CA1262353A - Aromatic ketone derivative intermediates for the preparation of antidepressant pyrido [1,4] benzodiazepines - Google Patents

Abstract

ABSTRACT
Disclosed are novel aromatic ketone derivatives of the formula:
(IIIb) (wherein Ar is pyridinyl, thienyl, phenyl or substituted phenyl;
Z is hydrogen, halogen, alkyl, alkoxy, hydroxy or nitro;
alk1 is hydrocarbon chain; and Q2 is -NR1R2, -N=CH-OC2H5 or tetrahydropyranyloxy;
R1 and R2 are each alkyl or CO2-alkyl or R1 and R2 together with the adjacent nitrogen atom form 1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholino, 1-piperazinyl or 4-substituted 1-piperazinyl). The aromatic ketone derivatives are useful as intermediates for producing pyrido(1,4)benzodiazepines of the formula:
(I) (wherein Ar and Z are as defined above;
Y i hydrogen or substituent on the pyridine ring; and R is hydrogen, alkali metal or -alk1-Q1, Q1 is hydrogen, halo, -NR1R2, N=CH-O-C2H5 or tetra-hydropyranyloxy). Some of the pyrido(1,4]benzodiazepines are useful as antidepressant.

Description

- 1 - AHR Case 425 DI~. I

l~his is a divisional application of Application Serial No. 478,110 filed April 2, 1985.
BA~KGROUND OF THE INVENTION
1. Field of Invention.
The parent application relates to a process for the preparation of certain known pyrido[l,4]benzodiazepines and this application relates to novel chemical intermediates useful for preparing the pyrido[l,4]benzodiazepines.
An important aspect of the process is the utiliza-! 10 tion of a strong non-nucleophilic base such as sodium hydride to bring about condensation of an aminochloropyridine and an aryl(aminophenyl)methanone in admixture with mobile inert liquid carrier to produce the pyrido[l,4]benzodiazepines. Alternative-ly, the condensation may be started with titanium tetrachloride and finished with the non~nucleophilic base, in which case novel intermediates are produced and used.
The present application provides a compound of the formula:
,Ar (IIIb) alkl Q2 (wherein:
Ar is 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals which are the same or different and are selected from the group consisting of halo, loweralkyl, loweralkoxy, trifluoromethyl and nitro;

Z is hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro;
alkl is a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms;

- la - 66197-166D

Q is -NR R , -N=CH-OC2H5 or -0-CHCH2CH~CH2CH2; and ~ 1 and ~2 are each Cl 8alkyl or C(O)-O-Cl ~alkyl or Rl and R2 -taken together with the adjacent atom form a hetero-cyclic residue selected from the group consisting of l-piperi-dinyl, l-phthalimido, l-pyrrolidinyl, 4-morpholino, l-piper-azinyl and 4-substituted-1-piperazinyl, in which the substituen-t in the 4-position is Cl ~alkyl or Cl galkoxy-carbonyl)r or an acid addition salt thereof.
The present application also provides a process for producing the compound of the formula (IIIb) as defined above or an acid addition salt thereof, which comprises reacting a compound of the formula:
~ ~ Ar z ~ (IIIa) (wherein Ar and Z are as defined above), with a halide of the formula:
X-alkl-Q2 ~wherein X is halogen, and alkl and Q2 are as de~ined above), in a reaction inert solvent, and zO if desired, converting the thus-obtained product into an acid addition salt thereof.
In the following description, the expression "present inventlon" includes the subject matters of this appli-cation and of the parent application.

9~

- lb - 661g7-166D

Some of the compounds of the formula (IIIb) are broadly krown.
The broadly known compounds are those in which alk1 i5 a hydrocarbon chain con~aining 1 to 3 carbon atoms and Q2 is -NR1R2 whexein R1 and R2 are each C1 8 alkyl or R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic residue selected from the group consisting of 1-piperidinyl, 1-pyrrolidinyl and 4-morpholino. However, the specific compound produced in Preparation 1 described hereinafter is not known.

2. Information Disclosure Statement.
The aryl substituted pyrido[1,4]benzodiazepines prepared by the process of this invention are disclosed in S.
African Patent 8:l/7866 and are the subject of a corresponding commonly assigned United States Patent No. 4,447,361 :issued May 8, 1984. In the method of preparation disclosed in these references, amino-halo pyridine and aminoarylphenones are heated neat to give pyrido[1,4]benzodiazepines.

3~

ommonly asslgned U. S. Patent No. 4,480,110, describes preparation of C2-C(nitropyridinyl)amino]phenyl]arylmethanones, useful in preparation of the pyrido~l,4~benzodiazepines, by heating neat a halonitropyridine with an aminoarylphenone.
Heating and reaction of such mixtures as described in the foregoing disclosures involves dïfficult handling o viscous, sticky reactants and reaction products which adhere to the reaction vessel. In contras~, in the present invention the diazepine ring is formed by a strong non-nucleophilic base such as sodium hydride in a solvent or liquid carrier which provides high mobility, ease of operation and increased yields and direct formation of the sodium salts of the pyrido l,~-benzoidazepines.
Relating to the preparation o certain chemical intermediates used in the process of the present invention, yamamoto, M. and Yamamoto H. in chem. Pharm. Bullo 29(8) J
2135-2156 (1981) describe the reaction of 2-amino-4-chlorobenzophenone and an amine in tha presence of titanium tetrachloride a~ represen~ed by the following equation:
/C~Hs / ~H5 Cl ~ - O Ti Cl4 Cl ~ C - ~-Rl wherein Rl-alkyl/ cycloalkyl, phenylalkyl, dialkylamino-alkyl and 4-morpholinoalkyl.
Also relating to preparation o~ certain other intermediates used in the process is a disclosure of phase-transfer catalyzed ~-monoalkylation of 2-aminobenzophenones o Mouzin, G., et al, in Synthesis Communications Georg.
Thieme Verlag 1981, p. 448-4~9. as represented by the ~ollowing e~uation:

~ ~ X2 ~ C = o _alkylatinq a~ent/ _ ~ C = 0 ,0 r ~aOH/THF/(n-C4Hg)4N Br Xl~NH
R

wherein R=CH3, -CzH5 or allyl; Xl=Cl or Br; X2=H, Cl or F.
SUMMARY QF TB I~VENTI0~
Pyridobenzodiazepine compounds which are prepared directly by the novel process o~ the present invention have the fo3~ula:
Ar Z~Y

R Formula I

wherein R is selectad from the group consisting of alkali-metal cation ~M+),.hydrogen, ~alkl-Q wherein Q is selected from hydrogen, halo, -NRlR2, -~=CH-O-Cz~5 or . ~0 -0-CHCH2CH2CH2CH~;
- 25 Rl and R2 are selected from the group consisting of loweralkyl, -c(0)0-loweralkyl or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the grol~p consisting of l-piperidinyl, l-phthalimido, l-pyrrolidlnyl, 4-morpholinyl, l-piperazinyl, and 4-substituted-piperaz.in-1-yl;
Ar is elected from the group consisting of 2, 3 and

4 pyridinyl, 2 or 3-thienyl, phenyl or phenyl substituted by 1 to ~ radicals selected ~rom halo, loweralkyl, lower-alksxy, trifluoromethyl or nitro and may be the same or 3~; different;

alkl i9 a straight or branched hydrocarbon chain containing 1~8 carbon atoms;
Z is selected ~rom 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, and the acid addition salts thereof except when R=M~.
The compounds of Formula I have utility as anti-depressant pharmaceuticals or as intermediates in ~he preparation of other compounds of Formula I and of Formula Ip described hereinbelow.
Additionally, the compounds of Formula I wherein R is -alkl-O~CHCI~CH2CH~CH2 have been used to prepare compounds f Formula I wherein R is -alkl-RlR2 via novel intermediates wherein R is alkl-OH and.alkl-OS02W wherein W is as defined hereinbelow.
In the ~urthPr definition of symbols in the formulas hereon and where they appear elcewhere throughout this specification and claim~, the terms have the following significance.
The "alk" stxaight or branched connecting hydro~
carbon chain containing 1-8 car~ons is exemplified by methy~ene (-CH2-), ethylene (-CHz-CI~-), propylene (-CH2C~I2CH2-), ethylidene ~-CH-], 1,2-propylene CH-CH2- or -CH~ , isopropylidine ~-C- ~, or CH3 CH3 c~3 1,~-butylene [-CH-CH2-CH2-~, and the like.

