CA1151166A - 5-phenyl-1,3,4,5-tetrahydro-2h-1,4- benzodiazepin-2-ones, process for the preparation thereof and pharmaceutical compositions containing them - Google Patents
5-phenyl-1,3,4,5-tetrahydro-2h-1,4- benzodiazepin-2-ones, process for the preparation thereof and pharmaceutical compositions containing themInfo
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- CA1151166A CA1151166A CA000358371A CA358371A CA1151166A CA 1151166 A CA1151166 A CA 1151166A CA 000358371 A CA000358371 A CA 000358371A CA 358371 A CA358371 A CA 358371A CA 1151166 A CA1151166 A CA 1151166A
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- phenyl
- hydrogen
- benzodiazepin
- tetrahydro
- chloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to new optically active or racemic 5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula (I) (I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in the racemic compounds R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, and a process for their preparation. The new compounds show valuable enzyme inducing activity and are substantially devoid of the sedative effect of related compounds. They can therefore be employed as active ingred-ients of pharmaceutical compositions, which are also within the scope of the present invention.
The invention relates to new optically active or racemic 5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula (I) (I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in the racemic compounds R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, and a process for their preparation. The new compounds show valuable enzyme inducing activity and are substantially devoid of the sedative effect of related compounds. They can therefore be employed as active ingred-ients of pharmaceutical compositions, which are also within the scope of the present invention.
Description
~5~ 6 N~
-th~reof a~ ~
~ .
enti~ relate~ to ne~ 5-phenyl 1~3949 5-tetrah9-dro-2H-1~4-b0nzt)di~l2;epin-2-one derivatire~ a~d proce~ for theix prep~ra~io~
M~re particularly~ ~he i~entioR COnCe:r~18 new 5 opti¢ally active or racemic 5-pher~yl~1,3,4,5~tstra-h~dro~ 1,4 benzodi~zepin~2-ona d~ri~atlre~, ~7hl~h contsi~ centres of a~ymmet~ in the 3- and 5-posi-tio~e s~d in ~lhich said c~tre~ are ill the same sbsoluta configuratlonQ ~ in~ention æl~o i~olud~
10 ~: proc~a ~or the preparation o~ ~aid compou~d~ and pJn~aoe~tical ¢ompo~ition~ co~tai~ing th~m.
q~ne nelR 5-p~e~ 1,3,4,5-tetrah~rdr~
be~zodiazepill-2~one derlYat~e~ ~e~rdi~g t~ the l~renti~ are Gnoompso~d by tha ~e~eral ~ormula (I~
~5 ~2 p~l ~ \ R4 ~ l~
x-~- IJ
~/
~ 1975 ~7 ~
1g;6 wherein R stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R is hydrogen or alkyl having 1 to 6 carbon atoms;
R represents a Cl 6 alkyl group, a phenyl-(Cl 4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarhonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso -that if in a racemic compound of the general formula (I) R represents hydrogen, R3 does not stand for an unsubstituted lower alkyl group.
The pharmaceutically acceptable acld addition salts of the compounds o:E the general formula (I) are also within the scope of the present invention.
The term "halogen" used throughout the specification relates to fluo-rine, chlorine, bromine or iodine.
The term "alkyl having 1 to 6 carbon atoms" as used herein means straight or branched chained aliphatic hydrocarbon groups, having 1 to 6 carbon atom~ ~e.g. met~yl t ethyl, n~propyl, isoprop-yl, n-butyl, ~eo.-butyl, tcrt. butyl, n-pe~t~ o-pe~tyl, n-h0xyl or isohe~yl, etc,).
The term ~'a group oonventionally att~¢hed to tho -OEI(N~I2)-COO~ group of the known optically active or raoemic ~-amino-aoids" pre~erably relate~
to methyl, i~opropyl, benzyl 4-hydroxybenzyl~ 3_ -indolyl-methyl, eto~ groups~
~ ccording to the invention compounds of t,he ge~eral formula (I) (in which Rl~ R2, R3, R~ and X have the same m~aning as defined above) are pre-pared by reducing optlcnlly active or raoemic dihydro-1,4-benzodiazepin-2-one derivatives o~
the ge~eral formula (II) ~ C~l R3 (II~
Rl C --J~
X ~ ' 11 ", ,,. ', , .
~Rl, R2, R3 and ~ are as de~i~ed ab~e), whioh oo~tai~ a oe~tre o~ a~ymmet~y in the 3-po~ition, and i~ da~ired, oonverti~g a oompound o~ the ~e~eral formula (I) obtained, i~ ~hioh ~
repre~ents a hydroge~ atom (R ~ R2~ R3 a~d X are a~ defined above~ into ~ aoid addikion salt thereo~ a~d/or rsaotin~ it with an al~ali metal cyanate or phosgene, a~d i~ de ired, reaoti~g a compound o~ the general formula ~I) obtained by the ~eaotion with phosge~e, in sYhioh R4 sta~ds for ohlorooarbonyl (R , R2, R3 and X ars as defined above) with ammonia, and/or ir de~ired, reaoti~g a oompou~d of the general formula (I3 obtained~ in s~hioh R2 is hydrogen (Rl, R3, R4 and X are as de~i~ed above) a~d/or co~erti~g a oompound Or the ge~eral formula (I), in ~hioh R~
i9 hydrogen (Rl~ R2, R3 and X are a~ defi~ed ~bo~e) i~to a pharma¢eutioally aooaptabla aoid addition salt thereof.
The oompound~ o~ the ge~eral foI~la ~I) po~es9 valuable e~zyme i~duoing aoti~ity and are praotioally devoid o~ the ~edati~e effect o~ the related compou~ds, The mo9t olo~ely related tetrahydro-1,4-
-th~reof a~ ~
~ .
enti~ relate~ to ne~ 5-phenyl 1~3949 5-tetrah9-dro-2H-1~4-b0nzt)di~l2;epin-2-one derivatire~ a~d proce~ for theix prep~ra~io~
M~re particularly~ ~he i~entioR COnCe:r~18 new 5 opti¢ally active or racemic 5-pher~yl~1,3,4,5~tstra-h~dro~ 1,4 benzodi~zepin~2-ona d~ri~atlre~, ~7hl~h contsi~ centres of a~ymmet~ in the 3- and 5-posi-tio~e s~d in ~lhich said c~tre~ are ill the same sbsoluta configuratlonQ ~ in~ention æl~o i~olud~
10 ~: proc~a ~or the preparation o~ ~aid compou~d~ and pJn~aoe~tical ¢ompo~ition~ co~tai~ing th~m.
q~ne nelR 5-p~e~ 1,3,4,5-tetrah~rdr~
be~zodiazepill-2~one derlYat~e~ ~e~rdi~g t~ the l~renti~ are Gnoompso~d by tha ~e~eral ~ormula (I~
~5 ~2 p~l ~ \ R4 ~ l~
x-~- IJ
~/
~ 1975 ~7 ~
1g;6 wherein R stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R is hydrogen or alkyl having 1 to 6 carbon atoms;
R represents a Cl 6 alkyl group, a phenyl-(Cl 4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarhonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso -that if in a racemic compound of the general formula (I) R represents hydrogen, R3 does not stand for an unsubstituted lower alkyl group.
The pharmaceutically acceptable acld addition salts of the compounds o:E the general formula (I) are also within the scope of the present invention.
The term "halogen" used throughout the specification relates to fluo-rine, chlorine, bromine or iodine.
The term "alkyl having 1 to 6 carbon atoms" as used herein means straight or branched chained aliphatic hydrocarbon groups, having 1 to 6 carbon atom~ ~e.g. met~yl t ethyl, n~propyl, isoprop-yl, n-butyl, ~eo.-butyl, tcrt. butyl, n-pe~t~ o-pe~tyl, n-h0xyl or isohe~yl, etc,).
The term ~'a group oonventionally att~¢hed to tho -OEI(N~I2)-COO~ group of the known optically active or raoemic ~-amino-aoids" pre~erably relate~
to methyl, i~opropyl, benzyl 4-hydroxybenzyl~ 3_ -indolyl-methyl, eto~ groups~
~ ccording to the invention compounds of t,he ge~eral formula (I) (in which Rl~ R2, R3, R~ and X have the same m~aning as defined above) are pre-pared by reducing optlcnlly active or raoemic dihydro-1,4-benzodiazepin-2-one derivatives o~
the ge~eral formula (II) ~ C~l R3 (II~
Rl C --J~
X ~ ' 11 ", ,,. ', , .
~Rl, R2, R3 and ~ are as de~i~ed ab~e), whioh oo~tai~ a oe~tre o~ a~ymmet~y in the 3-po~ition, and i~ da~ired, oonverti~g a oompound o~ the ~e~eral formula (I) obtained, i~ ~hioh ~
repre~ents a hydroge~ atom (R ~ R2~ R3 a~d X are a~ defined above~ into ~ aoid addikion salt thereo~ a~d/or rsaotin~ it with an al~ali metal cyanate or phosgene, a~d i~ de ired, reaoti~g a compound o~ the general formula ~I) obtained by the ~eaotion with phosge~e, in sYhioh R4 sta~ds for ohlorooarbonyl (R , R2, R3 and X ars as defined above) with ammonia, and/or ir de~ired, reaoti~g a oompou~d of the general formula (I3 obtained~ in s~hioh R2 is hydrogen (Rl, R3, R4 and X are as de~i~ed above) a~d/or co~erti~g a oompound Or the ge~eral formula (I), in ~hioh R~
i9 hydrogen (Rl~ R2, R3 and X are a~ defi~ed ~bo~e) i~to a pharma¢eutioally aooaptabla aoid addition salt thereof.
