CA1044697A - Novel disubstituted azabicycloalcanes - Google Patents
Novel disubstituted azabicycloalcanesInfo
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- CA1044697A CA1044697A CA295,124A CA295124A CA1044697A CA 1044697 A CA1044697 A CA 1044697A CA 295124 A CA295124 A CA 295124A CA 1044697 A CA1044697 A CA 1044697A
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- aza
- bicyclo
- ethyl
- octane
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Abstract
L'invention se rapporte à des nouveaux azabicycloalcanes de la formule générale: dans laquelle n représente 0, 1 ou 2, R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, et M représente -CH2NH2 ou =CH NO2 ou =O. Ces intermédiaires servent à préparer des composés utiles dans le traitement des ulcères gastroduodénaux de l'hyposécrétion gastrique, des syndromes nauséeux d'origine centrale et de l'hypertension.The invention relates to new azabicycloalkanes of the general formula: in which n represents 0, 1 or 2, R represents a saturated or unsaturated aliphatic hydrocarbon radical having from 1 to 5 carbon atoms in straight or branched chain, and M represents -CH2NH2 ou = CH NO2 ou = O. These intermediates serve to prepare compounds useful in the treatment of gastroduodenal ulcers of gastric hyposecretion, nausea syndromes of central origin and hypertension.
Description
~ ~ 4 ~ ~ 7 La presente invention a pour objet la preparation de nouveaux intermediaires pour la preparation des nouveaux aza- ~
bicycloalcanes disubstitues de formule g~nerale I: . :
(CH2)n Xl x2 CH2-NH-C0 ~ ~ ~ X3 dans laquelle: ~ -- n represente 0, 1 ou 2j - R represente un radical aliphatique hydrocarbone ;
sature ou non sature ayant de 1 a 5 atomes de carbone en cha~ne droite ou ramifi~e, et - Xl, X2, X3, X4 et X5, qui peuvent être identiques ou differents, reprêsentent chacun un atome d'hydrogène ou d'halogene, un radical hydroxy, un radical alkyle ou alcoxy contenant chacun de 1 a 5 atomes de carbone, un radical trifluoromethyle, nitro, amino ou sulfamoyle.
Parmi les radicaux aliphatiques hydrocarbones repre- .
sentes par le substituant R, on peut citer, par exemple, les radicaux methyle, ethyle, propyle, butyle, allyle, methyl-prop~nyle et butenyle.
Dans la signification de Xl, X2, X3, X4 et X5, on peut mentionner, par exemple, comme atomes d'halogène, les atomes de fluore, chlore et brome, comme radicaux alkyles les radicaux methyle, ethyle et propyle et comme radicaux alcoxy les radicaux methoxy, ethoxy et propoxy.
Les azabicycloalcanes peuvent être obtenus sous forme -de sels d'addition acides et, notamment, des sels d'addition : :
acides physiologiquement tolerables, en traitant les composes de formule generale I avec des acides mineraux et organiquesi .. :
-: : .
1(~44~'7 comme acides utilisables pour la formation de ces sels, on peut citer, par exemple, dans la serie minerale: les acides chlorhydrique, bromhydrique, sulfurique et phosphorique et, dans la serie organique: les acides acetique, propionique, maleïque, fumarique, tartrique, citrique, oxalique, benzoïque ~:
et methanesulfonique.
Les derives de la formule generale I sont prepares par un procede caracterise en ce que: ~
- l'on traite une azabicycloalcanone de formule .
generale I I ~
(CH2)n :.', ~e I I
N : -H
par un halogenure de formule generale III:
Hal - R III
dans laquelle Hal represente un atome d'halogene, en presence d'hydrure de sodium - l'on traite le compose ainsi obtenu de formule -:
generale lV: :
(CH2)n , I V
7 ;
R; :'.
respectivement par le dimethyle sulfate, le .
,: ......
methylate de sodium et le nitromethane, - l'on r~iduit le compos~ nitre ainsi obtenu de :.; .
formule generale V~
.:~ '. ,; .' ' "
.. ..
~ - 2 -~ ~4~'7 (CH2)n N
R
en presence de nickel de Raney ou d'hydrure double de lithium et d'aluminium, - puis l'on condense l'aminom~thyl-aza-bicycloalcane forme de formu1e generale VI:
(CH2)n ~ VI
avec un chlorure de benzoyle substitue de formule g~nerale VII:
X2 Xl ~
X3 ~ C0 - Cl VII ` .
n, R, Xl, X2, X3, X4 et X5 ayant dans ces formules ~
la même signification que dans la formule I. ~ : .
La reaction des derives II et III en presence ..
d'hydrure de sodium est effectuee convenablement dans un hydro-carbure anhydre tel que, par exemple, le xylene.
Il est avantageux d'effectuer la reduction des ~ .
derives de la formule V en utilisant une pression d'hydrogene .
d'environ 5 kg/m2, en presence de nickel de Raney ou d'hydrure double de lithium et d'aluminium comme catalyseur et en operant dans un alcool anhydre tel que, par exemple, le methanol. ;;
La condensation des derives VI et VII est avantageu- .
sement effectuee dans un solvant anhydre tel que, par exemple, le tetrahydrofuranne, en presence d'un accepteur de l'acide .
' . , ,''' .' " .:
- 3 - ~ .
lU4~ 7 chlorhydrique forme au cours de la reaction, tel que, par ~ -exemple, la triethylamine.
La presente invention concerne les derives de formule ~ -~
generale IV, V et VI qui sont nouveaux et leur procede de preparation. ~es derives IV, V et VI sont utilises comme produits intermediaires dans la synthese des derives de formule generale I.
L'intermediaire VI de la presente invention peut aussi servir dans un proc~de de preparation des derives de 10 formule gen~rale I dans laquelle au moins un des substituants -;
Xl, X2, X3, X4 et X5 est un radical amino caracterise en ce que:
- l'on condense un aminomethyl-aza-bicycloalcane de formule generale VI ci-dessus definie, avec un acide acetyl-aminobenzo~que de formule generale VIII:
X ~ ~X 2 HOOC ~ X~3 VIII
dans laquelle au moins un des substituants X'l, X'2, X'3, X'4 et X'5 est un radical acetylamino et les autres ont la même signification que Xl, X2, X3, X4 et X5 a 1 ~exception de la valeur amino, - puis l'on desacetyle le derive ainsi obtenu de formule generale IV:
rcH2)nl ~ X 2 CH2-NH-CO ~ xl3 IX
dans laquelle n, R, X'l, X'2~ X'3~ X'4 et X'5 ont les significations enoncees ci-dessus.
