CH535214A - Hypoglycaemic substituted benzenesul- - Google Patents

Abstract

N- 4-(beta-(2-methoxy-5-chlorobenzamido) ethyl) benzenesulphonyl -N'-cyclopentylurea is prepd. by reacting an e.q. benzene sulphonyl isocyanate, necessarily containing the group with a cyclopentyl amine. Cpds. are good hypoglycaemic agents.

Description

  

  The invention relates to a process for the preparation of N- {4 - [# - (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfonyl} -N'-cyclopentylurea of the formula
EMI0001.0002
    which, as a substance or in the form of its salts, has blood sugar-lowering properties and is characterized by a strong and long-lasting lowering of the blood sugar level.



  The process according to the invention for producing this benzenesulfonylurea is characterized in that correspondingly substituted benzenesulfonyl-iso urea ether-isothiourea ethers, isourea esters, parabanic acids or haloformic acid amidines or compounds of the formula are hydrolyzed
EMI0001.0005
    or their parabanic acid derivatives or compounds of the formula
EMI0001.0006
    where U is in each case O-lower alkyl, S-lower alkyl or halogen (preferably chlorine), saponified or added to appropriately substituted carbondiimide water. and the reaction products are optionally treated with alkaline agents to form salts.



  The hydrolysis of the benzene sulfonyl parabanic acids, isourea ethers, isothiourea ethers, isourea esters or haloformic acid amidines mentioned as starting materials is expediently carried out in an alkaline medium. Isourea ethers and isourea esters can also be hydrolyzed with good success in an acidic medium.



  The chloroformic acid amidines or carbodiimides can be obtained, for example, from thioureas by treatment with phosgene or phosphorus pentachloride.



  The embodiments of the process according to the invention can generally be varied widely with regard to the reaction conditions and adapted to the particular circumstances. For example, the reactions can be carried out in the absence or presence of solvents, at room temperature or at elevated temperature. The blood sugar-lowering effect of the benzenesulfonylurea described can be determined by feeding it in the form of its sodium salt in doses of 10 mg / kg to rabbits with a normal diet and checking the blood sugar level using the well-known method from Hagedorn-Jensen or with an autoanalyzer determined a longer period of time.



  For example, it was determined that the N- (4- [ss - (2-methoxychlorobenzamido) -ethyl] -benzenesulfonyl} -N'- -cyclopentylurea (I) caused the blood sugar lowering shown in the table.



  For comparison, the table shows the blood obtained with the known N- {4- [ss- (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfonyl} -N'-cyclohexylurea (II) sugar reduction listed.
EMI0002.0005
  
    Blood sugar reduction <SEP> on the <SEP> rabbit <SEP> in <SEP>% <SEP> after <SEP> Verabr.
<tb> of <SEP> 10 <SEP> mg / <SEP> kg <SEP> p.o. <SEP> after <SEP> ...

   <SEP> hours
<tb> 1 <SEP> 3 <SEP> 6 <SEP> 24 <SEP> 48 <SEP> 72 <SEP> 96 <SEP> 120 <SEP> h
<tb> <B> 1 </B> <SEP> 18 <SEP> 39 <SEP> 36 <SEP> 45 <SEP> 50 <SEP> 41 <SEP> 27 <SEP> 0
<tb> II <SEP> 19 <SEP> 23 <SEP> 28 <SEP> 13 <SEP> 0 The benzenesulfonylurea described is intended to be used preferably for the production of orally administrable preparations with blood sugar-lowering effectiveness for the treatment of diabetes mellitus and can be used as sol cher or in the form of its salts or in the presence of substances that lead to salt formation, who applied. For example, alkaline agents such as alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates can be used for salt formation.



  Tablets which, in addition to the benzene sulfonylurea described, contain the usual auxiliaries and carriers such as talc, starch, milk sugar, tragacanth or magnesium stearate are preferably used as medical preparations.



  A preparation containing the described benzenesulfonyl urea as an active ingredient, e.g. a tablet or a powder with or without additives is expediently brought into a suitably dosed form. The dose to be selected is that which is adapted to the effectiveness of the benzenesulfonylurea used and the desired effect. The dosage per unit is expediently about 0.5 to 100 mg, preferably 2 to 10 mg, but dosage units considerably above or below can also be used, which if necessary have to be divided or multiplied before administration.



  The following examples illustrate the invention: <I> Example 1 </I> a) Potassium salt of N- {4- [ss- (2-methoxy-5-chloro-benzamido) -ethyl] -benzenesulfonyl} -iminodithiocarbonic acid . 74 g of 4- [ss- (2-methoxy-5-chloro-benzamido) ethyl] - -benzenesulfonamide are dissolved in 350 ml of dimethylformamide. 23 g of carbon disulfide and then a solution of 34 g of potassium hydroxide in 50 ml of water are added dropwise with stirring. The mixture is stirred for three hours at room temperature and the clear solution is poured into 4 liters of ethanol.

