~04: C963.96, H,50~7;
~9 11 . S
Found C964.18, H95-33, ~ 7 Example 16 8~Chloro~~ 3 N -d ime thyl 6-ph~nyl llH~pyrido~2 9 3 -b ~ ~ 1, 4 ~ -benzodiazepin~ ethanamine oxalate ~
To a stirred suspension of 1.05 g (0.044 mole) o:E 30dium hydride (in mineral oil) in 5- ml of ~nhydrous dimethyl-formamide was added, portionwise9 6.1 g (0.02 mole~ of 8-35 chloro-6-phenyl~ pyridor~2,3-b~C 13 ~ ~benzodia zep l.ne . The reaction mixtur~ ~7as stixred at room temperature ~or 1.5 hr, ~95 during which time ~volution of hydrogPn ceas~d. qhe ~actio~
mixture was cool~d to 5C. and 3.2 g (0.022 mole) of 2-dimethylaminoethyI chloride hydrochloride was added, portion-wise, followed by stirrin~ at too~ temperatur~ for about 60 hr.
The reaction mixtur~ was poured into 1600 ml of water and the mixture e~tracted ~hree ~imes with 500 ml portions of m~thylene chloride. The combined extracts wer~ shed with two 500 ml portions of water, dried over magnesium ~ulfate and evaporated under reduc~d pres~ure. Thin lay~r chrom~
togr~p~y (20~ methanol ~enz~ on silica gel~ indic~ted the presence of fre~ base of the title compound and of starting material. The residue ~as dissol~ed in benzene and chromatographed on a 200 g colu~l of florisil p~cked in benzene. Starting material, 1.3 g of 8-chlo~o-6-phenyl-llH-pyrido~2,~-b~1,4~henzodiazepine was eluted with benzen~ and the free bas~ of the title compound wa~ eluted with mixtures of acetone in benzene. Th~ free base was reacted with an equal molar amount of oxalic acid dihydrate in refluxing isopropyl alcohol and product recrystallized from isopropyl alcohol weighed 1.6 gJ m.p. 228-5-232C. Drying conditions prior to analysis were 6 hr at 82C/0.1 mm ~g, overni5ht at room temperature .
Analysis: calculated for C~H23ClN~0~: C,61.74; H,4.96;
~,12.~0 Found : C,61.62; H,4.95, N,11.98 Example 17 8-Chloro-ll methyl-6-phenyl-~lH-pyridor2?3~b~rl,4 ben~odiazepine.
To a ~tirred susp~nsion of 0.25 g (0.01 mole) of sodium 30 hydride (in mineral oil) in 15 ml of anhydrous dime~hyl-formamide was addQd, portionwise, 3.05 g (0.01 mole) of 8-chloro-6-phenyl~llH-pyrido~ 9 3-b~[l 9 4~benzodiazepin2. Th~
mixture was warmed at ~bout 60 C ~or one hr. ~ solution of 1.42 g (0.01 mole) of methyl iodid~ in 10 ml of anhydrous dimethylformamide was added drop~7i5e over ~ 0.5 hx period and the reaction rnixture ~tirred o-Jernight at xoom ~emperature after which i'C was poured into 400 rnl of w~t~r and stirred ~ 3 3~
for 2 hr. The precipitat~d solid was recrystallized twice from isopropyl alcohol to give 2.0 y of product, m.p- 153--6 C.
Drying conditions prior to analyses were 1 hr at 82 C~/0.1 mm Hg.
5 Analysis: calculated for ClgHl4ClN3: C,71.36; H~ll.4l; ~,13.14 Found : C,71.64; H,4.43; N,13.32 Example 18 N5N-Dimethyl-6-(4-methylphenyl)-llH-pyrido~2,3-b~[1,4 benzodiazepine-ll-propanamine fumarate ~
To a stirred suspension of 0.51 g (0.022 mole~ of sodium hydride in 25 ml of anhydrous dimethylformamide under nitrogen atmosphere was added, portionwise, 4.2 g (0.0147 mole~ of 6-(4-methylphenyl)-ll~-pyrido~293-b][1J4~benzo-diazepine over a 45 min period. The mixture was stirred for 15 1 hr at room temperature, warmed at 75-80~C. for 1 hr9 cooled to room temperature and a ~olution of 0.C184 mole of 3-dimethylaminopropyl chloride in 10 ml of anhydrous dimethyl formamide was ~dded dropwise. The mi~ture was stirred over-night at room temperature and poured into 1000 ml of water.
20 ~he suspension was extracted with three 150 ml portions of methylene chloride and the combined methylene chloride extracts were extracted with two 150 ml portions of 3 hydrochloric acid. A precipitate formed in the acidic solution which was removed by filtration and discarded. The 25 filtrate was basi~ied with 3 ~ MaO~ and extracted with three 10~ ml portions of methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressur~ to give an oil, thc free base of the title compound. This residual oil was dissolved 30 in hot isopropyl alcohol and reacted with an equa~ molar amount of fum~ric ~cid. The fumarate salt crystallized as the solution cooled to room temperature and was recrystal-lized twice from isopropyl alcohol-isopropyl ether to yive 1.7 g product, m.p. 187-189c.,(decomp~).
~nalysis: Calculated for Cz8~l30N~O~: C,69.12, H96.22; N911.52 ~ound : C,68.86; ~,6~32, N,11.36 ~9 Ex~mple 19 6-(~ Methoxyphenyl)-N,N-dimethyl-llH-pyridor2,3-blrlJ4 benzodia~epine~ pr~p~namirle fumarate ~
To a stirred suspension of o.ll5 g (0.01~37 mole~ of sodium hydride in 25 ml of anhydrous dimethylforrnamide unde:r nitrogen atmosphere was added 4.5 g (0.015 mole) of 6 (4-methoxyphenyl)-llH-pyrido[2,~-b~1,4]benzodiazepine over a 30 min p~riod. Th~ mixture was 6tirred for 30 min at room temperature followed by warming at 80 90C. for one hr) cooling to room temperature and a solution of 0.019 mole of ~-dimethylaminopropyl chloride in 5 ml o anhydrou~ dimethyl-formamide was added dropwi~e. The reaction mix~ure was stirred overnight at room temperature and poured into 800 ml of water. The suspension was extracted with two 150 ml portions of methylene chloride. q~e combined extracts w~re washed with 500 ml of water then extractcd with two 100 ml portions of 3 ~ hydrochloric acid. Th~ solid which precipi-tated from the combined acidic extracts was filtered off and discarded. The filtrate was basified with 3N sodium hydroxide and extracted with three 100 ml portic)n~ ~iE methylene chlorideO
20 T~e combined methyl~3ne chloride ~xtracts were dried over magnesium sulfate and evaporated under reduced pressurf3. The residual oil had partially cry~talli;zed ans~ was triturated in methylene chloride and :Eiltered, leaving in a residue of 0.32 g. The filtrate was evaporated under reduced pressure and the residual oil triturated in hot benzene and filtered, leaving a residue of o.8 g. The benzene ~iltrate was evaporated under reduced pressure and the residual oil was reacted with 1.02 g fumaric acid in hot isopropyl alcohol.
Upon cooling, an oil separated fxom ~olu~ion. The supern~an~
liquid wa~ decanted and the oil seeded. Ater cry~talli2ing partially, the mixture wa~ filter~d to give 2.5 g ~olid~ m.p.
157--60 C. An attempted r~cry~tallizati.on from isopropyl alcohol-i~opropyl ether again produced an oil-~olid mixtur~.
The mixture was reheated with ~ddition~l isopropyl alcohol~
~olubilized, filter~d, ~eded and cool~d. rrhe umarate salt precipitated and was coll0cted by ~iltering to give 2.0 g, m.p. 159-161C.
Analysiso calrulated for C~2BH3~,N~05:C,66.92; H,6.o2; ~,11.15 Found : C~66.90; H,6008; 21,11.08 Example 20 6-( 3-Chlorophenyl ) -llH-pyrido~2 ,3~blr 1, 4 ~benzodiazepine .
A mixture o 14 g (0.0433 mGle~ c>f ~2~ amino-2-pyridinyl)aminc>]phenyl~(3 chlorophenyl)-methanone and 0.3 g of para toluene sulonic acid in 5(30 ml o toluene we.re heated at reflux s)vernight u~ing a r)ean-Stark trap to s~ollect water. At the ~nd of the reflwc time~ some of the to:Luene (ca 250 ml) wa~ distilled off and the hot solution was iltered. Pet. ther ( ~iO 6C)C. ) was added to ~he cloud point .
The solution was refrigerat~d overnight and fil~ered to yive ~fter air drying, 10 g (76,~5) gold colored crystals. A
portion was recry~talli~ed from isopropyl alcohol-iaoprapyl ~ther, m.p. 160-~60.5 C.
Analysis~ calculated fsr CleHl2N3Cl: C,70.71, El,~.96, ~J13.74 Found ~ C770.47; 11,~.98; M,13.62 Example 2 1 6~ Chlorophenyl)-~,~-dim~hyl-llH-pyridor2,~-b][~1,4 benzodiazepine~ prop~n~m; r~e fumarate r 1 1 ]
To a stirred au~pen~ion of ~i.4 g (0~07 mole~ of sodium hydride ( in mineral oil) in 25() ml of anhydrou6 dimethyl-formamide wa~ added und~r nitrogen atmosphere in portions 8.5 g (oOo28 mole) of 6-~-chlorophenyl)-llEI-pyrido[2~
tlJ4~enzGdiazepine. q~he mixture was ~tirred f~r 50 min at room temperature. qhe temperatur~ was raised lto 80co ~or 3 hr and thereafter ~llowed to c:ool 'co rovm temperature. To the reaction mixture was added dropwis~ a ~olution oX 4 ~ 9 g ~iO ( O .031 mole1 oi~ 3-dimethylamirlopropyl chlorid~ hydrvchloride in 30 ml o dLmethyl:Eormamide ovex a 20 minutP p~riod. qqla~
reaction mixture wa~ al~ow~d to ~tir ak room ~emperature overnight under nitrogen a~mo~pher2. T31in layer ;:hromatograp~y indi~ated ~3ome ~tartirlg material wa~ pr~entO ~dditional ~odium hyarid~ 1~4 g (0.05 mole) wa~ ~dded ~nd ~~r 15 min 4.7 g (0.03 mole) of 3-dimethylamirlopIopyl ~hloride hydro ~3 ~ 3 chloride was added followed by ~ti.rriny for 4-1/2 hr. ~7ater ~20 ml) w~6 added dropwi~e and the reaction mixture filtered and concentxat~d on a rotary evaporator. The r~idue w~s partitioned betwe~n diethyl ether and dilute ~odium hydroxide.
The ether layer was washed with water ~ times and extract~d with dilute aqueous hydrochloric acid. The water layer was basiied with sodium hydroxide pellets and extracted with methylene chloride. The methylene chloride layer wa~ dried and eoncentrat~d to give a resldue of 7.5 g product. The free ba~e was reacted with fum~rie acid and the fumarate E,alt recrystallized fxom ethyl acetate~ethanol, m.pO 167.5-168.5~.
Analysis: Calculated for C23H29~Cl: C,6~.96; H,5.47; ~911.05 Found ~ CJ63.95; E~5.~59, ~911.00 Example 22 6-(4 Fluorophenyl)-llH-pyrido~2,3-b~rl,4~benzodiaæepine.
A mixture o 11.5 g (0~037 mole) of L2-~(3~amin~-2-pyridinyl)amino]phenyl~(4-fluorop~enyl)meth~none and 0.6 g of para toluene sulonic acid in toluene was refluxed for 24 hr using a Dean-StarX ~rap ~o collect water. ~t the end of reflux, some of the tsoluen~ ~300 ml~ was distilled off and the hot ~olution was filtered. Pet.-ether (~o-60 ) was added to clQud point. The æolu~ion was refrigerated overnight (0C.~ and filtered to give 10.7 g crystals. A
portion of the material was recrystalliz~d from i~opropyl alcohol and dried in vacuo overnight at 65C. 9 m.P. 20~-205C.
Analysi~7 Calculated for Cl8~l2~F: C,74.739 H74.18, ~,14.52 Found s C~74.61, H94.17; ~,14.54 Example 23 6-t4-Fluorophenyl)~ dimethyl ~lH-pyrido~2g~ b~l,4 benzodiazepine~ propanami~ hydrochlorid~ hemihydrate.
To a ~tirred ~uspen~ion o 3.6 g (0O075 mol~) o ~odium hydride (in mineral oil) in 250 ml of anhydrou~ dLmethyl-fo~mamide wa~ added under nitrogen atmo~phere n portion~ of 35 B.7 g (0.03 mol2) ~f 6~4-fluorophenyl?- llH-pyrido~273~b~
C1,4~benzodiazepineO The mixtuxe was ~tirre~ or ~0 min at room temperature. ~h~ temperatuxe Wa3 rai~e~ to 80~CO or 3.5 hr. ana there~ft~r allowed to c~ol ~o 45~C. ~o th~ reaction ~95 mixture was added dropwise a ~olution of 5.~ g (0.033 mole) of ~-dimethylaminopropyl chloride hydrochloride in ~0 ml of dimethylformamide. Aftex stirring overnight at room tcmperature, thin layer chromatography indicated the presence 5 of starting material. Additional ~30dium hydride, ~.6 g (~.075 mole) was add~d and after 45 min ~tirring, ~he reaction mixture was heatPd to 50-60C. for 1/2 hr. A green color developed with formation of gas. l~e mi~ture was ~tirred at room temperature ox 3 hr. A solution of 5.2 g ~0.0~ mole) of 3-dimethylaminopropyl chloride in ~0 ml of dimethylormamide was added dropwi~e. (About half way through th~ addition, a green color develop~d and a,ddition was hal'ced temporarily for about an hour). The reaction mixture was stirred overnight at room temperature. ~o the 15 mixture was added 30 ml o:E water while cDoling. Ar'ter gas evolution had stopp~d the mixture was filter~3d and concen-trated in a rotary evaporator. ~he residue was partitioned between di~thyl ether and wat~3r ~nd the ether layer e~tracted with dilut~ aqueous hydrochloric acid 601ution. The acrueou~
20 lay~3r was :Eiltered after 1~ hr to remov~ 6C>I id. The filtrate WaL5 basified with 50dium hydroxide pellets and extracted wit~ methylE3n~ chlorideO The extrEIct was dried and c~nc~ntrated. Ihe residue was divid d int:> two equal parts and purif ied by dry column chromatography on two 20" x 1~ '1 columns of ~ilica gel which had beerl deacti-vated by the development ~olvent (105~ metharlol~ 1% concen-trated ammonium hydroxide, 89~ methylene chlorid~). q'he cent~r portis~n oiE ~he column was cut out ancl extracted with ~he development solvent. The combined extracts were c:oncen-30 trated under reduc~d pres~ure and the r~3idu~ di~so:l ved in~l3thyl acetate~ethanol mixtuxe and acidi:Eisd with concentrated hydr~chloric acid. The hydrochloric acid ~allt was recrystal-liz~d from e'chanol-ethyl ac~tate mixture. ~ e solid obtained by filtration wa~ dried at 99C. for 48 hr to giv~ the title ~ compound a~ the monohydrochloride hemihydrat~, m.p~ 120 C.
~naly~is~ calcul~d f~r C4~0~8F2C12 C,~5-7~, ~9~-~,~3.~4 ~o~na : ~,65.~ I,5.77, ~13~7 :L~3~;3i~