The term "loweralkyl" includes straig~t and branched chain hydrocarbon radicals of up to eight carbon atoms inclusive and is exemplifi2d by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiarv butyl, ~5 amyl, isoamyl, hexyl~ heptyl, octyl, and the like.
The term "halogen" includes chlorine, bromine) fluorine, and iodinel pre~erably chlorine, bromine and fluorine.

~ 3~ ~
- ' 425 The term "4-substituted-l-piperazinyl7' re~ers to piperazine substitut~d in the 4~position by loweralk~l or alkoxy-carbonyl blocking group which may subsequen~l~ be removed to give the unsubstituted piperazine.
Pharmaceutically acceptable acid addition salts are those salks formed by the pyridobenzodiazepines prepared by the process of this invention with any acid which is physiologically compatible in warm blooded animals, such salts being formed either by strong or weak acids. Repre-sentative of strong acids are hydrochloric, sulfuric and phosphoric acids. Representative of weak acids are fumaric, maleic,' succinic, oxalic, cyclohexamic and the lik~.
The 6-aryl-llH-pyrido~2~3-b]~l~4~benzodiazepines and the 5,6-dihydxo derivatives thereof encompassed by Formula I have the formula:
' Ar Z ~ ~ Y
R ' Iw l'he 6-ary~ H-pyrido~3~4-b]~lJ4]benzodiazepines and the 5,6-dihydro derivatives thereof encompassed by Formula I
have the formula:

Z ~ I~

The ln-~r~ r~'~^r~,~-k~Ll,4J~ ~ -~r ' ~ ~
the 10,11 dihydro derivatives thereof encompassed by Formula I have the formula:

"s~3 ~25 Z ~ Y
R Iy The 10-aryl-5H-pyrido~3,2-b~C1,4]benzodiazepines and the 10,11-dihydro derivatives thereof encompass2d by Formula I have the ormula:
Ar ~=~
Z ~ ~ ~ Y

R Iz In all the formulas Iw to Iz, the symbols R, Ar, z and Y have the definition given hereinabove under Formula I.
For the purpose of testing antidepressant activity of the present invention compounds, the procedura given by Englehardt, E. L., et al., J. Med. Chem. 11(2): ~25 (1968) which has been indicative in the past of usefulness of compounds for treating human depression was used as follows:
20 mg/kg of the compound to be tested was administered to five adult female mice (ICR-DUB strain) intraperitoneally 30 minutes prior to the administration of a ptotic dose (32 mg ~g IP) of tetrabenazine (as the methanesulfonate salt). Thirty minutes later the presence or absence of complete eyelid closure (ptosis) was assessed in each animal.
An EDso (Median Effective Dose) may be established for each tested compound in blocking tetrabenazine-induced pto~i~ in mice following the procedure given by Litchfield et al.
. Pharmacoi. ~xp. ~l~n~rap. ~: ~y~ 154y;.
~5 Compounds preparable by the process of the invention or from the intermediates thereof which have antidepressant activity in the foregoing antidepressant test procedure have the Formula Ip Ar ~N

z1~7~
R
Ip wherein;
R is selected from the group consisting of hydrogen, loweralXyl or -alk1~ R1R2;
Rl and R2 are selected from the group consisting of hydroyen, loweralkyl or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected ~rom the group consisting of l-pyrrolidinyl, 4-morpholinyl, l-piperazinyl or 4-loweral~yl-1-piperazinyl;
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, lower-alXoxy, trifluorome~hyl or nitro and may be the same or different-Alk1 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 i9 qelected from the group consisting of hydrogen~
or 1-2 radicals selected from loweralkyl~ loweralXoxy or hydroxy and may be the same or different, and the pharmaceutically acceptable acid addition salts.
The compounds of Formula Ip wherein R is -alkl-NRlR2 and ~L and RZ are loweralkyl or hydrogen have been shown to have low incidence of antihistaminic~ anti-cholinergic and cardiotoxic side effects when tested in animals.

The preferred pyridobenzodiazepines useful in the method of treating depression are as follows:

dimethyl 6-phenyl-llH-pyrido~2,3-b~rl,4 benzodiazepine-ll-propanamine.
6-(4-fluorophenyl)-N,N-dimethyl-llH-pyrido ~2,3-b]~1~4]benzodiazepine-11-propanamine.
6-phenyl-lH-pyrido~2,3-b]C1,4]benzodiazepine-ll-propanamine.
N-methyl-6-phenyl-llH-pyrido~2,3-b]~1,4 benzodiazepine-ll-propanamine.
6-(2-chlorophenyl)-N,~-aimethyl-lLH-pyrido ~2~3-b~ 4]benzodiazepine-ll-propanamine.
6-(2-fluorophenyl)~ -dimethyl-llH-pyrido -~2~3-b][l~4]benzodiazepine-ll-propanamine .
The generalized schematic equation for the preparation of pyridobenzodiazepines according to the process of the invention is yiven in Chart I.

, ~Z~ ~ 3~ ~

CH~RT I

Z ~ ~ ~ ~ ~ Y

III rv Strong non-nucleophi].ic alkali-metal base and Ar ~ liquid carrier >=~
Z-~

When R3=alkali-metal ion 1 When R3=alkali-metal ion a) Add Cl-alkl-Q ¦ Add aqueous proton donor to reaction mixture ¦ to reaction mixture b) **~*

\~
alkl_Q*** H
Ib Ic *R=hydrogen, lowerOlkyl, -alkl-~RlR2, -alkl-~=CH-OC2H5 or alkl-O-CHCH2CH2CH2~H2 and Rl and RZ are as defined under Fo~mula I
X=chlorine, bromine, fluorine or iodine.
**R3=alkali-matal ion, loweralkyl, -alk~ R2, -alXl-~=CH-OC2H5 or -alkl-O-CHC~I2CHzCH2CH2 and Rl and R2 are as defined under Formula I.
~**Q=hydrogen, halo, -alkl-~=CH-OC2H~, alkl-NRlR2 or -alkl-O-CHCHzCHzCH2CH2 and Rl and R2 are as defined under Formula I.
****Add dimeth~lformamide to the reaction mixture when Q i5 --C~CH2CHzCH2CH2 J hydrogen, halo and -alk1~=CH-OCzH5.
Compounds of Formulas IaJ Ib and Ic are encompassed by Formula I.

3~ ~

Additional procedures for converting compounds o~
Formu~as Ia or Ib wherein Q is -O-CHCH2CH2CH2CH2 which have been separated from the reaction mixture (or which have bs~n prepared by reacting isolated compounds wherein R3 is H with godium hydride and reagent Cl-alkl-CHCHzCH2CH2CH2) to useful antidepressant agents ~Formula VIII) are illustrated in the schematic equation of Chart II.
C~RT II
Ar >~

~ 1 ~o Ie alkl-CHC~zCHzCH2CH2 1 Strong concentrated acid;
e.g., conc. HCl Ar ~ ,protic solvent;e.g., ethanol ~ N
Z~Y
V /~ alkl-OH \ WS02Cl ~ Ar / \ (W=loweralkyl, phenyl N ~ SO2Cl Ar ~ tolyl radicals) llk~Cl VI VII alklOSO2W
1H~R1R2 *

Z~N~
alkl-~RlR2 VI~I

*R~ and R2 are a defi~ed in Formula I + hydrogen.
Colll~OUfid~ OL rG;illUla ~e ~lid 'v~ drc æ.com~a-s~d ~y ~L'm~a and Formula VIII is encompassed by Ip.
Csmpounds of Formula Ie~ V and VII are novel.