.: ;
1~ 4 ~ ~'7 Il est avantageux d'effectuer cette desacetylation en chauffant le derive IX avec une solution hydroalcoolique d'hydroxyde de sodium.
Les composes de la presente invention poss~dent des proprietes pharmacologiques et therapeutiques remarquables, notamment des proprietes antiemetique, stimulante de l'evacua-tion gastrique, antisecretoire gastrique, depresseur du systeme nerveux central et hypotenseur.
Leur toxicite est faible et la DL50 evaluee chez la souris a jeun, par voie intraperitoneale, varie de 60 a 750 mg/kg.
L'activite antiemetique a ete recherchee chez le chien en determinant la dose inhibant le vomissement provoque par une injection sous-cutanee de 100 ~g/kg d'apomorphine. On ~ -a pu constater que l'activite des produits de l'invention etait ~ -superieure a celle du sulpiride et qu'elle se manifeste aussi bien par la voie orale que par la voie injectable.
Il a ete ~galement observe que les nouveaux composes possédaient une action stimulante sur l'evacuation gastrique.
Cette propriete a ete etudiee par la technique de D.A. BRODIE
et S.K. KUNDRATZ (Fed. Proc. 25, 714, 1965) qui mesure la vltesse d'evacuation de pellets d'amberlite calibr~s a 1 mm, introduits par tubage chez le rat a jeun depuis la veille de l'epreuve. Administres par voie sous-cutanee les produits de l'invention ont une DE50 inferieure a celle du meilleur produit de reference.
L'activite inhibitrice sur les secretions gastriques .
a ete mise en evidence sur le rat par la technique de SHAY et Coll. (Gastroent. 5, 43, 1945). On enregistre une baisse de 40 a 60% du d~bit d'acidite quatre heures apres la ligature du pylore avec des doses de 20 a 30 mg/kg par voie intraperito-- -:
neale ou intraduodenale.
L'examen neurologique de la souris et du rat traites par les composes selon l'invention montre une diminution de l'activite motrice et une diminution significative des reflexes conditionnes en bo~te de Skinner.
Enfin, on observe chez le chien anesthesie, une action hypotensive de ces produits due ~ leur propriete adreno-lytique.
La faible toxicite et les propriet~ ci-dessus rela-tees permettent l'utilisation des derives de l'invention entherapeutique, en particulier dans le traitement des ulcères gastroduodenaux, de l'hypers~cretion gastrique, des syndromes nauseeux d'origine centrale et l'hypertension.
La presente invention a egalement pour objet les compositions pharmaceutiques comprenant un derive de formule :
g~n~rale I ou un de ses sels physiologiquement tolerables, melange ou associ~ à des excipients pharmaceutiques appropries, comme, par exemple, l'eau distillee, le talc, l'amidon, le glucose ou le beurre de cacao. Ces compositions pharmaceu- ~;
tiques peuvent revêtir la forme de comprimes, dragees, gelules, suppositoires ou solutions injectables ou buvables pour être administr~es par les voies orale, rectale ou parenterale. Les doses adminlstrees peuvent varier, selon les cas, de 10 a 200 mg, de preference entre 20 et 100 mg, de une a cinq fois par jour.
Les exemples suivants illustrent l'invention, les parties ~tant exprimees en poids et les points de fusion etant :
d~termines au bloc Kofler.
-. . -~4~5~7 N-ethyl (methoxy-2 sulfamoyl-5 benzamido m~thyl)-2 aza-3 bicyclo (3,3,0) octane ~ ~ 4 ~ ~ 7 The present invention relates to the preparation of new intermediaries for the preparation of new aza- ~
disubstituted bicycloalkanes of general formula I:. :
(CH2) n Xl x2 CH2-NH-C0 ~ ~ ~ X3 in which: ~ -- n represents 0, 1 or 2d - R represents an aliphatic hydrocarbon radical;
saturated or not saturated having from 1 to 5 atoms of carbon in straight or branched chain, and - Xl, X2, X3, X4 and X5, which can be identical or different, each represents an atom hydrogen or halogen, a hydroxy radical, a alkyl or alkoxy radical each containing 1 a 5 carbon atoms, a trifluoromethyl radical, nitro, amino or sulfamoyl.
Among the aliphatic hydrocarbon radicals repre-.
by the substituent R, mention may be made, for example, of methyl, ethyl, propyl, butyl, allyl, methyl- radicals prop ~ nyle and butenyle.
In the meaning of Xl, X2, X3, X4 and X5, we may mention, for example, as halogen atoms, the fluorine, chlorine and bromine atoms, such as alkyl radicals methyl, ethyl and propyl radicals and as alkoxy radicals methoxy, ethoxy and propoxy radicals.
Azabicycloalkanes can be obtained in the form -acid addition salts and, in particular, addition salts:
physiologically tolerable acids, treating compounds of general formula I with mineral and organic acidsi ..:
-::.
1 (~ 44 ~ '7 as acids which can be used for the formation of these salts, it is possible to cite, for example, in the mineral series: acids hydrochloric, hydrobromic, sulfuric and phosphoric and, in the organic series: acetic, propionic acids, maleic, fumaric, tartaric, citric, oxalic, benzoic ~:
and methanesulfonic.
The derivatives of the general formula I are prepared by a process characterized in that: ~
- An azabicycloalcanone of formula is treated.
general II ~
(CH2) n:. ', ~ e II
NOT : -H
by a halide of general formula III:
Hal - R III
in which Hal represents a halogen atom, in the presence of sodium hydride - the compound thus obtained is treated with formula -:
general lV::
(CH2) n, IV
7;
R; : '.
respectively by dimethyl sulfate,.
,: ......
sodium methylate and nitromethane, - We re ~ iduit the compos ~ nitre thus obtained from:.; .
general formula V ~
.: ~ '. ,; . ' '"
.. ..
~ - 2 -~ ~ 4 ~ '7 (CH2) n NOT
R
in the presence of Raney nickel or double hydride lithium and aluminum, - then we condense the aminom ~ thyl-aza-bicycloalcane general form VI:
(CH2) n ~ VI
with a substituted benzoyl chloride of formula General VII:
X2 Xl ~
X3 ~ C0 - Cl VII `.
n, R, Xl, X2, X3, X4 and X5 having in these formulas ~
the same meaning as in formula I. ~:.
The reaction of derivatives II and III in the presence ..
sodium hydride is carried out properly in a hydro-anhydrous carbide such as, for example, xylene.
