BENZODIAZEPINE DERIVATIVES

DERIVES DE LA BENZODIAZEPINE

English Abstract

Abstract
The present invention provides tricyclic benzodiazepines
of the general formula
<IMG> I
wherein A represents the group -?-; Z is
-O-
R1 is hydrogen or halogen,
R2 is lower alkoxy-lower alkyl, amino-
lower alkyl, mono-lower alkylamino-lower alkyl, di-
lower alkylamino-lower alkyl or [cyclo-lower alkyl]-
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 alkoxy-lower
alkyl or di-lower alkylamino; and R5 is
phenyl or phenyl substituted
with halogen,
Compounds of formula I are useful as sedative, muscle
relaxant and anti-convulsant agents.

Claims

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>
wherein A represents the group -?-; Z is -O-; R1 is
hydrogen or halogen; R2 is lower alkoxy-lower alkyl, amino-
lower alkyl, mono-lower alkylamino-lower alkyl, di-lower
alkylamino-lower alkyl or [cyclo-lower alkyl]-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
alkoxy-lower alkyl or di-lower alkylamino; and R5 is phenyl
or phenyl substituted with halogen, which comprises
a) cyclizing a compound of the general formula
24

<IMG> II
wherein R1, R2, R3, R5, A, Y and Z are as defined
above,
b) N-substituting a compound of the general formula
<IMG> III
wherein R1, R3, R5, A, Y and Z are as defined above, to
introduce the required group R2,
or
c) for the preparation of compounds of the general formula
- 25 -

<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> IV
wherein R1, R2, R3, R5 and A are as defined above, with an
epoxide compound of the general formula
<IMG> V
wherein R'4 is as defined above in the presence of an acidic
agent and,
d) if 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 X, if
26

present, is chlorine, bromine, lower alkoxy-lower alkyl or
di-lower alkylamino and wherein a compound of formula II
wherein R2 is lower alkoxy-lower alkyl or [cyclo-lower alkyl]-
lower alkyl is used as the starting material.
3. A process as claimed in Claim 1 wherein X, if pre-
sent, is chlorine, bromine, lower alkoxy-lower alkyl or di-
lower alkylamino and wherein a compound of the general formula
III is substituted by a lower alkoxy-lower alkyl group.
4. A process as claimed in Claim 1 wherein X, if
present, is chlorine, bromine, lower alkoxy-lower alkyl or
di-lower alkylamino and wherein a compound of formula IV
is reacted with a compound of formula V in the presence of
an acidic agent.
5. A process as claimed in Claim 1 wherein X is lower
alkoxy and wherein a compound of formula II is used as the
starting material or a compound of formula III is N-substi-
tuted by a lower alkoxy-lower alkyl, amino-lower alkyl,
mono-lower alkylamino-lower alkyl or di-lower alkylamino-
lower alkyl group or a compound of formula IV is reacted with
a compound of formula V in the presence of an acidic agent.
27

6. A process as claimed in claim 1 wherein R1 is hydrogen or
halogen which is joined to the benzene ring in para-position with respect to
the -?- group, 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 sub-
stituted at the ortho position with halogen.
7. A process as claimed in claim 6 wherein R1 is chlorine, Y is
a dimethylene group which may be substituted by methyl or chloromethyl and R5
is phenyl or o-fluorophenyl.
8. A process as claimed in claim 3 wherein 10-chloro-11b-(2-chloro-
phenyl)-7-methoxymethyl-2,3,5,11b-tetrahydro-oxazolo[3,2-d][1,4]benzodiazepin-
6(7H)-one is prepared by reacting 10-chloro-11b-(2-chlorophenyl)-2,3,5,11b-
tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in the form of its 7-sodio
salt with chlorodimethyl ether.
9. A process as claimed in claim 4 wherein 10-chloro-7-cyclo-
propylmethyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-
6(7H)-one is prepared by reacting 7-chloro-1-cyclopropylmethyl-1,3-dihydro-5-
phenyl-2H-1,4-benzodiazopin-2-one with ethylene oxide.
10. A process as claimed in claim 4 wherein 10-chloro-7-(2-diethyl-
aminoethyl)-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzo-
diazepin-6(7H)-one is prepared by reacting 7-chloro-1-(2-diethylaminoethyl)-5-
(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one with ethylene oxide.
11. A process as claimed in claim 1 wherein 10-chloro-7-(2-diethyl-
aminoethyl)-11b-(2-fluorophenyl)-2,3,5,11b-tetraoxazolo[3,2-d][1,4]benzodiazepin-
6(7H)-one is prepared by reacting 10-chloro-11b-(2-fluorophenyl)2,3,5,11b-tetra-
hytrooxazolo-[3,2-d][1,4]benzodiazepin-6(7H)-one with (2-bromoethyl)diethyl-
amine.
12. A process as claimed in claim 6 wherein R1 is chlorine, A is
-CO-, Y is -CH2.CH2-, R5 is 2-chlorophenyl and R2 is methoxymethyl.
13. A process as claimed in claim 6 wherein R1 is chlorine, A is -CO-,
28

