DE1159937B - Process for the preparation of hydrindene sulfonylureas - Google Patents

Description

It is known that sulfonylureas have blood sugar-lowering properties (see e.g. drug research, Vol. 8 [1958], p. 425 if.). For example, N-4-methylbenzenesulfonyl) -N'-butylurea has been introduced into therapy as an antidiabetic. From the British patent specification 814 234 is also known that naphthalene and 5,6,7,8-tetrahydronaphthalenesulfonylureas lower blood sugar levels.

The invention relates to the production of hydro- ίο aromatic sulfonylurea derivatives of the general formula

SO ₂ -NH-CO-NH-R (I) ^a5

in which R denotes an alkyl, cycloalkyl or aralkyl radical.

According to the invention, a hydrindene sulfonamide of the formula is brought

- SO. —NH,

(H)

which is preferably in the form of one of its salts, with an isocyanic acid ester of the formula RCNO for Implementation. As isocyanic acid esters, for example, n-butyl isocyanate, cyclohexyl isocyanate or Phenylethyl isocyanate in question.

A further embodiment of the process consists in that the hydrindene sulphonamide is first converted into a hydrindene sulphonyl carbamic acid ester by reaction with a chloroformic acid ester. By reaction with an amine of the formula R - NH ₂ , the sulfonylurea derivative according to the invention is then obtained from the hydrindene sulfonylcarbamic acid ester. Amines of the formula RNH ₂ are, for example, ethylamine, n-propylamine, isobutylamine, cyclopentylamine and phenylethylamine.

In all cases, the reaction conditions may vary depending on the particular requirements imposed by the Substitutions to be made on the hydrindene sulfonamide molecule are largely varied will. For example, the reactions using solvents at normal or be carried out at an elevated temperature.

The hydrindene sulfonylureas obtainable by the process are characterized in particular by an excellent and long-lasting blood sugar process for their production
of hydrindene sulfonylureas

Applicant:
Heyden Chemical Factory,

Corporation,
Munich 23, Leopoldstr. 4th

Dr. Hermann Breuer and Dr. Hans Höhn,

Regensburg,
have been named as inventors

lowering effect and are therefore ideally suited for therapeutic use.

example 1

19.7 g of hydrindane-5-sulfonamide are dissolved in 50 cm ^{3 of} 2N sodium hydroxide solution and 150 cm ^{3 of} acetone. The solution is added dropwise with stirring at 15 ° C. with 16.2 g of cyclohexyl isocyanate. The mixture is stirred for 2 hours, diluted with five times the amount of water, filtered and the filtrate is acidified with dilute acetic acid. There are obtained 25.2 g of N- (hydrindene-5-sulfonyl) -N'-cyclohexylurea, which has a melting point of 153 to 155 ° C after recrystallization from 7O ° / pc alcohol acetone and drying in vacuo at 5O ⁰ C.

Example 2

17 g of hydrindene-4-sulfonamide are brought into solution ^{with 43.5 cm 3 of} 2N sodium hydroxide solution and 120 cm ^{3 of acetone. A solution of 11 g of n-butyl isocyanate in 40 cm 3 of} acetone was added dropwise to this solution with stirring at 10 to 15 ° C. over a period of 45 minutes. The mixture was then stirred for a further 2 hours at room temperature, diluted with 500 cm ^{3 of} water and the acetone was distilled off in vacuo. The precipitate was then filtered off with suction and the filtrate was acidified to Ph 5 with dilute hydrochloric acid. The precipitated N- (hydrindane-4-sulfonyl) -N'-butylurea was filtered off with suction. For cleaning, it was dissolved again in dilute sodium hydroxide solution and precipitated again with dilute hydrochloric acid. Yield: 17.5 g with a melting point of 163 to 164 ° C. According to

309 770/475

recrystallization from 8O7oigem acetone is the Melting point at 163 to 164.5 ° C.

The following was represented in the same way:

N- (hydrindene-4-sulfonyl) -N'-cyclohexylurea, m.p. 176-177 ⁰ C.

Example 3

In a 4-1 three-necked flask, 160 g of hydrindene-5-sulfonamide, 162 g of finely powdered anhydrous potassium carbonate and 2.8 l of anhydrous acetone Cooked back for 1 hour. Then 84 g of ethyl chloroformate were added added dropwise at boiling point. It was then re-boiled for a further 3 hours. After cooling, the thick white paste was sucked off. The dried filter residue was registered in 3 l of water and completely dissolved with a little dilute sodium hydroxide solution. Then became adjusted to pH 7.5 with dilute hydrochloric acid while stirring vigorously. Here, some hydrindene-5-sulfonamide separated from which was filtered off. The filtrate is now further acidified and the precipitate vacuumed and dried. Melting point 120 to 123 ° C.

