Note: Descriptions are shown in the official language in which they were submitted.
7~
~ XADIAZOLYL IMIDAZOBENZODIAZEPINE DERIVATIVES,
A METHOD OF PREP~IN~ T~IE SAME, P~IA~M~EUTICAL COMPOSITIONS
lHEREOF, AND METHOD OF TREATING THEREWITH
This is a divisional application of application Serial No.
503,329 ~iled Marcll 5, 1986.
~ield o_Invention
This invention rela~es to new oxadiazolyl imid~zobenzo-
diazepine derivatives, to a method oE preparing them, to
pharmaceutical compositions thereo, and to a method oE
trea~ing therewitl1. rr~-ese new compounds and pharmaceutical
compositions thereof are useful for the amelioration,
mitigation, allevia tiol1~or elimination oE central nervous
system disorders or ailments related to benzodiazepine
receptors, and especially in psychopharmaceutical prepara-
tions as anticonvulsants, anxiolytics, and nootropics due to
thelr high capacity for blnding ~o benzodiazepine receptorsO
.
;The most relevant prior art is to be found in European
Patent Application No. 109,921 in which other oxadiazolyl
; derivat~Yes of imidazo~enzodiazepines are disclosed. The
compounds are described as being able to displace fluni-
trazepam Erom benzodiazepine re~eptors.
European Patent ~pplication No. 150,040 also discloses
oxadiazolyl derivatives oE imidazobenzodiazepines. ~lthough
the generi~ claims o that patent application include com
pounds having the general formula Il
~ ~l \ 5
:. :...
, .
~L~i6~7~ FerrOco D9/ju
wherein R3, R4, R5, and R~ ha~e meanings as defined below,
this European Patent Application No. 150,040 does not dis-
close any examples of compounds wherein RA is alkoxy or lower
alkyl.
Objects of the Invention_
It is an object of the present invention to provide
certain novel oxadiazole imidazobenzodiazepines and pharma-
ceutically-acceptable acid addition salts thereof, which are
useful in the treatment of central nervous system disoraers
or ailments, especially as anticonvulsants~ anxiolytics, and
nootropics, a process for producing the same, pharmaceutical
compositions thereof, intermediates therefor, and a method
of treating therewith. Additional objects will become
apparent hereinafter, and still others will be obvious to
one skilled in the art.
: ~ Summary of the Invention
: The invention, then, comprises the following, inter
a~ia: certain novel oxadiazole imidazobenzodiazepines as
.
set forth in the following formula, pharmaceutical composi-
tions thereof, a method of treating a central nervous system
: : ailm:ent in a subject in need of such treatment comprising
: :: . .
the step of administering to the said subject an amount-of
such a compound which is efEective for the alleviation of
such ailment, preferably wherein the compound is adminis-
tered~i:n the form of a~ pharmaceut~ical composition thereof
in~ which it is present:together with a pharmaceutically-
acceptable carrier or diluent, as well as an intermediate
compound having the formula CN-CH2-~3 wherein R3 has
' ' ~'`' '' ''
~L26~7~
the meaning defined below in formula I, and a method of preparing
such pharmacologically-active compounds.
The present divisional application is partlcularly dlrected
to a ~nethod of prepar1ng a compound havlng the formula
CN-C1~2-n where~n
R3 ls ~ _ R'' or ~ N-~ R''
wherein
R'' is hydrogent C~ 6-alkyl, C1 6-al~oxymethyl, or
: C3 6-cycloalkyl characterized in dehydra~iny a compound
having the ~ormula
..
0~C Nll-C~2-R3
This application is also direc~ed to a compound having
~ : the formula CN-CH -R wherein
::: 2
R3 ls ~;~ or ~N;~
whe re i n
;' ' 1s .hydrogen, Cl_6-alkyl, C~ -alkoxymetlly1, s~r
C3_ 6-cycloalkyL
; ~ ~ - 2a -
- .:
Ferroco D9
~he Present Invention
It has been found that the novel compounds of the
present- invention have improved pharmaceutical properties
when compared to well-known related compounds.
The new compounds of the present invention are oxa-
diazolyl imidazobenzodiazepine derivatives having the
general formula I:
N ~ 3
:
:whereln R3 has the ~ormula
'' or ~ ~ R"
wh~ereln ~R " is hydrogen, C1_6~alky:l, C~ 6 alkoxymethyl, or
C3_6 cycloalkyl
hyd~ogen;
R5~is~C~1_6 alkyl or~R4 and n5 together form a 2-4 membered
alkylene bridge; and~R~ is C1_6 alkyl, C1-6 alkoxy, or
C1_3 tri~luoroalkyl. ::
: : It is well known ~Squires, R.F. and Braestrup, C., Nature
. (London) 266, 734 ~1977))~that specific sites in the central
: nervou~ sy~te~s~of vertebrates e~hiblt a high speci~ic
: af~inity for blndlng 1,4 and 1,5-benzodiazepines. ~ ~hese
~ites are called benzodiazepine receptors.