~2 Novel intermediates useful in the preparation of pyridobenzodiazepines of Formula ~ have the formula:

N

z ~1 H X~--Y
.Formula II

wherein Ar, Y and z are the same as defined under Formula I;
X=halo (C1, Br, F, I) and R is selected from the group consisting of hydrogen, loweralXyl, -alkl-NRlR2, -alkl-N=
CH OC2H5 or -alkl-O-CHOEI2CH2CH2CH2 wherein alkl, Rl and R2 are the same as defined under Formula I and the acid addition salts thereo~.
All positions of the pyridinyl nitrogen encompassed by Formula II are illustrated as follows:

X~ Y Z
R R
IIa IIb R R
IIc IId Compounds of Formula II are novelly prepared according to '~.;e rO; o~ g y~r.era;l~d Sc;~e.~la~ic equation:

~2 T~l Dtert amine, z ~ ~ ~ y aprotic solvent; I X
e.g., methylene R
chloride (Room Temp.~ II
X=halo, R=H or -alkl-Q, wherein Q = H or -~RlRZ.
Compounds of Formula II are novel.
'~ Compounds of Formula IV are available commercially or can he,readily pr,epared by known methods.
Compound~ of Formula III wherein R is H and corre-~ponding to the Formula IIIa O~

IIIa are available commercially or may be prepared by known methods.
~ovel compounds of Formula III wherein R is -alkl-Q
and Q is H or -~RlRZ are prepared according to the following generalized schematic equation from compounds of Formula IIIa O Ar 25Ar THF - "C' z ~ + x-alk-Q ~aOH III~
~H2 alkylating agent;
e.g., tert-n-butyl-IIIa ammonium bromide wherein X is halo, R is selected from -alkl~RlRZ, alkl-N=CH-OCzH5 or alkl-O-CHCH2CH2CH2CH2 and Ar, z and Rl~R~ are ~s dccir.ad ur.daL- rormula I,and tha acid addition salts thereof.

s~
4~5 It is therefore an object of the present invention to provide a novel process for the preparation of aryl-llH-pyrido~ll4]benzodiazepines which are either antidepressant pharmaceutical agents or useful in the preparation of other aryl~ -pyridoC1,4~benzodiazepine agents wlnich have antidepressant activity which utilizes a strong nucleophilic base in the condensation of (aminophenyl)arylmethanones and an amino-chloropyridine or partially condensed intermediates from those reactants all in stirrable admixture with inert liquid carrier.
Another object is to provide novel chemical inter-mediates and process therefor, such intermediates being useful in the preparatlon of arylpyridobenzodiazepines, which intermediates in general terms are phenylamines linked adjacent to the amine function via phenyl-substituted iminomethylene bridge to halopyridine and process therefor.
Still another object is to provide certain no~el (aminophenyl) arylmethanones useful as intermediates in the process of the invention.
DETA:I:LED DESCRIPTIO~ OF TEIE I~ TIO~
The novel process of the invention for preparing compounds of Formula I is comprised of the following four steps 1 to 4 with an optional preliminary step A.
Step 1, reacting a compound of the formula Ar >~

X~Y

or a mixture of compounds of the formulas o~ /Ar ~,C H2 ~7 III R IV

w~erein Ar, Y and z are as defined under Formula I, X i3 halo (chlorine, bromine, fluorine or iodine), R is hydrogen or alkl~Q wherein alXl is as defined above and Q is selected ~rom hydroge~, -~RlR2, -N=cH-oc2Hs~ or -o-c~cH2cH2cH2cHz and ~1 and R2 are selected from loweralkyl, -C(0)0-loweralkyl or Rl and R2 taken -together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-piperidinyl, l-phthalimido, l-pyrrolidinyl, 4-morpholinyl, l-piperazinyl and 4-substituted-piperazin-1-yl ~ogether with at least a stoichiometric amount of astrong non-nucleophilic alkali-metal base in stirrable admixture with inert liquid carrier to give a compound of the ~ormula Ar z " ~

in stirrable admixture with inert liquid carrier, wherein Ar, Y and Z are as defined above and R3 is an alkali-metal ion selected from sodium, potassium or lithium or -alkl-Q, whereln alkl is as defined above and Q is the same as in the starting compound~
Step 2, optionally when desired, r~acting a compound as prepared in step 1 in admixture with said liquid carrier wherein R3 is an alkali-metal ion with a proton source to give a compound of the foxmula Ar ~Y
H

J

in admixture with inert liquid carrier wherein Ar, Z and Y
axe as defined above.
Step ~, when desired, reacting a compound as prepared i~ admi:xture with liquid carrier in step 1 wherein R3 is an alkali-metal ion with a reagent having the formula halo-alX l~
wherein Q is selected ~rom hydrogen, -NRlR2, ~N=CH-0-C2EI5, ~0 or -0-CHCH2CH~CH2CH2 and Rl and R2 are selected from the group consisting of loweralkyl, -C(0)0-loweralkyl or Rl and R2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of l-piperidinyl, 1-phthalimido, l-pyrrolidinyl, 4-morpholinyl, l-piperazinyl and 4-substituted-piperazin-1-yl, to give a compound of the formula Ar . ~7~Y
alkl-Q

in admixture with liquid carrier wherein Q has the startin~
value of the reagent and Ar~ Y, Z and -alkl are as defined above.
Step 4, separating a compound prepared in step 1 oth~r than a compound whPrein R9 is an alkali-metal cation, and in steps 2 and 3 by conventional means from the carrier and the reaction mixture to give a compound of the formula Ar Z

3 ~ 425 wherein Ar, Y, Z and R are as defined above, except R is not alkali-metal cation, and the acid addition salts thereof.
In another novel variation of the process in a preliminary Step A, compounds of Formula II, when used in step 1, see Chart 1, are prepared as follows.
Step A, reacting a mixture of a compound of the formula O~ ~Ar ~[~
I III
R

wherein Ar, Z and R are as defined in step 1 of the rormula H2 ~ ~

IV
wherein X is halogen and Y is as defined under Formula Ig together with titanium tetrachloride and an excess of a tertiary organic amine in an inert liquid carrier and separating the product from the reaction mixture.
Obviously, Step A also serves as a single process step for preparing compounds of Formula II, see Chart I, which, as stated above~ are novel chemical intermediates.
The following description iq applicable to the foregoing process:
In step 1, ~uitable liquid carriers must be non-reactive with the strong non-nucleophilic base; e.g., sodium hydride and other reactants free of moisture and stable enough to prevent development of alkaline metal hydroxides which lead to impurities which are difficult to remove. Carrierq generally classified as strictly protic are not suitable. Suitable liquid carriers may or may not solubilize the reactants or products but some solubility o~ organic reactants and products in the carrier is usually ~ 3~ 3 ~25 desirable. Examples of aprotic aromatic non-polar qolvents which are suitable as carriers are toluene7 xylene and benzene. Examples of aprotic non-polar ether solvents which are suitable carriers are tetrahydrofuran, dioxane, and ethyleneglycol dimethyl etherO Examples of aprotic polar solvents which are suitable as carriers are dimethyl-formamide, morpholinoformamide, alkyl-~-pyrrolidinones, pyridine and dimethylsulfoxide. A preferred carrier is toluene. Use of mixtures of these carriers have been demon-strated to have advantage and such advantage will depend onthe specific reactants or products involved, particularly when solubility is a factor. One such preferred mixture involves toluene and tetrahydrofuran. Another preferred combination is toluene and dimethyl~ormamide as in the case when the radical -alkl-O-CHCH2CHzCH2CH2 is involved.
The amount of carrier may vary widely ranging from as little as about 5 part per 100 parts by weight of reactants to as much as 100 parts or more per 100 parts by weight of reactants. Generally, the minimum amount of carrier which can be used is that amount of carrier which will provide sufficient mobility for the reaction mixture to become stirrable and to provide flowability to the mix.
When toluene is used, about 8 12 parts by weight of carrier to reaction mixture is a preferred range. A wide range of 25 temperatures in step 1 may be employed, suitably about 20Co to 150C., about 40C. to 120C. being preferred.
The more specific prefexred temperature is that obtained with boiling tetrahydrofuran and refluxing ~oluene; i.e 65C. to 110C. While it is possible to conduct the reaction using a stoi~hiometric amount of sodium hydride, more complete reaction is ob~ained by using at least one molar excess of base. Two molar equivalents of strong alkali-metal non-nucleophilic base; e.g., sodium hydride~
is therefore preferxed. One preferred mode of conducting the reaction in step 1 i~ to slurrv or di~solve the amino-halopyridine in a suitable aprotic carrier, pre~erably toluen~, and simultaneouqly add a slurry of the non-nucleophilic alkali-metal base in the same carrier and a solution of the amino~enzophenone in a suitable aprotic non-polar solvent, pref~rably tetrahydrofuran or dioxane, at a temperature such that the tetrahydrofuran boils off during the addition as the aminobenzophenone is reacted.
As indicated above, sodium, potassium or lithium hydrides are suitable strong non-nucleophilic bases which facilitate the reaction, making possible the use of the solvent carriers and are preferredJ sodium hydride being especially preferred. Among other strong, non-nucleophilic bases which may be used are potassium tertiary butoxide, sodium triphenylmethane, sodium dimethylsulfoxide, ~nd alkali-metal amides.
The following illustrates the balanced equation involved in step 1 for each type of reactants when the strong non-nucleophilic alkali-metal base is sodium hydride.

P,r z ~NH2 ~-- + 2~aH aprotic solvent ~,>=N~ ~ ~ NaCl + 2H2 Z~Y
. Ar ~a C=N
~ ~ ~+ ~aH aprotic solvent z ~ NH ~~Y Ar llk l-Q __~NaC1 + Hz 0~ /Ar alkl_Q

z _~NH2 C~ 3NaH aprot ic solvent Ar ~>=~ + ~oH~acl*H2 Z~I~Y
Na 0~ Ar E N y~ 2~aHaprotic solv>nt alk 1 _Q
Ar >=~+ ~aoH~acl+2H2 Z ~ I ~ Y
alkl~
In each instance it is pre:Eerable to use an excess o sodium hydride.