The oompound~ o~ the ge~eral foI~la ~I) po~es9 valuable e~zyme i~duoing aoti~ity and are praotioally devoid o~ the ~edati~e effect o~ the related compou~ds, The mo9t olo~ely related tetrahydro-1,4-
2~ -be~zodiazepi~-2-o~es k~otm i~ th~ art ~xe un-~ubstituted in the 4-po~ition and oo~tai~ a lower alkyl group in the 3~po si~ion~ Their preparatio~
lL6~
is for ~xample dl~closed i~ the ~ollowi~g publioa-tions: the Ge~an Patent Speoification No.
1,199~776 desoribe~ the catalytio ~ydroganation o~ the oorrespo~ding dihydro-derivativas, and aooordi~g to the U.S. Patent Speoifioatio~ No~
lL6~
is for ~xample dl~closed i~ the ~ollowi~g publioa-tions: the Ge~an Patent Speoification No.
1,199~776 desoribe~ the catalytio ~ydroganation o~ the oorrespo~ding dihydro-derivativas, and aooordi~g to the U.S. Patent Speoifioatio~ No~
3,~22,28~ the oompound~ are prepared by intra-moleoular condensatio~ o-f the amlnoaoetio aoid a~ters N-~ubstituted by an 2-ami~o-benzhydrile ~roup~ The Austria~ Patent Speoifioation No8 10 1~199~776 disoloses ~ method along whioh the pxoteot-ing ~roup of the oorre~pond~ng 2-ami~o-benzhydrole deri~atlves acylated by proteoted amino aoid~ i9 splitted off by aoydolysis, while acoordt~g to ths Austria~ Patent Specification NoO 311~ 3~6 the 1~ oompou~ds are prepared ~rom the oorrespondin~ aJ~no-benzophenone derivatives acylatsd by pretected ~mino aoid~ by catalytio hydrogc~ation, Fi~ally~ the ~ustrian Patent Speoi~icatio~ No~ 309,439 di~close~
the re~olution of racemio tetrahydro-1,4-be~zo-diazepin-2-o~e~ containin~ a oentre of a~y~metry i~ ths ~-po~ition through the preparatio~ of salt~
It has surprisingly baen found that by reduoin~ dihydro-1,4-benzodiazepi~-2~o~e derivatives oontai~ing a ca~tr0 of a~y~metry i~ the 3-po~itio~
2~ n~w t9~rahydro-1,4-benzodiazepin_2_o~e~ c~n be pre-parad, ~ich oo~tai~ oentre~ of a~ymmetry in the 3- and S-positio~ a~d ln which the absolute ' ' . ' '' ' ': ' '' '', . . . .
., =~ 6 _ co~figuration of the oentre in the ~-position 19 identical with the absolute co~iguratlon o~
the oentre i~ ~he 3-position whioh i9 prese~t also i~ the etarting material~
The prooess aooordin~ to the i~ventio~
is ~tereospeol~io, i,e. starti~g ~rom the 3S~ 3R
and 3SR dihydro-oompounds of the general ~ormula (II)~ respectively the corresponding 35~S; 3R~R
and 3SR,SSR tetrahy.dro-oompounds, respeotively oa~ be prepared without resolutio~.
The oompou~ds o~ the general ~ormula (II) (l~herein Rl, R2~ ~3 and X are as herei~be~ore dofined) used as starti~ oompou~ds in the prooess acoording to the inveD~lo~ oan be prepàred by the 1~ prooe~s di~olosed in the ~ustria~ Patent Speoi~i-ca~ion No, 281~03~.
The oom~ound~ o~ the general formula (II) oan be reduoed by reduoing agents, ~Jhioh are oapable of saturating the 4~5-double bond (a~omethlne group)~ without in~lue~oing other parts o~ the moleoulev The reduotion oan ~or example bs oarr~ed out ~ith a oomple~ metal hydride~ ~uch as ~od~um ~orohydride, with a mot al and an acid ~ suoh as zi~c a~d acetio acids, wlth nasoent hydrogcn or by 2.~ oataly-tic hydrogenation w~ereî~ a~ a oatalyst any comre~tional metal o}l the sur:f aoe o~ a oarrier7 ~i :
: ; ~
~L5~L~66 suoh as palladlum-on-charcoal catalyst or a-metal o~ide~ suoh as platinum oxide ca~ be usedO
The reduotion of the compounds of 5 the ~e~eral ~ormNla (II) is per~ormed in a reao-tion i~ert organio solvent, suoh as a~
aliphatio aloohol havi~g 1 to 6 oarbon ~toms, e.~. methanol, ethanol; or an allphatio oarboxylic aoid havin~ 1 to 6 carbon atoms, e,g~ aoatic aiod, eto.
The reactio~ temp~xabure oan be varied withi~ a wldo ran~e but pre~erably i9 betwee~ 0 C and 1~0 C~ ~ore pre~erably about room temperature~ The reaotio~ tim0 stron~ly 1~ dcpends o~ the startlng oompo~nd and solve~t employed and on the reaotion temperature, a~ :
gen0rally i8 about 1 to 24 hours t pre~erably 0,~
to 8 hours, The oompounds of the general formMla (X)~ i~ whioh R4 represent~ a hydro~en abom oan be oonverted into aoid additlo~ ~alts by reaot-in~ with corre~ponding aoids~ The prsparation o~ salt~ can be used also ~or the puri~îoatio~
o~ the compounds, and ~rom the aoid additio~
salts obtained9 optlo~ally a~ter reorystallisat~o~, the oompou~ds o~ the general ~ormula (I) ca~
be set ~res b~ kno~n methods.
., ~ ~5~6 ~ or the preparatio~ o~ salts ~or example the following acids oan be u9ed: inorga~ic aoids, ~uoh as hydrogen halides~ e.g, hydroohlorio aoid, hydrogcn bromide; ~ul~uric acid; pho~phorlc aoid;
nltrio acid; or psrhaloio aoids, ~uoh as parchlorio aoid; or organio aoids, ~uoh as ~ox~ic aoid~
aoetio aoid, propionic acid, glyoolio acid, m~leic aoid, hydro~ymaleic ao~d, ~u~ario aoid~ salicilio aoid~ milk aoid, oin~amic aoid~ benzoic a¢id9 pb~nylaoetio aoid, ~ami~o-benzoio acid~ ~-hydro_ benzoio aoid, ~-amlno-~alioilio aoid, eto~: alkyl-sulfonio aoids, suoh as methanesul~o~io acld, eth~nesul~onio aoid, oto,; cyoloaliphatic ~ul~onio aoid~ ~uch as oyclohexalsulfonic aoid; arylsul~onio 1~ acid~ suoh as p-tolue~e sulfonio aoid, naphthyl-sul~onic aold~ sulfanilio acid, eto,j amino aoids~
suoh a9 asparginio aoid, glutaminio aoid, eto, The aoid additio~ salts oan be pre-pared in any oonve~tional inert organio solvent, whioh i~ oapable 20 of di~solving the oompou~d o~ the general ~o~mula ~I) u~ed as starting oompound, and ln w~ioh tho acid additlon salt o:E said oompou~d is in~oluble~ In ~his oase the acid additio~ salt prseipitated f~om the reaction. mlxture oa~ easily be separated by 2~ oo~ve~tional teohni~ue9, e~ filtratio~, Alter~ative_ ly, the preparatioll of a~ld additlon ~alt~ oa~ ~e carried out al90 in inert or~amic sollra~t ~ 9 in ~1 . ~
' .
g which ~ot o~ly the oompounds of the genoral formula (I) but also their aoid additio~
salts are soluble~ In thi`s oase the aoid addition salt oan be preoipitated'by a~ apolar organio solvent, e~g~ by p0troleum sther~
The oompou~d~ of the ~e~eral formula (I) in s~hich R4 stands for a hydrogen atom are pre~erably reacted with alkali metal oyanated v~a their acid addition salt~. The correspo~di~g compou~d o~ the general ~ormula (I) ~R4 is hydro~en) is oo~verted into an aoid additlon sRlt, pre~erably hydro~en halide thereo~ the salt o'btained is separated and ~uspe~ded or dis-solved in a~ inert organic solvent, ~uch as aoetio 1~ aoid, whereupon the alkali metal oyanate is added to the su~penaion or solution o'btai~ed~
As an alkali metal oyanate potassium or sodium oyanate can ~or example be used.
The re~otion temperature oan be varied within a wide range but the reaotio~ i~ pre~erably performed at about room te~perature~ The reaotion time ~enerally is betwee~ 0,~ and 10 hour~, depen~in~ o~ the startin~ oompou~ds, solvent and temperature.
