BE784531A - 1-(substd phenyl)biguanides - for treating gastric ulcers and spasms and hypertension and as minor tranquillizers - Google Patents

1-(substd phenyl)biguanides - for treating gastric ulcers and spasms and hypertension and as minor tranquillizers

Info

Publication number
BE784531A
BE784531A BE784531A BE784531A BE784531A BE 784531 A BE784531 A BE 784531A BE 784531 A BE784531 A BE 784531A BE 784531 A BE784531 A BE 784531A BE 784531 A BE784531 A BE 784531A
Authority
BE
Belgium
Prior art keywords
emi
hal
alk
phenyl
biguanides
Prior art date
Application number
BE784531A
Other languages
French (fr)
Inventor
J Diamond
G H Douglas
Original Assignee
Rorer Inc William H
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US00015967A external-priority patent/US3821406A/en
Priority claimed from US142794A external-priority patent/US3864496A/en
Priority claimed from US00142797A external-priority patent/US3830933A/en
Priority claimed from US00189388A external-priority patent/US3826843A/en
Priority claimed from US00189195A external-priority patent/US3800043A/en
Application filed by Rorer Inc William H filed Critical Rorer Inc William H
Publication of BE784531A publication Critical patent/BE784531A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
    • C07C317/38—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atom of at least one amino group being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfones
    • C07C317/42—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
    • C07C311/47—Y being a hetero atom

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cpds. of formula: (I) A is phenyl subs. by (R)n, Hal, Alk, (II) A is phenyl subst. by X, Y, Z and (III) A is phenyl subst. by Y', X' and medicaments contg. them and medicaments cotng. cpds. (IV) (where n is 1-3, Alk, Hal, and R are in any position, alk is 1-7C-alky or alkenyl, Hal is F, Cl, Br or I, R is H, F, Cl, Br or I, provided Alk is not 2-Me when Hal is Cl or 4-Br and R is H or when Hal and R are 3,5-di-Cl and also provided Alk is not 4-Me or 4-Bu when Hal is 3-Cl and R is H, X, Y and Z may be in any position, provided one of X and Y is not 2-Br when the other is 4-Cl or 4-Br and Z is H, and also when X and Y are other than 2,6-Cl Z is other than H and further provided than when X, Y and Z are Cl and X and Y are in the 3 and 4 positions, Z is always in the 2 position, X' is 2-CF3 when Y is halo, NO2 or CF3 or X' is 3-CF3 when Y' is halo, NO2 or CF3 provided Y' is other than 4-halo or 4-NO2 or X' is 4-CF3, when Y' is NO2 or CF3 and X' is H when Y' is CF3O, F2CH CO, F3CCO or F3SO2, and R2-R6 are H, alkyl, alkenyl, halo, NO2, NH2 (Alkyl)2N, haloalkyl, haloalkoxy, haloalkanoyl, OH, CN, NCS, COOH, COOALkyl, (Alkyl)2 NSO2, Alkyl SO2, HaloalkylSO2, PhO acyloxy, halophenoxy, Ph or halophenyl) are prepd, by reacting an aniline with a cyanoguanidine or by alkylating, halogenating, nitrating etc. an unsubstd 1-phenyl biguanido and if required prepg unit dosage forms for oral or parenteral administration.

Description

       

   <EMI ID=1.1>  <EMI ID=2.1> 

  
de relaxation du système nerveux central. 

  
Les compositions pharmaceutiques que 1'on utilise actuel- 

  
 <EMI ID=3.1> 

  
sécrétion gastrique sont l'atropine, 1lhomatropine, le'bromure de

  
 <EMI ID=4.1> 

  
qui ne ressemblent pas, d'un point de vue structural, aux biguani&#65533; des de la présente invention. Du fait des propriétés anticholiner&#65533;

  
gigues des composés utilisés antérieurement, on sait qu'ils produisent des effets secondaires indésirables, tels que la mydriase, la

  
 <EMI ID=5.1> 

  
aides de l'invention sont des agents pharmacologiques de valeur,

  
présentant des propriétés spasmolytiques et des propriétés d'arrêt 

  
de la sécrétion gastrique. 

  
On a aussi trouvé que les composés de l'invention ne

  
présentent pas d'effets secondaires anticholinergiques qui accompagnent "habituellement l'utilisation des agents spasmolytiques et des

  
agents arrêtant la sécrétion gastrique. On a en outre trouvé que

  
les composés de l'invention sont d'un faible ordre de toxicité.

  
Ces composés permettent un traitement efficace des affec1:ions gastro-intestinales, comme les ulcères du duodénum et les 

  
ulcères peptiques. 

  
 <EMI ID=6.1> 

  
 <EMI ID=7.1> 

  
hypertension et d'activité de relaxation du système nerveux cen- 

  
 <EMI ID=8.1> 

  
L'invention englobe également des compositions pharmaceu- 

  
 <EMI ID=9.1> 

  
l'invention à titre d'ingrédient actif, de telles compositions étant

  
intéressantes pour les indications thérapeutiques mentionnées. 

  
 <EMI ID=10.1> 

  
intéressants dans le traitement des affections gastro-intestinales  que l'on peut vaincre ou soulager par l'utilisation d'un agent spasmolytique ou d'un agent arrêtant la sécrétion gastrique. Ces

  
 <EMI ID=11.1> 

  
d'activité contre l'hypertension et de relaxation du systole nerveux central, et ils sont en outre intéressants comme tranquilli-  sants modérés.

  
 <EMI ID=12.1> 

  

 <EMI ID=13.1> 


  
 <EMI ID=14.1> 

  
 <EMI ID=15.1> 

  
Dans la description suivante, il faut tenir compte des  définitions générales données ci-après.

