Note: Descriptions are shown in the official language in which they were submitted.
~3~ 3
RAN 4008/301 k
The present invention relates to pyrimido-2-benza-
zepines o~ the general formula
R>= ~ ()n
N~ ~
X~3
wherein A is one of the groups
, . ..
~C--N/ ` =N/ ~ ~NH CH--N/
I T 'o f and l lower alkyl
( a ) ( b ) ( ~ ) ( d )
Bt/7.1.80
~ .
-- 2 --
R1 is hydrogen, chlorine, bromine, lower alkyl, the group
NR4R5, the ~roup -CH2-Co-R7, the group
-NH(CH~)mNR R9, hydroxy, lower alkoxy, mercapto or lower
alkyl mercapto,
. R3 is hydrogen, lower acyloxy or
hydroxy, X is hydrogen, halogen, trifluoromethyl, ethyl,
~-hydroxy ethyl or acetyl, Y i 9 hydrogen or halogen, R4
and R5 each are hydrogen or lower alkyl or, together with
the co-bonded nitrogen atom, represent a five to seven
10 membered heterocycle which may contain an oxygen or sulphur
atom or the group ~ N-lower alkyl, R7 i 9 hydroxy, lower
alkoxy or NR8R9, R8 and R9 each are hydrogen or lower
alkyl, n is O or 1 and m is 1 to 7, with the proviso that
(i ) when R3 is lower acyloxy or hydroxy, A is group
(a), X is hydrogen, halogen, tri~luoromethyl, ethyl
or acetyl and, i~ R1 representq the group
-NH(CH2)mNR8R9, then R~ and Rg each
are lower alkyl;
(ii ) when A is group (d) and R1 represents the group
-NH(CH2)mNR8R9, then R8 and R9 each
are lower alkyl; and
~i~ when n is 1, R is hydrogen, lower alkyl, lower
alkoxy, chlorine, bromine or the group -CH2-Co-R7
(wherein R7 is as above) and A is group (a) or
(b);
and pharmaceutically acceptable acid addition salts there
of. These compounds exhibit pharmacological activity as
30 anxiolytics and sedatives.
As used herein, the term "lower alkyl" means straight
or branched hydrocarOon groups having from 1 to 7 carbon
atoms, prefereably 1 to 4 carbon atoms such as methyl,
ethyl, propyl, isopropyl and the like.
~'
.- ~ 0 ,~,
~3~38 Ei3
-- 3 --
The term "halogen" represents all four forms thereo~,
i.e., fluorine, chlorine, iodine and bromine unless ex-
pressly indicated otherwise.
The terms "lower alkoxy" and "lower alkyl mercapto"
denote a moiety of the formula -0-lower alkyl and -S-lo-
wer alkyl, respectively, wherein lower ~lkyl is as above.
Where the term "heteroatom" or "carbon atom nucleo-
10 philes" is utilized there are meant moieties as described
in Belgian Patent No. 833,249.
The expression "pharmaceutically acceptable salt~3"
15 is used to include salts with both inorganic and orga-
~nic pharmaceutically acceptable strong acids, such as!
~ul~uric acid, hydrochloric acid, nitric acid, methane-
sulfonic acid and p-toluene sulfonic acid. Such salts
can be formed quite readily by those skilled in the art
20 with the prior art and the nature of the oompound to be
placed in salt ~orm in view.
Among the compounds of formula I, above, those whe-
rein A is group (a), above, and n is o are preferred.
Particularly preferred compounds o~ formula I are those
wherein A is group (a), above, n is o and
R3 is h~droaen and Rl is hvdro-
gen, lower alkyl, the group NR4R5 (wherein R4 and
R5 each are hydrogen or lower alkyl), hydroxy,
chlorine, bromine, the group -NH-(CH2)mNR8R9 (wherein
R8 and R9 each are lower alkyl) or the group
-CH2-Co-R7 (wherein R7 is as above), with hydrogen9
amino and lower alkyl being especially preferred;
or
35 - R3 is hydroxy and R1 is hydro-
gen, lower alkyl or the group NR4R5 (wherein R4 and
R5 each are hydrogen or lower alkyl).
~l3~
4 -
Furthermore, those among the compounds of formula
I are preferred wherein X is halogen, with chlorine being
particularly preferred, and/or wherein Y is hydrogen,
chlorine or fluorine.
A particularly pre~erred compound of the invention
is 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benza~
zepine.
Further examples of pre~erred compounds of the inven-
15 tion are
~ 9-chloro-7-(2-fluorophenyl)-5H-pyrimido~5,4-d][2]-
benzazepine;
-9-ohloro-7-~2-chlorophenyl)-2-methyl-5H-pyri.mido-
~5,4-d]~2]benæazepine;
-9-chloro~7-(2-fluorophenyl)-5H-pyrimido[5,4-d]~2]-
benzazepin-2-ol; and
-9-chloro-N,N-dimethyl-7-(2-fluorophenyl)-5H-pyrimi-
do[5,4-dj[2]benzazepin-2-amine.
In accordance with the present invention, compounds
of formula I and pharmaceutically acceptable acid addi-
tion salts thereof can be prepared by
a) cyclizing a compound of the general formula
`` ~13~3~63
>=N
N~
~jf \CH2--NH2
X~=O
¢~
wherein X and Y are as above and R11 is hydrogen,
lower alkyl or NR8R9 wherein R8 and R9 are as above,
or
15 b) dehydrogenating a compound of the general formula
R11
HN
X/~ III
~Y
Il I
wherein X, Y and R11 are as above,
or
c) reacting a compound of the general formula
~3~3
-- 6
S X~H--R ~l
~(oJp
~ ~y
W.
wherein X and Y are as above, p is O or 1 and R
reprasents di-lower alkyl amino,
with eyanamide,
15 or
d) reacting a compound of the general formula IV, above,
with a compound of the general ~ormula
NH
R1~ V
.
wherein R12 is hydrogen, mercapto, lower alkyl
mercapto, lower alkyl or NR R9 wherein R and R9
are as above,
or
e) reducing a compound o~ the general formula
~=N
N~
> I~
X/~ r~N
/ ~Y
~3 W
-;-
wherein x, Y, and Rl are as above,
or
~) lower-alkylating a compound of the general formula
R1
~=N~
~ Ib
~H
~ ~Y
wherein x, Y, and Rl are as above,
15 or
g) oxidizing a compound o~ the general formula
~13
/>
~ Ic
X~=N
~ y
W
wherein X, and Y are as above and R13 represents
hydrogen, lower alkyl, hydroxy, lower alkoxy, NR41R51
(wherein R41 and R51 each are hydrogen or lower alkyl
or, together with the co-bonded nitrogen atom,
represent a 5 to 7 membered heterocycle which may
contàin an oxygen atom), chlorine, bromine or the
group -CH2-Co-R7 ~wherein R7 is as above),
or
~3
"
~3~3
8 --
h) lower alkylating a compound of the general formula
~>=N
wherein X, Y and p are as above and R14 represents
merc~pto or hydroxy,
or
15 i) converting a compound of the general formula
H2N
>=N
N\\ /~
X~;> Ie
~ O)p
Il J
~
wherein X, Y and p are as above,
into the corresponding 2-hydroxy compound,
or
k) converting a compound of the general formula
~`
.
~8~316~
- _ 9 _
HO
>=N
, ~ I:f
X~N~
~Y
W
wherein X and Y are as above,
into a corresponding 2-chloro or bromo compound,
or
1) treating a compound of the general formula
R15
\\ /~
~ Ig
XJ~= ~
~ (O)p
wherein X, Y and p are as above and R15 represents
chlorine or bromine,
with hydrogen sulfide, with a lower alkylmercaptan, with
a lower alkanol, with a compound of ~ormula HNR~R5 w~erein
R4 and R5 are a3 above, with a compound of formula
30 H2N-(CH2)mNR8R9 wherein R8, R9 and m are as above or with
the carbanion o~ a compound of the formula
~ .
1 0 --
/COR71 CoR
CH2
coR7l or ~ OR
wherein R71 is lower alkoxy and R21 is as above,
or
10 m) converting a compound of the general formula
R71--CC)--CH2
/ \
lS X ~ Ih
(O)p
W
wherein R71, X, Y and p are a~ above,
into the corresponding free acid or into a corresponding
amide, lower alkyl amide or di-lower alkyl amide,
or
~ reacting a compound o~ the general formula
R16
~ Ii
~Y
~
wherein Y is as above, R16 is hydrogen,
chlorine, bromine, lower alkyl, the group NR4R5,
~,~3~3
the group -CH2-Co-R7, the group
-NH(CH2)mNR81R91 J hydroxy, lower alkoxy,
mercapto or lower alkylmercapto, X' is hydro~en,
halogen, trifluoromethyl, ethyl or acetyl, R 1 and
R91 each are lower alkyl and R4, R5 and R7 are as
above,
with a lower acylating agent or
o) hydrolyzing a compound of the genera:L formula
~16
>=N\
~.R31 Ik
15 X~N
~'
wherein X~, ~, and Rl6 are as above and R3
is lower acyloxy,
or
p) deoxygenating a compound of the general formula
R1 7
~ \
N\\ /)
Il
¢~Y
wherein X, and Y are as above, R17 is hydrogen,
lower alkyl, the group NR4R5, the group -CH2-CO R7,
..,, ...,~
3LIL~8~3
- 12 -
the group NH-(CH2)m-NR8R9, hydroxy, lower
alkoxy, mercapto or lower alkylmercapto and Rl, R5,
R7, R8 and R9 are as above,
or
q) removing the elements of H-Z from a compound of the
general formula
R~
~ '
¦~ III t
X~N~
W
wherein X, a~d Y are as above, R18 is hydro-
gen, lower alkyl, lower alkoxy, chlorine, bromine
or the group -CH2-Co-R7 ~wherein R7 is a~ above)
and Z represent~ hydrogen or an easily cleavable
ac~l group,
or
r) converting a compound o~ formula I into a pharma-
ceutically acceptable acid addition salt.
It will be appreciated and readily apparent to those
skilled in the art that when the compound to be subjec-
ted to any of the aforementioned reactions contains, in
addition to the groupls)involved in the reaction, groups
which may be vulnerable under the conditlons of such reac-
tion, then either a method for performing such reaction
has to be utilized which does not affect such vulnerable
group, if such method is available, or such vulnerable
group has to be protected before carrying out the reac-
'~'
~i~3~3
- 13 -
tion and thereafter the protecting group has to be remo-
ved.
Process embodiments a) and b), above, and the prepara-
tion of the startin~ materials therefor are, by way of
example, illustrated by the following Reaction Scheme
I wherein X, Y and R11 are as above:
2Q
~l3~ ;3
- 14 -
Reaction Scheme I
,~\~NH2 ~C02H ~C02CH3
_~ l l ~
5 XJ~ , ~; X/~ J~ X~ ~/ ~0
~ VI [~ YII ¦ ~VIII
CCH2CN ~CoO2C H3
X~ CH2CI ~ CH2CI
~ ~ X ~ IX
Rll
C--C-C N ~ C N
X~C~12CI X~O
[~ XI ~ XII
X ` ~ X ; ~ ;
In II
The compounds VI, VII and VIII are generically known
in the art. A method to produce them is included Eor com-
pleteness of disclosure.
~ VII
The compound of ~ormula VI which is a well-known
prior art compound is reacted with cuprous cyanide after
being previously treated with sulfuric acid, sodium ni-
~ trite and optionally sodium tetra~luorborate in seria-
tium. Thereafter the mixture is hydrolysed with an al-
kali metal hydroxide, e.g., sodium or potassium hydro--
xide at reflux temperatures.
15 VII~ VIII
The compound of formula VIII is formed by the re-
action of the carboxylic acid of formula VII which metha-
nol in the presence of an acid catalyst, such as, sulfu-
20 ric acid at about the reflux temperature of methanol forabout 3 to 18 hours.
VIII ~ IX
The compound of formula VIII is thereafter reacted
with 1-chloro-2,3-epoxy propane or other suitable epoxi~
de ketalizing reagents such as ethylene oxide and 1,2
epoxypropane in the presence of a Lewis acid, such as,
aluminum chloride or boron trifluoride or preferably stan-
nic chloride in an inert organic solvent, such as, to:Lu-
ene, carbon tetrachloride, or benzene. Suitable reaction
temperatures range from about 20C to 110C with about
25C being preferred.
- 16 -
IX ~ X
Thereafter the compound of formula IX i~ reacted
with acetonitrile (CH3CN) in the presence of an alkali
metal amide, such as, ~odium or potassium amide, in liquid
ammonia in the presence of an inert organic solvent, such
as, diethyl ether, tetrahydrofuran or dio~ane. Reaction
temperature may vary from about the reflux tempera~ure
of liquid ammonia to room temperature.