3 -
~.
~7q
Ferroco D9
The pharmaceutical potency of the compounds of the
present invention is evidenced by determininy their capa-
bility for displacing radioactively-labelled flunitrazepam
and the imidazobenzodiazepine 3H-Ro 15-1788 from such
benzodiazepine receptors.
The displacement activity of the compounds of the
invention has been determined by determining their ICso
and EDso values. The ICso value represents the concen-
tration (nM, 30C) which causes a displacement of 50~
of the specific binding of 3H-Ro 15-1788 in samples com-
prising a total volume of 1 ml.
The displacement test is performed as follows:
, 750~ 1 of rat cerebral cortical membrane homogenate was
incubated with 100~ 1 of 5 nM 3~1-Ro 15-1788 in water at
30C. Then lO0~ l of a solution of the test compound and
50 ~ 1 of Krebs bu~fer was added. After incubation the
binding reaction was terminated by filtration through
Whatman GF/B glass ibre filters followed by 2~5 ml wash
with;ice-cold buffer and the radioactivity was measured by
;~ scintillation counting. The ICso was determined by
including at least four concentrations of the test compound
and log/probit analysis of the resulting data.
The ~Dso value~represents the dose ~mg/kg) of a te~$
substance which causes the specific binding of flunitrazepam
to benzodiazepine receptors in a living brain to be reduced
to 50% of the control value.
Such an in vivo test is carried out as follows:
Groups of mice are injected with the test substance at
diferent doses and usually subcutaneously. Fifteen minutes
~4-
:
Ferroco D9
later 3H-flunitrazepam is given intravenously to the mice
and, after a further twenty minutes, the mice are killed.
Their forebrain membranes are removed and the radioactivity
of these forebrain membranes is measured by scintillation
counting. The ED50 value is determined from dose-response
curves.
The results obtained in the above-described tests for
some of the compounds of the invention will appear from the
following Table 1.
; '
:
, .. , , . . :.. ... ..
:, ~ , . .:
Ferroco D9
.
Table 1
~_R3
~ 5 -.
RA, o
in vl tro in vivo
A~ R4 R5 R3 50 ED50 ~g/kg .
R
H ~ CH3 ~ 44 . E3 ~ 2 . 2
Cu2C~ 0 ~ D . 4
CH3~ ~ C~ 4~0
33CO ~ N
~: ~ :: :
Ferroco D9
Method in General
.
The invention also relates to a method of preparing
the above-identified compounds. This method comprises
the steps of:
a) reacting a reactive derivative of a compound
having the general formula III
~ ~ A
wh~rein R4, R5, and RA have the meanings set
forth above,with a compound having the formula
~: IV
NGH
R''-C f (IV)
NH2
1 ' ~ :
1 ~: , '
::
};~ : wherein R ' has~the meaning~set orth above to form
a compound having the ~formula I:in which R is
Wber~ln R has ~tbe ~an~ng se~ forth abo e,
; b) ~ reacting~a compound having ~he~ general formula
~ ~ ~; V)
~ 7-
:, , :
.
~2~6~ Ferroco D9
wherein RA, R4 and R5 have the meanings set forth
above,with a compound of the formula VI
R''-C~OCH3)2N(CH3~ 2 ~V~)
wherein R'' has the meaning set forth above, to form
a compound having the general formula VII
CON=CR N(CH3)2
~A ~ (VII)
: ~
: : :
wherein RA, R4,~ RS and R have the meanings set
for~h above,-and~reacting the compound having the
formula VII~ with N~ OH or ano~ther aminating~ agent to
f~orm a compound having:~'the formula I;in which R3 is
wherein R'' has the meaning:set forth above,
or;
; c~) reacting~a compound having the general formula VIII
~: ~
~i ~:: : :
:: :
~ ~ --8--
~ n Ferroco D9
/~C~ .
~ ~ ~ 4 (VIII)
RA o
.
wherein RA, R , and RS have the meanings set forth
above, with NH20H to form a compound having the
general formula IX
:.
, :. :
~, :
C~
wherein ~ ,~R4, and RS have the meanings set:forth
above,~and:~reac:ting the:~compound having ~he formula
with`a~compound~having:the general formula X
''c~r:2o~ (yj ~ i :
wherei:n~R''~has the:meaning~se~orth~above, to form
a compound~having~ the~formula I~in which R is~
: wherein R :has the meaning set forth abo~e,or
., ~ . .
Ferroco D9
d) reacting a compound having the general formula XI
R (XI~
RA O R
wherein
R4, R5, and RA have the meanings defined above, and Y is
a leaving group, with a compound having the formula XII
CN - CH2 R3 (XII)
whereln R3 has the meaning deflned above, to form a compound
having the formula I.
The~ substituent Y ~may be any ~suitable leaving group,
such as the -OP(O)~O-ethyl?2 group~of E~ample~S(c) hereof.
