EP0057227A1 - Imino-alkyl and amino-nitrile cyano-guanidines - Google Patents

Imino-alkyl and amino-nitrile cyano-guanidines

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Publication number
EP0057227A1
EP0057227A1 EP19810902295 EP81902295A EP0057227A1 EP 0057227 A1 EP0057227 A1 EP 0057227A1 EP 19810902295 EP19810902295 EP 19810902295 EP 81902295 A EP81902295 A EP 81902295A EP 0057227 A1 EP0057227 A1 EP 0057227A1
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Prior art keywords
imino
methyl
cyano
ethyl
acid
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EP19810902295
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German (de)
French (fr)
Inventor
Pierre Baudet
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Recherches Et De Syntheses Organiques SA Ste
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Recherches Et De Syntheses Organiques SA Ste
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the imino-alkyl and amino-nitrile cyano-guanidines claimed in application no. 1 404 / 79-7 and in the present application are not in equilibrium with the corresponding stable imino-nitrile and amino-alkyl cyano-guanidines.
  • our invention which makes it possible to obtain irreversibly, by a new reaction of organic chemistry and for the first time described in Swiss application No.
  • cyano-guanidines iminoalkyl and amino -nitrile basic by their guanidine function from cyano-guanidine imino-nitrile and amino-neutral alkyl function-Spar their guanidine function, we have prepared the following four new guanidines:
  • guanidines have a structure allowing a higher gastric anti-secretory activity (volume of secretion and gastric acidity) higher than the same activity of the cyano-guanidines imino-nitrile and amino-alkyl already known. In addition, their toxicity (anti-androgenic effect and prolactin effect) is significantly reduced.
  • R 1 -N ⁇ -NHCN NHCH 3 ,
  • Said compounds of the invention and their therapeutically suitable salts can be used for the treatment of gastric and duodenal ulcer.
  • excipients suitable for their pharmaceutical applications are, for example. lactose, sucrose, talc, gelatin, gum arabic, olive oil.
  • Example 3 N-methyl-N'-cyano-N '' - imino- [2 - ((5-dimethylamino-methyl-2-furanyl) -methylthio) -ethyl] -guanidine.dichlorhydrate. It is brought to reflux 21 ⁇ 2 h. a solution in ethanol containing 32.5 ml of HCl, 1 N, of 4.3 g of N-methyl-N'-iraino-cyano- N'- '2- ((5-dimethylamino-raethyl-2 -furanyl) -methylthto) -ethyl -guanidine. The solvent is evaporated off under reduced pressure; the residue, as oil, is dissolved in raethanol and the solvent is again evaporated; the residual oil is subjected to the vacuum 0.05 T, 3 hours,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cyano-guanidines de structure imino-alkyle et amino-nitrile, caracterisees par la formule generale: (FORMULE) dans laquelle R est un reste alkyle de 1 a 5 atomes de carbone, ou dans laquelle R1 est le reste 2-((2-guanidino-4-thiazolyl)-methylthio)-ethyle, ou dans laquelle R1 est le reste 2-((5-dimethylamino-methyl-2-furanyl)-methylthio)-ethyle, ou dans laquelle R1 est le reste 2-((3-methoxy-2-pyridinyl)-methylitho)-ethyle, ou dans laquelle R1 est le reste 2-((3-ethoxy-2-pyridinyl)-methylthio)-ethyle. Differentes methodes de syntheses des cyano-guanidines imino-alkyle et amino-nitrile presentees en 1.Cyano-guanidines of imino-alkyl and amino-nitrile structure, characterized by the general formula: (FORMULA) in which R is an alkyl residue of 1 to 5 carbon atoms, or in which R1 is the residue 2 - ((2- guanidino-4-thiazolyl) -methylthio) -ethyle, or in which R1 is the remainder 2 - ((5-dimethylamino-methyl-2-furanyl) -methylthio) -ethyle, or in which R1 is the remainder 2 - (( 3-methoxy-2-pyridinyl) -methylitho) -ethyle, or in which R1 is the remainder 2 - ((3-ethoxy-2-pyridinyl) -methylthio) -ethyle. Different methods for synthesizing imino-alkyl and amino-nitrile cyano-guanidines presented in 1.