X --~ XI
The compound of formula X is thereafter reacted with
a dialkoxy acetal of dimethylformamide, such as, dimethyl-
15 formamide dimethylacetal. Suitable reaction temperaturesrange from about 25C to 120C with the reflux temperature
of the dimethylacetal as preferred.
XI~ XII
The conversion of the compounds of formula XI into
the compounds of formula XII involves ~wo steps, viz.
reaction with a suitable acid addition salt of an ami-
dine or guanidine of the formula
y
NH2
wherein R11 is as above,
and acid hydrolysis of the ketal function. Where X and
Y both are hydrogen, the acid hydrolysis of the ketal
function is preferably effected before the reaction with
the amidine or guanidine salt whilst where X and/or Y
is/are other than hydrogen, the acid hydrolysis of the
ketal function is preferably effected after the reaction
with the amidine or guanidine salt. By-products formed
3 ~
- 17 -
have to be removed from the reaction mixture before pro-
ceeding further.
The reaction with a suitable acid additional salt
of an amidine or guanidine of the formula Va, such as,
formamidine acetate, acetamidine hydrochloride, guanidine
carbonate or a substituted guanidine carbonate is expe-
diently effected in an aprotic polar organic sol~ent,
such as, dimethylsulfoxide at a temperature range of ~rom
10 about 25C to 125C with a pre~erred range of about 90
to 95C.
The ketal function is hydrolysed by means o~ an aque-
ous inorganic acid, such as, sulfuric, phosphoric or pre-
15 ferably a hydrohalic acid, such as, hydrochloric acidin the presence of a lower alkyl organic alcohol solvent,
preferably, ethanol. The reaction is run at about room
temperature.
20 XII~
The compound of formula II is formed by the hydro-
genation ~f the compound of formula XII in the presence
of a mekal catalyst such as platinum, palladium or Raney
25 nickel and cyclizes spontaneously to give compound In.
The hydrogenation may be carried out in a suitable or-
ganic solvent such as Iower alkyl organic alcohols or
lo~er alkyl carboxylic acids, i.e., acetic acid. Depen-
ding on the conditions used in the aforementioned hydro-
3~ genation, a dihydro pyrimido compound of formula III maybe formed in addition to, or instead o~, the compound
of formula In. This dihydropyrimido compound may be con-
verted into the compound of formula In by treatment with
a mild oxidizing agent, such as, manganese dioxide, air
and the like.
Process embodiment c) is, by way of example, illus-
- 18 -
trated by the following Reaction Scheme II:
H2\ (CH3) ~N
N~C113)~
X~=N X~=N .~. X~N
[3~Y ~Y ~Y
IVa Io Ip
IVa ~ Io and Ip
The compound of the formula IVa is known in the
prior art, see, for example, U.S. Patent Nos. 3,947,585;
- 4,022,800 and 4,028,381. The compound i9 reacted with
~5 cyanamide in a C1 to C4 alcohol, e.g., ethanol, at a
temperature range of about 25C to 80C with a preferred
temperature at rePlux of the particular alcohol chosen.
There is obtained a mixture of the amino compound
and the N,N-disubstituted amino compound which can be
separated by, e.g. ~ractional cry~tallization and/or chro-
matography.
Process embodiment d), above, involves the reaction
of a compound of formula IV with an amidine or guanidine
salt or with thiourea or an S-lower alkyl isothiourea.
For the reaction with the amidine or guanidine salt, any
:~13~ ;`3
, 9
inert organic solvent such as dioxane, tetrahydrofuran
or dimethylformamide may be utilized with a reaction tem-
perature ranging from about room temperature to reflux
temperature of the solvent with about room temperature
as preferred. The reaction with thiourea or with an S-
lower alkyl isothiourea oan be effeoted in the presence
of an alcoholic e.g., methanolic, solution of an alkali
metal alkoxide, e.g. sodium methoxide. The reaction may
be carried out at from about 0C to 65C with about room
10 temperature as preferred.
Process embodiments e) and f) are, by way of exam-
ple, illustrated by the following Reaction Soheme III,
wherein R11 is as above:
~ ~3~
- 20
Reaction Sc:heme III
X ~ lower alkyl
Io' Ip'
~ Rl1
X~H XIII
~/ ,
. . .
3~
- 21 -
In ~ Io'and In or Io ~ XIII
_ _ _
The compound of ~ormula In ~see Reaction Scheme I)
is treated with a reduoing agent ~uch a~ zinc in acetic
acid at a reaction temperature of about -40C to 20C
to give Io~. The solvent utilized may be a halogenated
hydrocarbon such as methylene chloride.
The compound of formula In or Io~is reacted with
10 hydrogen in the presence of platinum oxide or prehydro-
genated platinum oxide and as a solvent acetic acid to
give XIII. The reaction is normally run at about room
temperature.
Other u~eful reducing agents for proce~ embodiment
e) include sodium cyanoborohydride, qodium borohydrid~
and the like.
In many instance~, mixture~ o~ the 6,7-dihydro and
20 the 4,5,6,7-tetrahydro compound~ are obtained. The said
475,6,7-tetrahydro compounds also exhibit use~ul CNS pro-
perties.
Io` -~ Ipl
The compound of ~ormula Io~is reacted with formalde-
hyde in ~ormic acid with heating, e.g. about re~lux tem-
perature to methylate the dihydro compound. Methylation
can also be accomplished with e.g. methyl iodide, dimethyl-
sulfate or the like.
Lower alkyl substituents other then methyl may beproduced by utilizing the appropriate alkyl halides, sul-
fates, alkylsulfonates, tosylates or the like in a sol-
vent, such as, dimethyl-formamide, tetrahydrofuran, glyme
and diglyme, or etherial Qolvents or by utilizing the
appropriate aldehydes under reducing reaction conditions.
,~
~3~ 3
- 22 _
Process embodiment g) is, by way o~ example, illus-
trated by the ~ollowing Reaction Sche~e IV wherein R
is as above:
~3~ 3
_ 23
React~ on Scher~
11
X~,~=N~
¦ ~ In
R11
`2 ~
Iq o Ir
3~3~ti~
_ 2~ -
The compound of formula In is reacted with a Aui-
table oxidizing agent such as metachloroperbenzoic acid
in an inert organic solvent, such as, methylene chlori-
de. The reaction may be run at between about 0C to room
temperature with about room temperature as preferred.
The reaction time may be varied depending on whether the
N-oxide or di-N-oxide product is desiredO The N-oxide
Iq is produced predominantly where the reaction time i9
varied batween about 2 and 25 hours whereas the di-N
10 oxide Ir is produced in predominance where the reaction
time is between about 40 and 60 hours.
According to process embodiment h), above, a mer-
capto or hydroxy group is lower alkylated according to
15 methods known per se. The alkylation of the mercapto group
i9 expediently effected by means of an appropriate alkyl
halide in the presence of a mixture of an alkali metal
hydroxide, such as, sodium hydroxide and a C1 to C4
aloohol, such as~ ethanol. The reaction may be carried
20 out preferably at about room temperature.
.
The alkylatlon of the hydroxy group is expediently
effected with a dialkyl sulfate such as, dimethyl or die-
thyl sulfate in the presence of basic conditions, e.g.,
25 with sodium hydroxide present. The reaction may be run
at from about 0C to 65C with about room temperature
as preferred.
The conversion of a 2-amino compound into the corres-
ponding 2-hydroxy compound according to process embodi-
ment i), above, can be effected by means of an acid, such
as, sulphuric acid. The reaction temperature may be varied
from about 25C to 125C with about 100C as the preferred
temperature.
Other methods which may be used for this conversion
include alkaline hydrolysis and displacement of diazo-
.", . ,~ .
~L~3~
- 25 -
nium salts.
The conversion of a 2-hydroxy compound into the cor-
responding 2-chloro or bromo compound according to pro-
5 cess embodiment k), above, can be effected, reqpective-
ly, with a suitable chlorinating agent, such as, phos-
phorus trichloride at reflux temperature of the mixtu-
re, and with a suitable brominating agent, suoh as, phos-
phoryl bromide or phosphorus pentabromide at from about
10 room temperature to reflux.
According to process embodiment l), above9 the chlo-
rine or bromine atom in position 2 of the compound of
formula Ig can be displaced by nucleophilic substitution
15 with a number of heteroatom and carbon atom nucleophiles
such as methanol, 3-dimethylaminopropylamine, methylamine,
dimethylamine, N-methylpiperazine, the carbanion o~ die-
thylmalonate and the like, in an inert polar organic sol-
vent, such as, dimethylformamide at from 0C to reflux
20 temperature of the solvent, preferably at room tempera-
ture.
The conversion of a compound of formula Ih into the
corresponding free acid according to process embodimant
25 m), above, is e~pediently effected by hydrolysis under
alkaline conditions, e.g. by means of an a}kali or earth
alkali metal hydroxyde, such as, sodium or potassium hy-
droxide or the like, in the presence of a suitable ~ol-
vent such as a lower alkanol, e.g. ethanol.
The conver~ion of a compound of formula Ih into a
corresponding amide according to process embodiment m),
above, oan be effected either by treatment with ammonia
or an appropriate mono- or di-lower alkylamine at room
temperature or at an elevated temperature (suitably about
50-130C), in the presence of an inert organic solvent
such as a lower alkanol, e.g. ethanol, or by hydrolysis
_ 2~ ~
to the corresponding free acid, conversion of the free
acid into a reactive derivatiYe, such as an acid chlo-
ride or a mixed anhydride, and subsequent treatment o~
this reactive derivative with ammonia or an appropriate
5 mono- or di-lower alkylamine.
Process embodiments n) and o) are by way o~ example
illustrated by the following Reaction Scheme V wherein
X' Y R11 and ~31 are as above:
3~
l~lL3hB~i3
_ 27 ,.
Reaction Scheme V
R11 ' R11
31
Ig It
R11
25 ,~
Iu
~3~ 3
_ 28
Is ~ It
The compound of formula Is can be reacted with an
acid anhydride of a suitable carboxylic acid such as ace-
tic- or trifluoroacetic-anhydride. The reaction is pre-
ferably done at about the reflux temperature of the an-
hydride chosen. Instead of an acid anhydride, also an
acid chloride can be utilized.
l It -~ Iu
The compound of formula It can be reacted with an
alkali metal carbonate, such as, sodium or potassium car-
bonate in a C1 to C4 alcohol, such as, methanol at a
15 temperature range of about 0C to 65C with about room
temperature as preferred. Other reaction conditions
suitable for this step include the use o~ alkali metal
hydroxides, e.g., sodium or potassium hydroxide9 and a
C1 to C5 alcohol in the presence of water or, in the
20 alternative, an acid hydrolysis utilizing an aqueous mine-
ral acid such as hydrochloric or sulfuric acid with a
solvent such as THF or dioxane with a reaction tempera-
ture from about 0C to room temperature with 0C as
preferred.
The deoxygenation according to process embodiment
p), above, can be effected by methods known per se, e~g.
by means of reagents such as phosphorus trichloride, tri-
lower alkyl phosphites ~e~g. triethyl phosphite), hexa-
chlorodisilane, Raney-nickel and the like.
Process embodiment q), above, and the preparation
of the starting rnaterials therefor are, by way of exam-
ple, illustrated by the following Reaction Scheme VI,
wherein X, Y and R18 are as above and Z' represents an
easily cleavable acyl group:
~3~
_ 29
Reaction Scheme VI
R18 R18
~ Iv _ ~ XIV
X~N~H X~N~ ,
~ Iv ¢~
R18 ~,~ ~ R18 ~,~
>=N~ )~N~
~ f~ XVI -- f~ XV
X~/~N~ X~N~,
~ 18 ~,~ [3
3~=N
X'J~N~ Iw
~lL3~ ;3
- 30 -
Iv ~ XIV
Thls conversion involves an acylation utilizing a
suitable acylating agent to yield the easily cleavable
aoyl group Z', such as trifluoroaoetylchloride, p-tolue-
nesul~onylchloride, methanesulfonylchloride, the mixed
anhydride of formic acid and acetic acid, ethyl chloro-
formate, benzyloxycarbonylchloride and the like. The con-
ditions for carrying out an acylation of this kind will
10 be readily apparent to those skilled in the art.
XIV - ~XV
The compound of formula XIV is reacted with a suita-
15 ble oxidizing agent such as metachloroperbenzoic acidin an inert organic solvent, such as, methylene chlori-
de. The reaction may be run at between about 0C to about
room temperature with about room temperature as preferred.
The reaction time is between about 40 to 60 hours.
XV~ XVI
The acyl group Z' is split off by methods known per
se which are readily apparent to those skilled in the
art. The choice of the method to be utilized depends of
course, from the nature of the acyl group Z'0 Thus, for
example, the trifluoroacetyl or ethoxycarbonyl groups
can be removed by alkaline hydrolysis, the formyl group
by acid hydrolysis and the benzyloxycarbonyl group by
means of hydrogen bromide etc.
