DE1668199C3 - Benzenesulfonyl-3- (2-hydroxycyclohexyl) ureas - Google Patents

Description

OH

NH-C- NH-SO,

R (D

OH NH-C — NH-SO-, -

Il ο

R (D

in the R CH ₃ -. Represents Cl- and CH ₃ S-.

2. 1 - (p - methylbenzenesulfonyl) - 3 - (cis - 2 - hydroxycyclohxyl !-urea.

3. Process for the preparation of benzenesulfonylureas of the general formula 1 according to claim I, characterized in that in in a manner known per se

a) a reactive derivative of a sulfonylcarbamic acid of the general formula II

ίο in which R is CH ₃ -, Cl- or CH ₃ S-

The compounds of general formula I will be produced according to the invention by in a manner known per se

a) a reactive derivative of a sulfonylcarbamic acid of the general formula

Z — CO— NH-SO,

Z— CO — NH — SO,

(H)

in which R has the meaning given in claim 1 and Z is a lower alkoxy, aryloxy, lower Aikylthio or arylthio group, an imidazolyl (l) - or represents 3,5-di-lower-alkylpyrazolyl- (1) radical, or a sulfonyl isocyanate of the general formula IH

-Su ₂ NCO

(III)

in which R has the meaning given in claim 1

and Z has a lower alkoxy, aryloxy, lower R

Aikylthio or arylthio group, an imidazo-IyHl) - or 3,5-di-lower-alkylpyrazolyl- (I) radical

represents, or a sulionyl isocyanate which generally reacts 30 with 2-aminocyclohexanol or that one

nen formula HI b) a compound of the general formula IV

SO ₂ NCO

(III)

with 2-aminocyclohexano! converts or that b) a compound of the general formula

35

OCO-NH-SO ₂ -

NH-CO — NH-ί

(IV)

OCO-NH-

NH-CO-NH-SO

40 with one molar equivalent of 2-aminocyclohexanol or that one

c) a compound of the general formula V or VI

with one molar equivalent of 2-aminocyclohexai oil or that one

c) a compound of the general formula V or VI

= N-SO,

CO — NH-SO,

treated with alkali.

R (V)

(Vl)

C = O

R (V)

iVI)

55 treated with alkali.

In a particularly preferred embodiment of process variant a), a compound is used of the general formula II, in which Z stands for the imidazolyH 1) radical. One uses appropriately Sulphonamide, preferably as an alkali salt, with carbonyldiimidazole in a suitable, anhydrous, non-hydroxyl-containing, inert to carbonyl compounds organic solvent of the type mentioned above and then leaves the sulfonylcarbamic acid imidazolide formed in situ react with 2-amino-cyclohex.anol.

When converting a sulibnylcarbamic acid derivative or a sulfonyiisocyanate with 2-aminocyclohexanol, compounds of the general Formula IV can be obtained. These compounds can be converted into one molar equivalent 2-Aminocyclohcxanol in compounds of the general Formula I convert.

According to another embodiment of the invention Process one treats a compound of the general formula V or Vl with alkali, such as sodium hydroxide solution, preferably at elevated temperature, e.g. B. reflux temperature of the reaction mixture, whereby a compound of the general formula I is obtained.

The compounds of the general formula V can be prepared by reacting l-iodo-2-isoryanocyclohxane can be obtained with a corresponding sulfonamide. In the compounds obtainable according to the invention The general formula I can contain the hydroxy group in the cyclohexane ring, depending on the synthetic route chosen have cis or trans configuration. Received Mixtures of isomers, as well as the pure translsomers, can be converted into pure cis isomers will. This conversion can be achieved by treating a compound of general formula I. the hydroxy group has trans configuration, with dehydrating agents such as thionyl chloride will. The compounds of the general formula V thus obtained are then as above described, converted into compounds of general formula I by treatment with alkali, in which the hydroxy group has the cis configuration.

The compounds of the general formula VI can be prepared by reacting a compound of the general Formula VII

(Viii

Variant a) for the reaction of a sulfonylcarbamic acid derivative or a sulfonyiisocyanate with one of the cyclohex- ^ derivatives mentioned.
The compounds of the general formula I are distinguished by an exceptional blood sugar-reducing activity when administered orally. The dosage range is about 250 to about 1 (KM) mg per day for adults. The compounds have a short useful life in the organism and are

ίο left largely unchanged. The beneficial ones Properties of the p-methylbenzenesulfonyl according to the invention - 3 - (2 - hydroxycyclohexyl) - urea (A) in comparison to the known, structurally related diaboral - [(p-methylbenzenesulfonyl) -3-cyclohcxylurea. B] becomes clear from the test results given below:

Influence of blood glucose in animal experiments Blood glucose after a single application

al normal rat

The substances were as a suspension in Polyäthylcnglykol (Carbowax 400) miciels Schlundsondc in groups of five normal, fed, males each Albino rats weighing 60 to 80 g from closed, randomized breeders were administered. Control animals received suspension vehicle alone. The blood was obtained by decapitalion and immediately deproteinized (Somouy. M. J. ^ Biol. (Hem. 16 (V 69 73 [1945]).