Y is -CH2.CH2-, R5 is phenyl and R2 is cyclopropylmethyl.
14. A process as claimed in claim 6 wherein R1 is chlorine,
A is -CO-, Y is -CH2.CH2-, R5 is 2-fluorophenyl and R2 is 2-diethyl-
aminoethyl.
15. A tricyclic benzodiazepine of the general formula
<IMG> I
wherein A represents the group -?-; Z is -O-; R1 is hydrogen
or halogen, R2 is lower alkoxy-lower alkyl, amino-lower alkyl,
mono-lower alkylamino-lower alkyl, dilower alkylamino-lower
alkyl or [cyclo-lower alkyl]-lower alkyl; R3 is hydrogen or
lower alkyl; Y is a di- or trimethylene group which may be sub-
stituted by R4, R4 being lower alkyl or -CH2X where X is chlorine,
bromine, lower alkoxy, lower alkoxy-lower alkyl or dilower alkyl-
amino; and R5 is phenyl or phenyl substituted with halogen,
whenever prepared according to the process claimed in claim 1
or by an obvious chemical equivalent thereof.
16. A compound as claimed in claim 15 wherein X, if
present is chlorine, bromine, lower alkoxy-lower alkyl or di-
lower alkylamino and R2 represents lower alkoxy-lower alkyl or
[cyclo-lower alkyl]-lower alkyl, whenever prepared according
29

to the process claimed in Claim 2 or by an obvious chemical
equivalent thereof.
17. A compound as claimed in Claim 15 wherein X, if
present is chlorine, bromine, lower alkoxy-lower alkyl or
di-lower alkylamino and R2 represents lower alkoxy-lower
alkyl, whenever prepared according to the process claimed
in Claim 3 or by an obvious chemical equivalent thereof.
18. A compound as claimed in Claim 15 of the general
formula
<IMG> I-A
wherein R1, R2, R3, R5 and A are as defined in Claim 15,
R'4 represents hydrogen, lower alkyl or CH2X where
X is chlorine, bromine, lower alkoxy-lower alkyl
or di-lower alkylamino,
whenever prepared according to the process claimed in Claim 4 or
by an obvious chemical equivalent thereof.
19. A compound as claimed in Claim 15 wherein X is lower
alkoxy, whenever prepared according to the process claimed in
Claim 5 or by an obvious chemical equivalent thereof.

20. A compound as claimed in Claim 15 wherein Z is -O-,
R1 is hydrogen or halogen which is joined to the benzene ring
in para-position with respect to the -?- group, 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 sub-
stituted at the ortho-position with halogen, whenever prepared
according to the process claimed in Claim 6 or by an obvious
chemical equivalent thereof.
21. A compound as claimed in Claim 15 wherein Z is -O-,
R1 is chlorine, Y is a dimethylene group which may be sub-
stituted by methyl or chloromethyl and R5 is phenyl or o-fluoro-
phenyl, whenever prepared according to the process claimed
in Claim 7 or by an obvious chemical equivalent thereof.
22. 10-Chloro-11b-(2-chlorophenyl)-7-methoxymethyl-
2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-
one, whenever prepared according to the process claimed in
Claim 8 or by an obvious chemical equivalent thereof.
31

23. 10-Chloro-7-cyclopropylmethyl-2,3,5,11b-tetra-
hydro-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one,
whenever prepared according to the process claimed in Claim 9
or by an obvious chemical equivalent thereof.
24. 10-Chloro-7-(2-diethylaminoethyl)-11b-(2-fluoro-
phenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-
6(7H)-one, whenever prepared according to the process claimed
in Claim 10 or by an obvious chemical equivalent thereof.
25. 10-Chloro-7-(2-diethylaminoethyl)-11b-(2-fluoro-
phenyl)-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

Description

104Z886
The present invention relates to benzodiazepin de-
rivatives. More particularly it relates to tricyclic benzo-
diazepines and to the preparation thereof.
In accordance with the present invention, there is
provided a tricyclic benzodiazepine of the general formula
~ '
5 Y ,
O ' ~ .
wherein A represents the group -C-; Z is -0-; R1 is hydrogen
or halogen; R2 is lower alkoxy-lower alkyl, amino-lower alkyl,
mono-lower alkylamino-lower alkyl, di-lower alkylamino-lower
alkyl or [cyclo-lower Plky~ -lower alkyl; R3 is hydrogen or
lawer 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 alkoxy-lower
aIkyl or di-lower alkylamino; and R5 is phenyl or phenyl
substituted with halogen. -
' ' ' .
.. `: ,....
~ ;:
~. .... ~ .
. . .
. :
- ~ . i - - . , -: , ~ . ., . , . .... ~