~ 3~ ~ 425 .

In ~tep 2, an alXali-mPtal salt of compounds as prepared in step 1 still in the liquid carrier are converted to the \N~ compounds by reacting with any reagent H

capable o providing a proton source. Examples of suitable agents are water~ weak or strong acids~ and water containing bufering salts. The latter agent is preferred and the preferred buffexing salt is ammonium chloride. Blueish green color of the solution present initially in this step is indicative of the sodium salt of the pyridobenzo-diazepine and as the proton source is added such as aqueousammonium chloride solution, a golden yellow solid precipi-tates.
In step ~, the halo-alkl-Q reagent in a suitable organic solvent i5 added to the reaction mixture containing a metal salt, i.e., R3=alkali-metal ion,and the reaction mixture is heated until reaction is complete. Solvents used to dissolve the reagent are generally the same as used for the carrier in step 1, except when Q is pyranoyloxy =
-0-CHCEI2C~2CH2CH2, halo or -N=CH~OC2H5, dimethylformamide is used. The reaction mixture is filtered to remove halo salt by-product.
In step 4, the products may be isoLated, a) by extraction, preferably by partitioning between water and methylene chloride; b) by chromatographic separation, c) by conversion to acid addition salts and recrystallizing from suitable solvent or solvent combinations; d) by dissolving the strong acid salts such as the hydrochlorlde in water and extracting out impurities with a solvent such as toluene.
~0 In preliminary step A, compounds of Formula II are substantially separated from li~uid carrier by conventional means such as evaporating solvents and par~itioning between water and organic solvent, iltering to remove titanium oxide, washing,drying and evaporating the solvent layer to ~5 give the product as residue which can be used directly in step 1. The product may be further purified by chroma-tography or recrystallization from organic solvents.

~ 3 ~25 A preferred procedure for conducting the combination of step~ 1 and 3 (i.e., when step 2 is not involved) iq to simultaneously add a tetrahydrofuran o~ dioxane solution of a compound of the formula o~ ~ r Z~
R

wherein Ar, R and z are as defined in step 1 and a slurry of sodium hydride in toluene to a hot toluene solution o.f a pyridine compound of the formula H2N~ " ^~

~ ~ Y
wherein X and Y are as defined in step 1 at a rate such that the tetrahydrofuran or dioxane i5 distilled away at about the same rate it is being added and thereafter adding 0 a toluene solution containing a reagent having the formula halo-alkl-Q
wherein alkl and Q are as defined in step 3, except in the in the instance w~ere Q is -O-CHCH2CH2CH~CH2, halo or -N=OEI-OC2Hs in which case the solvent for the halo-alkl-Q
reagent preferred is dimethylformamide.
A preferred embodiment is the use in s~ep 1 of a mixture of compounds of said formula~
o~ Ar ~ C and H2~ ~

III . IV
Another preerred embodiment is the use in step 1 of a mixture of compound~ of formulas III and IV and a strong base consisting of sodium hydride.

~6 ~ 3~ ~ 425 A furthex preferred embodiment is the use in step 1 of a mixture of compounds of formulas III and IV wherein R is H.
A still further preferred embodiment is the use in step 1 of a mixture of compounds o formulas III and IV
wherein R is H and the strong base is sodium hydride.
~ nother preferred embodiment is the use in step 1 of a mixture of compounds of formulas III and IV consisting o 2-aminob~nzophenone and ~-amino-2-chloropyridine and a strong base cons isting of sodium hydride in step 1 to produce the sodium salt of 6-phenyl-llH-pyrido~2,3-b]
~1,4~benzodiazepine in step Z.
As an extension of the process outlined in steps 1-4 above with or without optional step A, the following further optional steps (see Chart II) are novelly employed to obtain certain compounds of Formulas I and Ip in steps 5 to 8. As will be recognized, the generic sccpe of compounds preparable is extended to include R=OH, -alkl-oSO2-alkyl, alk1-OSO2-phenyl and one or both of Rl and R2 are H.
Step 5, reacting a novel compound obtained in step 4 of the formula Ar >~
~ ~ ~

Ie alkl-O-CHCH2CH~CH~CH2 wherein Ar~ Y, z and alkl are as defined under Formula I
~0 with a strong concentrated acid in protic solvent, pre~erabLy e~hanol, to give a novel compound of the formula Ar alklOEI
I~

353 ~2 w~erein Ar, Y~ z and alkl are as defined above.
Step 6, reacting a compound prepared in step 5 with thionyl chloride to obtain a compound of the formula Ar Z ~ y Ib alkL-chloride wherein Ar, Y, Z and alkl are as defined above.
Step 7, reacting a compound prepared in step 5 with a reagent WSO2Cl wherein W i~ loweralkyl, phenyl or tolyl to give a compound of the formula Ar ~ N
Z-~Y
Ig alkl-OS0zW

wherein Ar, Y, Z, alkl and W are as defined above.
Step 8, reacting a compound prepared in steps 6 or 7 with a secondary or primary amine of the formula HNRlR2 wherein Rl and R2 are selected ~rom hydrogen, loweralkylg and -NRlR2 may be a heterocyclic radical as defined under Formula I, to give a compound of the formula ~ Ar Z- ~ ~ ~N
alklNRlR2 ~5 w~erein Ar, Y, Z, alkl and Rl, R2 and -NRlR2 are as deined above.

- ~ f ~25 Primary amines may be prepared by reacting compounds wherein ~NRlR~ is phthalimido with hydrazine hydrate and acid ~r ~ N

alkl ~H2 Compounds prepared by the process wherein Q is ~MHC(O)O-loweralkyl may be reacted with lithium aluminum hydride to prepare secondary amines of the formula Ar ~ N
Z~l~
alklN-CE9 Compounds wherein Q is -~=CH-OCzH5 may also be reacted with sodium borohydride to prepare secondary amines.

3~ 3 The following preparations 1 and 2 illustrate the method for preparing ary,-(2-amino-substituted-phenyl) methanone of Formula ~II wherein R is other than hyarogen (see Chart II) and are not to be construed as being limiting in nature.
PreParation 1 ~ 2-~3-(Dimethylamino)propyl]aminO]phenyl]phenyl-methanone monohydrochloride.
- To a mixture of 78.8 g (004 mole) of 2-aminoben~o-phenone, 160 g (4.0 mole) of crushed sodium hydroxide and 8 g of tetra-n-butyl ammonium bromide was added a dry solution of 145.8 g (1.2 mole) of 3-dimethylaminpropyl chloride in 700 ml of tetrahydrofuran. The mixture was stirred mechanically and was maintained at reflux overnight.
The tetrahydrofuran solution was decanted and concentrated.
The concentrate was dissolved in toluene. The solid from which the tetrahydrofuran was decanted was dissolved in water and extracted with the toluene solution. The resulting toluene layer was separated and washed twice with water and th~n extracted three times with portions of 20% acetic acid totaling 600 ml. The combined acetic acid solution was washed once with tol~ene and then made basic with 50~ sodiu-m hydroxide in the presence of toluene. Th~
a~ueous layer was separated and extracted once with toluene.
The toluene layers were combined and washed with water, dried over sodium sulfate and evaporated to give 112.8 g (100~) of nearly pure ~ee base o the title compound. A
20 g sample was dissolved in 75 ml of isopropyl alcohol to which was added o.o76 mole of hydrogen chloride dissolved in about 35 ml isopropyl alcohol. Additional isopropyl alcohol and isopropyl eth,r (about 1:1 ratio) were added to make a total volume of about 200 ml. The mixture was stirred overnightO The yellow solid was collected by filtration, washed once with 1:1 isopropyl alcohol/
isopropyl ether and twice with isopropyl ether. Weight of product obtained from the 20 g samrle was 16.4 a.
m.p. 182-183C.

353 ~25 Analysis: Calculated for Cl8H23~zOCl C,67.81; H,7.27;
~,8.79 Found : C,67.68; ~,7.29;
N,8.70 PreParation ?
Following the procedure of Preparation 1 but substi-~uting the following for 3-dimethylaminopropyl chloride, 3-(1-pyrrolidinyl)propylamine, ~ -(l-piparidinyl)propylamine, and 3-(4-morpholinyl)propylamine, there are obtained:
[2-~3-(l-pyrrolidinyl)pxopyl]amino]ph2nyl]phen methanone, ~2-~3~ piperidinyl)propyl~amino]phenyl]phenyl-methanone, and ~2-~C3-(4-morpholinyl)propyl]amino]phenyl]phenyl-methanone.