Example 24 ~ (19~-Dihydro-l,~-dioxo-2H i~oindol-2-yl)pxopyl~-6-phenyl-llH-pyridor2~3-b~[l~4~benzodiazepine.
To a stirred ~usp~nsion of 0.56 g ~0.023 mole) of sodium hydride in 25 ml o~ anhydrou~ dimethylformamide was add~d, portionwise, 5.0 g (0.0181i mole) of 6-phenyl llH-pyrido~2~-b]~l~4~benzodiazepine. The reaction mi~ture was warmed to 80 ~ 2C. or 1 hr ~nd cooled to room tempe~ature.
A ~olution of 5.55 g (0.020 ~ole) of ~-(3-bromopropyl) phthali~nide in 10 ml of anhydrous dimethylforrnamide was added dropwise and af~er ~tirring :Eor 16 hr the reaction mixture wa~ poured intc> 650 ml of water and stirred for 3() min. The yellow solid was collect~d by filtxation and recrystallized three times from i~opropyl alcohol to give 3 . 7 g oiE product " m . p . 170-172C .
Analysis: Calculated :Eor C2~,EI22~402- C,75.97, H,4.8JI; ~312.2~
Found v C~76~25; h~4.87; ~912.34 Exampl e 2 ~
6-PhenY1-1 1H-PYridOC2, 3-b~ E 1 y 4 ~benzodia:~epine-11 propanamine, dihydrochlorida, hemihydrate.
A mixture o:f 16 .2 g ( 0 ~ 035 mol~ 6-~enyl~ 3-( phthal imido ) propyl ~ -11H-PYridC~C 2, ~S-b~ C 19 4 ~ben~odiaz~pin~
and 2.29 g (0.0387 mole) o hydrazin~ hydrate~ 85j'g in 175 ml o:E 190 proof ethyl alcohol was reiEluxed :Eor 205 hr and allowed to stand or 72 hr. A ~olution of lL0 ml concO
25 hydrochloric acid in 50 ml o:E wat~r was added to the mixture.
T~e mixture was stirred overnlght. The ~olid precipitate was collected by filtratio~ and discarded. ~he :Eiltrate was evaporated und~r reduc~d pressure~ The residue, slightly wet, was ~u~pended in 200 ml o:!E water, the mixture 30 was stirred fior 2 hr ~nd :filter~d throl:lgh c~l.ite~) The f iltrate was evaporat~d under reduced lpr~s3ur~S and the residu~ su~pellded in l()t) ml of 200 proof ethyl alcohol and ~3vapoxated under r~duc~d pre~ur~ h~ latter p.rocedure was repsa ed. ~ c~d~, damp residue (42.1 g) was recrystal-35 lized from i~opropanol with standing ~or about 15 hr. ~Ihe ~ 1id, collects~ by filtratiorl, was ~qried ;~t 82 over ~95 phosphoru~ anhydride at 0.1 mm Hg. for 3 hr; m.p. 210-220C.
(decomp.).
Analysi~: calculated fsr C~4~Cl~0: C,61.47, ~,5.65;
~,13.65 ~ound : C,61.36; H,5.72;
~,13.9G
~xample 26 6-Phenyl-llH-pyrido~2,3-b~1,4~benzodia~eplne-11-propanamine.
A portion sf the 6-phenyl~ll~-pyrido~29~-b~rl~4~benzo-diazepine~ propanamine, dihydrochloride hemihydrate ~btained in Example 25 wa~ di~solved in water, ba~ified with di~u~e ~odium hydroxide, and extracted with thre~
portions of methylene chloride. 7~he combined methylene chloride extracts were filt~red through a 50-60 g b~d of florisil in a sinter~d glass :~unnel. ~he bed was washed in succession with 1,~, 2%, 3% and 5% methanol~methylene chloride mixtures, th~ :Eiltrates combined and evaporated under reduced pres~ur~ to giVF the free base, the title comp~und .
Example 27 N-r 3-~6~Phenyl~ pyrido~2, 3~blr 1 9 4 ~b~zodiazepin-ll-yllpropyl]methanimidic acid ethyl ester.
A solution of 8.8 g (0.021 mole) of 6-phenyl llH-pyrido ~2,~ b~c1,4~benzodiazepine~ propanamin2 in 150 ml of triet~ylvrthoformate ~ heated at reflux for 4-1/2 hr and allowed to ætand overnight. The mixture was concentrated in vacuo, the residue wa~hed with pet-ether (30-60 C.3.
__ Chemical ionization mass ~pec indi~at~d the product wa~ a mixture containing the title compound.
Example 28 3~ ~-Methyl-6-phenyl llH-pyrido~2,~-b~1,4~benzodiazepine-ll-propanamine, dihydrochloride.
Pre~aration of Imidate Est0r eProcedure o~ Croc~et, To A. ~ Blantong C. D.~ J.r.
Synthesis 1974 (1) 55-56 6-Phenyl-llEI-pyri~2, 3-b~ t 1, 4 ~ben~odiazeplne~
~5 propanamine dihydrochloride hemihydrate~, 25 g (o.o6 mole) I~5 from ~:xample 25 was converted ~o ~he free base by par-titioning between dilute ~odium hydxoxide arld methylerle chloride, drying and concentratiny the methylene chloride layer to dryness) adding dry benzene and again concer~trating 5 to drive off the benz~ne. qhe reRulti~g fr~e base was dissolved in 300 ml (267 g; 1.8 mole) ~f fr~shly di~tilled triethyl orthoformate with rafluxing ~or 9 hr. The mixture was concentrated in vacuo, zthanol was ~dded and the mixl:ure concentrated aga in .
Conver3ion oiE Amidate to Amine The 23.4 g (o.o6~ mole) amidate prepared in the fore~
going was dissolved in 200 ml ~f e~hanol and sodium boro-hydrate added with stirring at 15-20C. un~ hin layer chrc>matography indicated r~ac~cion was essential:Ly compl~te 15 as indicated by a~sence of ~;ubstantial ~tarting materiali Fifty ml of water was add~d ~3lowly with stirring and cooling continued 15 min a:Fter ~he water addition. Thç mixture was then flooded with 2 liters of w~ter and extracted wi~h ethyl aceta~e. The ethyl ace~ate layex w~s w~shed wi~h water until neutral wa~h was obtained and ~hen ~aturated with ~odium chloride. The re~ulting ethyl acetate layer was dried and concentrated. Diethyl ether was ~dded and the mixture chilled. Some insoluble material was filtered off and discarded. The ~ther layer was concentrated and the product chromatograp~ed on an alumina column ~neutral9 activity-l) eluting with ethyl acetate ~ methanol -~ traces of triethyl amine. The fractions containing ~ubstantial product (TLC) were partitioned b~tw~en ethyl acetate and aqueous ~odium hydroxide. Ethereal hydrogen chloride was added to the ethyl acetate layer and the crystalline product recry~tallized from acetonitrile~water mixture.
Melting point of the product was 139-141~.
Analy~ Calculated for C2ZH2~Cl2: C,63.62; ~95.82;
~,~3.49 Found : C,63.8i: H,6.15, ~J ~3.6 ~95 Example 29 ~-~3-~6-Phenyl-llH pyrido~2,3-b~rl,~]benzodiazepine-11-yl~propyl]carbamic acid ethyl e~ter.
To a Bolution o~ 106 y ~0.0045 mol~) of 6-pheny~
pyridoC2,3-b~C1~4~benzodi.aæepine~ propanamine in dry methylene chloride wa~ added 0.53 g (0.0052 mole) of kri-ethylamine. To this 801ution wa~ added dropwi~e9 while cooling, 0.54 g ~0.0050 mole) of ~khyl chlorGfo~make. The mixture w~s ~tirred at room temperature for 2 hr. The methy~ene chloride solu~ion of th2 product ~as indicaked by chemical ionization mass ~pec) wa~ w~shed with di.lute ~odium hydroxide~odium ehloride ~aturated aqueous ~olukion and dried and concentrated to dr~ne~s. The residue was trikur-ated in i~opropyl ether. Yield wa~ 1.5 g of ~itle product.
Example ~0 576-Dihydro~ -dimethyl 6-pheny~ H-pyrido~2~3-b~ 4]
benzodiazepine-ll-prop~n~mine, dihydrochloride hem~hydrake.
A ~olution of ~.0 ~ (o.oo64 mole) of ~ dimethyl-6-phenyl-llH-pyrido[2,3-b3~1,4~benzodiazepine-11-propanamine in absolu~e methanol was adjusted to pH 5.6 with methanolic hydrogen chloride ~olution. To this solution was added at one time~ 0.7 g (0.011 mole) o~ ~aB~3C~ ~nd the r~action mixture was refluxed for 20 min. ~he ethanol ~as removed in vacuo and the re~idue was partitioned betw~en dilute sodium hydroxide and methylene chloride. ~h~ methylene chloride layer was dried over magnesium ~ulfate and concen~
trated to leave a residue w~ich was twice cry~allized from 2-pxopanQl and i30propyl ether. A yellow solldg 106 g (57%) wa6 obtained which lo~e~ it~ crystalline structure on heating starting at 156-160~C. wi~h decompD~ition at 180-lg5C.
Analysi~o Cal~ulated for C~8H~a~8OCl~: C,62.73; H,6.64;
~,12.72 Found : C,62.40, ~,6~go ~,12.6 Examples ~la to 31r Following the procedu:re of Example 6, the following methanon~ compounds:
~2-~(3~amino-2-pyridinyl~amino]phenyl~-~4-ethylphenyl) methanon~, r2-[(3-amino-2-pyridinyl)amino~phenyl~-(4-isopropyl~
phenyl) methanone, ~2-~(~-amino-2~pyridinyl~amino~phenyl]-(4-bromophenyl) me thanone g ~2-[(~-amino-2-pyridinyl)amino~phenyl~-(4-fluorophenyl) 10 methanone, c2-~(3-amino-2-pyridinyl)amino~phenyl]-(4-e~hoxyphenyl) methanone, t2-~(3-amino-2-pyridinyl)amino]phenyl]-(4-nitrophenyl) methanone, ~2-~(3-amino-2-pyridinyl)amino~phenyl]-(4-trifluoro methylphenyl)methanone~
[2-[(3-amino-2-pyridinyl)amino]phenyl~-(3-methylphenyl) methanone, c2-~3-amino-2-pyridinyl~amino]phenyl]-(3-ethylphen methanone, ~2-~ amino-2 pyridinyl)amino~phenyl~-(3-methoxyphenyl) methanone, [ 2 -r ( 3-amino-2-pyridinyl)amino~pheny11-( 3- ~thoxyphenyl ) methanone, ~2-C(~-amino-2-pyridiny~)amino]phenyl ~-(2-nitrophenyl) methanone, [2~[(3-amino-2-pyridinyl)amino~phenyl]-(3-tri1uoro-methylphenyl)methanone, ~2-[(3-amino~2-pyridinyl~amino]phenyl~-(2-methylphenyl) 3 methanone, [2-~ amino-~-pyridir,yl)amino~phenyl~-(2-ethylphenyl)-methanone, r2-~ (3-amino~2 -pyridinyl~amino]p~lenyl~-(2-methoxyphenyl) me~hanon~, r2 ~ amino-2-pyridinyl)amino~phenyl~-2,4-dichloro-phenyl)methanone, and ~8 ~2-r(3-amino-2-pyridinyl)amino]phenyl]-(3,4J5-trimethoxy-phenyl)methanone, are cyclized to the following pyridobenzodiazepines:
a) 6-(4-ethylphenyl)-llH-py.rido[2,3-b]~1,4~benzodiazepine7 b) 6 (4-isopropylphenyl)~llH-pyrido[2 J 3-b]~1,4~benzo-diazepine, c) 6-(4-bromopherlyl)-llH-pyrido~2,3-b]rl,ll]ben~odiazepineJ
d) 6-(4-fluorophenyl)-llH-pyrido[2,3-~rl,4]benzodiazepine, e) 6-(4-ethoxyphenyl)-llH-pyrido~2,3-b~lJ4~benzodiazepine, ~) 6-(4-nitrophenyl)-llH-pyrido~2,~-b]~1,4~benzodiazepine, g) 6-(4-trifluoromethylphenyl)-llH-pyrido~2,3-b3[1,4 ben~odiazepine, h) 6-(3-methylphenyl)-llH-pyrido~2,~-b~[1,4Jbenzodiazepine, i) 6-( 3-ethylpherly~ H-pyrido~2 9 3-bl [ l ~ 4 ]benzodiazepirle ~
i) 6-(3-methoxyphenyl)-llH-pyrido~2,3-b][1,4~ben~odiazepine, k) 6-(3-ethoxyphenyl)-llH-pyridor2,3-b][1,4]benzodiazepineg 1) 6-(2-nitrophenyl)-llH~pyrido[2,3-b]C1,4]benzodiazepine, m) 6-( 3-trifluoromethylphenyl) -llH-pyrido[2 ,~S-b~ 1, 4 benzodiazepine, 20 n) 6~(2-m~thylphenyl)~ pyrido~29~-~]C1,4]ben odiazepine, ~ 6-(2~ethylpheny~ I pyrido~2~3-b]~ 41benæodiaz~plne~
P) 6-(2-methoxypheny~ H-pyrido~3-b~[l9lllhenzodiazepine~
~ ) 6- ( 2, 4-dichloropheny~ H-pyridor2g~-b~[l 9 4 Jbenzo-di~zep in~ 9 and r~ 6-(3,4,5-trimethoxyphenyl)-llH-pyrido~2,3-b~1,4~benzo-diazepine .
Example~ 32a tG 320 Following the procedure of ~xampl~ ~, the ~ollowing meth~none compounds:
~ ( 3-amino-2 -pyridinyl ) amino ~-5-chlorophenyl ~ ( ph~3nyl ) methanone, [2 -~ ( 3 -amino-2 -pyridinyl ) amino ]-6~chlorc)phenyl ~ ( phenyl ) methanone, ~2-~(3-amino-2-pyridinyl) amino ~ --4~bromoph~nyl ~ ~ phenyl m0thanon~
~ 2-~ (3~amino-2-pyridinyl)amino]-4~1uorop~nyl~(phenyl) methanone, ~2-C (~-amino-2~pyridinyl)amino~-4-trifluoromethylphen (phenyl)methanone, ~2-~(3-amino-2-pyxidinyl)aminol-4-met}lylphenyl~(phenyl) methanon~ 9 ~2-~(3~amino-2-pyridinyl)amino~-5-methylphenyl~(phenyl) methan~ne, ~2-~ (3-amino-2-pyridinyï.)amino~ 6 methylphenyl3(p~enyl) methanone, t2-~(~-amino-2-pyxidinyl)amino~-4-ethylphenyl]~phenyl) methanone, [2-~(3-amino-2-pyridinyl)amino~-4-methoxyph~nyl~(p~enyl) methanone 3 ~ 2-~(3 amino-2-pyridinyl)amirlo~-4-e~hoxyph0nyl](phenyl) methanone, ~2-r(3-amino-2-pyridinyl)amino~-4-nitrophenyl~(phenyl) methanoneg ~ 2-[(3-amino-2-pyridinyl)amino]-5~nitroph~nyl~(phenyl) methanone~
C2-~(3 amino 2-pyridinyl)a~ino~-3-methylphenyl~ph~yl) methanone, and ~2-~(3-amino-2 pyridinyl)amino ~3-chlorophenyl~(p~enyl) m~thanone, are cyclized ~o the following benzodiazepine :
a) 8-chloro 6-phenyl-llH-pyrido~2~3-h]~1,4~benzodiazepine, b) 7-chloro-6-phenyl-llH-pyrido~2J3 b~l94~benzodiazepine~
c) 9~bromo 6-phenyl-llH-pyrido~2~-b~ 4]benzodiazepineg d) 9-~luoro-6-phenyl~llH-pyrido~2~3-b~1,4 benzodiazepineg e) 6-phenyl~g~trifluorome~.hyl-llH-pyridoC2g3-b~1,4 b~n20diazepin2, ~ g-methyl-6-pheny~ H-pyridoc2~3~ 4~b~n~odiayepine~
g) 8-methyl-6~phenyl~11EI-pyrido~2,3-b~rl,4~benzc~diazeplne, h) 7-methyl-6~phenyl-ll~-pyrido~293~b~174]bPnzodiazepln~, i) 9-ethyl-6-phenyl~ -pyrido~2"3~b~tl,4~benzodiaz~pine, j) 9-methoxy-6-pheny~ H-pyrido~2~3-b]rl~4]benz~diazepineJ
k~ 9-ethoxy-6-pheny~ -pyridoC2,~-b~1,4~ben~odi~zepine J
1) 9-nitro-6-ph~nyl-llM-pyrido~2,3-b~194~benzodiaz2pine~
m) 8 ni~ro-6-phenyl~ pyrido~2,~-b~[1,4~b~nzvdi~pin~9 5o n) 10-me~hyl-6-phenyl-llH pyridoc2,3-b~ 4~benzodiazepin~, and o) lO~chloro-6-phenyl-llEI-pyridoC2,3-b~1,4~b~nzOdiazepine.
Examples ~3a to 33r Utilizi~g the procedure o Example 15 hut ~ubstituting ~qual molar a unts o~ each o* the compounds prep~red in Example 31, th~ following 6-phenyl-substituted pyrido-benzodiaz~pines are prepared:
a) 6-(4-ethylphenyl3 ~,~-dimethyl~llH-pyrido~2,3-b~194 benzodiazepine~ propanamine5 b) ~,~-dimethyl-6-r4~ methylethyl)phenyl~ -pyridc ~2,3-b]~1,4]benzodiazepine~ propanamineg c) 6-(4-bromophenyl)-~,~-dimethyl llEI~pyrido~3-b]~l~4 benzodiazepine-ll-propanamine, d) 6-(4-1uoxophenyl)~ -dimathyl~llH~pyridoL2,~-b~[1,4 benzodiazepine-ll-propanamine, e) 6-(4-ethoxyp~enyl)-~,~-d~methyl-llH-pyridoE2,3-b~1,4 benzodiazepine~ propanamine, f) ~ dimethyl-6-(4-nitrophenyl)-llE-pyxido~2 r 3 b~l,4 23 benzodiaz~pin~ propanamlne, g) ~,~-dimethyl-6~4-(trifluoromethyl)phenyl~ -pyr~do 2, 3-b~ [ 1, 4 ~benzodiazepine~ propan~mine, h) ~ dim~thyl~6 ( 3-methylphenyl)~ pyrido~2 3 ~S-benzod ia zepin~-l l-propanam ine 9 2 5 i ) 6 ~ e~hylph~ nyl 3 -N g ~-dime thyl -1 lH-pyr ido ~ 2, ~ 1 ] ~ 1, 4 benzodiazepine-ll-p:ropanamine, i3 6-(3-methoxyphenyl)~ -dim~thyl--llH pyrido~2,~-b~
~1, 4 ~benzodia z~pine-ll prop~n~Tn i ne "
k) 6-(3~ethoxyphenyl)-~ thyl~ py:rido~2~,3~b~1"4 3Q benzodiazepin~ prop~mi n~
1 ) ~J ~-dLmethyl 6-(2-nitrop~2nyl 3 -llH-py.rido~2,3-b~l 3 4 b~nzodiaæepin~-ll propanamine, m) ~ dim~thyl-6-~4-(trifluoromethyl)phenyl~ llH~pyrido e2,3-b~1,4~benzodiazepin~ prop~n~ e, ~) ~5~-dimethyl-6-(2~-met~ylphenyl)-llH py.ridor29~ b~C1~4 benzodiazepine-ll-propanamir~