1~4288~ ~
. ~ :
As used herein, the term "lower alkyl", either alone
or in combination as in di-lower alkylamino, comprehends
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 "~cyclo-
lower alk~ lover alkyl" encompasses hydrocarbon groups
having 4-6 carbon atoms, such as cyclopropylmethyl, cyclo-
butylmethyl, cyclopropylethyl and the like. The term "acyl"
; encompasses an organic radical derived by removal of a hydroxyl
group from an organic acid, such as an alkanoic acid containing
from 2-7 carbon atoms, for ex~mple 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" repre-
sents all four forms thereof, i.e., fluorine, chlorine, bromine
;, and iodine, unless expressly indicated otherwise. The term
"lower alkanol" connotes primary, seconaary, or tertiary
saturated aliphatic alcohols such as methanol, ethanol, pro-
panol, isopropanol and the like.
11 prel`erred e=bodirent oi 1:he pre~ent in-
' ~ '
.. ~
~ .
,, ~

104Z886
vention encompasses the compounds of formula I wherein Z is -0-, Rl is
hydrogen or halogen, with chlorine being the preferred halogen, and is
joined to the benzodiazepine moiety at the 7-position thereof; R3 is hydro-
gen; 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 fluorine being the most
preferred 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; 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 provided a
process for the preparation of tricyclic benzodiazepines of the general : ~ -
; formula :
R12 : ::
, Rl ~ ~ X
\ 3 ; -~:~
: :
O . .. - . '; . .
wherein A represents the group -C-; Z is -0-; Rl is hydrogen or halogen;
R2 is lower alkoxy-lower alkyl, amino-lower alkyl, mono-lower alkylamino- ~:
lower alkyl, di-lower alkylamino-lower alkyl or [cyclo-lower alkyl]-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 alkoxy-lower alkyl or di-lower alkylamino; and
R5 ls phenyl or phenyl substituted with halogen, which comprises
a) cyclizing a compound of the general formula
.' - '~:
~ ~ - 4 -
. . . :
.. . . . . . .. . ... .. . .. ..

14:)4Z886
IR2 13
N A CH NH - Y - Z - H
1 ~ II
C O
wherein Rl, R2, R3 R5, A~ Y and Z are as defined above,
t
~,',~ ' '~ .
`:.' ~'' ',''
- 4a -
"`` k~ . - .
.'' ' ' ' .
, ~ , -, ;t ... . ,,: . - . ~,. -.. - . . -. - -

1~)42886 -
b) N-substituting a compound of the general formula
H
N A
Rl ~Z '1\ R3 111
wherein Rl, R3, R5, A, Y and Z are as defined above, to introduce the
required group R2,
or
c) for the preparation of compounds of the general formula
72
Rl ~ <H l-A
~ 5 0
c R'
.~ .. ....
wherein Rl, 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 ;
, lZ :
Rl ~ IV
:-
1, .
,~ .' ' ' ',',':
- 5 - ~

1042886
wherein Rl, R2, R~, R5 and A are as defined earlier
wlth an epoxlde compound of the general formul~
C~H? CH R'4
~0/ -:
whereln R'4 ls as deflned above
ln the presence Or an acldic agent and
d) ir a mixture Or eplmeric compounds Or rormula I ls ob-
talned, separatlng, lr deslred, the sald mlxture into its
components.
Thus, ln one process aspect Or the present lnvention,
Io compounds Or ~ormula I are obtained by cycllzatlon Or a
compound Or the rormula II, above. The compounds Or the
ormula II above whlch are used as the startlng materials in thls
process aspect are convenlently prepared by reactlng a
i~ corresponding 2-substltuted amlnophenyl ketone Or the ge-
, 15 neral rormula
Rl2 l3
N _A _CH _X'
Rl + ll VI
, ~/\C=O
~ whereln Rl, R2, R~, R5 and A are as defined earlier -
-, and X~ ls chlorlne, bromlne or lodine
. wlth a diamlne or aminoalkanol o~ the general formula
. 20 H2N -Y -ZH VII
. ~ .
, -

~4Z886
wherein Y and Z are as deflned earlier.
The reaction between the compounds of formulae VI and
VII above is conducted in a reactlon medium containing a
base and an inert organic solvent. Suitable bases ror the
purposes of this lnvention are inorganic bases, such as sodium
- acetate and organic bases such as the tertiary amines, for
example, trialkylamines, with triethylamine and pyridine
being preferred. A variety of organic solvents are use~ul rOr
the purposes o~ this lnvention. Among these suitable solvents
are lower alkanols, such as methanol, ethanol, propanol, etc., ~;
with ethanol being prererreds aromatic hydrocarbonsJ such as
benzene, toluene, xylene, etc~ high boillng point ethers,
such as tetrahydroruran and dioxane; and amides, such as
~i~ dlmethylformamide, diethylformamide and the like. I~, ln
3 15 the compounds Or rormula VI, X' ls chlorlne or bromlne, the
reaction mlxture may also contain sodium iodide in order
to convert such X' substltuent to the more reactive lodlne
, . .
; atom. Examples Or compounds of formula VII useful ln thls
invention lnclude 2-aminoethanol, ethylenediamlne, 3-amino-
propanol, etc.
;~ ' , '' "
The intermediate of the general formula II above thus
` rormed need not be isolated from the reaction mixture as it
readily cyclizes to the desired compound Or formula I and
~ ln a prererred embodiment, the intermediate is not lsolated
`J 25 but is permitted to cyclize ln the reaction medlum in which
lt is prepared by conducting the reaction between the com-
pounds o~ formula VI and VII above at a temperature in the
_ 7 -
.~ ,.

