DERIVES DE LA BENZODIAZEPINE

BENZODIAZEPINE DERIVATIVES

Abrégé anglais

ABSTRACT
Tricyclic benzodiazepines of formula:
<IMG> I
wherein A represents the group -CH2- or -?-; Z is -O- or -?-, where R6 is
hydrogen, lower alkyl or acyl; R1 is hydrogen, halogen, or trifluoromethyl,
R2 is hydrogen or lower alkyl; R3 is hydrogen; Y is a di- or trimethylene
group which may be substituted by R4, R4 being lower alkyl or -CH2X where X
is chlorine, bromine, lower alkoxy-lower alkyl or di-lower alkylamino; and R5
is phenyl or phenyl substituted with halogen or trifluoromethyl are prepared
by cyclization of the corresponding open compounds. Compounds of formula I
wherein Z is -O- and Y is a dimethylene group which may be substituted by R4
may also be prepared by treating the corresponding 4,5-unsaturated benzodiaze-
pines with an epoxide compound in the presence of an acid catalyst. The com-
pounds of formula I are useful as sedative, muscle relaxant and anti-convulsant
agents.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of tricyclic benzodiazepines of the
general formula:
<IMG> I
wherein A represents the group -CH2- or -?-; Z is -O- or -?-, where R6 is
hydrogen, lower alkyl or acyl; R1 is hydrogen, halogen or trifluoromethyl;
R2 is hydrogen or lower alkyl; R3 is hydrogen or lower alkyl, Y is a di-
or trimethylene group which may be substituted by R4, R4 being lower alkyl
or -CH2X where X is chlorine, bromine, lower alkoxy-lower alkyl or di-lower
alkylamino; and R5 is phenyl or phenyl substituted with halogen or trifluoro-
methyl with the exclusion of those compounds in which (a) Z is -O-, R1 is
chloro in the 7-position of the benzodiazepine moiety, -A is -?-, R2 and
R3 are hydrogen, R5 is phenyl and Y is -CH-CH2-; and (b) Z is -O-, R1 is
chloro in the 7-position of the benzodiazepine moiety, A is -?-, R2 and R3
are hydrogen, R5 is 2-chlorophenyl and Y is -CH2-CH2- which comprises
a) cyclizing a compound of the general formula:
<IMG> II
28

wherein R1, R2, R3, R5, A, Y and Z are as defined above, but excluding those
compounds of formula II in which A is - ? - when R3 is hydrogen, Y is di-
or trimethylene which may be substituted by lower alkyl and Z is -O-, and
if a compound of formula I wherein Z represents -NH-- is obtained and it
is desired to produce a compound of formula I wherein Z is <IMG>, R?, being
lower alkyl or lower acyl, alkylating or acylating the said -NH- group or
b) for the preparation of compounds of the general formula
<IMG>
I-A
wherein R1, R2, R3, R5 and A are as defined above, R'4 represents hydrogen,
lower alkyl or CH2X where X is as defined above, reacting a 4,5-unsaturated
1,4-benzodiazepine of the general formula
<IMG>
III
wherein R1, R2, R3, R5 and A are as defined above, with an epoxide compound
of the general formula
<IMG> IV
29

wherein R'4 is as defined above with the proviso that (a) when R1 is 7-
chloro, R2 and R3 are hydrogen, A is - ? - , and R5 is phenyl R'4 is other
than methyl; and (b) when R1 is 7-chloro, R2 and R3 are hydrogen, R5 is
2-chlorophenyl, A is - ? - R4 is other than hydrogen, in the presence of an
acidic agent and isolating the compound of formula I-A thus formed and, if
following either method a) or b) a mixture of epimeric compounds of
formula I is obtained, separating, if desired, the said mixture into its
components.
2. A process as claimed in claim 1 wherein the starting material of
formula II as defined in claim 1 is prepared by reacting a corresponding
2-substituted aminophenyl ketone of the general formula
<IMG>
V
wherein R1, R2, R3, R5 and A are as defined in claim 1 and X' is chlorine,
bromine or iodine, with a diamine or aminoalkanol of the general formula
H2N- Y-ZH VI
wherein Y and Z are as defined in claim 1 in the presence of a base.
3. A process as claimed in claim 1 wherein Z represents <IMG> where
R6 is hydrogen, lower alkyl or acyl and R1, R2, R3, R5, Y and A are as
defined in claim 1.
4. A process as claimed in claim 1 wherein A represents -CH2- and R1;

R2, R3, R5, Y and Z are as defined in claim 1.
5. A process as claimed in claim 1 wherein A represents - ? - , Z is
-O-, Y is a di- or trimethylene group substituted by CH2X where X is
chlorine, bromine, lower alkoxy-lower alkyl or di-lower alkylamino and R1,
R2, R3 and R5 are as defined in claim 1.
6. A process as claimed in claim 1(a) wherein Z is -O-, A, R1, R2, R3,
R5 and Y are as defined in claim 1.
7. A process as claimed in claim 1(b) wherein Z is -O- and A, R1, R2,
R3, R5 and Y are as defined in claim 1.
8. A process as claimed in claim 6 wherein R1 is hydrogen or halogen
which is joined to the benzene ring in para-position with respect to the
-N- group, R2 is hydrogen, or lower alkyl, R3 is hydrogen, Y is a di- or
trimethylene group which may be substituted by lower alkyl or chloromethyl
and R5 is phenyl or phenyl substituted at the ortho position with halogen.
9. A process as claimed in claim 7 wherein R1 is hydrogen or halogen
which is joined to the benzene ring in para-position with respect to the
-?- group, R2 is hydrogen, or lower alkyl, R3 is hydrogen, Y is a di- or
trimethylene group which may be substituted by lower alkyl or chloromethyl
and R5 is phenyl or phenyl substituted at the ortho position with halogen.
10. A process as claimed in claim 8 or 9 wherein R1 is chlorine, R2 is
hydrogen or methyl, Y is a dimethylene group which may be substituted by
methyl or chloromethyl and R5 is phenyl or o-fluorophenyl.
11. A process as claimed in claim 1(b) wherein 7-chloro-5-(2-fluoro-
phenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one and ethylene oxide are used
as the starting materials.
31

12. A process as claimed in claim 1(b) wherein 7-chloro-1,3-dihydro-
1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 1-chloro-2,3-epoxypropane
are used as the starting materials.
13. A process as claimed in claim 1(b) wherein 7-ch1oro-2,3-dihydro-
1-methyl-5-phenyl-1H-1,4-benzodiazepine and ethylene oxide are used as the
starting materials.
14. A process as claimed in claim 2 wherein 5-chloro-2-(2-chloroethyl-
methylamino)benzophenone and 2-aminoethanol are used as the starting material.
15. A process as claimed in claim 2 wherein 2-(2-chloro-N-methyl-
acetamido)-5-chlorobenzophenone and ethylenediamine are used as the starting
materials.
16. A process as claimed in claim 2 wherein 5-chloro-2-(2-chloroethyl
methylamino)benzophenone and 3-aminopropanol are used as the starting
materials.
17. A procesa as claimed in claim 2 wherein 5-chloro-2-(2-chloroethyl-
methylamino)benzophenone and ethylenediamine are used as the starting
materials.
18. A process as claimed in claim 1 wherein the reaction between the
compounds of formulae III and IV is conducted in an anhydrous inert organic
so1vert in the presence of an acidic agent.
19. A process as claimed in claim 18 wherein the said reaction is
carried out at a temperature in the range of from about -10°C to the reflux
temperature of the reaction medium.
20. A process as claimed in claim 18 wherein the said solvent is an
aromatic hydrocarbon, an ether or carbon disulfide.
32