Alternatively, the le;aving~group may be any disclosed in
U.S.~;~Patents 4,031,079 or 4,35~9,~4~20,~for~example, halogen,
alkylthio,~ e.g., ~methylthio,~ ~aralkylthio, N-nitrosoalkyl-
amino,~ alkoxy,~ mercapto,~ -OP~O)~OR~2~whereln R is lower-
alkyl~;or -OP(O)(NR'R'')~wherein R~and R'' each represent~
lower-alkyl,~allyl,~or phenyl~or together with the nitrogen
atom; to~which they are ~attached represent a heterocyclic
radi~cal~such a~s~morpholino,~ pyrrolidino, piperidino, or
methylpiperaxino.~ ~The rea~tion is preferably carried out
:: :: ~ : :
: :: ~
æ ~ ~ Ferroco D9
under alkaline conditions, i.e., in the presence of a base,
and among bases alkali metal, e.g., potassium or sodium,
alkoxides or hydrides are preerred~ The reaction is
preferably conducted in the presence of an organic solvent
which is nonreactive with the reactants and products
of reac~ion under the conditions of reaction, especially
an anhydrous solven~ and preferably an anhydrous aprotic
solvent such as dimethylformamide (DMF) or the like. The
temperature range employed may be any range suitable for the
reaction to proceed at a reasonable rate and without undue
delay or decomposition and a range from a minus forty (-40)
degrees Celsius to about room tempexature is accordingly
usually particularly suitable.
The starting materials for the foregoing reactions are
known or readily preparable from commercially available
benzene derivatives using the methods described in European
Patent Applications Nos. 109,921 and 27,214 and in Synthesis,
Vol. 10, pp. 681-682.
. .
FerroCO D9/ju
Detailed Description of the Invention
The preparation of the compounds of the invention will
now be described in further detail with reference to the
following Examples, which are given by way of illustration
only and are not to be construed as limiting.
Example
;
A. Isatoic anhydride
, 7.5 9 of 2-aminobenzoic acid hydrochloride was
` mixed with 10 ml of diphosgeneand the mixture
was stirred in 150 ml dioxanefor 40 minutes at
reflux. The resulting mixture was cooled and
filtered.
Yield: 5~7 g of title compound.
In the same manner, from the appropriate
aminobenzoic acids, ~he following compounds
are synthesized:
!~
-12-
Ferroco D9
6-methylisatoic anhydride,
6-methoxy~satoic anhydride, and
6-trifluoromethylisatoic anhydcide,
5-methylisato iC anhydride, - ;
5-methoxyisatoic anhydride t and
5-tri~luoromethylisatoic anhydride.
B. 3,4-dihydro-4-methyl-2H-1,4-benzodiazePine-2~5tlH)-dione
64.8 9 of isatoic acid anhydride was mixed with
35.4 9 o ~arcosine and the resultinq mixture
stirred with 420 ml dimethylsulfoxide at 100 C
for 4 hours. The mixture was cooled and was
poured into 1.5 l water. The precipitated
product was washed with water and dried.
Yield: 57~ 9 of title compound.
- ' .
In the same manner, from appropriate isatoic
anhydride derivatives,~he ~ollowing compounds
- are synthesized.
6-methoxy-3,4-dihydro-4-methyl-2H-1~4-benzodiazepine-2,5(1H)-
dione
': , . . .
; (S)-6-methyl-1,2,3,11a-~etrahydro-5~-pyrrolo (2,1-c)
~1,4) benzodiazepine-5,11(10H)-dione by reaction
;~ with L-proline. M.p. 207.6-209.9C.
. .
6-tri~lu~rom2thyl-3~-dihydro-4-methyl-2H-l~4-benzodiazepine-2l5
~lH)dione M.p. 223.7-?25.9C.
7~ethyl-3~4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-
dione. M.p. 260.0-260.6C.
.
~5~-7-methyl-1,2,3,11a-tetrahydro-5~l-pyrrolo (2,1-c)
~ 1,4) benzodiazepine-5,11(10H)-dione by reaction
with L~proline. M.p. 243.1-244.5C. ~~
13-
~ ~ ~ Ferroco D9
6~methyl-3,4-dihydro-4-methyl-2}1-1,4-benzodiazepine-2,5(1
dione . M~p. 204.4-205.4C.
(S)-6-methyl-1,lOa~dihydro-a~eto (2,1-c)(1,4)
benzodiazepine-4,10-(2H,9~I)-dione by reaction with
L-azetidine
7-methoxy-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-
dione. M.p. 206C.
(S~-7-methoxy-1,2,3~11a-te~rahydro-5H-pyrrolo (2,1-c~
(1,4) benzodiazepine-5,11(lOH)-dione by reaction
with L-proline. M.p. 216.8-217.6C.
~S~-5-methyl-l,lOa-dihydro-azeto (2,1-c)(1,4 ]
benzodiazepine-4,10-t2H,9H)-dione by reaction with ;~
L-azetidine
, - . , .