Description

DESCRIPTION DESCRIPTION
Imino-alkyle et amino-nitrile cyano-guanidinesImino-alkyl and amino-nitrile cyano-guanidines
Dans une demande de brevet suisse, nº1 404/79-7, nous avons pour la première fois revendiqué et décrit des cyano-guanidines imino-alkyle et amino-nitrile. Dans le demande nº1 404/ 79-7,nous avons expliqué pour quelle raison les cyano-guanidines imino-alkyle et amino-nitrile de l'invention ne sont pas les tautomères des cyano-guanidines imino-nitrile et ami no-alkyle correspondantes. Ces dernières guanidines sont obtenues par la réaction d'aminé sur des réactif de formule généraleIn a Swiss patent application, nº1404 / 79-7, we have for the first time claimed and described imino-alkyl and amino-nitrile cyano-guanidines. In application n ° 1 404 / 79-7, we explained why the imino-alkyl and amino-nitrile cyano-guanidines of the invention are not the tautomers of the corresponding imino-nitrile cyano-guanidines and no-alkyl friend. These latter guanidines are obtained by the amine reaction on reagents of general formula
dans laquelle A = -SCH3 ou -OCH3 in which A = -SCH 3 or -OCH 3
Ainsi, les cyano-guanidines imino-alkyle et amino-nitrile revendiqués dans la demande nº1 404/79-7 et dans le présente demande ne sont pas en équilibre avec les cyano-guanidines imino-nitrile et amino-alkyle stables correspondantes. Dans le but de développer les possibilités de notre invention, qui permet d'obtenir irréversiblement,par une réaction nouvelle de la chimie organique et pour la première fois décrite dans la demande suisse n 1404/79-7, des cyano-guanidines iminoalkyle et amino-nitrile basiques par leur fonction guanidine, à partir de fonction cyano-guanidine imino-nitrile et amino- alkyle neutre-Spar leur fonction guanidine, nous avons préparé les quatre nouvelles guanidines suivantes:Thus, the imino-alkyl and amino-nitrile cyano-guanidines claimed in application no. 1 404 / 79-7 and in the present application are not in equilibrium with the corresponding stable imino-nitrile and amino-alkyl cyano-guanidines. In order to develop the possibilities of our invention, which makes it possible to obtain irreversibly, by a new reaction of organic chemistry and for the first time described in Swiss application No. 1404 / 79-7, cyano-guanidines iminoalkyl and amino -nitrile basic by their guanidine function, from cyano-guanidine imino-nitrile and amino-neutral alkyl function-Spar their guanidine function, we have prepared the following four new guanidines:
(1) N-méthyl-N-'cyano-N'-' imino- [2-(2-guanidino-4-thiazolyl)-méthylthio)-éthyl]-guanidine, comme base ou monochlorhydrate ou dichlorhydrate,(1) N-methyl-N-'cyano-N'- 'imino- [2- (2-guanidino-4-thiazolyl) -methylthio) -ethyl] -guanidine, as the base or monohydrochloride or dihydrochloride,
(2) N-méthyl-N'-cyano-N'-'imino- [2-( 5-diméthylamino-méthyl- 2-furanyl)-méthylthio)-éthyl]-guanidine, comme base, monochlorhydrato, dichlorhydrate,(2) N-methyl-N'-cyano-N '-' imino- [2- (5-dimethylamino-methyl-2-furanyl) -methylthio) -ethyl] -guanidine, as the base, monochlorhydrato, dihydrochloride,
(3) X-raéthyl-N'-cyano-N'-'imino [2-(( 3-méthoxy-2-pyridinyl)- méthylthio)-éthyl]-guanidine, comme base, monochlorhydrate, dichlorhydrate,(3) X-raethyl-N'-cyano-N '-' imino [2 - ((3-methoxy-2-pyridinyl) - methylthio) -ethyl] -guanidine, as base, monohydrochloride, dihydrochloride,
(4) N-méthyl-N'-cyano-N'-'imino- [2-((3-éthoxy-2-pyridinyl)-méthylthio)-éthyl]-guanidine, comme base, monochlorhydrate, dichlorhydrate.(4) N-methyl-N'-cyano-N '-' imino- [2 - ((3-ethoxy-2-pyridinyl) -methylthio) -ethyl] -guanidine, as the base, monohydrochloride, dihydrochloride.
Ces nouvelles guanidines possèdent une structure permettant une activité anti-sécrétoire gastrique(volume de la sécrétion et acidité gastrique) plus élevée que la même activité des cyano-guanidines imino-nitrile et amino-alkyle déjà connues. De plus, leur toxicité(effet anti-androgénique et effet prolactine) est notablement réduite.These new guanidines have a structure allowing a higher gastric anti-secretory activity (volume of secretion and gastric acidity) higher than the same activity of the cyano-guanidines imino-nitrile and amino-alkyl already known. In addition, their toxicity (anti-androgenic effect and prolactin effect) is significantly reduced.
Ces nouvelles guanidines se distinguent des guanidines déjà décrites, de structure imino-nitrile et amino-alkyleThese new guanidines are distinguished from the guanidines already described, of imino-nitrile and amino-alkyl structure
(1) par la basicité supplémentaire de leur fonction(1) by the additional basicity of their function
R1-N=Ç-NHCN NHCH3,R 1 -N = Ç-NHCN NHCH 3 ,
(2) par l'éclipsage de l'absorption IR de la fonction nitrile du à l'abbaissement du moment électrique de cette fonction,(2) by eclipsing the IR absorption of the nitrile function due to the lowering of the electric moment of this function,
(3) par l'existence d'un équilibre dans leurs solutions ou dans les huiles avec différents conformées qui apparaissent au moment de la neutralisation de leur chlorhydrate, chauffage de leur base dans des solvants de constante diélectrtrique élevée, comme l 'acétonitrile, le diméthylformaraide.Ces confor mères sont caractérisés par l'absorption lit de leur fonction nitrile 2250,2150 ou 2050 cm-1. Jamais,aucun de ces conformères ne se transforment dans les cyano-guanidines stables iminonitrile et amino alkyle. La neutralisation de leur base par HC1 les transforment dans le dichlorhydrate d'origine. Ainsi, ces quatre nouvelles guanidines imino-alkyle et aminonitrile se distinguent par toutes leurs propriétés chimiques et physiques des guanidines imino-nitrile et amino-alkyle connues.(3) by the existence of an equilibrium in their solutions or in oils with different conformities which appear at the time of neutralization of their hydrochloride, heating of their base in solvents of high dielectric constant, such as acetonitrile, dimethylformaraide. These conforms are characterized by the absorption of their nitrile function 2250,2150 or 2050 cm -1 . None of these conformers ever transform into the stable cyinoganidines iminonitrile and amino alkyl. The neutralization of their base by HC1 transforms them in the original dihydrochloride. Thus, these four new imino-alkyl and aminonitrile guanidines are distinguished by all their chemical and physical properties from the known imino-nitrile and amino-alkyl guanidines.