  
L'expression "alkyle inférieur" désigne un groupe hydrocarburé de 1 à environ 8 atomes de carbone, pouvant être à chaîne  droite ou ramifiée. Le radical "acyle" peut être constitué par tout  radical organique dérivant d'un acide organique par enlèvement de  son groupe hydroxyle, et il peut s'agir du radical acétyle, propio-   <EMI ID=16.1> 

  
 <EMI ID=17.1> 

  

 <EMI ID=18.1> 


  
 <EMI ID=19.1> 

  
invention concerne une classe de nouveaux composés chimiques* Clam

  
 <EMI ID=20.1> 

  
suivante -:

  

 <EMI ID=21.1> 
 

  
 <EMI ID=22.1> 

  
 <EMI ID=23.1> 

  
l'iode* et Z représente l'hydrogène, le fluor, le chlore, le brosse ou l'iode, à la condition que X ou Y soit autre qu'un substituant

  
 <EMI ID=24.1> 

  
dition aussi que, lorsque X et Y sont tous deux un substituant chlore et se trouvent en- des positions autres que les positions

  
 <EMI ID=25.1> 

  
 <EMI ID=26.1> 

  
 <EMI ID=27.1> 

  
 <EMI ID=28.1>  <EMI ID=29.1> 

  
 <EMI ID=30.1> 

  
 <EMI ID=31.1> 

  
invention concerne une fiasse de nouveaux composés chimiques qui *

  
 <EMI ID=32.1> 

  
 <EMI ID=33.1> 

  
Ces composés sont illustrés par la formule développée

  
 <EMI ID=34.1> 

  

 <EMI ID=35.1> 


  
 <EMI ID=36.1>   <EMI ID=37.1> 

  
 <EMI ID=38.1> 

  
des sels d'addition d'acide non toxiques de composés aminés, actifs  * au point de vue armacologique, ne diffèrent pas des activités de 

  
 <EMI ID=39.1> 

  
lisibilité approprié. 

  
 <EMI ID=40.1> 

  
invention. en leurs sels d'addition d'acide non toxiques par des 

  
 <EMI ID=41.1> 

  
 <EMI ID=42.1> 

  
doses envisagées, de tels sels englobant ceux préparés à partir 

  
 <EMI ID=43.1> 

  

 <EMI ID=44.1> 


  
On peut préparer les composés de la présente invention 

  
par les procédés généraux suivants.*  C'est ainsi qu'on peut envisager la condensation d'un 

  
 <EMI ID=45.1>  

  

 <EMI ID=46.1> 


  
 <EMI ID=47.1> 

  
l'acide chlorhydrique, l'acide bromhydrique, l'acide iodhydrique,

  
 <EMI ID=48.1> 

  
acides ,les phosphates acides alliés, et des composés fortement: ;  acides similaires.

  
Au lieu d'ajouter un tel composé acide au mélange de 

  
 <EMI ID=49.1> 

  
 <EMI ID=50.1> 

  
soit dans un milieu polaire, soit sans solvant, et en employant des températures accrues. Le sel utilisé peut être n'importe quel  sel aminé d'addition d'acide mais il s'agit dont de préférence du sel d'un acide minéral. Le milieu polaire peut être une solution 

  
 <EMI ID=51.1> 

  
sir un solvant qui refluera à la température de réaction désirée. Les solvants tout particulièrement préférés sont l'eau ou un alcool, mais on peut employer d'autres solvants, tels que le suif oxyde de

  
 <EMI ID=52.1>   <EMI ID=53.1>  oeuvre la réaction à un* température suffisamment élevée pour qu'une  condensation se produise facilement, mais non suffisante pour provo- 

  
 <EMI ID=54.1> 

  
procédé connu en pratique.. 

  
Une forme de réalisation spéciale de l'invention englobe un nouveau procédé de préparation des composés biguanides en cause. On a trouvé que," de façon inattendue, lorsque la réaction de l'ani-

  
 <EMI ID=55.1> 

  
 <EMI ID=56.1> 

  
que cette réaction se développe sur des anilines comportant un fort empêchement stérique, aussi bien que sur des anilines très

  
 <EMI ID=57.1> 

  
 <EMI ID=58.1> 

  
de précipiter le sel du produit à partir du mélange de réaction

  
 <EMI ID=59.1> 

  
alcalin le mélange de réaction et de procéder à une extraction  avec de l'éther.. 

  
Les anilines de départ sont bien connues ou peuvent être

  
 <EMI ID=60.1> 

  
 <EMI ID=61.1> 

  
acétanilide ou d'une aniline dans de l'acide acétique ou en pré-  sence d'une petite quantité d'iode dissoute dans un solvant inerte,

  
 <EMI ID=62.1> 

  
de chlore ou de brome tour en maintenant la température au voisinage  <EMI ID=63.1> 

  
que ou en présence d'unie petite quantité d'iode dissous dans un

  
 <EMI ID=64.1>   <EMI ID=65.1> 

  
On peut faire réagir un composé halo, dans lequel le radical hale représente du chlore, du-brome ou de l'iode, avec du

  
 <EMI ID=66.1> 

  
des produits substitues. 

  
 <EMI ID=67.1> 

  
 <EMI ID=68.1> 

  
efficaces pour réduire le volume et l'acidité du suc gastrique   <EMI ID=69.1> 

  
On peut utiliser les composés de l'Invention seuls ou 

  
en combinaison avec d'autres antiacides connus, tels que l'hydroxyde l'aluminium, l'hydroxyde de magnésium, le trisilicate de magnésium, le glucinate d'aluminium, le carbonate de calcium, etc. 