1042886
range of from about 25 C to the reflux temperature. However ~
by using less enereetic reaction conditions, e.g. by con- ;
ducting the reaction between the compounds of formulae VI and
VII above at about or below room temperature, the intermediate
compound of the formula II can be isolated and subsequently
cyclized to the desired product, e.g. by heating in pyridine,
ethanol, xylene and the like.
In a further process aspect of the present invention,
the R2 substituent can be introduced into a compound of
formula III above by reacting said compound with a suitable
aIkylating agent. Thus, one can prepare a compound of the
formula I by first preparing the l-sodio derivative of a compound
of the formula III, above, and without isolation reacting
said l-sodio derivative with a suitable alkylating agent,
e.g. with ~yclo-lower alky~-lower alkyl halides, halo-di-
lower alkyl ethers or with amino-lower alkyl halides of the
formula
r 2r ~ ~ VIII
,
~ 8
, .

104Z~86
wherein m is a whole integer from 2 to 7,
R7 and R8 each are hydrogen or lower alkyl
and X' is as defined earlier.
Representative of such alkylating agents are chlorodimethyl
ether, bromo-diethyl ether, cyclopropylmethylbromide,
(2-bromoethyl)dlmethylamlne, 3-bromopropylamlne, (2-bromo-
ethyl)-dlethylamine.
The l-sodlo derlvatlve o~ a compound o~ formula III
above can be prepared by treatlng sald compound with a
sodium lower alkoxide, such as sodlum methoxide or with sodium ;
hydride. This reaction is expediently e~ected in the pre-
sence of an lnert organic solvent such as dimethylformamide,
aromatic hydrocarbons, e.g., benzene, toluene and the
like, with dimethylrormamide being the preferred solvent.
; 15 For the purposes o~ this reaction, temperatures above and
below room temperature may be employed. In a preferred
embodiment temperatures between about 0 and 10C are uti-
lized.
The alkylation Or the l-sodio derivative of a compound
of formula III above is expediently effected in the presence
' o~ an inert solvent such as dimethyl~ormamide, aromatic hydro-
carbons, e.g. benzene, toluene and the like, with dimethyl-
~ormamide being the prererred solvent. This alkylation reaction
- may be er~ected using temperatures above and below room tem-
perature, with temperatures between about 10C and room tem-
perature belng pre~erred.
' .
; In accordance with a ~urther process aspect Or the
~) ~
_ g _ ; .:
.

104;~i
present invention compounds of formula I above wherein Z
is -0- and Y is a dimethylene group which may be substituted
by R4, i.e. compounds of the formula I-A above, are prepared
by reactlng a 4,5-unsaturated 1,4-benzodiazeplne of formula IV
above with an epoxide compound of formula V above in the
presence Or an acidic agent, such as, for example, an aprotlc
acid, e.g., alumlnum chloride, ferrlc chlorlde, zlnc chloride,
titanium tetrachloride, boron trifluoride, etc.; or p-toluene
sul~onic acld, benzene sulfonic acid, and the like. The most
preferred acidlc agent for the purposes of this invention ls
alumlnum chloride. Examples of compounds Or formula V useful
ln this lnvention include ethylene oxide, propylene oxide,
l-chloro-2,~-epoxy propane, etc.
..~
- The reaction whereby compounds of formula I-A above
are prepared rrom the compounds of formula I~ and V is con-
/ venlently conducted in the presence of an anhydrous inert
- organic solvent. Suitable inert organic solvents for this
purpose include, ~or example, aromatic hydrocarbons such as
benzene, toluene, xylene, etc., ethers, such as tetrahydro-
furan and diethyl ether, or carbon disulflde. This reactlon
may be carrled out at a temperature in the range of from
about -10C to the reflux temperature of the reaction medium,
most pre~erably from 10C to the reflux temperature. The
selection of temperatures ls not crltical for the purpose
of the present invention and will, o~ course, depend upon the
characteristics of the compounds selected as reagents, the
~, solvent medium employed and the nature of the acidic agent
used.
.
-- 10 --
.~ .