Les quatre composés de l'invention comme base, monochlorhydrate ou dichlorhydrate et autres sels thérapeutiquement convenables, antagonisent l'activité de l'histamine dans les récepteurs H2 et par lesquels l'histamine stimule la production de la sécrétion et de l'acide chlorhydrique gastrique par les cellules pariétales. Les dits composés de L'invention et leurs sels thérapeutiquement convenables peuvent être utilisés pour le traitement de l'ulcère gastrique et duodénal.The four compounds of the invention as base, monohydrochloride or dihydrochloride and other therapeutically suitable salts, antagonize the activity of histamine in H 2 receptors and by which histamine stimulates the production of secretion and hydrochloric acid gastric by parietal cells. Said compounds of the invention and their therapeutically suitable salts can be used for the treatment of gastric and duodenal ulcer.
Les excipients convenables pour leur mises en oeuvre pharmaceutiques sont par ex. le lactose, le saccharose, le talc, la gélatine, la gomme arabique, l 'hiile d'olive.The excipients suitable for their pharmaceutical applications are, for example. lactose, sucrose, talc, gelatin, gum arabic, olive oil.
Exemple 1Example 1
N-méthyl-N'-cyano-N''-imino-[2- ((2-guanidino-4-thiazoIyl)- méthylthio)-éthyl]-guanidine dichlorhydrate.N-methyl-N'-cyano-N '' - imino- [2- (((2-guanidino-4-thiazoIyl) - methylthio) -ethyl] -guanidine dihydrochloride.
On porte une solution de 3,12 g de N-méthyl-N'-imino-cyano- N'-' [2-((2-guanidino-4-thiazolyl)-méthylthio)-éthyl]-guanidi ne dans 50 ml HCl 1N,4 heures, à 40º .Une prise de la solution est évaporée sous press ion réduite et le résidu est examiné en IR: absence de l'absorption de la fonction-HCN, présence des absorptions de la fonction provenant de l'addition de HCl à la fonction -CN:1675,1630,1575 cm-1 et présence de l'absorption IR caractéristique de la fonction N-méthyl-N'-amino cyano-N''-imino-R1.chlorhydrate à 1720 cm-1.A solution of 3.12 g of N-methyl-N'-imino-cyano-N'- '[2 - ((2-guanidino-4-thiazolyl) -methylthio) -ethyl] -guanidi ne is carried in 50 ml 1N HCl, 4 hours, at 40º. A solution taken is evaporated under reduced pressure and the residue is examined in IR: absence of the absorption of the HCN function, presence of the absorptions of the function originating from the addition of HCl with the function -CN: 1675.1630.1575 cm-1 and presence of the IR absorption characteristic of the function N-methyl-N'-amino cyano-N '' - imino-R 1. hydrochloride at 1720 cm -1 .
On porte la solution à 65 durant trois heures et éliminé le solvant sous pression réduite;on obtient une huileThe solution is brought to 65 for three hours and the solvent is removed under reduced pressure; an oil is obtained
IR(film): 1715,1670,1605 cm-1.IR (film): 1715.1670.1605 cm -1 .
C10H16N8S2.2πcl(385) Calc.C 31,1 H 4,1 N 29,1 S 16,6 %C 10 H 16 N 8 S 2 .2πcl (385) Calc.C 31.1 H 4.1 N 29.1 S 16.6%
Tr. C 3i,0 H 4,2 N 28,8 S 16,3Tr. C 3i, 0 H 4.2 N 28.8 S 16.3
Titration de HCl ( dichl orhydrate ) Calc. 18 , 9 %Titration of HCl (dichl orhydrate) Calc. 18.9%
Tr. 18 , 6 %Tr. 18, 6%
Exempl e 2Example 2
N-m éthyl-N'-cyano-H '-' imino- [2- ( ( 2-guanidino-4-thiazolyl )- méthyl thio )-éthyl ]-guanidine dichl orhydrate.N-m ethyl-N'-cyano-H '-' imino- [2- (((2-guanidino-4-thiazolyl) - methyl thio) -ethyl] -guanidine dichl orhydrate.