  
Les composés de la présente invention présentent des

  
 <EMI ID=70.1> 

  
les comme agents réduisant l'hypertension. 

  
Pour tous les besoins mentionnés, on peut normalement

  
 <EMI ID=71.1> 

  
Mettes, de suspensions aqueuses ou huileuses, de granulés ou de poudres pouvant se disperser, d'émulsions, de capsules dures ou 

  
 <EMI ID=72.1> 

  
l'utilise ici .englobe les injections sous-cutanées, intraveineuses, intramusculaires ou intrasternales, ou encore des techniques d' infusion .

  
On peut préparer les compositions destinées à une utili-

  
 <EMI ID=73.1> 

  
pour la fabrication de compositions pharmaceutiques, de telles  .compositions pouvant contenir un ou plusieurs agents choisis dans le groupe comprenant les agents adoucissants, les agents aromatisants, les agents colorants, et les agents de conservation, afin de présenter une préparation appropriée du point de vue pharmaceutique et agréable au gant. Dans le cas de tablettes, on peut utiliser des tablettes contenant l'ingrédient 1-aryle ou aralkyl bigua-  <EMI ID=74.1> 

  
 <EMI ID=75.1>   <EMI ID=76.1> 

  
vent aussi contenir un ou plusieurs agents de conservation, -par   <EMI ID=77.1>   <EMI ID=78.1> 

  
 <EMI ID=79.1> 

  
1.*aptitude des composés de 18 invention à présenter des réactions 

  
 <EMI ID=80.1>   <EMI ID=81.1> 

  
On réalise cet essaime la façon suivante. On met des rats à la  diète pendant 4 à 8 jours et on leur donne de l'eau à volonté. on 

  
 <EMI ID=82.1> 

  
traite les animaux dans le duodénum en utilisant le composé essayé

  
 <EMI ID=83.1> 

  
au sphincter du pylore. Les animaux sont ensuite sacrifiés au 

  
 <EMI ID=84.1> 

  
lorsqu*on- les soumets aux essais précédents de sécrétion gastrique, montrent une aptitude remarquable à diminuer le volume gastrique et l'acidité gastrique- On connaît ces essais comme étant en Tienne corrélation avec l'activité gastrique chez les êtres humains et il

  
 <EMI ID=85.1> 

  
période de 24 boires, on enlève les estomacs et on les examine pour déterminer l'ulcération. Les ulcères sont cotés sur une échel-

  
 <EMI ID=86.1>   <EMI ID=87.1>  <EMI ID=88.1> 

  
 <EMI ID=89.1> 

  
 <EMI ID=90.1> 

  
 <EMI ID=91.1> 

  
 <EMI ID=92.1> 

  
tensifs pour les êtres humains. Un essai de ce genre est défini par Ryo Tabei, Sydney Spector, William J. louis et Albert Sjoerdsma

  
 <EMI ID=93.1> 

  
2,269-74 (1970). Cette méthode d'essai est connue comme étant bien

  
 <EMI ID=94.1> 

  
et constitue un essai classique utilisé pour déterminer les propriétés de lutte contre l'hypertension. En raison des résultats

  
 <EMI ID=95.1> 

  
 <EMI ID=96.1> 

  
tension. 

  
Pour déterminer l'activité de relaxation du système nerveux central des composés de l'invention, on estime la suppression de l'activité motrice spontanée chez des souris normales (18-22 gr) et chez de jeunes rats (90-100 gr) par une variante de la méthode

  
 <EMI ID=97.1> 

  
essai montrent une augmentation relative de l'activité de relaxation. 

  
 <EMI ID=98.1> 

  
lés illustrant la préparation des composés de- la présente invention, ces exemples n'étant cependant que de pures illustrations de celle-

  
 <EMI ID=99.1> 

  
 <EMI ID=100.1> 

  
dant 15 minutes. On dissout lé produit de réaction résultant, ressem-

  
 <EMI ID=101.1>   <EMI ID=102.1> 

  
250 ml d'éther. On lave deux fois la couche éthérée avec 10 ml d* 

  
 <EMI ID=103.1> 

  
 <EMI ID=104.1> 

  
On immerge un mélange agité de 4,3 gr (0,03 mole) de 

  
 <EMI ID=105.1> 

  
dine dans un bain d'huile à 210[deg.]C pendant 15 minutes. On dissout le  ! produit de réaction résultant, ressemblant à du verre, de couleur ambre ,dans 100 ml d'eau, on alcalinise avec une solution à 40%

  
 <EMI ID=106.1> 

  
 <EMI ID=107.1> 

  
nate de sodium, on filtre et on rend la solution éthérée fortement  acide avec une solution éthérée acide d'acide chlorhydrique - On

  
 <EMI ID=108.1> 

  
 <EMI ID=109.1> 

  
 <EMI ID=110.1> 

  
puis 1,74 gr (0,0164 mole) de chlorate de sodium dans 4 ml d'eau.

