IL22743A - N1-benzene-sulphonyl-n2-azabicyclooctyl and nonyl urea compounds and a process for their production - Google Patents

Description

The present invention relates to new heterocyclic compounds and a process for their The present invention provides heterocyclic sulphonyl urea derivatives of the formula a halogen or hydrogen and signifies 2 or and their alkali alkaline earth metal or ammonium The Invention also provides a for the production of compounds of formula wherein a heterocyclic amine of the formula is reacted with a compound the ormula in which and have the same significance as signifies a hydrogen atom and Z signifies an radical of 1 to 4 carbo or an amino or and together signify a second bond between the oarbon atom and the nitrogen is the resulting compound of formula I reacted with a alkali alkaline earth metal or ammonium formation of salts takes place the nitrogen atom between the and groups where One method of performing the process of the invention for in that or drate and a compound of formula or acid methyl or ethyl are reacted in an inert anhydrous organic absolute absolute toluene or absolute and the solvent and the alkanol and water resulting during the reaction are distilled from the solution for 2 to 3 fresh solvent being continuously at such a rate that the initial volume is The final product is isolated in manner known and purified by When a sulphonyl isocyanate is used as starting material of formula III the process for performed in that or dissolved in an iner organic anhydrous absolute or absolute is added slowly at room temperature to the solution of the isocyanate or dissolved in the same The reaction mixture is left to stand for some time to ooinplete the reaction or is slightly heated and the final product is isolated and purified in manner per compounds of formula I and their salts have valuable pharmacodynamic Thus they possess a marked blood sugar lowering while they have a 1 2 relatively low and are particularly effective from the pharmacodynamic point of The compounds of formula I indicated for as for oral the treatment of Diabetes The compounds of the invention may be used for administration perorally in the form of capsules or In order to produce appropriate medicinal preparations the compounds are formulated with organic or inorganic adjuvants which are inert and gically Examples of such adjuvants dicalcium methyl stearic acid and sorbic The preparations may furthermore contain suitable preserving synthetic sweetening and colouring substances and The present invention therefore further provides pharmaceutical compositions in addition to a physiologically acceptable a compound of formula I or a salt In the following Examples all temperatures are indicated in degrees Centigrade and are t The solvent is distilled off from a solution of g of acid ethyl ester and g of in 200 cc of absolute toluene at in the course of 3 hours while fresh toluene is added at such a rate that the initial vo is The ethanol by the reaction and the liberated water are removed this Subsequently the toluene is completely distilled off at 15 mm and the residue is taken up three times in ethanol which is each time residue is an oil which is subsequently crystallised from point The ortropane used as starting material is produced as A solution of g of in 90 cc of absolute ether is added to a suspension of g of lithium aluminium hydride in 210 cc of absolute ether in the of one hour while the mixture is The reaction mixture is then stirred for a further 15 hours at room temperature and then refluxed for 2 After the reaction mixture has been cooled in an ice bath 10 cc of water and then 50 cc of a aqueous potassium hydroxide solution are carefully added to The the mixture is filtered through highly purified diatomaceous the organic phase is separated from the filtrate and the aqueous phase is extracted with altogether 300 of The combined ether extracts are dried over magnesium the ether is evaporated and the crystalline is recrystallized from Melting point 2 solvent is slowly distilled off from a acid ethyl ester and g of in 100 cc of absolute toluene at in the course of 3 hours while fresh toluene is added dropwise at such a rate that the initial volume is ethanol by the reaction and the liberated water are removed in this The toluene is then completely distilled off at 15 mm Eg and the residue is taken up three times in which each time The residue is an oil which is tallized from and recrystallized from Melting point EXAMPLE oc A solution of g of hydrate and g acid ethyl ester in 30 cc of absolute is heated to with stirring for 12 In the course of this operation K urea precipitates in crystalline After cooling to room temperature the derivative is filtered off and twice point 4 A solution of g of hydrate in 40 cc of absolute toluene is slowly added at room temperature with stirring to a solution of g of in cc of absolute The reaction mixture is left to stand for some time and the toluene is then the solvent The resulting oil is then crystallised from urea melts at 5 A solution of of in 30 cc of absolute toluene is added dropwise to a solution of g of in 60 cc of absolute toluene in the course of with In o order