XVI or XV ~ Iw
The conversion of XVI into Iw involves a dshydroge-
nation which can be effected by methods known per se,e.g. by means of diethylazodicarboxylate or by N-halo-
- genation (preferably N-bromination) follo~ed by a dehy-
_ 31 ~
drohalogenation under alkaline conditions, e.g. by means
of a tertiary amine such as triethylamine.
When Z' in formula XV is a group such as tosyl or
mesyl, there can be carried out an elimination of H-Z'
under alkalîne conditions, e.g. by means of an alkali
metal alkoxide in the corresponding alkanol, such as,
methanolic sodium methoxide.
Any 7H-isomer of the compound of formula Iw formed
can be isomerised to the compound of formula Iw by treat-
ment with a suitable base, e.g. methanolic sodium metho-
xide.
For the sake of completness, the preparation of tho-
se among the intermediates of formula IV wherein p is
1 is, by way of example, illustrated by the following
Reaction Scheme VII wherein X and Y are as above:
~13~J3
Reaction Scheme VII
_
f ~HN(CH3)2 ~>
X~=N~a X/~\~N
~ IVb ~ X TII
O O
X~ t XJ~
¢~ XIX ~ XVIII
363
_33
The compound of formula XVII can be reacted with
a peracid such as, metachloroperbenzoic acid in an inert
organic solvent such as a halogenated hydrocarbon, e.g.
methylene chloride, or an ether. The reaction may be car-
ried out from about QC to 40C with room temperatureas preferred. The mixture of products may thereafter be
separated from one another by fractional crystallization.
Analysis by thin-layer chromatography indicates the
presence of both products.
The compound of Pormula XVIII can be reacted with
dimethylformamide dimethylacetal in an inert solvent,
such as, a halogenated hydrocarbon, e.g. methylene chlo-
ride, or dimethylformamide or high boiling ethers. The
15 reaction temperature may range from about 0C to 100C
with room temperature as preferred.
The pyrimido-2 benzazepines of formula I, above,
and their pharmaceutically acoeptable acid addition salts,
20 are useful as pharmaoeuticals and are characterized by
activity as sedative and anxiolytic agents. These com-
pound~ can be used in the form of conventional pharma-
ceutical preparations; for example, the aforesaid com-
pounds can be mixed with conventional organic or inor-
25 ganic, inert pharmaceutical carriers suitable for paren-
teral or enteral administration such as for example, wa-
ter gelatin, lactose, starch, magnesium stearate, talc,
vegetable oil, gums, polyalkylene glycols, ~aseline or
the like. They can be administered in conventional phar-
30 maceutical forms, e.g., solid forms, for example, tablets,dragees, capsules, suppositories or the like, or in liquid
forms, for example, solutions, suspensions or emulsions.
Moreover, the pharmaceutical compositions containing com-
pounds of this invention can be subjected to conventional
pharmaceutical expedients such as sterilization, and can
contain conventional pharmaceutical excipients such as
preservations, stabilizing agents, wetting agents, emul-
~8~3~i3
34 _
3ifying agents, salts for the adju3tment of 03motic pres-
sure, or buffers. The composition~ can also contain other
therapeutically active materials.
The following table ~hows the re~ult~3 obtained when
the following compounds were subjected to certain well-
known tests such a~ the inclined ~creen te~t, the foot
shock test, the unanesthetized cat test and the antipen-
tamethylenetetrazole test (metrazol test) as well as indi-
10 cations as to their toxicity:
A: 9-Ghloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido-
~5,4-d][2]benzazepine
15 B: 9-Chloro-7-(2~chlorophenyl)-5H_pyrimido[5~4_d]E2
benzazepine
C: 9-Chloro-7-t2-fluorophenyl)-5H-pyrimido[5,4-d][2]-
benzazepin-2~amine
D: 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-2-methyl-
5H-pyrimido~5,4-d][2]benzazepine dihydrochloride
E: 9-Chloro-7-~2-chlorophenyl)-4,5,6,7-tetrahydro 2-
methyl-1H-pyrimido~5,4-d][2]benzazepine dihydro-
chloride
F: 9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-2,6-dimethyl-
5H-pyrimido[594-d][2]benzazepine methanesulfonic
acid salt (1:2)
G: 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]-
benzazepin-2-ol
35 H: 9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]-
benzazepine
rl~',~
.~
;i3
I: 9-Chloro-7-(2-fluorophenyl)-2-methoxy-5H-pyrimido~
[5,4-d][2]benzazepine
K: 9-Chloro-7-(2-fluorophenyl)-N,N-dimethyl-5H-pyrimi-
do;[5,4-d][2]benzazepin-2-amine
~5
~L3~
7~ H t~ ~ 3 _ ~ (~ ~ :: ~
_ _ _ _ _ _ _ _ _ _
V V V V V V V V V 9 H
~P ~ .P ~ .P .P ~ IP ~ .C~ Q n
8 8 8 8 8 8 8 8 Y o ~
E~ ~ g g 3
;~' ~ ;~' ;~ ~ ;~ ~ ~ ;~' ~ O U~
~4 ~ ~a ~4 l~l ~ ~:1 _ Q
~ ~a ~ ~ ~a ~a ~1:1 ~ ~0 1~
O O O O O O O O O O ::S
_ _ _ _ __
I_ V W ~ ~3 ~
o o ~ o 8 8 o Y ~n ~Db n O
a g g U:~ g g g g E3 g 1~ g ~
;~ ~ ;~ ;~ ~ 7~ 7¢ x ~ ;~ ~ o~ n
q a ta la ~ ~ ~a
o o o o o o o o o o
_ _ _ _ _ _ __
O O I_ O V ~ O r~
ll . ul ~ tD
g g ~ ~ ~4 g .
' 1
~q ~ ~ ~ ~ ~ ~q
o ,o o o o o o o
_ _ _ . _ _ _ ~ __ .
~ ~ ,o ~ ~, ~ ~ ,o ,o ,o ~ ~
W ~ ~I W Ul Ul ~I ~
~, ~ ~o ~ ~ ~t
~ 3 ~ ~ ~ g g g g g ~z~ o
a ~ ~ ~ 4 ~q ~q ~ (4 ~q o
~ ~a ~ ~a ~ ~a ~ ~ ~
o o o o o o o o o o
. . . . . . . . . .
. . _ _ ~ . _ __
~ ~ v I v v ~ a ~03
oo 8 o o 8 ~ oo 8 8 8 n x
o o o o o o o o o ~ t).
a g g g g g ~ g 3 3 t~ ~
O
~4 ~ ~ ~R ~ ~ ~ ~ ~q ~q
~a ~ ta ~ ~a ~ ~a ~ ta
o o o o o o o o o ~o
l- ll v l- v ~
c~ o o o ~ l- w l- o ~
8 g 8 8 o o o 8 8 o
g g g ~ a 3 a a g B
X ~ ;¢ ~ ;c ~ ~
a ~4 ~4 ~ ~ ~a ~ ~a
~- 1~. 1.. ~' 1- ~' 1' 1'- 1' ~'
. . . . . . . . . .
3i3
A suitable pharmaceutical dosage unit can contain
from about 1 to about 500 mg of a compound o~ ~ormula
I or a pharmaceutically acceptable acid addition salt
thereo~ with a dosage range of from about 1 mg to about
100 mg being the pre~erred oral administration and a do-
sage range of from about 1 mg to about 50 mg being prefer-
red for parenteral administration. However, ~or any parti-
cular subject, the specific dosage regimen should be ad-
justed according to individual need and the professional
10 judgment o~ the person administering or supervising the
administration of the aforesaid compounds. It is to be
understood that the dosages set forth herein are exem-
plary only and that they do not, to any extent, limit
the scope or practice of this invention.
The term "dosage unit" as employed throughout this
specif`ication refers to pharmaceutically discrete units
suitable as unitary dosages ~or mammalian subjects each
containing a predetermined quantity of active material
20 calculated to produce the desired therapeutic ef~ect in
association with the required pharmaceutlcal diluent,
carrier or vehicle.
The following examples are illustrative, but not
limitative o~ this invention. All temperatures given are
in degrees centigrade, unless indicated otherwise.
3L~3~
38
Example 1
2-Amino-9-chloro-7-phenyl-5H-pyrimido[5,4-d] [2] benzazepine
A stirred suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4-
(dimethylaminomethylene)-l-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047
5 mol) of guanidine carbonate in 250 ml of methanol was treated at room
temperature, under argon, with 5.1 g (0.094 mol~ of sodium methylate in one
portion. Methylene chloride (150 ml) was added after 10 min and stirring WRS
continued. The same quantities of sodium methylate and guanidine carbonate
were added two more times at 2 hr intervals and stirring was continued
10 overnight. After diluting with 250 ml of methylene chloride, the mixture was
washed with water, dried over sodium sulfate and evaporated at reduced
pressure. Crystallization of the residue from ethanol gave light tan crystals:
mp 209-210C. Recrystallization of a sample from methylene chloride/ethyl
acetate gave off-white prisms: mp 210-211 C.
ExamE le 2
2-Amino-9-chloro 7~(2-fluorophenyl)-5H-eyrimido[574-d~ [2] benzazepine
A stirred suspension of 16 g (0.047 mol) of 8-chloro-1-(2-fluorophenyl)-
3,4-dihydro-4-[~dimethylamino)methylene]-5H-2-benzazepin-5-one and 12.5 g
(0.07 mol) of guanidine carbonate in 460 ml of methanol was treated at room
20 temperature, under argon, with 7.5 g (0.14 mol) of sodium methylate in one
portion. Methylene chloride (290 ml) was added after 10 min. and stirring was
continued. The same quantities of sodium methylate and guanidine carbonate
were added two more times at 2 hr intervals and stirring was ~ontinued
overnight. After diluting with 460 ml of meti-ylene chloride, the mixture was
25 washed with water, dried over sodium sulfate and evaporated at reduced
pressure. Recrystallization of the residue from ethanol/methylene chloride
solution gave off-white crystals: mp 245-248 C.
~13h8~i3
_ 39
Dihydrochloride salt
A warm solution of the above end product in 100 ml of 1:1
methanol/methylene chloride was filtered and concentrated on a steam bath to
1/2 volume. The filtrate was treated with 5 ml of 5.7 N ethanolic hydrogen
5 chloride solution and kept at room temperature for 2 hr. The paIe yellow
crystals were filtered, washed with ethanol and air dried to yield the
dihydrochloride salt: mp 232-237 C
Example 3
9-C:hloro-2-methyl-7-~henyl-SH-pyrim_do~52~d] [2] benzazepine
A suspension of 1.6 g (0.005 mol~ of 8-chloro-3,4-dihydro-4-(dimethyl-
aminomethylene)-l-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of
acetamidine hydrochloride in 50 ml of methanol was stirred at roorn
temperature, under argon, and treated with O.B g (0.015 mol) oE sodium
methylate in one portion. After stirring for 10 min, 30 ml of methylena chloride
lS was added and stirring was continued. Another 0.8 g (0.015 mol) of sodium
methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added after
2 hrs. The addition of O.OlS mol of sodium methylate and 0.0075 mol of
acetamidine hydrochloride was repeated after another 2 hr and stirring at room
temperature was continued overnight. After diluting with 50 ml of methylene
20 chloride, the mixture was washed with water, dried over sodium sulfate and
evaporated at reduced pressure. Crystallization occurred when the residue was
dissolved in 20 ml of warm hexane and cooled. Evaporation of the solvent gave
a second crop of product. Recrystallization from hexane (charcoal) gave off-
white crystals: mp 120-122 C.
Example 4
9-Chloro-7-(2-fluoro~hen~1)-2-methyl-SH-pyrimido[5,4-d] [2] benzazepine
_ 40
A suspension of 5.1 g ~O.OlS mol) of 8-chlor~1~2-fluorophenyl)-3,4-
dihydro~-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 2.1 g (0.0225
mol) of acetamidine hydrochloride in 150 ml of methanol was stirred at room
temperature under argon, and treated with 2.4 g (0.045 mol) of sodium
5 methylate in one portion. After stirring for 10 min, 90 ml of methylene chloride
was added and stirring was continued. Another 2.4 g ~0.045 mol) of sodium
methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added after
2 hrs. The addition of 0.045 mol of sodium methylate and 0.0225 mol of
acetamidine hydrochloride was repeated after another 2 hr interval and stirring
10 st room temperature was continued overnight. After diluting with 150 ml of
methylene chloride, the mixture was washed with water, dried over sodium
sulfate and evaporated at reduced pressure. Recrystalliza$ion of the residue
from hexane (charcoal) gave white crystals: mp 104-107 C.