7-trifluoromethyl-3,4-dihydro-4-methyl-2H-1,4-benzo-
diazepine-2,5llH)-dione
' .
9-methyl-3,4-dihydro-4-methyI-2H-1,4-benzodiazepine-2,5(1H~- ,-
dione
C. Ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a~
benzodiazepine-3-carboxYlate
16.5 g of 4-methyl-3,4-dihydro-2H-1,4-benzodiaze-
pine-2,5(1H)-dione and 11.7 9 of K-t-butoxide was
dissolved in 100 ml of dry dimethyl formamide
(D~IF~ and the mixture was stirred for 10 minutes.
Then 13.2 ml of diethylchlorophosphate was added
and the resulting mixture was cooled to -20C and
stirred for 10 minutes.
A mixture oE I0~8 9 ~-t-butoxid~ and 10.5 ml ethyl
-I4--
:: .:
~ ~ ~ ~ Ferroco D9
isocyanoacetate in 30 ml o~ dry D~F was added to the
above prepared mixture at -10 to -20 C and the
resulting mixture was sticred for one hour at RT,
whereafter it was poured into 8.7 ml acetic acid in
300 ml water. This mixture was extrac~ed 2 tisnes
with 150 ml methylene chloride. The organic phase
was dried and evaporated. The resulting residue ~as
crystallized leaving 10 9 of the title compo~nd as
crystals.
In the same manner, from the appropriate
benzodiazepine-diones,the following compounds are
s~nthesized.
Ethyl 5,6-dihydro-5-methyl-6-oxo-7-methoxy-4H-imidazo-
.
(1,5-a~ (1,4) benzodiazepine-3-carboxylate.
,
Ethyl (S~-8-methyl-11,12,13,13a-tetrahydro-9-oxo- ;;
9H-imiaazo~1,5-a)pyrrolo~2,1-c)(1,4)benzodiazepine-1- -
carboxylate. M.p. 150.4-150.5C.
Ethyl
5,~-dihydro-5-methyl-6-oxo-7-methoxy-4~-imida2O-
J5~a) ~1,4)bénzodiazepine-3-carboxyl~te as an oil
. ~ . :
: ~ - - : -
Ethyl 8-methyl-S,6-dihydro-5-methyl-6-oxo- 4~-
idazo(l,S-a~(1,4)benzodiazepine-3-carboxylate .
M.p. 195.5-195.8C.
'
Ethyl (S)-7-methyl-11,12,13,13a-tetrahydro-9-oxo-9H-
imidazo(l,S a~pyrrolo(2,1-c)(1,4)benzodiazepine-1-
carboxylate. M.p. 271.0-2?1.7C.
Ethyl 7-methyl-5,6-dihydro-S-methyl-6-oxo-41l-imidazo
(1,5-a)(~4)benzodiazepin~-3-carboxylate. M.p. 147.7-148.1~C.
Ethyl (S)-7-methyl-lo,~ 2,l2a-tetrahydro-9-oxo-9ll-
--1 5-
~ . `
~ ~ Ferroco D9
imidazo(l,5-a)azetoi2,1-c)(1,4)benzodiazepine-1-
carboxylate. M.p. 257.6-259.1C.
Ethyl 8-methoxy-5,6-dihydro-5 methyl-6-oxo-4H-imida-
zo(l,5-a)~1,4)benzodia~pine-3-carboxYlate. M.p. 228.1C.
Ethyl (S)-7-methoxy-11,12,13,13a-tetrahydro-9-oxo-
9H-imidazo(1,5-a)pyrrolo(2,1 c)(l,4)benzodiazepine-
l-carboxylate. M.p. 196.6-197.1C.
Ethyl (S)-8-methyl-10,11,12,12a-tetrahydro-9-oxo-
9H-imidazo(1,5-a)azeto(2,1-c)~1,4)benzodiazepine-1-
carboxylate. M.p. 166.0~
Ethyl 7-methoxy-5,6-dihydro-5-methyl-6-oxo-4H-imida-
zo(l,5-a)(1,4)benzodiazepine-3-carboxylate as an oil.
Ethyl 10-methyl~5,6-dihydro-5-methyl-6-oxo-4H-imidazo
ll,5-a)~1,4)ben~odiazepine-3-carboxylateO M.p. 196.3-196.9C.
D. ~l- t!~y~r-'t~ o ~
2.3 9 o so~ium in 33 ml of dry methanol and 6,65 g
of hydroxylamine hydrochloride in 66 ml of dry
methanol was mixed. ~o the filtrate was added
dropwise 7.8 9 methoxyacetonitrile. The m;xture was
le~t fo~ 48 hours. The mixture was then cooled to
~C. ~iltration and e~apocation of the filtrate gave
8.7 9 of the title compo~nd.