40.3 g of the thus obtained crude hydrindene-5-sulfonylcarbaminsäureäthylesters ³ of water with 25 cm of n-propylamine and 9 g for 1 hour at 12O ⁰ C heated. The batch was then left at this temperature for a further 80 minutes in a water jet vacuum. The viscous residue was ^{brought into solution with 300 cm 3 of} 17oig ^em ammonia and 300 cm ^{3 of} water with gentle heating, the solution clarified with animal charcoal, filtered and, after cooling, the N- (hydrindene-5-sulfonyl) -N'-propylurea with precipitated dilute hydrochloric acid. The precipitate was dissolved in dilute sodium hydroxide solution and reprecipitated with dilute hydrochloric acid. 29.4 g of substance with a melting point of 127 to 128 ^° C. were obtained. The substance melted after recrystallization from 7O7oigem acetone at 128-129 ⁰ C.

The following were represented in the same way:

N- (Hydrinden-5-sulfonyl) -N'-butylurea, melting point 126 to 127 ° C,
N- (Hydrinden-5-sulfonyl) -N'-isobutylurea, melting point 128 to 129 ° C,
N- (hydrindene-5-sulfonyl) -N'-phenyläthylharnstoff, melting point 129 to 131 ⁰ C.

Test report

About the superiority of the compounds according to the invention over known sulfonylureas to prove, pharmacological tests were carried out in which the N- (hydrindane-5-sulfonyl) -N'-cyclohexylurea (A) and the N- (hydrinden-5-sun ° onyl) -N'-butylurea (B) with the chemically closely related sulfonylureas N- (5,6,7,8-tetrahydronaphthalene ^ -sulfony ^ -N'-cyclohexylureas) known from British patent specification 814 234 and N - (5,6,7,8 - tetrahydronaphthalene - 2 - sulfonyl) -N'-butylurea (D) as well as with the well-known N- (4-methylbenzenesulfonyl) -N'-butylurea introduced into therapy (Tolbutamide) can be compared. The experiments were carried out on rabbits, rats and dogs. The preparations were administered orally, after the animals had fasted overnight. At certain time intervals after the oral preparation blood samples were taken in which the blood sugar content was determined. The comparison The respective percentage lowering of the blood sugar level resulting from the control values is in the the following tables.

s 1. Reduction of the blood sugar level in rabbits after oral administration of compound A in comparison with C.

link Dose (mg / kg) Lowering blood sugar
After 3 hours ία
^A ί
^c { 200
100
400
200 24%
15 7o
21%
27o

2. Lowering of the blood sugar level in the rat after oral administration of compound A in comparison

with C and D

²⁰ connection ί Dose (mg / kg) Blood sugar lowering after 3 hours 1 IStd. 37 Vo Λ ί 75 30 "/ ο 42Vo Ά ι 35 16 Vo 437 « 25 c 75 18% 25% 35 OVo 14% D. 35 OVo

3. Lowering of the blood sugar level in the dog after oral administration of the compounds A and B in comparison with C and D

link 35 A. Dose (mg / kg) Blood sugar lowering after 31% 36 Vo 47 Vo B. IStd. 13 hours 15 hours i 7 hours 27 V ₀ 29 Vo 37 Vo C. 16% 11% 35 Vo D. 12th 31 Vo OVo 14% 23% 12th 22 Vo 12th 4% 12th OVo

4. Lowering the blood sugar level in the rat after oral administration of compound A compared with

Tolbutamide

link

A.
Tolbutamide!

Dose (mg / kg)

150

75
150

75

Blood sugar lowering according to IStd. [3hrs to 17hrs

32% 29%

31% 40%

52 Vo

547

45 Vo 44% 48% 131% 52% 26%

⁰ I.

32 Vo

38 Vo

5. Lowering of the blood sugar level in the dog after oral administration of compound A compared with Tolbutamide

Table 1 shows that compound A is considerably more effective in rabbits than the comparison substance D. According to Table 2, the same applies to the rat as the test animal. According to Table 3 show the

link Dose (mg / kg) Blood sugar lowering after
IStd. 13 hours 15 hours 17 hours 36%
18%
30 Vo
14% 35%
30%
28 Vo
22% 26%
24%
32 Vo
21% ^A ί
Tolbutamidj 12.5
4.0
12.5
4.0 31 Vo
19%
15%
10%

Compounds A and B in dogs also have a stronger effect than the comparison substances C and D. In addition, A and B cause blood sugar levels to drop much more promptly and evenly than the comparison substances.

As can be seen from Tables 4 and 5, Compound A is the tolbutamide in potency think. In addition, the experiments on the rat show that A has a longer duration of action than Has tolbutamide.

Claims (1)

PATENT CLAIM: Process for the preparation of hydrindene sulfonylureas the formula SO ₂ -NH-CO-NH-R wherein R denotes an alkyl, cycloalkyl or aralkyl group, characterized in that a hydrindene sulfonamide of the formula is used in a manner known per se - ¹ LSO ₂ NH ₂ either a) with an isocyanic acid ester of the formula R - CNO, in which R has the above meaning, implements or b) with chloroformic acid ester and the resulting hydrindene sulfonylcarbamic acid ester with an amine of the formula R - NH ₂ , in which R has the abovementioned meaning, is reacted. Considered publications:
German patent specification No. 965 400. © 309 770/475 12.63