CH491939A - Process for the preparation of a compound of the benzodiazepine series - Google Patents
Process for the preparation of a compound of the benzodiazepine seriesInfo
- Publication number
- CH491939A CH491939A CH255070A CH255070A CH491939A CH 491939 A CH491939 A CH 491939A CH 255070 A CH255070 A CH 255070A CH 255070 A CH255070 A CH 255070A CH 491939 A CH491939 A CH 491939A
- Authority
- CH
- Switzerland
- Prior art keywords
- oxo
- nitro
- preparation
- compound
- benzodiazepine
- Prior art date
Links
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
ProcH# de pHparation d'un composd de la s#rie des benzodiaz#pines Method for the preparation of a compound of the benzodiaz#pine series
Dans son brevet fran#ais <B>N,1</B> 1455048. la titulaire a Ucrit, entre autres, des 5-(1-cyclohex#nyl)-2-oxo-2,3-di hydro-IH-benzodiaz#pines-(1,4) qui poss#dent des pro pri#tds pharmacologiques intdressantes, ainsi que la pre paration <B>de</B> ces benzodiaz#pines par d#shydrohalog#na tion des composds 5-(1-halog#nocyclohexyliqties) corres pondants. In its French patent <B>N,1</B> 1455048, the owner has described, inter alia, 5-(1-cyclohex#nyl)-2-oxo-2,3-di hydro-IH- benzodiaz#pines-(1,4) which have interesting pharmacological properties, as well as the preparation <B>of</B> these benzodiaz#pines by dehydrohalog#na tion of 5-( 1-halogenocyclohexyliqties) corresponding.
Or. la titulaire a trouv# qu'ä partir <B>de</B> la 7-nitro-5-(1 <B>-</B> chlorocyclohexyl) <B>- 1</B> -m#thyl-2-oxo-2,3-dihvdro- <B>1</B> H-benzo diazdpine-(1,4), inconnue jusqu'ici, on pouvait, par Us hydrohalog#nation, obtenir une substance, dgalement in connue jusqu'ici, offrant des propridt#s particuli#rernent Interessantes au point de vue physiologique, en l'esp & c la 7-nitro-5-(1-cyclohex#nyl)-1-m#thyl-2-oxo-2,3-dihydro <I>IH-benzodiaz#pine-(1,4)</I> de formule: However, the holder has found that from <B>de</B> 7-nitro-5-(1 <B>-</B> chlorocyclohexyl) <B>- 1</B> -m# ethyl-2-oxo-2,3-dihvdro- <B>1</B> H-benzo diazdpine-(1,4), unknown until now, it was possible, by Us hydrohalogenation, to obtain a substance, also known hitherto, offering particularly interesting properties from a physiological point of view, in particular 7-nitro-5-(1-cyclohex#nyl)-1-m#thyl-2- oxo-2,3-dihydro <I>IH-benzodiaz#pine-(1,4)</I> of formula:
Le tableau suivant donne les principales activit#s de ce produit <B>:</B> The following table gives the main activities of this product <B>:</B>
Dose efficace Concerne Epreuve <B>50</B> (),/o en nia,/kg voie orale Vie <B>de</B> relation Actographie spontan#e (souris) <B>22,5</B> <B>d"</B> Motricit# spontan#e (rat) env. <B>25</B> <B>d-,</B> Equilibration-Tige tournante (souris) ActivIt# iiiyorelaxante Traction (souris) <B>9</B> Activit# antiC0nVL11sivant,2 Anti-pentdtrazol (souris) 12 <B> & </B> Anti-#Jectrochoc (souris) env. <B><I>50</I></B> Activitd anxtolvtique Exploration (souris) env. <B>25</B> <B>do</B> Cornbativit# provoqu & (rat') <B> < 10</B> Effective dose Concerns Test <B>50</B> (),/o in nie,/kg oral Life <B>of</B> relationship Spontaneous actography (mouse) <B>22.5</B > <B>d"</B> Spontaneous motor# (rat) approx. <B>25</B> <B>d-,</B> Balancing-Rotating rod (mouse) iiiyorelaxing ActivIt# Traction ( mouse) <B>9</B> AntiC0nVL11sivant activity,2 Anti-pentdtrazol (mouse) 12 <B> & </B> Anti-#Jectroshock (mouse) approx.<B><I>50</I> </B> Anxtolvtic activity Exploration (mouse) about <B>25</B> <B>do</B> Cornbativity # induced & (rat') <B> < 10</B>
Ces valeurs d#montrent une forte activitd sur Je syst#me nerveux central. These values show strong activity on the central nervous system.