In the same manner, from appropriate nitriles,the
following compounds are synthesized.
propionamide oxime
iscpropyl carboxamide oxime
acetamide oxime
valecylamide oxime
cyclopfopyl carboxalnidc oxim~
16-
~ ~ Ferroco ~9
E. 3-(5-~3-methoxymethyl-1,2,4-oxadiazol)-yl~-5,6--
dihydro-S-methyl-6-oxo-4h-imidazo[1,5-a3[1~benzo-
benzodiazepine
240 mg of sodium was dissolved in 12 ml of dry ethanol
with 4 9 of molecular sieves ~4A~. 2~2 g o~ methoxy-
acetami~ oxime and 1 9 of ethyl 5,6-dihydro-5-methyl-
-6-oxo-4H-imidazo~1,5-a)(1,4)-benzodiazepine-3-carboxy-
late in 5 ml of dry ethanol was added. This mixture
was refluxed for 15 hours and was then evaporated.
The residue was recrystallized from water yielding
0.6 g of the title compound.
., .
M.p. 193.8-194.1C.
In the same manner the following compounds are
synthesized from the appropriate carboxylate.
3-(5-(3-ethyl-1,2,4-oxadiazol)-yl~-8-trifluoro-
methyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo
~1,5-a](1,4)benzodiazepine
.p. 172-lis C.
.
3-(5-(3-ethyl-1,2,4-oxadiazol)-yl)-8-methyl-5,6-
dihydro-5-methyl-6-oxo-4H-imidazo (1,5-a)(1,4)
benzodiazepine
~.p. 195.4-195.7C.
(S) -1- (5- ~3-ethyl-1, 2,4-oxadiazol)-yl~-7-methyl-
11,12~13,13a-tetrahydro-9-oxo-9H-imidazo(1,5-a)
pyrrolo(2,1-c~(1,4)-benzodiazepine
M.p. 270C.
3- (5- (3-methoxymethyl-1, 2,4-oxadiazol)-yl)-8-
methyl-$,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)
ll,4)benzodiazepine
M.p. 215.3-216.1 C.
-17-
.
~l W ~ ~ Ferroco D9
.
(S)~ 5-(3-ethyl-1,2~4-oxadiazol)-yl)-8-methyl-11,
12,13,13a-tetrahydro-9-oxo-9H-imidaæo(1,5-a)
pyrrolo(2,1-c)(1,4)- benzodiazepine
M.p. 170.3-170.5C
3-~5-(3-ethyl-1,2,4-oxadiazol)-yl~-7-methyl-5,6-
dihydro-5-methyl-6-oxo-4H-imidazo(l,S-a)(1,4)
benzodiazepine
M.p. 164.1C
~S)-1-(5-(3-ethyl-1,2,4-oxadiazol)-yl)-7-methyl-
10,11,12,12 a-tetrahydro-9-oxo-9H-imidazo~1,5-a)
azeto(2,1-c~(1,4)benzodiazepine
M.p. 210.1-212.4C
(S)~1-(5-(3-isopropyl-1,2,4-oxadiazol)-yl)-7-
methyl-10,11,-12,12a-tetrahydro-9-oxo-9H-imidazo
(1,5-a)azeto(2,1-c)(1,4)-benzodiazepine
M.p.~193.4-195.4~C.
3-(5-(3-methyl-1,2,4-oxadiazo~yl)-8 methoxy-5,6-
dihydro-5-methyl-~-oxo-4H-imidazo~1,5-a)(1,4)
benzodiazepine -
M.p~ 222-222.3C.
3-(5-~3-ethyl-1,2,4-oxad;azol)-yl)
-8-methoxy-5,6-dihydro-5-methyl-6-oxo-4H-imidazo
~1,5-a)(1,4)benzodiazepine
M.p. 209.3-210.4C.
1 :
::
:~l (S)~ 5-(3-ethyl-1,2,4-oxadiaz~ ~yl)
7-methoxy-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo
(l,S-a)pyrrolo~2,1-c)(1,4~benzodiazepine
.p. 237~238C.
:
~S~ (5-(3-ethyl-1,2,4-oxadiazol~yl)
, -8-methyl-10,11,12,12a-teteahydro-9-oxo-9H-imidazo
: (l,S-a)azeto~2/1-c)~1,4)benzodiazepine
, -18-
~ ~ ~ - Ferroco D9
M.p. 204.4-204.6C.
,
3-(5-(3-ethyl-1,2,4-oxadiazol~ylj-7-methoxy-5,6-
dihydro-S-methyl-6-oxo-4H-imidazo(1,5 a)~1,4)
benzodiazepine .
M.p. 211.3-213.0C.
3-~5-(3-ethyl-1,2,4-oxadiazol)-yl~-10-methyl-5,6-
dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)~1,4)
benzodiazepine . M.p. 162.6-163.3C.
~S)-1-(3-cyclopropyl-1,2,4-oxadiazol-
5-yl)-8-methyl-11,12,13,13a -
tetrahydro-9-oxo-9H-imida~o(1,5-a)pyrrolo(2,1-c)
~1,4]benzodiazepine
M.p. 171.1-171.2C.