  
 <EMI ID=111.1> 

  
 <EMI ID=112.1> 

  
 <EMI ID=113.1> 

  
et on extrait à l'éther. On traite la couche éthêrée avec de l'eau,

  
on sèche sur sulfate de magnésium et on évapore jusqu'à siccité.  On prépare ensuite le sel chlorhydrate avec de l'acide chlorhydri- 

  
 <EMI ID=114.1>   <EMI ID=115.1>  <EMI ID=116.1> 

  
 <EMI ID=117.1> 

  
 <EMI ID=118.1> 

  
 <EMI ID=119.1>   <EMI ID=120.1> 

  
 <EMI ID=121.1> 

  
rend bas igue avec de l'hydroxyde de sodium à 40% et on extrait avec

  
 <EMI ID=122.1> 

  
On chauffe au bain-marie bouillant pendant 1 heure, un

  
 <EMI ID=123.1> 

  
300 ml de m-crésol. On refroidit ensuite le mélange de réaction

  
 <EMI ID=124.1> 

  
 <EMI ID=125.1> 

  
 <EMI ID=126.1> 

  
 <EMI ID=127.1> 

  
te 250 ml d'éther. On sépare le précipité par filtration et on dissaut dans 100 ml d'eau chaude, puis on traite au charbon, on filtre 5 et on refroidit dans un bain de glace. On ajoute alors une solutionà 10% d'hydroxyde de sodium pour rendre le mélange fortement basi-

  
 <EMI ID=128.1>   <EMI ID=129.1> 

  
chlorate de sodium dans 15 ml eau. On maintient la température

  
 <EMI ID=130.1> 

  
alors une solution à 40% d'hydroxyde de sodium ;ainsi que de la

  
 <EMI ID=131.1> 

  
l'eau, on sèche sur sulfate d e magnésium et on évapore jusqu'à

  
 <EMI ID=132.1> 

  
 <EMI ID=133.1> 

  
 <EMI ID=134.1> 

  
mélange de réaction et on décharge le brome n'ayant jpas réagi avec  du bisulfite de sodium. On rend le mélange fortement alcalin et on

  
 <EMI ID=135.1> 

  
tion et on décharge le brome n'ayant pas réagi avec du bisulfite de sodium. On rend le mélange fortement alcalin et on extrait dans

  
de l'éther. On sèche la couche éthérée sur du Na&#65533;SO&#65533;, on traite au

  
 <EMI ID=136.1>   <EMI ID=137.1> 

  
A ce mélange, on ajoute goutte à goutte avec agitation une solo-

  
 <EMI ID=138.1> 

  
 <EMI ID=139.1> 

  
 <EMI ID=140.1> 

  
 <EMI ID=141.1>  .dans de l'éther et on lave la solution avec de la saumure, <EMI ID=142.1> 

  
cessaire. A la fin Se l'addition de lucide nitrique,, on agite le

  
 <EMI ID=143.1> 

  
2,41 % à température et pression normales, on cesse de secouer et   <EMI ID=144.1> 

  
 <EMI ID=145.1> 

  
 <EMI ID=146.1> 

  
les produits correspondants. 

  

 <EMI ID=147.1> 
 

  

 <EMI ID=148.1> 
 

  

 <EMI ID=149.1> 
 

  

 <EMI ID=150.1> 
 

  

 <EMI ID=151.1> 
 

  

 <EMI ID=152.1> 
 

  

 <EMI ID=153.1> 


  

 <EMI ID=154.1> 
 

  

 <EMI ID=155.1> 
 

  

 <EMI ID=156.1> 


  
 <EMI ID=157.1> 

  
On prépare 10.000 tablettes pour une utilisation orale, 

  
 <EMI ID=158.1> 

  
 <EMI ID=159.1> 

  

 <EMI ID=160.1> 


  
 <EMI ID=161.1> 

  
séchage, on ajoute les ingrédients suivants : - 

  

 <EMI ID=162.1> 


  
 <EMI ID=163.1> 

  
 <EMI ID=164.1> 

  
 <EMI ID=165.1> 

  
 <EMI ID=166.1> 

  
 <EMI ID=167.1> 

  

 <EMI ID=168.1> 


  
 <EMI ID=169.1> 

  
 <EMI ID=170.1> 

  
solution pour remplir des ampoules qui sont stérilisées à chaud de  la manière 'habituelle. 

  
 <EMI ID=171.1>   <EMI ID=172.1> 

  
total de 1 litre. On mélange la solution à fond, on la filtre et

  
 <EMI ID=173.1> 

  
On prépare des capsules en utilisant les quantités et  types suivants de matières:, 

  
 <EMI ID=174.1> 

  
.On mélange à fond les ingrédients et on place ce mélange  <EMI ID=175.1> 

  
 <EMI ID=176.1> 

  
 <EMI ID=177.1> 

  
 <EMI ID=178.1>   <EMI ID=179.1> 

  
mélange les granules desséchés _avec de. l'amidon et du stéarate de magnésium' et on comprisse en .noyaux de - dragée, pesant chacun 225 mgr. On enrobe alors ces- noyaux par -une première couche élastique d* une 

  
 <EMI ID=180.1> 

  
 <EMI ID=181.1> 

  
couche de gélatine et .le saupoudrage sont répétés environ 5 fois. Les noyaux ainsi traités sont enrobés de sucre dans le récipient

  
 <EMI ID=182.1> 

  
 <EMI ID=183.1> 

  
 <EMI ID=184.1>   <EMI ID=185.1> 

  
solution résultante isotonique. On fait, passer la solution finale 

  
 <EMI ID=186.1> 

  
 <EMI ID=187.1> 

  
 <EMI ID=188.1> 



   <EMI ID = 1.1> <EMI ID = 2.1>

  
relaxation of the central nervous system.

  
The pharmaceutical compositions currently in use

  
 <EMI ID = 3.1>

  
gastric secretions are atropine, homatropin, bromide

  
 <EMI ID = 4.1>

  
which do not resemble, from a structural point of view, the biguani &#65533; of the present invention. Due to the anti-choliner properties &#65533;

  
of compounds previously used, they are known to produce unwanted side effects, such as mydriasis,

  
 <EMI ID = 5.1>

  
aids of the invention are valuable pharmacological agents,

  
exhibiting spasmolytic and arresting properties

  
of gastric secretion.