La toxicit# algu# pour la sourts est faible (DL <B>1000</B> mg/kg i.p. entre <B>2500</B> et <B>3000</B> mg/kg p.o.) et, con- The algal toxicity for sourds is low (LD <B>1000</B> mg/kg i.p. between <B>2500</B> and <B>3000</B> mg/kg p.o.) and, con -
trairement <B>ä</B> toute attente, le nouveau compos# est moins toxique que le compos# correspondant dans Iequel un atome de chlore figure dans la position <B>7 ä</B> la place du groupe nitro. Unsurprisingly, the new compound is <B>ä</B> less toxic than the corresponding compound in which a chlorine atom appears in position <B>7 ä</B> in place of the nitro group.
On peut obtenir <B>le</B> compos# chlorocyclohexyliqtic servant de mati#re prerni#re en traitant la 7-nitro-5-cyclo hexyl- <B>1</B> -m#thyl-2-oxo-2,3-dihvdro-IH-benzodiaze'pine (1,4) par un Uriv# N-chlore ä'un amide d'acide car boxylique ou sulfonique. en particulier le chloro-succin imide. <B>The</B> chlorocyclohexyliqtic compound serving as a starting material can be obtained by treating 7-nitro-5-cyclohexyl- <B>1</B> -m#thyl-2-oxo -2,3-dihydro-1H-benzodiazepine (1,4) by an N-chlorine Uriv# to a carboxylic or sulfonic acid amide. especially chloro-succin imide.
L'exemple suivant, dans Iequel l'abreviation F" <B>dd-</B> signe le point de fusion pris au bloc <B>de</B> Kofler, illustre la pr#paration de la mati#re prerni#re ainsi que le pro c & i# selon l'invention, c'est-ä-dire la d#shydrohalog#na tion de la 7-nitro-5-(1-chlorocyclohexyl)-1-m#thyl-2-oxo 2,3-dihydro-IH-benzodiazdpine-(1,4) qui aboutit <B>ä</B> la <B>7-</B> nitro-5-(1-cyclohexdnyl)-1-mdthyl-2-oxo-2,3-dihvdro-IH benzodiazdp)ne-(1,4),. The following example, in which the abbreviation F" <B>dd-</B> stands for the melting point taken from Kofler's <B>block</B>, illustrates the preparation of the raw material. #re as well as the pro c & i # according to the invention, that is to say the d#shydrohalog#na tion of 7-nitro-5-(1-chlorocyclohexyl)-1-m#thyl-2 -oxo 2,3-dihydro-1H-benzodiazdpine-(1,4) which results in <B>ä</B> the <B>7-</B> nitro-5-(1-cyclohexdnyl)-1-mdthyl -2-oxo-2,3-dihvdro-1H benzodiazdp)ne-(1,4),.
<I>Exernple</I> a) Nitro-7 (chloro-1 cyclohexyl)-5 mdthyl-1 oxo-2 dihydro-2,3 IH-benzodiaz#pine-1,4. <I>Example</I> a) Nitro-7-(1-chlorocyclohexyl)-5-methyl-1-oxo-2,3-dihydro1H-benzodiaz#pine-1,4.
<B>A</B> une solution de <B>32g de</B> nitro-7 cyclohexyl-5 me thyl-1 oxo-2 dihydro-2,3 IH-benzodiazepine-1,4 dans 450m1 de t6trachlorure de carbone, on ajoute <B>16g</B> de N-chloro succinimide et on chauffe <B>ä</B> reflux pendant <B>1</B> heure <B>30.</B> La rdaction, qui Umarre assez vivernent, doit 8tre moddr#e <B>ä</B> son Ubut. L'op#ration termin#e, on ajoute <B>250</B> ml d'eau au mdlange chaud et on agite vigou reusernent pendant <B>15</B> minutes. On laisse refroidir jus qu'ä cristallisation compl & e et on essore la suspension. On lave avec de Peau et un peu de t#trachlorure de car bone. On recristallise dans l'acdtate d'#thvie. On re cueille ainsi, en deux jets, <B>32.35 g</B> d'un proäuit dont <B>Je</B> point de fusion F" <B≥ 190,1.</B> Par Evaporation du t & ra chlorure r#siduaire, on recueille encore <B>0,9 g</B> de produit ayant le Mime point de fusion. Le rendement total, cal cul# sur <B>33,15 g,</B> est de <B>92,9</B> 0,/o. <B>A</B> a solution of <B>32g</B> of</B> 7-nitro-5-cyclohexyl-1-methyl-2-oxo-2,3-dihydro-1,4-H-benzodiazepine in 450m1 of tetrachloride of carbon, <B>16g</B> of N-chloro succinimide is added and <B>ä</B> refluxed for <B>1</B> hour <B>30.</B> , which Umarre quite lively, must be modded <B>ä</B> its Ubut. When finished, add <B>250</B> ml of water to the hot mixture and stir vigorously for <B>15</B> minutes. The mixture is allowed to cool until complete crystallization and the suspension is drained. Wash with water and a little carbon tetrachloride. It is recrystallized in #thvie acetate. Thus, in two squirts, <B>32.35 g</B> of a product is collected whose <B>I</B> melting point F" <B≥ 190.1.</B> By Evaporation of the t & ra residual chloride, we still collect <B>0.9 g</B> of product having the same melting point. The total yield, calculated on <B>33.15 g,</B > is <B>92.9</B> 0,/o.