2~ The reaction o~ the compounds o~ the ~, general ~ormula (I) (~herein R , R2~ R3 and ~ are as dafined above and R4 stand~ ~or phos~a~e) with , , ~5~66 phosgene is oarried out in an i~ert or~a~c ~olvo~t~ ~uch as ~romatio hydrooarbons~ e,~.
benzQ~ ln the presenoe o~ an aoid binding ; age~t, suoh QS magnesium oxide Qr ~odlum hydrogen oarbonate, The oompounds of the general formula (I) obtained, in whioh R4 stand~ ~or a ohloro~
oarbonyl group (Rl, R2, R3 a~d X are as de~ined above) are treated with a ooRcentrated aqueous a~mo~ium hydroxide solution or with a 901ution of a~mo~ia in an aliphatic aloohol ha~i~g 1 to 6 oarbon atom, preferably methanol~ optionally in an inert organio solvent, e.g, an aliphatio aloohol having 1 to 6 oarbon atoms, Alternati~ely, '~ the ammonia solution can also bs added to the 1~ reaotion mixture obtained when prepari~g the compounds of the general formula (I), in which R~ 3tands for a ohlorooarbonyl ~roup, i~ the compounds of the ~enQral ~onmula (I) need ~ot ~eoessarily be isolated before reaction wlth ammo~iaO
The oompou~ds of the general ~ormMla in which R2 sta~ds ~or hydrogen (Rl, R3 R4 and X are a~ harei~abo~ d~ined) oa~ be oonverted i~to the oorrespo~di~g l-alkyl deriva-2~ tives by reaoti~g with a~ alkylati~g a~ent~ ~salkylati~ age~ts oonventional reactants, suoh as alkyl halides~ preferably alkyl iodide, or ~i , 11 ~
dialkyl sulfates ca~ bs usad~ Be~ora oarryi~g out the alkylatio~ the oompounds o~ the general formula (I~ are preferably conv0rted into alkali metal derivativss thereofO I~ this oase the oompounds are dissolved in a~ i~ert or~anic aolvent, such as dioxane, dimethyl ~ormamide~ ben~ene or toluene a~d are reaoted with an alkali metal, al~alî metal hydride or alkali metal amide, pre~erab-ly with sodium or sodium hydrode or sodium am~de at 0 to 1~0 C~ The al~ali metal compound obtai~ed i9 the~ reaoted wlth the corresponding alkylatin~
age~t, The new oompounds o~ the ~eneral ~ormula (I) ca~ be prepared by the prooe~s aocording to 1~ the i~ve~tion with a good yield, irl a well ide~t~iable form, The results of ohemioal analysis are i~ good agreeme~t with the oaloulated ~alue~.
The pur~ty of the oompo~ds was oo~trolled by thi~ layer chro~ato~raphy, The retention ~otor~
(R~) of the oompou~ds ~llustrated i~ the working examples were determi~ed o~ a St~hl GF 2~ (Merck~
silioa gel plate by a 1:1 mi~ture of ether a~d diw ohlorometha~eO The detectio~ was performed in UOV~ ligh~ at 2~4 nm, The meltin~ points were 2~ determined i~ an equipmellt aocordir~ to dr~ Tottoli (no~-oorreoted value3) 4 ~or the struct~lral analysis IR, oircular dichrois~ or NMR ~peotro~oopy was use~O
.~ ~
:
The pharmaoological properties o~ tho racemic or optioally active 1~3~4~5-tetrahydro--2H-1,4-ben~odiazepin-2-one derivati~es aooording to the inventio~, which oo~tain two centre~ of asymmetry, first of all their exoellent enzyma induoi~g activi~y~ the pregnant reduotion of the 3edative e~ect and their low toxicity are lllustrated by tha ~ollowing pharmacolo~i¢al tests, The biologioal aotivity and duration of aotivity o~ difrerent e~do~e~ic and exoge~lc oompounds are ~reatly lnfluenoed by the activity o~ tha NADPE- (nicoti~io acld ~nide-adenine-di~uoleotide phosphate-) depending multi~unotional oxyda~e enzyme ~ystem of the liver~ There are numerous oo~pounds 1~ k~own in the art, sho~ing various pharmaoologioal activities~ w~ioh are oapable of inoreasi~g or i~duoing the aotivlty o~ the metabolisl~g~ ~ulti-funotional oxydase enzyme -~ystem o~ the liver ~oe e,~, Sher~ SOP~: Toxicol, appl~ Pharmaool. 18, 780 /1971/; G,J, Mannering: in A~ Burg~r's Selected Pha~maoologioal Tasting Methods, 51-1~ 9 S,, Maroel Dekker Inc., New York /1968~ ~ It is well k~ow~
~ ~ that phenobarbital shows an i~duoi~g aoti~ity i~
the oase o~ human diseases causad by the d0~eoti~e-2~ Iless o:f the metabolysing anzama system of the liver,~herefore phe~obarbital can suocessfully be usad i~ the treatmen,t of Czig:Ler-Na,~Jar a~d Cilbert ~-, ~ , ' ~ -syndroms and ~u~at~lis hyporbili~lbln~mia, though due to its hypnotio-sedative e~ect the induoing activity of thi3 oompou~d is not optimal ~e~sel and J0 E. Page: J, Clin, Invest~
8~ 2202 /1969/j J, T~ Nil~on: Pediatrics L~3 424 /196g~ , For screening the enzyme induoin~
aotivity the chaoge in the he~obarbital-indu~ed sleepi~g time is conventionally msasured, 'rhe inducing activity of the oompounds of the ~e~eral ~orm~la (I) aooording to the i~vention was oompared to the oorresponding acti~ity of phenobarbital and to their own sedative e~ect, using the ~o~low-ing test methods, 1~ Determination o~ the sleeping time induoed by hexo-barbital ~measurement o~ en~ymQ induoin~ aotivity) After a) one hour and b) after 24-hour :pretreat~e~t ~th a 40 mg~/k~ p,o~ dose o~ the ta~t oompound~ the ~roup~ o~ test animals were administered a 60 mg./k~ v, dose o~ hexobarbital.
The average ~laeping tlme (~SD~ and the perce~tage ohanga related to the control (0 are gi~en in Table 1 below.
b-rb~t-l (mea~urement o~ the seda~ive aotivity) Na-barbital is ~ot metahol~sod 1~ the ~ ~ :
S~6 liver, thus the potentiation o~ the activity of Na-barbital oan be co~siderod ~s a dir~ct CNS
e~fectO In the tests oarried out ~ee S~ Gold- :
schmidb and R, Wohr: Z. physiol, Chem~ 308, 9 /lgg7/i D. V, Parker: J~ Pharm, Pharmac, 27~ 729 /197~ the test animals were pretreated with a 20 mg,/~g. i,~, dose o~ th~ test compounds o~ th~ :
~e~eral formula (I) and af~er o~e hour were ad-ministered a 100 mg./lc~, i.p~ dose o~ Na-barbital, The administered (100 mg,/kg~) dose o~ Na barbital still has ~o narootio ef~eot, ~he ~u~iber o~ the anima}s ~alling asleep (in ~ is give~ in Table 2, Aout0 toxioity (p~o,) To the test animals 2~0 ~d ~00 m~/kg, 1~ do~es, resp, of the test compou~ds were admini~tered orally a~d the number o-~ the dead animals was regi~tered for 14 daysO The re~ults are ,shown in Table 3 As test animals CFLP male mloe weig~n~
8 to 22 ~ were u~ed, '~;f ~ ~7 ; ., ' '.
' ' ~,~
T~bl~ 1 .. . . . . . . . . . ~ . . . .
T~st oomp~und Dose mg,/kg~ ~exobarbital-~lQepi~g tim~
(Exa~ple No,) p~o. (min,~
l-hour prctreat- 24-hour pre-ment treatm0ll*
a~erag0~SE ~ avera~e~SE 4 Co~trol 0 3~ ~ 2~38 34 + 2.60 1 40 67~2 ~ 7,01~glx 19,~ + ~,84 -~3 2 l~0 61,2 + ~21 ~73 13*3 ~ 0~4 -61 3 40 4303 ~ 4~18~23 12.0 ~ 0.83~_6~
the re~olution of racemio tetrahydro-1,4-be~zo-diazepin-2-o~e~ containin~ a oentre of a~y~metry i~ ths ~-po~ition through the preparatio~ of salt~
It has surprisingly baen found that by reduoin~ dihydro-1,4-benzodiazepi~-2~o~e derivatives oontai~ing a ca~tr0 of a~y~metry i~ the 3-po~itio~
2~ n~w t9~rahydro-1,4-benzodiazepin_2_o~e~ c~n be pre-parad, ~ich oo~tai~ oentre~ of a~ymmetry in the 3- and S-positio~ a~d ln which the absolute ' ' . ' '' ' ': ' '' '', . . . .
., =~ 6 _ co~figuration of the oentre in the ~-position 19 identical with the absolute co~iguratlon o~
the oentre i~ ~he 3-position whioh i9 prese~t also i~ the etarting material~
The prooess aooordin~ to the i~ventio~
is ~tereospeol~io, i,e. starti~g ~rom the 3S~ 3R
and 3SR dihydro-oompounds of the general ~ormula (II)~ respectively the corresponding 35~S; 3R~R
and 3SR,SSR tetrahy.dro-oompounds, respeotively oa~ be prepared without resolutio~.
The oompou~ds o~ the general ~ormula (II) (l~herein Rl, R2~ ~3 and X are as herei~be~ore dofined) used as starti~ oompou~ds in the prooess acoording to the inveD~lo~ oan be prepàred by the 1~ prooe~s di~olosed in the ~ustria~ Patent Speoi~i-ca~ion No, 281~03~.
