CA1266671A

CA1266671A - Oxadiazolyl imidazobenzodiazepine derivatives, a method of preparing the same, pharmaceutical compositions thereof, and method of treating therewith

Info

Publication number: CA1266671A
Application number: CA000590382A
Authority: CA
Inventors: Leif Helth Jensen; Frank Watjen; Mogens Engelstoft; John Bondo Hansen
Original assignee: Ferrosan ApS
Current assignee: Novo Nordisk AS
Priority date: 1985-03-08
Filing date: 1989-02-07
Publication date: 1990-03-13
Anticipated expiration: 2007-03-13

Abstract

Abstract of the Disclosure New oxadiazolyl imidazobenzodiazepine derivatives having the formula (I) wherein R3 has the formula wherein R'' is hydrogen, ?-6 alkyl C1-6 alkoxymethyl or C3-6 - cycloalkyl;
R4 is hydrogen; ;
R5 is C1-6 alkyl or R4 and R5 together form a 2-4 membered alkylene bridge; and RA is C1-6 alkyl, C1-6 alkoxy, or C1-3 trifluoroalkyl, pharmaceutical composi-tions thereof, and method of treating therewith, are disclosed.
The compounds and pharmaceutical compositions are useful in the amelioration, mitigation, or elimination of central nervous system disorders related to benzodiazepine receptors and especially as anticonvulsants, anxiolytics, hypnotics, and nootropics. The compounds of this application are critical intermediates in the production of compounds of formula (I).

Description

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.

~.

~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) 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:

!~

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. ~~

~ ~ ~ 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 :: .:

~ ~ ~ ~ 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-~ . `

~ ~ 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~

~ ~ 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.

.

~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 , ~ ~ 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.

~ ~ ~ ~ Ferroco D9 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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. .' :
~ .

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.
' -23-' .. : :, ' ~ Ferroco D9 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).

"~ ~

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.
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~ 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.
;:

~ 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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~28-~::

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Claims

Ferroco D9 Div Ca The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of preparing a compound having the formula CN-CH2-R3 wherein wherein R'' is hydrogen, C1-6-alkyl, C1-6-alkoxymethyl, or C3-6-cycloalkyl characterized in dehydrating a compound having the formula

2. A compound having the formula CN-CH2-R3 wherein R3 is wherein R'' is hydrogen, C1-6-alkyl, C1-6-alkoxymethyl, or C3-6-cycloalkyl.

Claims page 1