The following examples are provided merely by way of illustration and are not to be construed as being limiting in nature.

~-c(2-Aminophenyl)phenylmethylene]-2-chloro-3 pyridinamine.
To a stirred suspension o ~.94 g (0.02 mole) of 2-aminoben~ophenone and 2.58 g (0~02 mole) of 3-amino-2-chloropyridine in 20 ml of toluene and 6.2 ml (o.o48 mole) of triethylamine under a nitrogen blanket in an ice bath was added a solution of 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of toluene over a 5 min period. After the addition was complete, the ice bath was removed. The mixture became dark red in color and solid material was in evidence. About 15 ml of toluene was added followed by 15 ml o methylene chloride. After 1 hr total time, TLC showed starting material and product were present. Ater ~ hr total time, additional titanium chlorideg1.52 g (o.o8 mole), in 4.15 ml (0.032 mole~ of triethylamine and methylene chloride was added to the reaction mixture which was th~n stirred overnight. The mixture was evaporated. The residue was partitioned between water and methylene chloride. Solid precipitate was removed by filtration. The aaueous layer was separated and extracted again wikh methylene chloride. The methylene chloride layers were combined and back washed with sodium chloride solution, dried over sodium sulate and evaporated to give 6.2 g of orange oil. The chemical ionization mass spectrometer gave product peak at m/e 308 and starting materials peaks at m/e 198 and m/e 1290 NMR
analysis as follows indicated the product was composed of about 75% of the title compound. The lH~MR spectrum of the crude subject product was obtained in CDC13 containing 1~ tetramethylsilane (T~1~). The chemical shifts, multi-~5 plicities and assianments are ~i~ten belo~.

3~ 3 425 Mixture C~H5 and A B C

Chemical Shifts ~muLtiplici~ie~) at_ppm Assignments 7.50 (multiplet) Ha in Compound A
7.~5 (multiplet) Hb in Compound B
7.30-5.95 (multiplet) signals from other protons attached to carbons on Compounds A, B and C

5 ~ (broad singlet) -~H signals 4.83 (singlet) CH2C12 (methylene = chloride) Ratio o~ the integrations at 7.50 ppm to ~hat at 7.35 ppm is roughly 3:1, thus the product iq about 75% A.
Example 2 N-r(2-Aminophenyl pyridinamine.
To a stirred suspension of 7.88 g (0.04 mole) of 2-aminobenzophenone and 5.14 g (0.0~ mole) of ~-amino-2-chloropyridine in 100 ml of methylene chloride and 27.2 ml (0.2 mole) of triethylamine undex nitrogen blanket was added a solution of 5.28 ml of titanium tetrachlo~ide in 20 ml of methylene chloride dropwise over a 10 min period. The reaction mixture was stirred at room temperatur2 for 22 hr. Water was added slowly to the reaction mixture until a thick suspension was formed. The suspension was poured into 150 ml of water and the resulting mixture was stirr~d ror ;7 min. ~he mixtur~ was filtered to remove ti~anium dioxide. The filter cake was rinsed with ~5 methylene chloride. The organic layer of the filtrate was separated. The aqueous layer was extracted once with methylene chlorîde. The methylene chloride layers were combined, washed with dilute sodium bicarbonate solution, dried and evaporated to give 12.6 g of brown syrup. MMR
analysis as follows indicated the product was composed mainly of title compound with about 15~ 3-amino-2-chloro-pyridine starting material contaminant. The lHNMR spectrum of the crude subject product was obtained in CDC13 containing 1~ ketramethylsilane (TMS). The chemical shifts, multiplicities and assignments are given below.

Mixtu~e of CBH5 ~ ~ , Hb ~ H
Ha A B C

Chemical Shi~ts ~multiplicities) Assiqnments at Ppm 7.70 (multiplet) Ha in compound A
7.55 (multiplet) Hb in Compound B
5.55 (broad singlet) ~H 3ignals 5.00 (singlet) CH2Cl2 (methylene ~ chloride) 7.40-610 (multiplet) signals from remaind~r of protons on Compounds A, B and C.
Ratio of the integrations at 7.70 ppm to that at 7.55 ppm is roughly 13 to 2; thus the product is about 85% A.
Example ~
3a Following the procedure of Example 2 but substituting the following for 3-amino-2-chloropyridine, 4-amino-3-chloropyridine, 3-amino-4-chloropyridine, and 2-amino-5 chloropyridine there are obtained:

. 42 a~ (2-aminophenyl)phenylmethylene~-3-chloro-4-pyridineamine, b) N-C(2-aminophenyl)phenylmethylene]-4-chloro-3-pyridinamine, and c) N-~(2-ami.nophenyl)phenylmethylene]-3-chloro-2-pyridinamine .
Exam~e 4 Following the procedure of Example 2 but substituting the ollowing for 2-aminob~nzophenone, 2-amino-4-chlorobenzophenone~
2-amino-4-methylbenzophenone, 2-amino-4-methoxybenzophenone, 2-amino-4~hydroxybenzophenone, 2-amino-4-nitrobenzophenone J
2-amino-5-chlorobenzophenone, 2-amino-4l-chlorobenzophenone, and 2-amino-4'-methylbenzophenone, there are obtained:
a) ~-~t2-amino-4-chlorophenyl~phenylmethylene]-2-chloro-3-pyridinamine, b) ~-[(2-amino-4-methylphenyl)phenylmethylane]-2-chloro-3-pyridineamine, c) ~-~(2-amino-4-methoxyphenyl)phenylmethylene]-2-chloro-3-pyridinamine, d) ~-[(2-amino-4-hydroxyphenyl)phenylmethylene~-2-chloro-3-pyridinamine, e) ~-~t2-amino-4-nitrophenyl)phenylmethylene]-2-chloro-3-pyridinamine, f) N-~(2-amino-5-chlorophenyl)phenylmethylene]-2-chloro-pyridinamine, g) ~-~(2-aminophenyl)-4-chlorophenylmethylene]-2-chloro-3-pyridinamine, and h) ~ C(2-aminophenyl)-4-methylphenylmethylene]-2-chloro-3-pyridinamine.

'-~2 r (2-Chloro-3-pyridinyl mino)phenylmethyl~phenyl~-N,~-dimethyl lj~-propanediamine.
To a mixture of 2.82 g (0.01 mole) of i2-C~-(dimethyl-amino)propyl~amino~phenyl]phenylmethanone and 1.29 g (0.01 mole) of 3-amino-2-chloropyridine, 6.2 ml (o.o48 mole) of triethylamine and 20 ml of methyl~ne chloride stirred in an ice bath under nitrogen atmosphere was added 2.28 g (0.012 mole) of titanium tetrachloride in 10 ml of methylene chloride during a 5 minute period. The mixture was then stirred at room temperature for 2 days during which time mass spec-CI showed little change in relative intensity of M.W. 129 (starting pyridine) and M.W. 393 (title product~.
Water was added to the reaction mixture and ~tirring was continued for 1.5 hr. The mLxture was filterad to remove solid and the filter cake was rinsed with methylene chloride. Saturated sodium chloride solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more sodium chloride solution.
The aqueous layer having a p~ of about 6 was basified to about pH 8-9 with potassium carbonate and then extracted twice with methylene chloride. The latter methylene chloride layers were washed with sodium chloriae solution.
All the methylene chloride extracts were combined, dried and evaporated to give 4.8 g o~ semi-solid product. TLC
o~ the product showed it contained very little starting 3-amino-2-chloropyridine. Mass SpecO analysis showed the presence of compounds with molecular weight corresponding to title product (39~), 3-amino-2-chloropyridine ~129) and triethylamine (102) but no r2-C~3-(dimethylamino)propyl~
amino]phenyl]phenylmethanone~ l~NMR ~pectrum in CDC13 containing l$ TMS indicated the product was mostly title compound and some triethylamine. ~o 3-amino-2-chloro-pyridine was seen. The chemical shi~ts, multiplicities and assignments are given below.