The oom~ound~ o~ the general formula (II) oan be reduoed by reduoing agents, ~Jhioh are oapable of saturating the 4~5-double bond (a~omethlne group)~ without in~lue~oing other parts o~ the moleoulev The reduotion oan ~or example bs oarr~ed out ~ith a oomple~ metal hydride~ ~uch as ~od~um ~orohydride, with a mot al and an acid ~ suoh as zi~c a~d acetio acids, wlth nasoent hydrogcn or by 2.~ oataly-tic hydrogenation w~ereî~ a~ a oatalyst any comre~tional metal o}l the sur:f aoe o~ a oarrier7 ~i :
: ; ~
~L5~L~66 suoh as palladlum-on-charcoal catalyst or a-metal o~ide~ suoh as platinum oxide ca~ be usedO
The reduotion of the compounds of 5 the ~e~eral ~ormNla (II) is per~ormed in a reao-tion i~ert organio solvent, suoh as a~
aliphatio aloohol havi~g 1 to 6 oarbon ~toms, e.~. methanol, ethanol; or an allphatio oarboxylic aoid havin~ 1 to 6 carbon atoms, e,g~ aoatic aiod, eto.
The reactio~ temp~xabure oan be varied withi~ a wldo ran~e but pre~erably i9 betwee~ 0 C and 1~0 C~ ~ore pre~erably about room temperature~ The reaotio~ tim0 stron~ly 1~ dcpends o~ the startlng oompo~nd and solve~t employed and on the reaotion temperature, a~ :
gen0rally i8 about 1 to 24 hours t pre~erably 0,~
to 8 hours, The oompounds of the general formMla (X)~ i~ whioh R4 represent~ a hydro~en abom oan be oonverted into aoid additlo~ ~alts by reaot-in~ with corre~ponding aoids~ The prsparation o~ salt~ can be used also ~or the puri~îoatio~
o~ the compounds, and ~rom the aoid additio~
salts obtained9 optlo~ally a~ter reorystallisat~o~, the oompou~ds o~ the general ~ormula (I) ca~
be set ~res b~ kno~n methods.
., ~ ~5~6 ~ or the preparatio~ o~ salts ~or example the following acids oan be u9ed: inorga~ic aoids, ~uoh as hydrogen halides~ e.g, hydroohlorio aoid, hydrogcn bromide; ~ul~uric acid; pho~phorlc aoid;
nltrio acid; or psrhaloio aoids, ~uoh as parchlorio aoid; or organio aoids, ~uoh as ~ox~ic aoid~
aoetio aoid, propionic acid, glyoolio acid, m~leic aoid, hydro~ymaleic ao~d, ~u~ario aoid~ salicilio aoid~ milk aoid, oin~amic aoid~ benzoic a¢id9 pb~nylaoetio aoid, ~ami~o-benzoio acid~ ~-hydro_ benzoio aoid, ~-amlno-~alioilio aoid, eto~: alkyl-sulfonio aoids, suoh as methanesul~o~io acld, eth~nesul~onio aoid, oto,; cyoloaliphatic ~ul~onio aoid~ ~uch as oyclohexalsulfonic aoid; arylsul~onio 1~ acid~ suoh as p-tolue~e sulfonio aoid, naphthyl-sul~onic aold~ sulfanilio acid, eto,j amino aoids~
suoh a9 asparginio aoid, glutaminio aoid, eto, The aoid additio~ salts oan be pre-pared in any oonve~tional inert organio solvent, whioh i~ oapable 20 of di~solving the oompou~d o~ the general ~o~mula ~I) u~ed as starting oompound, and ln w~ioh tho acid additlon salt o:E said oompou~d is in~oluble~ In ~his oase the acid additio~ salt prseipitated f~om the reaction. mlxture oa~ easily be separated by 2~ oo~ve~tional teohni~ue9, e~ filtratio~, Alter~ative_ ly, the preparatioll of a~ld additlon ~alt~ oa~ ~e carried out al90 in inert or~amic sollra~t ~ 9 in ~1 . ~
' .
g which ~ot o~ly the oompounds of the genoral formula (I) but also their aoid additio~
salts are soluble~ In thi`s oase the aoid addition salt oan be preoipitated'by a~ apolar organio solvent, e~g~ by p0troleum sther~
The oompou~d~ of the ~e~eral formula (I) in s~hich R4 stands for a hydrogen atom are pre~erably reacted with alkali metal oyanated v~a their acid addition salt~. The correspo~di~g compou~d o~ the general ~ormula (I) ~R4 is hydro~en) is oo~verted into an aoid additlon sRlt, pre~erably hydro~en halide thereo~ the salt o'btained is separated and ~uspe~ded or dis-solved in a~ inert organic solvent, ~uch as aoetio 1~ aoid, whereupon the alkali metal oyanate is added to the su~penaion or solution o'btai~ed~
As an alkali metal oyanate potassium or sodium oyanate can ~or example be used.
The re~otion temperature oan be varied within a wide range but the reaotio~ i~ pre~erably performed at about room te~perature~ The reaotion time ~enerally is betwee~ 0,~ and 10 hour~, depen~in~ o~ the startin~ oompou~ds, solvent and temperature.
2~ The reaction o~ the compounds o~ the ~, general ~ormula (I) (~herein R , R2~ R3 and ~ are as dafined above and R4 stand~ ~or phos~a~e) with , , ~5~66 phosgene is oarried out in an i~ert or~a~c ~olvo~t~ ~uch as ~romatio hydrooarbons~ e,~.
benzQ~ ln the presenoe o~ an aoid binding ; age~t, suoh QS magnesium oxide Qr ~odlum hydrogen oarbonate, The oompounds of the general formula (I) obtained, in whioh R4 stand~ ~or a ohloro~
oarbonyl group (Rl, R2, R3 a~d X are as de~ined above) are treated with a ooRcentrated aqueous a~mo~ium hydroxide solution or with a 901ution of a~mo~ia in an aliphatic aloohol ha~i~g 1 to 6 oarbon atom, preferably methanol~ optionally in an inert organio solvent, e.g, an aliphatio aloohol having 1 to 6 oarbon atoms, Alternati~ely, '~ the ammonia solution can also bs added to the 1~ reaotion mixture obtained when prepari~g the compounds of the general formula (I), in which R~ 3tands for a ohlorooarbonyl ~roup, i~ the compounds of the ~enQral ~onmula (I) need ~ot ~eoessarily be isolated before reaction wlth ammo~iaO
The oompou~ds of the general ~ormMla in which R2 sta~ds ~or hydrogen (Rl, R3 R4 and X are a~ harei~abo~ d~ined) oa~ be oonverted i~to the oorrespo~di~g l-alkyl deriva-2~ tives by reaoti~g with a~ alkylati~g a~ent~ ~salkylati~ age~ts oonventional reactants, suoh as alkyl halides~ preferably alkyl iodide, or ~i , 11 ~
dialkyl sulfates ca~ bs usad~ Be~ora oarryi~g out the alkylatio~ the oompounds o~ the general formula (I~ are preferably conv0rted into alkali metal derivativss thereofO I~ this oase the oompounds are dissolved in a~ i~ert or~anic aolvent, such as dioxane, dimethyl ~ormamide~ ben~ene or toluene a~d are reaoted with an alkali metal, al~alî metal hydride or alkali metal amide, pre~erab-ly with sodium or sodium hydrode or sodium am~de at 0 to 1~0 C~ The al~ali metal compound obtai~ed i9 the~ reaoted wlth the corresponding alkylatin~
age~t, The new oompounds o~ the ~eneral ~ormula (I) ca~ be prepared by the prooe~s aocording to 1~ the i~ve~tion with a good yield, irl a well ide~t~iable form, The results of ohemioal analysis are i~ good agreeme~t with the oaloulated ~alue~.
The pur~ty of the oompo~ds was oo~trolled by thi~ layer chro~ato~raphy, The retention ~otor~
(R~) of the oompou~ds ~llustrated i~ the working examples were determi~ed o~ a St~hl GF 2~ (Merck~
silioa gel plate by a 1:1 mi~ture of ether a~d diw ohlorometha~eO The detectio~ was performed in UOV~ ligh~ at 2~4 nm, The meltin~ points were 2~ determined i~ an equipmellt aocordir~ to dr~ Tottoli (no~-oorreoted value3) 4 ~or the struct~lral analysis IR, oircular dichrois~ or NMR ~peotro~oopy was use~O
.~ ~
:
The pharmaoological properties o~ tho racemic or optioally active 1~3~4~5-tetrahydro--2H-1,4-ben~odiazepin-2-one derivati~es aooording to the inventio~, which oo~tain two centre~ of asymmetry, first of all their exoellent enzyma induoi~g activi~y~ the pregnant reduotion of the 3edative e~ect and their low toxicity are lllustrated by tha ~ollowing pharmacolo~i¢al tests, The biologioal aotivity and duration of aotivity o~ difrerent e~do~e~ic and exoge~lc oompounds are ~reatly lnfluenoed by the activity o~ tha NADPE- (nicoti~io acld ~nide-adenine-di~uoleotide phosphate-) depending multi~unotional oxyda~e enzyme ~ystem of the liver~ There are numerous oo~pounds 1~ k~own in the art, sho~ing various pharmaoologioal activities~ w~ioh are oapable of inoreasi~g or i~duoing the aotivlty o~ the metabolisl~g~ ~ulti-funotional oxydase enzyme -~ystem o~ the liver ~oe e,~, Sher~ SOP~: Toxicol, appl~ Pharmaool. 18, 780 /1971/; G,J, Mannering: in A~ Burg~r's Selected Pha~maoologioal Tasting Methods, 51-1~ 9 S,, Maroel Dekker Inc., New York /1968~ ~ It is well k~ow~
~ ~ that phenobarbital shows an i~duoi~g aoti~ity i~
the oase o~ human diseases causad by the d0~eoti~e-2~ Iless o:f the metabolysing anzama system of the liver,~herefore phe~obarbital can suocessfully be usad i~ the treatmen,t of Czig:Ler-Na,~Jar a~d Cilbert ~-, ~ , ' ~ -syndroms and ~u~at~lis hyporbili~lbln~mia, though due to its hypnotio-sedative e~ect the induoing activity of thi3 oompou~d is not optimal ~e~sel and J0 E. Page: J, Clin, Invest~
8~ 2202 /1969/j J, T~ Nil~on: Pediatrics L~3 424 /196g~ , For screening the enzyme induoin~
aotivity the chaoge in the he~obarbital-indu~ed sleepi~g time is conventionally msasured, 'rhe inducing activity of the oompounds of the ~e~eral ~orm~la (I) aooording to the i~vention was oompared to the oorresponding acti~ity of phenobarbital and to their own sedative e~ect, using the ~o~low-ing test methods, 1~ Determination o~ the sleeping time induoed by hexo-barbital ~measurement o~ en~ymQ induoin~ aotivity) After a) one hour and b) after 24-hour :pretreat~e~t ~th a 40 mg~/k~ p,o~ dose o~ the ta~t oompound~ the ~roup~ o~ test animals were administered a 60 mg./k~ v, dose o~ hexobarbital.