A une solution de 2,33 g de N-méthyl-N-'N'-'imino-(2-mercaptoéthyl)-guanidine chlorhydraze dans de l'éthanol contenant au préalable 2,5 g d'éthoxyde de sodium,on ajoute, à 2-4°, sous agitation, dans une atmosphère d'azote, une solution dans de l'éthanol de 2,80 g e de 2-guanidino-4 chlorométhyl-thiazole chlorhydrate.Après 15 h. de réaction, à temp. ordinaire, on filtre la suspension. Le solvant du filtrat est évaporé, l 'huile résiduelle est extraite par du tétrahydrofuranne.La fraction insoluble est dissoute dans de l'éthanol et neutralisée par par HCl conc.On évapore le solvant sous pression réduite, soumet l'huile résiduelle à un vide de 0,05 T,à 45º, durant 4 heures.To a solution of 2.33 g of N-methyl-N-'N '-' imino- (2-mercaptoethyl) -guanidine chlorhydraze in ethanol containing beforehand 2.5 g of sodium ethoxide, the following is added , at 2-4 °, with stirring, in a nitrogen atmosphere, a solution in ethanol of 2.80 g of 2-guanidino-4 chloromethyl-thiazole hydrochloride. After 15 h. of reaction, at temp. ordinary, we filter the suspension. The solvent of the filtrate is evaporated, the residual oil is extracted with tetrahydrofuran. The insoluble fraction is dissolved in ethanol and neutralized by with conc. HCl. The solvent is evaporated off under reduced pressure and the residual oil is subjected to a vacuum of 0.05 T, at 45 º , for 4 hours.
Méemes caractéristiques analytiques(dichlorhydrate) que dans l'exemple 1.Same analytical characteristics (dihydrochloride) as in Example 1.
Exemple 3 N-méthyl-N'-cyano-N''-imino-[2-((5-diméthylamino-méthyl-2-furanyl)-méthylthio)-éthyl]-guanidine.dichlorhydrate. On porte à reflux 2½ h . une solution dans de l ' éthanol contenant 32,5 ml de HCl,1 N,de 4,3 g de N-méthyl-N'-iraino-cyano- N'-' 2-( (5-diméthylamino-raéthyl-2-furanyl)-méthylthto)-éthyl -guanidine.On évapore le solvant sous pression réduite;le résidu, comme huile, est dissout dans du raéthanol et le solvant à nouveau évaporé; l'huile résiduelle est soumise au vide 0,05 T, 3 heures,Example 3 N-methyl-N'-cyano-N '' - imino- [2 - ((5-dimethylamino-methyl-2-furanyl) -methylthio) -ethyl] -guanidine.dichlorhydrate. It is brought to reflux 2½ h. a solution in ethanol containing 32.5 ml of HCl, 1 N, of 4.3 g of N-methyl-N'-iraino-cyano- N'- '2- ((5-dimethylamino-raethyl-2 -furanyl) -methylthto) -ethyl -guanidine. The solvent is evaporated off under reduced pressure; the residue, as oil, is dissolved in raethanol and the solvent is again evaporated; the residual oil is subjected to the vacuum 0.05 T, 3 hours,
IR(film): absence de l'absorption de la fonction =N-CN,1720, 1675,1605 cm-1.IR (film): absence of absorption of the function = N-CN, 1720, 1675.1605 cm -1 .
C13H21N50S.2HCl(368) Cale. C 42,4 H 5,7 N 19,0 S 8,7%C 13 H 21 N 5 0S.2HCl (368) Wedge. C 42.4 H 5.7 N 19.0 S 8.7%
Tr. C 42,2 H 5,5 N 19,6 S 8,5% Teneur en HCl ( dichlorhydrate) Cale . 19 , 8 %Tr. C 42.2 H 5.5 N 19.6 S 8.5% HCl content (dihydrochloride) Wedge. 19.8%
Tr. 19,6 &Tr. 19.6 &
Exemple 4Example 4
N-méthyl-K -cyano-N''-imino-[2-((5-diméthylamino-méthyl-2- furanyl)-méthylthio)-éthyl]-guanidine. dichlorhydrate. A une solution de 2,92 g de N-méthyl-N '-cyano-N''.imino-N-methyl-K -cyano-N '' - imino- [2 - ((5-dimethylamino-methyl-2-furanyl) -methylthio) -ethyl] -guanidine. dihydrochloride. To a solution of 2.92 g of N-methyl-N '-cyano-N' '. Imino-
(2-mercapto-éthyl)-guanidine chlorhydrate, dans de l'éthanol contenant 3,0 g d'éthoxyde de Na,à 2-4º.dans une atmosphère d'azote, sous agitation, on ajoute goutte à goutte, en 60 min. une solution dans de l'éthanil de 3,15 g de 5-diraéthylaminométhyl-2-chlorométhyl-furanne. .Apres 17 heures de réaction, on filtre, évapore le solvant du fitrat et extrait l'huile résiduelle par du tétrahydrofuranne. La fraction insoluble est soumise à un vide de 0,05 T,à 45°, durant 3 h.(2-mercapto-ethyl) -guanidine hydrochloride, in ethanol containing 3.0 g of sodium ethoxide, at 2-4º. In a nitrogen atmosphere, with stirring, is added dropwise at 60 min. a solution in ethanil of 3.15 g of 5-diraethylaminomethyl-2-chloromethyl-furan. .After 17 hours of reaction, it is filtered, the solvent of the fitrat is evaporated and the residual oil is extracted with tetrahydrofuran. The insoluble fraction is subjected to a vacuum of 0.05 T, at 45 °, for 3 h.
Les caractéristiques analytiques sont les mêmes que cel les qui sont données à l'exemple 3.The analytical characteristics are the same as those given in Example 3.
Exemple 5Example 5
N-méthyl-N' -cyano-N ' '-imino[-2 ( ( 3-méthoxy-2-pyridinyl )- méthyl thio )-éthyl ]-guanidine dichlorhydrate.N-methyl-N '-cyano-N' '-imino [-2 ((3-methoxy-2-pyridinyl) - methyl thio) -ethyl] -guanidine dihydrochloride.