It is advantageous to carry out the reduction of ~.
derivatives of formula V using hydrogen pressure.
about 5 kg / m2, in the presence of Raney nickel or hydride double of lithium and aluminum as catalyst and by operating in an anhydrous alcohol such as, for example, methanol. ;;
The condensation of derivatives VI and VII is advantageous.
ment carried out in an anhydrous solvent such as, for example, tetrahydrofuran, in the presence of an acid acceptor.
'. ,, '''.'".:
- 3 - ~.
lU4 ~ 7 hydrochloric acid formed during the reaction, such that, by ~ -example, triethylamine.
The present invention relates to the derivatives of formula ~ - ~
general IV, V and VI which are new and their method of preparation. ~ derivatives IV, V and VI are used as intermediate products in the synthesis of derivatives of formula general I.
Intermediate VI of the present invention may also be used in a process for preparing derivatives of 10 general formula I in which at least one of the substituents -;
Xl, X2, X3, X4 and X5 is an amino radical characterized in that than:
- an aminomethyl-aza-bicycloalkane of general formula VI defined above, with an acetyl acid aminobenzo ~ that of general formula VIII:
X ~ ~ X 2 HOOC ~ X ~ 3 VIII
in which at least one of the substituents X'l, X'2, X'3, X'4 and X'5 is an acetylamino radical and the others have the same meaning as Xl, X2, X3, X4 and X5 except 1 ~
the amino value, - then the derivative thus obtained is deacetylated general formula IV:
rcH2) nl ~ X 2 CH2-NH-CO ~ xl3 IX
in which n, R, X'l, X'2 ~ X'3 ~ X'4 and X'5 have the meanings stated above.
.:;
1 ~ 4 ~ ~ '7 It is advantageous to carry out this deacetylation by heating the derivative IX with a hydroalcoholic solution sodium hydroxide.
The compounds of the present invention have remarkable pharmacological and therapeutic properties, including antiemetic properties, stimulating evacua-gastric tion, gastric antisecretory, system depressant central nervous and hypotensive.
Their toxicity is low and the LD50 evaluated in fasting mice, intraperitoneally, ranges from 60 to 750 mg / kg.
Antiemetic activity has been sought in dog when determining the dose that inhibits vomiting causes by a subcutaneous injection of 100 ~ g / kg of apomorphine. On ~ -was able to observe that the activity of the products of the invention was ~ -superior to that of sulpiride and that it also manifests both orally and by injection.
It has also been observed that the new compounds had a stimulating action on gastric evacuation.
This property has been studied by the technique of DA BRODIE
and SK KUNDRATZ (Fed. Proc. 25, 714, 1965) which measures the evacuation speed of amberlite pellets calibrated at its 1 mm, introduced by tubing in the fasted rat since the day before the ordeal. Subcutaneously administered the products of the invention have an ED50 lower than that of the best product reference.
Inhibitory activity on gastric secretions.
was highlighted on the rat by the SHAY technique and Coll. (Gastroent. 5, 43, 1945). There is a drop of 40 to 60% of the acidity rate four hours after ligation of the pylorus with doses of 20 to 30 mg / kg intraperitoneally - -:
neale or intraduodenale.
Neurological examination of the treated mouse and rat by the compounds according to the invention shows a decrease in motor activity and a significant decrease in reflexes packaged in Skinner boxes.
Finally, we observe in dogs anesthesia, a hypotensive action of these products due to their adreno-lytic.
The low toxicity and the properties above tees allow the use of the derivatives of the entherapeutic invention, in particular in the treatment of ulcers gastroduodenaux, gastric hyperscretion, syndromes nausea of central origin and hypertension.
The present invention also relates to pharmaceutical compositions comprising a derivative of formula:
general ~ I or one of its physiologically tolerable salts, mixed or combined with suitable pharmaceutical excipients, such as, for example, distilled water, talc, starch, glucose or cocoa butter. These pharmaceu- ~ compositions;
ticks can take the form of tablets, dragees, capsules, suppositories or solutions for injection or drink to be administered by the oral, rectal or parenteral routes. The administered doses may vary, depending on the case, from 10 to 200 mg, preferably between 20 and 100 mg, from one to five times per day.
The following examples illustrate the invention, the parts ~ both expressed by weight and the melting points being:
defined in the Kofler block.
-. . -~ 4 ~ 5 ~ 7 N-ethyl (2-methoxy-5-sulfamoyl-benzamido m ~ thyl) -2 aza-3 bicyclo (3,3,0) octane
2 2 I ~ L cH2-NH-CO
- On introduit 57.6 parties (1.2 mole) d'hydrure de sodium a 50% dans la paraffine a 1500 parties de xyl~ne anhydre.
A cette suspension, on ajoute peu a peu en 1 heure, a temperature ambiante, une solution de 150 parties (1.2 mole) d'aza-3 bicyclo (3,3,0) octanone-2 dans 600 parties de xyl~ne anhydre. Le melange est maintenu a reflux pendant 45 minutes.
Apres refroidissement on ajoute en 30 minutes, 187 parties (1.2 mole) d'iodure d'ethyle, puis le melange reactionnel est chauff~ a 110C pendant une heure. Apres refroidissement, on ajoute 400 parties d'eau. On separe la couche organique, la seche sur sulfate de magnesium anhydre puis la concentre sous vide. Par distillation, on obtient 95.5 parties de N-ethyl aza-3 bicyclo (3,3,0) octanone-2, Eb/0.2 mm Hg: 76-7~C, n D5 - 1,4872, Apres extraction de la couche aqueuse par 500 parties de chloroforme, sechage, puis concentration et distil1ation, on obtient a nouveau 46 parties de N-ethyl aza-3 bicyclo (3,3,0) octanone-2, ayant le même point d'ebullition et le même indice de refraction que le produit obtenu a partir de la couche orga-nique.
- A 91 parties de N-ethyl aza-3 bicyclo (3,3,0) octanone-2, on ajoute en 20 minutes 74.7 parties (O.S9 mole) de .`"' ~' ' 1~4~
dimethyl sulfate. On chauffe alors le melange reactionnel a 60-65C pendant 90 minutes. Apres refroidissement et addition d'eau glacee, le melange reactionnel est traite par 182 parties d'une solution 3.25 N de CH30Na dans le methanol. On le main-tient sous agitation a temperature ambiante pendant 30 minutes puis on ajoute 54.3 parties (0.89 mole) de nitromethane. Apres -agitation pendant 1 heure a temperature ambiante, le melange est concentre sous vide. Le residu est traite par 200 parties d'eau et le precipite ainsi forme est seche a l'air ~ tempera-ture ambiante. On obtient 62.5 parties de N-ethyl nitro-methylène-2 aza-3 bicyclo (3,3,0) octane qui, apres cristalli- -sation dans un melange de benzene cyclohexane fond ~ 86C.