21. A process as claimed in claim 18 wherein the said acidic agent is
aluminium chloride, ferric chloride, zinc chloride, titanium tetrachloride,
boron trifluoride, p-toluene sulfonic acid or benzene sulfonic acid.
22. A tricyclic benzodiazepine of the general formula
<IMG> I
wherein A represents the group -CH2- or <IMG>; Z is -O- or <IMG>, where R6
is hydrogen, lower alkyl or acyl; R1 is hydrogen, halogen or trifluoromethyl
R2 is hydrogen or lower alkyl; R3 is hydrogen; Y is a di- or trimethylene
group which may be substituted by R4, R4 being lower alkyl or -CH2X where X
is chlorine, bromine, lower alkoxy-lower alkyl or di-lower alkylamino; and
R5 is phenyl or phenyl substituted with halogen or trifluoromethyl with the
exclusion of those compounds in which (a) Z is -O-, R1 is chloro in the 7-
position of the benzodiazepine moiety, A is <IMG>, R2 and R3 are hydrogen,
R5 is phenyl and Y is <IMG> ; and (b) Z is -O-, R1 is chloro in the 7-
position of the benzodiazepine moiety, A is <IMG>, R2 and R3 are hydrogen
and R5 is 2-chlorophenyl and Y is -CH2-CH2-, whenever prepared according
to the process claimed in claim 1 or by an obvious chemical equivalent
thereof.
23. A compound according to claim 22 wherein Z represents <IMG> wherein
R6 is hydrogen, tower alkyl or acyl and R1, R2, R3, R5, Y and A are as
defined in claim 22, whenever prepared according to the process claimed in
claim 3 or by an obvious chemical equivalent thereof.
33

24. A compound according to claim 22 wherein A represents -CH2- and
R1, R2, R3,R5, Y and Z are as defined in claim 22, whenever prepared accord-
ing to the process claimed in claim 4 or by an obvious chemical equivalent
thereof.
25. A compound according to claim 24, wherein A represents <IMG>, Z is
-O-, Y is a di- or trimethylene group substituted by CH2X where X is chlorine,
bromine, lower alkoxy-lower alkyl or di-lower alkylamino and R1, R2, R3 and
R5 are as defined in claim 22, whenever prepared according to the process
claimed in claim 5 or by an obvious chemical equivalent thereof.
26. A compound according to claim 22 of the general formula:
<IMG> I-a
wherein A, R1, R2, R3, R5 and Y are as defined in claim 22, whenever prepared
according to the process claimed in claim 6 or by an obvious chemical equi-
valent thereof.
27. A compound of the general formula:
<IMG> I-b
34

wherein R1" is hydrogen or halogen, R2 is as defined in claim 8, Y' is a
di- or trimethylene group which may be substituted by lower alkyl or chloro-
methyl, and R7 is hydrogen or halogen whenever prepared according to the
process claimed in claim 8 or by an obvious chemical equivalent thereof.
28. A compound of the general formula I given in claim 22 wherein R1,
R2, R3, Y and R5 are as defined in claim 9 and Z is -O- whenever prepared
by the process of claim 9 or by an obvious chemical equivalent thereof.
29. A compound according to claim 27 wherein R1" is chlorine, R2 is
hydrogen or methyl, Y' is a dimethylene group which may be substituted by
methyl or chloromethyl and R7 is hydrogen or fluorine, whenever prepared
according to the process claimed in claim 10 or by an obvious chemical
equivalent thereof.
30. A compound of the formula I in which Z is -O- and A, R1, R2, R3,
R5 and Y are as defined in claim 7 whenever prepared by the process of
claim 7 or by an obvious chemical equivalent thereof.
31. 10-Chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d]-
[1,4]benzodiazepin-6-(7H)-one, whenever prepared according to the process
claimed in claim 11 or by an obvious chemical equivalent thereof.
32. 10-Chloro-2-chloromethyl-2,3,5,11b-tetrahydro-7-methyl-11b-phenyloxa-
zolo[3,2-d][1,4]benzodiazepin-6-(7H)-one, whenever prepared according to
the process claimed in claim 12 or by an obvious chemical equivalent thereof.
33. 10-Chloro-2,3,5,6,7,11b-hexahydro-7-methyl-11b-phenyloxazolo[3,2-d]-
[1,4]benzodiazepine, whenever prepared according to the process claimed in
claim 13 or 14 or by an obvious chemical equivalent thereof.
34. 10-Chloro-1,2,3,5,7,11b-hexahydro-7-methyl-11b-phenyl-6H-imidazo-

[1,2-d][1,4]benzodiazepin-6-one, whenever prepared according to the process
claimed in claim 15 or by an obvious chemical equivalent thereof.
35. 11-Chloro-3,4,6,7,8,12b-hexahydro-8-methyl-12b-phenyl-2H-[1,3]
oxazino[3,2-d][1,4]benzodiazepine, whenever prepared according to the
process claimed in claim 16 or by an obvious chemical equivalent thereof.
36. 10-Chloro-2,3,5,6,7,11b-hexahydro-7-methyl-11b-phenyl-1H-imidazo-
[1,2-d][1,4]benzodiazepine, whenever prepared according to the process
claimed in claim 17 or by an obvious chemical equivalent thereof.
37. A process for the preparation of tricyclic benzodiazepines of the
general formula VII which comprises reacting a compound of the general
formula V with an epoxide of the general formula VI
<IMG>
V VI
<IMG>
VII
36

wherein R2 is as defined in claim 1, R1 is hydrogen, halogen, nitro or
trifluoromethyl, R3 is hydrogen, halogen or trifluoromethyl and R4 is
hydrogen or lower alkyl, with the proviso that (a) when R1 is 7-chloro, R2
and R3 are hydrogen, R4 is other than methyl; and (b) when R1 is 7-chloro
or 7-nitro, R2 is hydrogen, R3 is 2-chloro, R4 is other than hydrogen, and
isolating the compound of formula VII thus formed.
38. A tricyclic benzodiazepine of the general formula VII, defined in
claim 37, whenever prepared by the process of claim 37 or by an obvious
chemical equivalent thereof.
39. A process according to claim 37 for the preparation of 10-chloro-
2,3,5,11b-tetrahydro-11b-phenyloxazolo [3,2,d][1,4]benzodiazepin-6(7H)-one
which comprises reacting 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-
2-one with ethylene oxide and recovering the required product from the
reaction mixture.
40. 10-Chloro-2,3,5,11b-tetrahydro-11b-phenyloxazolo [3,2-d][1,4]
ben odiazepin-6-(7H)-one, whenever prepared by the process of claim 39 or
by an obvious chemical equivalent thereof.
41. A process according to claim 37 for the preparation of 10-chloro-
2,3,5,11b-tetrahydro-7-methyl-11b-phenyloxazolo [3,2-d][1,4]benzodiazepin-6-
(7H)-one which comprises reacting 7-chloro-1,3-dihydro-1-methyl-5-phenyl-
2H-1,4-benzodiazepin-2-one with ethylene oxide and recovering the required
product from the reaction mixture.
42. 10-Chloro-2,3,5,11b-tetrahydro-7-methyl-11b-phenyloxazolo [3,2-d]
[1,4]benzodiazepin-6-(7H)-one, whenever prepared by the process of claim 41
or by an obvious chemical equivalent thereof.
43. A process according to claim 37 for the preparation of 10-chloro-
37

2,3,5,11b-tetrahydro-2,7-dimethyl-11b-phenyloxazolo [3,2-d][1,4]benzodiazepin-
6-(7H)-one which comprises reacting 7-chloro-1,3-dihydro-1-methyl-5-phenyl-
2H-1,4-benzodiazepin-2-one with propylene oxide and recovering the required
product from the reaction mixture.
44. 10-Chloro-2,3,5,11b-tetrahydro-2,7-dimethyl-11b-phenyloxazolo
[3,2-d][1,4]benzodiazepin-6-(7H)-one, whenever prepared by the process of
claim 43 or by an obvious chemical equivalent thereof.
38