104Z886
It would appear that when a compound Or formula IV ls
reacted with a compound of rormula V wherein R'4 is other
than hydrogen, the R'4 bearing carbon atom can be attached
- relatlve to the benzodiazepine ring in one Or two alternate
- 5 posltlons, depending upon the point where the epoxide ring
cleaves during the reaction. However, experimentation has
shown that the epoxlde ring evidences a propensity to favor
cleavage between the oxygen and the unsubstituted carbon atom.
Thus, when cleavage occurs at thls point, the carbon atom
bearing the R'4 substituent ls bonded to the oxygen atom
ln the heterocyclic rlng.
It wlll be appreciated that in following the methods
dlscussed above ror the preparatlon of the tricycllc benzo-
dlazepine derlvatives Or formula I, the product obtalned
- 15 ln many cases will be a mixture Or eplmers whlch can be
separated lnto lts components by methods known ln the art.
Ir a solution containing either Or the isolated
epimers is permitted to stand, a mixture containing both the
cls and trans epimers results. Epimerlzation can also be
erfected by means Or e.g. boron trlrluorlde etherate.
,',
Examples o~ compounds which correspond to formula I
and whlch are thus representatlve Or the present inventlon may
be llsted as follows:
10-Chloro-llb-(2-chlorophenyl)-7-methoxymethyl-2,3,5,11b-
tetrahydrooxazolo[~2-dl[l~4]benzodiazepin-6(7H)-one;
10-Chloro-llb-(2-rluorophenyl)-7-(2-dimethylaminoethyl)-
.
-- 11 -- , .
' ,

1~42886
2,3l5,11b-tetrahydrooxazolo[3,2-d~[1,4]benzodiazepin-6(7H)-one;
10-Chloro-llb-(2-fluorophenyl)-7-(3-aminopropyl)-2,3,5,
llb-tetrahydrooxazolo~,2-d]~1,4]benzodiazepin-6(7H)-one
10-Chloro-llb-(2-fluorophenyl)-7-(3-methylamino-
propyl)-2,3,5,11b-tetrahydrooxazolo[~,2-d][1,4]benzodiazepin-
6(7H)-ones
10-Chloro-llb-(2-fluorophenyl)-~-(2-diethylamlnoethyl)-
2,~,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one;
10-Chloro-7-cyclopropylmethyl-2,~,5,11b-tetrahydro-llb-
phenyloxazolol~,2-d]~1,4]benzodiazepin-6(7H)-one.
The compounds Or rormulae VI and VII, above, are readily
prepared ln a manner known in the art.
The ¢ompounds of rormula III above are readily prepared in
analogy to the epoxlde method and the cyclizatlon method
~or preparing the compounds Or rormula I.
.'. ,
The compounds Or formula IV above wherein R2 is
Icyclo-lower alkyl]-lower alkyl, amlno-lower alkyl, mono-lower
alkylamino-lower alkyl and dl-lower alkylamino-lower alkyl -
` are readlly prepared ln a manner known ln the art. The
compounds of formula IV above wherein R2 ls lower alkoxy-lower
alkyl can be prepared by reactlng a compound of formula III
wlth a halo-dl-lower alkyl ether.
. ' . .
The trlcycllc benzodlazeplne derlvatives Or formula I
above are userul as pharmaceutlcals and are characterized by
` 25 actlvlty as sedative, muscle relaxant and anti-convulsant
agents. These compounds can be used in the rorm of conventlonal
- 12 -
' .. . .
, .

1042886
pharmaceutical preparations; for example, the aforesaid
compounds can be mixed wlth conventional organic or inorganic.
inert pharmaceutical carriers suitable for parenteral or
enteral administration such as for example, water,gelatin,
lactose, starch, magneslum stearate, talc, vegetable oil,
gums, polyalkylene glycols, Vaseline or the like. They can
be administered in conventional pharmaceutical forms, e.g.,
solid rorms, ~or example, tablets, dragees, capsules,
suppositories or the like, or in liquid forms, ror example,
solutions, suspensions or emulsions. Moreover the pharma-
ceutical compositions containing compounds o~ this invention
can be sub~ected to conventional pharmaceutical expedients
such as sterilization, and can contain conventional pharma-
ceutlcal excipients such as preservatives, stabilizing
agents, wetting agents, emulslrylng agents, salts ~or the
adJustment Or osmotic pressure, or bu~rers. The compositions
can also contain other therapeutically active materials.
." , .
A sultable pharmaceutlcal dosageunit can contain from
about 1 to about 500 mg Or the aforesaid compounds Or formula
I with a dosage range of rrom about 1 mg to about 100 mg being
preferred for oral admlnistration and a dosage range Or ~rom
about 1 mg to about 50 mg belng prererred for parenteral
! adminlstratlon. However, rOr any particular sub~ect, the
specirlc dosage regimen should be adJusted according to
indlvidual need and the proresslonal ~udgment Or the person
administering or supervising the administration of the
aroresaid compounds. It is to be understood that the dosages
set rorth hereln are exemplary only and that they do not, to
any extent, limlt the scope or practice of this invention.
- 13 -