~3~
15 9 Chloro-7-~2-nuoropheny~ pyrimido[5~4-d] [2] benzazeein-~-amine and
9-chloro-7-(2-fluorophenyl)-N,N-dimethyl-5H-pyrimido[5~4-d] [2] benzaze~in=
2-amine
A solution of 7.0 g (0.0204 mol) of 8-chlor~1-(2 fluorophenyl)-3,4-
dihydr~4-[(dimethylamino~methylene]-5H~2-benzazepin-5~ne and 3.5 g (0.0833
20 mol) of cyanamide in 300 ml of absolute ethanol was refluxed for 18 hours, and
evaporated to dryness. The residue was washed with water, filtered and
recrystallized twice from methanol to give the N,N-dimethyl amino compound.
The filtrates were concentrated, filtered and recrystallized from methanol to
give the amino compound. The filtrates were evaporated, dissolved in
25 dichloromethane and chromatographed over Florisil. The column was eluted
with dichloromethane which was evaporated and crystallized from methanol to
give further N,N-dimethyl amino compound. A sample was recrystallized from
~'
;3
_41
dichloromethane/ether to give white needles: mp 175-180 C.
The column was next eluted with a 5% solution of ether in dichloro-
methane, and then with ether. The ether fraction was evaporated and
crystallized from methanol to give ~urther amino compound. A sample was
recrystallized from methanol to give white prisms: mp 242-247 C.
To a solution of 0 2 g (0.5 mmol) of the N,N-dimethyl amino compound
in 5 ml of methanol was added 0.05 g (0.5 mmol) of methane sulfonic acid. The
methanol was evaporated and the oil was crystallized from isopropanol and
recrystallized from methanol/ether to give yellow prisms: mp l90-195 C.
Example 6
A solution of 2.0 g (7.19 mmoles) of [2-(2-fluorobenzoyl)-4-chlorobenzoic
acid3, in 40 ml of meth~nol and 0.3 ml of sulfuric acid was refluxed for lO hrs
and then evaporated. The residue was partitioned between 50 ml of
15 dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer
was dried and evaporated. The resulting oil was dissolved in 20 ml of
dichloromethane, filtered through 25 g of Florisil and eluted with dichloro-
methane. The solvent was evaporated and the oil was crystallized from ether
and recrystallized from dichloromethane/ether/petrol to give white rods: mp
20 115-116 C.
Example 7
4-Chlor~2-[4-(chloromethyl)-2-(2-fluoropheny~1,3-dioxolan-2-yl] benzoic acid
methyl ester
To a solution of 47 ~ (0.16 mol) of the end product of Example 6 in 350
~38~63
42
ml of dry toluene was added 21.4 ml (0.18 mol) of stannic chloride, and after 5
hrs a solution of 24 ml (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of
toluene was added with stirring over a 30 min period. After 18 hrs an additional12 ml (0.154 mol) of 1-chloro-2,3-epoxypropane was added over a 15 min period.
Af~er 4 hrs the reaction was cooled in an ice bath and made basic with
concentrated ammonium hydroxide. The reaction was filtered through celite,
and the celite was washed with toluene. The combined filtrates were washed
with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting
oil was dissolved in 100 ~nl of dichloromethane and chromatographed through 500
g of alumina. The column was eluted with 41 of dichloromethanetpetrol (2/1) to
give an oil, which was about 90-95% pure by TLC. A sample was crystallized
and recrystallized from ether/petrol to give white prisms, mp 117-122 C.
Example 8
2- 4-Chloromethyl-2-(2-fluoro~henyl)-1,3-dioxolan-2-yl~ - ~C E(di-rnethYlamino)-rmethylene]~oxo-(4-chlorophenyl?propanenitrile
To 800 ml of liquid ammonia was added a small piece of sodium and a
few crystals of ferric nitrate. A total of 8.7 g (0.378 mol) of sodium was addedwith stirring over a 30 min period, and after 15 mins a solution of 20.1 ml (0.378
mol) of acetonitrile in 70 mI of ether was added over a 15 min period. After 10
mins a solution of 56 g (0.145 mol) of the end product of Example 7 in 250 ml ofether was added over a 10 min period. The reaction was stirred for 2 hrs, and
then 700 ml of ether was added. After allowing the ammonia to evaporate
overnight, ice was added and the reaction was acidified with acetic acid. It wasneutralized with a saturated sodium bicarbonate solution, and the water was
separated and extracted again with 500 ml of ether. The combined ether layers
were washed with brine (200 ml), dried over sodium sulfate and evaporated to
dryness. The crude oil was dissolved in 150 ml of dichloromethane and filtered
~3~ 3
43
through 400 g of Florisil. The column was eluted with 1.51 of dichloromethane
to give an oil, which was about 9U-95% pure by TLC.
The 48 g of the oil was refluxed and stirred for 90 mins with N,N-
dimethylformamide dimethylacetal and the mixture was then evaporated to
5 dryness. The residue was triturated with 300 ml of ice water, which was then
decanted. The remaining oil was dissolved in 300 ml of dichloromethane,
washed with 200 ml of water, and then dried over sodium sulfate. The solution
was evapora~ed and the residue was crystallized from dichloromethane/ether to
give end product. The filtrates were evaporated, dissolved in 100 ml of
dichloromethane an~ filtered through 300 g of Florisil. Elution with
dichlorcmethane (400 ml) and ether (1.5 1) gave upon ~vaporation and
then crvstallization from dichloromethane/ether end ~roduct. The fil-
trates contained end product as an oil which wa~s about &5% pure by
TIC. An analytical sa~ple was recrystallized from the same solvents to
give of~-white prisms, mp 143-147C.
~e~
2-Amino-4-~2-[4-(chloromethyl)-2-(2-fluorophenyl)-1,3-dioxolan-2-yl~ -4-chloro-
eb~=
To a solution of l.û g (û.00223 mol) of the end product of Example 8 in 8
20 ml of dry dimethylsulfoxide was added 4 g OI molecular sieves (type 5A~ and 0.7
g (0.00389 mol) of guanidine carbonate. The reaction was stirred at 90-95 C
for 5 hrs, cooled and 50 ml of dichIoromethane was added. The solution was
decanted and the solîds were washed with dichloromethane and water several
times. The combined solutions were separated, and the organic layer was
2 5 washed with dilute brine (2x), and then dried over sodium sulfate and
concentrated to a small volume. This solution was developed on 4 silica gel
thick layer plates in dichloromethane/ethyl acetate (3~1). The band at Rf 0.4
*Trade mark
~l~r1~
~'
.
~3~
~4
was removed and crystallized and recrystallized from methanol to give off-
white prisms, mp 184-191 C.
Example 10
2-Amino-4-~2-(2-fluorobenzoyl)-4-chloroe~n~ pyrimidine-5-carbonitrile
A solution of 0.2 g (0.448 mmoles) of the end product of Example 9 in 20
ml of methanol and 10 ml of 3N hydrochloric acid was refluxed for 20 mins and
the solvent was evaporated. The residue was partitioned between 50 ml of
dichloromethane and 30 ml of dilute ammonium hydroxide, and the organic layer
was dried, concentrated and filtered through 15 g of Florisil. The column was
eluted with 200 ml of ether which was concentrated, filtered and recrystallized
from dichloromethane/ether/petrol to give white prisms, mp 153-157 C.
Exam~Ie n
2-Amino-9-chloro-7-(2-fluorophenyl)-SH-pyrimido[5t4-d] ~2] benzaze~ ne
A solu~ion of 50 mg (0.142 mmoles) of the end product of Example 10 in
10 ml of acetic acid was treated with 1/4 spatula of Raney nickel, and
hydrogenated for 2.5 hrs. The reaction was filtered through celite, evaporated,
and partitioned between 30 ml of dichloromethane and 15 ml of dilute
ammonium hydroxide. The organic layer was dried with sodium sulfate,
evaporated and the residue was refluxed in ethanol for 1 hr, and then evaporatedto dryness. The solid was dissolved in dichloromethane and developed on a thick
layer of silica gel plate in ethyl acetate/ethanol (20/1). The band of Rf 0.3 was
removed and crystallized from ether to give white prisms, mp 243-248 C, and a
mixed mp of 244-248 C with authentic material obtained as in Example 2.
Example 12
2-[4-( Chloromethyl)-2-phenyl-1,3-dioxolan-2-yll benzoic acid, methyl ester
~3~ 3
To a solution of 33 g ~0.138 mol) of 2-benzoyl benzoic acid methyl ester
in 200 ml of dry carbon tetrachloride was added 10.1 ml (0.13 mol) of l-chloro-
3,4-epoxypropane. The reaction was cooled in an ice bath and a solution of 1.5
ml (0.013 mol) of stannic chloride in 10 ml of carbon tetrachloride was added
S with stirring over a 20 min period. The reaction was allowed to stand over the
weekend, and then the same quantities of 1 chloro-213-epoxy-propane and
stannic ehloride were added. After 18 hours the reaction was cooled in an ice
bath, and neutralized with concentrated ammonium hydroxide. The precipitate
was filtered off and washed with dichloromethane and the combined filtrates
were washed with 15~ ml of water, dried with sodium sulfate and evaporated.
The resulting oil was dissolved in 100 ml of dichloromethane and chromato-
graphed through 500 g of neutral alumina. Elution with 3 l of dichloromethane
gave the end product as an oil which was about 95% pure by TLC.
Crystallization and recrystallization of a small sample from ether/petrol gave
white rods, mp 90-91 C.
Example 13
2-[4-(Chloromethyl)-2-phenyl-1,3-dioxolan-2-yll -~-[(dimethylamino)-
methylene] -~xo-benzenepropanenitrile
To a stirring solution of 75 ml of liquid ammonia was added a smaIl
piece of sodium and a few crystals of ferric nitrate. A total of 1.15 g (0.0502
mol) of sodium was added over a 20 min period, and after 5 mins a solution OI
2.9 ml (0.050 mol) of acetonitrile in 10 ml of ether was added dropwise. A
solution of 6.6 g (0.0198 mol) of the end product of Example 12 in 40 ml of ether
was added dropwise, and after 2 hrs 100 ml of ether was added and the ammonia
was allowed to evaporate. About 100 g of ice was added to the reaction, which
was then acidified with acetic acid, followed by neutralization with a saturatedsolution of sodium bicarbonate. The water layer was separated and extracted
~38~;i3
_ 46
once more with ether. The combined ether layers were washed with 100 ml of
water, dried over sodium sulfate and evaporated. The oil was dissolved in 15 ml
of dichloromethane and filtered through 100 g of Florisil. Elution with
dichloromethane? and evaporation gave 2-[4~chloromethyl)-2-phenyl-1,3-dioxo-
lan-2-yl~ benzenepropanenitrile which was used without further purifica-
tion.
A solution of 20 g (0.0585 mol) of the above propanenitrile in 75 rnl of
N,N-dimethylformamide dimethylacetal was refluxed and stirred for 90 mins,
and evaporated to dryness. The oil was triturated with ice water which was
decanted, and the residue was partitioned between 150 ml of dichloromethane
and 150 ml of water. The organic layer was dried with sodium sulfate,
concentrated, and filtered through 150 g of Florisil. The column was eluted with
ether which was evaporated, and the resulting oil was crystaUized from ethanol
to give end product. A sample was recrystallized from dichloromethane/ether
to give white prisms, mp 107-110 C.
:~3~i~63
-- ~17
Example 14
2-amino-4-(2-benzoylphenyl)pyrimidine-5-carbonit_e and 1-oxo-3-phenyl-lH~
indene-2-carbonitrile
To a solution of 200 g ~0.00504 mol) of the end product of Example 13 in
10 ml of dichloromethane was added 10 ml of methanol and 2 ml (0.0192 mol) of
9.6 N ethanolic hydrogen chloride. After 90 mins the solvent was evaporated
and the oil was partitioned between 50 ml of dichloromethane and 30 ml of a
saturated sodium bicarbonate solution. The organic layer was dried with
sodium sulfate and evaporated. The 1.5 g of oil obtained was dissolved in 30 ml
of methanol, and 1.5 g (0.00833 mol) of guanidine carbonate was added. The
solution was stirred for gO minutes and then refluxed for 2 hours. The reaction
was evaporated and then partitioned between 50 ml of dlchloromethane and
30 ml of dilute ammonium hydroxide. The organic layer was drieà with sodium
sulfate and filtered through 50 g of Florisil. The column was eluted with
lS dichloromethane (200 ml) and then ether (300 ml). The dichloromethane
fraction was evaporated~ crystallized and then recrystallized from dichloro-
methane/petrol to give the indene as yellow rods, mp 173-175 C.
The ether fraction was evaporated and crystallized from dichlorome-
thane/petrol to give the pyrimidine mp 195-199 C. An analytical sample was
recrystallized from methanol to give off-white prisms, mp 197-200 C.