~ 3 4~5 A mixture of ~ 6H5 (C2Hs)3 ~T HCl Ha C~2CH2C~z-~(CH3~ 2 Chemical Shifts-(multiplicities) at ppm Assiqnments 9.85-9.40 (multiplet) ~H on A as well as TEt)3~.H
7.85 (multiplet) Ha 7.50-6.23 (multiplet) protons attached to aromatic rings 5.25 ( 9 inglet) CH2Cl2 (methylene = chloride) 2.25 (singlet) N(Me)2 (methyl group signal) 3.70-1.70 (multiplat) signals ~rom alkylene groups (-CH2-) on compound A as well as triethylamine 1.35 (triplet) methyl group signals on triethylamine Exam~le 6 2-L (2-Chloro-3-pyridinyl~mino)phenyl_ethyllphenyl~-~,M-dimethyl-1,3-propanediamine.
To a mixture of 6.~7 g (0.02 mole) of ~2 ~3-(dimethyl-amino)propyl~amino]phenyl]phenylmethanone and 2.57 g (0.02 mole) o~ 3-amino-2-chloropyridine, 16.8 ml (0.12 mole) of triethylamine in 80 ml of methylene chloride stirred in an ice bath under nitrogen atmosphere was added dropwise 2.64 ml (0.024 mole) of titanium tetrachloride in 20 ml of methylene chloride over a 10 min period. The mixture was allowed to cool to room temperature with concinue~ agica~ion~ l~ne roLlowing day cnemlcal ionization mass spectrometry showed that the reaction had essentially gone to completion with no starting methanone 3~ 3 ~25 compound present. ~LC showed little of the s~arting pyridine was present. The mixture was stirred over the weekend. Water was added to the reaction mixture and stirring was continued for 1.5 hrO The mixture was filtered to remove solid and filter cake was rinsed with methylene chloride. Saturated sodium bicarbonate solution was added to facilitate separation of layers. The methylene chloride layer was washed once with more bicarbonate solution. The a~ueous layer was washed with methylene chloride and all the methylene chloride extracts were combined, dried and evaporated to give 7.35 g (93.5%) of brown oil. The chemical ionization mass spectrometer gave a signal corresponding to a molecular weight of the title compound at m/e ~9~.5 and showed a trace of compound at m/e 282 (starting methanone ~ree base) and some compound at m/e 102 (triethylamine) and some compound at m/e 129.5 (staxting amino-chloropyridine). ~he lHNMR spectrum of the subject product was obtained in CDCl~ containing 1% tetra-methylsilane (TMS) and is consistent with the proposed structure and with methylene chloride as minor impurity.
~o signal from starting materials were detected~ The chemical shifts, multiplicities and assignments are given below.

arom. C H arom.

C~
\ CH2-C~2-CH~-~(CH~)2 c d e f ~5 Example 7

6-Phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine-11-pyranoyloxypropyl.
To a solution of 10.82 g (0.04 mole) of 6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine in 60 ml of dimethyl-formamide was added 3.2 g (0.08 mole) of sodium hydride as 60% suspension in mineral oil followed by 13.2 ml (0.08 mole) of 1-chloro-3-pyranoyloxypropane. Progress of the reaction was followed via TLC and an additional 0.7 g of 60% sodium hydride was added. After the reaction had stirred for about 3 days, a trace of starting pyrido-benzodiazepine remained. The reaction mixture was treated with aqueous ammonium chloride and extracted three times with toluene. The toluene layer was back-washed with water, dried) treated with activated charcoal and filtered. The filtrate was evaporated to give 22.8 g of black oil. The oil was passed through a short column of 45 g silica gel, eluting first with toluene and then toluene-ethyl acetate, Fraction A was concentrated to give 16.3 g of a mixture consisting of 85% title product and 15% 1-chloro-3-pranoyloxy propane + mineral oil + toluene. Fraction B
was concentrated to give 2,4 g residue. Mass spectra of Fraction A showed the following:
m/e 179 which is starting 1-chloro-3-pyranoyloxy propane used in excess, m/e 330 which is a fragment from the product, and m/e 414 which is the title product.

~2~ 2 ~ ~ 425 The lHNMR spectrum of the subject crude product was obtained and is consistent with the proposed structure and with toluene and l-chloro-3-pyranoyloxypropane. The chemical shifts, multiplicities and assignments are given below.

C~Hs f + Cl-CH2 -Cf 2 -Cd2 ~

CHz - CH2 - CH2-0 ~ d d f d H c + ~CeH3 Chemical Shifts (multiplicities) at ppm ~ E~
8.15 (multiplet) Ha

7.95-6.90 (multiplet) remainder of aromatic protons 4.58 (broad singlet) Hb 4.48 (broad singlet) ~Ic 4.25 (multiplet) d protons 2.35 (singlet) e protons 2.25-1.15 (multiplet) f protons Example 8 6-Phenyl llH-pyrido ~ ne-ll-A mixture of 3.6 g (o.oo88 mole) of 6-phenyl-llH-pyrido~2,3-b][1,4]benzodiazepine-11-pyranoyloxypropyl, 3.6 ml of 37~ aqueous hydrochloric acid and 15 ml of 190 proof ethanol was stirred overnight. Sodium hydroxide pellets, 1.7 g, was added and the mixture stirred until the pellets had disintegrated. The solvent was evaporated and ~he residue was partitioned between methylene chloride and water. The aqueous layer was extracted once more with methylene chloride. The combined methylene chloride layers were washed with water, dried and evaporated to give 2.93 g of brown oil which crystalliæed. The crystals were separated by filtration and washed with isopropyl ether-~25 petroleum ether. On drying, the yellow crystals weighed1.91 g, m.p. 131-13~C. Mass spectra of the product showed the following:
m/e 10~ which is isopropyl ether which was used as cry~talliæation solventg m/e 414 which is starting material, trace amount, and m/e 330 which is title product.
The lE NMR spectrum o the subject crystaLline product was obtained and is consistent with the proposed structure C~5~ and (cH3)2cHocH(cH3)2 b c a d The chemical shifts, multiplicities and assignments are given below~
Chemical Shifts (multiplicities) at Ppm Assiqnments

8.20-6.80 (multiplet) all aromatic protons 4.45-3.50 (multiplet) a protons ~.65 (where triplet centered) b protons 2.65 (singlet) d protons 2.15-1.65 (multiplet) c protons 1.10 (doublet) e protons Example 9 Nl-r 2-c~loro-6-L-(3-chloro-4-pyridinylimino)phenylmethylJ
phenyl~-M,~-dimethyl-1,3-propanediamine.
Following the procedure of Example 6 and substituting ~2-C~3-(dimethylamirlo)prop~,rl]amino]-6-chlorophenyl~phenyl-methanone, the title compound is prepared.

~2~
~Z3~3 ~7 Example 10 6-Phe~y~-llH-pyridoC?,3-bJ~l ~ nzodiazepine sodium Salt (Crude Mixture).
To a solution of 516 g (4 mole3 of 3-amino-2-chloro-pyridine in ~.8 liters of toluene were added simultaneously in batches a solution o~ 830 g (4.2 mole~ of 2-amino-benzophenone in 2~2 liters of pyridine and a slurry of 290 g ~12 mole) (as 60~ in mineral oil) of sodium hydride slurried in 500 ml of toluene over a 2 hr period at reflux.
Re~lux continued for 3 hr additional. Evolution of hydrogen was vigorous. After stirring overnight at ambient temperature, the mixture was heated to remove a volume of distillate o~ 3.8 liters which ~MR indicated to be 65 toluene and 35~ pyridine.
Example 11 6-Phenyl-llH-pyrido ~ ~-b~,4Lbenzodiazepine.
To the residual mixture in Example 10 was added cautiously a solution of 440 g (8 mole) of ammonium chloride in 700 ml of water (much foaming). The mixture was heated to remove 1.5 litsrs of distillate comprised of water, pyridine and toluene. To the residual solution was added 500 ml of toluene and the mixture heated a second time to remove 900 ml of distillate. To the residual solution 500 ml more toluene was added and the mixture was again heated to remove 500 ml of distillate. The orange residual slurry was diluted with 7.2 liters of tetrahydrofuran.
The mixture was filtered~ The cake was washed by slurrying in 3 liters of hot tetrahydrofuran and the slurry filtered.
The Xiltrates were combined and passed through a silica gel column. The eluent was concentrated and the residue ~0 slurried in isopropyl ether-toluene i3:1~. Brown-orange solid was collected by filtrationO The filtrate was concentrated and azeotroped with toluene to remove pyridine The xesidual solution was diluted with i~opropyl ether-t~ r.~ 1J ^r.~ V~ Vr1 -n-a;, I ~ CrC~G~ ~V Vb~airl yellow crystals. The combined yield of the title compound was 813 g (75~ based on starting materials in Example 10.