1~42886
The ~ollowing examples are lllustrative of this
inventlon. All temperatures given are in degrees centigrade,
unless lndicated otherwise.
Exam~le 1
A solution o~ 2.8 g o~ 10-chloro-llb-(2-chlorophenyl)-
2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodlazepin-6(7H)-
one ln 50 ml Or dimethylformamide was cooled to -10 and
treated with o.65 g of sodlum methoxide. After stirring rOr
5 minutes, the mixture was cooled to -40 and 1 ml o~
' 10 chlorodlmethyl ether was added. The cooling bath was removed
and when the temperature had reached 0 the reaction mixture
was poured into 300 ml Or ice-water. The precipitated material
was collected by suctlon and dissolved ln methylene chloride.
The solution was drled over sodium sulrate, riltered and
evaporated. The residue was crystallized ~rom a mixture o~
ether and hexane to give, a~ter recrystalllzation ~rom
ethanol, 10-chloro-llb-(2-chlorophenyl)-7-methoxymethyl-2,3,5,
llb-tetrahydrooxazolo[~,2-d]~1,4]benzodiazepin-6(7H)-one as
whlte prlsms, m.p. 144-147.
The starting materlal can be prepared as rOllOws: :
.
A suspenslon Or 4.3 g (0.0328 M) Or alumlnum chloride
ln 200 ml o~ dry benzene under nltrogen was treated with
5.0 ~ (0.0164 M) Or 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-
2H-1,4-benzodiazepin-2-one and the mixture was stirred in an ice
bath ror 20 min. when 2.2 g (0.0492 M) of ethylene oxide was
added and arter 18 hr. at room temperature, an additional 2.2 g
14

104Z886 :
Or ethylene oxlde was added. Arter 3 hr., the mixture was
heated under re~lux for 10 min., then evaporated to dryness.
The resldue was made basic wlth ammonlum hydroxlde,
dichloromethane (100 ml) was added and the mixture was
rlltered. The organic layer was separated, washed with
- saturated brine, dried over anhydrous sodium sul~ate and eva-
porated to dryness. The residue was crystallized rrom ether
and recry~talllzed rrom a mixture of dlchloromethane and
petroleum ether to glve 10-chloro-llb-(2-chlorophenyl)-2,3,5, :
llb-tetrahydrooxazolo[3~2-d311,4¦benzodiazepin-6(7H)-one
as whlte prisms, m.p. 213-216.
Example 2
In an analogous manner to the procedures described in
Example 1, the foll dng compounds may be prepared using
10-chloro-llb-(2-rluorophenyl)-2,3,5,11b-tetrahydrooxazolo-
[3,2-d]¦1,4]benzodiazepin-6(7H)-one as the starting materlal:
~ .
10-Chloro-llb~2- rlu orophenyl)-7-(2-dimethyl-
aminoethyl)-2,3,4,11b-tetrahydrooxazolo-
[3,2-d][1,4]benzodlazepln-6(7H)-one, ~rom
. ~ . .
(2-bromoethyl)dlmethylamine
,
10-Chloro-llb-(2-fluorophenyl)-7-(3-amino-
propyl)-2,3,5,11b-tetrahydrooxazolo-
[3,2-d][1,4]benzodiazepin-6(7H)-one, from
3-bromopropylamine
.
. .
.~
.

1~4Z886
10-Chloro-11b~2-~luorophenyl)-7-(3-methylamlno-
propyl)-2,~,5,11b-tetrahydrooxazolol3,2-d~1,4]-
benzodiazepin-6(7H)-one, from (3-bromopropyl~-
methylamine
10-Chloro-llb-(2-fluorophenyl)-7-(2-diethylamino-
ethyl)-2,3,5,11b-tetrahydrooxazolo13,2-d~1,4]-
benzodlazepin-6(7H)-one, rrom (2-bromoethyl)diethyl-
amine.
ExamPle 3
A solutlon of 2.8 g (0.0108 M) Or stannic chloride in
40 ml Or dry ethylene dlchlorlde was cooled in an ice bath
and 0.7 g ~0.00216 M) of 7-chloro-1-cyclopropylmethyl-1,3-
dlhydro-5-phenyl-2H-1,4-benzodlazepin-2-one was added wlth
stirring under nltrogen. A solution o~ 1.1 g (0.025 M~ of
ethylene oxlde ln 5 ml Or ethylene dichloride was added drop-
; wlse, and arter 6 hr at room temperature, the reactlon was
made basic wlth a mlxture o~ lce and ammonlum hydroxlde.
The pre¢lpltate was ~lltered, washed wlth dlchloromethane
and the comblned flltrates were washed with 50 ml of water,
drled over anhydrous sodlum sul~ate and evaporated to dryness.
' m e resldue was dlssolved ln 20 ml o~ benzene and chromatogra-
phed over 150 g o~ Florisil. The product was eluted with 1 1.
o~ benzene and 1.5 1 o~ ether whlch were comblned and eva-
porated. The resldue was crystalllzed from ether. The product
was recrystalllzed ~rom a mixture o~ dichloromethane and
hexane to give 10-chloro-7-cyclopropylmethyl-2,3,5,11b-tetra-
- 16 - :