- 54 parties de N-ethyl nitromethylene-2 aza-3 bicyclo (3,3,0) octane en solution dans 500 parties de methanol ;
anhydre sont reduites sous une pression d'hydrogene de 5 kg/m2, en presence de 20 parties de nickel de Raney. Apres filtration et lavage du catalyseur par le methanol, le filtrat est evapore sous vide, puis distille. On obtient 30 parties de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane, Eb./0.25-0.30 mm Hg: 88-90C. Cette reduction peut egalement etre effectuee avec un hydrure double de lithium et d'aluminium.
- A une solution de 10.77 partles de N-ethyl amino-methyl-2 aza-3 bicyclo (3,3,0) octane et 6.46 parties de triethylamine dans 100 parties de tetrahydrofuranne anhydre on ajoute peu a peu une solution de 17 parties de chlorure de m~thoxy-2 sulfamoyl-5 benzoyle dans 250 parties de tétrahydro-furanne. Le mélange est chauffé a 45C pendant 1 heure, puis le chlorhydrate de triethylamine forme est filtre et le filtrat -est dilue avec 50 parties d'ether. Apres 24 heures, le preci-pite est filtre puis traite par 130 parties d'ethanol bouil-lant. Apres sechage on obtient 13.5 parties de N-ethyl ~ ~...
~.~fl~ 7 (methoxy-2 sulfamoyl-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 232C.
- Le chlorure de methoxy-2 sulfamoyl-5 benzoyle, ci-dessus utilise comme matière première, a ete prepare comme s u i ~ :
On ajoute, en 45 minutes à une temperature de 0C, 233 parties d'acide chlorosulfonique à une suspension de 125 parties (0.82 mole) d'acide o.anisique dans 450 parties de ~ ;
chloroforme anhydre. On maintient le melange reactionnel a la temperature ambiante pendant 90 minutes, puis on augmente pro-gressivement la temperature jusqu'au reflux que l'on maintient pendant 90 minutes. On separe le chloroforme et traite le ~ -residu par 800 parties d'un melange eau glace sous agitation.
Après filtration, le precipite est lave à l'eau puis seche.
On obtient 34 parties d'acide methoxy-2 chlorosulfonyl-5 benzo9que, P.F. 145C. -On traite le produit brut ainsi obtenu par 135 ~-parties d'ammoniaque concentre et 135 parties d'eau. On laisse le melange reactionnel au repos pendant 4 heures a la tempera-ture ambiante, puis on ajoute 320 parties d'eau tout en refroi-dissant le melange par de la glace. Après acidification avec 170 parties d'HCl concentre, l'acide qui precipite est filtr~, lave à l'eau et seche. On obtient 26.8 parties d'acide methoxy-2 sulfamoyl-5 benzo~que, P.F. 224-225C.
On ajoute rapidement 27.5 parties de chlorure de thionyle a une suspension de l'acide methoxy-2 sulfamoyl-5 benzo~que precedemment obtenu dans 600 parties de tetrahydro-furanne anhydre. Le melange est maintenu a reflux pendant 2 heures, puis la solution est evaporee sous vide. Le residu est alors trait~ par 500 parties de benzêne anhydre. Après elimination du benzène sous vide, on obtient 29 parties de -x.,::
9'~
chlorure de methoxy-2 sulfamoyl-5 benzoyle, P.F. 148-150C, qui, apr~s recristallisation dans le benzène, fond à 156C.
EXEMPIES 2 a 19 ::
Les derives suivants ont et~ prepares selon le procede decrit dans l'exemple 1.
2) N-propyl (methoxy-2 sulfamoyl-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, ~ partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-propyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. Ce dernier a ete prepare a partir de N-propyl nitromethylêne-2 aza-3 bicyclo (3,3,0) octane, lui-même prepare à partir de N-propyl aza-3 bicyclo (3,3,0) octanone-2 obtenue partir d'aza-3 bicyclo (3,3,0) octanone-2. 2 2 I ~ L cH2-NH-CO
- 57.6 parts (1.2 mole) of hydride are introduced.
50% sodium in paraffin has 1500 parts of xyl ~ ne anhydrous.
To this suspension, little by little is added in 1 hour, at room temperature, a solution of 150 parts (1.2 mole) aza-3 bicyclo (3,3,0) octanone-2 in 600 parts of xyl ~ ne anhydrous. The mixture is kept at reflux for 45 minutes.
After cooling, 187 parts are added in 30 minutes (1.2 mole) of ethyl iodide, then the reaction mixture is heating ~ 110C for one hour. After cooling, we add 400 parts of water. We separate the organic layer, the dried over anhydrous magnesium sulfate and then concentrated under empty. By distillation, 95.5 parts of N-ethyl are obtained.
aza-3 bicyclo (3,3,0) octanone-2, Eb / 0.2 mm Hg: 76-7 ~ C, n D5 - 1.4872, After extraction of the aqueous layer by 500 parts chloroform, drying, then concentration and distillation, we again obtains 46 parts of N-ethyl aza-3 bicyclo (3,3,0) octanone-2, having the same boiling point and the same index of refraction as the product obtained from the organic layer fuck.
- 91 parts of N-ethyl aza-3 bicyclo (3,3,0) octanone-2, 74.7 parts (O.S9 mole) of .` "'~'' 1 ~ 4 ~
dimethyl sulfate. The reaction mixture is then heated to 60-65C for 90 minutes. After cooling and adding of ice water, the reaction mixture is treated with 182 parts of a 3.25 N solution of CH30Na in methanol. We keep it stirred at room temperature for 30 minutes then 54.3 parts (0.89 mole) of nitromethane are added. After -stirring for 1 hour at room temperature, the mixture is concentrated in vacuo. The residue is treated by 200 parts of water and the precipitate thus formed is air dried ~ tempera-ambient ture. 62.5 parts of N-ethyl nitro- are obtained.
2-methylene aza-3 bicyclo (3,3,0) octane which, after crystalli- -sation in a mixture of benzene cyclohexane background ~ 86C.
- 54 parts of N-ethyl nitromethylene-2 aza-3 bicyclo (3,3,0) octane dissolved in 500 parts of methanol;
anhydrous are reduced under a hydrogen pressure of 5 kg / m2, in the presence of 20 parts of Raney nickel. After filtration and washing the catalyst with methanol, the filtrate is evaporated under vacuum, then distill. 30 parts of N-ethyl are obtained aminomethyl-2 aza-3 bicyclo (3,3,0) octane, Eb./0.25-0.30 mm Hg: 88-90C. This reduction can also be carried out with a double hydride of lithium and aluminum.