~ ~3~3~
~8 _
Esample lS
7-phenyl-5H-pyrimido~594-d] [2~ benzaze~in-2-amine
A solution of 3.1 g (0.0103 mol) of the pyrimidine compound of Example
14 in 60 ml of glacial acetic acid was treated with 1 teaspoon of Raney nickel
and then hydrogenated for 8.5 hours. The reaction was filtered through celite,
and evaporated. The filtrate was partitioned between 50 ml of dichlorome-
thane and 30 ml of dilute ammonium hydroxide, and the organic layer was
dried with sodium sulfate and evaporated. The resulting oil was refluxed in 75
ml of methanol for 15 minutes, evaporated and dissolved in 100 ml of
dichloromethane. This was treated with 3 g of activated manganese dioxide,
and then refluxed and stirred for 30 rnins. The reaction was filtered,
concentrated and chromatographed over lûO g of Florisil. The column was
eluted with 300 ml of dichloromethane, S00 ml of ether and 1.5 1 of ethyl
acetate. The ethyl acetate fraction was evaporated, and the oil WflS
crystallized from ether and recrystallized from dichloromethane~ether to give
white rods, mp 239-242C. The filtrates and the ether fraction from the
column were evaporated and developed on silica gel thick layer plates in ethyl
acetate/methanol (20/1) to give additional product. An analytical sample was
recrystallized from ether to give white prisms, mp 201-205C which reset to
form rods, mp 24D-243 C.
1~3~3
_ 49
Example 16
In five equal portions 5.5 g (5B mmole) of acetamidine hydrochloride and
15 ml (~2 mmole) of a 4.12 _ methanol solution of sodium methoxide was added
over 3 hr. to a solution of 3.5 g (10 mmole) of 8-chloro-1-(2-chlorophenyl~3,4-
dihydro-4-[(dimethylamino)methylene]-SH-2-benzazepin-5-one in 140 ml of
methanol and 140 ml o~ methylene chloride. The mixture was diluted with
water and extra~ted with methylene c~oride. The methylene chloride solution
was waslled with water dried with anhydrous sodium sulfate, and concentrated
at reduced pressure to give an amber oil. The amber oil was dissolved in 10 ml
(lû mmole) of a 1 M methanol solution of methanesulfonic acid and the
resulting salt was precipitated by the addition of ether to give yellow prisms,
mp 193-197C. Recrystallization from a mixture of methanol and ether gave
yellow prisms, mp 19~-198 C.
Example 17
9-chl ro-7-(2-chloroehenyl)-5H-pyrimido[5,4-d][2]benzazepine
In five equal portions 21 g (200 mmole) of formamidine acetate and 32.5
ml (135 mmole) of a 4.12 M methanol solution of sodium methoxide was added
over 3 hr to a solution of 7.2 g (20 mmole) of 8-chloro-1-(2-chlorophenyl~3,4-
dihydr~[(dimethylamino)methyleneJ-5H-2-benzazepin-5-one in 270 ml of
methanol and 270 ml of methylene chloride. The solution was diluted with
water and extracted with methylene chloride. The methylene c~doride solution
was washed with water, dried over anhydrous sodium sulfate, and concentrated
at reduced pressure to give an amber oil. Purification by column chromato-
graphy (100 g silica gel; eluent 1:1 methylene chloride and ethyl acetate) gave
end poduct mp 122-124C. Recrystallization from ether gave pale yellow
prisms, mp 122-125 C.
~3~ 3
-- 50
Example 18
g-chlo_o-7-(2-chloro~henyl)~-isoerop~1-5H-pyrimido[5,4-dl [2] benzazepine
A mixture of 3.5 g (10 mmole) of 1-~2-chlorophenyl)-3,4-dihydro-4-
[(dimethylamino)methylene]-5H-2-benzazepin-5-one, 4.8 g (40 mmole) of
isobutyramidine hydrochloride, 10 ml (41 mmole) of A 4.12 M methanol solution
of sodium methoxide and 100 ml of methanol was stirred Elt room temperature
for 2 hr. The mixture was diluted with water and lextracted with methylene
chloride. The methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give a yellow oil. Crystalliza-
tion of the oil with ether gave a light yellow solid, mp 127-129 C.
Recrystallization from a mixture of ether and petroleum ether gave colorless
rods, mp 127-129 C.
Examples 19
2-amino-9-chloro-7-(2-chlorophen~ 5H-pyrimido~5,4-d][2}-
-
1~ benzazèpine
In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20
ml (82 mmole) of 4.12 _ methanol solution of sodium methoxide was added
over 90 min to a solution of 3.6 g tlû mmole) of 8 chloro-1-(2-chlorophenyl)-
3,4-dihydro-4-~(dimethylamino)methylene]-5H-2-benzazepin-5-one in 100 ml of
20 methanol. The mixture was diluted with water and extracted with methylene
chloride. The methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give a yellow oil. Crystalliza-
tion of the oil with methylene chloride gave a white solid, mp 240-241C.
Recrystallization from a mixture of ethr and methylene chloride gave colorless
2 5 needles, mp 240-241 C.
~38~3
_ 51
Example 20
7-(2-chloroe~yl)-2-methyl-5H-pyrimido[5,4-d] [2] benzaæe~ine methanesulf~
nate
In four equal portions 7.2 g (78 mmole) of acetamidine hydrochloride
and 18 ml (80 mmole) of a 4.46 M methanol solution of sodium methoxide was
added over a 3 hr period to a solution of 4.5 g (14 mmole) of 1-(2-chlorophenyl)-
3,4-dihydro-4-~(dimethylamino)methylene]-SH-2-ben~azepin-5-one in 180 ml of
methanol and 18û of methylene chloride. The mixture was diluted with water,
and extracted with methylene chloride. The methylene chloride solution was
washed with water, dried with anhydrous sodium sulfate, and concentrated at
reduced pressure to give an amber oil. The amber oil was dissolved in a
mixture of lS ml of isopropanol and 1.3 g (14 mmole) of methanesulfonic acid,
and the isopropanol was removed at reduced pressure. The residue was
crystallized from a mixture of ether and methylene chloride to give a ligh
yellow solid, mp 147-151C. Recrystallization from a mixture of ether anà
methylene chloride gave yellow prisms as the half hydrate, mp 159-160 C.
3~8Ç;;3
_ 52 --
Example 21
2-methyl-7-phen~l-SH-pyrimido[5~-d] ~2] benzazepine dihydrochloride
In five equal portions 9.0 g (9S mmole) of acetamidine hydrochloride and
22.5 ml (0.1 mole) of a 4~46 M methanol solution of sodium methoxide was
added over 3 hr to a solution of 4.5 g (lS mmole) of l-phenyl-3,4-dihydro-4-
~(dimethylamino)methylene]-SH-2-benzazepin-5-one in 180 ml of methanol and
180 ml of methylene chloride. The methylene chloride solution was washed
with water, dried over anhydrous sodium sulfate, and concentrated at reduced
pressure to give an oil. The oil was dissolved in an excess of 6% methanolic
hydrogen chloride and the solvent was removed at reduced pressure to dryness.
The residue was crystallized from a mixture of ether and methylene chloride
to give a white solid mp 211-221 C. Recrystallization from a mixture of
methanol and ether gave white flakes, mp 217 227 C.
Example 22
9-chlor~7-(2-chlorophen~ )-2-meth~1-5H-pyrimido[5,4-d] [2] benzazepine 6-
o ide
A solution of 2.0 g (5.6 mmole) of 9-chloro-7-(2-chlorophenyl~2-methyl
SH-pyrimido[5,4-d] [2] benzazepine and 2.2 g (10.8 mmole) of 85% meta-chloro-
perbenzoic acid in 130 ml of methylene chloride was stirred at room tempe-
rature for 21 hr. The methylene chloride solution was washed with cold dilute
aqueous sodium hydroxide, dried over anhydrous sodium sulfate, and concen-
trated at reduced pressure to dryness. Purification by plug filtration (silica
gel, 25 g; eluent 1000 ml 1:1 ether methylene chloride) gave a colorless solid,
mp 215-216 C.
~:~L38~3
_ 53
Example 23
9-chloro-7-(2-chlorophen~1)-2-methyl-5H-p~imido~5,4-d] [2] benzazepine-3,6-
dioxide
A solution of 3.8 g (10.7 mmole) of 9-chlor~7-(2-chlorophenyl)-2-
S methyl~5H-pyrimido[5,4-d] [2] benzazepine and 9.6 g (47 mmole) of 85% meta-
chloroperbenzoic acid in 400 ml of methylene chloride was stirred at room
temperature for 55 hr. The methylene chloride solution was washed with cold
dilute aqueous sodium hydroxide, dried over anhydrous sodium sulfate, and
concentrated at reduced pressure to dryness. Purification by plug filtration
(silica gel, 25 g; eluents 400 ml 1:1 ether, methylene chloride followed by 200
ml 9:1 methylene chloride, methanol) gave colorless solid, mp 2~1-243 IC.
zepine dihydrochloride
A mixture of 3.7 g (lO.S mmole) of 9-chlor~7-(2-chlorophenyl)-2-
methyl-SH-pyrimido[5,4-dl[2]benzazepine, 1.3 g of zinc dust, and 40 ml of
acetic acid in 90 ml of methylene chloride was stirred at -15C to-20C for
30 min. The mixture was filtered over hyflo, and the filtrate was basified with
cold dilute aqueous sodium hydroxide and extracted with methylene chloride.
The methylene chloride solution was dried over anhydrous sodium sulfate and
concentrated at reduced pressure to give a yellow oil. The yellow oil was
crystallized from an excess of 6% methanolic hydrogen chloride to give the
title compound as a white solid, mp 272-274 C. Recrystallization from
methanol gave colorless rods, mp 272-274 C.
54
A sample of the above material was partitioned between dilute aqueous
sodium hydroxide and methylene chloride. The methylene chloride solution
was dried over anhydrous sodium sulfate and concentrated at reduced pressure
to dryness. The residue crystallized from ether to give the free base as cream
colored prisms, mp 176-177 C.
If the reaction is carried out in acetic acid using hydrogen over a
prehydrogenated platinum oxide catalyst two equivalents of hydrogen are
consumed to yield on work up the tetrahydro compound described in example
40. These tetrahydro derivatives also exhibit useful CNS properties.
Example 25
8-chlor~1-(2-chlorophenyl~3, 4-dihydr~4=[tdimethylamino)methylene3 -5H-2-
benzazepin~5-one
A mixture of 18.6 g (61 mmole) of 8-chloro 3,4-dihydr~1-(2-chloro-
phenyl)-5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl
acetal was gently heated (ca 50) for 12 hr. The mixture was concentrated at
reduced pressure to dryness. The residue was crystallized from a mixture of
ether and methylene chloride to give the end product as a yellow solid, mp 170-
171 C. Recrystallization from ether gave yellow prisms, mp 170-171 C.
~L~3~3
Exam~le 26
_2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-2-benzazepin-
-5-one
A mixture of 3.4 g (12.5 mmole) of 1-(2-chlorophenyl)-3,4-dihydro-5H-2-
5 benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal was
refluxed for 2 hr. The mixture was concentrated at reduced pressure and the
resulting solid was triturated with ether to give a tan solid, mp 155-157C.
Recrystallization from a mixture of methylene chloride and ether gave yellow
prisms, mp 158-158 C.
3,4 Dihydro-l-phen~ 4-[(dimethylamino)methylene]-5H-2-benz_epin-5-one
A mixture of 5.2 g (22 mmole) of 3,4-dihydro-1-phenyl-5H-2-benzazepin-
S-one and 43 ml of dimethylformamide dimethyl acetal was refluxed for 4 hr.
15 The mixture was concentrated at reduced pressure to dryness. The residue was
crystallized with ether to give a yellow solid, mp 131-133 C. Recrystallization
from ether gave yellow prisms, mp 131-132 C.
i3
56
9-chloro-7-(2-chlorophenyl)-2-(met~7lthio)-5H pyrimido[5,4-d] [2] benzazepine
A mixture of 1.1 g (3.0 mmole) of 9-chloro-7-(2-chlorophenyl)-SH-pyri-
mido[5,4-d] E2] benzazepin-2-thiol, 1.0 ml (10 mmole) of dimethyl sulfate, 20 ml
5 of lN sodium hydroxide and 10 ml of ethanol was stlrred at room temperature
for 15 min. The mixture was diluted with water and extracted with methylene
chloride. The methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give an oil. Crystallization
from ether gave colorless prisms, mp 187-188 C.
9-chlor~7-(2-chlorophenyl~-2-(meth~hio?-5H-e3~rimido[5L4-d] ~?] benzaz~
pine methanesulfonate
The methanesulfonate salt of 9-chloro-7-(2-ehlorophenyl)-2-(methyl-
15 thio)-5H-pyrimido~5,4-d] [2] benzazepine was prepared by the addition of
equimolar amounts of the above compound and methanesulfonic acid to
methanol and by precipitating the resulting salt by the addition of ether.