3-~3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-S-
methyl-6-oxo-7-methoxy-4H-imidazo~l,S-a)~1,4)
behzodiazepine . . .
.p. 161.3C. . ~--
3-(3-cyclopropyl-1,2,~-oxadiazol-5-~ 5,6-dihydro-S-
methyl-6-oxo-7-methyl-4~-imidazo(1l5-a)(1,4
benzodiazepine ~
p~ 15~.5-153.1 C0
3-(3-isopropyl-1,2,4-oxadiazol-5-yl~-5,6-dihydro-S-
methyl-6-oxo-7-methyl-4H-imidazo~l,S-a)ll,4)
benzodiazepine .
M.p.173.2-175.9C.
(S]-1-~3-cyclopropyl-1,2,4-oxadiazol-S-yl~-8-~ethyl-
10,11,12,12a-tetrahydro 9-oxo-9~l-imidazo(l,S-a)
azets~2,1-c)~1,9)benzodia7epine
M.p. 173.1~174.5C~ -
' - 1 9 - .
.: .
~ ~ Ferroco D9
Example 2
A. 3-carbamoyl-8-methyl-5,6-dihydro-5-methyl-6-oxo-
4H-imidazQ-~1,5-a)(1,4) benzodiazepine
A mixture of 3.5 g imidazole and 0.95 ml thionylchloride
was stirred for 15 min in 35 ml of tetrahydrofurane.
The mixture was filtered and the iltrate wa~ added
to 1.7 9 of 8-methyl-5,6-dihydro-5-methyl-6-oxo-4H--
imidazo~l,5-a)(1,4)benzodiazepine-3-carboxylic acid
in 4 ml DMF. This mixture was stirred for 2 hours at
RT and NH3-gas was led to the mixture for 15 min.This
mixture was then reduced to 15 ml and loo ml of
water was added. The precipitate was washed with
water. Yield 1~6 9.
M.p. 290-294C
B. 3-cyano-8-methyl-5,6-dihydro-5-methyl-6~oxo-4H
imidazo(l,5-a)(1~4)benzodiazepine
0,4 ml Br2 in 10 ml methylene chloride was added to
a solution of triphenyl phosphine in 40 ml methylene
chloride at 0C. ~o this mixture the product of A
was addded together with 3.3 ml triethylamine~ This
mixture was stirred at RT for 30 min. Then 100 ml o
water was added. The organic phase was reduced to 20
ml at reduced pressure and 1.2 9 o the title
compound precipitated by adding 50 ml of ether.
; M.p. 252-252.3 C.
.
C. 8-methyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo
(1,5-a)~1,4)benzodiazepine-3-carboxamide ~xime.
1~ g of the product of B, 600 mg of hydroxyl amine
hydrochloride and 600 mg of potassium carbonate was
stirred in 50 ml 96% ethanol and ~ ml of water at 50
C for 4 hours. Then further 300 mg of hydroxyl amine
hydrochloride was added and the mixture was stirred
for 1 hour. The mixture was then reduced at reduced
-20-
,
~ ~ Ferroco D9
pressure to 20 ml and 50 ml water was added
whereupon l,~ g of the title compound precipitated
~.p. 227 229C.
D 3-(5-ethyl-l,2,4-oxadiazol-3-yl)-8-methyl-5,6-
methyl-6-oxo-4H-imidazo(l,S-a)(l,4~benzodiazepine
A mixture of 450 mg of the prod~ct of C and 15 ml
propionic anhydride was stirred at 100C for lO min.
Then 25 ml of dry ethanol, 3 y molecular sieves (3A)
and 50 mg of sodium was added and the resulting
mixture was refluxed for 4 hours. The mixture was
then filtered and the filtrate was reduced to lO
ml.Then 70 ml of water was added whereupon the tit~e
compound precipitated. The precipitate was washed
with water and petroleum ether~ Yield 150 mg. M.p.
4 ~ 6-17~i ~ 4Co
.
In the same manner by react;on with acetic anhydride
; the following compounds are synthesizea.
3-(3-l5-~ethyl-l,2,4-oxadiazol-3-yl~-8-methyl-5,6-
dihydro-5-methyl-6-oxo-4~-imidazo~l,5-a)~l,4)benzo-
diazepine M.p. 276C dec.
.
3~5-ethyl-1,2,4-oxadia~ol 3-yl)-5,6-dihydro-5-methyl-
~6-oxo~4~l-7-tri~luoromcthyl-~uGazo~1~5-a)(l~4)benzodiazep~e~
3,4-dihydro-4-methyl-6-triluorolnethyl-2H-1,4-
benzodiazepine-2,5(lll)dion~ (2mmol~ was dissolved in
15 ml of dry dimethyl formamide lDtiF) and charged
- with 2.5 mmol of K-t-butylate~ This solution was
cooled undec N2 to 20 C, wherea~ter 2.6 mmol of
chloK~icthylphosphate was added.
