CA1042886A - Benzodiazepine derivatives - Google Patents
Benzodiazepine derivativesInfo
- Publication number
- CA1042886A CA1042886A CA109,679A CA109679A CA1042886A CA 1042886 A CA1042886 A CA 1042886A CA 109679 A CA109679 A CA 109679A CA 1042886 A CA1042886 A CA 1042886A
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- Prior art keywords
- lower alkyl
- compound
- phenyl
- chloro
- chlorine
- Prior art date
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- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract The present invention provides tricyclic benzodiazepines of the general formula 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.
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.
Description
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-' ~ ' .. ~
~ .
,, ~
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 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 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 - ~
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 -.~ ,.
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.
.
.~ .
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
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-' ~ ' .. ~
~ .
,, ~
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 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 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 - ~
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 -.~ ,.
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.
.
.~ .
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 ' .. . .
, .
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.
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 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
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 ' .. . .
, .
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.
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 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 - :
- 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 '`~ .
::
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 ., ~.
:~ :
.' :~
:
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 ?
`
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 .
.
1, . , . . .. . .. . . . ... . - -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 -.. . .. .. . .. . . . . . . ......... . ... -. .. . . . .
:
~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~ -..... ... . . ... .
. .
.~
.
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 - :
- 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 '`~ .
::
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 ., ~.
:~ :
.' :~
:
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 ?
`
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 .
.
1, . , . . .. . .. . . . ... . - -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 -.. . .. .. . .. . . . . . . ......... . ... -. .. . . . .
:
~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~ -..... ... . . ... .
Claims (25)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of tricyclic benzodiazepines of the general formula 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 II
wherein R1, R2, R3, R5, A, Y and Z are as defined above, b) N-substituting a compound of the general formula 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 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 IV
wherein R1, R2, R3, R5 and A are as defined above, with an epoxide compound of the general formula 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.
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 II
wherein R1, R2, R3, R5, A, Y and Z are as defined above, b) N-substituting a compound of the general formula 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 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 IV
wherein R1, R2, R3, R5 and A are as defined above, with an epoxide compound of the general formula 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 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.
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.
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.
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-, 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 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.
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 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 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.
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.
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.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US026068A US3905956A (en) | 1969-10-02 | 1970-04-06 | Tricyclic benzodiazepines |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1042886A true CA1042886A (en) | 1978-11-21 |
Family
ID=21829705
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA109,681A Expired CA1041499A (en) | 1970-04-06 | 1971-04-06 | Process for the preparation of benzodiazepine derivatives |
CA109,679A Expired CA1042886A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
CA109,680A Expired CA946385A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA109,681A Expired CA1041499A (en) | 1970-04-06 | 1971-04-06 | Process for the preparation of benzodiazepine derivatives |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA109,680A Expired CA946385A (en) | 1970-04-06 | 1971-04-06 | Benzodiazepine derivatives |
Country Status (15)
Country | Link |
---|---|
JP (1) | JPS5320520B1 (en) |
AR (3) | AR192875A1 (en) |
AT (2) | AT307427B (en) |
BE (2) | BE765252A (en) |
CA (3) | CA1041499A (en) |
CH (7) | CH579088A5 (en) |
DE (2) | DE2116499A1 (en) |
ES (1) | ES389911A1 (en) |
FR (2) | FR2092007B1 (en) |
GB (1) | GB1281499A (en) |
HU (1) | HU163551B (en) |
IL (2) | IL36551A (en) |
NL (3) | NL165169C (en) |
YU (3) | YU35026B (en) |
ZA (2) | ZA712179B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3914215A (en) * | 1967-11-27 | 1975-10-21 | Sankyo Co | Benzodiazepine derivatives and process for preparing the same |
-
1971
- 1971-03-24 CH CH103774A patent/CH579088A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH81774A patent/CH574960A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH433471A patent/CH558807A/en not_active IP Right Cessation
- 1971-03-24 CH CH81674A patent/CH574443A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH103674A patent/CH579569A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH425671A patent/CH569015A5/xx not_active IP Right Cessation
- 1971-03-24 CH CH425771A patent/CH547810A/en not_active IP Right Cessation
- 1971-04-01 NL NL7104373.A patent/NL165169C/en not_active IP Right Cessation
- 1971-04-05 ES ES389911A patent/ES389911A1/en not_active Expired
- 1971-04-05 IL IL36551A patent/IL36551A/en unknown
- 1971-04-05 BE BE765252A patent/BE765252A/en unknown
- 1971-04-05 AT AT392172A patent/AT307427B/en not_active IP Right Cessation
- 1971-04-05 ZA ZA712179A patent/ZA712179B/en unknown
- 1971-04-05 BE BE765253A patent/BE765253A/en unknown
- 1971-04-05 IL IL36550A patent/IL36550A0/en unknown
- 1971-04-05 FR FR7111884A patent/FR2092007B1/fr not_active Expired
- 1971-04-05 FR FR7111882A patent/FR2092006B1/fr not_active Expired
- 1971-04-05 ZA ZA712178A patent/ZA712178B/en unknown
- 1971-04-05 DE DE19712116499 patent/DE2116499A1/en active Pending
- 1971-04-05 DE DE19712116532 patent/DE2116532A1/en active Pending
- 1971-04-05 AT AT288071A patent/AT308119B/en not_active IP Right Cessation
- 1971-04-06 JP JP2132371A patent/JPS5320520B1/ja active Pending
- 1971-04-06 YU YU852/71A patent/YU35026B/en unknown
- 1971-04-06 CA CA109,681A patent/CA1041499A/en not_active Expired
- 1971-04-06 HU HUHO1368A patent/HU163551B/hu unknown
- 1971-04-06 AR AR234883A patent/AR192875A1/en active
- 1971-04-06 NL NL7104585A patent/NL7104585A/xx unknown
- 1971-04-06 CA CA109,679A patent/CA1042886A/en not_active Expired
- 1971-04-06 CA CA109,680A patent/CA946385A/en not_active Expired
- 1971-04-06 NL NL7104592A patent/NL7104592A/xx unknown
- 1971-04-19 GB GB26331/71A patent/GB1281499A/en not_active Expired
-
1972
- 1972-04-12 AR AR241431A patent/AR200636A1/en active
- 1972-04-12 AR AR241430A patent/AR200635A1/en active
-
1978
- 1978-09-21 YU YU2238/78A patent/YU35005B/en unknown
- 1978-09-21 YU YU2239/78A patent/YU35006B/en unknown
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