o3 6-(2~ethylpheny~ N-dimethy~ pyrido~273-b~[l~4 benzodiazepine~ propanamine~
p) 6-(2-methoxypheny~ -dimethy~ pyrido[2J3-b]
r1.,4~benzodi~epirl~11-prop~namine, q) 6-(2,4-dichlorop~enyl 3 ~ dimethyl-ll~ pyxido~2,3-b]
~1,4~benzodiazepine~ propanamine, and r) ~,~-dimethyl-6-(3,4,5-trimethoxyphenyl)-llH-pyrido t2,~-b]C1,4~benzodiazepine-11-propanamine.
Examples 34~ to 340 Utilizing the procedure of Example 1~ but ~ub3tltuting e~ual molar amount6 of the compounds prepared in Example 32 for 9-chloro~6-phenyl-llH-pyr.ido~2 J 3 b~[l,4~benzodiazepine, the following pyridobenzodia~epines are prepar~d~
a) 8-chloro-~31~-dimethyl-6-phenyl-llEI-pyriRo~2,3-b~194 benzodiazepine-ll-propanamineg b) 7-chloro ~,M~dimethyl-6-pherly:l-llH-pyridot2,3-b3~1,4]
benæodiaz~pine~ propanamine3 c~ 9-bromo-~,~-dimethyl~6-phenyl-llH~pyrido~233-b~1,4 benzodiazepine-ll propanamine, d) 9-fluoro-~N-dimethyl-6-pheny~ pyrido~2~-b3~l~4]
benzodiazepine-ll-propanamine~
e) ~-dimethyl-6-pheny~-9-(trif~uoromethyl)-llH-pyrido ~27 3-b~ ]benzodiazepine~ propanamineJ
f) N,N,9-trimethyl-6-phenyl-llH-pyrido~2 J 3-b ~ ~ 1 g 4 ~ ben zo-diazepine-ll-propanamine, g) ~,~,8-~rimethyl-6-phellyl-ll~I-pyrido~2,3-b~3El,43benæo-diaæepine-ll-prop~n~mi n~ ~
h) ~,7-trim~thyl-6-phenyl 11~-pyrido~2~3~b~1J4~benzo-~iazepine~ propan~mine~
i) 9-e~hyl~7,~ dimethyl-6-phenyl~ -pyrido~2,3~b~ 4 benzodiazepine-ll-propanamin~
j) 9-methoxy~ dimethyl-6-phenyl~llH~pyrido~2~3-bJ~
benæodiazepine ll prop~n~mine~
k~ 9w~thoxy~ d~n~thyl 6-phe~yl llHwpyrido~2~j~b~1,4 ~5 benzodiaz~pine-ll-propanamine, ~ -dLmethyl ~-nitro--6~ph~nyl~ pyrido~2,3 b~ 'J
benxodiaz~pir.e-l~-prop~mi n~ ~