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The reaction mixture was kept under N2 with stirring
at -20C and charged with a -30C cold solution of
5-ethyl-3-isocyanomethyl-1,2,4-oxadiazole (2.7 mmol~
and K-t-butylate 2.6 mmol in 15 ml dry DMF.
The resulting mixture was allowed 'ço heat to room
temperature, whereafter it was evaporated to dryness
n vacuo. The oily residue was tr~ated with H~O/
ether. The oryanic phase was evaporated to dryness
in vacuo and the residue was crystallized from
diethyl ether giving 50 mg of the title compound.
~pO 230.4-231.3C.
.
Example 3A
3-(3-ethyl-1,2,4-oxadiaæol 5-yl)-7-methyl-5,6-
dihydro-5-methyl-6-oxo-4-H-imidazo[1,5-a]~1,4]
- . benzodiazepine
In exactly the same manner, by reaction with 3-ethyl-
5-isocyanomethyl-1,2,4-oxadiazole, the compound 3-(3-
: ethyl-1,2,4-oxadiazol-5-yl)-7-methyl-5,6-dihydro-5-
:~: : methyl-6-oxo-4-H-imidazo[1,5-a][1,4~benzodiazepine,
: : M.p. 164C, is produced from 6-methyl-3,4-dihydro-4-
' methyl-2N-1,4-benzodlazepine-2,5(15)-dione.
.
::
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. .' :
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Ferroco D9
~xample 4
3-cyclopropyl-5-isocyanomethyl-1,2,4-oxadiazole
a 3-cyclopropyl-5-formylaminomethyl-1,2,4-oxadiazole.
A solution of ethyl formylaminomethyl-carboxylate
~150 mmD1) an~cyclopropylcarboxamidoxime (100 mmol) in
100% EtOEI (100 ml) was charged with Na (200 mg) and a
crushea molecular sieve ~4 A) (10 9). The stirred
reaction mixture was heated to reflux for 8 h. The
mixture was cooled to room temperature, filtered
through filter aid and the filtrate was evaporated
in vacuo. The oily residue was partitioned into a
CHC13 phase, dried with Na2SO4,and evaporated.
i , b 3=~ æ~eyl-5-isocyanomethyl-1,2,4-oxadiazole
A stirred solut;on of 3-cyclopropyl~5-formylamino-
methyl-1,2,4-oxadiazole (60 mmol~ and triethylamine
(176 mmol) in CH2C12 (100 ml) was charged at 0C
~ ~ dropwise with POC13 ~60 mmol~. The mixture was then
i ~ left for 30 min. with stirring at 0C, whereafter a
; solution of Na2C03 (60 mmol) in H20 (50 ml) was
added. The mixture was heated to room temperature,
' ~ - whereafter the organic phase was separatea, dried
j ana evaporated in vacuo. The residue was treated
with ether~ decanted,and the solution was evaporated
to give the title compound as an oil.
I : ,
The oil was processed without any further
purification.
: ~
IR: cm 1~ 2160.
3-ethyl-5-isocyanomethyl-1,2,4-oxadiazole was
prepared from
3-ethyl-S-formylaminomethyl-1,2,4-oxadiazole in a
similar manner.
IR: cm : 2170.
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'
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e 5
a. Formylaminomethyl-carboxamideoxime
To 53.6 g ~0.638 mol) N-formylam;no-ace-
tonitrile was added 0.55 mol freshly liberated
hydroxylamine dissolved in 370 ml methanol. An ice
bath was used to keep the temperature below 20C
during addition. The solution was allowed to stand
at room temperature overnight, whereafter i~ was
evaporated to give the title compound as pale
crystals.
Decomp~ 104-110C.
:'
b7 3-Formylaminomethyl-5-ethyl-1,2,4-oxadiazole
~ A mixture of 70 ml ethyl propionate, 20 9
i~ formylaminomethylcarboxamideoxime, l g sodium and 30
g crushed mol. sieves (4A) was refluxed in 300 ml
abs. EtOH~for 5 hours. The reaction mixture was
filtered ~nd the filtrate was evaporated. The oily
residue was ~uspended in 300 ml CHC13, filtere~ and
the filtrate was evaporated to give the title
compound as an oil. ~
HNMR (60 HMZ, CDC133 o' 5ppm): 1.4(3H, tt J=8 Hz),
2.9(2 H, q,J= Hz),~4.55 (2 H, s), 7.8 ~1 H),
broad-NH), 8.25 (1 H, s~.
, ~ :
The following compounds were synthesized
from the appropriate ethyl esters:
3-Pormylaminomethyl-5-cyclopropyl-lt2,4-oxadiazole
H-N~R ~60 M~z, CDC13) o' (ppm): 1.2 (4 H, m),2.8
-~ : (1 H, m~, 4.5 ~2 H, dt J=6Hz), 7.8 ~1 ~, broad-NH),
8.2 (1 H, s~.
3-Formylaminomethyl-5-methyl-1,2,4-oxadiazole
H-NM~ (60 M~IZf CDC13) o (ppm): 2.6 (3 H, s),
.6 ~2 ~1, d,J=3 ~), 7.4 (1 H, broa~-N~ 8.25
(1 ~1, s).