to the reaction the mixture is heated to 80 with stirring for a further The toluene is then evaporated at 15 the residue is taken up each at 15 mm The resulting oil is then time in 50 cc of ethanol which is evaporated each from and recrystallized from the same solvent Melting point EXAMPLE 6 1 2 The solvent is distilled off from a solution of g of acid ethyl ester and of in 200 cc of absolute toluene at in the of 3 hours while fresh toluene is added dropwise at such a rate that the initial volume is The ethanol formed by the reaction and the liberated water are removed in this The toluene is then ly distilled off at 15 mm the residue taken up three times in ethanol and the latter evaporated each The resulting oil is recrystallized from Meltin oint The of a solution of g of aqueous glutaric g of ammonium chloride and g of sodium acetate in 5000 cc of water is adjusted to then the solution is left to stand for three days at room solution is then alkaline with potassium saturated with chloride and extracted with portions of altogether 3000 cc of chloroform extracts are dried over magnesium the solvent is evaporated in a vacuum and the residue is distilled in a high distils at and mm and crystallizes in the points 229 from A mixture of g of g of sodium g of hydrazine hydrate and 182 cc of diethylene glycol ie heated to with stirring in a distillation flask for one The teinperature is then slowly raised to whereby excess hydrazine hydrate and are distillate is then extracted with portions of altogethe 300 cc of the combined ether extracts are dried over magnesium sulphate and the ether is The residue is onane distils as a colourless oil between and at mm Hg and crystallizes in the melting from cc of aqueous sulphuric acid are added slowly at with stirring and to a solution of g of in 7 cc of An ice cold solution of g of sodium nitrite in 68 cc of water is then added to the clear solution of the salt at with stirring in the course of 1 reaction mixture is extracted with portions of altogether 500 of ether and the combined ether extracts are washed with a total of 105 cc of aqueous concentrated sodium hydroxide After drying over magnesium sulphate the ether is distilled off in a The solid is recrystallized from ethanol and melts at A solution of g of in 115 cc of absolute ether is slowly added dropwise at with cooling in the course of hours to a suspension of g lithium aluminium hydride in 50 cc of absolute The reaction mixture is then further stirred at room temperature for 20 hours and subsequently fluxed for a further 2 7 cc of aqueous saturated potassium carbonate solution are added to the reaction mixture with Anhydrous potassium carbonate is then added until a granular suspensio is After filtration the filter residue is extracted once more with 100 cc of The ether extract and filtrate are combined and dried over magnesium After evaporating the ether in a vacuum the crystalline is recrystallized Melting point 7 This compound is obtained from g of acid ethyl ester and g of in 100 of absolute toluene in a manner analogous to that described in the preceding Melting point after from β The solvent is slowly distilled off from a solution of g of acid ethyl ester and g of in lOOce of absolute benzene at in the course of 16 hours and while fresh benzene is added The ethanol formed by the reaction and the liberated water are removed in this The reaction solution then concentrated at 15 mm whereby urea is precipitated in crystalline After cooling the derivative is filtered off and recrystallized from Melting 9 g of in 20 cc of absolute are added with stirring in the course of 50 minutes a solution of g of in 50 cc absolute In order to complete the the mixture is heated to with for a further toluene is then distilled off at 15 Hg and residue is taken up three times in ethanol and the latter is evaporated each resulting oil is crystallised from and recrystalliaed the same solvent Melting point insufficientOCRQuality

Claims (2)

1.

2. NOW particularly described and ascertained the nature of our said invention and in what manner the same is to be we declare that what we claim Heterocyclic sulphonyl urea derivatives of the formula in which signifies a ethyl or acetyl radical or a halogen or hydrogen and n signifies 2 or and their alkali alkaline earth metal or ho A process for the production of compounds of formula I in Claim wherein a heterocyclic amine of the formula is reacted with a compound of the 0 in which and n have the same meaning as in Claim signifies a hydrogen atom and 2 signifies an alkoxy radical of 1 or to 4 carbon or an amino and together signify a second bond between the carbon atom and the nitrogen atom when salt is the resulting compound of formula I is reacted with a alkali alkaline earth metal or ammonium A process for the production of the compounds of formula I Claim substantially as herein with reference to any one of the Compounds of the formula I in Claim 1 and their whenever produced by a process as claimed in Claim 8 or Pharmaceutical compositions in addition to a physiologically acceptable a compound claimed in any one of Claims 1 to 7 or Dated this 7th day of January For the Applicants RC insufficientOCRQuality