The average ~laeping tlme (~SD~ and the perce~tage ohanga related to the control (0 are gi~en in Table 1 below.
b-rb~t-l (mea~urement o~ the seda~ive aotivity) Na-barbital is ~ot metahol~sod 1~ the ~ ~ :
S~6 liver, thus the potentiation o~ the activity of Na-barbital oan be co~siderod ~s a dir~ct CNS
e~fectO In the tests oarried out ~ee S~ Gold- :
schmidb and R, Wohr: Z. physiol, Chem~ 308, 9 /lgg7/i D. V, Parker: J~ Pharm, Pharmac, 27~ 729 /197~ the test animals were pretreated with a 20 mg,/~g. i,~, dose o~ th~ test compounds o~ th~ :
~e~eral formula (I) and af~er o~e hour were ad-ministered a 100 mg./lc~, i.p~ dose o~ Na-barbital, The administered (100 mg,/kg~) dose o~ Na barbital still has ~o narootio ef~eot, ~he ~u~iber o~ the anima}s ~alling asleep (in ~ is give~ in Table 2, Aout0 toxioity (p~o,) To the test animals 2~0 ~d ~00 m~/kg, 1~ do~es, resp, of the test compou~ds were admini~tered orally a~d the number o-~ the dead animals was regi~tered for 14 daysO The re~ults are ,shown in Table 3 As test animals CFLP male mloe weig~n~
8 to 22 ~ were u~ed, '~;f ~ ~7 ; ., ' '.
' ' ~,~
T~bl~ 1 .. . . . . . . . . . ~ . . . .
T~st oomp~und Dose mg,/kg~ ~exobarbital-~lQepi~g tim~
(Exa~ple No,) p~o. (min,~
l-hour prctreat- 24-hour pre-ment treatm0ll*
a~erag0~SE ~ avera~e~SE 4 Co~trol 0 3~ ~ 2~38 34 + 2.60 1 40 67~2 ~ 7,01~glx 19,~ + ~,84 -~3 2 l~0 61,2 + ~21 ~73 13*3 ~ 0~4 -61 3 40 4303 ~ 4~18~23 12.0 ~ 0.83~_6~
4 4 4~.3 ~ 23 9,g ~ 0~62X-71 S ~o 37~ 3 ~ 30 01 ~ 6 9 ~ 0~ 43 -73 i Phenobarbi*al40 86.2 ~ 7.~1~14~ 11.2 ~ 0,3~_69 (~ p 0,001 compared to -the control) Tabls 2 Te~t oompou~d Dos~ m~,/kg, Numb~r o~ the *e~t (Example No,3 i,p. animal9 falle~ as~eep in ~ o-f the oon*rol 20 1 . 20 ~0 ~ 20 20 25 Phe~obarbi-tal 20 60 :~
i ~LS~6 .. . .. ..
Test con~ou~d L~o mg~/~g, (E~ampl~ ~o") pqO.
_, . . . . . .
`' ,~ 1 ~00 2 ~00 3 ~00 4 ~00 ~00 10 Phenobarbital 1~0,9 The known oompo~mds havin~ enz~me lndu¢lng aotivity generally ~how an Inhibltin~ ef~eot inmediately a~ter administration, which result~ in the prolo~ga-; tion o~ the 91eQPing time~
1~ From the data listed in Table 1 lt can clearly be see~ that i~ the oase o~ the compound~
aocording to the i~ventio~ the sleepin~ t.ime determine~
a~ter 1 hour ~fter.~admi~istration.is.o~ay slightly i~cr~ased~ In thi~ respeot the oo~pou~ds of ~xal~ples 20 3, 4-and ~ have the most fa~ourabls properties~ It ~' oan also be seen that phe~obarbital i~crease~ the ~leepin~ time to almost 3-times o~ it~ original valueO
24 hours a~ter admi~iatration t~e compounds aooord-in~ to the i~vention show the ~ame on~yme i~duoin~
2~ activity as phenobarbital, there~ore ths deoompo~i-tion o~ he~obarbital in the organism is aocelerated and acco~dingly $he slaepi~g~ tima is raduced, The sleepi~ time i~duced by he~obarbital, '~i ,:
.,. ~ , in addition to tha decompo~itio~ tim~ o~ he~o-barbital in the liver o~n also be i~lue~oed by a CNS activity~ ~rom Table 2 it oan ba oonoluded that the test oompound~ ~rh~n compar~d to phenobarbital~ have a very small~ almQst negligibl~ sedative ef~ect~ Aocordingly, tho mai~ biologioal e~fect o~ the compounds i9 *hsir enzyme i~duoi~g ao-tivity, ~he data o~ Table 3 u~ambl~uously prove that the oompou~ds aooording to ~he inYen tion are far less to~io tha~ phenobarbital, To sum it upt it oa~ be oo~oluded that aftsr a 2L~ hours pretreatment the new oompou~cls o~ the general formula (I) acoordi~g to the inv~ntio~ show appro~imately the s~me e~ym0 i~duoing activity a~ phenob~rbital. Th0ir main adva~tage is~ ho~ever, that after a l-hour pre-treatment they potentiat~ less or (see the compounds o~ Examples 3 to ~) not al all the aotivlty of hexobarbital, in other ~ords they are praotically devoid o~ the di~adva~ta&eous inhibiti~g period, ~hich is ~e~erally oharaoteri~tio of the kno~n col~pounds hari~g enæ~me i~d~ol~g activity~ A ~urther adva~tag0 of the instarlt compounds that they show ~o sedativ~ activity a~d are ~ar 1~99 to~ic then phanobarbital, The oompo~mds o~ the ~eneral ~or~la ', S~ 6 ,.
(I) oa~ be used i~ the therapy in th~ ~orm o~
pharmaceutioal compositio~s oontaining thase active i~gredie~ts in admixture wlth solid or liquid carriers and/or other additives~ The compositions are prapared by methods of pharma-ceutioal ind~lstry knos~ ~ eO
The pharmaoeutioal compositio~s oa~
be ~ormulated i~ forms suitable for parenteral or e~teral admi~is~ration, As oarriers fo:r example water, gelati~e, laotose, milk su~ar9 staroh~ peotine, magnesium steara~e~ steario aoid~ talo, vegetable oils, suoh as peanut oil~
olive oil, eto. oan be used. The oompositio~s may be ~inished in the form o~ solid, e~gO tablets, 1~ lozen~es, drag~es~ oapsules, such as hard gelatine oapsule, suppositories, eto, or liquid, e,g, oily or aqueous ~olutions, suspe~sions, emul~io~s, sy~up~ so~t ~elati~e oapsules~ injectable o~ly or aqueous ~olutions or suspe~sions~ eto, formula-tio~s, ~he quantity o~ the solid carrier oan bevaried withi~ a s~i~e range but pre~arably is about between 2S mg~ and 1 ~ Tha pharmaceutlcal ¢omposi-tio~s optio~ally oan oontain also oonve~tional phar~aoeutical additives, suoh a~ presar~ativas~
2~ stabiliæing~ wetti~g~ emulsifyi~g agent~, salts capable of adJusting the 05moti~ pressura~ buffars 3 flavouri~g age~ts 3 aroma age~ts~ atoO
.: .~
- 19 _ Optionally further pha~maoeu~ioally active oompou~d~ can also be present in the formula-tions, The pharmaoeutical compo si t ion9 arc pre~erably fini~hed as unit doses, ~hioh oorrespo~d to the desired rout~ of administrationa The pharma-oeutical compo sitions are preparecl by co~v~tional techniquq~ wh~h comprise ~or example soreening~
admixi~g, granulatlng~ pre~sing or dissolvi~ of the oomponents, The compo~itions obtained oan be subjected to furthor oparations co~ventionally used in the ph~rmaceutical i~du~try~ ~or example ~terilization, Further details o~ the present i~vention 1~ are to be found in the follo~ng E~mples, It is~
however~ by no means intendod to llmit our i~e~-tion to t~e Examples~
Example 1 3S,~S-1, 3_Dimethyl-~_phenyl-7-ohloro_ -1,3,4,5-tetrahydro-2H-1,4 benzodiazepin-2 o~e 10 g~O of 3S-1~3~dimethyl-5-phenyl-7--chloro-1,3-dihydro-2~-1,4-be~zodiazepin-2-o~e ars dis~olved in ~0 ml, of acetic acid a~d to the ~olution obtained 5 gO of sodium borohydride 2~ is portio~ise addsd~ with stirring, under cooling~
Stirrin~ is continusd ~or a ~urther hal~ an hourJ
~hereupo~ the mixture i~ ~utraliz~d with a 8 $
, aqueous sodium hydrogencarbonate solution under ioe ¢ooling. The 910wly solidifying produot is filtered off, washed wlth water and is subs0quent-ly dried~ 9.~ g, of the title compound ~ra obtained~
meltin~ at 102 to 103 C (after reorystallization from ethanol).