Description

The present invention relates ~o benzodiazepine derivatives. More
particularly it relates to tricyclic ben30diazepines and to the preparation
thereof.
In accordance with the present invention3 there is provided a tri
cyclic benzodiazepine of the general formula: -
~ ~XR
~ 6
wherein A represents the group --CH2- or -C-; 2 is -0- or -~-, where R6 is
i ~ ... .
hydrogen, lower alkyl or acyl; ~ is hydrogen~ halogen or trifluoromethyl;
R2 is hydrogen or lower alkyl; R3 is hydrogen; Y is a di- or trimethylene
group which may be substituted by R4, R4 being lower alkyl or -CH2X where X
is chlorine, bromine, lower alkoxy_lower alkyl or di-lower alkylamino; and
R5 is phenyl or phenyl substituted with halogen or trifluoromethyl~with the
exclusion of those compounds in which (a) 2 is -0-, ~ is chloro in the 7-
position of the benzodiazepine moiety, A is -C-, R2 and R3 are hydrogen,
phenyl and is -C~-CH2-; and (b) Z is -0-, ~ is chloro in the 7
position of the benzodiazepine moiety, A is -C-, R2 and R3 are h~drogen,
R5 is 2-chlorophenyl and Y is -CH2-CH2-.
As used herein, the term "lower alkyl"~ either alone or in combina-
tion such as in di~lower alkylamino, co~prehends straight or branched chain
hydrocarbon groups having from 1-7 carbon atoms, preferably 1-4 carbon atoms,
.:
such as methyl, ethyl, propyl, isopropyl and the like. The term 'iacyl"
enco~passes an~organic radical deriv~d by removal of a hydroxyl group from -
an organic acid, such as an alkanoic acid containing from 2-7 carbon atoms~
,, -, .
~ for e~ample propionyl and the like. The term "lower alkoxy" comprehends a

lower alkyl group having an oxygen function substituted therein, such as
methoxy, ethoxy, propoxy~ etc. The term "halogen" represents all four forms
thereof, i.e., f]uorine, chlorine, bromine and iodine, unless express]y
indicated otherwise.
One particular aspect of the present invention relates to compounds
IR~
of formula I above wherein Z represents the group -N- where R6 is hydrogen,
lower alkyl or acyl~ Rl, R2, R3, R5~ Y and A being as defined above. ;~
" . ,~ ' '
':
~'. .... -, ,.
,, ~,
.. .......... .
~!
, .
J, :~ :
~ ~ ' ','''',' '."
'' ,,
~''; '" . '' '
, . ' :'.
'` ' ,"~' ';'
~ - la - ~

A further particular aspect of the present invention relates to com-
pounds of formula I above wherein A represents the group -CH2-, Rl, R2, R3,
R5, Y and Z being as defined earlier.
A still further particular aspect of the present invention relates
to compounds of formula I above wherein A represents the group -C-, Z is -0-,
Rl, R2, R3 and R5 are as defined earli~r and Y is a di- or trimethylene group
substituted by CH2X where X is chlorine, bromine, lower alkoxy-lower alkyl or
di-lower alkylamino.
A preferred group of compounds falling within the scope of formula ~ -~
I are those wherein Z is -0- i.e. compounds of the general formula:
12 '"
R~
R ----Y
; wherein A, Rl, R2, R3, R5 and Y are as defined earlier.
A particularly preferred embodiment of the present invention encompas-
ses the compounds of formula I wherein Z is -0-, Rl is hydrogen or halogen,
wlth chlorine being the preferred halogen~ and is joined to the benzodiazepine
moiety at the 7-position thereof; R2 is hydrogen or lower alkyl, with methyl
being preferred; R3 is hydrogen; Y is a di- or trimethylene group which may be
substituted by lower alkyl, most preferably methyl, or chloromethyl; and R5 ..
is phenyl or phenyl substituted at the ortho position with halogen, with
1uorine being the most preferred halogen; i.e. compounds of the general for-
; mula:~
~ Rl~ ~ N\ I-b
~ ~--Y' ', : "
~ ~ 7 ~ ~
; ~ ; . .
.,~ :

wherein R"l is hydrogen or halogen; A is as defined earlier; R2 is as
defined earlier; Y' is a di- or trimethylene group ~hich may be substituted
by lower alkyl or chlorome~hyl; and R7 is hydrogen or halogen.
Most preferred among the compounds of formula I above are those
wherein Z is -0-; Rl is chlorine and is joined to the benzodiazepine moiety
at the 7-position thereof; R2 is hydrogen or methyl; R3 is hydrogen; Y is a
dimethylene group which may be substituted by methyl or chloromethyl; and R5
is phenyl or phenyl substituted in the ortho position with fluorine~ :
In accordance with the present invention, there is furthermore pro-
vided a process for the preparation of benzodiazepine derivatives of the
formula I above, which comprises a) cycli~ing a compound of the general
formula:
R2 3
N - A - CH - NH - Y - Z - H
1 ~ II
C= O
. .. . ..
wherein ~, R2, R3, R5, .A, Y and Z are as defined éarlier but excluding those
compounds of formula II in which A is -C- when R3 is hydrogen, Y is di-
or trimethylene which may be substituted by lower alkyl and Z is -0- and if
: a compound of formula I wherein Z represents -NH- is obtai~ed and it is
desired to produce a compound of ~ormula I wherein Z is -~-, R6t being lower
alkyl or lower acyl, alkylating or acyla~ing the said -NH- group o:r b) for
the preparation of compo~mds of ~he general formula:
- 3 - ;:

1 2
R3
R5 0 \ I-A
R' ~
,
wherein Rl, R2, R3, R5 and A are as defined earlier and R~4 represents
hydrogen~ lower alkyl or C~2X where X is as defined earlier~ reac~ing a 4,5-
unsaturated 1~4-benzodia~epine of the general formula
l2 ; `~
i: .
: wherein R1, R2, R3~ R5 and A are as defined earlier with an epoxide compound : :
of the general formula
, .
wherein R'4 lS as defined above with the proviso that (a) when ~ is 7-
IO:~ chloro~ R2~and~R3 are hydrogen~ A is ~C~g and R5 is phenyl R4 is other then
methyl;:and (b~ ~hen Rl is 7-chloro~ R2~and R3 are hydrogen~ R5 is 2 :.;chIorophenyl~ S--C-, R~ is other than hydrogen in the presence of an
: acidic ~gent and isola~ing ~he compound of formula I-A ~hus formed and, if
:following method a~ or b) a mixture of epimeric compounds of form~lla I is ~ .:
ob~ained~:separating, if desired~ the said mixture into its components~ :
: : ~: ~ :
:,
~ ~ !l ; .:
: ~ , ~ :,