<B>b)</B> Nitro-7 cyclohex#nyl-5 mdthyl-1 oxo-2 dlhvdro <B>2.3</B> IH-benzodiaz#pine-1,4. <B>b)</B> Nitro-7 cyclohex#nyl-5 mdthyl-1 oxo-2 dlhvdro <B>2.3</B> IH-benzodiaz#pine-1,4.
On chauffc <B>ä lft,</B> avec agitation, <B>lOg</B> du produit pr#par6 selon a) dans 100m1 <B>de</B> dirn#thyl formamide avec <B>10 g</B> de carbonate <B>de</B> lithium. La rdaäion est com pl & te <I>lorsque</I> cesse <B>le</B> ddgagement de gaz carbonique. L'op8ration termin & . on refroidit, on filtre pour enie ver les sels min#raux et on #vapore le filtrat au bain marie sous vide <B>;</B> on traite le rdsidu par <B>de</B> Nther et <B>de</B> Peau et on refroidit la suspension dans la glace. De la <B>1ft,</B> is heated with stirring, <B>10g</B> of the product prepared according to a) in 100m1 <B>of</B> dirn#thyl formamide with <B>10 g</B> of lithium <B>carbonate</B>. The rdaäion is complete <I>when</I> the release of carbon dioxide ceases. The operation finished & . cool, filter to remove the mineral salts and evaporate the filtrate in a water bath under vacuum <B>;</B> treat the residue with <B>de</B> Nther and <B> of</B> skin and the suspension is cooled in ice. Of the
solution #th#r#e. on recueille ainsi, en deux jets. <B>8,35 g</B> que Pon recristallise dans Pac & ate d'#tliyie. On obtient des cristaux jaunes pesant <B>5,1 g -</B> F, <B># 1591>.</B> Par con centration de Facetate d'dthyle rdsiduaire, on recueille <B>1,5 g</B> de produit ayant un point <B>de</B> fusion <B>Fk = 157-,.</B> Rendement <B>:</B> 74 %. #th#r#e solution. one collects thus, in two jets. <B>8.35 g</B> that Pon recrystallizes in #tliyie's Pac & ate. Yellow crystals weighing <B>5.1 g -</B> F, <B># 1591> are obtained.</B> By concentration of residual ethyl facetate, <B>1.5 g </B> of product having a <B>melting</B> point <B>Fk = 157-,.</B> Yield <B>:</B> 74%.
L'analyse #l#mentaire du compose intermediaire et du produit final a dt# en tr#s bonne concordance avec ]es valeurs th#oriques. Les spectres dans l'infrarouge et l'ultraviolet, ainsi que les spectres de rdsonance magn# tique nucMaire sont en accord avec la structure. The elemental analysis of the intermediate compound and the final product was in very good agreement with the theoretical values. The infrared and ultraviolet spectra, as well as the nuclear magnetic resonance spectra are in good agreement with the structure.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR117190A FR1545694A (en) | 1967-08-08 | 1967-08-08 | Preparation of compounds of the benzodiazepine series |
| CH1176568A CH488711A (en) | 1967-08-08 | 1968-08-05 | Process for the preparation of compounds of the benzodiazepine series |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH491939A true CH491939A (en) | 1970-06-15 |
Family
ID=25708868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH255070A CH491939A (en) | 1967-08-08 | 1968-08-05 | Process for the preparation of a compound of the benzodiazepine series |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH491939A (en) |
-
1968
- 1968-08-05 CH CH255070A patent/CH491939A/en not_active IP Right Cessation
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |