Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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
-- 2 --
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
395
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:
-- 6
~ 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
NH2
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
395
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
395
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
11
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
595
12
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
395
13
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
14
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
395
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
16
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~,
395
17
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
18
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
19
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.
395
~ 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
395
~ ~~ 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
3 4-CH3-C6H4- EI H
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
33
26
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
27
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
28
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
395
3 3
~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 ~ ~
31
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
395
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
395
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~
36
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
37
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
395
~ 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
395
~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,
395
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
395
~3 ~ 3
41
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
42
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
395
:L~3~;3i~
43
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
44
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)
395
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
46
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
395
47
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
395
~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,
49
~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
395
433
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~
395
51
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~ ~
395
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
54
~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
395
3 ~ ~ ~
56
~) 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
395
57
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,
395
59
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 .
395
Table 2
~r N,(H)n
~Y
Ex-
R Ar Y ~ n Salt
1 H C8H5- H H O
2 H C~H5 E3 8-C1 O
3 H C8H5 H 9-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
1/2 H20
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
OC2H5
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 ~
1/
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
395
62
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
395
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:
100 250 5
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
66
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
CHART 5
~ 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)-.
70 -
CHART 6
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.
- 71 -
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
- 73 -
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
2 4 6 5 1 I H 2 3 H
--c~ - (CH3) 2