Une solution dans de l ' eau de 4,73 g de N-méthyl-N-'imino cyano-N'-' [2-((3-méthoxy-2-ρyridinyl)-méthylthio)-éthyl} guanidine chlorhydrate, contenant 2,2 g de HCl, est portée à 50º,durant 5 heures. On évapore le solvant sous press sion réduite, reprend le résidu par du oéthanol, évapore à nouveau, soumet l'huile résultante à un vide de 0,05 T, à 45º , durant 4 heures. C12H27N5OS.2 HC1(352) Calc. C 40,9 H 7,6 N 19, 8 S 9,1 %A solution in water of 4.73 g of N-methyl-N-'imino cyano-N'- '[2 - ((3-methoxy-2-ρyridinyl) -methylthio) -ethyl} guanidine hydrochloride, containing 2.2 g of HCl, is brought to 50º, for 5 hours. The solvent is evaporated off under reduced pressure, the residue is taken up in ethanol, evaporated again, the resulting oil is subjected to a vacuum of 0.05 T, at 45 °, for 4 hours. C 12 H 27 N 5 OS.2 HC1 (352) Calc. C 40.9 H 7.6 N 19.8 S 9.1%
Tr. C 40,4 H 7,3 N 19,5 S 8.9 % Teneur en HCl (dichlorhydrate) Calc. 20,7 %Tr. C 40.4 H 7.3 N 19.5 S 8.9% HCl content (dihydrochloride) Calc. 20.7%
Tr. 20,4 % IR(film): absence de l'absorption de la fonction -NC N, 1718,1675,1600 cm-1.Tr. 20.4% IR (film): absence of absorption of the function -NC N, 1718.1675.16 600 cm- 1 .
Exemple 6Example 6
N-méthyl-N'-cyano-N''-imino[-2((3-méthoxy-2-pyridinyl)- méthylthio)-éthyl ]-guanidine dichlorhydrate.N-methyl-N'-cyano-N '' - imino [-2 ((3-methoxy-2-pyridinyl) - methylthio) -ethyl] -guanidine dihydrochloride.
A une solution dans de l'éthanol contenant 3,5 g d'éthoxyde de sodium et refroidie à 0º ,on ajoute en plusieurs petites portions 3,29 g de N-methyl-N'-cyano-N'-'imino-To a solution in ethanol containing 3.5 g of sodium ethoxide and cooled to 0º, 3.29 g of N-methyl-N'-cyano-N '-' imino- are added in several small portions
(2-mυrcapto-éthyl)-guanidine chlorhydrate.A cette suspension et sous agitation et atmosphère d'azote, on ajout- te, goutte à goutte, une solution de 3,3 g de 3-méthoxy- 2-chlorométhyl-pyridine chlorhydrate, dans de l'éthanol. Apeés 16 h. de réaction, on fil tre, évapore le filtrat, obtient une huile qui est extraite trois fois par du tétra- hydrofuranne.On reprend la fraction insoluble par du méthanol et neutralise par de l'acide chlorhydrique con.On évapore à sec soumet l'huile à un vide 0,05 T à 50°, du rant 3 h.(2-mυrcapto-ethyl) -guanidine hydrochloride. To this suspension and with stirring and nitrogen atmosphere, a solution of 3.3 g of 3-methoxy-2-chloromethyl-pyridine hydrochloride is added dropwise , in ethanol. Apeés 4 p.m. of reaction, it is filtered, the filtrate is evaporated, an oil is obtained which is extracted three times with tetrahydrofuran. The insoluble fraction is taken up in methanol and neutralized with hydrochloric acid con.On evaporated to dry submits the oil at a vacuum 0.05 T at 50 °, rant 3 h.
Les caractéristiques analytiques sont les mêmes que celles qui sont présentées dans l'exemple 5 Exemple 7The analytical characteristics are the same as those presented in Example 5 Example 7
N-méthyl-N-cyano-N'-'imino-[2-((3-éthoxy-2-pyridinyl)- méthylthio)-éthyl]-guanidine dichlorhydrate.N-methyl-N-cyano-N '-' imino- [2 - ((3-ethoxy-2-pyridinyl) - methylthio) -ethyl] -guanidine dihydrochloride.
Une solution de 4,61 g de N-methyl-N-'imino-cyamo-N''— [2-( (3-éthoxy-2-pyridinyl)-méthylthio)-éthyl]-guanidine comme base dans de l'éthanol contenant 2,89 ol de HCl à 37° est portée à reflux 2 ½ h. On évapore le solvant sous pression réduite,reprend par du méthaol, évapore à nouveau le solvant et soumet l'huile résultante à un vide de 0,05 T,3 h à 40°.A solution of 4.61 g of N-methyl-N-'imino-cyamo-N '' - [2- ((3-ethoxy-2-pyridinyl) -methylthio) -ethyl] -guanidine as base in ethanol containing 2.89 ol of HCl at 37 ° is brought to reflux for 2 ½ h. The solvent is evaporated under reduced pressure, taken up in methaol, the solvent is evaporated again and the resulting oil is subjected to a vacuum of 0.05 T, 3 h at 40 °.