m) ~ dimethyl-8~nitro-6-phenyl-llH-pyrido~2~3-bJ~1,4 benzodiazepin~ propanamine, n) ~,~-lO,t~Imethyl-6-p~enyl-llH-pyrido~73-b~[174 henzodiazepin0~ propanamine, and o) 10-chloro~,M-dimethyl-6-phen5,rl~ -pyrido~2,~-b~1,4 benzodiazepine-ll-propanamine.
~xamples 35a to 35c Following the procedure of Example 1 and ~ubs~i~uting e~ual molar amount~ of the following for ~-amino-2-chloro-pyridine:
4-aminc)-3-chloropyridine ., ~-amino-4-chloropyrldine, and 2-amino-3-chloropyridine~
there are obtained:
a) 6 phenyl-llH-pyrido~3,4-b~1,4]benzodi~zepine, b) 10-phenyl-5H-pyrido~4~ b~[lJ49benzodiazepine, an~
c) lo-phenyl~5H-pyrido~3g2-b~lg4]benzodiazepine~
Examples 36a to 36c Following the procedure c:~f Example ~9 ~he follc>willg:
~2-~(4-amino~3-pyridinyl)amino]p~enylmethanone~
t2-~ (3-amino-4 pyridinyl)amino]plleny~nethanon~" and ~2 e ( 2-amino-3-pyr.idiny:L)amino~phenylmethanone, are converted ~o:
a) 6-phenyl~ pyrido[3,4-bJ~1,4Jbenzodiazepine, b~ 10-phenyl-5H-pyrido~4,~-b~ benzodia2epine9 and c) lo-p~enyl-5H-pyridoc~2-b]~l~4 Ibellzc~diazepin0.
~xampl~ 37a to 37c Following the procedure of ~xampl~ 9 and ~ubstituting ~qual molax amount~ ~f the following for ~ phenyl~
30 pyrido~293-bJ~1~4Jbenæodia 2~p ine:
6-phenyl llH-pyrido~3,4-b~ 4~h~nzodiazepine~
10-ph~nyl-5~-pyrido~9~ b~C1~4Jbenæodiazepine, and lO~ph~3nyl-5H-pyridc~3,2~b]~1~4~benzodiazepln0,, there are obtai~ed a) ~,~7 dirne~yl~6-phenyl~ pyrido~3,4~b~1,4~b~næo-diaæepin0-ll-proparlamine fumarate, ~95 b) ~s~-dimethyl-lO~phPnyl-5H-pyrido~4,3-~][1,4~benz~-diazepine-5-propanamine umarat~, and c) ~,N-dimetllyl-10-phenyl-5fi[-pyrido~,2-b~C1,4~benzo-di~zepine-5-propanamine fumarate, Example 38 5~6-Dihydro-6-phenyl-~-methy~ -pyrido~2J~-b~[l~4 benzodiazepine~ propanamine.
To a ~olution of 104 9 (0.0035 mole) of ~-~3-[6-phenyl) llEI-pyrido[2J3-b~1,4~benzodiazs~pine-11-yl~propyl~carbamic acid ethyl e~ter ( from Example 29) in tetrahydrofuran under nitroye~ gas wa~ added 0.4 g (0.0105 mole) of lithium aluminum hydride and slight exothenmic r~action ~ccurred.
The mixture was cooled to prev nt overheating. The mixture was ~tirr~d at reflux tampPratura for 16 hrO Thin layer chromatography indicated only partial corlversi~n had occurred. An additional 0.4 g (0.0105 mc>le) of lithium aluminum hydride was added and the mixture refluxed over-night. Tllin-layer chromatography indicated the product was predominantly the title compound.
Example ~9 6 (2-Thienyl)-llH-pyrido~2,3-b~ benzodiazepine.
Following the procedure vf Example 20~ ~2~r(~-amino-2-pyridinyl)amino~phenyl](2-thienyl)methanone is heated with para toluene ~ulfonic acid cataly~t in organic ~o~vent whi~e removin~ water in a Dean-Stark trap to giv~ ~he title compound.
Example 40 6-(3-Thi~nyl)~ py~idor2 ~ ~ b~ [ 1 7 4~benzodia2epine.
Following the procedure of Example 20, ~2-~(3~amino~
2-p~ridinyl)aminophenyl~ thienyl)methanone is heated with para toluene ~ulfonic aci~ ~ataly~t in organic ~olvent while rem~ving water in a Dean 5tark trap to give the title compound.

~95 ~xa~ple 41 6-(2-pyrldiny~ H-pyrido~2~ b~l,4~benzodiazepine.
Following the procedure of Example ~, ~2-t~-amino-2-pyridinyl~amino~phenyl3(2-pyridinyl)anethanone i~ cycli2~d to the title compound.
Example 42 6-(~5-Pyridinyl)-llH-pyrido~2,3-b~1,,4~berlzodiazepinP.
Following the procedure of Example 37 ~ 2-~ (3-amirao~2-pyridinyl)amino~phenyl~(~i pyridinyl)m0thanone i~ cyclized to the t itle compound .
Example 43 6-(4-Pyridinyl)~ I-pyrido~2,3-b~1,,4~benzodizlzepine.
Following the procedure o~ Example ~ ~2-[~-ami~o-2-pyridinyl)amino3p~enyl~(4-pyridinyl)methanone is cyclized to the title compound.
~xample 44 ~,N-Dimethyl-6-(2-thienyl)-11~-pyrido~2,3-b~rl~4 benzodiazepine-ll-pxopanamine.
Following the proc~dure of Example 2~, 6-(2-thienyl)-llH-pyrido~2,3-b~[174]benzodiazepine is reacted with ~:;odium hydride iEollowed by reaction with 3-dime~hylaminopropyl chlori~le to give thE3 titl~ compoundO
apl~ 4 Dimethyl-6-~3-thienyl)~ yrido~2~3 bl~l,4 benzodiazepine~ propanamine.
Following the pxocedure of Example 2~, 6-(3-thienyl)-llH-pyrido~293-b~ 4]benzodia~epine i~ reactea with F,odium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the tit7e compound.
Exampl~ 46 ~ Dimethyl 4-(2-pyridinyl)-llM-pyrido~2~3-b~ 4 benzo~iazepine~ pxopanamine.
Followlng the procedure o Example 23, 6-(2~pyridlnyl)-llE-pyrido~2,3~b]C1~4]benzo~ pine i~ reac~d wi~h sodium hydrid~ followed hy re~ction with 3~imethyl~m.invpxopyl c~loride to give ~he titl~ comp~und.

~95 ~ 3'~

Ex~mple 47 N,N-Dimethyl-6-t3-pyridinyl)-llH-pyrido~2,,3~b]~1,4 benzodiazepine~ propanamine.
~ ollowing the procedure of ~xample 2~J 6~(3-pyridinyl) llH-pyrido~2,~-b~[1,4]benæodiazepine is reacted with ~odium hydride followed by reaction with 3-dirnethylaminoprGpyl chloride to give the title compound.
Exampl~ 48 ~ N-Dimethyl-6-(4-pyridinyl~-llH~pyrido~2,3-b~
benzodiazepine-ll-propanamine.
~ollowing ~he proc~dure o ~ampl~ 23, 6-~pyridinyl)-llH-pyrido~2,3-b~[1,4~b~nzodiazepine i~ reacted with ~odium hydride followed by reaction wi~h 3 dimethylaminopropyl ch ~ cr ide .
~:xamples 49a to 49q Following the prc>cedure of Exarnple 69 the following me~hanone compounds o~ ntermediat~ 15:
~2-[ (3-amino-4~methyl-2-pyridinyl)amirlo~p~enyl]-phenylme thanone, ~2-~ ( 3~amino-5-me~hyl-2-pyridinyl ~ amino~phenyl~-phenylmethanone"
~2-~ (3-amino 6-methyl 2-pyridinyl)amino~phenyl~-phenylmethanone, ~2-~ ( 3-amino-5,6-dimethyl-2-pyridirlyl~a[ninolphenyl~-phenylme thanone, ~2-~(3-amino-6-meJchoxy-2-py:ridinyl)~mino~p~enyl]-~enylme'chanone, ~2 ~r ( ~ ~minG-2-m~t~yl-~-pyridirlyl) ~mlno]p~y~-phenylmethanone, and ~2 ~ ( 3~hmino-5-methoxy-2 ~pyridinyl ~ amiTlo]phenyl~ -phenylmetha}lone, are convertes3 to the following pyridoben~odiazepine~
~) 4-m~thyl-6-ph~rlyl-11H-pyridoC2 ,~i~b~ 19 4]benzs~diiazlE!pine9 b) ~-methyl-6~phenyl-llH-pyrido~2,3~b~1,4~berlzodiii~zepine"
c) 2-methyl-6-phenyl 11~-pyridor2,3-b~1,4~benzodiaæepine, ~5 d) 2,3-dimethyl-6-phenyl llE~pyridor2~3~ 1943benz~
diazepin 3 ~ ~ ~

~) 2-methoxy-6-phellyl-llEl-pyxido~2, 3-b~ 4]benzodiazepine~
f) l-methyl-10 phenyl-5H-pyrido~4,3-b][1,4~benzodiaæepineg and g) ~-methoxy-6-phenyl~llH-pyxido~2~-b~1,4~benzodiazepine.
Examples 50a to 50q Following the procedur~ of Example 23, the pyrido-benzodiazepines prepared in Example 49 are react~d with ~odium hydride and 3-dimethylaminopropyl chlorisle ~o give the fcsllowing:
a) 1~,~,4-trLmethyl-6-phenyl-llH-pyrido~2,3-b~lg4~benzo-diazepine-ll-pFopanamine, b) ~,~,3-trimethyl-6-phenyl-:i lH-pyrido~2 ,3-b~ 194~benzo-diazepine-ll-propanamine, c) N,~,2-trimethyl-6-phenyl-llH-pyrido~2,3-b~1,4~b13n2:o~
diazepine-ll-propanamine, d~ ~,~,2~3-tetramethyl-6-ph~nyl~ -pyrido~2g3-b~[1,4 benzodiazepine-ll-propanamin~, e~ 2-methoxy-N,~-dimethyl 6-phenyl-llH-pyridor2,3-b~lg4J
b~nzodi~zepine~ prop~n~;ne, f) ~ trLmethyl-10-p~eny7-5~-pyridot49~-b~ 4~benzo-diazepine-5-propanamineg and ~) 3-methoxy-~,M-dim~thyl-6-phenyl~ pyrido~2~3-b~13~]
benzodiazepine~ proparlamine.
~3xamples 51a to 51c Following the procedure of E:xample 22 but subs~ u~ing the ollowing fc:>r ~2-r (3-amino-2-pyridinyl~ami:no~phenyl 4-fluorop~enyl)methanone:
~2-~ ( 3-amino-2 pyridinyl ) amino~phenyl ] ( 2 -:~luoxc~p~enyl ) methanone, ~2-t(:3-amino 2~pyridinyl)a~mino~phenyl~(2~chlc:~rophenyl) methanone, and r2-~(3~amino~2-pyrldin~l)amino~phenyl~2-bromop~enyl) methanQne, ~here are obtained~
a~ 6-(2-fluorophenyl)~ pyrid~2,3-b~[1,4~benzodiazepine, b) 6-(2-chlor~phenyl)-llEI-pyrido~2~3-b~ 4~benæodiazepineg and c) 6~(2~bromophenyl)-llH-pyrido~2,3-b~1,4~benzodia~pine.
Exampl~s ~2a to C~2c Following the procedure of Example 23, ~;ub~tituting the ollowing pyrido~ 4~benzodiazepines for 6-( 4-~luoro-phenyl ) 1 lH-pyr ido~ 2 7 3-b ~ [ 1, 4 ~ benzod ia z~p ine:
6-(2-fluorc~phellyl) ~llEI-pyrido~2 ,3-b~ 1, 4~benzo-diazepine, 6-(2-chloropheny~ H~pyrido~2~3-b~ 4]ben dlazeplne, 6- ( ~ -bromophenyl ) -llH-pyrido~ 2, 3-~ ] ~ 1, 4 ~ benzo -diazepine, ~here ~re obtained:
a~ 6-~2-fluorophenyl)-N,N-~l~meth~ llH pyridor2,3~b3~194 benzodiazepine~ propanamine, m.p. ~2-94~C.; recrystal-lizing ~olvent i90propyl alco~ol~isopropyl ether, b~ 6-(2-chlorophenyl) ~ dim~thyl ll~-pyrido~293]~194~
benzGdiazepine-ll-propanamine, m.p. 104-105C.; recrystal-lizing solvent: i~opropyl ether, and c) 6-(2 bromophenyl~-N,~-dimethyl~~ pyrido[2~3~b]~1g43 benzodiazepine~ propanamine, m.p. 96-98~C.; recry~tal-lizing solvent~ propyl ether.
Examples 53a and 53b Following ~h~ procedur~ of Exampl~ 99 the following are ~ubstituted for ~ dim~thylamirlopropyl chloride-3~dimethy~ amino-2 methyl~propyl chloride, and 4-dimethyl~m;nobutyl chlorideg ther~3 are obtained:
a) ~J~ trimethyl-6-phen3,1-llH-pyrido~2,3-b]rl,4]bPnzo-dia~epine ll-pr~ an~mine fumara e9 and b) ~ dim~khyl-6---pheny~ pyrido~2~3~b]~l~4]ben dia~pine~ ut~ min~ fumarate.
~xample~ 54a ~nd 54b ~hen in ~he procedure o Example 11 the ollowing ~re ~ubstitute~ :Eor 4~(~5-c~lorophopy:L)morpholixle hydroch:loride~
1 (3-chlc:~ropropyl~pyrr~l:Ldin0 hydrochloride, and 1-(3-chlc)ropropyl) 4-methylpipera~in~ hydrochlorideg ~95 ~8 there are ob~ained:
6-phenyl~ r3~ pyrx~ inyl)propyl~ -pyrido ~2~3-b~rl,4-benzodiazepinP, and 6-phenyl~ -(4-methyl-1-piperazinyl)propyl~-llH-5 pyr idot2, 3-b] r 1,4~benzodiaz~pine.
Examples ~5a ~o 55c WheTI in the proceduxe of ~xamplP 9 the following are 6ubstituted for 6-phenyl-llH-pyridoC2,3-b~lJ4~benzo-diazepine:
8-methyl-6-p~enyl-llH-pyrido~3,4-b]~1,4~enzodiazepine, 6-(4-chloropheny~ pyrido~4-b][l~4~ben diaz~pine, and 3-~ethoxy-6-pheny~ H-pyrido[~l4~b~ 4~ben diazepine, there are obtained:
a) ~JNJ8-trimethyl-6-phenyl-llH-pyrido~3,4-b]~1,4~benzo-diazepine-ll-propanamine, and b) 6-(~-chlorophenyl)-~g~-dimethyl-ïlH-pyrido~3,4-b][194 benzodiazepine-ll-propa~amine, ~nd c) 3-methoxy ~M~d~methyl-6 phenyl~ pyrido~3,4-b~1,4 benzodiazepine-ll-propanamins.
Examples 56a to 56d ~hen in the procedure of E~ample 17 the following are substituted or B-chloro-6-phenyl-11~-pyrido~2~3-b~1,4 benzodiazepins:
6-pheny~ H~pyridoc293-b~ 4]benzodiazepine~
8-chloro-6-(2-nitrophenyl~-llH-pyrido~2,~-b~1,4 benzodiazepine, 8-chloro-6-(2~chlorophenyl3~11EI-pyrido~2~3-b]~194]
~0 benzodiazepin~, and 8-chloro-6 (2-bromophenyl)-llH pyrido~2,~-b~1,4J
benzodiazepine, th2re ~re obtained:
~) ll-methyl-6-phenyl~ pyridoe2,3 b~l,4~benzodia~epine~
b) 8-chloro-ll~methyl-6-(2~nitrophenyl)-llH pyrido E 2,3-b~1,4~benæodiazepine, m.p. 165~166~C.~ recry~tal~
lizing ~olvent: ethyl alc~ohol, c) 8 chloro-6-(2-clllorophenyl)-11 methyl-llH-pyrido ~2~ 5-b~lJ4~benzodiazepine, m.p. 150-152C., recrystal-lizing solvent~ ~sopropyl alcohol-i~opropyl eth0r) and d) 6-(2-bromophenyl)-8-chloro-11-methyl~ ]-pyrido i2,~-b~1,4~enæodia~epine, m.p. 121-12~C., recrystal-li.æing solvent: 180p:1:0pyl ether.
Example ~7 ~-Methyl~ (llH-pyrido[2J3-b~1,4~benzodiazPpine-ll-yl)propyl~carbamic acid methyl ester.
The title compound i~ prepared by reacting 6-phenyl~
llH-pyrido ~ 2 9 3-b] ~ 3, 4 ]benxo dia ~ep ine and ( ~-c~h loropropyl ) methylcarbamic acid m~3thyl ester.
Examp 1 e 5 8 9-Hydroxy-~,~-dimethyl-6-phenyl-llH-pyrido~2,3-b~[1,4 benzodiazepine-ll propanamine.
The title compound is prepared by reacting 11-~3-( dimethylamino)propyl]-9-methoxy-6-pheny~ -llH-pyrido~2, S-b~
~1,4~benzodiazepine with hydrogen iodide and glacial acetic acid .
Example 59 ~-Hydroxy-N, ~-d~lethyl-6-pheny~ -llH-pyrido~2, 3-b~ [ 1, 4 ]
benzodiazepine-ll- propanaminP .
The title compound is pr~pared by reactiIlg ~S-methoxy~
~ dim~thyl-6-pheny~ H-pyrido~2~3-b]~l~4~benzodia2epine ll~propanami.ne with hydrogen iodide and glacial acetic:
acid .