  
It has also been found that the compounds of the invention do not

  
have no anticholinergic side effects which "usually accompany the use of spasmolytic agents and

  
agents that stop gastric secretion. It was further found that

  
the compounds of the invention are of a low order of toxicity.

  
These compounds provide effective treatment of gastrointestinal ailments, such as duodenal ulcers and ulcers.

  
peptic ulcers.

  
 <EMI ID = 6.1>

  
 <EMI ID = 7.1>

  
hypertension and relaxation activity of the central nervous system

  
 <EMI ID = 8.1>

  
The invention also encompasses pharmaceutical compositions.

  
 <EMI ID = 9.1>

  
the invention as an active ingredient, such compositions being

  
interesting for the therapeutic indications mentioned.

  
 <EMI ID = 10.1>

  
useful in the treatment of gastrointestinal disorders which can be overcome or alleviated by the use of a spasmolytic agent or an agent which stops gastric secretion. These

  
 <EMI ID = 11.1>

  
of activity against hypertension and relaxation of the central nervous systole, and they are further useful as moderate tranquilizers.

  
 <EMI ID = 12.1>

  

 <EMI ID = 13.1>


  
 <EMI ID = 14.1>

  
 <EMI ID = 15.1>

  
In the following description, account must be taken of the general definitions given below.

  
The term "lower alkyl" denotes a hydrocarbon group of 1 to about 8 carbon atoms, which may be straight chain or branched. The "acyl" radical can be constituted by any organic radical deriving from an organic acid by removing its hydroxyl group, and it can be the acetyl radical, propio- <EMI ID = 16.1>

  
 <EMI ID = 17.1>

  

 <EMI ID = 18.1>


  
 <EMI ID = 19.1>

  
invention relates to a class of new chemical compounds * Clam

  
 <EMI ID = 20.1>

  
next -:

  

 <EMI ID = 21.1>
 

  
 <EMI ID = 22.1>

  
 <EMI ID = 23.1>

  
iodine * and Z represents hydrogen, fluorine, chlorine, brush or iodine, provided that X or Y is other than a substituent

  
 <EMI ID = 24.1>

  
further states that when X and Y are both a chlorine substituent and are in positions other than the positions

  
 <EMI ID = 25.1>

  
 <EMI ID = 26.1>

  
 <EMI ID = 27.1>

  
 <EMI ID = 28.1> <EMI ID = 29.1>

  
 <EMI ID = 30.1>

  
 <EMI ID = 31.1>

  
invention relates to a package of new chemical compounds which *

  
 <EMI ID = 32.1>

  
 <EMI ID = 33.1>

  
These compounds are illustrated by the structural formula

  
 <EMI ID = 34.1>

  

 <EMI ID = 35.1>


  
 <EMI ID = 36.1> <EMI ID = 37.1>

  
 <EMI ID = 38.1>

  
non-toxic acid addition salts of amino compounds, armacologically active *, do not differ from the activities of

  
 <EMI ID = 39.1>

  
proper readability.

  
 <EMI ID = 40.1>

  
invention. in their non-toxic acid addition salts by

  
 <EMI ID = 41.1>

  
 <EMI ID = 42.1>

  
contemplated doses, such salts including those prepared from

  
 <EMI ID = 43.1>

  

 <EMI ID = 44.1>


  
The compounds of the present invention can be prepared

  
by the following general procedures. * This is how the condensation of a

  
 <EMI ID = 45.1>

  

 <EMI ID = 46.1>


  
 <EMI ID = 47.1>

  
hydrochloric acid, hydrobromic acid, hydriodic acid,

  
 <EMI ID = 48.1>

  
acids, acid alloyed phosphates, and strongly:; similar acids.

  
Instead of adding such an acidic compound to the mixture of

  
 <EMI ID = 49.1>

  
 <EMI ID = 50.1>

  
either in a polar medium or without solvent, and using increased temperatures. The salt used can be any amino acid addition salt, but it is preferably the salt of a mineral acid. The polar medium can be a solution

  
 <EMI ID = 51.1>

  
sir a solvent which will reflux at the desired reaction temperature. The most preferred solvents are water or an alcohol, but other solvents, such as tallow oxide, can be employed.

  
 <EMI ID = 52.1> <EMI ID = 53.1> carries out the reaction at a * temperature high enough for condensation to occur easily, but not high enough to cause

  
 <EMI ID = 54.1>

  
method known in the art.

  
A special embodiment of the invention encompasses a novel process for the preparation of the subject biguanide compounds. It was found that, "unexpectedly, when the reaction of the animal

  
 <EMI ID = 55.1>

  
 <EMI ID = 56.1>

  
that this reaction develops on anilines having a strong steric hindrance, as well as on anilines very

  
 <EMI ID = 57.1>

  
 <EMI ID = 58.1>

  
to precipitate the salt of the product from the reaction mixture

  
 <EMI ID = 59.1>

  
alkali the reaction mixture and extract with ether.

  
The starting anilines are well known or can be

  
 <EMI ID = 60.1>

  
 <EMI ID = 61.1>

  
acetanilide or an aniline in acetic acid or in the presence of a small amount of iodine dissolved in an inert solvent,

  
 <EMI ID = 62.1>

  
chlorine or bromine tower while maintaining the temperature in the vicinity <EMI ID = 63.1>

  
that or in the presence of a small amount of iodine dissolved in a

  
 <EMI ID = 64.1> <EMI ID = 65.1>

  
A halo compound, in which the hale radical represents chlorine, bromine or iodine, can be reacted with

  
 <EMI ID = 66.1>

  
substitute products.