Yield: 9~6~ %.
[~]2~ _ ~318.9 ( o = 1~03, chloro~orm) ~nalysis ~or Cl~I17N20Cl (molecular weight; 300,79):
calculated:~ C = 67~88 ~ .69 ~p~ N - 9,31 round : C = 67.72 ~ H = 7,0g %, N = 9~49 Example 2 3R~R-1~3-Dimethyl~ henyl-7 ohloro--1,3,L~-tetrahydro-2H-1,4-be~odiazepi~-2-one 1~ 5 g, of 3R-1,3-dlmethyl-~-phenyl-7-ohloro--1~3-dihydro-2~ 4-benzodiazepin-2-one are dis~olved i~ ~0 ml, of acetic acid and *o the stirred solu-tio~ ~ g~ of zinc powder are added~ u~der ooo7ing wit-h water. Stirring is oonti~ued ~for further o~e hour, whereupon the mixture o~ zinc a~d zi~¢ 9alt iS
~iltor~d of~ i~ the filtrate ace*io aci~ is neutralîz0d by a 8 ~ aqueous sodium hydroge~oarbo~ate solutio~
u~der ice coolingO The slowly ~olidi~yin~ pro~uot ls *iltered off, wa~hed with water and dried~
2~ 4~28 g, o-f the title compound are obtai~ed, melting at 102 to 104 C (after recrystalli-~atlo~ ~rom etha~ol)0 :: :
:~
Yield: 86.2~ %, ~]2~ _ _322.6 (c = 1.015, ohloro-form), Rf _ 0.~8~
Analysis for Cl~Il7N20Cl (moleoular weight: 300,79):
oalculated: C = 67.88 %~ H = ~,69 '~ N = 9.31 ~
fou~d :~ C = 67,7~ %~ H = 6~9~ ~ N = 9,3~ ~p, Example ~
3S~S-1,3-Dimethyl 4-oarbamoyl-~-phenyl--7_chloro~1,3,4~-tetrahydro-2E-1,4-bs~zodiazepin-_2_on 1~5 g, (4~97 mmoles) of 3S~5S 1~3-cli-meth~l-5-phenyl-7-chloro-1~3~4 t ~-tetrahydro-2~-1,4-_benzodiazepi~-2-ones are dissolved in a mixture o~ 10 ml~ of etha~ol and 2 ml. o~ ether and to the 501ution dry hydroohloric aoid gas ls introduoed~
ter cooling s~ith ioe for lO mi~utes the pre-cipitated hydroohlorio acid is filtered off a~d suspe~dèd in 10 ml. of aoetic aoid without previous dryi~g, To tho suspa~sio~ 0.~ g~ (6~16 mmoles) of potassium oyanate are portionwise added, under ZO coolin~ with water and the mixture is stirred ~or 4 hour~ Therea~ter 50 g. of ice ~ieces are added to the mi~ture a~d it is ~eutrali~ed with a co~oe~trated aqueous a~monium hydroxide so~ution~ -~he produot~ l~hioh sol~dlfies upon cooli~ is filtered off~ ~a~hed with ~ter and dried~ 1~4 g~
of the ti-tle compound are obtainedt meltin~ at 208 to 209 C (after r~cry~tallizatio~ ~rom ~`
6~
~thanol), Yield: 81,87 ~ [~]D7 = ~2,9 (¢ = 0,897~ chloro-~orm), Rf = 0,0~
Analysis ~or C18~1~N32Cl (moleeular we~ht:
31~3~2) caloulated: C = 62.8~ .28 ~, N - 12.2Z ~
~ound : C = 62,6~ E - 6~68 ~ N = 12007 ~oc Ex~Ple 4 3R~R-1~3-Dimethyl-4-oarbamoyl-5-phenyl--7-chloro-1,3,4,~-tetrahydro-~I-1~4-benzodiazepin--2-one Following the prooedure desoribed 1 ~xample 3 but ~tarting ~rom 1.~ ~. of 3R,~R-1,3-di~
methyl-~-phenyl-7-ohloro~1,3~ t3trahydro-2H-1~4~
1~ -be~zodiazepin-2-one, the titlQ compou~d i~ obtained, melti~g at 207 to 208 ~]D~ oD4 ~c = 1,19 ohloroform)~ Rf = o~o6, ~a~ele ~
3RS~RS-1~3-DimHthyl-l~-carbamoyl-~--pheny1-7-chloro-1,3,4,~-tetra~ydro-2H~ -benzo-diazepi~-2-one Followin~ the procedure described i~
EæRmple 3 but starting ~rom 1~ g, of 3RS,~RS~1,3--d~methyl-~-phenyl-7-ohloro-1~3,4~-tetrahydrv~
2~ -benzodlaze~in-2-o~e~ the title compou~d is obtai~ed~ melti~ at 241 to 2~2 C~ R~ - o~o6 .: .
i ~LS~6 .. . .. ..
Test con~ou~d L~o mg~/~g, (E~ampl~ ~o") pqO.
_, . . . . . .
`' ,~ 1 ~00 2 ~00 3 ~00 4 ~00 ~00 10 Phenobarbital 1~0,9 The known oompo~mds havin~ enz~me lndu¢lng aotivity generally ~how an Inhibltin~ ef~eot inmediately a~ter administration, which result~ in the prolo~ga-; tion o~ the 91eQPing time~
1~ From the data listed in Table 1 lt can clearly be see~ that i~ the oase o~ the compound~
aocording to the i~ventio~ the sleepin~ t.ime determine~
a~ter 1 hour ~fter.~admi~istration.is.o~ay slightly i~cr~ased~ In thi~ respeot the oo~pou~ds of ~xal~ples 20 3, 4-and ~ have the most fa~ourabls properties~ It ~' oan also be seen that phe~obarbital i~crease~ the ~leepin~ time to almost 3-times o~ it~ original valueO
24 hours a~ter admi~iatration t~e compounds aooord-in~ to the i~vention show the ~ame on~yme i~duoin~
2~ activity as phenobarbital, there~ore ths deoompo~i-tion o~ he~obarbital in the organism is aocelerated and acco~dingly $he slaepi~g~ tima is raduced, The sleepi~ time i~duced by he~obarbital, '~i ,:
.,. ~ , in addition to tha decompo~itio~ tim~ o~ he~o-barbital in the liver o~n also be i~lue~oed by a CNS activity~ ~rom Table 2 it oan ba oonoluded that the test oompound~ ~rh~n compar~d to phenobarbital~ have a very small~ almQst negligibl~ sedative ef~ect~ Aocordingly, tho mai~ biologioal e~fect o~ the compounds i9 *hsir enzyme i~duoi~g ao-tivity, ~he data o~ Table 3 u~ambl~uously prove that the oompou~ds aooording to ~he inYen tion are far less to~io tha~ phenobarbital, To sum it upt it oa~ be oo~oluded that aftsr a 2L~ hours pretreatment the new oompou~cls o~ the general formula (I) acoordi~g to the inv~ntio~ show appro~imately the s~me e~ym0 i~duoing activity a~ phenob~rbital. Th0ir main adva~tage is~ ho~ever, that after a l-hour pre-treatment they potentiat~ less or (see the compounds o~ Examples 3 to ~) not al all the aotivlty of hexobarbital, in other ~ords they are praotically devoid o~ the di~adva~ta&eous inhibiti~g period, ~hich is ~e~erally oharaoteri~tio of the kno~n col~pounds hari~g enæ~me i~d~ol~g activity~ A ~urther adva~tag0 of the instarlt compounds that they show ~o sedativ~ activity a~d are ~ar 1~99 to~ic then phanobarbital, The oompo~mds o~ the ~eneral ~or~la ', S~ 6 ,.