- To a solution of 10.77 partles of N-ethyl amino-methyl-2 aza-3 bicyclo (3,3,0) octane and 6.46 parts of triethylamine in 100 parts of anhydrous tetrahydrofuran on gradually add a solution of 17 parts of chloride of m ~ 2-thoxy-5-sulfamoyl benzoyl in 250 parts of tetrahydro-furan. The mixture is heated at 45C for 1 hour, then the triethylamine hydrochloride form is filtered and the filtrate -is diluted with 50 parts of ether. After 24 hours, the preci-pite is filtered and then treated with 130 parts of boiled ethanol lant. After drying, 13.5 parts of N-ethyl are obtained ~ ~ ...
~. ~ fl ~ 7 (2-methoxy-5-sulfamoyl-benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 232C.
- 2-methoxy-5-sulfamoyl-benzoyl chloride, above used as raw material, has been prepared as follow ~:
We add, in 45 minutes at a temperature of 0C, 233 parts of chlorosulfonic acid to a suspension of 125 parts (0.82 mole) of o.anisic acid in 450 parts of ~;
anhydrous chloroform. The reaction mixture is maintained at the room temperature for 90 minutes, then increase pro-gradually the temperature until the reflux is maintained for 90 minutes. We separate the chloroform and process the ~ -residue from 800 parts of an ice water mixture with stirring.
After filtration, the precipitate is washed with water and then dried.
34 parts of 2-methoxy-5-chlorosulfonyl acid are obtained benzo9que, PF 145C. -The crude product thus obtained is treated with 135 ~ -parts of concentrated ammonia and 135 parts of water. We let the reaction mixture at rest for 4 hours at room temperature room temperature, then add 320 parts of water while cooling spreading the mixture through ice. After acidification with 170 parts of concentrated HCl, the acid which precipitates is filtered ~, wash with water and dry. 26.8 parts of acid are obtained 2-methoxy-5-sulfamoyl benzo ~ que, PF 224-225C.
27.5 parts of chloride are rapidly added thionyl has a suspension of 2-methoxy-5-sulfamoyl acid benzo ~ than previously obtained in 600 parts of tetrahydro-anhydrous furan. The mixture is kept at reflux for 2 hours, then the solution is evaporated in vacuo. The residue is then treated ~ with 500 parts of anhydrous benzene. After elimination of benzene under vacuum, 29 parts of -x., ::
9 '~
2-methoxy-5-sulfamoyl-benzoyl chloride, PF 148-150C, which, after ~ s recrystallization from benzene, melts at 156C.
EXAMPLES 2 to 19 ::
The following derivatives have been prepared according to the process described in example 1.
2) N-propyl (2-methoxy-5-sulfamoyl-benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, ~ from methoxy-2 chloride 5-sulfoyoyl benzoyl and N-propyl 2-aminomethyl aza-3 bicyclo (3,3,0) octane. The latter was prepared from N-propyl nitromethyl-2 aza-3 bicyclo (3,3,0) octane, itself prepared from N-propyl aza-3 bicyclo (3,3,0) octanone-2 obtained from aza-3 bicyclo (3,3,0) octanone-2.
3) N-allyl (methoxy-2 sulfamoyl-5 benzamido m~thyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 163-164C (isopropanol) ~ partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-allyl aminomethyl-2 aza-3 bicyclo t3,3,0) octane, Eb/5 mm Hg: 112C.
Ce dernier a ete prepare ~ part;r de N-allyl nitromethylene-2 aza-3 bicyclo (3,3,0) octane, P.F. 99-100C (benzene), lui-même prepare a partir de N-allyl aza-3 bicyclo (3,3,0) octanone-2, Eb/0.4 mm Hg: 86-88C, obtenue a partir d'aza-3 bicyclo (3,3,0) octanone-2. 3) N-allyl (2-methoxy-5-sulfamoyl-benzamido m ~ thyl) -2 aza-3 bicyclo (3,3,0) octane, PF 163-164C (isopropanol) ~ from 2-methoxy-5-sulfamoyl benzoyl chloride and N-allyl aminomethyl-2 aza-3 bicyclo t3,3,0) octane, Eb / 5 mm Hg: 112C.
The latter was prepared ~ part; r of N-allyl nitromethylene-2 aza-3 bicyclo (3,3,0) octane, PF 99-100C (benzene), itself prepared from N-allyl aza-3 bicyclo (3,3,0) octanone-2, Eb / 0.4 mm Hg: 86-88C, obtained from aza-3 bicyclo (3,3,0) octanone-2.
4) N-ethyl (methoxy-2 sulfamoyl-5 benzamido methyl)-2 aza-3 bicyclo (3,2,0) heptane, a partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,2,0) heptane. Ce dernier a ete prepare a partir de N-ethyl nitromethylene-2 aza-3 bicyclo (3,2,0) heptane, lui-même prepare a partir de N-ethyl aza-3 bicyclo (3,2,0) heptanone-2 obtenue à partir d'aza-3 bicyclo (3,2,0) heptanone-2. -4) N-ethyl (2-methoxy-5-sulfamoyl-benzamido methyl) -2 aza-3 bicyclo (3,2,0) heptane, from 2-methoxy chloride sulfamoyl-5 benzoyl and N-ethyl aminomethyl-2 aza-3 bicyclo (3,2,0) heptane. The latter was prepared from N-ethyl nitromethylene-2 aza-3 bicyclo (3,2,0) heptane, itself prepared from N-ethyl aza-3 bicyclo (3,2,0) heptanone-2 obtained from aza-3 bicyclo (3,2,0) heptanone-2. -
5) N-allyl (methoxy-2 sulfamoyl-5 benzamido methyl)-2 aza-3 bicyclo (3,2,0) heptane, a partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-allyl aminomethyl-2 aza-3 bicyclo .. - 1 0 - ~ -,''' '.: ' ~ 4tj~7 (3,2,0) heptane. Ce dernier a ete prepare ~ partir de N-allyl nitromethylene-2 aza-3 bicyclo (3,2,0) heptane, lui-même prepare a partir de N-allyl aza-3 b~cyclo (3,2,0) heptanone-2 obtenue a partir d'aza-3 bicyclo (3,2,0) heptanone-2. 5) N-allyl (2-methoxy-5-sulfamoyl-benzamido methyl) -2 aza-3 bicyclo (3,2,0) heptane, from 2-methoxy chloride 5-sulfoyoyl benzoyl and N-allyl 2-aminomethyl aza-3 bicyclo .. - 1 0 - ~ -, ''''.:' ~ 4tj ~ 7 (3,2,0) heptane. The latter was prepared from N-allyl nitromethylene-2 aza-3 bicyclo (3,2,0) heptane, itself prepared from N-allyl aza-3 b ~ cyclo (3,2,0) heptanone-2 obtained from aza-3 bicyclo (3,2,0) heptanone-2.