Table 2 ~r N,(H)n ~Y
Ex-R Ar Y ~ n Salt 2 H C~H5 E3 8-C1 O

II H 2-Cl-C~H4- H 8-Cl H 4-C1-C5H~ H H 0 6 H 4-CH3-CuH4~ H H o 7 H 4-OCH3-CsH~~ H H O
8 -;CHz~3-N(CH3)2 C8H5- H 8-C1 0 oxalate g -~,CH2~9-N(CH3~2 CoH5- H H 0 fumarate -,CH2 2-N/CH3)2 C5H5 H El 0 fumarate CH2 3-4- C3H5- H H O fumarate morpholinyl

12 _ CH2~3-N(C2H5)2 C~H5- H H 0 oxalate

13 ~ CH2~3_N~CH3)2 CaH5_ H 9-C1 O fumarate

14 _ CH2)3-1- C~H5_ H H O fumarate piperidinyl ~ CH2)3-N(CH3)2 4-C1-C~H~- H H O fumara~e 16 _ CHZ-N(CH3)2 C3H5_ H 8-Cl 0 cxalate 17 -CN3 C8H5- H 8-Cl o 18 -;C~2)3-N(CH3~2 4_CH3_C3H4_ H H o fumarate 19 - CH2)3-N(CH3~2 4-oCH3-CeH4- H H O fumarate :1 3-C1-C5H4- H H 0 21 - CH2)3-N(OEI3)2 3-C1-C~H4- H H 0 fumarate 22 `3 4-F-CsH4- H H 0 23 -1CH2)9-~(CH3)2 4-P-C6H4- H H O HC1 24 -(CH2)3-1- C3H5- H H 0 phthalimi~oyl -(CH2)9-NN2 C~H3- H H O 2 HC1, 26 -(CH2)3-NH2 C3H5 H H o 2 H20 27 -~CH2)3-~=CH- C5H5- H H 0 28 -(CH2~3-NHCH3 CsHs- N H 0 2 HCl 29 -( CH2)3_NHC(O)_ C~N5- H H O
OC2H5 C8H5_ H H 1 2 NCl, 0.5 ~2 31 a H 4-C2H5-C~H4- H H O
b, H 4-i-C3H7-C~E~4- H 0 C
C,~ H 4-Br-C ~H4- H H O
d~ H 4-F-C~H~- H H O
e, H 4-OC2EI5-C6H4- H H 0 f,l H 4 No2-caH4- 8 N O
g, H 4_CF3_C3H~_ H H O
h( H 4-CH3-C8H~- H H O
i H 3_C2H5_C~H~_ H H 0 i, H 3-oCH3-C8H~- H H O
k~ H 3-OC2Hs-Cu31~-- E3 H O
1) H 2 N0z-C~El~- H E3 3 m) H 3-CP3-C~H4- ~3 ~ 0 n H 2-CH3-CoH4~ ~ H 0 o ~ 2-C2H5-C8H~- H H 0 P) H 2-oCH3-C~H4 3~ H O
Y H 2~4(C1~Z -C8H3- H H 0 r H 3,4,5-(oCH3)~- 3-l H O
C ~

o~U~ ~ n) ~ o w c~ ~ ' ~J
Q ~ 3 ~ Q ~ ~ a o ~ J~ ~h ID ~ n ~ v o 3 3 1~ tD
~_~___ _ 7nn 1 Qnnn~nnnnnnnnn~ nnnn~nn~nnnnnl~-~no ` o li~ M 1~ 1~ N 1~ M N M 1~ N M N 1~ M M N ,t nn~n nnnnnn nnnnn~n ~n~nn~ ~n~nxnn tD W ~ ~ ~ W ~ W ~ ~ C ~ ~ W ~ W '~ D ~ W ~
N ~1 IV li! N N N N lU N IU N N b~ N N lV IU t~ N 10 N 10 N 1~ N h/ =N N N N n~ N
~n nnnnnnnnnnnnnnn ~ nnnnnnn~nnnnnn ~ ' '~ ~ ~ ~ J~ n ~ ~ t~ t~ ~ t t ~ t n t~ ~ ~ t~ n ~ I ~n~n~o~n~ ~ n ~ ~
.. ~, ~ ~ ,,. ~ . I nt ~I n n ~t~' tnl n n n,~ ~ n ~ ~ nN~n~ nl~l~

o o ~D ~ ~ ~ I O~o ~O ~O ~ ~ o o c~ ~D ~D ~ ~ CD~ ~ W ~ N
l~O~on~n~.~ nl~oonn~n~nn O O O O O O O O O O 1-- 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Cl O O 0 13 ~,1 Table 2 (cont.) Ex-am~le R Ar Y Z n Salt 49 a) H C~HS~ 4-CH3 H O
b~ ~I C~HS~ 3-CH9 H O
C) H CaH5~ 2-CH9 H O
d? H Co~s- 2,3-(CH3)2 H
e) H CBHs- 2-OCH3 H O
9~ H C~Hs- 3-oCH3 H O
50 a~-;CH2 3-N;CH3)2 CBHS- 4-C~I3 H O
b) -~CHZ 3-N CH3)2 C9H5_ 3_CH3 H O
C~ _,CH2 9-N1CH3)Z C~HS~ 2-CH9 H O
d1 _,C~2)9_N CH9)2 C9HS- 2,3-(C~9)2 H
e) -~CH2 9_NlC~3)2 CaH5_ 2-OCH3 H O
g) ~CH2 3-N(C~3)Z ~H5- ~-OCH9 H O
51 a~ H 2-F-C~H~- H H O
b~ H 2-Cl-CBH4- H H O
C) H 2-Br-C8H4- H H o 52 a -(CH2 9-N~CH3~2 2-F-C~H4- ~ ~
b -~CH2 3-N CH3)2 2-Cl-C8H~- H H o C _(CH2 3-N CH3)2 2-Br-C~H4 H H O
53 ~) _CH2CH(CH3~CH2_ CBHS- H H O fumara~e N(CH3)2 b) -(cH2~4-N~cH9)2 C9H~_ H H O fumara~e 54 a) -(CH2~3-l- C9H5_ H H O
pyrrolidinyl b) -(CH2~3-4- CBHs- ~ H O
methylpipera~in-l-yl 56 a -CH3 CB~_ H H O
b -CH3 2-No2-CsH4- H B-cl o C -CH3 2-Cl-C8H4- H 8-Cl O
d CH3 2-Br-CBH4- H 8-Cl o 57 -(CH2~ -N CH3) CBH5- H H O
~ )3 58 -~CH2)9-~;CH3~2 CB~S- ~ 9-H O
59 -(CH2)3-N~CH3)2 C~H5- 3-oH H O
Ar (H)n Z~Y

35 a) H CsHs- ~ H
36 a) H C~HS~ H H O
37 a) -(CH2)3-N(CH3)2 C~Hs- H H O Pumarate 55 ~) _ CH2)3-N(CH3)z CoHs- H 8-CH3 0 b~ _ CH2)9-N(CH3~2 CsHs- 3-CH3 H O
C) _ CH2)3_~(CH3~2 CBHS- H H O
~ N ~
R

6~

~a~le 2 ( cont . ) Ex -~mple R Ar Y æ n Salt 3', b `~ 19 C ~Hs ~ H H O
75 b) ~ CaH5- H H O
37 b) -(CH2 )9-N(CH9)~ CoHs- H El 1~ ~Eula~r3te 49 f ) H CoHs~ l-CH3 H O
50 ~) (CH2)s~M(CH3)2 CoHs~ l-C113 H o N~( H)n Z~~ ~_y 35 c) H C~H5- H H O
~5 c ) H C ,~ H5 - H H O
37 c( -(CH2 )3-N(CH3)2 CesH5- H H 0 fumarate 3g5 6l~
Formulati~n and Administration Effective quantities of the foregoing pharmacologically active compounds of Fonmula Ip or ~onmula II may be a~nini~-tered to humans for ther~peutic purposes according to usual modes of admini~tration ~nd in usual forms 7 ~uch ~s oralJ.y in ~olution6~ emulsions, su~pen~ion~, pill6, tablet6 and capsules, in pharmac~utically accep~abl~ carriers and parentexally in the fo.rm of sterile ~olutions.
Exemplary of ~olid carrier~ for oral administration are ~uch as lactose, magnesiumJ stearate, terra alba, sucrose~
talc~ tearic acid, gelatin~ agar~ pectin or acacia.
Exemplary of liquid carriers fox ~ral a~ministration are vegetable oils and water.
For intxamuscular administratic)n the carrier or excip.ie~t may be a sterile, parenterally acceptable liquid;
e.g., water ~r a parenterally acceptable oil: e.g.g arachis oil contained in ampules.
Although very ~mall quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects 20 having a relativ~ly low body weight, unit dosages are usually from five mi~ liyrams or above and preferably 10, 25~ 50J or 100 milligrams or even higher, pr~ferably ad}ninistered three or four times per day, depending, of course9 upon the emergency of the situation, the compound used, and the 25 particular rfasult desired. Twenty-five to 200 milligrams appears optimum p~r unit dose or usual broader ranges appear to ~e about 10 to 500 milligrams per unit doseO I)aily dosages usually required ~hould range frc>m about 0.3 ~o about 20 mg/~g/day, pxeferably 0.3 lto 10 mg/kg for the more active compc~und~. The active ingredients of the invention may be s::ombined with other compatible p~arrnacolc)gically active agents. It is only necessary that the active ingredient constitllte an effect ive amount ; i . e ., ~uch ~ha~
a suitab].e effective dosage will be obtained consistent with the do~ag~ forrn employed. Obviou~ly, ~everal unit doE;age form~ r~y be ~dministered at about the ~amQ tim~O The exact individual dosages as well as daily dosages will, of cour~e, ~95 be determin,ed according ~o 6tandard medlcal p~inciples under the direction of a physician~
The followiny ~Eormulatiolls are repr~sentative for the p}larmacologically a~ctive compound~ of ~his invention.
FO~[UI.~TIONS
1 . Capæu le s Capsules OI 10 mg and 50 mg of active ingr dient per capsule are prepared. With the higher amounts of active ingredient, reduction may be made in the amount of 10 lactc:>se, 10 mg. 50 mg.
Typical blend for encapsulation Per Capsule Per Capsule Active ingredient, as salt 10 50 Lactose 259 219 Starch 126 126 Magn sium stearate 4 4 Total 3gg 399 Additional capsule :Eormulations preferably contain a higher dosage of active ingredient and are as follows:

rng. permg. permg. per Inqredients CapsuleCapsuleCapsule 20 Active ingredient, 100 250 5 ) as salt Lacto~e 214 16~ 95 Starch 87 ~1 47 Magnes ium stearate 4 6 8 Total ~599 5 650 In each case, uniforrnly blerld the &elec~ed active ingredient with lactose, s'carch, and magnesium stearate and encapsulate the blend.
2~ Tablets A typical :Eormulation for a tablet containing ~G 5 . 0 mg of active ingredient per tablet follows . The formulation may be used for other ~trerlgths o:E ac:tive ingredient by adju~tment of weight oE dicalcium phosphate.