IR(film):absence de l'absorption de la fonction—NC N, 1720.1680,1610 cm-1.IR (film): absence of absorption of the function — NC N, 1720.1680,1610 cm- 1 .
C13H19N5OS 2 HCl(366) Cale. C 42,6 H 5,1 N19,1 S 8,7 %C 13 H 19 N 5 OS 2 HCl (366) Wedge. C 42.6 H 5.1 N19.1 S 8.7%
Tr. C 42,3 H 4,9 N18.8 S 8,5 % Teneur en HCl (dichlorhydrate) Cale. 19,9 % Tr. 19,6 % Tr. C 42.3 H 4.9 N18.8 S 8.5% HCl content (dihydrochloride) Wedge. 19.9% Tr. 19.6%

Claims

REVENDI CATIONS REVENDI CATIONS
1. Cyano-guanidines de la formul e général e :1. Cyano-guanidines of the general formula:
caractérisé par la s tructure imino-al kyl e et amino-ni tri le , dans laquelle R est un reste alkyle de 1 à 5 atomes de carbone, dans laquelle R1 est le reste 2-(( 2-guanidino-4-thiazo lyl)-méthylthio)-éthyle, ou characterized by the structure imino-al kyl e and amino-ni tri le, in which R is an alkyl residue of 1 to 5 carbon atoms, in which R 1 is the residue 2 - ((2-guanidino-4-thiazo lyl) -methylthio) -ethyl, or
R1est le reste 2-( (2-diméthylamino néthyl-5-furanyl)- méthylthio)-éthyle, ouR 1 is the residue 2- ((2-dimethylamino nethyl-5-furanyl) - methylthio) -ethyl, or
R1est le reste 2-(( 3-méthoxy-2-pyridinyl)-méthylthio)- éthyle, ouR 1 is the remainder 2 - ((3-methoxy-2-pyridinyl) -methylthio) - ethyl, or
R1est le reste 2-((3-éthoxy-2-pyridinyl)-méthylthio)- éthyle.R 1 is the remainder 2 - ((3-ethoxy-2-pyridinyl) -methylthio) - ethyl.
2. Procédé selon la revendication 1 pour la préparation du composé de la formule:2. Method according to claim 1 for the preparation of the compound of the formula:
N-méthyl-N-'cyano-N'--'imino[-2-((2-guanidino-4-thiazolyl)- méthylthio)-éthyl]-guanidine, comme base, monochlorhydrate ou dichlorhydrate, caractérisé par ce que l'on fait réagir la N-méthyl-N'- imino-cyano-N'-'[2-((2-guanidino-4-thiazolyl)-méthylthio)- éthylj-guanidine avec un halogéno-acide ou un phosphoacide inorganique ou organique ou un sulfo-acide inorganique ou organique, qui en quantité au minimum deux fois la quantité stoechiométrique transforment la fonction N-méthyl-N-'imino-cyano-N'-'R1 en fonction N-methyl-N'- cyano-N'-'imino-R1; R1 représente le reste 2-((2-guanidino—4-thiazolyl)-méthylthio)-éthyle.La nouvelle fonction guanidine ainsi obtenue, forme un sel avec l'acide chloisi pour la transformation.N-methyl-N-'cyano-N '-' imino [-2 - ((2-guanidino-4-thiazolyl) - methylthio) -ethyl] -guanidine, as the base, monohydrochloride or dihydrochloride, characterized in that l 'N-methyl-N'- imino-cyano-N' is reacted - '[2 - ((2-guanidino-4-thiazolyl) -methylthio) - ethylj-guanidine with a halo-acid or an inorganic phosphoacid or organic or an inorganic or organic sulfo-acid, which in quantity at least twice the stoichiometric quantity transform the function N-methyl-N-'imino-cyano-N '-' R 1 depending on N-methyl-N'- cyano-N '-' imino-R 1 ; R 1 represents the remainder 2 - ((2-guanidino-4-thiazolyl) -methylthio) -ethyl. The new guanidine function thus obtained forms a salt with chloisi acid for transformation.
Cette transformation est caractérisée par un intermédiaire de réaction dans lequel la fonction imino-nitrile a additionné une molécule de l'acide inorganique ou organique mentionné plus haut. Cet intermédiaire est caractérisé par une réaction acide et des absorptions IR caractéristiques de la fonction de la formule générale:This transformation is characterized by a reaction intermediate in which the imino-nitrile function has added a molecule of the inorganic or organic acid mentioned above. This intermediate is characterized by an acid reaction and IR absorptions characteristic of the function of the general formula:
dans laquelle X représente le reste anionique de l'acide inorganique ou organique choisi pour effectuer la transformation. in which X represents the anionic residue of the inorganic or organic acid chosen to carry out the transformation.
L'intermédiaire de la formule III se transforme dans un composé de la formule générale I, comme sel de l'acide engagé initialement dans la réaction.The intermediary of formula III is transformed into a compound of general formula I, as the salt of the acid initially engaged in the reaction.