1042886
- hydro-llb-phenyloxazolo[3,2-d][1,4~benzodiazepin-6(7H)-one
as white rods, m.p. 1~1-135.
ExamPle 4
. .
- To a solution o~ 17 g (0.065 M) o~ stannic chloride
in 200 ml Or dry ethylene dlchloride under nitrogen was added
5.0 g (0.0129 M) o~ 7-chloro-1-(2-diethylaminoethyl)-5-(2- ;
rluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one. The
reaction was stirred in an ice bath and 6.8 g (0.156 M) o~
ethylene oxlde in 25 ml Or ethylene dlchloride was added
dropwise. A~ter 18 hr at room temperature, the reaction was
heated under reflux ror 4 hr., and then cooled. A mixture
Or ice and ammonlum hydroxide was added until the reaction
mixture was basic. The solutlon was riltered, and the
precipitate was washed with dlchlorometh~ne. The combined fil-
trates were washed wlth 100 ml Or water, dried over anhydroussodium sulrate and evaporated to dryness. The residue was
dissolved in 50 ml of benzene and ~lltered through 150 g
Or Florlsil. The Florisil was then eluted with 400 ml Or
~, ether and 700 ml o~ ethyl acetate. The ~ractions were com-
; 20 bined and solvents were removed under reduced pressure.
The residue was re M uxed ror 10 mlnutes in 500 ml o~ hexane
whlch was decanted from insoluble tars, and then charcoal
lltered. The solvent was evaporated, and the residue was
crystallized ~rom ether and then recrystallized ~rom a
mixture Or ether and petroleum ether to give 10-chloro-7-(2-
diethylaminoethyl)-llb-(2-~luorophenyl)-2,3,5,11b-tetra-
hydrooxazolol3,2-d]11,4]benzodiazepin-6(7H)-one as white
17
'`~ .

104Z886
::
plates, m.p. 129-136.
: ~
Exam~le A
'" ,~ '
Suppository Formulstion
Per 1.3 Gm
Suppository
10-Chloro~7-(2-diethylaminoethyl)-
llb-(2-fluorophenyl)-2,3,5,11b-
tetrahydro oxazolo [3,2-d7 ~1,4~
benzodiazepin-6-(7H)-one 0.010 Gm
Cocoa butter m.p. 36-37 1.245 Gm
Carnauba Wax 0.045 Gm ~-
me cocoa butter and the carnauba wax were melted
in a suitable size glass-lined container (stainless steel
may also be used), mixed ~ell and cooled to 45 C. The 10-
't chloro-7-(2-diethylaminoethyl)-11b-(2-fluorophenyl)-2,3,5,11b-
tetrahydrooxazolo l3,2- ~ 7 benzodiazepin-6-(7H)-one which
had been reduced to a fine powder with no lumps, was added and
stirred until completely and uniformly dispersed. The mixture
- wa~ poured into suppository molds to yield suppositories having
an individual weight Or 1.3 grams. The suppositories were
cooled and removed from molds. They were then individually
wrapped in wax paper for packaging (foil may also be used).
~:
',' ' .
' '
..
~ - 18 -
" . ' .
..

~o4z886 :
Example B
Capsule Formulatlon
Per Capsule
10-Chloro-7-(2-diethylaminoethyl)-
llb-(2-~luorophenyl)-2,3,5,11b-
tetrahydrooxazolol3,2-d][1,4]-
benzodiazepin-6(7H)-one 10 mg
Lactose 165 mg
Corn Starch ~0 mg
~ 10 Talc 5 mg
: Total Weight 210 mg
'`' " :
10-Chloro-7-(2-diethylaminoethyl)-llb-(2-rluorophenyl)-
2,3,5,11b-tetrahydrooxszolo[3,2-d][1,4~benzodlazepin-6-(7H)-
one, lactose and corn starch were mixed in a suitable mlxer.
~, 15 The mlxture was rurther blended by passing through a comminutlng
machlne. The blended powder was returned to the mixer, the
talc added and blended thoroughly. The mixture was ~illed into
hard shell gelatin capsules on a capsulating machine.
..
. ~
Example C
Tablet Formulation
Per Tablet
10-Chloro-7-(2-diethylamlnoethyl)-llb-
(2-fluorophenyl)-2,~,5,11b-tetrahydro-
A oxazolo[7,2-d][1,4]benzodiazepin-~(7H)-one 25.00 mg
j 25 Dicalclum Phosphate Dlhydrate, Unmilled 175.00 mg
Corn Starch 24.00 mg
~ Magnesium Stearate 1.00
;~; Total Weight 225~00 mg
., ~.
:~ :
.' :~