In the protein-free filtrate
Glucoscoxidasc. Peroxidase
by Watson (Watson.
131 [1962])

with a reactive derivative of a sulfonylcarbamic acid of the general Γ-'ormelll or with a sulfonyl isocyanal of the general formula III getting produced.

This conversion can be done in the same way as in the procedure above Glucose means and tolidine after a D .: Anal. Biochem. 3: method based on the

Technicon Autoanalyzer was adapted.

b) Normal dog

The substances were given in gclatin capsules to normal, female. 16 hours of fasted mixed breed dogs (Average body weight 10 kg) administered. Before trying and? .. 4. 6 and 24 hours After application, blood samples were taken from the leg vein, immediately proteinized and analyzed as described under a).

preparation

: itnol kg
(p.ovl

rat

dog

% Deviation hours after application% deviation hours after application I 3 16 2 4 ft

1000 -41 -35 _2 -34 -31 -25 -3 500 -39 -39 + 4 -49 -37 -26 + 4 250 -49 -35 + 3 -15 -20 -28 _9 125 -25 -35 _ T ₁ -19 -28 -16 -9 62 - Ή -28 + 1 - "> 3 - "Ί -9 + 2 31 16 -49 -36 -48 -3 KX) O -51 -63 -37 125

Biological half-life and metabolism
a) half-life

Assuming that in terms of absorption rate there are no significant differences between the test compounds from the intestine, the half-times of elimination from the blood plasma after parenteral administration were measured.

The rat, from which tolbutamide is metabolized in the same way as from man, was chosen as the experimental animal. For this purpose, six female albino rats weighing 170 to 90 g, fed ad libitum, from closed, randomized outbringing were given equal doses (see table) of the preparation to be tested (solution of 200 mg in 115 molar Na ₂ HPO ₄ ) injected intraperitoneally. After 1, 3 and 5 hours or after 40, 60 and 80 minutes, 2 animals each were killed by decapiticren and oxalate plasma was obtained. The determination of sulfonylureas in the plasma was carried out according to the Spingier method (Spingier. H .: Klin. Wochenschrift 35: 533 [1957]). However, before adding the dinitrofluorobenzene reagent, the amyl acetate extracts of the plasmas were washed with phosphate buffer pH 6.8 (lowering of the plasma blanks, elimination of relatively hydrophilic metabolites).

Biological half-life of sulfonylurea compounds in the rat

Pr.i ready Dose,
mi! ku 1 b) HalhwcrlN / cii
P. B.
A. 20th
40 3.5 4 hours
20-30 hours metabolism

40

After oral administration of A to rats and dogs, blood and urine were treated with methylene chloride at pH 5 extracted. Virtually only unchanged A was found in the extracts. In the urine of the dog, 5 to 10% was in conjugated form (glucuronide).

From the above results it can be seen that between compound A and the reference preparation B sees a clear difference in duration of action; the effect of A sets in more quickly and is of shorter duration. Compound A is practically not metabolized by rats, dogs and humans and passed out very quickly.

example 1

55

Fine suspension of 9.65 g of p-methylbenzenesulfonamide sodium salt / in 50 ml of dimethylformamide, 8.5 g of carbonyldiimidazole are added at -IOC. The reaction mixture is stirred for a further 20 minutes at -10.degree. C. and then with 7.5 g of cis-2-aminocyclohexanol hydrochloride offset. The reaction mixture is allowed to warm up to room temperature, stirs for a further 2 hours and evaporates in vacuo. The residue is taken up in 60 ml of 1N sodium hydroxide solution. The solution is washed with ether and the ethereal wash solution is diluted with 40 ml of 1N sodium hydroxide solution extracted, and the combined aqueous solution L'cn are made with 3N sal / acid Congo acid.

The solution is extracted with ethyl acetate. Working up the vinegar extract yields p-methylbenzoisulfonyl-3 - (ice - 2 - hydroxycyclohexyl) - urea, melting point 156 to 160 C (from ethanol - water).

Example 2

In analogy to Example 1, p-chlorobenzenesulfonylcarbamic acid imidazolide (formed in situ from p-chlorobenzenesulfonamide and carbonyldiimidazole) and cis-2-amino-hexanol are converted into l- (p-chlorobenzenesulfonyl) - 3 - (cis - 2 - hydroxy - cyclohexyl) - urea. Melting point 139 to 143 "C ₁ obtained.

Example 3

In analogy to Example 1, p-methylthiobenzene sulfonamide is converted and cis-2-aminohexanol of 1 - (p - methylthiobenzenesulfonyl) - 3 - (cis - 2 - hydroxycyclohexyl !-urea. Melting point 142 to 144 C, receive.

Example 4

A mixture of 7.8 g of ethyl p-methylbenzolsulfonylcarbamic acid, 3.7 g of trans-2-aminocyelohexanol and 1.5 ml of absolute pyridine is heated to 120 ° C. for 3 hours with the exclusion of moisture. The oily reaction product is dissolved in 100 ml of 1N sodium hydroxide solution. After extraction with ether, the aqueous phase is _{saturated with CO 2} and filtered. The filtrate is acidified with acetic acid. The precipitating p-methylbenzenesulfonyl-3- (trans-2-hydroxycyclohexyl (urea) crystallizes on standing and is recrystallized from ethyl acetate. The product decomposes from 160 ° C.