.. . ~95 Per Tabl e'c, mq .
1. Active ingr~3dient 10.0 2. Corn ~tarch 15.0 3. Corn E;tarch (pa~te) 12.0 4 . Lactose 35 . 0 5. Dicalcium p~osphat~ 132.0 6. r:alcium ~tearate 2.0 ~otal 202.0 Unifonnly blend 1, 2 J 4 and 5 . Prepare ~ a~ a 10 per cent paste in water. Granulate the blend with ~tarch paste and pass the wet mass through an 8 mesh ~;cr~erl. The wet granulation is dried and sized ~hrough a 12 mesh screen.
The dried granules are blended with the calcium steaxa~e and compressed.
. ~njectable - 2% sterile s~lution Per cc Active ingredient . mg. 20 Preservative, e.g.~
chlorobut~nol, w/vol. percent 005 Water fvr injection q.s.
Prepare solutiong clarify by filtration, fill in~o vials, ~eal and autoclave.
Various modifications and equivalents will be apparent tG one skilled in the art and may be made in the compounds, 20 compositions and methods of the present invention without departing from the spirit and scope th2reo, and it is therefore understood that the invention i~ to be limit~d only by the scope of the appendPd claims.

SUPPLE~ENTARY DISCLOSURE
The present invention further relates -to novel [2-[(a~inopyridinyl) amino]phenyl]arylmethanones or their analogs which form in the reaction mix-ture prior to cycli~ation to dia~pines and certain of which have additional utility as antidepressan-ts for -treating depression. They are represented hy the formula:

"~ Ar \ N / ~ Y Formula II' R
wherein B is selected from carbonyl, thiomethyl, ke-tal or thio-ketal, R is selected from the group consis-ti:ng oE hydrogen, lower alkyl, -alk --NR R or -alk -N = CH-OC2H5, and Ar, Z and Y are as defined under formula I above, with the proviso that when B is carbonyl, R is no~ hydrogen.
The thioxomethyl, keta3. or thioke-tal analogs of formula II' can be in the form of a pharmaceutically acceptable acid addition salt with an acid which is physiologically compatible in warm blooded ~n;~l.s.
Compound~s of the invention encompassed by formula II' which have antidepressant activity in the foregoing procedure have the formula II'p ~ A II'p R

wherein;

R is selected from the group consisting of hydrogen, loweralkyl or -alkl_~RIR2;

' ~ ~,7 -~.~g~

R and R are selected from the group consisting of hydrogen, lower-alkyl, -C(0)0-loweralkyl or R and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selec-ted from the group consisting oE
l-piperidinyl, l-phthalimido, l-pyrrolidinyl, 4-morpholinyl, and l-piperazinyl;
B is selected from carbonyl or thloxome-thyli Ar, Z and Y are as defined under forrnula I and III above, and the pharmaceutically acceptable acid addition salts thereof, with the proviso that when B is carbonyl, R is no-t hydrogen, The compounds of Formula II' wherein R moiety carries a phthalimido, chloro, carbamoyl or imidate component are chemical intermediate rather than antidepressant aqents, and compounds of formula II' wherein B is ketal or thioketal are also chemical intermediates rather than antidepressants.
Reaction sequence by equation for the preparation of the compounds of Formula II~ and for the use thereof as intermediates is given in Chart 1'~
Alternate procedures for preparat~on of certain oE the compounds are given by equation in Ch.arts 5 and 6.
The methanones or their analogs are prepared by heating a mixture of the halo~amino pyridine and an Am~-nohPn~ophenone (or analog) for a shorter period of tlme than that required for cyclization to the pyridobenzodiazepine as lndtcated by chemical ionization mass spec. analys-is ~see Chart 1'). The methanones and analogs may be isolated as the prerlnmin~nt product, if desired, by cooling and adding a suitable organlc solvent such as, for example, methyl-ene chloride which ~ill dissol~e unreacted s*ar-ting materials and some cycllzed compound (Ia') followed by usual methods of isolating such as partitionlng between the solvent and aqueous base or methanolic aqueous base followed by washing, drying, evaporating the solvent layer and recrystalliz;.ng from a sui:table solventO
Compounds of Formula II' wherein R i5 hydrogen may be alkylaminated by reaction with sodium hydride and an appropriate reagent represented by halo-alk -NR R wherein "alk " has the meaning as defined above with -the pro-~iso that ~oth ~ and ~2 are not hydrogen. See Chart 5 for the equa-tion.

~ s The addition and subsequent removal of blocking agent on the NH2 radical on the pyridine ring is anticipated as a means of improving yields. These compounds may then be cyclized to the pyrido[l,4~benzodiazepines.

Compounds of ~ormula II' wherein B ls carbonyl may be prepared by hydrolysing the appropriate pyrldo[1,4]benzodiazepines with cold concentrated hydrochloric acid. See Chart 6 for the equation.

Chart 1' Ar ,B_Ar 2 ~ Y h~ Z ~ N

III' IV \ R II' Heat \ /Additional longer \ / heating Ar H Period ~ Ar _H20 \ 2 ~ W

Ia'-l R \ R

\ when R=H
\ MaH ~ solvent \ halo alk1-Q
when R = H

Ar /(H) }y alkl Q* Ib *Q is. 5elected from the group consistlng of hydrogen, -N-(lower-alkyl)2, l-pyrrolidi~yl, 1-pipe~idinyl, 4-substituted-1-piperazinyl, Y~ - 69 ~

~3~33~
o 4-morpholinyl, l-phthalimido, -N-C-O-loweralky] or halo lower alkyl R = H, methyl or ethyl ~ , ~
B = -C(a)-, -C(S)-, O O or S S
/C C

~ Ar~
H

NaH -~ Solvent halo - alkl-Q*
V

B - Ar B ~ Ar when B = / H N
H2N ketal or ~ 2 ~
N / thioketal ~ ~ ~ / ~ y 1 llkl Q**
alk -Q**

Q** is -N-R R wherein R1 and R are as defined above.
B is -C(O)-, -C(S)-, ~ I or O O S S
\/ \ /
/ C \ ~0 B* is -C(O)~ or -C(S)-.

Ar 7, \ N
lQ*

Hydrolyze

15 - 37% hydrochloric acid OC .
V

- Ar N
¦ .HCl salt alk -Q*

Q* is as defined in Chart l, B is -C(O)-.
Interrnediate 17a - c Following the procedure of Intermediate l and substituting equal molar amounts of the following for 2-aminobenzophenone and adding an inorganic base to neutralize the acid formed:
(,2-aminophenyl)phenylmethanethione, 2-(2-phenyl-l,3-dioxolan-2-yl)benz~ne~m-ine, and 2-l,2-phenyl-l,3~dithiolan-2-yl)~enzeneamirle, there are obtained a) [2-~(3-amino-2-pyridinyl)amino]phenyllphenylmethane-thione, b) N2-[2-(2~phenyl-l,3-dioxolan-2-yl)phenyl]-2,3-pyridinediamine, and c) N [2-(2-phenyl-1,3-dithiolan~2-yl)phenyll 2,3-pyridinediami:ne.

3~

Intermediate 18 [2-[(3-Amino-2-pyridinyl)-N-methylamino]phenyl]phenylmethanone hydrochloride.
Following the procedure of Intermediate l, 2-N-methyl amino-benzophenone is reacted with 3-amino-2-chloropyridine to give the title compound. The free base of the title compound is ob-tained also by the latter part of the procedure of Intermedlate 1.
Int~ te 19 [2-[(.3-~mino-2-pyridinyl)-N-ethylamino]phenyl]phenyl-methanone hydrochloride.
Following the p.rocedure of Intermediate l, 2-N-ethyl-aminobenzOphenone is reacted with 3-amino-2-chloropyridine to give the title compound. The ~ree base of the title compound is obtainea also by the latter part of the procedure of Intermediate l.
Intermediate 20 [2- L (3-Amino-2 pyridinyl)[3-(dimethylamino)propyl~amino]phenylj phenylmethanone.
A solution of N,N-dimethyl-6-phenyl-llH-pyrido[2,3-b][1,4]benzo-diazepine-ll-propanamine in isopropyl alcohol is treated with 25% hydrochloric acid at 0 C. to give a solution of the title compound.
Intermediate 21 [2-[[3-(Dimethylamino)propyl](3-amino-2-pyridinyl)amino]phenyl]
phenyl~ethanone.
To a stirred suspension of sodium hydride (i.n mineral oil) in anhydrous dimethyl~orm~m;de, under nitrogen a-tmosphere was added, portionwise, [2-[~3-amino-2-pyridinyl)amino]phenyl~phenylmethanone. I'o -the mixture was added 3-dimethylaminopropyl chloride hydrochloride to yive a solution containing some of the title compound as indica-ted by chemical ioniza-tion mass spectrascopy analysis. With time, this cyclized spontaneously to -the corresponding pyrido[2,3-b]~1,4]benzodiazepine.

, ..~"
~ - 72 -Intermediate 22 [2-[(3-Amino-2-pyridinyl)[3-(dimethylarnino~propyl]amino¦phenyl¦
phenylmethione.
To a stirred suspension of sodium hydride (in mineral oil) in anhydrous dimethylEormamide under ni-trogen atmosphere is added, portionwise, [2-[(3-amino-2-pyri.dinyl)amino]phenylJphenylmethanethione~ To the mix-ture is added 3-dimethylaminopropyl chloride hydrochloride to give a solution containing the title compound.
Intermediate 23 N -[3-~Dimethylamino)propyl]-N2-[2-(2-phenyl-1,3-dioxolan-2-yl) phenyl]-2,3-pyridinediamine.
To a stirred suspension of sodium hydride (in mineral oil) in anhydrous dimethylformamide under nitrogen atmosphere is added, portionwise, N2-[2-~2-phenyl-1,3-dioxolan-2-yl)phenyl]-2,3-pyridinediamine. To the mixture is added 3-dimethylaminopropyl chloride hydrochloride -to give a solution containing the title compound~
Intermediate 24 N2 [3-(Dimethylamino)propyl]~N2-[2-(2-phenyl-1 r 3-di-thiolan~2-yl) phenyl]-2,3-pyridinediamine.
To a stirred suspension of sodium hydride ~in mineral oil) in anhydrous dimethylformamide under nitrogen atmosphere is added, portionwise, ~ -~2 (2-phenyl-1,3-dithiolan-2-yl)phenyl]-2,3-pyridinediamine. To the mixture is added 3-dimethylaminopropyl chloride hydrochloride to give a solution containing the title compound, Ta~le 1 33~9L

Table 1 (cont. ), Inte.rmediate Ar B Y R Z
17a C6H5- -C (S) - H H H
b C6H5-o\ ~o H H H
~ c --C C6H5~
s\ ~s H H H
-- c--18C6H5- -C (0) - H -CH3 H
19 C6H5- -C (o) - H -C2H5 H
C6H5- -C (0) _ H ~ (CH2) 3N- H
- (CH3) 2 21 C6H5- ~C (0) - H - (CH~) ~N- H
(C 3 2 22 C6H5- -C (S) - 2 3 H
- (CH3) 2 23 C6H5 O /O - (CH3) 2 H

--c~ - (CH3) 2

Claims (136)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of [2-[(aminopyridinyl)amino]phenyl]-arylmethanones having the formula II

wherein;
Ar is selected from the group consisting of 2, 3 or 4-pyridinyl, 2 or 3 thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same or different, Z is selected from the group consisting of hydrogen, halogen, lower-alkyl, loweralkoxy, hydroxy, nitro and trifluoromethyl, Y is selected from the group consisting of hydrogen or 1 - 2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different, comprising the step of heating a mixture of halo-aminopyridine hav-ing the formula IV

wherein Y is as defined above, and an (aminophenyl)arylmethanone having the formula III

wherein Z and Ar arc as defined above for a shorter time than that required for cyclization to the pyridobenzodiazepine at 170° - 200°C. optionally separating and isolating the resulting [2-[(aminopyridinyl)amino]phenyl]
arylmethanone using solvents to separate it from starting materials and some cyclized pyridobenzodiazepine.

2. A process for the preparation of pyrido[1,4]benzodiazepines having the formula I' wherein Ar is selected from the group consisting of 2, 3 or 4-pyridinyl, 2 or 3 thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy trifluoromethyl or nitro and may be the same or different, Z is selected from the group consisting of hydrogen, halogen, lower-alkyl, loweralkoxy, hydroxy, nitro and trifluoromethyl, Y is selected from the group consisting of hydrogen or 1 - 2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or dif-ferent, comprising the steps of (1) heating a mixture of halo-amine pyridine having the formula IV

and an (aminophenyl)arylmethanone having the formula III

or a reaction product thereof having the formula II

wherein Y, Z and Ar are as defined above for a period of time and under conditions to remove water of reaction to cyclize to a pyrido[1,4]benzodiazepine having the formula Ia wherein Ar, Y and Z are as defined above, and (2) optionally reducing the double bond in the compound prepared in step 1 to a compound having the formula Ia-1 wherein Ar, Y and Z are as defined above.