Recrystallization from ethanol gave eream colored needles, mp 165-166 C.
~L3~ ;3
_ 57 _
Example 30
9-chloro-7-~2-chloro~hen~1)-5H-pyrimido[5,4-d] [2] benzazepine-2-thiol
A mixture oP 2.8 g (7.8 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-
dihydro-4-[(dimethylamino)methylenel-5H-2-benzazepin-5 one, 2.8 g (37
mmole) of thiourea, and 8.0 ml (32 mmole) of a 4.0 M methanol solution of
sodium methoxide in 80 ml of methanol was stirred at room temperature for 18
hr. The mixture was diluted with water and extracted with ether. The
aqueous layer was neutralized with acetic acid and extracted with methylene
chloride. The methylene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to give a yellow solid, mp 238-
239 C. Recrystallization from tetrahydrofuran gave yellow crystals, mp 232-
234 C.
~L3~3~
_ 5~ ~
Example 31
Preparation of 9-chloro-7-(2~fluorophenyl)-5H-pyrimido[5,4-d] [2] benzaze~in-
2-ol
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-
pyrimido[5,4-d] [2] benzazepine in 2U ml of concentrated sulfuric acid and 20
ml of water was refluxed for 12 hr, and then cooled. After the addition OI ice,
the reaction mixture was basified with ammoniurn hydroxide and extracted
with 100 ml of diehloromethane. The solids were collected by filtration and
recyrstallized from dichloromethane/methanol to give the end product as
white prisms, mp 297-299 dec. The dichloromethane extract was dried,
evaporated and the residue crystallized from dichloromethane/methanol to
give additional product.
Example 32
Preparation of 2,9-dichloro-7-(2-fluoro~henyl)-5H~Qrimido~5,4-dl [2] benzaze-
lS E~
A solution of 1.0 g (0.00294 mol) of 9-chloro-7-(2-fluorophenyl)-SH-pyrimido-
[5,4-d] [2] benzazepin-2-ol in 5 ml of phosphorous oxychloride WQS heated on
the steam bath for 4 hr, and evaporated to dryness. The solid was crystallized
from dichloromathane/ether, and the precipitate was partitioned between 50
ml of dichloromethane and 40 ml of saturated solution of sodium bicarbonate.
The organic layer was dried, evaporated and crystallized from ether.
Recrystallization from dichloromethane/ether gave the end product as off-
white prisms, mp 157-160 .
~L~L3~8~3
ss
Example 33
Preparation of 9-chloro-N-methyl-?-(2-fluorophenyl?-5H-~rimido[5L4-d] [2]-
benzazepine-2-amine
A solution of 1 g (0.00279 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-
5 pyrimido~5,4-d] [2] benzazepine in 4 ml of N,N-dimethylformamide was cooled
in an ice bath and saturated with methylamine. After 64 hr at room
temperature, 50 ml of ice water was added and the reaction was filtered. The
precipitate was partitioned between 50 ml of dichloromethane and 50 ml of
water, and the organic layer was washed with 25 ml of brine solution, dried and
10 evaporated to dryness. The oil was crystallized from ether and then
recrystallized from dichloromethans/ether and then from methanol to give the
end product as white prisms, mp 172-179.
Preparation of 9-chloro-N,N-dimethyl-7-(2-fluoroehenyl)-SH-eyr mido~S~-
lS [2] benzazepin-2-amine
A solution of 4.0 g (0.0112 mol) of 2,9-dichloro-7-(2-fluorophenyl)-5H-
pyrimido~5,4-d] [2] benzazepine in lS ml of N,N-dimethylformamide was cooled
in an ice bath and saturated with dimethylamine. After 18 hr at room
temperature, 80 ml of ice water was added and the precipitate was collected
20 by filtration and recrystallized twice from methanol to give the end product as
white rods, mp 175-179.
_ 60
E~ample 3S
Preparation of 9-chloro-7-(2-fluoro~henyl)-N-(3-N,N-dimethylamino~p~
5H-p~imido[5~-d} [2] benza~pin-2-amine
To 3.5 g (0.00978 mol) of 2,9-dichloro-7-~2-fluorophenyl)-5H-pyrimido[5,4-
d~ [2] benzaæepine in 7 ml of N,N-dimethylformamide was added 2.7 ml (0.0215
mol) of 3-dimethylaminopropylamine while cooling the reaction in an ice bath.
After 66 hr at room temperature S0 ml of ice water was added and the
reaction was filtered. The preeipitate was dissolved in 50 ml of dichlorometh-
ane, washed with 40 mI of water, and evaporated. The oil was dissolved in
dilute hydrochloric acid and brought to pH 2 with ammonium hydroxide. The
acidic solution was extracted with dichloromethane (2x50 ml), and the acid
layer was then made basic with ammonium hydroxide and extracted with 75 ml
of dichloromethane which was dried and ~nd evaporated. The residue was
crystallized and recrystallized from ether/petrol to give white needles, mp 90-
101.
Exam~le 36
Preparation of _-chloro-2-methoxy-7-(2-fluorophenyl)-5H-~yrimido[5,4-d~ [2] -
benzazepine
To 25 ml of methanol was added l.û g (0.00279 mol) of 2,9-dichloro~7-(2-
fluorophenyl)-5H-pyrimido[5,4-d] ~2] benzazepine and 0.18 g ~0.00335 mol) of
sodium methoxide. The reaction was stirred for 18 1~, and evaporated to
dryness. The solid was dissolved in 50 ml of dichloromethane and washed with
40 ml of water, dried and evaporated to dryness. The oil was crystallized and
recrystallized from ether/petrol and then from ether to give the end product
as white prisms, mp 137-141.
61
Exam~le 37
9-Chloro-7-(2-fluorophenyl)-5H-pyrimido~4-d]-[2] benzaze~e
A mixture of 34.2 g (0.1 mole~ of 8-chloro-3,4-dihydro-1-(2-fluorophenyl)-
4-[(dimethylamino)methylene]-5H-2-benzazepin-S-one, 62.4 g (0.6 mole) of
formamidine acetate, and 35 g (0.63 mole) of sodium methoxide in 700 ml of
methanol was stirred at room temperature for 3 hr, while bubbling nitrogen
through the solution. The mixture was diluted with water and extracted with
methylene chloride. The methylene chloride solution was dried over anhydrous
sodium sulfate and concentrated at reduced pressure to give a red oil. The oil
was suspended in boiling hexane and the hexane solution decanted. Upon
cooling the end product was collected by filtration. Recrystallization from
cyclohexane gave off-white crystals, mp 123-125 C.
Exame~
9-Chloro-7-(2-fluorophenyl)~5H-pyrim_0[524-d} [2]-benzazepine-6-oxi~le
A solution of 3.2 g (10 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido-
[5,4-d] [2] ben~azepine, 3 g (15 mmoles) of 85% m-chloroperbenzoic acid in 100
ml of methylene chloride was stirred at room temperature for 4 hours. The
reaction mixture was washed with an excess of ice cold dilute sodium
hydroxide, dried over anhydrous sodium sulfate and filtered over hyflo. The
filtrate was concentrated at reduced pressure to dryness. The residue was
crystallized from a mixture of methylene chloride and ether to give the crude
product, m.p. 185-186 C. Recrystallization from a mixture of methylene
chloride and ether gave the pure product, m.p. 187-188 C.
Example 39
9-Chloro-7-(2-fluoro~henyl)-5H-pyrim_do[5,4-d] [2] benzaze~n-S-ol acetate
A mixture of 2.5 g (7.4 mmoles) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido-
~5,4-d] [2] benzazepine-6-oxide and 50 ml of acetic anhydride was heated on the
5 steambath for 24 hours. The reaction mixture was concentrated at reduced
pressure to dryness and the residue was crystallized from a mixture of
methylene chloride and ether to give the crude product, m.p. 197-198 C.
Recrystalli7ation from a mixture of methylene chloride and ether gave the
pure product as cream colored prisms, m.p. 200-201 C.
Example 40
9-Chloro-7-(2-chlorophenyl~4?5,6,7-tetrahydro-2-methyl-lH-pyrimido[5,4-d] -
[2] benzazepine, hydrochloride salt
.
A solution of 3.8 g (10.7 mmole) of 9~chloro-7-(2-chlorophenyl)-2 methyl-5~-
pyrimido[5,4-d] ~2] benzaæepine in 50 ml of acetic acid was hydrogenated at
15 room temperature and atmospheric pressure in the presence of 0.5 g of
prehydrogenated platinum oxide. After 3 hours about 500 ml tca a equivalent)
of hydrogen was absorbed and the catalyst was separated by filtration. The
filtrate was concentrated at reduced pressure to dryness. The residue was
dissolved in methylene chloride, washed with an excess of dilute ice cold
20 sodium hydroxide, and dried over anhydrous sodium sulfate. The methylene
chloride solution was diluted with an excess of methanolic hydrogen chloride
and concentrated at reduced pressure. The residue was triturated with
isopropanol and the crude product was collected by filtration. Recrystal-
lization from methanol gave the pure product, m.p. 275-276 C.
38
_ 63
Example 41
2-Amino-9-chloro-7-(2-fluorophenyl)-SH-~rimido[5,4-d] [2] benzazepine-6-
oxide
In two equal portions 28 g (150 mmole~ of guanidine carbonate and 38 ml
5 (lS0 mmole) of a ~.09 M methanol solution of sodium methoxide was added over
a 2 hr period to a solution of 7.0 g (20 mmole) of 8-chloro-1-(2-fluorophenyl)-
3,4-dihydro-4-[~dimethylamino)methylene]-5H-2-benzazepin-S-one-2-oxide in
210 ml of methanol. The mixture was diluted with water and extracted with
methylene chloride. The methylene chloride solution was dried over anhydrous
10 sodium sulfate and concentrated at reduced pressure to give a red solidO
Recrystallization from a mixture OI methanol and ethyl acetate gave the
product as fine yellow needles, m.p. 320-323 C.
9 hloro-7-(2-chlorophenyl)-6,7-dihydro-2,6-dimethyl-5H-pyrimidoE5,4-d]-
15 ~2~ benzazepine
A mixture of 4 g (11 mmole) of 9-chloro-7-(2-chlorophenyl)-6,7-dihydro-2-
methyl-5H-pyrimido[5,4-d] [2] benzazepine 2 ml of 88% formie acid and 2 ml of
37.596 formaldehyde solution was heated on the steambath for 3 hours. The
reaction mixture was poured into an excess of dilute ice cold sodium hydroxide
20 and extracted with methylene chloride. The methylene chloride solution was
dried over anhydrous sodium sulfate and concentrated at reduced pressure to
dryness. The residue was crystallized from ether to give the crude productJ
m.p. 155-156 C. Recrystallization from ether gave the pure product as
colorless prisms, m.p. 156-157 C.
~3~
_ 64 _
Example 43
8-Chloro-1-(2-fluorophenyl)-3~4-dihydro-4-~(dimethylam_no?methylene] -5H-
2-benzazepin-5 -one
Method A. A mixture of 7.2 g (25 mmole) of 8-chloro-1-(2-
, .
fluorophenyl)-3,4-dihydro-5H-2-benzazepin-5-one and 50 ml of dimethyl-
formamide dimethyl acetal was refluxed for 1 hr. The mixture was
concentrated at reduced pressure to give tan crystals. Recrystallization from
ether gave yellow prisms7 mp 228-233 C.
Method B. A mixture of I0 g (35 mmole) of crude 8-chloro-3,4-dihydro-
1-(2-fluorophenyl)-5H-2-benzazepin-5-one and 10 g (84 mmole3 of dimethyl-
formamide dimethyl acetal in 10 ml of dimethylformamide was stirred at room
temperature for 12 hr. The resulting precipitate was collected by filtration, and
washed successively with ethanol and ether to give tan crystals which were
identical in every respect to an authentic sample.
Example 44
8-Chloro-l-phenyl-3,4-dihydro-4-[(dimethylamino)methylene} -5H-2-benzazepin-
5-one
The preparation of 8-chloro-1-phenyl-3,4-dihydro-4-[(dimethylamino)-
methylene]-5H-2-benzazepin-5-one was conducted in the same manner as the
preparation of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)-
methylene]-5H-2-benzazepin-5-one (Method A) to give yellow prisms, mp 180-
183 C.
~L3~63
65 _
Example 45
8-Chloro-1-(2-fluorophen~1)-3,4-dihydro-S H-2-benzaæeein-5-one-2-oxide
A mixture of 6.4 g (22 mmole) of 8-chloro-1-~2-fluorophenyl)-3,4-
dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmole) of m-chloroperbenzoic
5 acid in 350 ml of methylene chloride was stirred at room temperature for 2 hr.