6) N-ethyl (methoxy-2 sulfamoyl-5 benzamido methyl)-7 aza-8 bicyclo (4,3,0) nonane, P.F. 241-242C se decomposant (dimethylformamide/eau), a partir de chlorure de m~thoxy-2 sulfamoyl-5 benzoyle et de N-ethyl aminom~thyl-7 aza-8 bicyclo (4,3,0) nonane, Eb/0.3 mm Hg: 76-78C. Ce dernier a ete 10 prepare a partir de N-ethyl nitromethylene-7 aza-8 bicyclo -(4,3,0) nonane, P.F.: 101-102C (cyclohexane), lui-meme prepare a partir de N-~hyl aza-8 bicyclo (4,3,0) nonanone-7, Eb/0.5 ;
mm Hg: 99-102C obtenue à partir d'aza-8 bicyclo (4,3,0) nonanone-7. 6) N-ethyl (2-methoxy-5-sulfamoyl-benzamido methyl) -7 aza-8 bicyclo (4,3,0) nonane, PF 241-242C decomposing (dimethylformamide / water), from chloride of m ~ thoxy-2 sulfamoyl-5 benzoyl and N-ethyl aminom ~ thyl-7 aza-8 bicyclo (4,3,0) nonane, Eb / 0.3 mm Hg: 76-78C. The latter was 10 prepared from N-ethyl nitromethylene-7 aza-8 bicyclo -(4,3,0) nonane, PF: 101-102C (cyclohexane), itself prepared from N- ~ hyl aza-8 bicyclo (4,3,0) nonanone-7, Eb / 0.5;
mm Hg: 99-102C obtained from aza-8 bicyclo (4,3,0) nonanone-7.
7) N-allyl (methoxy-2 sulfamoyl-5 benzamido methyl)-7 aza-8 bicyclo (4,3,0) nonane, ~ partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-allyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane. Ce dernier a ete prepare a partir de N-allyl nitromethylene-7 aza-8 bicyclo (4,3,0) nonane, lui-même prepare a partir de N-allyl aza-8 bicyclo (4,3,0) nonanone-7, obtenue a partir d'aza-8 bicyclo (4,3,0) nonanone-7. 7) N-allyl (2-methoxy-5-sulfamoyl-5 benzamido methyl) -7 aza-8 bicyclo (4,3,0) nonane, ~ from 2-methoxy chloride sulfamoyl-5 benzoyl and N-allyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane. The latter was prepared from N-allyl nitromethylene-7 aza-8 bicyclo (4,3,0) nonane, itself prepared from N-allyl aza-8 bicyclo (4,3,0) nonanone-7, obtained from aza-8 bicyclo (4,3,0) nonanone-7.
8) N-(methyl-2 propene-2 yl) (methoxy-2 sul~amoyl-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 183-185C
(ethanol), a partir de chlorure de methoxy-2 sulfamoyl-5 benzoyle et de N-(methyl-2 propene-2 yl) aminomethyl-2 aza-3 bicyclo (3,3,0) octane, Eb/0.1 mm Hg: 75-77C. Ce dernier a et~ prepare a partir de N-(methyl-2 propene-2 yl) nitro-methylene-2 aza-3 bicyclo (3,3,0) octane, P.F. 128-129C
(isopropanol), lui-même prepare a partir de N-(methyl-2 propene-2 yl) aza-3 bicyclo (3,3,0) octanone-2, Eb/0.3 mm Hg:
100-102C, obtenue a partir d'aza-3 bicyclo (3,3,0) octanone-2.
''~ ' -:~: '. .
7 ~:
. . . 8) N- (methyl-2 propene-2 yl) (methoxy-2 sul ~ amoyl-5 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 183-185C
(ethanol), from 2-methoxy-5-sulfamoyl chloride benzoyl and N- (methyl-2 propene-2 yl) aminomethyl-2 aza-3 bicyclo (3,3,0) octane, Eb / 0.1 mm Hg: 75-77C. The latter has and ~ prepared from N- (methyl-2 propene-2 yl) nitro-2-methylene aza-3 bicyclo (3,3,0) octane, PF 128-129C
(isopropanol), itself prepared from N- (methyl-2 propene-2 yl) aza-3 bicyclo (3,3,0) octanone-2, Eb / 0.3 mm Hg:
100-102C, obtained from aza-3 bicyclo (3,3,0) octanone-2.
'' ~ '-: ~: '. .
7 ~:
. . .
9) N-ethyl (methoxy-2 benzamido m~thyl)-2 aza-3 bicyclo t3,3,0) octane, P.F. du chlorhydrate correspondant: 137-138C
(acetate d'ethyle/isopropanol), a partir de chlorure de methoxy-2 benzoyle et de N-~thyl amlnomethyl-2 aza-3 bicyclo (3,3,0) octane. 9) N-ethyl (2-methoxy benzamido m ~ thyl) -2 aza-3 bicyclo t3,3,0) octane, PF of the corresponding hydrochloride: 137-138C
(ethyl acetate / isopropanol), from 2-methoxy benzoyl and N- ~ thyl amlnomethyl-2 aza-3 bicyclo (3,3,0) octane.
10) N-ethyl (trifluoromethyl-3 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 101C (cyclohexane), a partir de chlorure de trifluoromethyl-3 benzoyle et de N-ethyl amino-m~thyl-2 aza-3 bicyclo (3,3,0) octane. 10) N-ethyl (trifluoromethyl-3 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 101C (cyclohexane), from 3-trifluoromethyl benzoyl chloride and N-ethyl amino-m ~ 2-thyl aza-3 bicyclo (3,3,0) octane.
11) N-ethyl (methyl-2 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 94C (cyclohexane) à part;r de chlorure de methyl-2 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 11) N-ethyl (methyl-2 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 94C (cyclohexane) apart; r chloride 2-methyl benzoyl and N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane.
12) N-ethyl (nitro-2 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 133C (isopropanol) a partir de chlorure de nitro-2 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 12) N-ethyl (2-nitro benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 133C (isopropanol) from nitro chloride 2 benzoyl and N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane.