3. A process according to claim 2, wherein the tempera-ture in step (1) is 170 - 200°C.

4. A process according to claim 2, wherein in step (1) water is removed under reflux in an aprotic solvent.

5. A process for the preparation of pyrido[1,4]benzo-diazepines having the formula I

wherein R is selected from the group consisting of hydrogen, loweralkyl, -alk1-halo, -alk1-NR1R2 or -alk1-N=CH-OC2H5;
R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, -C(O)O-loweralkyl, or R1 and R2 taken together with the adjacent nitrogen atom may form a hetero-cyclic residue selected from the group consisting of 1-phthalimido, 1-pyrrolidinyl, 4-morpholino, 1-piperazino, and 4-substituted piperazine-1-yl;
Ar is selected from the group consisting of 2, 3 or 4-pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same or different;
Alk1 is a straight or branched hydrocarbon chain con-taining 1 - 8 carbon atoms;
Z is selected from the group consisting of hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro and tri-fluoromethyl;
Y is selected from the group consisting of hydrogen or 1 - 2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different;

n is 0 and 1 and when n is zero the dotted line is a double bond, or an acid addition salt thereof, which com-prises the steps of:
(1) heating a mixture of halo-amino pyridine having the formula IV
and an (aminophenyl)arylmethanone having the formula III

or a reaction product thereof having the formula II

wherein Y, Z and Ar are as defined above, for a period of time and under conditions to remove water of reaction to cyclize to pyrido[1,4]benzodiazepine having the formula Ia wherein Ar, Y and Z are as defined above;

(2) optionally reducing the double bond in the compound prepared in step 1 to a compound having the formula Ia-1 wherein Ar, Y and Z are as defined above;
(3) reacting a product of either step 1 or step 2 with a halo-lower alkyl or a halo-alk1Q reagent wherein Q is selected from the group consisting of -N-(loweralkyl)2, 1-pyrrolidinyl, 1-piperidinyl, 4-substituted-piperazin-1-yl, 4-morpholino, 1-phthalimido, loweralkyl or halo, and when n is 0 optionally reducing the double bond in the re-action product to give a compound selected from those hav-ing the formula Ib (4) when Q is 1-phthalimido, reduce the product of step (3) to the amino group, and when n is 0, optionally reducing the double bond of the amino compound to give a compound having the formula Ic (5) optionally reacting a compound produced in step 4 with triethyl ortho formate for a period of time sufficient to form the methanimidic ester having the formula Id and thereafter reducing the methanimidic ester with sodium borohydride, and when n is 0, optionally reducing the double bond to give a compound having the formula Ie (6) optionally reacting a compound produced in step 4 with ethyl chloroformate in the presence of triethylamine, followed by reduction with lithium aluminum hydride to give a compound of the formula Ie-1 (7) optionally hydrolyzing a compound produced in step 3 wherein Q is to give a compound having the formula Ie-5 wherein Ar, Y, Z alk1 and n are as given above, or (8) alternately, when Q is chloro in a compound pre-pared in step 3, reacting with dialkyl amine to give a com-pound having the formula Ib-3

6. A compound of formula II defined in claim 1, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

7. A compound of formula I defined in claim 5, when prepared by the process of claim 5 or by an obvious chemical equivalent thereof.

8. A compound of formula I' defined in claim 2, when prepared by the process of claim 2 or by an obvious chemical equivalent thereof.

9. A process according to claim 2, wherein the reduc-tion of the double bond in step (2) is carried out using sodium cyanoborohydride.

10. A process according to claim 5, wherein the reduc-tion of the double bond in step (2), (3), (4) or (5) is, if necessary, carried out using sodium cyanoborohydride.

11. A process for the preparation of a pyrido[1,4]ben-zodiazepine having the formula:

Ip wherein; Ar is 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted by 1 to 3 substituents sel-ected from the group consisting of halogen, lower alkyl, lower alkoxy, trifluoromethyl and nitro and may be the same or different when there are 2 or 3 substituents;
R is hydrogen, lower (C1-8)alkyl, or alk1-NR1R2, R1 and R2 are each hydrogen or lower (C1-8) alkyl or R1 and R2 are taken together with the adjacent nitro-gen atom form a heterocyclic residue selected from the group consisting of 1-pyrrolidinyl, 4-morpholinyl, 1-piperidinyl and 4-lower (C1-8)alkyl-piperazin-1-yl;
Alk1 is a straight or branched alkylene chain containing 1 to 8 carbon atoms;
Z is hydrogen, halogen, lower (C1-8)alkyl, lower (C1-8)alkoxy, hydroxy, nitro or trifluoromethyl;
Y is hydrogen or 1 or 2 radicals selected from the group consisting of lower (C1-8)alkyl, lower (C1-8)alkoxy, and hydroxy may be the same or different when there are two radicals, n is 0 or 1, the dotted line indicate a single bond when n is 1 and a double bond when n is 0, or a pharmaceutically accep-table acid addition salt thereof, which process comprises:
(1) heating a mixture of halo-amino pyridine having the formula IV

and an (aminophenyl)arylmethanone having the formula III

or a reaction product thereof having the formula II

wherein Y, Z and Ar are as defined above, for a period of time and under conditions to remove water of reaction to cyclize to pyrido[1,4]benzodiazepine having the formula Ia wherein Ar, Y and Z are as defined above;
(2) optionally reducing the double bond in the compound prepared in step 1 to a compound having the formula Ia-1 wherein Ar, Y and A are as defined above;
(3) reacting a product of step 1 or 2 with a halo-lower alkyl or halo-alk1Q reagent wherein Q is -N(lower(C1-8) alkyl)2, 1-pyrrolidinyl, 4-morpholino, l-piperidinyl, 4-lower (C1-8)alkyl-piperazin-1-yl, 1-phthalimido, (C1-8)alkyl or halo, and when n is 0 optionally lower (C1-8)alkyl reducing the double bond in the reaction product to give a compound of the formula:

Ib wherein the symbols are as defined above, (4) when Q is 1-phthalimido, reduce the product of step (3) to the amino group, and when n is 0, optionally reducing the double bond of the amino compound to give a compound having the formula Ic (5) optionally reacting a compound produced in step 4 with triethyl ortho formate for a period of time sufficient to form the methanimidic ester having the formula Id and thereafter reducing the methaneimidic ester with sodium borohydride, and when n is 0, optionally reducing the double bond to give a compound having the formula Ie (6) optionally reacting a compound produced in step 4 with ethyl chloroformate in the presence of triethylamine, followed by reduction with lithium aluminum hydride to give a compound of the formula Ie-1 and (7) optionally hydrolyzing a compound produced in step 3 wherein Q is to give a compound having the formula Ie-5 wherein Ar, Y, Z, alk1 and n are as given above, or (8) alternately, when Q is chloro in a compound pre-pared in step 3, reacting with a dialkyl amine to give a compound having the formula Ib-3 and optionally converting a compound of formula Ip prepared by any process of (1) to (8) into a pharmaceutically accep-table acid addition salt thereof.

12. A pyrido[1,4]benzodiazepine of formula Ip as defined in claim 11 or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of claim 11 or by an obvious chemical equivalent thereof.

13. A process for the preparation of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating a mixture of 2-aminobenzophenone and 3-amino-2-chloropyridine for a period of time and under conditions to remove water of reaction to cyclize to the desired compound.

14. 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine when prepared by the process of claim 13.

15. A process for the preparation of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating a mixture of 2-amino-5-chlorobenzophenone and 3-amino-2-chloropyridine for a period of time and under con-ditions to remove water of reaction to cyclize to the de-sired compound.

16. 8-Chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodia-zepine when prepared by the process of claim 15.

17. A process for the preparation of 9-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating {2-[(3-amino-2-pyridyl)amino]-4-chlorophenyl}-(phenyl)methanone or a mixture of 2-amino-4-chlorobenzophen-one and 3-amino-2-chloropyridine for a period of time and under conditions to remove water of reaction to cyclize to the desired compound.

18. 9-Chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodia-zepine when prepared by the process of claim 17.

19. A process for the preparation of 6-(4-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process com-prises heating a mixture of 2-amino-4'-chlorobenzophenone and 3-amino-2-chloropyridine for a period of time and under conditions to remove water of reaction to cyclize to the desired compound.

20. 6-(4-Chlorophenyl)-11H-pyrido[2,3-b] [1,4]benzodia-zepine when prepared by the process of claim 19.

21. A process for the preparation of 6-(4-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating {2-[(3-amino-2-pyridyl)amino]phenyl}(4-methylphenyl) methanone for a period of time and under conditions to re-move water of reaction to cyclize into the desired compound.

22. 6(4-Methylphenyl)-11H-pyrido[2,3-b][1,4]benzodia-zepine when prepared by the process of claim 21.

23. A process for the preparation of 6-(4-methoxy-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating a mixture of 2-amino-4'-methoxybenzophon-one and 3-amino-2-chloropyridine for a period of time and under conditions to remove water of reaction to cyclize to the desired compound.

24. 6-(4-Methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzo-diazepine when prepared by the process of claim 23.

25. A process for the preparation of 8-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazopine-11-propanamine or a pharmaceutically accpetable acid addition salt thereof, which process comprises reacting 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethyl-aminopropyl chloride, and if desired, converting the product into a pharmaceutically acceptable salt thereof.

26. A process according to claim 25, wherein the pro-duct is converted to its oxalate.

27. A process according to claim 24 or 25, wherein the starting benzodiazepine compound is prepared by the process of claim 15.

28. 8-Chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of claim 25.

29. A process for the preparation of N,N-dimethyl-6-phenyl 11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine with 3-dimethylaminopropyl chloride, and if desired coverting the product into a pharmaceutically acceptable acid addition salt thereof.

30. A process according to claim 29, wherein the start-ing benzodiazepine compound is prepared by the process of claim 13.

31. A process according to claim 29 or 30, wherein the reaction product is converted to its fumarate.

32. N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzo-diazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 29.

33. A process for the preparation of N,M-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepin-11-ethanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine with 2-dimethylaminoethyl chloride, and is desired, converting the reaction product into a pharma-ceutically acceptable acid addition salt thereof.

34. A process according to claim 33, wherein the starting benzodiazepine compound is prepared by the process of claim 13.

35. A process according to claim 33 or 34, wherein the reaction product is converted to its fumarate.

36. N,N-Dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzo-diazepin-11-ethanamine or a pharmaceutically acceptable acid addition salt thereof when prepared by-the process of claim 33.

37. A process for the preparation of 11-[3-(4-morpho-linyl)propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine with 4-(3-chloropropyl morpholine chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

38. A process according to claim 37, wherein the starting benzodiazepine compound is prepared by the process of claim 13.

39. A process according to claim 37 or 38, wherein the reaction product is converted to its fumarate.

40. 11-[3-(4-Morpholinyl)propyl]-6-phenyl-11H-pyrido [2,3-b][1,4]benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 37.

41. A process for the preparation of N,N-diethyl-6-phenyl-11H pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine with 3-diethylaminopropyl chloride, and if desired, converting the reaction product into a pharma-ceutically acceptable acid addition salt thereof.

42. A process according to claim 41, wherein the starting benzodiazepine compound is prepared by the process of claim 13.

43. A process according to claim 41 or 42, wherein the reaction product is converted to its oxalate.

44. N,N-Diethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzo-diazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 41.

45. A process for the preparation of 9-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 9-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethyl-aminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

46. A process according to claim 45, wherein the starting benzodiazepine compound is prepared by the process of claim 17.

47. A process according to claim 45 or 46, wherein the reaction product is converted to its fumarate.

48. 9-Chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 45.

49. A process for the preparation of 6-phenyl-11-[3-(1-piperidinyl)propyl]-11H-pyrido[2,3-b][1,4]benzodiazo-pine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6 phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with N-(3-chloropropyl) piperidine, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

50. A process according to claim 49, wherein the starting benzodiazepine compound is produced by the process of claim 13.

51. A process according to claim 49 or 50, wherein the reaction product is converted to its fumarate.

52. 6-Phenyl-11-[3-(1-piperidinyl)propyl]-11H-pyrido [2,3-b][1,4]benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 49.

53. A process for the preparation of 6-(4-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-pro-panamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-(4-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylamino-propyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

54. A process according to claim 53, wherein the starting benzodiazepine compound is prepared by the process of claim 19.

55. A process according to claim 53 or 54, wherein the reaction product is converted to its fumarate.

56. 6-(4-Chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 53.

57. A process for the preparation of 8-chloro-N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-ethanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine and 2-dimethyl-aminoethyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

58. A process according to claim 57, wherein the starting benzodiazepine compound is prepared by the process of claim 15.

59. A process according to claim 57 or 58, wherein the reaction product is converted to its oxalate.

60. 8-Chloro-N,N dimethyl-6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepin-11-ethanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 57.

61. A process for the preparation of 8-chloro-11-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with methyl iodide, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

62. A process according to claim 61, wherein the starting benzodiazepine compound is prepared by the process of claim 15.

63. 8-Chloro-11-methyl-6-phenyl-11H-pyrido-[2,3-b][1,4]benzodiazepine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 61.

64. A process for the preparation of N,N-dimethyl-6-(4-methylphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepin-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-(4-methyl-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine and 3-dimethyl-aminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

65. A process according to claim 64, wherein the starting benzodiazepine compound is prepared by the process of claim 21.

66. A process according to claim 64 or 65, wherein the reaction product is converted to its fumarate.

67. N,N-Dimethyl-6-(4-methylphenyl)-11H-pyrido[2,3-b]
[1,4]benzodiazepin-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 64.