ThusJ in on~ process aspect of the present inventlon~
compoun~ of rormula I are obtalned by cycliz~tlon o~ a compound
o~ th~ formula II, above. The compound~ of the formula II ..
above which ar~ u~d a~ the starting mal;erials ln this process :~
a~pect are conveniently prepared by reacting a corresponding
2-~ub~tituted ~minophenyl ketons o~ the general rormula : ~ ;
2 l~ .
N-A-CH-X'
Rl t ll V
~C=O ':
R5
wherein R1J R2P R3~ R5 and A are as derined earlier
and X' i~ chlorine, bromine or iodine ~:
lo wlth a dlamine or aminoalkanol of the general formula
H2N -Y ZH Vl
whor~ln Y and Z are as de~ined earlier.
~he compound~ Or rormulae V and VI above are readlly
preparod in a manner known in th~ art, The reaction between
the compound~ Or rormulae V and VI above ls conducted in a
react1on medlum ~ont~ nlng a ba3e and ~n inert organlc solvent~
Suitabl~ bases ~or the purpo~e~ Or this invention are lnorganic
bas~s, ~uoh as ~odlum acetate and organlc bases such as the
: t~rtlary ~mine~p for example9 trialkyl~mine~ with triethyl-
: ; 20 amine and pyrldlne being preforred. A vari~ty o~ organic 301- ;:
v~nt~ ar~ u~ul ~or th2 purpo~es Or thl~ lnventlon. Amon~
th~ u~tabl~ 301~nt~ are lower alkanols 9 such as methanol,

r~ ~
ethanol, propanol, etc., wlth ethanol being preferred~ aromatic
hydrocarbon3, such as benzene, toluene, xylene, ~tc.; high
bolling point etherq3 ~Yuch as tetrahydro~uran ~ld dloxane;
and amides, such as dlmethylformamlde, dlethylformamlde and
th~ llke. Ir, in the compound~ of formula V~ X' i~ chlorine
or bromin~, the reactlon mlxture ma~ al30 contain sodlum iodide
in order to convert ~uch X' substituent to the mor~ r~active
iodine atom. Examples of co~pounds of formula VI useful. ln
thls invention lnclude 2-amlnoethanol, ethylenedlamine,
3-amlnopropanol J etc. ~ .
.
The intermediat~ o~ the general formula II above thus ~:.
~or~ed need not b~ lsolated rrom the reactlon mlxture as lt
readily oyclize~ to the da~ired oompound of formula I and
in a pre~erred embodiment, the intermediate is not i~olated
but i8 pormitted to cy~lize ln the rea~tion medium in which
it is prepared by conducting the reactlon betw~en the com- :
pounds of formula V and VI above at a temperature in the : -
range Or ~rom about 25C to the rerlux-temperature o~ the
roactlon medlum, prerorably at about the reflux temperature. :
However by uslng less energetic reaetion condition~9 ~.g. by
conductl n~s th~ reactlon between the compounds of ~ormulae
Y ~d VI abov~ at about or below room temp~rature, the inter
m~diate oompound Or th~'rormula II can be isolated and Yub-
~equontly cyollzed to the desired produot, o.g. by heating
: ?5 in pyrldin~, eth~nol, xyle~e ~nd the llke~
,
Compounds Or ~ormula I wher~ln Z is -NH~ thu3 obtalned
o~n bo ¢onv~rt~d into the correspondlng compounds Or formula I
~ ~ 6 -

~` "" ~ .
whersin Z ls -N- , R ' 6 bein~ lower alkyl or acyl, by conven-
tional alkylation or acylation procedures. By controlling
the reaction conditions~ alkylation or acylatlon can be
accompllshed on the nltrogen of the heterocyclic ring without
afrccting other vulnerable positlons on the b~nzodi~zepine
moiety~
In accordance with a rurther and partlcularly lmportant
proce3s aspect Or the present inventlon compounds of formula
I above wherein Z i~ -0- and Y is a dimethylene group which
may be substi~uted by Rl~ , i.e. compounds of the formula I-A
above, are prepared by reacting a 4,5-unsaturated 1,4-benzo-
diazepine o~ rormula III above with an epoxi-le compound o~
formula IV above in the presence of an acidic ag~nt, such asJ
for example, an aprotlc acid~ e.g., aluminum chloride, ferrlc
chloride, zinc chlorlde, tltanium tetrachloride, boron trl- :~
~luoride, etc.; vr p-toluene xulfonic acid, benzene sulfonlc ~. .
~cid, and the like, Tho most pre~erred acidic agent for the
purpo3es of this lnvention i~ aluminum chloride. Examples Or
compounds of ~ormula IV u~erul ln this lnv~ntion lnclude ethyl~ne
o~ld~, propylene o~lde, l-chloro-2,3-epoxy propane, etc.
~' . .
: The reactlon whereby compounds o~ formula I-A above are
prepar~d:from the compounds of formulae III and IV ls con-
v~niently conducted 1D the presence Or an anhydrous inert
or~anic ~olvent~ Suitable inert org~nic solv~nts for this
; : 25 purpo~s include/ for example, aromat~o hydrocarbons such as
benzen~, toluene, xyl~ne, etc., ethor~J such as tetrahydro-
~uran and dlethyl ~ther, or carbon disulfide. mls reactlon
: 1' ' '' , ' : .
q

may be carried out at a temperature in the range Or ~rom about
-10C to the reflux temperatur~ of the reaction medlum ~05t
pre~er~bly from lO~C to the reflux temperature. The selectlon
Or kemperature i5 not critical ~or the purpose3 of th¢
present lnventlon and will, o~ course, depend upon the
¢haracteristlcs Or the compound~ selected ~5 reagents, the
solvent medium employed and the natur~ of th~ acidlc ag~nt
us~d.
It would appear that when a compound of formula III is
r~acted wlth a compound of formula IV whereln R'l~ is other
than hydrogen, the R'4 bearing carbon atom can be attached
relatlv~ to the benzodiazepin~ rlng ln on~ o~ two altsrnat~ :
posltions, depending upon the ~int where the epox-lde rlng
cleaves during the reaction. However, experimentation h~
shown that the epoxlde ring evidences a propenslty to f'avor
cleavage between the oxygen and the unsubstituted carbon atom.
Thus, when cleavage occurs at this point, the carbon atom bear-
lng the R~ substituent i8 bonded to the oxygen atom in the
heterocyclic rlng. .:
It should be noted that oompound~ of ~ormula rv abov~
may, ln addition to forming the heterocyclic ring between the ..
4 and 5 po~ltion~ Or the benzodlazepln~ moiety upon reaction
wlth the compound of ~ormula III, al80 react wlth the nitrogen
: ato~ in the l-posltion o~ the compounds Or formula III when
the nitrogen i5 unprot~cted, that i~ when R2 is hydrogen. Thus,
~th~ reactlon of a compound of ~ormula III wher0in R2 1~ hy-
drogen w~th a compound Or rormula ~V can result ln a mixture
of ~mpound~ the -~lrst showing no ~ub~tltution on the 1-
: ni~ro~cn a~d the ~e¢ond b~ln& ¢orrespondlngly subs~ituted on
r~, .;, I , ,
the l-nltrogenL For examplo9 1~ a compo~ld of form1l1a III wherein ~ ~ :
: '.

-
R2 is hydrogen is reacted with a compound of formula IV wherein R'~ is
hydrogen, i.e. ethylene oxide, one is able to iso]ate from the reaction
mixture both the corresponding compound of formula I-A above wherein R2 is
hydrogen and the corresponding compound of formula I-A above wherein the A-
nitrogen is substituted by ~ -hydroxy ethyl. Experimentation has shown
that by controlling ~he reaction conditions~ substitution at the l-nitrogen
can be avoided.
It will be appreciated that in following both the epoxide method
~ involving the reaction between compounds of formula III and IV and the
- 10 cyclization method discussed above for the preparation of the tricyclic
benzodiazepine derivatives of formula I, the produce obtained in many cases
will be a mixture of epimers which can be separated into its components by
methods known in the art. Thus~ for example~ in the preparation of a compound
of the formula
H O
~ (ll-b) >
Cl/~
.1 3 .
,,
follow~ng either synthetic route, it was noted that the reaction produced
a mixture of two epimers show~ing~ a difference in configuration at the 2-
and ll-b positions of the molecule. Upon separating the mixture into its
~ two components~ the following cis and trans isomers were obtained:
''': ' '
: .
';
3~ - 9 ~

~f~
Cl ~ \ and C
C~13
(2,11b cis) (2,11b trans) ~ : :
If a solution containing either of the isolated epimers .is pe~nitted
to stand~ a mixture containing both the ~i~ and ~ epimers results~
~pimerization can also be effected by means of e.g. boron trifluoride ether- ~
ate~ :
Examples of compounds which correspond to formula I and which are
thus represen*ative of the present invention may be lis~ed as follows:
10-Chloro-2,3,5,11b-tetrahydro-llb-phenyloxazolo ~332-d]~lJ4
benzodia~epin-6(7H)-one;
10-Chloro~llb-(2-fluorophenyl)-2,3~5gllb-tetrahydrooxazolo~3,2-d~ -:
~1~4]benzodiazepin~6-~7H)-one;
',,'~ ~ '
' ' ',:
' .
`~ - 10 ~ ., :
: . ~

diaz~pin-6-(7H~-one~
10-Chloro-293,5,11b-tetrahydro-7-methyl-llb-
phenyl OXRZ olo[3,2-d]11,4]benzodiazepln-6-(7H)-onei
10-Chloro-2,3,5,11b-tetrahydro-2,7 dimethyl-llb-
phenyloxazolol~,2-d~[194]benzodiazepin-~7H)~one
(2,11b cis)S
10-Chloro-2-chloromethyl-2J~i,5,11b-tetrahydro--
7-methyl-llb-phenyloxazolol~,2-d~[1,4~benzodiazepin-
6(7H)-on~
10-Chloro-2~5,6,7,11b-hexahydro-7-methyl-llb-
phenyloxazolo[3,2-d] [1,43benzodiazeplne;
10-Chloro-192,~,5,7,11b-hexahydro-7-methyl-llb-
phonyl-6H-lmldazo 11~2-d]ll, 4~ b~nzodiazepln-6-one ~
ll~Chloro-~,4,6J7,8,12b-hexahydro-8-methyl--12b-ph~nyl-
~Hl133~o~aæino[3,2~d]~1,4]benzodiazepino;
10-Chloro~2,395,6,7,11b-hexahydro-7-m~thyl-
llb-ph~nyl-lH~lmidazo[1,2-d][1,4]benzodiaz~pine,~
10-5hloro-2,3,5,11b-t~tr~hydro-2-methyl -llb-
phenyloxazolo~3,2-d~1,4]benzodiazepln-6(7H)-
ono (2,11b ~
10 Chl oro-2, 3 " 5 " llb - te trahydro 2 -me ~hyl - llb -
ph~nylo~cazolo[ ~5,2-d] 119 4]b~nzodlazepin--6(7H)-
one (2 jllb tr~J3) p
10-Chloro-2,~5J5,11b tetrahydro-3 methyl-llb-
.
phenyloxazolo[3~2-d][194~b~nzadiazepin~6(7H)~
one (~,llb cls ~.
m~ tricyclic bonzod~az~pine d~rlvatlves o~ rormula I
abov~ ar~ u~e~ul a~ pharm~coutlcal~ and are ¢hara.cterlzed by
_ ~ ~ .

g8
activity as sedative, muscle, relaxant and anti-convulsant agents.
The pharmacological acti~ity of a series of compounds of the present
invention was determined in standard screening tests. Compo~ds which
were employed in these experiments were as follows:
10-chloro-llb-(2-fluorophenyl)-2,3,5,11b-tetrahydro-
oxazolo[3,2-d][1,4]ben~odiazepin-6-(7H)-one (COMPOUND C)
10-chloro-2,3,5,11b-tetrahydro-llb-phenyloxazolo-
[3~2-d][1,4]benzodia~epin-6-(7H)-one (COMPOUND D)
10-chloro-2~3~5~11b-tetrahydro-7-methyl-llb-phenyloxa-
zolo[3,2-d][1,4]benzodiazepin-6-(7H)-one (COMPOUND E)
10-chloro-2,3,5~11b-tetrah~dro-2,7-dimethyl-llb-
phenyloxazolo[3~2-d][1~4]benzodiazepin-6-¦7H)-one
(COMPOUND F)
10-chloro-2-chloromethyl~2,3~5~11b-tetrahydro-7-methyl-
llb-phenyloxazolo~3,~-d][1,4]benzodiazepin-6-(7H)-one
!~iCOMPOUND G)
10-chloro-2,3,5~6~7~11b-hexahydro-7-methyl-llb-phenyl-
oxazolo[3,2-d]~1~4]benzodiazepine ¦COMPOUND H)
The tests employed in this experiment where the following: ~ ;
`'':,".
.
~;; ;~ ., - ,
j, , ,.: : ~:
' ':
~ - 12 ~ ~ ~
... , . . . ,. . . , , .. . ... . - . .

~ 8
Foot Shock
mls test ls a screen for compounds having mu~cle
rel~xant and/or anti~anxiety ~tranquilizer) activity. A pair
Or mioe is conrined under a one llt~r beaker placed on a grid
whlch prasents shock to the fee~. At leaqt 5 fighting episode~
aro ~liclted in a two-minute period. Pairs o~ mlce are mark~d
and pretreated by oral dosage 1 hour prior to a second
shockln~.Logarithmic dose intervals are utilized up to a
maximum Or lOO mg~ g. At the lO0 per cent blocklng dose, 3
out of 3 pair~ must be blocked ~rom ~ightlng
Inclined ~creen
The te~t ls useful in determining muscle relaxant ~nd/or
~odative activlty. Groups of 6 male mice are given the test
drug (maxlmum dose of 50Q mg/k~) and then are lert one the
inclined screen at least rOur hours for abserv~tion of
paralyzing effects severe enough to cause them to slide off
the ~ereen. If activity is observed, additlonal doses are tested
until at least two are re~ched at which ~ome, but not all the
anlms,l~ ~lid~ O.~r the scr~erl. Doses at which mlce rall O~r
the soroon due to lcoxicity or excitation are not lnclud~d in
tho ~alculation of PD50. Ihe PD50 is determined ~rom a gr~ph
on whleh dose i~ plotted agalrlst per c~nt of mice paralyz~d. ~hls
PD50 value 1~ derln~d as the dose in mg/kg which can be
~: ~p~otod to C~U8~ 50 p~r cent Or mio~ to slide o~ the screen. ~ .
'
~5 ~ YC~YU~ol:
,
;~ Cat~ arc tr~ated orally ~nd ob~erved ~or m:Lni~m
B ~ ~ymptoms~usually ataxia. One cat is used at a do~ o~ 50 mg/kg.
' /~ ..
"' '`
,,, , . ., . ., - ~ ". ~ .. ... .. .. . .. . . . . .

~;`i,
9~
:~ actlvity ls pre~ent ~ up to three cats per dose ar~s used.
Results are glven as mlnlmum eff'ective da~e. This test ls
use~ul ln detcrminlng muscle relaxant actlvlty.
Ant Imetrazol
mis test determines antlconvulsant and/or sedative
activity oi` compounds in micc. The test c~mpound i6 adrnir~istered
oral}y to groups Or ~our mlc~ at varlous dose levels. One hc)ur
later, m~traæol (at a dose level previously determirle to ~e
sur~lcient to lnduce convulsive selzu~es ln all test animais
approxlmately 125 mg~ g) ts ad~inistered subcu~aneout~y ~nd
the anLmals are observed ~or protection rrom eonvulsive
seizures. R~s~llts are recorded as the number of` animals
protected ae;alnst convulsions. The dose at which 50 per cent
Or the animals are protected rrom convulslv~ selzur~s i~
expr~s~ed as the ED50-
Tb~ test result~ Irom the above tes'cs uslng in~ic~ted ~:
compounds Or the pre~ent inv~nt1 on are summarized below ir
. Tablo I.
:
;' ' '~ :
, ~ , .; . :.
- .
,; , ,
,, , ,: ~ ~: .
:B
, , , ,~ .
. .
... .. ., ..... ;............ . .. . . . . . .. . .. . .. .

O bO bO
~5 O ~ O ~ bO
~ L~ : L~
~;
J O '
~15I ~I bO bO
r ~~ ~I O bO ~O
J~L ~ ~ ~ L~ I I I O I
OC)
.,.
~ O I D t bO bO bO bO bO b,O
E~ ~ ~ ~ ~
C) ! ! D bO bO bO bO bO t~
E~ Ei f3 ~3 ~ Ei '
~0 ~1 c ~ L ~ ~ O O O O O
~ P~ L I N O L ~ O O
H
~ : '
O I O bO bO ~ bO tlO
bO , O I D ~O bO ~1 bO ~O
~:,X I 3 e ~ 5~3 E e
ooq~ ~ ~: ,~ooooI
~o~ ~ ~ r~ o~ oo o~
o
r~
I ~ Q ~
,~ ~ ~ i ~ ~ 5
5 1 ~ 5, ~
~: : O ~ ) O O O O O O
:~ ~ ~ 4 1 4 ~ P. C~ ~ C~
Ei I ~ E3 5~ E Ei E
O ~ ~ O O O O O O
~) ~ ~ . C ' C~ C) V C~
, . .
, .
:
'' ' .
, ~

The compounds of formula I can be made up in the form of
conventional pharmaceutical preparations; for example, the aforesaid
compounds can be mixed with conventional organic or inorganic9 inert
pharmaceutical carriers suitable for parenteral or enteral administration
such as for example, water, gelatin, lactose, starch, magnesium stearate,
talc, vegetable oil, gums, polyalkylene glycols, ~aseline or the like. They
can be administered in conventional pharmaceutical forms, e.g., solid forms,
for example~ tablets~ dragees, capsules, suppositories or the like, or in
liquid forms, for example, solutions, suspensions or emulsions. MoreGver,
the pharmaceutical compositions containing compounds of this invention can
be subjected to conventional pharmaceutical expedients such as sterilization,
and can contain conventional pharmaceutical excipients such as preservatives,
stabili~ing agents, wetting agents~ emulsifying agents, salts for ~he
adjustment of osmotic pressure, or buffers. The compositions can also
contain other therapeutically active materials.
.::
A suitable pharmaceutical dosage unit can contain from about 1 to
about 500 mg of the aforesaid compounds of formula I, with a dosage range
of from about 1 mg to about 100 mg being the preferred oral administration
and a dosage range of from about 1 mg ~o about 50 mg being preferred for
parenteral administration. However, for any particular subject, the
specific dosage regimen should be ad~Justed according to individual need and
the professional judgment of the person adminlstering or supervising the
administration of the aforesaid compoundsO ~t is to be understood that the
dosages set
, ~, . . . :
' '', -' .
.~ .: .
.: .
: : .
' :.
: ' .: '. '.'
- 16 -
~J ~
. ` . . . ..... ~:'.
, .. . . . . ...

forth h¢rein are exemplary only ~nd that they do not, to ~ny
extent, limit the scope or practice o~ thls in~entlon.
; The term "dosage unit" a~ employed throughout this
specl~ication rerers to pharmac~utically discrete unit~ sultable
a3 unltary do~ages for mammallan subJects each containing a
pradet~rmined quantity o~ active materi~l calculated to pro-
duce the de~lr~d therap~utlc e~ ct in a~ociation wlth th~
r~qulr~d pharmaceutical dilu~ntg carrier or vehlcle.
me following ~xampl~ ara illu3tratlve Or khi~ in-
v~ntion. All temperaturo~ giv~n are in de~r~ contigr~de,
unl~ss lndioated otherwi~e. :;
To 5 g (18.5 mmole) o~ 7-~hloro~ -dihydro-5-ph~nyl-
2H-lJ4-benzodiazepin-2-one in 90 ml Or dry benzene was added
5.0 g (37 mmole) of aluminum ~hlorlde. Th~ reactlon mixtur~
wa~ ~tlrred 6 hour~ at r~flux, cooled to roo~ temperature and
treat~d wlth 4~4 g (0.1 mole) o~ ethyl~ne oxide~ The reactlon
i mixture wa stirr~d 18 hour~, the benz~ne was then remov~d and
the r~idue was tr~at~d with aqueous ammonlum hydroxld~ and
:i .
20 100 ml Or m~thyl~n~ chlorid~. The r~sultln~ pr~cipitate wa~
1~ removed by riltratIon~ Th~ organic lay~r wa~ then ~parat~d3
.,: washed wlth aqueou3 ~o~ium chloride, dried and the solvent
J,~ ~apor~ted to yield ~ r~sldu~ whl~h ~a~ cry~talli3~d ~rom 0th~r
~nd r~cr~stal}iz~d ~rom m~th~len~ chloride-hexan~ to glve
B~ 25 10-chloro-2D3,5~11b-t~trahydro-llb-phenylo~azolo~2-~][1,~]~
: b~nzod~a2~pl~ 7H~-on~, a~ colorles~ prlsm~ 9 m. p. 125~1~5
~,
. 1 .

338
and then resetting, m.p. 17~-177.
The above filtrates were dlssolved in methylene
chlor1de and chromatographed over silica gel (200 g) with
m~thylene chlorid~ (~00 ml) and with 700 ml of ethyl acetat~.
The ethyl acetate rraction w~s evaporated to dryness and
crystallized from ether. Recrystalli~ation ~rom methylene
chloridc-hexane gave 10-chloro-2,~,5,11b-tetrahydro-7-~2-
~ hydroxyethyl)-llb-phenyloxazolot3,2-d][1,4~benzodiazepin-6-
: (7H)-one a~ colorless prisms, m.p. 134-137.
Example 2
,. ~ : ` ! '. '
To 15 g (51.9 mmole) of 7-chloro-5~t2-fluorophenyl)-
1,3-dihydro-2H-1,4-benzodiazepin-2-one in 150 ml of dry
benzene, 9 g (67.7 mmole~ of alumlnum chloride was added ~nd ~;
the mixture was stirred ror 15 minutes. The reaction mlxture
was cooled in an lce bath and 8.8 g (0.2 mole~ o~ ethylene
oxid~ was add~d dropwls~. Ar~er 18 hours of stirring at room
temperature, the reaction mixture wa~ heated to 40 for 1 hour
~ and thon cooled to room temporature and treated wlth 5 g
;. : (37.6 mmole) o~ aluminum chlorlde, follow~d by 4.4 g tO.l mole)
.` ~ 20 ~ Or ~thylen~ oxid~. The reaction mixture was heated 4 hours
t 45-50~and then evaporated to dryness. Methylene chlorlde,
ic~ and ammonlum hydroxlde were added and the solid r~moved
" ....................................................................... . . .
~ by ~iltr&tlon. The riltrato was separated and the organic
~ .
phasD reduced to dryn~R~ ln vacuo. me residue waq dlssolved
.. ; :25 ~ :ln dllute hydrochlorlc acid and ~he pH o~ the solution -~
~ adJusted to 5 wlth ammonium hydroxide. Th~ acldic solutlon
'.~,.' : : .
... . .
~ - 18- ..
``. ; ~J :~

was washod with e~Gh~r, made ba~i~ and ~xtract~d ~ith m~thylene
chlorld~. Th~ organic phase wa~ wa~hed wlth agueou~ ~odlum
chlorid~, dried and ~vaporat~d to dryn,ess~ Reory~talllzatlon
~rom msghylone ~hlorq ~-hcxan~ gavo 10-chloro-llb-(2 ~luoro-
ph~nyl)-2,355.~11b-~Getrahydrooxazolo[3,2-dJ [1,4]benzodlazepln-
6- (7H3 -on~ a~ colorl~ss rod~, m. p. 18~ 4.
Th~ ether ~a~h of th~ said solution at pH 5 w~s eva-
porated to dryne3~, dl~solv~d in methylen~ chloride and ~-
chromato~raph~d ov~r 20û g Or ~ilica g~l with methylene chlo-
rld~ and ethyl ace~t~ ~hlch rraotion~ were combined and tho
solv~n'c~ rornoved to ~lv~ a cruds product. Reorystalli2~tlons
~ro~ ~eth~lene-chloride~p~troleum ethor gave 10-chloro~llb-
(2-~luorophonyl)-2,~,5,11b-t~trahyaro-7-(2-hydr~xyethyl)-
oxazolo[~,2-d][1,4Jbenzodlaz~pln-6(7~)-one as colorless pl~tes,
~-P~ 147-151~.
A mlxtur~ of 100 ml of` dri~d benz~ne and 5. 0 g Or
aluminum chlorid~ undor a dry lco-aceton~ d condens~r
W~3 stlrrod and tr~ated wlth lû.O g (35 mmole) o~ 7-chloro-
dlhydro-l-mothyl ~-ph~nyl-2H-1,4-b~nzodlazepln-2-one
glvlng a yellow ~olld. ~tirring wa~ continu~d ~or 20 minut~
and ~t~r tho ~ddltlon o~ ~5 ml Or h~n~, the mixture wa~
oool~d ln an lc~--bath. Upon th~ addltlon Or 7 ml o~ ethyl~ne
sxid~ th~ yollo~ ~olid di~solv~d, The reaction mlxture w~
war~od to ~oom temp~ratur~ ~nd wa~ ~irred ov~rnl~ht~ m @
b~nz~n~ ~olutl~n N~ r~partlti~n~d b~kwe~n m~thyl~n~ ehlorldo
~nd i~d aquoou~ a~onlu~ Aydroxid~3 Filtr2~kion r~mov~d ~

~ the
large portion of the aluminum salts an organic layer was separated~
washed with water~ dried and evaporated. The resultant residue was washed
with ether to give 10-chloro-2~3~5,11b-tetrahydro-7-methyl-llb-phenyl-
oxazolo[3~2-d][1,4]-benzodia~epin 6-(7H)-one as colorless crystals, m.p.
179-184 . Two recrystallizations from methylene chloride-hexane gave
colorless rods~ m.p. 182-184.
E_ample 4
A mixture of 10.0 g (35 mmole) of 7-chloro-1,3-di-hydro-1-methyl-5-
phenyl-~H-1,4-benzodiazepin-2-one~ 6.7 g of aluminum chloride, 300 ml of
10 benzene and 30 ml of hexane was chilled in an ice-bath and was treated with ~ `
10 ml of propylene oxide. The reaction mix~ure was warmed to room
temperature and was stirred overnight. Wor~-up as in Example 3, yielded a
mixture of the epimers o~ 10-chloro-2~3,5~11b-tetrahydro-2,7-dimethyl-llb-
phenyloxa~olo~3,2-d~1,4]ben~odiazepin-
. .
,
'' '
1 ~
~ '' ' '''
l~ ,' ,. '
' ': :' .
1 "~ ""' ' `
~ ~ - 20 - ~ ~

c-
g~ :
6(7H~-one. A ~olutlon of 1.0 g Or thls mixture was ~tlrred
overnight at 80 ln 25 ml of boron trifluoride etherate. The
r~actlon mixture wa~ pour~d carerully into ice water and made
ba~ic wlth ammonium hydroxlde. The mixtur~ was extract~d wlth
chloroform, wat~r wa~hed, dried and concentrated to a ~olld
r~iduc. Thre~ r~crystallization~ ~rom methylone chlorid~-
hexane ga~e the 2911b ci~ i~omer o~ the abo~re compound, m.p.
142-143~ ~
.,
A mixture o~ 10 g ~35 mmole) o~ 7-~hloro-1,~ dihydro-l-
methyl-5-ph~nyl-~H-1,4-bonzodlazcpin-2-one, 10 g of aluminum
ahloride " and 200 ml o~ dricd. benz0ne wa~ treated with 30 ml
Or l-chloro-2,3-epoxypropane in 100 ml of bçnzen~. r~he
reactlon mlxkure wa~ stirred overni~sht. Work-up a~ in Exampl~ .
5, above ga-re ~i2 g Or a crude oil. me oil was di~solved
in b~nz~ne, ~ er~d over Florlsil, ~vaporated to dryne~
and cry~tallized rrom e~her-p~troleum ether to glve 10 chloro- :~
2-chloromethyl-2,~,5,11b tetrahydro-7-methyl-llb-phenyloxazolo
~3,2-d] [194]benzodiazepin-6(7~)-one BS colorle~s needle~,
2Q m. p. 140-142 .
. ~ ~ ~,' '.
.
A mixture o~ 12.5 g (46 mmol~) o~ 7-chloro-2,3-dlhydro~
l~mothyl 5-ph~nyl~ 1,4-benzodlaz~pln~ hydrochloride, 5~0 g of
a}umlnum chlorid~, 200 ml of bonzene and 30 ml o~ h~xan~.was
stirr~d ~Qr ?0 mlnut~, chlllcd ln ~n ice-bath and th~n tr0at~d ~ .
wlth 7.0 ml o~ ethyl~ne oxlde. The r~actlon mlxture w~; warm~d ~ ~-
_ 21 - :
~ .

to room kempera~ur~ ~nd ~lrred overnlght. The benzene wa~
r~moYed by ~vaporation and the resldu~ was partltloned b~twe~n
methyl~ne chloride and dilute ammonium hyd:ro~id~. The 301id
wa~ r~moved by rlltratlon ~nd the organlc layor washed wlth
. ".. ~
~at~r, drled and ev~porated to ~ive an or~ge oll. Upon
standln~, the oll cry~talllz~d ~nd the re~ultant solid ~a~
~ recrystalllz~d from hex~ne to give 10 chloro-2,3J5J6,7,11b-hexa-
: hydro-7-methyl-llb-phenyloxazolo~,2-d][1,4]~enzodiazopine.
An analytical sample was obtaln~d as colorles~ prism~, m.p.
109-110~, by r~crystallizatlon ~rom eth~r.
,
A ~olutlon of 5.6 g (18.2 mmole) of 5-chloro-2-(2-chloro-
ethylmethylamino)benzophenone, 5.0 g o~ sodlum lodide, 50 ml
2-amlnoethanol, 50 ml Or tri~thylamlne and 100 ml of
~th~nol ~a~ heated at re~lux ~or 17 hour~. Th~ reaction
mixture wa~ poured lnto lc~ wat~r ~nd was extracted with
m~thylene chloride. ~he organic phase was washed with wator,
driod ~nd evapor~t~d to an oll~ The oil wa~ cooked ouk with
petroloum ethor and 10-chloro-2~3,5,6,7Jllb-h~xahydro-7- :
m~thyl-llb-phenylo~azolo~3,2-d3[1~43benzodiazeplne crystalllzed
' rrom th~ solv~nt, m.p. 107-109~. .
.,,: ~ ' ': '''
A ~oltulon o~ 6~4 g (20 mmol~) Or 2-(2-chloro-N-methyl-
~c~tamido~-5 chlorob~nzoph~none, 12~0 g (0.2 mole~ Or ethyl~n~
diamlno~ 50 ml ~f trl~thylamln~ and 250 ml o~ ~thanol was
,
~ 22 -
.; ~
Ii