13) N-ethyl (amino-2 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 115C (cyclohexane), a part;r de chlorure d'amino-2 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 13) N-ethyl (2-amino benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 115C (cyclohexane), apart; r of amino chloride 2 benzoyl and N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane.
14) N-ethyl tsulfamoyl-4 benzamido m~thyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 235-236C (isopropanol), a partir de .
chlorure sulfamoyl-4 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 14) N-ethyl tsulfamoyl-4 benzamido m ~ thyl) -2 aza-3 bicyclo (3,3,0) octane, PF 235-236C (isopropanol), from.
4-sulfoyoyl benzoyl chloride and N-ethyl 2-aminomethyl aza-3 bicyclo (3,3,0) octane.
15) N-ethyl (sulfamoyl-3 benzamido m~thyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 110C (acetate d'ethyle), a partir de chlorure de sulfamoyl-3 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 15) N-ethyl (3-sulfamoyl benzamido m ~ thyl) -2 aza-3 bicyclo (3,3,0) octane, PF 110C (ethyl acetate), from 3-sulfoyoyl benzoyl chloride and N-ethyl 2-aminomethyl chloride aza-3 bicyclo (3,3,0) octane.
16) N-ethyl (fluoro-4 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 112-113C (isopropanol/eau), a partir de 1~4~ 7 ::
chlorure de fluoro-4 benzoyle et de N-~thyl aminométhyl-2 aza-3 bicyclo (3,3,0) octane. -16) N-ethyl (4-fluoro benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 112-113C (isopropanol / water), from 1 ~ 4 ~ 7 ::
4-fluoro benzoyl chloride and N- ~ thylaminomethyl-2 aza-3 bicyclo (3,3,0) octane. -
17) N-ethyl (hydroxy-2 benzamido methyl~-2 aza-3 bicyclo (3,3,0) octane, Eb/O.l mm Hg: 175-178C, a partir de chlorure d'hydroxy-2 benzoyle et de N-ethyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane. 17) N-ethyl (2-hydroxy benzamido methyl ~ -2 aza-3 bicyclo (3,3,0) octane, Eb / Ol mm Hg: 175-178C, from chloride 2-hydroxy benzoyl and N-ethyl 2-aminomethyl aza-3 bicyclo (3,3,0) octane.
18) N-ethyl (sulfamoyl-3 chloro-4 benzamido methyl)-7 aza-8 bicyclo (4,3,0) nonane, P.F. du chlorhydrate correspondant 262-264C (acide acetique), a partir de chlorure de sulfamoyl-3 chloro-4 benzoyle et de N-ethyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane. 18) N-ethyl (sulfamoyl-3 chloro-4 benzamido methyl) -7 aza-8 bicyclo (4,3,0) nonane, PF of the corresponding hydrochloride 262-264C (acetic acid), from sulfamoyl-3 chloride 4-chloroyl benzoyl and N-ethyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane.
19) N-ethyl (methoxy-2 chloro-5 benzamido methyl)-7 aza-8 bicyclo (4,3,0) nonane, P.F. du chlorhydrate correspondant:
170-174C (isopropanol), a partir de chlorure de methoxy-2 chloro-5 benzoyle et de N-ethyl aminomethyl-7 aza-8 bicyclo ~f (4,3,0) nonane.
N-ethyl (methoxy-2 amino-4 chloro-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane `~
~ Cl :, ~ CH2-NH-CO ~ NH2 On ajoute 2.5 parties de triethylamine a une suspen- ' slon de 6 parties d'acide methoxy-2 acetylamino-4 chloro-5 benzoique dans 50 parties de tetrahydrofuranne anhydre. La solution ainsi obtenue est versee peu a peu dans un melange de -2.7 parties de chloroformiate d'ethyle et 80 parties de tetra-hydrofuranne, maintenu a oc . Apres agitation pendant 10 minutes, on ajoute 4.1 parties de N-ethyl aminomethyl-2 aza-3 " `'~ ;". " ~ " -~ .:
1~44tj9'7 ~
bicyclo (3,3,0) octane. Le melange reactionnel est laisse à la temperature ambiante pendant 10 minutes, puis progressivement -on augmente la temperature jusqu'au re~lux que l'on maintient pendant 60 minutes.
Après r~froidissement, le melange est filtre et le filtrat est evapore sous vide. Apres recristallisation dans 50 parties d'acetate d'ethyle on obtient 5.5 parties de N-ethyl (methoxy-2 acetylamino-4 chloro-S benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 156-157C (acetate d'~thyle). .
. :. .
On chauffe pendant 30 minutes 7 parties de N-ethyl (methoxy-2 acetylamino-4 chloro-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, en pr~sence de 17.7 parties d'une ~
solution 2 N de soude et 15 parties d'~thanol. Apres refroi- ~ .
dissement, le pr~cipite est filtre, puis recristallise dans 40 parties d'acetonitrile. On obtient 5 parties de N-~thyl ~-~
(m~thoxy-2 amino-4 chloro-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 128-129C.
EXEMPLES 21 - 22 ;
Les derives suivants ont ete prepares selon le proced~ decrit dans l'exemple 20.
21) N-ethyl (methoxy-2 amino-4 chloro-5 benzamido methyl)-7 aza-8 bicyclo (4,3,0) nonane, P.F. 165C (isopropanol), a partir d'acide methoxy-2 acetylamino-4 chloro-5 benzo~que et de N-ethyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane.
22) N-allyl (methoxy-2 amino-4 chloro-5 benzamido methyl)-2 aza-3 bicyclo (3,3,0) octane, P.F. 115C (acetonitrile), a ., partir d'acide m~thoxy-2 acetylamino-4 chloro-5 benzo~que et ;
de N-allyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane.
La presente demande est une divisionnaire de la ;
demande N.S. 215.940 deposee le 13 decembre 1974, L. Beregi ;
et al.
; ~ 14 ~ - ~
:,'~:' :' ' 19) N-ethyl (2-methoxy-5 chloro-benzamido methyl) -7 aza-8 bicyclo (4,3,0) nonane, PF of the corresponding hydrochloride:
170-174C (isopropanol), from 2-methoxy chloride 5-chloroyl benzoyl and N-ethyl aminomethyl-7 aza-8 bicyclo ~ f (4,3,0) nonane.