  
 <EMI ID = 67.1>

  
 <EMI ID = 68.1>

  
effective in reducing the volume and acidity of gastric juice <EMI ID = 69.1>

  
The compounds of the invention can be used alone or

  
in combination with other known antacids, such as aluminum hydroxide, magnesium hydroxide, magnesium trisilicate, aluminum glucinate, calcium carbonate, etc.

  
The compounds of the present invention exhibit

  
 <EMI ID = 70.1>

  
them as hypertension reducing agents.

  
For all the needs mentioned, we can normally

  
 <EMI ID = 71.1>

  
Mets, aqueous or oily suspensions, granules or powders which can disperse, emulsions, hard capsules or

  
 <EMI ID = 72.1>

  
it is used here. includes subcutaneous, intravenous, intramuscular or intrasternal injections, or even infusion techniques.

  
Compositions for use can be prepared.

  
 <EMI ID = 73.1>

  
for the manufacture of pharmaceutical compositions, such compositions may contain one or more agents selected from the group consisting of softening agents, flavoring agents, coloring agents, and preservatives, in order to present a suitable preparation from the point of view pharmaceutical and glove-friendly. In the case of tablets, tablets containing the ingredient 1-aryl or aralkyl bigua- <EMI ID = 74.1> can be used.

  
 <EMI ID = 75.1> <EMI ID = 76.1>

  
may also contain one or more preservatives, -par <EMI ID = 77.1> <EMI ID = 78.1>

  
 <EMI ID = 79.1>

  
1. * ability of compounds of the invention to exhibit reactions

  
 <EMI ID = 80.1> <EMI ID = 81.1>

  
We realize this swarm in the following way. Rats are put on a diet for 4 to 8 days and given water at will. we

  
 <EMI ID = 82.1>

  
treats animals in the duodenum using the test compound

  
 <EMI ID = 83.1>

  
to the pyloric sphincter. The animals are then sacrificed to the

  
 <EMI ID = 84.1>

  
when subjected to previous gastric secretion tests, show remarkable ability to decrease gastric volume and gastric acidity. These tests are known to correlate with gastric activity in humans and are known to be correlated with gastric activity in humans.

  
 <EMI ID = 85.1>

  
24 feedings, the stomachs are removed and examined for ulceration. Ulcers are rated on a scale

  
 <EMI ID = 86.1> <EMI ID = 87.1> <EMI ID = 88.1>

  
 <EMI ID = 89.1>

  
 <EMI ID = 90.1>

  
 <EMI ID = 91.1>

  
 <EMI ID = 92.1>

  
tensives for human beings. An essay of this kind is defined by Ryo Tabei, Sydney Spector, William J. louis and Albert Sjoerdsma

  
 <EMI ID = 93.1>

  
2,269-74 (1970). This test method is known to be well

  
 <EMI ID = 94.1>

  
and is a standard test used to determine hypertension control properties. Due to the results

  
 <EMI ID = 95.1>

  
 <EMI ID = 96.1>

  
voltage.

  
To determine the central nervous system relaxation activity of the compounds of the invention, the suppression of spontaneous motor activity in normal mice (18-22 g) and in young rats (90-100 g) is estimated by a variant of the method

  
 <EMI ID = 97.1>

  
test show a relative increase in relaxation activity.

  
 <EMI ID = 98.1>

  
these illustrating the preparation of the compounds of the present invention, these examples being however only pure illustrations thereof.

  
 <EMI ID = 99.1>

  
 <EMI ID = 100.1>

  
for 15 minutes. The resulting reaction product is dissolved, resem-

  
 <EMI ID = 101.1> <EMI ID = 102.1>

  
250 ml of ether. The ethereal layer is washed twice with 10 ml of *

  
 <EMI ID = 103.1>

  
 <EMI ID = 104.1>

  
Immerse a stirred mixture of 4.3 gr (0.03 mol) of

  
 <EMI ID = 105.1>

  
dine in an oil bath at 210 [deg.] C for 15 minutes. We dissolve it! resulting reaction product, glass-like, amber in color, in 100 ml of water, basified with 40% solution

  
 <EMI ID = 106.1>

  
 <EMI ID = 107.1>

  
sodium nate, filtered and made the ethereal solution strongly acidic with an acidic ethereal solution of hydrochloric acid - On

  
 <EMI ID = 108.1>

  
 <EMI ID = 109.1>

  
 <EMI ID = 110.1>

  
then 1.74 gr (0.0164 mol) of sodium chlorate in 4 ml of water.

  
 <EMI ID = 111.1>

  
 <EMI ID = 112.1>

  
 <EMI ID = 113.1>

  
and extracted with ether. We treat the ethereal layer with water,

  
it is dried over magnesium sulfate and evaporated to dryness. The hydrochloride salt is then prepared with hydrochloric acid.

  
 <EMI ID = 114.1> <EMI ID = 115.1> <EMI ID = 116.1>

  
 <EMI ID = 117.1>

  
 <EMI ID = 118.1>

  
 <EMI ID = 119.1> <EMI ID = 120.1>

  
 <EMI ID = 121.1>

  
made low with 40% sodium hydroxide and extracted with

  
 <EMI ID = 122.1>

  
Heat in a boiling water bath for 1 hour, a

  
 <EMI ID = 123.1>

  
300 ml of m-cresol. The reaction mixture is then cooled.

  
 <EMI ID = 124.1>

  
 <EMI ID = 125.1>

  
 <EMI ID = 126.1>

  
 <EMI ID = 127.1>

  
te 250 ml of ether. The precipitate is filtered off and dissolved in 100 ml of hot water, then treated with charcoal, filtered and cooled in an ice bath. A 10% sodium hydroxide solution is then added to make the mixture strongly basic.