3. Procédé selon la revendication 1 pour la préparation du composé de la formule II, caractérisé par ce que l'on fait réagir la N-méthyl-3. Method according to claim 1 for the preparation of the compound of formula II, characterized in that the N-methyl-
N-' cyano -N'-'imino-(2-mercapto-ethyl)-guanidine chlorhydrate avec le 2-guanidino-4-chlorométhyl-thiazole chlorhydrate dans un solvant convenable, par ex. un alcool inférieur,dans une atmosphère d'azote, par ex., en présence d'un agent alcalin.N- 'cyano -N' - 'imino- (2-mercapto-ethyl) -guanidine hydrochloride with 2-guanidino-4-chloromethyl-thiazole hydrochloride in a suitable solvent, e.g. a lower alcohol, in a nitrogen atmosphere, e.g., in the presence of an alkaline agent.
4. Procédé selon la revendication 1 pour la préparation du composé de la formule: comme base, mono-chlorhydrate, dichlorhydrate, N-raéthyl-N'-cyano-N'-'imino-[2-((5-diméthylaraino-méthyl-2 fu ranyl)-méthylthio)-éthyl]-guanidine, caractérisé par ce que l'on fait réagir la N-méthyi-N'-imi no-cyano-N''-[2-((5-diméthylamino-méthyl-2-furanyl)-méthyl- thio)-éthyl]guanidine avec un halogéno acide ou un phospho- acide inorganique ou organique ou un sulfo-acide inorganique ou organique, qui en quantité au minimum deux fois la quantité stoechiomètrique transforπieent la fonction N-méthyl-N'- imino-cyano-N'-'R1 en fonction N-méthyl-N'-cyano-N'-'imino-R1, R1 représente le reste 2-((5-diméthylaraino-méthyl-2-furanyl)- méthylthio)-éthyle-La nouvelle fonction, ainsi obtenue,forme un sel avec l'acide choisi pour la transformation. Cette transformation est caractérisée par un intermédiaire de réaction dans lequel la fonction imino-nitrile a additionné une molécule de l'acide inorganique ou organique mentionné plus haut. Cet intermédiaire est caractérisé par la formule générale III.4. Method according to claim 1 for the preparation of the compound of the formula: as base, mono-hydrochloride, dihydrochloride, N-raethyl-N'-cyano-N '-' imino- [2 - ((5-dimethylaraino-methyl-2 fu ranyl) -methylthio) -ethyl] -guanidine, characterized by what is reacted N-methyl-N'-imi no-cyano-N '' - [2 - ((5-dimethylamino-methyl-2-furanyl) -methyl-thio) -ethyl] guanidine halo acid or an inorganic or organic phospho acid or an inorganic or organic sulfo acid, which in an amount at least twice the stoichiometric amount transform the N-methyl-N'-imino-cyano-N '-' R 1 function into N-methyl-N'-cyano-N '-' imino-R 1 function , R 1 represents the remainder 2 - ((5-dimethylaraino-methyl-2-furanyl) - methylthio) -ethyl-The new function thus obtained , forms a salt with the acid chosen for the transformation. This transformation is characterized by a reaction intermediate in which the imino-nitrile function has added a molecule of the inorganic or organic acid mentioned above. This intermediary is characterized by the general formula III.
5. procédé selon la revendication 1 pour la préparation du composé de la formule IV, caractérisé par ce que l'on fait réagir la N-raéthyl-N'-cyano- imino -(2-mercaptc-ethyl)-guanidine chlorhydrate avec le 5-diméthylamino-méthyl-2-chlorométhyl-furanne, dans un solvant convenable, par ex. un alcool inférieur, dans une atmosphère d'azote par ex., en présence d'un alkoxyde alcalin.5. Method according to claim 1 for the preparation of the compound of formula IV, characterized in that the N-raethyl-N'-cyanoimino - (2-mercaptc-ethyl) -guanidine hydrochloride is reacted with the 5-dimethylamino-methyl-2-chloromethyl-furan, in a suitable solvent, e.g. a lower alcohol, in a nitrogen atmosphere, for example, in the presence of an alkaline alkoxide.
6. Procédé selon la revendication 1 pour la préparation du é de la formule V,6. Method according to claim 1 for the preparation of e of formula V,
comme base, monchlorhydrate, dichlorhydrate, as base, hydrochloride, dihydrochloride,
N-mcthyl-N'-cyano-N''-imino-[2-((3-méthoxy-2-pyridinyl)- méthylthio)-éthyl]-guanidine, caractérisé par ce que l'on fait réagir la N-méthyl-N'-imino-cyano-N''-[2-((3-méthoxy-2-pyridinyl)-methylthio)-éthyl]- guanidine avec un halogéno-aide ou un phospho-acide inorganique ou organique ou un sulfo-acide inorganique ou organique, qui en quantité au minimum deux fois la quantité stoechiométrique transforment la fonction N-méthyl-N'-imino- cyano-N''-R1 en fonction N-raethyl-N'cyano-N''-imino-R1,N-methyl-N'-cyano-N '' - imino- [2 - ((3-methoxy-2-pyridinyl) - methylthio) -ethyl] -guanidine, characterized by reacting N-methyl-N'-imino-cyano-N '' - [2 - ((3-methoxy-2-pyridinyl) -methylthio) - ethyl] - guanidine with a halo-aid or an inorganic or organic phospho-acid or an inorganic or organic sulfo-acid, which in an amount at least twice the stoichiometric amount transform the N-methyl-N'-imino-cyano- function N '' - R 1 according to N-raethyl-N'cyano-N '' - imino-R 1 ,
R1 représente le reste 2-((3-méthoxy-2-pyridinyl)-méthylthio- éthyle.La nouvelle fonction, ainsi obtenue, forme un sel avec l ' acide choisi pour la transformation.R 1 represents the remainder 2 - ((3-methoxy-2-pyridinyl) -methylthioethyl. The new function, thus obtained, forms a salt with the acid chosen for the transformation.