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æ~ Ferroco D9
3-Formylaminorr.ethyI-s~ ethoxymethyl-1, 2, 4-oxad iazole
H-NMR ~60 MHz, CDCL3) o (ppm): 3.5 (3 H, s),
4.7 (4 H, s+d, J=6 Hz), 7.8 (1 H, broad-NH) ,8.25
(1 H, s).
c. 5-Cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole
A stirred solution of 5-cyclopropyl-3-formyl-
amino-methyl-l, 2,4-oxad iazole (60 mmol) and
triethylamine (176 mmol) in CH2C12 (100 ml) was
charged dropwise with POCl (60 mmol) at 0C.
The mixture was then left ~or 30 min. with stirring
at 0C, whereafter a solution of Na2C03 (60 mmol)
::in H2O (50 ml) was added. The mixture was heated
to room temperature, whereafter the organic phase
was separated, dried and evaporated ~ vacuo. The
j~:: residue was treated with ether, decanted and the
- solution was evaporated to give the title compound
, as an oil.
¦~The oil was processed without any fur$her
purification.
~ :,
IR: cm 1 2160.
I
; ~~ 5-Ethyl-3-isocyanomethyl-1,2,4-oxadiazole,
: 5-methyl-3-isocyanomethyl-1,2,4-oxadiazole, and
5-methoxymethyl-3-isocyanomethyl-1,2,4-oxadiazole
are prepared in a similar mannPr. All compounds
are oils and are characterized by ~heir IR
stretching band at 2160 cm 1.
'~:. .
:;
:
--~5
: ~ ' , ' :: `"'' ' `' -~
-,.: . :. -
' :.. ` :'': :
~ FerroC D9/ju
Pharmaceutical Compositions and Method of Treating
The compounds of this invention can be used for theformulaticn of pharmaceutical preparations, e.g., for oral
and parenteral administration to mammals including humans,
in accordance with conventional methods of galenic pharmacy.
Conventional excipients are such pharmaceutically-
acceptable organic or inorganic carrier substances suitable
Eor parenteral or enteral application which do not deleteri~
ously affect or react with the active compounds.
Examples of such carriers are water, salt solutions,
alcohols, polyethylene glycols/ polyhydroxyethoxylated
castor oil, gelatine, lactulose, amylose, magnesium stearate,
talc, ~ilicic acid, fatty acid monoglycerides and diglycer-
ides, pentaerythritol fatty acid esters~ hydroxymethycellu-
lose, and polyvinylpyrrolidone.
The pharmaceutical preparations can be sterilized and
mixed, if desired, with auxiliary agents, such as lubricants,
preservatives, stabilizers, wetting agents, emulsifiers,
salt for influencing o~motic pressure, buffers and/or
coloring substances, and the like, which do not deleteri-
ously affect or react with the active compounds.
For parenteral application, particularly suitable are
injectable solutions or suspensions, preferably aqueous
solutions with the active compound dissolved in polyhy-
droxylated castor oil.
Ampoules are conveniently unit dosages.
;For oral application, particularly suitable are
tablets, dragees, or capsule~ having a talc and/or a
carbohydrate carrier or binder or the like, the carrier
preferably ~eing lactose and/or corn starch and/or potato
starch. A syrup, elixir, or the like can be used when a
sweetened vehicIe can be employed.
Generally, the compounds of this invention are dis-
pensed in unit dosage form comprising 0.05-100 mg in a
; pharmaceutically-acceptable carrier per unit dosage.
;:
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~ FerroC D9/; u
The dosage of the compounds according to khis
invention is 0.1-300 mg/day, preferably 1-30
mg/day, when administered to patients, e.g. humans,
as a drug.
A representative tablet which may be prepared by
conventional tabletting techniques contains:
Active compound 1.0 mg
Lactosum 67.8 mg Ph.Eur.
Avicel 31.4 mg
~ (ml ~ crystalline
cellulose~
Amberlite IRP 88 1.0 mg
¦ Magnesii stearas 0.25 mg Ph.Eur.-
~ .
~:
~: :
:
. .
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: ~' ':' `
~ ~ Ferroco D9
In conclusion, from the foregoing, it is apparent
that the present invention provides novel oxadiazolyl
imidazobenzodiazepine compounds which are useful for the
amelioration of central nervous system disorders related
to benzodiazepine receptors, especially as anticonvulsants,
anxiolytics, and nootropics, having the aforesaid highly
advantageous properties.
Further, a new synthesis is provided by the present
invention, as well as a new intermediate therefor.
It is to be understood that the invention is not to be
limited to the exact details of operation, or to the exact
compounds, compositions, methods, procedures, or embodiments
shown and described, as obvious modifications and equiva-
lents will be appar~nt to one skilled in the art, and the
invention is therefore to be limited only by the full scope
of the appended claims.
~ .
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