heat~d at reflux ~or 20 hour~. The re~ction mixture was
concentrated to a resldu~ whlch was partitloned between ether
and wat~r. The ether layer was washed wlth water, dried and
conc~ntrated to a ~mall amount of llquid which was treat~d
5 with a small amount o~ ethanol to glv~ upon ~tandlng 10-chloro-
1,2,~5,5,7,11b-hexahydro-7-methyl-llb-phenyl-6H-lmidazol1,2-d]-
~lJ4~benzodlazepin-6-one as colorless crystals, m.p. 164-
167~.
Example 9
A solution o~ 5.0 g (16 mmole) Or 5-¢hloro-2-~-chloro-
2thylmathylamino)benzoph~none, ~.75 g (50 mmole) of 3-amlno-
propanol, 50 ml Or trlethylamlne and 250 ml o~ ethanol was
stlrred at reflux ror 48 hours. The reaction mixture was
then ~vaporated to a residue whlch was washed with water,
dl3~01ved in methylene chloride and chromato~raphed over a ~-
¢olumn o~ Florl311. Th@ first fraction ylelded the r~covery
Or 2.7 g Or ~tartin~ matorial. Elution wlth ~cotone9 ethanolJ ~ .
mothanol and finally wlth ammonlal mothanol g~ve a compound
o~ vory low Rf on ~luore~c~nt ~ilica eluted with ~thanol.
Crystallization from acetone and recry~talllzations from ether-
po~roleum eth~r gave ll-chloro-3,4,6J7,8,12b-hexahydro-8-
methyl~l2b-phenyl-2~ [l,~}oxazlno[~,2-d][1,4]benzodiaz~pine
a3 colorl~ss prl~ms, m,p. 142-144~
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~ :25~ A solution Or 5.0 g (16 mmol~) of 5-~hloro-2~chloro-
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ethylmethylamino)benzophenone, 3.0 g (50 mmole) of ethylenedia~ine, 50 ml
of triethylamine and 250 ml of ethanol was stirred at reflux for 48 hours.
The solvents were removed by evaporation and the residue containing
starting material and the product was washed with water, chromatographed
over Florisil, and recrystallized from petroleum ether to give 10-chloro-
2,3,5,6,7,11b-hexahydro-7-methyl-llb-phenyl-IH-imidazo~1,2-d][1,4]
benzodiazepine as yellow prisms, m.p. 100-102 .
Example 11
~ mixture of 79.4 g (225 mmole) of 2-(2-bromoacetamido) 5-
chlorobenzophenone, 25 g of 2-aminopropanol hydrochloride, 95 ml of
triethylamine and 500 ml of ethanol was stirred overnight at room temperature,
and then at reflux for 5 hours. The solution was concentrated under
reduced pressure to a residue which was partitioned between ether and
waterO The organic layer was washed with water, dried and treated with
hydrogen chloride to give 18 g of a colorless solid. Recrystallizations
from ethanol-ether gave prisms of 5-chloro-2-C2-(1-hydroxy-2-propylamino3
acetamido]benzophenon0 hydrochloride7 m.p. 183-186.
A solution oP 5 g (13 mmol) of the free base 5~chloro-2-[2-
~hydroxy-2-propylamino)acetamido]benzophenone was heated 16 hours in re~luxing
pyridine (100 ml~. The solution was concentrated in vacuo to an oil which
was chromatographed over silica. The first material taken in 60~ ethyl
acetate, 40% hexane ~as 2-amino-5-chlorobenzophenone. The next material
eluted was combined to gi~e 10-chloro-2,3~5,11b-$et~ahyd~o-3~-methyl-llb-
pheny1Oxazolo-[3~2-d][lg4]benzodiazepin-6(7H)-one ~3,11b cis) which was re- ~
crystallized 3 tI~es to give colorless prisms, m.p. 88-96. Sublimation ``
~ ~ under reduced pressure gave a colo~less solid9 m.p. 84-98. ~ i
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~ COMPOUND C (lO-chloro~llb-~2-fluorophenyl)-2~3,5,11b-tetrahydro-
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oxa7olo[3~2-d][1,4]benæodia3epin-6(7H)-one) was prepared in the form of
several pharmacological formulations as follows:
A. Su~pository Formulation
Per 1.3 g
Suppository
10-Chloro-llb-(2-fluorophenyl)-2,3,5,11b-
tetrahydrooxazoloL3,2-d][1,4]benzodiaze-
pin-6(7H~-one 0.010 g
Cocoa butter m.p. 36 - 37C 1.245 g
Carnauba Wax 0 045 g
Procedure:
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The cocoa butter and the carnauba wax were melted in a suitable
size glass-lined container (stainless steel may also be used), mixed well
and cooled to 45C. The 10-chloro-llb-(2-fluorophenyl)-2,3,5,11b-
tetrahydrooxazolo[3~2-d][1,4]benzodiazepin-6(7H)-one which had been reduced
to a fine powder with no lumps, was added and stirred until completely and
uniformly dispersedu The mixture was poured into suppository molds to
'! yield suppositories having an individual weight of 1.3 g. The suppositories
were oooled and removed from molds. They were then individually wrapped in
wax paper for packaging (foil may also be used).
B. Capsule Formulation
.. . .
Per Capsule
10-Chloro-llb-(2-fluorophenyl)-2,3,5~11b_
tetrahydrooxazolo[3,2-d]~1,4]benzodiazepin-
6(7H)-one 10 mg
Lactose 165 mg
Corn Starch 30 mg
, Talc 5 ~g
;~ Total ~eight210 mg
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Procedur~:
10-Chloro-llb-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2~-d]
[1,4]ben3Odiazepin-6(7H)-one, lactose and corn starch were mixed irl a
suitable mixer. The mixture was further blended by passing through a
comminuting machine. The blended powder was returned to the mixer, the
talc added and blended thoroughly. The mixture was filled into hard shell
.
gelating capsules on a capsulating machine.
C. Parenteral Formulatio
Per ml
10-Chloro-llb-(2-fluorophenyl)-2~3~5,11b-
tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-
6(7H)-one 5.0 mg
Propylene Glycol 0.4 ml
Benzyl Alcohol (Benzaldehyde free) 0.015 ml
Ethanol 95 per cent 0.10 ml
Sodium Benzoate 48.8 mg
Benzoic Acid 1.2 mg
Water for Injection q.s. loO ml
Procedure (For 10,000 ml):
50 g of 10-chloro-llb-(2-fluorophenyl)-2~3,5~11b-tetrahydrooxazolo
[3,20d][1,4]benzodiazepin-6(7H)-one were dissolved in 150 ml of ben~yl
alcohol; 4,000 ml of propylene glycol and 1,000 ml of ethanol were added.
12 g of benzoic acid were dissolved in the above. 488 g of sodium benzoate
dissolved in 3,000 ml of water for injec~ion were added. The solution was
brought up to final volume oP 10,000 ml with water for injection. The
solution was filtered through a candle filter, filled into suitable size
ampuls3 gassed with nitrogen and sealedO It was then autoclaved at 0.7
atmospheres for 30 minutes.
- 26 -

D Tablet Formulation
.
Per T~blet
10-Chloro-llb-(2-fluorophenyl)-2~3~5~11b-tetra-
hydrooxazolo~3~2-d~ 4]benzodiazepin-6(7H)-one 25.00 mg
Dicalcium Phosphate Dihydrate, Unmilled 175.00 mg
Corn Starch 24.00 mg
Magnesium Stearate 1.00 mg ~`
Total Weight225.00 mg
Procedure:
10-Chloro-llb-~2-fluorophenyl)-2~3~5~11b-tetrahydrooxazolo~3~2-d~
[1,4]benzodia epin-6(7H)-one and cor~ starch were mixed together and passed
through a comminuting machine. This premix was then mixed with dicalcium
phosphate and one-half of the magnesium stearate, passed through a
comminuting machine and slugged. The slugs were passed through a comminuting
machine and the remaining magnesium stearate was added. The mixture was
mixed and compressed.
The abo~e formulation were repeated using COMPOUND D ~10-chloro-2,
3,5,11b-tetrahydro-llb-phenyloxazolo-[3,2-d]~1,4]benzodiazepin-6(7H)-one]. -~
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