   The precipitated potassium salt of N- (4- - [ss - (2-methoxy-5-chlorobenzamido) -ethyl] - benzenesulfonyl} -iminodithiocarbonic acid is filtered off with suction, washed with alcohol and dried. Yield: 60 g. B) N - (4 - [# - (2-Methoxy - 5-chloro-benzamido) -ethyl] - -benzenesulfonyl} -iminodithiocarbonic acid dimethyl ester.



  3.6 g of the potassium salt obtained according to a) are dissolved in 60 ml of 1 normal sodium hydroxide solution. 12.6 g of dimethyl sulfate are added to the clear solution with shaking. Warming is observed. After standing for 30 minutes, a precipitated semi-solid grease is decanted off. After washing with water, the grease crystallizes. It is recrystallized from dilute methanol and 30 g of the N- {4- [ss- (2-methoxy-5-chloro-benzamido) -ethyl] -benzenesulfonyl} -iminodithioic acid dimethyl ester with a melting point of 94 are obtained - 96.



  c) N- {4- [ss- (2-methoxy-5-chlorobenzamido) -ethyl] - -benzenesulfonyl} - N'-cyclopentyl-isothiourea-methyl-ether.



  4.73 g of the ester obtained according to b) are dissolved in 100 ml of dioxane. 0.85 g of cyclopentylamine are added and the mixture is heated on the steam bath for 1 1/2 hours. After pouring it into water and acidifying it with hydrochloric acid, the above isothiourea methyl ether is obtained as a smear.



  d): N - (4- [ss- (2-methoxy-5-chlorobenzamido) -ethyl] - -benzenesulfonyl} -N'-cyclopentylurea. The smear obtained according to c) is dissolved in dioxane, 2 -normal caustic soda to u. heat the solution on the steam bath for 1 hour. After pouring into water and acidifying with acetic acid, the N- {4- [ss- (2-methoxy-5-chlorobenzamido) ethyl] -benzenesulfonyl} -N'-cyclopentylurea is obtained as crystallized Precipitation. After recrystallization from methanol, the substance melts at 183 - 185 C.



  <I> Example 2 </I> a) 4.9 g of cyclopentylparabanoic acid (melting point 111-113) and 2.5 g of triethylamine are dissolved in 200 ml of benzene and 8.9 g of 4- [ss = (2-Methoxy-5-chloro-benzamido) -ethyl] -benzenesulfochloride (melting point 102-103) was added. The mixture is refluxed for three hours and the triethylamine hydrochloride formed is filtered off while hot. The cooled filtrate is ver with petroleum ether and the crystals which precipitate out after a short time are filtered off with suction.

   After two recrystallizations from methanol / dimethylformamide, pure {4- [ss- (2-methoxy-5-chlorobenzamido) ethyl] -benzenesulfonyl} -3-cyclopentyl-parabanic acid with a melting point of 181-183 ° C. is obtained.



  b) 0.5 g of the substance obtained under a) are heated with 5 ml of dioxane and 10 ml of 1 normal sodium hydroxide solution for 45 minutes on the steam bath. Water is then added, the mixture is acidified and the precipitate obtained is recrystallized from methanol. The melting point of the N- {4- [ss- (2-methoxy-5-chlorobenzamido) ethyl] -benzenesulfonyl} -, N'-cyclopentylurea obtained in this way is 183-185 C.



  <I> Example 3 </I> 0.5 g of N- {4- [ss- (2-methoxy-5-chlorobenzamido) -ethyl] - -benzenesulfonyl} -N'-cyclopentyl-thiourea are dissolved in 50 ml Dissolved methanol. 0.22 g of mercury (II) oxide and a little K2CO3 are added with stirring, and the mixture is heated to 50-55 for 3 hours with continued stirring. After filtering off the mercury (II) sulfide formed, the mixture is concentrated and the N- {4 - [# - (2-methoxy-5-chloro-benzamido) - ethyl] - benzenesulfony} - N'-cyclopentyl-isourine is obtained - Substance methyl ether as a tough resin.

   A sample of the above-mentioned isourea ether is poured with concentrated hydrochloric acid in a test tube and heated on the steam bath for a few minutes while stirring. The resulting crystals of N- {4 - [# - (2-methoxy-5-chlorobenzamido) -ethyl] -benzenesulfonyl-N'-cyclopentylurea are recrystallized from methanol. Melting point 181-183 C.

 

Claims (1)

PATENT CLAIM Process for the preparation of N- {4- [ss- (2-methoxy- -5-chlorobenzamido) -ethyl] -benzenesulfonyl} -N '- cyclopentyl urea with the formula EMI0003.0007 characterized in that correspondingly substituted benzenesulfonyl isourea ethers, isothiourea ethers, isourea esters, parabanic acids or halo formic acid amidines or compounds of the formula are hydrolyzed EMI0003.0012 or their parabanic acid derivatives or compounds of the formula EMI0003.0013 to lie means saponified or water attached to appropriately substituted carbodiimide. <B> SUBClaims </B> 1. Process according to patent claim, characterized in that the process product is converted into the corresponding salt by treating with alkaline agents. 2. The method according to claim, characterized in that one starts from a compound in which U is chlorine.