68. A process for the preparation of 6-(4-methoxy-phenyl)-M,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addi-tion salt thereof, which process comprises reacting 6-(4-methoxyphenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylaminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

69. A process according to claim 68, wherein the starting benzodiazepine compound is prepared by the process of claim 23.

70. A process according to claim 68 or 69, wherein the reaction product is converted to its fumarate.

71. 6-(4-Methoxyphenyl)-N,N-diethyl-11H-pyrido[2,3-b]
[1,4]benzodiazeplne-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 68.

72. A process for the preparation of 6-(3-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating {2-[3-amino-2-pyridyl)amino]phenyl}-(3-chlorophenyl) methanone for a period of time and under conditions to re-move water of reaction to cyclize into the desired compound.

73. 6-(3-Chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodia-zepine, when prepared by the process of claim 72.

74. A process for the preparation of 6-(3-chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propan-amino or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-(3-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylamino-propyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

75. A process according to claim 74, wherein the re-action product is converted to its fumarate.

76. A process according to claim 74 or 75, wherein the starting benzodiazepine compound is prepared by the process of claim 72.

77. 6-(3-Chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 74.

78. A process for the preparation of 6-(4-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating {2-[3-amino-2-pyridyl)amino]phenyl}-(4-fluorophenyl) methanone for a period time and under conditions to remove water of reaction to cyclize into the desired compound.

79. 6-(4-Fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodia-zepine, when prepared by the process of claim 78.

80. A process for the preparation of 6-(4-fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-pro-panamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting 6-(4-fluoro-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethyl-aminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

81. A process according to claim 80, wherein the re-action product is converted to its hydrochloride.

82. A process according to claim 80 or 81, wherein the starting benzodiazepine compound is prepared by the process of claim 74.

83. 6-(4-Fluorophenyl)-N,N-dimethyl--1H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 80.

84. A process for the preparation of 11-[3-(1,3-dihydro-1,3 dioxo-2H-isoindol-2-yl)propyl]-6-phenyl-11H
pyrido[2,3-b][1,4]benzodiazepine which process comprises reacting 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine with N-(3-bromopropyl)phthalimide.

85. A process according to claim 84, wherein the starting benzodiazepine compound is prepared by the process of claim 13.

86. 11-[3-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl) propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, when prepared by the process of claim 84.

87. A process for the preparation of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a phar-maceutically acceptable acid addition salt thereof, which process comprises reducing 11-[3-(1,3-dioxo-2H-isoindol-2-yl) propyl]-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine, and if desired, converting the reduction product into a pharmaceuti-cally acceptable acid addition salt thereof or into the free amine.

88. A process according to claim 87, wherein the re-duction is carried out using hydrazine hydrate.

89. A process according to claim 88, wherein the re-duction product is converted to its dihydrochloride.

90. A process according to claim 87 or 88, wherein the starting phthalimide compound is prepared by the process of claim 84.

91. 6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 87 or 88.

92. A process for the preparation of N-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11 propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
reacting 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine with triethyl orthoformate to give an inter-mediate N-[3-(6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepin-11-yl)propyl]methaimidic acid ethyl ester, reducing the intermediate imidate with sodium boro-hydride to give the desired secondary amine, and if desired, converting the reduction product into a pharmaceutically acceptable acid addition salt thereof.

93. A process according to claim 92, wherein the re-duction product is converted to its dihydrochloride.

94. A process according to claim 92 or 93, wherein the starting primary amine is produced by the process of claim 83.

95. N-Methyl-5-phenyl-11H-pyrido[2,3-b][1,4]benzodia-zepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 92.

96. A process for the preparation of N-[3-(6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl)propyl]carbamic acid ethyl ester, which process comprises reacting 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine with ethyl chloroformate.

97. A process according to claim 96, wherein the starting amine is prepared by the process of claim 87.

98. N-[3-(6-Phenyl-11H-pyrido[2,3-b][1,4]benzodia-zepine-11-yl)propyl]carbamic acid ethyl ester when prepared by the process of claim 96.

99. A process for the preparation of 5,6-dihydro-N,N-dimethyl-6-phenyl-11H pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reducing the double bond in N,N-dimethyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodia-zepine-11-propanamine, and if desired, converting the re-duction product into a pharmaceutically acceptable acid addi-tion salt thereof.

100. A process according to claim 99, wherein the re-duction is carried out using sodium cyanoborohydride.

101. A process according to claim 100, wherein the re-duction product is converted to its dihydrochloride.

102. A process according to claim 99 or 100, wherein the starting material is produced by the process of claim 29.

103. 5,6-Dihydro-N,N-dimethyl-6-phenyl-11H-pyrido [2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceuti-cally acceptable acid addition salt thereof, when prepared by the process of claim 99 or 100.

104. A process for the preparation of 8-chloro-6-(2-chlorophenyl)-5,6-dihydro-11H-pyrido[2,3-b][1,4]benzodia-zepine, which process comprises reducing the double bond in 8-chloro-6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzo-diazepine; or heating 3-amino 2-chloropyridine and 2-amino-2', 5-dichlorobenzophenone.

105. 8-Chloro-6-(2-chlorophenyl)-5,6-dihydro-11H-pyrido[2,3-b][1,4]benzodiazepine, when prepared by the pro-cess of claim 104.

106. A process for the preparation of 5,6-dihydro-N-methyl-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, which process comprises reducing N-[3-(6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-yl)propyl]
carbamic acid ethyl ester with lithium aluminum hydride, and if desired, converting the reduction product into a pharmaceutically acceptable acid addition salt thereof.

107. A process according to claim 106, wherein the starting material is prepared by the process of claim 96.

108. 5,6-Dihydro-N-methyl-6-phenyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 106.

109. A process for the preparation of 6-(2-fluoro-phenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addi-tion salt thereof, which process comprises reacting 6-(2-fluorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylaminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

110. A process according to claim 109, wherein the re-action product is not converted to its salt.

111. A process for the preparation of 6-(2-fluoro-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which pro-cess comprises heating {2-[(3-amino-2-pyridinyl)amino]
phenyl}-(2-fluorophenyl)methane for a period of time and under conditions to remove water of reaction to cyclize into the desired compound.

112. A process according to claim 109 or 110, wherein the starting benzodiazepine compound is prepared by the process of claim 111.

113. 6-(2-Fluorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 109.

114. 6-(2-Fluorophenyl)-11H-pyrido[2,3-b][1,4]benzo-diazepine, when prepared by the process of claim 111.

115. A process for the preparation of 6-(2-chloro-phenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addi-tion salt thereof, which process comprises reacting 6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylamino propyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

116. A process according to claim 115, wherein the re-action product is not converted to its salt.

117. A process for the preparation of 6-(2-chloro-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises heating {2-[(3 amino-2-pyridinyl)amino]phenyl}-(2-chlorophenyl)methanone for a period of time and under conditions to remove water of reaction to cyclize into the desired compound.

118. A process according to claim 115 or 116, wherein the starting benzodiazepine compound is prepared by the process of claim 117.

119 6-(2-Chlorophenyl)-N,N-dimethyl-11H-pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 115.

120. 6-(2-Chlorophenyl)-11H-pyrido [2,3-b][1,4]benzodia-zepine, when prepared by the process of claim 117.

121. A process for the preparation of 6-(2-bromo-phenyl)-N,N-dimethyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addi-tion salt thereof, which process comprises reacting 6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with 3-dimethylaminopropyl chloride, and if desired, converting the reaction product into a pharmaceutically acceptable acid addition salt thereof.

122. A process according to claim 121, wherein the re-action product is not converted to its salt.

123. A process for the preparation of 6-(2-bromo-phenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine, which pro cess comprises heating{2-[(3-amino-2-pyridinyl)amino]phenyl}-(2-bromophenyl)methanone for a period of time and under con-ditions to remove water of reaction to cyclize into the de-sired compound.

124. A process according to claim 121 or 122, wherein the starting benzodiazepine compound is prepared by the process of claim 123.

125. 6-(2-Bromophenyl)-N,N-dimethyl-11H pyrido[2,3-b]
[1,4]benzodiazepine-11-propanamine or a pharmaceutically acceptable acid addition salt thereof, when prepared by the process of claim 121.

126. 6-(2-Bromophenyl)-11H-pyrido[2,3-b][1,4]benzodia-zepine, when prepared by the process of claim 123.

127. A process for the preparation of 8-chloro-11-methyl-6-(2-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiaze-pine, which process comprises reacting 8-chloro-6-(2-nitrophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with methyl iodide.

128. 8-Chloro-11-methyl-6-(2-ni-trophenyl)-11H-pyrido [2,3-b][1,4]benzodiazepine, when prepared by the process of claim 127.

129. A process for the preparation of 8-chloro-6-(2-chlorophenyl)-11-methyl-11H-pyrido[2,3-b][1,4]benzodiaze-pine, which process comprises reacting 8-chloro-6-(2-chlorophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with methyl iodide.

130. 8-Chloro-6-(2-chlorophenyl)-11-methyl-11H-pyrido [2,3-b][1,4]benzodiazepine, when prepared by the process of claim 129.

131. A process for the preparation of 6-(2-bromophenyl)-8-chloro-11-methyl-11H-pyrido[2,3-b][1,4]benzodiazepine, which process comprises reacting 8-chloro-6-(2-bromophenyl)-11H-pyrido[2,3-b][1,4]benzodiazepine with methyl iodide.

132. 6-(2-Bromophenyl)-8-chloro-11-methyl-11H-pyrido [2,3-b][1,4]benzodiazepine, when prepared by the process of claim 131.

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE

133. A process for the preparation of an [2-[(amino-pyridinyl)amino]phenyl]-arylmethanone or an analog thereof having the formula II' wherein;
Ar is selected from the group consisting of 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl sub-stituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same or different;
Z is selected from the group consisting of hydro-gen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro and trifluoromethyl Y is selected from the group consisting of hydro-gen or 1 - 2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different;
B is selected from carbonyl, thiooxomethyl, ketal or thioketal;

R is selected from the group consisting of hydro-gen, loweralkyl, -alk1-NR1R2 or -alk1-N=CH-O-C2H5; and R1 and R2 are selected from the group consisting of hydrogen, lower alkyl, -C(O)O-loweralkyl or R1 and R2 taken together with the adjacent nitrogen atom form a hetero-cyclic residue selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-1-piperazinyl; with the proviso that when B is carbonyl, R is not hydrogen, or an acid addition salt thereof, which process comprises the step of heating a mixture of halo-aminopyridine having the formula IV

wherein Y is as defined above and an (aminophenyl)arylmethanone or an analog thereof having the formula III' wherein Ar, B, Z and R are as defined above, for a shorter time than that required for cyclization to the pyridobenzodiazepine, and optionally separating and isolating the resulting [2-[(aminopyridinyl)amino]phenyl]
arylmethanone or its analog using solvent to separate it from starting materials and some cyclized pyridobenzodia-zepine.

134. An [2-[(aminopyridinyl)amino]phenyl]arylmethanone or an analog thereof having the formula II' as defined in claim 134, whenever prepared or produced by the process of

claim 134 or by an obvious chemical equivalent thereof.

135. A process according to claim 134, wherein in the starting materials R is selected from the group consisting of hydrogen, loweralkyl or -alkl-NRlR2;

R1 and R2 are selected from the group consisting of hydrogen, loweralkyl, -C(O)O-loweralkyl or R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic residue selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpho-linyl and 1-piperazinyl;
B is selected from carbonyl or thioxomethyl;
Ar, Z and Y are as defined in claim 134, with the proviso that when B is carbonyl, R is not hydrogen, and if the compound is in the form of acid addition salt, the salt is pharmaceutically acceptable.

136. A process for the preparation of an [2-[(amino-pyridinyl)amino]phenyl]-arylmethanone or an analog thereof having the formula II' wherein;
Ar is selected from the group consisting of 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl sub-stituted by 1 to 3 radicals selected from halo, loweralkyl, loweralkoxy, trifluoromethyl or nitro and may be the same or different;
Z is selected from the group consisting of hydro-gen, halogen, loweralkyl, loweralkoxy, hydroxy, nitro and trifluoromethyl Y is selected from the group consisting of hydro-gen or 1 - 2 radicals selected from loweralkyl, loweralkoxy or hydroxy and may be the same or different;
B is selected from carbonyl, thiooxomethyl, ketal or thioketal;
R is selected from the group consisting of hydro-gen, loweralkyl, -alk1-NR1R2 or -alk1-N=CH-O-C2H5; and R1 and R2 are selected from the group consisting of hydrogen, lower alkyl, -C(O)O-loweralkyl or R1 and R2 taken together with the adjacent nitrogen atom form a hetero-cyclic residue selected from the group consisting of 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholinyl, 1-piperazinyl and 4-substituted-1-piperazinyl, or an acid addition salt thereof, which process comprises the step of heating a mixture of halo-aminopyridine having the formula IV

wherein Y is as defined above, and an (aminophenyl)arylmethanone or an analog thereof having the formula III' wherein Ar, B, Z and R are as defined above, for a shorter time than that required for cyclization to the pyridobenzodiazepine, and optionally separating and isolating the resulting [2-[(aminopyridinyl)amino]phenyl]
arylmethanone or its analog using solvent to separate it from starting materials and some cyclized pyridobenzodia-zepine.