The methylene chloride solution was washed with saturated aqueous sodium
bicarbonate and water, dried over anhydrous sodium ~sulfate and concentrated at
redu~ed pressure to give a yellow oil. The oil WRS crystallized from R mixture
of ether and petroleum ether to give off-white prisms, mp 166-168 C.
10 Recrystallization from a mixture OI ether and methylene chloride gave colorless
prisms, mp 168-170 C.
~ e~
8-Chloro-1-(2-chloroph_yl)-3,4-dihydr_-SH-2-benzazepin-5-one-2-oxide
The preparation of 8-chloro-1-t2-chlorophenyl)-3,4-dihydro-5H-2-benæa-
15 zepin-5-one-2-oxide was conducted in the same manner as the preparation of 8-
chloro-1-(2-fluorophenyl)-3,4-dihydro-5El-2-benzazepin-5-one-2-oxide to give
yellow prisms, mp 184-187 C.
Example 47
8-Chloro-1-(2-fluoro~hen~1)-3,4-dihydro-4-[(dimethylamino)methylene] -5H-
20 2-benzazepin-5-one-2-oxide
A mixture of 3.4 g ~11 mmole) OI 8-chloro-1-(2-fluorophenyl)-3,4--dihydro-
SH-2--benzazepin-5-one-2-oxide and 26 ml of dimethylformamide dimethyl
acetal was stirred at room temperature for 12 hr. The mixture was diluted with
ether and the precipitate collected to give a yellow solid, mp 175-178 C.
25 Recrystallization from a mixture of ether and ethyl acetate gave yellow
needles, mp 193-194 C.
~38~3
66
Example 48
8-Chloro-l-(?-chlorophenyl~-3,4-dih~dro-4-[(dimethylamino)methylene]-5H-
2-benzazepin-5 -one-2-oxide
The preparation of 8-chloro-1-(2-c}~orophenyl)-3,4-dihydro-4-[(dimethyl-
amino)methylene]-5H-2-benzazepin-5-one-2-oxide was prepared in the same
manner as the preparation of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(di-
methylamino)methylene]-SH-2-ben~azepin-5-one-2-oxide to give yellow prisms,
mp 196~198 C.
~8~1~3
67
Example 4g
9-Chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido~5,4-
d][2]~benzazepine-~-oxide
A mixture of 1 g (2.8 mmole) of 8-chloro-1-(2-chlo-
rophenyl)-4 [(dimethylamino)methylene]-3v4-dihydro-5H-
2-benzazepine-5-one-2-oxide, 1.0 g (11 mrnole) of aceta-
midine hydrochloride and 2.0 ml (9.9 mmole) of a 4.46M
10 methanol sulution of sodium methoxide in a mixture of
20 ml of methanol and 20 ml of methylene ohloride was
stirred at room temperature for 2 hr. The mixture was
diluted with water and extracted with methylene chloride.
The methylene chloride solution was washed with water~
15 dried over anhydrous sodium sulfate and concentrated at
reduced pressure to dryness. Recrystalliæation of the
residue ~rom a mixture of ether and methylene chloride
gave a colorless solid, mp 215-216C.
Example 50
9-Chloro-7 (2-fluoro~henyl)-5H-pyrimido~5,4-d]~2]benza-
zepin-5-ol
A solution of 3.7 g (9.7 mmole) of 9-chloro-7-(2-
fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-5-ol ace-
tate in a mixture of 25 ml of tetrahydrofuran, 50 ml of
methanol and 2 ml of 3N sodium hydroxide was stirred at
room temperature for 0.5 hr. The reaction mixture was
poured into ice water and extracted with methylene chlo-
ride. The organic layer was separated, dried over anhy-
drous sodium sulfate and concentrated in vacuo to dry-
ness. The residue crystallized from a mixture of methy-
lene chloride and ether to give a crude product melting
at 186-188C. Recrystallization from a mixture of ether
and methylene chloride gave the product as cream colored
prisms, mp 196-198C.
~IL38~
_ 6~ -
Example 51
9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepine-6-oxide
s
A solution of 6.8 g (20 mmole) oP 9-chloro-7-(2-
chlorophenyl) 5H-pyrimido[5,4-d][2]benzazepine, 6 g (30
mmole) oP 85% m-chloroperbenzoic aoid in 200 ml oP methy-
lene chloride was stirred at room temperature for 4 hrs.
10 The mixture was washed with an excess oP ice cold dilute
sodium hydroxide, dried over ahydrous sodium sulPate and
filtered over hyflo. The Piltrate was concentrated at
reduced pressure to dryness. The residue was crystalli-
zed from a mixture oP methylene chloride and ether to
15 give a crude product, mp 228-229C. Recrystallization
from a mixture oP methylene chloride and ether gave the
product, mp 216-217C.
Example 52
- 9-Chloro-7-(2-chlorophenyl)-5H-p ~imido~5,4-d][2]benza-
zepin-5-ol acetate
;
A mixture oP 3 g (8 mmole) of 9-chloro-7-(2-chloro-
25 phenyl)-5H-pyrimido~5,4-d][2]benzazepine-~-oxide and 50 ml
oP acetic anhydride was heated on the steam bath Por 22
hrs. The reaction mixture was concentrated at reduced
pressure to dryness and the residue was crystallized Prom
a mixture oP methylene chloride and ether to give a pro
30 duct oP mp 211-212C. Recrystallization Prom a mixture
oP methylene chloride and ether gave the pure product
as colorless prisms, mp 211-212C.
i3
.. .
_ 69 _
~.
.i
~ Example 53
.:
',, 9-Chloro-7-(2-chlorophen~ 5H-Pyrimido[5~4-d]-[2-]benza
,''! zepin-5 ol
`~ 5
' A solution of 4 8 g ~12 mmole) of 6-chloro-7-(2-
chlorophenyl)-5H pyrimido[~,4-d3[2]benzazepin-5-ol ace-
tate in a mixture of 50 ml of tetrahydro~uran, 50 ml of
methanol and 4 ml of 3N sodium hydroxide was stirred at
: 10 room temperature for 30 min. The reaction mixture was
poured into ice water and extracted with methylene chlo-
ride. The organic layer was separated, dried over anhy-
drous sodium sulfate and concentrated at reduced pres-
sure to dryness. The residue was crystallized from a mix-
15 ture of methylene chloride and ether to give a product
of mp 105~117C. Recrystallization from a mixture of
methylene chloride and acetone gave the pure product as
colorle~s prisms, mp ~74-175C.
. .
~ 20 Exam~le 54
;
9-Chloro-7-(2-fluorophenyl)-2-(4-meth~ piperaz ~yl)-
5H-pyrimido~5,4-d~E2]benzaze~ine hydrochloride
.~,
To a solution of 3.0 g (0.00838 mol) of 2,9-dichlo-
; ro-7-~2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepine
in 8 ml of N,N-dimethylformamide was added 2 g tO.02 mol)
of N-methylpiperazineO A~ter 20 hr ic~ water (40 ml) was
added to the reaction which was then filtered. The so-
lid wa~ partitioned between 50 ml of dichloromethane and
50 ml of 1N hydrochloric acid, and the pH was adju~ted
t~ 1-2 with ammonium hydroxide. The resulting precipi-
tate was filtered and recrystallized twice from metha-
nol to give white prisms, mp 187-194C. The acid layer
was made basic with ammonium hydroxide, and extracted
with 100 ml of dichloromethane which was dried and eva-
porated. The oil was acidified with 1N hydrochloric acid,
_ 7C _
adjusted to pH 1-2 with ammonium hydroxide, cooled and
filtered. The precipitate was recrystallized from metha-
nol to give a further crop of the product.
Example 55
C
To 25 ml of methanol was added 1.0 g (0.00279 mol)
of 2j9-dichloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]-
benzazepine and 0.18 g (0.00335 mol) of sodium Methoxi-
de. The reaction was stirred for 18 hr, and evaporated
to dryness. The solid was dissolved in 50 ml of dichloro-
15 methane and washed with 40 ml of water, dried and evapo-
rated to dryness. The oil was crystallized and recrystal-
lized from ether/petrol and then from ether to give whi-
te prisms, mp 137-141C.
Example 56
9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepine-2-acetic acid eth~l ester
To 20 ml of diethylmalonate was added 1.9 g (16.8
mmol) of potassium tertiary butoxide with stirring under
nitrogen, and after 15 min, 2.0 g (5.59 mmol) of 2,9-
dichloro-7-(2-fluorophenyl)-5H-pyrimido~5,4-d][2]benza-
zepine was added. The reaction was kept at 110C for 2
hr and 140C for 4 hr. Ice was added to the reaction
mixture which was then acidified with concentrated hy-
drochloric acid, and extracted with 100 ml of ether. The
ether layer was extracted with 25 ml of 3N hydrochloric
acid, and the combined acid layers were made basic with
ammonium hydroxide and extracted with ether (2x100 ml).
The solution was dried, charcoal filtered and concentra-
ted to a small volume. Petroleum ether was added and the
~3~i3
_ 71 _
product was filtered and recrystallized from the same
solvents to give white rods, mp 98-103C~
Exam~le 57
9-Chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4 d][2]benza-
7epine-2-acetic acid
A solution of 4.0 g (9.76 mmol) of 9-chloro-7-(2-
10 fluorophenyl)~-5H-pyrimido~5,4-d]~2]benzazepine-2-acetic
acid ethyl ester in 30 ml of ethanol and 25 ml o~ 1N so-
dium hydroxide was heated on the steam bath for 3 hr.
The mixture was partitioned between 75 ml of water and
75 ml of ether. The basic layer was acidified with ace-
15 tic acid and extracted with dichloromethane (2x100 ml),which was dried and evaporated. The resulting oil was
crystallized from methanol and recrystallized from di-
chloromethane/ether/petroleum ether to give off-white
prisms, mp 138-140C.
Example 58
9-Chloro-7-(2-fluorophenyl)-N-methyl-5H-p~rimido[5,4-
d]~2]benzazepine-2 acetamide
Methylamine was bubbled into a solution of 2.6 g
(6.34 mmol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-
d]~2]benzazepine-2-acetic acid ethylester in 60 ml of
ethanol for 10 min. After standing for 18 hr, the reac-
tion was evaporated and the residue was partitioned bet-
ween 75 ml oP dichloromethane and 50 ml of water. The
organic layer was dried and evaporated. The residue was
crystallized and then recrystallized from dichlorometha-
ne/ether to give white rods, mp 175-177C.
~:~38~6~
_ 72 _
Example 59
9-Chloro-7-(2-chlorophenyl)_5H-pyrimido-[5,4-d][2]benza-
zeE~ne
A mixture of 90.5 g (0.25 mol) of 8-chloro-1-(2-
chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-
5H-2-benzazepine-5-one, 10b g (o.96 mol) o~ formamidine
acetate and 1.0 L o~ formamide was heated on a steam bath
lO ~or 16 hr. The mixture was cooled to 0 and the resul-
ting precipitate collected by filtration. The precipi-
tate was washed with water and dried to constant weight
to givP off-white crystals, mp 120-121C.
Example 60
9-Chloro-7-(2-fluorophenyl)-5H-p~__mido[5,4-d~[~Lbenza
zepine-6-oxide
A mixture of 0.4 g (1.1 mmol~ of 8-chloro-1-(2-fluo-
rophenyl)-3,~-dihydro-4-[(dimethylamino)methylene~-5H-
2-benzazepin-5-one-2-oxide, l.0 g (9.6 mmol) of formamidine ace-
tate and 20 ml of formamide was heated on a steam bath
for 6 hr. The mixture was poured over ice and extracted
2~ with methylene chloride. The methylene chlorid0 solution
was washed with water, dried over anhydrous sodium sulfa-
te and concentrated at reduced pressure. The residue crys
tallized ~ith the addition of a mixture o~ ether and methy
lene chloride to give off-white crystals, mp 186-188C.
~3~ j3
73
Exam~le 61
9-Chloro-7-(2-chlorophenyl)-5H-pyrimido~5,4-d]~2]benza
zepine-6-oxide
A mixture of 0.4 g (1.1 mmol) of 8-chloro-1-(2~chloro-
phenyl)-3,4-dihydro-4-[(dimethylamino)methylene] 5H-2-
benzazepin 5-one-2-oxide and 1.0 g ~9.6 mm~l) of ~on~dine ~ ~
tate in 20 ml of ~ormamide was heated on a steam bath
10 for 7 hr. The mixture was poured over ice and extracted
with methylene chloride. The methylene chloride solution
was washed with water, dried over anhydrous sodium sul-
fate and concentrated at reduced pressure. The residue
was triturated with ether to give an o~f-white solid,
15 mp 215-217C.