:
1042886
10-Chloro-7-(2-diethylaminoethyl)-llb-(2-fluorophenyl)-
2,~,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-
one and corn starch were mixed together and passed through
a comminutlng machine. This premix was then mixed with
dicalcium phosphate and one-hal~ Or the magnesium stearate,
passed through a comminuting machine and slugged. me slugs
were passed through a comminutlng machine and the remaining
magnesium ~tearate was added. The mixture was mixed and
compressed.
ExamPle D
Capsule Formulation
Per Capsule
10-chloro-7-cyclopropylmethyl-2,3,5,
llb-tetrahydro-llb-phenyloxoazolo-
[3,2-d][1,4]benzodiazepln-6(7H)-one10 mg
Lactose 165 mg
Corn Starch 30 mg
'' Talc 5 m~
,~ Total Weight 210 mg
.
10-Chloro-7-cyclopropylmethyl-2,3,5~11b-tetrahydro-llb-
` phenyloxoazolo[3,2-d]11,4]benzodlazepln-6(7H)-one, lactose and
corn starch were mixed ln a sultable mixer. The mlxture was
~urther blended by passlng through a commlnuting machine. The
, blended powder was returned to the mixer, the talc added and
blended thoroughly. The mixture was ~llled into hard shell
gelatin capsules on a capsulating machine. ~- -
~, . ~ ,.
~,' . .
r- 20
?

`
104Z886
Example E
Suppository Formulation
Per 1.~ Gm
- Suppository
10-Chloro-7-cyclopropylmethyl-2,3,5,11b-
- 5 tetrahydro-llb-phenyloxoazolo[3,2-d]-
[1,4~benzodlazepin-6(7H)-one 0.010 Gm
Cocoa butter m.p. 36-37 1.245 Gm
Carnauba Wax 0.045 Gm
:' "'
The cocoa butter and the carnauba wax were melted in a
suitable size glass-llned container (stalnless steel may
also be used), mixed well and cooled to 45C. The 10-chloro-
7-cyclopropylmethyl-2,~,5,11b-tetrahydro-llb-phenyloxoazolo-
¦3,2-d]llJ4~benzodlazepin-6(7H)-one which had been reduced
to a fine powder with no lumps, was added and stirred until
~ 15 completely and uni~ormly dispersed. The mixture was poured
;i lnto suppository molds to yield suppositorles havlng an
:l individual weight o~ 1.3 grams. The suppositories were
cooled and removed ~rom molds. mey were then individually
wrapped in wax paper ~or packaging (~oil may also be used).
.~ :
ExamPle F
Tablet Formulation
Per Tablet
10-Chloro-7-cyclopropylmethyl-2,~,5,
, llb-tetrahydro-llb-phenyloxoazolo-
[3J2-d][1,4]benzodiazepin-6(7H)-one25.00 mg
Dicalcium Phosphate Dlhydrate, Unmilled 175.00 mg ~ -
3 Corn Starch 24.00 mg
Magnesium Stearate 1.00 mg
Total Weight225.00 mg
.
- 21 -
.
1, . , . . .. . .. . . . ... . - -

1042886
10-Chloro-7-cyclopropylmethyl-2,3,5,11b-tetrahydro-llb-
phenyloxoazolo[3,2-d][1,4]benzodlazepin-6(7H)-one and corn
starch were mixed together and passed through a comminutlng
machlne. mls premlx was then mixed with dlcalclum phosphate
and one-half Or the magneslum stearate, passed through a
comminuting machine and slugged. The slugs were passed through
a commlnuting machine and the remaining magneslum stearate
was added. The mlxture was mlxed and compressed.
ExamPle G
Parenteral Formulation
Per cc
10-Chloro-7-cyclopropylmethyl-2,3,5,11b-
tetrahydro-llb-phenyloxoazolol3,2-d]-
[1,4]benzodiazepin-6(7H)-one 5.0 mg
Propylene Glycol o.4 cc
Benzyl Alcohol (Benzaldehyde ~ree)0.015 cc
Ethanol 95 percent U.S.P. 0.10 cc
Sodium Benzoate 48.8 mg
Benzoic Acid 1.2 mg
Water ~or In~ectlon q.s. 1.0 cc
. .
x The 50 grams Or 10-chloro-7-cyclopropylmethyl-2,3,5,
llb-tetrahydro-llb-phenyloxoazolo[3,2-d]11,4]benzodiazepin-
6(7H)-one were dissolved in 150 cc Or benzyl alcohol; 4,000 cc
Or propylene glycol and 1,000 cc Or ethanol were added. The ~-
12 grams Or benzoic acid were dissolved in the above. The
488 grams Or sodium benzoate dlssolved ln 3,000 cc Or Water ~-
ror In~ectlon were added. The solutlon was brought up to final
volume o~ 10,000 cc with Water rOr In~ectlon. The solutlon was
~,
~ - 22 -
.. . .. .. . .. . . . . . . ......... . ... -
. .. . . . .

:
1042886
~iltered through a candle, filled into suitable size ampuls,
gassed with nitrogen and sealed. It was then autoclaved
at 0,7 atm. for 30 minutes.
.~ :
... .
.~
- 2~ -
..... ... . . ... .