Example 5

8g 4,5-tetramethylene-2- (p-methylbenzenesulfonyI-imido) -oxazolidinone are refluxed for about 3 hours in 150 ml of 2N sodium hydroxide solution. To the reaction solution is cooled with 2N hydrochloric acid acidified. The oily reaction product that separates out crystallizes on standing and becomes by dissolving in soda solution and acidifying the solution with 2N hydrochloric acid. The p-methylbenzenesulfonyl - 3 - (ice - 2 - hydroxy - cyclohexyl) - urea melts at 157 to 161 C (from ethanol). The starting material can be made as follows:

A solution of 10.75 g of l-.lod-2-isocyanocyclohxane in 10 ml of acetone, while cooling with ice and stirring vigorously, a solution of 8.55 g of p-toluenesulfonamide is obtained given in 100 ml of I n-NaOH acetone (1: 1). The reaction mixture is 1 hour at 0 C. stirred and then left to crystallize. 4,5-Telramethylene-2- (p-methylbenzenesulfonylimidol-oxazolidinone) is obtained. Melting point 180 to 181 ° C. (from methanol).

Example 6

5.8 g of cis-2-aminocyclohexanol are in HX) ml absolute benzene with stirring with 15.7 g of N-lp-chlorobenzene sulfonyl) -3,5-dimethyl-1 - pyrazole carboxamide verset / t. The reaction mixture is 2 hours at Stirred at room temperature and then worked up. 1- (p-Chlorbcn / olsulfonyl) -3- (cis-2-hydroxy-cyclohexyl) -urea is obtained. which is identical to the product obtained according to Example 2.

The N- (p - ('chlorobenzene / olsulfonyl) -3.5 used as the starting material - dimethyl - I - pyra / olcarboxamid can be produced as follows:

To 10.1 g of 3,5-dimethylpyrazole in 200 ml of absolute Benzene is 19.7 g of p-chlorobenzenesulfonyl isocyanate given. The reaction mixture is refluxed for 2 hours and, after cooling, with petroleum ether added, the N- (p-chlorobenzenesulfonyl) -3,5 - dimethyl - 1 - pyrazole carboxamide crystallizes. Melting point 125 to 135 ° C.

Example 7

To a solution of 5.75 g of trans-2-aminocyclohexanol in 50 ml of abs. After adding 7.5 ml of triethylamine, dimethylformamide is slowly added dropwise, while stirring with ice, and 17 ml of p-methylbenzenesulfonyl isoyanate. After standing for 2 days at room temperature, the solvent is evaporated and the residue is dissolved in 50 ml of 2N NaOH. When the solution is _{saturated with CO 2} , a brown resin is deposited, which is decanted off. After exhaustive ether extraction, the aqueous solution is acidified with 2η hydrochloric acid. The oily O ₁ N - bis - tosylcarbamoyl - trans - 2 - aminocyclohexanol which separates out crystallizes on standing. Melting point after falling from dilute sodium hydroxide solution and recrystallization from alcohol 200 to 205 ^° C.

2.55 g of O, N - bis - tosylcarbamoyl - trans - 2 - aminocyclohexanol and 0.8 g of trans-2-aminocyclohexanol are mixed with 2 ml of abs. Pyridine heated to 120 ^° C. for 4 hours. After cooling, the reaction product is mixed with 20 ml of 1N NaOH. After filtration, the solution is _{saturated with CO 2} , filtered again and acidified with 2N hydrochloric acid. The p-methylbenzenesulfonyl - 3 - (trans - 2 - hydroxycyclohexyl) - urea crystallizes on standing.

Example 8

0.5 g of 4,5 - tetramethylene - N - (N '- ρ - methylbenzenesulfonylcarboxamido) oxazolidinone come in 10 ml

ίο 1 η-sodium hydroxide solution and 1 hour on the boiling Heated water bath. After cooling, the solution is acidified with 2η hydrochloric acid, whereby an oil separates which crystallizes on standing at room temperature. The crystals are filtered off, washed with water and dried. The product obtained in this way is identical to that according to Example 1 connection established identical.

Manufacture of the raw material

A solution of 4 g of 4,5-tetramethyleneoxazolidinone in 75 ml of absolute benzene is mixed with 6 ml of p-methylbenzenesulfonyl isocyanate added and heated under reflux for 4 hours. The solvent is then evaporated in vacuo and the residue from absolute Ether and then recrystallized from methanol. 4,5-Tetramethy.len-N- (N'-p-methylbenzenesulfonylcarboxamido) is obtained - oxazolidinone from melting point 135 to 138 ° C.

Claims (1)

Palent claims: I. Benzenesulfonyl - 3 - (2 - hydroxycyclohexyl) ureas of the general formula I The invention relates to new benzenesulfonyl-3- (2-hydrqxycyc1ohexyl) -urslofre of the general formula 1