N-ethyl (2-methoxy-4-amino-5 chloro-benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane `~
~ Cl:, ~ CH2-NH-CO ~ NH2 2.5 parts of triethylamine are added to a suspension.
slon of 6 parts of 2-methoxy-acetylamino-4 chloro-5 acid benzoic in 50 parts of anhydrous tetrahydrofuran. The solution thus obtained is gradually poured into a mixture of -2.7 parts of ethyl chloroformate and 80 parts of tetra-hydrofuran, maintained at oc. After shaking for 10 minutes, add 4.1 parts of N-ethyl aminomethyl-2 aza-3 "` '~;"."~" -~.:
1 ~ 44tj9'7 ~
bicyclo (3,3,0) octane. The reaction mixture is left at the room temperature for 10 minutes, then gradually -the temperature is increased until re ~ lux which is maintained for 60 minutes.
After cooling, the mixture is filtered and the the filtrate is evaporated under vacuum. After recrystallization in 50 parts of ethyl acetate we obtain 5.5 parts of N-ethyl (2-methoxy-acetylamino-4 chloro-S benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 156-157C (ethyl acetate). .
. :. .
7 parts of N-ethyl are heated for 30 minutes (2-methoxy-acetylamino-4 chloro-5 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, in the presence of 17.7 parts of a ~
2 N soda solution and 15 parts of ~ thanol. After cooling ~.
smoothing, the precipitate is filtered, then recrystallized in 40 parts of acetonitrile. We get 5 parts of N- ~ thyl ~ - ~
(m ~ thoxy-2 amino-4 chloro-5 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 128-129C.
EXAMPLES 21 - 22;
The following derivatives have been prepared according to the proced ~ described in Example 20.
21) N-ethyl (2-methoxy-4-amino 5-chloro-benzamido methyl) -7 aza-8 bicyclo (4,3,0) nonane, PF 165C (isopropanol), a from 2-methoxy-acetylamino-4 chloro-5 benzo acid ~ and of N-ethyl aminomethyl-7 aza-8 bicyclo (4,3,0) nonane.
22) N-allyl (2-methoxy-4 amino-5 chloro-5 benzamido methyl) -2 aza-3 bicyclo (3,3,0) octane, PF 115C (acetonitrile), a ., starting from acid m ~ thoxy-2 acetylamino-4 chloro-5 benzo ~ that and;
of N-allyl aminomethyl-2 aza-3 bicyclo (3,3,0) octane.
This application is a division of the;
application NS 215.940 filed on December 13, 1974, L. Beregi;
et al.
; ~ 14 ~ - ~
:, '~:': ''
Claims (31)
VI
dans laquelle n représente 0, 1 ou 2 et R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée caractérisé en ce que l'on réduit un composé nitré de la formule générale V:
V
dans laquelle R est comme défini antérieurement, en présence de nickel de Raney ou d'hydrure double de lithium ou d'aluminium. 1. Process for the preparation of an aminomethyl-aza-bicycloalkane of general formula VI:
VI
in which n represents 0, 1 or 2 and R represents a radical aliphatic saturated or unsaturated hydrocarbon having from 1 to 5 atoms of carbon in straight or branched chain characterized in that one reduces a nitro compound of the general formula V:
V
in which R is as defined previously, in the presence of Raney nickel or double lithium or aluminum hydride.
IV
dans laquelle R et n sont comme définis dans la revendication 1, respectivement par le diméthyl sulfate, le méthylate de sodium et le nitrométhane. 2. Method according to claim 1, in which the nitro derivative V is obtained by treating a compound of formula general IV:
IV
wherein R and n are as defined in claim 1, respectively by dimethyl sulfate, methylate sodium and nitromethane.
par un halogénure de formule générale Hal - R en présence d'hydrure de sodium, n et R étant comme définis dans la reven-dication 1 et Hal est un halogène. 3. Method according to claim 2, wherein the compound of formula IV is obtained by treating a azabicycloalcanone of general formula II:
by a halide of general formula Hal - R in the presence sodium hydride, n and R being as defined in the resale dication 1 and Hal is a halogen.
dans laquelle n représente 0, 1 ou 2, R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, et M représente -CH2NH2, -CH NO2 ou =0, lorsque préparé par le procédé de la revendi-cation 1, 2 ou 3 ou par un procédé chimique équivalent. 16. An azabicycloalkane of general formula:
in which n represents 0, 1 or 2, R represents a radical aliphatic saturated or unsaturated hydrocarbon having from 1 to 5 atoms of carbon in straight or branched chain, and M represents -CH2NH2, -CH NO2 or = 0, when prepared by the process of the claim-cation 1, 2 or 3 or by an equivalent chemical process.
VI
dans laquelle n représente 0, 1 ou 2 et R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, lorsque préparé par le procédé de la revendication 1 ou par un procédé chimique équi-valent. 17. An aminomethyl-aza-bicycloalkane of formula general VI:
VI
in which n represents 0, 1 or 2 and R represents a radical aliphatic saturated or unsaturated hydrocarbon having from 1 to 5 atoms of carbon in straight or branched chain, when prepared by the the process of claim 1 or by an equivalent chemical process are worth.
V
dans laquelle n représente 0, 1 ou 2 et R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, lorsque préparé par le procédé de la revendication 2 ou par un procédé chimique équi-valent. 18. A nitro derivative of general formula V:
V
in which n represents 0, 1 or 2 and R represents a radical aliphatic saturated or unsaturated hydrocarbon having from 1 to 5 atoms of carbon in straight or branched chain, when prepared by the the process of claim 2 or by an equivalent chemical process are worth.
dans lequel n représente 0, 1 ou 2 et R représente un radical aliphatique hydrocarboné saturé ou non ayant de 1 à 5 atomes de carbone en chaîne droite ou ramifiée, lorsque préparé par le procédé de la revendication 3 ou par un procédé chimique équi-valent. 19. An azabicycloalcanone of general formula IV:
in which n represents 0, 1 or 2 and R represents a radical aliphatic saturated or unsaturated hydrocarbon having from 1 to 5 atoms of carbon in straight or branched chain, when prepared by the the process of claim 3 or by an equivalent chemical process are worth.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB5803473A GB1458217A (en) | 1973-12-14 | 1973-12-14 | Distributed azabicycloalkanes a process for their preparation and pharmaceutical compositions containing them |
| CA215,940A CA1042905A (en) | 1973-12-14 | 1974-12-13 | Preparation of new bisubstituted azabicycloalkans_ |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1044697A true CA1044697A (en) | 1978-12-19 |
Family
ID=25667776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA295,124A Expired CA1044697A (en) | 1973-12-14 | 1978-01-17 | Novel disubstituted azabicycloalcanes |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1044697A (en) |
-
1978
- 1978-01-17 CA CA295,124A patent/CA1044697A/en not_active Expired
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