~ 3~ ~ 425 TLC analysis o the product gave a good comparative result with known title product.
ExamPle l?
~ -Dimethyl-6-phenyl-llH-pyrido~2,3-b~1,4~benzo-~
~ mixture of 920 g (3.4 mole) of 6-phenyl-llH-pyrido [2,3-b]~1,4~benzodiazepine prepared in Example 11 (and . another small run~ in 2 liters of toluene and 1.5 liter of tetrahydrofuran and 84 g (~.5 mole) of sodium hydride (as 60~ in mineral oil) was heated at reflux with vigorous evolution of hydrogen. The mixture became black-green in color. To the mixture was added a solution of 7.6 mole of 3-dimethylaminopropyl chloride in 2 liters of toluene and the reaction mixture was heated at reflux for 5 hr and then cooled overnight. The black-yellow mixture was filtered with difficulty mainly to remove sodium chloride. The ~iltrate was concentrated to remove all but about 1.5-2 liters of toluene. The residual toluene concentrate was diluted with 2 liters of methylene chloride and the solution washed with water. The washed solution was concentrated on a rotary evaporator at 80C. bath temperature. The remaining black syrup weighed 1400 g. The syrup was poured 910wly into a hot solution of 394 g (3.4 mole) of fumaric acid in 4 liters of isopropyl alcohol. The solution was treated with activated charcoal and filtered. The filtrate was seeded and refrigerated overnight. The yellow precipitate was collected by filtration and washed with a small amount of isopropyl e~her and dried to give 1491 g (93%) of the fumarate salt. The salt was dissolved in 17.2 liters of isopropyl alcohol and the solution was treated with 75 g of charcoal heated at reflux for 15 min and filtered through a column containiny 100 g of Celite which had been wetted with 200 ml of isop~opyl alcohol. Th~ filtrate was then stirred for 20 hr. The precipitate was collected ~y ~5 ~iltratjon wach~ng t~e f;lter C~ke ~?'th COld isopropyl alcohol followed by 3 liters of isopropyl ether and dried to give 1255 g (85%) of crystalline product. The crystals 2 3~ ~ 425 were triturated with 1 l1ter of isopropyl ether-methylene chloride (~:1 by vol.) and the mixture subjected to filtration. Tha cake was vacuum dried at 60C. overnight under high vacuum, m.p. 174-175C., uncorrected.
Ana1YSi5: Calculated for C27H28~04: CJ68~63~ H~5~97;
N, 11 .86 Found : C,60.48; H,6.00;
~911.80 Example 13 N,N~Dimethyl-6-phenyl-llH-pyridor2,3-b~l,4lbenzo-diazepine~ll-propanemine Fumarate ~
Preparation of Crude Free Base of Title Compound.
To a solution of 780 g (6 mole) of 3-amino-2-chloro-pyridine in 2 liters of toluene at re1ux was added simultaneously a solution of 1,320 g (6.6 mole) of 2-amino-15 benzophenone in 3 liters of tetrahydrofuran and a slurry o~ 444.0 g (18.5 mole) of sodium hydride in 1.2 liters of toluene over a 3 hr period. (During the addition at reflux, the tetrahydrofuran distilled out at about the same rate it was being added). To the reaction mixture was added 12 moles of 3-dimethylaminopropyl chloride in 3.5 liters of toluene. The mixture was heated at reflux for 5 hr then was allowed to COO1J standing overnight at ambient temperature. TLC indicated some 6-phenyl-llH-pyrido~2,3-b~
rlg4]benzodiazepine was present; ~herefore, 12 g more sodium hydride was added and the mixture was heated at re~lux to complete the reaction. The mixture wa~ allowed to cool somewhat and 2 liters of saturated ammonium chloride and 3 liters of water were added. The aaueous layer was discarded and the toluene layer was washed four times with 2 liters of water ~ach time. The toluene layer was con~entrated on a rotary evaporator and finally subjected to high vacuum distillation to remove unreacted 3-dimethylaminopropyl chloride. Yield of crude syrup containing primarily the free base of the title compound was 2.680 g.

Conversion to Fumarate Salt and Purification Thereof . _ , The crude syrup was mixed with 6 moles of fumaric acid in 10 liters of isopropyl alcohol. The precipitate was collected and washed with 3 liters of isopropyl alcohol and recrystalli2ed twice to give 2,200 g of yellow crystals. A
sample triturate~ with a mixture of hot isopropyl ether-methylene chloride ~3:1 by volume~ gave the following analysis:
Analysis: calculated for C27H2aN~0~: C,68.63; H,5.97;
N,11.86 Found C,68.23; H,5.99;
N,11.87 Example 14 ~ imethyl-6-phenyl-llH-pyridor2,3-b1 r 1,4~benzo-diazepine~ propanamine Fumarate r 1 1] .
Preparation of Crude Free Base of Title Com~und To a solution of 129 g (1 mole) of 3-amino-2-chloro-pyridine in 350 ml of toluene at reflux was added simul-taneously a solution of 217 g (1.1 mole) of 2-aminobenzo-phenone in 500 ml of tetrahydrofuran and a slurry of 74.5 g (3.1 mole) of sodium hydride in 250 ml of toluene over a 1.5 hr period. (During the addition at reflux the tetra-hydrofuran distilled out at about the same rate it was being added). To the reaction mixture was added 2 moles o~ 3-dimethylaminopropyl chloride in 600 ml of tolusne.
The mixture was heated at reflux for 5 hr.
To the black slurry comprised of free base of the title compound and some unreacted sodium hydride and 3-dimethyl-aminopropyl chloride in toluene (shown by TLC to be free of any 6-phenyl-llH-pyrido~2,3-b]~1,4~benzodiazepine~ was ~0 added 1 mole of ammonium chloride in 800 ml of water. The organic layer was separated and washed with four 500 ml portions of water. The organic layer was concentrated on a rotoevaporator to remove solvent and under high vacuum to remove unreacted 3-dimethylaminopropyl chloride. Yield `
~5 of dark brown-yellow syrup comprised principally of free base of the title compound was 433 g.

. , . , 425 Conversion to Fumarate Salt The syrup was dissolved in 800 ml of isopropyl alcohol and to the solution wa~ added 1 mole of fumaric acid in 1.5 liter3 of isopropyl alcohol. The salt crystallized by seeding and separated by filtration.
Example 15 6-(2-Thien~l~-llH-p~idor2,~-b~1,4]benzodiazepine.
Following the procedurss of Examples 10 and 11 but substituting 2-aminophenyl-(2-thienyl)methanone in Example 10 for 2-aminobenzophenone, the title compound is obtained.
Example 16 6-~-Thienyl)-llH-pyrido[2~3-b1rl,41benzo_iazepine.
Following the procedures of Examples 10 and 11 but substituting 2-aminophenyl-(~-thienyl)methanone in Example 10 for 2-aminobenzophenone, the title compound is obtained.
Example 17 6-t2-PYridiny~l)-llH-pyrido~2~3-b~ 4lbenzodiazepine.
Following the procedures of Examples 10 and 11 but substituting 2-aminophenyl-(2 pyridinyl)methanone for 2-aminobenzophenone in Example 10, the title compound is obtained.
a~E~ 8 6-(3-pyridinyl?-llH-pyrido~2~3-b]~l~4lbenzodiazepine .
Following the procedures of Examples 10 and 11 but substituting 2-aminophenyl-(~-pyridinyl)methanone for 2-aminobenzophenone in Example ~0, th~ title compound is obtained.
Example 19 ~0 6-(4-Pyridinyl)~ -pyrido~2,~5-bl~1,41benzodia7.epine.
Following the procedure3 of Examples 10 and 11 but substituting 2-aminophenyl-( -pyridinyl)methanone for 2-aminobenzophenone in Example 10, the ~itle compound is obtained.

~xample 20 Following the procedure of Example 12 but substi-tuting the following for 6-phenyl-llH-pyridoC2,3-b]~1,4]
benzodiazepine:
6-(2-thienyl)-lH-pyrido~2,3-b~1,4]benzodiazepine, 6-(3-thienyl)-llH-pyrido~2,3-b]~1,4~benzodiazepine, 6-(2-pyridinyl)-llH-pyridoc2,3-b][1,4~benzodiazepine, 6-(3-pyridinyl)~ -pyridoC2,3-b~1,4]benzodiazepine, and, 6-(4-pyridinyl)-llH-pyr~do[2,3-b]~1,4~benzodiazepine, there are obtained:
a) ~ dime~hyl-~-(2-thienyl)-llH-pyrido~2,3-b~[1,4]
benzodia~epine-ll-propanamine fumarate, b) N,N-dimethyl-6-(3-thienyl)-llH-pyrido~2,3-b][1,4]
benzodia~epine-ll-propanamine fumarate, c~ ~,N-dimethyl-6-(2-pyridinyl)-llH-pyrido~2,3-b][1,4]
benzodiazepine-ll-propanamine fumarate, d) ~,~-dimethyl-6-(3-pyridinyl)-llH-pyridor2,3-b]rl,4]
benzodiazepine-ll-propanamina fumarate, and e) N,N dimethyl-6-(4-pyridiny~ lH-pyrido~2~3-b]~l~4]
ben~odiazepine-ll-propanamine fumarate.