. ~
9-Chloro-7-(2--chlorophen~ 5H-pyrimido[5 ~4-d]~2]~benza-
20 zepine
A mixture of 0.5 g t1.3 mmol) of 9-chloro-7-(2-chlo-
rophenyl)-5H-pyrimidoE5,4-d][2]benzazepine-6-oxide and
1.0 ml (10 mmol) o~ phosphorous trichloride in 20 ml of
25 methylene chloride was refluxed for 3 hr. The mixture
was cooled, poured over ice, basified with ammonium hy-
droxide and extracted with methylene chloride. The methy-
lene chloride solution was washed with water, dried over
anhydrous sodium sul~ate and concentrated at reduced pres-
~ure. The residue cry~tallized upon the addition o~ etherto give colorless prism~, mp 121-123C.
$
74
Example 63
9-Chloro-7-(2-fluoroPhenyl)-5H-p~rimido[5,4-d][2]benza-
A mixture of 0.5 g (1.5 mmol) of 9-chloro-7-(2-fluo-
rophenyl)~-5H-pyrimido[5,4-d]~2]ben~azepine-6-oxide, and
1.0 ml (10 mmol) of phosphorous trichloride in 20 ml of
methylene chloride was heated at reflux for 2 hr. The
10 mixture was poured over ice, basified with ammonium hy-
droxide and extracted with methylene chloride. The methy-
lene chloride solution was dried over anhydrous sodium
sulfate and concentrated at reduced pressure to dryness.
The residue was crystallized from ether to give off-white
15 crystals, mp 122-124C.
Example 64
9-Chloro-7-(2-fluorophenyl)-5H-p~ _m do~5,4-d]~2]benza-
20 zepine-2-thiol-6-oxide
A mixture of 1.5 g (4 mmol) o~ 8-chloro-1-(2-fluo-
rophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-
2-benzazepin-5-one-2-oxide, 1.5 g (20 mmol) of thiourea
25 and 5 ml of a 4M methanol solution of sodium methoxide
in 30 ml of methanol was stirred at room temperature fvr
5 hr. The mixture was poured into water and extracted
with ether. The aqueous solution was acidified with ace-
tic acid and extracted with methylene chloride. The methy-
lene chloride solution was dried over anhydrous sodiumsulfate and concentrated at reduced pressure. The resi-
due was triturated with methylene chloride to give an
orange solid. Recrystallization from methylene chloride
gave the product as orange crystals, mp 323-325C (dec.).
~L13~
_ 75_
Example 65
9-Chloro-7-(2-chloro~hen~ 6,7-dihydro-5H-pyrimido[5,4-
d]~2~benzazepine
A mixture of 68 g (0.2 mol) of 9-chloro-7-(2-chloro-
phenyl)-5H-pyrimido~5,4-d]~2]ben~azepine, 27 g of zinc
dust and 250 ml of acetic acid in 600 ml of methylene
chloride was stirred at -30C for 2 hr. The mixture was
10 filtered over HYFLO into a stirred mixture of 600 ml of
concentrated ammonium hydroxide and 500 ml of ice. The
methylene chloride solution was separated, dried over
anhydrous sodium sulfate and concentrated at reduced pres-
sure. The residue crystallized from a mixture of methy-
15 lene chloride and ether to give the product as a color-
less solid. Recrystallization from a mixture of ether
and methylene chloride gave the product as oolorless need-
les, mp 169-170 ~- *Trade mark
9-Chloro-7-(2-chlorophenyl)-6~7-dihydro-6-[(4-methyl~
nyl)sulfonyl]-5H-pyrimido~5,4-dl~2]benzaz~pine
A solution of 14.5 g (42 mmole) of 9-chloro-7-(2-
chlorophenyl) 6,7-dihydro-5H-pyrimido[5,4-dl[2]benzaze-
pine, 14.5 g (76 mmols) of p-toluene-sulfonyl chloride,
30 ml of pyridine and 0.3 g o~ 4-dimethylaminopyridine
in 300 ml of methylene chloride was stirred at room tempe-
rature for 24 hr. The mixture was washed with an exce~s
of dilute ice cold hydrochloric acid and dilute aqueous
sodium hydroxide. The methylene chloride solution was
dried over anhydrous sodium sulfate and concentrated at
reduced pres~ure to dryness. The residue crystallized
from a mixture of methylene chloride and ether to give
the product as a white solid, mp 200-201C. Recrystal-
li7ation from a mixture of ether and methylene chloride
~L~3~
76
gave the pure product as colorless prisms, mp 200-201C.
Example 67
9-Chloro-7-(2-chlorophenyl)-6,7 dihydro-6-(trifluoroace-
tyl)-5H-pyrimido[5,4-d][2]benzaz~pine
Dropwise 5.0 ml (35 mmol) of trifluoroacetic anhy-
dride was added to a solution of 6.4 g (19 mmol) of 9-
10 chloro-7-~2-chlorophenyl)-6,7-dihydro-5H-pyrimido[5,4
d][2]benzazepine and 10 ml (12.8 mmol) of pyridine in
75 ml of methylene chloride which was cooled to 0C. After
stirring for I hr, the mixture was poured into ice cold
dilute hydrochloric acid. The methylene chloride solution
15 was separatedt washed with saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate and
concentrated at reduced pressure. The residue was cryqtal-
lized from ether to give the product as pink crystals,
mp 178-179C. Recrystallization from ether gave the product
20 as off-white crystals, mp 179-180C.
Example 68
9-Chloro-7-(2-chlorophenyl)-6,7-dihydro-6-[(4-methylphe-
25 nyl)sulfonyl~-5H-pyrimido[5,4-d][2]benzazepine-3-oxide
A solution of 7.6 g (15 mmol) of 9-chloro-7-(2-chlo-
rophenyl)-6,7-dihydro-6-[(4-methylphenyl)sulfonyl]-5H-
pyrimido[5,4-d][2]benzazepine and 4.0 g (20 mmol) of m-
30 chloroperbenzoic acid in 300 ml of methylene chloridewas stirred at room temperature for 48 hr. The mixture
was washed with cold dilute sodium hydroxide and satu-
rated aqueous sodium chloride. The methylene chloride
solution was dried over anhydrous sodium sul~ate and con-
centrated at reduced pressure to dryness. The residue(8.2 g) was purified by column chromatography (silica
gel, 20 g, eluents, methylene chloride then ethyl ace-
L3~B~i3
77 _
tate) the methylene chloride eluent gave 2.0 g oY thestarting material as a colorless solid. The ethyl ace-
tate eluent ~ave 2.1 g of the product as an off-white
solid, mp, 242-243 C. Recrystallization from a mixture
of ether and methylene chloride gave the product as
colorless crystals, mp 243-244C.
Example 69
10 9-Chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benza-
zepine-3-oxide
Method A. A mixture of 2~0 g (3.9 mmol) of 9-chloro-
7-(2-chlorophenyl)~6,7-dihydro-6-[(4-methylphenyl)sulfo-
15 nyl]-5H-pyrimido~5~4-d][2]benzazepine-3-oxide and 8 ml
of a 4M methanol solution of sodium methoxide in a mix-
ture o~ 130 ml of tetrahydro~uran and 180 ml of metha-
nol was ~tirred at room temperature ~or 19 hr. The mix-
ture was poured into an ice cold sodium chloride solu-
20 tion and extracted with methylene chloride. The methy-
lene chloride solution was washed with aqueous sodlum
chloride, dried over anhydrous sodium sulfate and con-
centrated at reduced pressure. The residue was purified
by column chromatography ~silica gel, 20 g; eluents 20~
ether in methylene chloride then 10% methanol in methy-
lene chloride) to give the product in the 10% methanol
in methylene chloride eluent as a white solid. Recrystal-
lization from a mixture of methylene chloride and ether
gave the product as long colorless prisms, mp 189-190C.
Method B. A mixture of 1.5 g (4.3 mmol) of 9-chloro-
7-(2-chlorophenyl)-6,7~dihydro-5H-pyrimido[5,4-d][2]benza-
zepine-3-oxide, and 6 ml of a 5% methylene chloride solu-
tion of bromine in 600 ml of methylene chloride was stir-
red at room temperature for 30 min. The mixture was basi-
fied with the addition of 4.5 ml (32 mmol) of triethyl-
amine and stirred for 10 min. The mixture was washed with
i3
7~ _
saturated aqueous sodium chloride, dried over anhydrous
sodium sulfate and concentrated at reduced pressure. The
residue was purified by column chromatography ~silica
gel, 50 g; eluents methylene chloride then ethyl acetate
then 30% tetrahydrofuran in methylene chloride). The ethyl
acetate eluent contained a colorless solid, mp 242-244C
which was identified a~ a compound isomeric about the
imine bond with the product. The 30% tetrahydrofuran in
methylene chloride eluent contained the product as co~
10 lorless prisms, mp 189-190C.
Example 70
9-Chloro-7-(2-chlorophenyl)-6,7-dihydro 6-~tr ~ uoroace-
15 tyl)-5H-pyrimido[5,4-d][2]benzazepine-3_oxlde
The preparation of 9-chloro-7-~2-chlorophsnyl)-6,7-
dihydro-6~(tri~luoroacetyl)-5H-pyrimido[5,4-d][2]benæa-
zepine-3-oxide wa3 conducted in the same manner as the
20 preparation of 9-chloro-7-(2-chlorophenyl-6,7-dihydro~
6-[(4-methylphenyl)sulfonyl]-5H-pyrimido[5,4-d][2]benza-
zepine-3-oxide to give the product as colorless crystals,
mp 209-211C.
Example 71
9-Chloro-7-(2-chlorophenyl)~6,7-dihydro-5H-pyrimido[5,4-
d][2]benzazepine-3-oxide
A mixture of 4.9 g (11 mmol) of 9-chloro-7-(2-chloro-
phenyl)-6,7-dihydro-6-(trifluoroacetyl)-5H-pyrimido[5,4-
d][2]benzazepine-3-oxide, 50 ml of 3N aqueous sodium hy-
droxide, 100 ml of ethanol and 100 ml of tetrahydrofuran
was stirred at room temperature for 30 min. The mixture
was concentrated at reduced pressure to a small volume.
The resulting precipitate was collected by filtration
to give a colorless solid, mp 259-260C. Recrystallization
79
from tetrahydrofuran gave the product as colorless
crystals, mp 263-264C.
Example A
TABLET FORM~LATION (Wet granulation)
Item ~ mg/tablet mg/tablet mg~ablet mg/tablet
10 1. 2-amino-9- 1 5 10 25
chloro-7-(2-
fluorophenyl)-
5H-pyrimido~5,4-
d]~2~benzazepine
or
7-phenyl-5H-pyri-
mido~5,4-d~benza-
zepin-2-amine
2. Lactose 202 232 261 280
20 3. Modified Starch 25 35 45 55
4. Pregelatinized20 25 30 35
Starch
5. Distilled
; Water q.s.
256. Magnesium 2 3 4 _ 5
Stearate
Weight of tablet250 mg 300 mg 350 mg 400 mg
~-~3~
_ &O _
Procedure:
1. Mix Items 1~4 in a suitable mixer.
2. Granulate with sufficient distilled water to proper
consistency. Mill.
3. Dry in a suitable oven.
4. Mill and mix with magnesium stearate for 3 minutes.
5. Compress on a suitable press equipped with appro-
priate punches.
~0
Example B
TABLET FORM~ILATION (Direct compression)
15 Item I_gredients ~ g~tablet mg/tablet m~/tablet
1. 2-amino-9- 1 5 10 25
chloro-7-(2
~luorophenyl)~
5H-pyrimido~5~4-
d]~2]benzazepine
or
7-phenyl-5H-pyri-
mido[5,4-d]benza-
zepine-2-amine
2. Lactose 221 217 212 181
3. Avicel 45 45 45 55
4. Direct Compres-30 30 30 35
sion Starch
5, Magnesium 3 3 3 4
Stearate
Weight of tablet300 mg300 mg 300 mg 300 mg
Procedure-
1. Mix Item 1 with an equal amount of lactose. Mix well.
2. Mix with items 3, and 4, and the remaining amount
of Item 2. Mix well.
3. Add magnesium stearate and mix for 3 minutes.
4. Compress on a suitable press equipped with appro-
priate punches.
Example C
CAPSULE FORMULATIOM
Item Ingredients m ~tablet m~tablet ~m~tablet
1. 2-amino-9 1 5 10 25
chloro-7-~2-
fluorophenyl)-
5H-pyrimido[5~4-
d][2]benzazepine
or
7-phenyl-5H-pyri-
mido~5,4-d]benza-
zepine-2-amine
2. Lactose 203 293.5 32~ 372.5
3. Starch 30 35 40 30
4. Talc 15 15 20 20
5. Aerosol OT 1 1.5 2 2.5
30 Capsule fill weight 250 mg 350 mg 400 mg 450 mg
6~
_ ~2 _
Procedure:
_
1. Mill Items 1, 2, 3, and 5 in a suitable mixer. Mill.
2. Add talc and mix well.
3. Encapsulate on suitable equipment.