Cette transformation est caractérisée par un intermédiaire de réaction dans lequel la fonction imino-nitrile a additionné une molécule de l'acide inorganique ou organique mentionné plus haut.Cet intermédiaire est caractérisé par la formule générale III.This transformation is characterized by a reaction intermediate in which the imino-nitrile function has added a molecule of the inorganic or organic acid mentioned above. This intermediate is characterized by the general formula III.
7. Procédé selon la revendication 1 pour la préparation du composé de la formule V, caractérisé par ce que l'on fait réagir la N-méthyl-N'-cyano-7. Method according to claim 1 for the preparation of the compound of formula V, characterized in that the N-methyl-N'-cyano- is reacted
N'-'imino-(2-mercapto-éthyl)-guanidine chlorhydrate avec le chlorhydrate du 3-méthoxy-2-chloro-raéthyl-pyridine dans un solvant convenable, par ex. un alcool inférieur, dans une atmosphère d'azote,par ex., en présence d'un alkoxyde alcalin.N '-' imino- (2-mercapto-ethyl) -guanidine hydrochloride with 3-methoxy-2-chloro-raethyl-pyridine hydrochloride in a suitable solvent, e.g. a lower alcohol, in a nitrogen atmosphere, e.g., in the presence of an alkaline alkoxide.
8- Procédé selon la revendication 1 pour la préparation du composé de la formule VI, VI comme bas e monochiorhydrate , di chlorhydrate ,8- Process according to claim 1 for the preparation of the compound of formula VI, VI as low monohydrochloride, di hydrochloride,
N-méthyl-N ' -cyano-N ' -' imino- [ 2- ( ( 3-éthoxy-2-pyridinyl )-méthyl thio)-éthyl]-guanidine, caractérisé par ce que l'on fait réagir la N-méthyl-N'-iminocyano-N'-'[2-((3-éthoxy-2-pyridinyl)-méthylthio)-éthyl]-guani- dine avec un halogéno-acide ou un phospho-acide inorganique ou organique, ou un sulfo-acide inorganique ou organique, qui en quantité au minimum deux fois la quantité stoechiomé trique transforment la fonction N-raéthyl-N' . imino-cyano-N-methyl-N '-cyano-N' - 'imino- [2- ((3-ethoxy-2-pyridinyl) -methyl thio) -ethyl] -guanidine, characterized in that the N- is reacted methyl-N'-iminocyano-N '-' [2 - ((3-ethoxy-2-pyridinyl) -methylthio) -ethyl] -guanidine with a halo-acid or an inorganic or organic phospho-acid, or a inorganic or organic sulfo acid, which in quantity at least twice the stoichiometric quantity transform the N-raethyl-N 'function. imino-cyano-
N''-R1 en fonction N-méthyl-N'-cyano-N''-imino R1 guanidine, R1 représente le reste 2-((3-éthoxy-2-pyridinyl)-méthylthio éthyle.La nouvelle fonction, ainsi obtenue, forme un sel avec l'acide choisi pour la transformation.N '' - R 1 according to N-methyl-N'-cyano-N '' - imino R 1 guanidine, R 1 represents the remainder 2 - ((3-ethoxy-2-pyridinyl) -methylthio ethyl. The new function , thus obtained, forms a salt with the acid chosen for the transformation.
Cette transformation est caractérisée par un intermédiaire de réaction dans lequel la fonction imino-nitrile a additionné une molécule de l'acide inorganique ou organique mentionné plus haut.Cet intermédiaire est caractérisé par la structure de la formule générale III.This transformation is characterized by a reaction intermediate in which the imino-nitrile function has added a molecule of the inorganic or organic acid mentioned above. This intermediate is characterized by the structure of the general formula III.
9 Procédé selon la revendication 1 pour la préparation du composé de la formule VI, caractérisé par ce que l'on fait réagir la N-raéthyl-N'-cyano- N''-imino-(2-mercapto-ethyl)-guanidine chlorhydrate avec ls 3-éthoxy-2-chloro-méthyl-pyridine chlorhydrate, dans un solvant convenable comme par ex. un alcool inférieur, dans une atmosphère d'azote par ex., en présence d'un alkoxyde alcalin. 9 Process according to claim 1 for the preparation of the compound of formula VI, characterized in that the N-raethyl-N'-cyano- N '' - imino- (2-mercapto-ethyl) -guanidine is reacted hydrochloride with ls 3-ethoxy-2-chloro-methyl-pyridine hydrochloride, in a suitable solvent such as eg. a lower alcohol, in a nitrogen atmosphere, for example, in the presence of an alkaline alkoxide.
EP19810902295 1980-08-11 1981-08-10 Imino-alkyl and amino-nitrile cyano-guanidines Withdrawn EP0057227A1 (en)

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EP0010893B1 (en) * 1978-10-16 1984-02-08 Imperial Chemical Industries Plc Antisecretory branched-chain heterocyclic guanidine derivatives, processes for their manufacture, intermediates, and pharmaceutical compositions containing said derivatives
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