Following the procedure o Example 5 but substituting the ~ollowing for ~2-~c3-(dimethylamino)propyl]amino]
phenyl~phenylmethanone:
~2-~3~ pyrrolidinyl)propyl~amino~phenyllphenyl-methanone, ~2-~3-(1-piperidinyl)propyl]amino]phenyl]phenyl-methanone, and c2-~C3-(4-morpholinyl)propyl~amino]phenyl]phenyl-methanone, there are obtained:
~-~2-~(2-chloro-3-pyridinylimino)-3-(1-pyrrolidinyl) propanamine, N-~2-~(2-chloro-3-pyridinylimino)-3-(1-piperidinyl) propanamine, and N-~2-~(2-chloro-3-pyridinylamino]-3-(4-morpholinyl) propanamine, 3~ 425 ~3 Example 2?
M,~-Dimethyl-6-phenyl-llH-pyrid~I2,3-b~[1,41benzo-diazepine~ propanamine Fumarate r 1 11 To a solution of 2.5 g t0.00637 mole) of ~ 2-~(2-chloro-3-pyridinylimino)phenylmethyl]phenyl]-N,N-dimethyl-1,3-propanediamine obtained in Example 5 in 20 ml of toluene (solution was dried by azeotroping using a Dean Stark trap and cooled) was added 0.62 g (0.0128 mole) of sodium hydride as 50% mineral oil suspension added to a small amount of toluene. The mixture was heated at reflux for 3 hr. Water was added cautiously. The toluene layer was washed twice with water and extracted twice with 1 N
aqueous hydrochloric acid solution. The aqueous acidic layer was washed with toluene. The aqueous layer was then basified with 50~ sodium hydroxide solution in the presence O~ toluene. The aqueous layer was extxacted twice with toluene. The toluene layers were combined, charcoaled, filtered and evaporated to give 2.03 g o~ brown oil, the free base of the title compound (89.5% yield). The oiL
was dissolved in isopropyl alcohol and 0.7 g fumaric acid was added with warming. The solution was seeded with known title compound and allowed to stand about 15 hr at room temperature. Isopropyl ether was added with stirring for 15 min9 The solid was collected by filtration and washed once with isopropyl alcohol-isopropyl ether mix and once with isopropyl ether. On air drying, 2.4 g (80O , m.p.
168-170C. was obtained. Th~ melting point, ~MR analysis and Mass Spec. analysis were comparable to known title compound.
Example ? 3 Following the procedure of Example 22 but substituting the following for ~ 2-~(2-chloro-3-pyridinylimino)phenyl-methyl~phenyl]~ -dimethy~ 3-propanamine:
~-~2-C(2-chloro-3-pyridinylimino)-3~ pyrrolidinyl) propanamine, M-~2-~(2-chloro-3~pyridinylimino~-3-(1-piperidinyl) propanamine, and 2~;~ 3~ ~ 425 M-~2-C(2-chloro-3~pyxidinylimino)-3-(4-morpholinyl3 propanamine, there are obtained:
6-phenyl-11-C3~ pyrrolidinyl)propyl]-llH-pyrido-5~2,3-b~1,4]benzodiazepine fumarat2, 6-phenyl-11-C~-(l-piperidinyl)propyl]-llH-pyrido ~2~3-b]~l~4~benzodiazepine fumarate, and 6-phenyl-11-~3-(4-morpholinyl)propyl]-llH-pyrido ~2~3-b]~l~4]benzodiazepine fumarate, using ethanol-e~hyl acetate recrystallizing solvent in the latter.

. ~

Claims (13)

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

1. A compound of the formula:
(IIIb) (wherein:
Ar is 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals which are the same or different and are selected from the group consisting of halo, loweralkyl, loweralkyoxy, trifluoromethyl and nitro;
Z is hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro;
alkl is a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms;

Q2 is -NR1R2, -N=CH-OC2H5 or ; and R1 and R2 are each C1-8 alkyl or C(O)-O-C1-8 alkyl 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-morpholino, 1-piperazinyl and 4-substituted-1-piperazinyl, in which the substituent in the 4-position is C1-8 alkyl or C1-8 alkoxy-carbonyl, provided that, alk1 is not a hydrocarbon chain containing 1 to 3 carbon atoms when Q2 is -NR1R2 and R1 and R2 are each C1-8 alkyl or R1 and R2 taken together with the - 45a -adjacent nitrogen atom form a heterocyclic residue selected from the group consisting of 1-piperidinyl, 1-pyrrolidinyl and 4-morpholino; notwithstanding the foregoing proviso, however, {2-[3-(dimethylamino)propylamino]phenyl}phenylmethanone is not excluded), or an acid addition salt thereof.

2. A process for producing a compound of the formula (IIIb):
(IIIb) (wherein:
Ar is 2-, 3- or 4-pyridinyl, 2- or 3-thienyl, phenyl or phenyl substituted by 1 to 3 radicals which are the same or different and are selected from the group consisting of halo, loweralkyl, loweralkyoxy, trifluoromethyl and nitro;
Z is hydrogen, halogen, loweralkyl, loweralkoxy, hydroxy or nitro;
alk1 is a straight or branched hydrocarbon chain containing 1 to 8 carbon atoms;

Q2 is -NR1R2, -N=CH-OC2H5 or ; and R1 and R2 are each C1-8 alkyl or C(0)-0-C1-8 alkyl or R1 and R2 taken together with the adjacent nitrogen atom form a heterocyclic residue selected from the group consisting of - 45b -1-piperidinyl, 1-phthalimido, 1-pyrrolidinyl, 4-morpholino, 1-piperazinyl and 4-substituted-1-piperazinyl, in which the substituent in the 4-position is C1-8 alkyl or C1-8 alkoxy-carbonyl) or an acid addition salt thereof, which process comprises reacting a compound of the formula:
(IIIa) (wherein Ar and Z are as defined above), with a halide of the formula:
X - alk1-Q2 (wherein X is halogen, and alk1 and Q2 are as defined above), in a reaction inert solvent, and if desired, converting the thus-obtained product into an acid addition salt thereof.

3. The process as claimed in claim 2, wherein the reaction is carried out in the presence of an acid acceptor and a quaternary ammonium compound.

4. The process as claimed in claim 3, wherein sodium hydroxide and tetra-n-butyl ammonium bromide are used as the acid acceptor and the ammonium compound, respectively.

5. A process for the production of [2-[3-(dimethyl-amino)propylamino]phenyl]phenylmethanone or an acid addition salt thereof which process comprises:
reacting 2-aminobenzophenone with 3-dimethylaminopropyl halide in a reaction inert solvent, and if desired, converting the thus-obtained product into an acid addition salt thereof.

6. The process as claimed in claim 5, wherein 3-dimethylaminopropyl chloride is used as the halide.

7. The process as claimed in claim 6, wherein the reaction is carried out in the presence of sodium hydroxide and tetra-n-butyl ammonium bromide.

8. (2-[3-(Dimethylamino)propylamino]phenyl)phenyl-methanone or an acid addition salt thereof.

9. The compound as claimed in claim 1, wherein Q2 is -NR1R2, R1 and R2 are each C1-8 alkyl or R1 and R2 together with the adjacent nitrogen atom form the heterocyclic residue defined in claim 1, provided that alk1 is not a hydrocarbon chain containing 1 to 3 oarbon atoms when R1 and R2 are each C1-8 alkyl or R1 and R2 together with the adjacent nitrogen atom form 1-piperidinyl, 1-pyrrolidinyl or 4-morpholino.

10. The compound as claimed in claim 1, wherein Z is hydrogen.

11. The compound as claimed in claim 1, wherein Ar is phenyl, chlorophenyl or fluorophenyl.

12. The compound as claimed in claim 1, wherein:
Ar is phenyl, chlorophenyl or fluorophenyl;
Z is hydrogen;
Q2 is -NR1R2; and R1 and R2 are each C1-8 alkyl or R1 and R2 together with the adjacent nitrogen atom form a heterocyclic residue selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl and 4-morpholino, provided that alk1 is not a hydrocarbon chain containing 1 to 3 carbon atoms.

13. The compound as claimed in claim 9, 10 or 11, wherein alk1 is propylene.