  
 <EMI ID = 128.1> <EMI ID = 129.1>

  
sodium chlorate in 15 ml water. We maintain the temperature

  
 <EMI ID = 130.1>

  
then a 40% solution of sodium hydroxide; as well as

  
 <EMI ID = 131.1>

  
water, dried over magnesium sulfate and evaporated to

  
 <EMI ID = 132.1>

  
 <EMI ID = 133.1>

  
 <EMI ID = 134.1>

  
reaction mixture and the unreacted bromine is discharged with sodium bisulfite. The mixture is made strongly alkaline and

  
 <EMI ID = 135.1>

  
tion and discharging unreacted bromine with sodium bisulfite. The mixture is made strongly alkaline and extracted into

  
ether. The ethereal layer is dried over Na SO, treated with

  
 <EMI ID = 136.1> <EMI ID = 137.1>

  
To this mixture is added dropwise with stirring a solo-

  
 <EMI ID = 138.1>

  
 <EMI ID = 139.1>

  
 <EMI ID = 140.1>

  
 <EMI ID = 141.1>. In ether and the solution washed with brine, <EMI ID = 142.1>

  
cessionary. At the end of the addition of nitric lucid, the

  
 <EMI ID = 143.1>

  
2.41% at normal temperature and pressure, shaking stops and <EMI ID = 144.1>

  
 <EMI ID = 145.1>

  
 <EMI ID = 146.1>

  
the corresponding products.

  

 <EMI ID = 147.1>
 

  

 <EMI ID = 148.1>
 

  

 <EMI ID = 149.1>
 

  

 <EMI ID = 150.1>
 

  

 <EMI ID = 151.1>
 

  

 <EMI ID = 152.1>
 

  

 <EMI ID = 153.1>


  

 <EMI ID = 154.1>
 

  

 <EMI ID = 155.1>
 

  

 <EMI ID = 156.1>


  
 <EMI ID = 157.1>

  
10,000 tablets are prepared for oral use,

  
 <EMI ID = 158.1>

  
 <EMI ID = 159.1>

  

 <EMI ID = 160.1>


  
 <EMI ID = 161.1>

  
drying, the following ingredients are added: -

  

 <EMI ID = 162.1>


  
 <EMI ID = 163.1>

  
 <EMI ID = 164.1>

  
 <EMI ID = 165.1>

  
 <EMI ID = 166.1>

  
 <EMI ID = 167.1>

  

 <EMI ID = 168.1>


  
 <EMI ID = 169.1>

  
 <EMI ID = 170.1>

  
solution for filling ampoules which are heat sterilized in the usual manner.

  
 <EMI ID = 171.1> <EMI ID = 172.1>

  
total of 1 liter. Mix the solution thoroughly, filter it and

  
 <EMI ID = 173.1>

  
Capsules are prepared using the following amounts and types of materials :,

  
 <EMI ID = 174.1>

  
.We mix the ingredients thoroughly and place this mixture <EMI ID = 175.1>

  
 <EMI ID = 176.1>

  
 <EMI ID = 177.1>

  
 <EMI ID = 178.1> <EMI ID = 179.1>

  
mix the dried granules with. starch and magnesium stearate 'and are included in dragee cores, each weighing 225 mgr. These cores are then coated with a first elastic layer of a

  
 <EMI ID = 180.1>

  
 <EMI ID = 181.1>

  
gelatin layer and dusting are repeated about 5 times. The cores thus treated are coated with sugar in the container

  
 <EMI ID = 182.1>

  
 <EMI ID = 183.1>

  
 <EMI ID = 184.1> <EMI ID = 185.1>

  
resulting isotonic solution. We do, pass the final solution

  
 <EMI ID = 186.1>

  
 <EMI ID = 187.1>

  
 <EMI ID = 188.1>

Claims (1)