(I) oa~ be used i~ the therapy in th~ ~orm o~
pharmaceutioal compositio~s oontaining thase active i~gredie~ts in admixture wlth solid or liquid carriers and/or other additives~ The compositions are prapared by methods of pharma-ceutioal ind~lstry knos~ ~ eO
The pharmaoeutioal compositio~s oa~
be ~ormulated i~ forms suitable for parenteral or e~teral admi~is~ration, As oarriers fo:r example water, gelati~e, laotose, milk su~ar9 staroh~ peotine, magnesium steara~e~ steario aoid~ talo, vegetable oils, suoh as peanut oil~
olive oil, eto. oan be used. The oompositio~s may be ~inished in the form o~ solid, e~gO tablets, 1~ lozen~es, drag~es~ oapsules, such as hard gelatine oapsule, suppositories, eto, or liquid, e,g, oily or aqueous ~olutions, suspe~sions, emul~io~s, sy~up~ so~t ~elati~e oapsules~ injectable o~ly or aqueous ~olutions or suspe~sions~ eto, formula-tio~s, ~he quantity o~ the solid carrier oan bevaried withi~ a s~i~e range but pre~arably is about between 2S mg~ and 1 ~ Tha pharmaceutlcal ¢omposi-tio~s optio~ally oan oontain also oonve~tional phar~aoeutical additives, suoh a~ presar~ativas~
2~ stabiliæing~ wetti~g~ emulsifyi~g agent~, salts capable of adJusting the 05moti~ pressura~ buffars 3 flavouri~g age~ts 3 aroma age~ts~ atoO
.: .~
- 19 _ Optionally further pha~maoeu~ioally active oompou~d~ can also be present in the formula-tions, The pharmaoeutical compo si t ion9 arc pre~erably fini~hed as unit doses, ~hioh oorrespo~d to the desired rout~ of administrationa The pharma-oeutical compo sitions are preparecl by co~v~tional techniquq~ wh~h comprise ~or example soreening~
admixi~g, granulatlng~ pre~sing or dissolvi~ of the oomponents, The compo~itions obtained oan be subjected to furthor oparations co~ventionally used in the ph~rmaceutical i~du~try~ ~or example ~terilization, Further details o~ the present i~vention 1~ are to be found in the follo~ng E~mples, It is~
however~ by no means intendod to llmit our i~e~-tion to t~e Examples~
Example 1 3S,~S-1, 3_Dimethyl-~_phenyl-7-ohloro_ -1,3,4,5-tetrahydro-2H-1,4 benzodiazepin-2 o~e 10 g~O of 3S-1~3~dimethyl-5-phenyl-7--chloro-1,3-dihydro-2~-1,4-be~zodiazepin-2-o~e ars dis~olved in ~0 ml, of acetic acid a~d to the ~olution obtained 5 gO of sodium borohydride 2~ is portio~ise addsd~ with stirring, under cooling~
Stirrin~ is continusd ~or a ~urther hal~ an hourJ
~hereupo~ the mixture i~ ~utraliz~d with a 8 $
, aqueous sodium hydrogencarbonate solution under ioe ¢ooling. The 910wly solidifying produot is filtered off, washed wlth water and is subs0quent-ly dried~ 9.~ g, of the title compound ~ra obtained~
meltin~ at 102 to 103 C (after reorystallization from ethanol).
Yield: 9~6~ %.
[~]2~ _ ~318.9 ( o = 1~03, chloro~orm) ~nalysis ~or Cl~I17N20Cl (molecular weight; 300,79):
calculated:~ C = 67~88 ~ .69 ~p~ N - 9,31 round : C = 67.72 ~ H = 7,0g %, N = 9~49 Example 2 3R~R-1~3-Dimethyl~ henyl-7 ohloro--1,3,L~-tetrahydro-2H-1,4-be~odiazepi~-2-one 1~ 5 g, of 3R-1,3-dlmethyl-~-phenyl-7-ohloro--1~3-dihydro-2~ 4-benzodiazepin-2-one are dis~olved i~ ~0 ml, of acetic acid and *o the stirred solu-tio~ ~ g~ of zinc powder are added~ u~der ooo7ing wit-h water. Stirring is oonti~ued ~for further o~e hour, whereupon the mixture o~ zinc a~d zi~¢ 9alt iS
~iltor~d of~ i~ the filtrate ace*io aci~ is neutralîz0d by a 8 ~ aqueous sodium hydroge~oarbo~ate solutio~
u~der ice coolingO The slowly ~olidi~yin~ pro~uot ls *iltered off, wa~hed with water and dried~
2~ 4~28 g, o-f the title compound are obtai~ed, melting at 102 to 104 C (after recrystalli-~atlo~ ~rom etha~ol)0 :: :
:~
Yield: 86.2~ %, ~]2~ _ _322.6 (c = 1.015, ohloro-form), Rf _ 0.~8~
Analysis for Cl~Il7N20Cl (moleoular weight: 300,79):
oalculated: C = 67.88 %~ H = ~,69 '~ N = 9.31 ~
fou~d :~ C = 67,7~ %~ H = 6~9~ ~ N = 9,3~ ~p, Example ~
3S~S-1,3-Dimethyl 4-oarbamoyl-~-phenyl--7_chloro~1,3,4~-tetrahydro-2E-1,4-bs~zodiazepin-_2_on 1~5 g, (4~97 mmoles) of 3S~5S 1~3-cli-meth~l-5-phenyl-7-chloro-1~3~4 t ~-tetrahydro-2~-1,4-_benzodiazepi~-2-ones are dissolved in a mixture o~ 10 ml~ of etha~ol and 2 ml. o~ ether and to the 501ution dry hydroohloric aoid gas ls introduoed~
ter cooling s~ith ioe for lO mi~utes the pre-cipitated hydroohlorio acid is filtered off a~d suspe~dèd in 10 ml. of aoetic aoid without previous dryi~g, To tho suspa~sio~ 0.~ g~ (6~16 mmoles) of potassium oyanate are portionwise added, under ZO coolin~ with water and the mixture is stirred ~or 4 hour~ Therea~ter 50 g. of ice ~ieces are added to the mi~ture a~d it is ~eutrali~ed with a co~oe~trated aqueous a~monium hydroxide so~ution~ -~he produot~ l~hioh sol~dlfies upon cooli~ is filtered off~ ~a~hed with ~ter and dried~ 1~4 g~
of the ti-tle compound are obtainedt meltin~ at 208 to 209 C (after r~cry~tallizatio~ ~rom ~`
6~
~thanol), Yield: 81,87 ~ [~]D7 = ~2,9 (¢ = 0,897~ chloro-~orm), Rf = 0,0~
Analysis ~or C18~1~N32Cl (moleeular we~ht:
31~3~2) caloulated: C = 62.8~ .28 ~, N - 12.2Z ~
~ound : C = 62,6~ E - 6~68 ~ N = 12007 ~oc Ex~Ple 4 3R~R-1~3-Dimethyl-4-oarbamoyl-5-phenyl--7-chloro-1,3,4,~-tetrahydro-~I-1~4-benzodiazepin--2-one Following the prooedure desoribed 1 ~xample 3 but ~tarting ~rom 1.~ ~. of 3R,~R-1,3-di~
methyl-~-phenyl-7-ohloro~1,3~ t3trahydro-2H-1~4~
1~ -be~zodiazepin-2-one, the titlQ compou~d i~ obtained, melti~g at 207 to 208 ~]D~ oD4 ~c = 1,19 ohloroform)~ Rf = o~o6, ~a~ele ~
3RS~RS-1~3-DimHthyl-l~-carbamoyl-~--pheny1-7-chloro-1,3,4,~-tetra~ydro-2H~ -benzo-diazepi~-2-one Followin~ the procedure described i~
EæRmple 3 but starting ~rom 1~ g, of 3RS,~RS~1,3--d~methyl-~-phenyl-7-ohloro-1~3,4~-tetrahydrv~
2~ -benzodlaze~in-2-o~e~ the title compou~d is obtai~ed~ melti~ at 241 to 2~2 C~ R~ - o~o6 .: .
Claims (17)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing an optically active or racemic 5-phenyl-l,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative of the general formula:
(I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in a racemic compound R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, which proaess comprises reducing a racemic or optically active 5-phenyl-1,3-dihydro-2H-1,4-diazepin-2-one derivative of the general formula:
(II) (wherein R1, R2, R3 and X are as defined above) having a centre of asymmetry in the 3-position and, when necessary, converting a racemic or optically active 5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative of the general formula (I) obtained, in which R4 stands for hydrogen (R1, R2, R3 and X are as defined above), and in which the centres of asymmetry in the 3-and 5-positions have the same absolute configuration, into an acid addition salt thereof and/or reaeting the same with an alkali metal cyanate or phos-gene and, when necessary, reacting a racemic or optically active compound of the general formula (I), in which R4 stands for a chlorocarbonyl group (R1, R2, R3 and X are as defined above) obtained by the reaction with phosgene, with ammonia, when necessary, reacting a racemic or optically active compound of the general formula (I), in which R2 stands for hydrogen (R1, R3, R4 and X
are as defined above) with an alkylating agent, and, when necessary, convert-ing a racemic or optically aetive compound of the general formula (I), in which R4 represents hydrogen (R1, R2, R3 and X are as defined above) and the centres of asymmetry in the 3- and 5-positions have the same absolute config-uration, into a pharmaceutically acceptable acid addition salt thereof.
(I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in a racemic compound R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, which proaess comprises reducing a racemic or optically active 5-phenyl-1,3-dihydro-2H-1,4-diazepin-2-one derivative of the general formula:
(II) (wherein R1, R2, R3 and X are as defined above) having a centre of asymmetry in the 3-position and, when necessary, converting a racemic or optically active 5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative of the general formula (I) obtained, in which R4 stands for hydrogen (R1, R2, R3 and X are as defined above), and in which the centres of asymmetry in the 3-and 5-positions have the same absolute configuration, into an acid addition salt thereof and/or reaeting the same with an alkali metal cyanate or phos-gene and, when necessary, reacting a racemic or optically active compound of the general formula (I), in which R4 stands for a chlorocarbonyl group (R1, R2, R3 and X are as defined above) obtained by the reaction with phosgene, with ammonia, when necessary, reacting a racemic or optically active compound of the general formula (I), in which R2 stands for hydrogen (R1, R3, R4 and X
are as defined above) with an alkylating agent, and, when necessary, convert-ing a racemic or optically aetive compound of the general formula (I), in which R4 represents hydrogen (R1, R2, R3 and X are as defined above) and the centres of asymmetry in the 3- and 5-positions have the same absolute config-uration, into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1 in which the reduction of the 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one of the general formula (II) is carried out with a complex metal hydride, a combination of a metal and an acid or with catalytically activated hydrogen.
3. A process according to claim 2 in which sodium borohydride is employed as reducing agent.
4. A process according to claim 1 in which the reaction of the compound of the general formula (I) wherein R4 is hydrogen (R1, R2, R3 and X are as defined in claim 1) with phosgene is carried out in the presence of an acid binding agent.
5. A process according to claim 1, in which the reaction of the com-pound of the general formula (I), wherein R4 represents a chlorocarbonyl group (R1, R2, R3 and X are as defined in claim 1) with ammonia is carried out in a reaction inert organic solvent.
6. A process according to claim 5, wherein the reaction is carried out in the reaction mixture obtained when preparing the starting compound and ammonia is used as a concentrated aqueous ammonium hydroxide solution or a solution of ammonia in an aliphatic alcohol having 1 to 6 carbon atoms.
7. A process for preparing 3S,5S-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,-5-tetrahydro-2H-1,4-benzodiazepin-2-one, which comprises reducing 3S-1,3-dimethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one with zinc and acetic acid.
8. A process for preparing 3R,5R-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,-5-tetrahydro-2H-1,4-benzodiazepin-2-one, which comprises reducing 3R-1,3-dimethyl-5-phenyl-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one with zinc and acetic acid.
9. A process for preparing 3S,5S-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, which comprises convert-ing 3S,5S-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodia-zepin-2-one to the hydrochloride salt thereor, reacting the salt with potass-ium cyanate and neutralizing the product with aqueous ammonium hydroxide solu-tion.
10. A process for preparing 3R,5R-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, which comprises convert-ing 3R,5R-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodia-zepin-2-one to the hydrochloride salt thereof, reacting the salt with potass-ium cyanate and neutralizing the product with aqueous ammonium hydroxide solu-tion.
11. A process for preparing 3RS,5RS-1,3-dimethyl-4-carbamoyl-5-phenyl-7-Chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, which comprises convert-ing 3RS,5RS-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodia-zepin-2-one to the hydrochloride salt thereof, reacting the salt with potass-ium cyanate and neutralizing the product with aqueous ammonium hydroxide solu-tion.
12. An optically active or racemic 5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one derivative of the general formula:
(I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in the racemic compounds R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process claimed in claim 1, 2 or 3, or by an obvious chemical equivalent thereof.
(I) wherein R1 stands for hydrogen, halogen, trifluoromethyl or a nitro group;
R2 stands for hydrogen or alkyl having 1 to 6 carbon atoms;
R3 represents a C1-6 alkyl group, a phenyl-(C1-4 alkyl) group optionally sub-stituted by a hydroxyl group, or a 3-indolylmethyl group;
R4 is hydrogen, chlorocarbonyl or carbamoyl; and X is hydrogen, halogen or trifluoromethyl, with the proviso that if in the racemic compounds R4 stands for hydrogen R3 is other than alkyl having 1 to 6 carbon atoms, in which the centres of asymmetry in the 3- and 5-positions have the same absolute configuration, and pharmaceutically acceptable acid addition salts thereof, whenever prepared by the process claimed in claim 1, 2 or 3, or by an obvious chemical equivalent thereof.
13. 3S,5S-1,3-dimethyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, whenever prepared by the process claimed in claim 7, or by an obvious chemical equivalent thereof.
14. 3R,5R-1,3-dimethyl-5-phenyl 7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, whenever prepared by the process claimed in claim 8, or by an obvious chemical equivalent thereof.
15. 3S,5S-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, whenever prepared by the process claimed in claim 9, or by an obvious chemical equivalent thereof.
16. 3R,5R-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one, whenever prepared by the process claimed in claim 10, or by an obvious chemical equivalent thereof.
17. 3RS,5RS-1,3-dimethyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetra-hydro-2H-1,4-benzodiazepin-2-one, whenever prepared by the process claimed in claim 11, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HURI-726 | 1979-08-16 | ||
| HU79RI726A HU187262B (en) | 1979-08-16 | 1979-08-16 | Process for preparing new tetrahydro-1,4-benzodiazepin-2-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1151166A true CA1151166A (en) | 1983-08-02 |
Family
ID=11001109
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000358371A Expired CA1151166A (en) | 1979-08-16 | 1980-08-15 | 5-phenyl-1,3,4,5-tetrahydro-2h-1,4- benzodiazepin-2-ones, process for the preparation thereof and pharmaceutical compositions containing them |
Country Status (11)
| Country | Link |
|---|---|
| JP (1) | JPS5668675A (en) |
| BE (1) | BE884788A (en) |
| CA (1) | CA1151166A (en) |
| CH (1) | CH647238A5 (en) |
| DE (1) | DE3030364A1 (en) |
| FR (1) | FR2463131A1 (en) |
| GB (1) | GB2056981B (en) |
| HU (1) | HU187262B (en) |
| IT (1) | IT1147764B (en) |
| NL (1) | NL8004564A (en) |
| SE (1) | SE441924B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3921677A1 (en) * | 1989-07-01 | 1991-01-10 | Basf Ag | SEALABLE PLASTIC FILM |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3109843A (en) * | 1963-11-05 | Process for preparing | ||
| DE1199776B (en) * | 1959-12-10 | 1965-09-02 | Hoffmann La Roche | Process for the preparation of 5-phenyl-2-oxo-1, 2, 4, 5-tetrahydro-3H-1, 4-benzodiazepine derivatives |
| NL131197C (en) * | 1963-06-28 | |||
| US3522289A (en) * | 1964-06-15 | 1970-07-28 | Hoffmann La Roche | Process for preparing a 2(1-(2-amino-5-phenyl) - 1 - phenylmethylamino)acetic acid derivative |
| CH510678A (en) * | 1966-12-03 | 1971-07-31 | Richter Gedeon Vegyeszet | 1 3 4 5-tetrahydro-2h-1 4-benzodiazepine 2-one derivs |
| AT281035B (en) * | 1966-12-28 | 1970-05-11 | Richter Gedeon Vegyeszet | Process for the preparation of 1,3-dihydro-2H-1,4-benzodiazepine derivatives and their acid addition salts |
| CH557358A (en) * | 1970-07-30 | 1974-12-31 | Richter Gedeon Vegyeszet | Optically active 1,4-benzodiazepine 2-ones - tranquilizers and muscle relaxants |
| CH558370A (en) * | 1970-07-30 | 1975-01-31 | Richter Gedeon Vegyeszet | 1,3,4,5-tetrahydro 2h 1,4-benzodiazepin 2-ones - by reductive cyclization of n-protected n-glycylamido-benzophenones |
| DE2204484B2 (en) * | 1971-02-09 | 1978-04-13 | Sumitomo Chemical Co | Process for the preparation of 5-phenyl-23-dihydro-IH-1,4-benzodiazepines |
| JPS4825199A (en) * | 1971-08-03 | 1973-04-02 | ||
| US3864330A (en) * | 1971-08-31 | 1975-02-04 | Sumitomo Chemical Co | Benzodiazepine derivatives and production thereof |
| HU171033B (en) * | 1974-05-29 | 1977-10-28 | Richter Gedeon Vegyeszet | Process for producing benzodiazepine derivatives |
| HU170623B (en) * | 1974-06-25 | 1977-07-28 |
-
1979
- 1979-08-16 HU HU79RI726A patent/HU187262B/en not_active IP Right Cessation
-
1980
- 1980-08-04 IT IT68248/80A patent/IT1147764B/en active
- 1980-08-11 DE DE19803030364 patent/DE3030364A1/en not_active Ceased
- 1980-08-12 NL NL8004564A patent/NL8004564A/en not_active Application Discontinuation
- 1980-08-13 FR FR8017856A patent/FR2463131A1/en active Granted
- 1980-08-14 BE BE0/201759A patent/BE884788A/en not_active IP Right Cessation
- 1980-08-15 CA CA000358371A patent/CA1151166A/en not_active Expired
- 1980-08-15 CH CH6185/80A patent/CH647238A5/en not_active IP Right Cessation
- 1980-08-15 SE SE8005779A patent/SE441924B/en not_active IP Right Cessation
- 1980-08-16 JP JP11231480A patent/JPS5668675A/en active Granted
- 1980-08-18 GB GB8026894A patent/GB2056981B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0325425B2 (en) | 1991-04-05 |
| SE8005779L (en) | 1981-02-17 |
| BE884788A (en) | 1981-02-16 |
| GB2056981A (en) | 1981-03-25 |
| IT8068248A0 (en) | 1980-08-04 |
| CH647238A5 (en) | 1985-01-15 |
| HU187262B (en) | 1985-12-28 |
| GB2056981B (en) | 1983-11-23 |
| SE441924B (en) | 1985-11-18 |
| NL8004564A (en) | 1981-02-18 |
| FR2463131A1 (en) | 1981-02-20 |
| FR2463131B1 (en) | 1985-04-26 |
| DE3030364A1 (en) | 1981-03-26 |
| JPS5668675A (en) | 1981-06-09 |
| IT1147764B (en) | 1986-11-26 |
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| Date | Code | Title | Description |
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| MKEX | Expiry |