<EMI ID=189.1> <EMI ID = 189.1> d'acide non toxiques, ces biguanides étant caractérisés par le fait qu'ils répondent à l'une dès formules suivantes non-toxic acid, these biguanides being characterized by the fact that they correspond to one of the following formulas <EMI ID=190.1> <EMI ID = 190.1> <EMI ID=191.1> <EMI ID = 191.1> <EMI ID=192.1> <EMI ID = 192.1> différent d'un substituant 2-méthyle lorsque Hal est un substituant different from a 2-methyl substituent when Hal is a substituent chloro ou 4-bromo en même temps que R représente de l'hydrogène ou chloro or 4-bromo together with R represents hydrogen or <EMI ID=193.1> <EMI ID = 193.1> l'hydrogène; X, Y et 2 peuvent se situer à n'importe quelle posi- hydrogen; X, Y and 2 can be in any position. <EMI ID=194.1> <EMI ID = 194.1> <EMI ID=195.1> <EMI ID = 195.1> dition aussi que, lorsque X et Y sont tous deux du chlore et dans also that when X and Y are both chlorine and in des positions autres que les positions 2 et 6, Z soit alors diffé- positions other than positions 2 and 6, Z is then different <EMI ID=196.1> <EMI ID=197.1> <EMI ID = 196.1> <EMI ID = 197.1> fluorosulfonyle. fluorosulfonyl. 2. Composé suivant la revendication 1^ caractérisé en 2. A compound according to claim 1 ^ characterized in <EMI ID=198.1> <EMI ID = 198.1> d'addition d'acide non toxiques, ce composé étant caractérisé en non-toxic acid addition, this compound being characterized by <EMI ID=199.1> <EMI ID = 199.1> <EMI ID=200.1> <EMI ID = 200.1> chloro ou bromo. chloro or bromo. 5. Composé suivant la revendication 1, caractérisé en ce 5. A compound according to claim 1, characterized in that <EMI ID=201.1> <EMI ID = 201.1> <EMI ID=202.1> <EMI ID = 202.1> <EMI ID=203.1> <EMI ID = 203.1> méthyle. methyl. <EMI ID=204.1> <EMI ID=205.1> <EMI ID = 204.1> <EMI ID = 205.1> 9. Compositions pharmaceutiques pour le traitement de <EMI ID=206.1> 9. Pharmaceutical compositions for the treatment of <EMI ID = 206.1> que approprié^ une quantité efficace du point de vue thérapeutique as appropriate ^ a therapeutically effective amount <EMI ID=207.1> <EMI ID = 207.1> <EMI ID=208.1> <EMI ID = 208.1> <EMI ID=209.1> <EMI ID = 209.1> <EMI ID=210.1> <EMI ID = 210.1> <EMI ID=211.1> <EMI ID = 211.1> <EMI ID=212.1> <EMI ID=213.1> <EMI ID = 212.1> <EMI ID = 213.1> <EMI ID=214.1> <EMI ID = 214.1> <EMI ID=215.1> <EMI ID = 215.1> <EMI ID=216.1> <EMI ID = 216.1> et Z représente de l'hydrogène ou un substituant fluoro, chloro, and Z represents hydrogen or a substituent fluoro, chloro, <EMI ID=217.1> <EMI ID = 217.1> tuant 4-chloro ou 4-bromo, tandis que Z est de l'hydrogène, à la killing 4-chloro or 4-bromo, while Z is hydrogen, at the <EMI ID=218.1> <EMI ID = 218.1> trouvent dans des positions autres que les positions 2 et 6, Z soit are in positions other than positions 2 and 6, Z is <EMI ID=219.1> <EMI ID = 219.1> <EMI ID=220.1> <EMI ID = 220.1> <EMI ID=221.1> <EMI ID = 221.1> <EMI ID=222.1> <EMI ID = 222.1> acétyle ou trifluorosulfonyle, ce procédé étant caractérisé en ce acetyl or trifluorosulfonyl, this process being characterized in that <EMI ID=223.1> <EMI ID = 223.1> <EMI ID=224.1> <EMI ID = 224.1> <EMI ID=225.1> <EMI ID=226.1> <EMI ID = 225.1> <EMI ID = 226.1> <EMI ID=227.1> <EMI ID = 227.1> <EMI ID=228.1> <EMI ID = 228.1> <EMI ID=229.1> <EMI ID = 229.1> exemple -du phénol du crésol on au xylénol. example - phenol from cresol to xylenol. <EMI ID=230.1> <EMI ID = 230.1> ce que la condensation de l'aniline substituée ou d'un sel d'addi&#65533; what the condensation of substituted aniline or a salt of add &#65533; <EMI ID=231.1> <EMI ID = 231.1> <EMI ID=232.1> <EMI ID = 232.1> <EMI ID=233.1> <EMI ID = 233.1> <EMI ID=234.1> <EMI ID = 234.1> <EMI ID=235.1> <EMI ID = 235.1> <EMI ID=236.1> <EMI ID = 236.1> <EMI ID=237.1> <EMI ID=238.1> <EMI ID = 237.1> <EMI ID = 238.1> dation aussi que, lorsque X et Y sont tous deux du chlore et Sans dation also that, when X and Y are both chlorine and Sans <EMI ID=239.1> <EMI ID = 239.1> <EMI ID=240.1> <EMI ID = 240.1> <EMI ID=241.1> <EMI ID = 241.1> <EMI ID=242.1> <EMI ID = 242.1> l'introduction d'un substituant consistant en un halogène ou en the introduction of a substituent consisting of halogen or <EMI ID=243.1> <EMI ID = 243.1> formules données ci-dessus mais ne comportant pas cet -halogène eu formulas given above but not comprising this -halogen eu <EMI ID=244.1> <EMI ID = 244.1> <EMI ID=245.1> <EMI ID = 245.1> <EMI ID=246.1> <EMI ID = 246.1> <EMI ID=247.1> <EMI ID = 247.1> <EMI ID=248.1> <EMI ID=249.1> <EMI ID = 248.1> <EMI ID = 249.1> <EMI ID=250.1> <EMI ID = 250.1> <EMI ID=251.1> <EMI ID = 251.1> 14. Les 1-phényl substitué biguanides, leurs prépara.- . 1:ions et leurs utilisations, comme décrit ci-dessus, notamment: 14. The 1-substituted phenyl biguanides, their preparations. 1: Ions and their uses, as described above, including: dans les exemples donnés. in the examples given.
BE784531A 1970-03-02 1972-06-07 1-(substd phenyl)biguanides - for treating gastric ulcers and spasms and hypertension and as minor tranquillizers BE784531A (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US00015967A US3821406A (en) 1970-03-02 1970-03-02 Therapeutic compositions containing 1-substituted biguanides and method of treating gastrointestinal disorders therewith
US8900570A 1970-11-12 1970-11-12
US13257871A 1971-04-08 1971-04-08
US142794A US3864496A (en) 1970-11-12 1971-05-12 1-Substituted biguanides for treating gastrointestinal hyperacidity or ulceration
US00142797A US3830933A (en) 1970-11-12 1971-05-12 1-substittuted biguanides as antihypertensive agents
US00189388A US3826843A (en) 1970-11-12 1971-10-14 1-substituted biguanides as gastrointestinal spasmolytic agents
US00189195A US3800043A (en) 1971-10-14 1971-10-14 1-substituted biguanides as gastrointestinal spasmolytic agents

Publications (1)

Publication Number Publication Date
BE784531A true BE784531A (en) 1972-12-07

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