DE1468922A1 - Process for the preparation of choleretically active derivatives of 3-alpha-hydroxy-7,12-diketocholanic acid - Google Patents

Description

noble - deliaen

Public company ran in 1047

File number: F lh 68 922.6

Process for the preparation of choleretically active derivatives der 3 ~ V ^ - ^ ydroxy-7.12-diketocholansUure

The invention relates to a method of making new ones Clioleretiea with long-term effects, which differ from the 3- <£ -

derive.

It is known that some bile acids have good choleretic effects. Above all, dehydrocholic acid is one of the best choleresis agents to date. These compounds have the disadvantage that, after administration, they increase choleresis considerably within a short time, but that the irlamg completely subsides within a few hours. Jo is 2UUi example, in the administration of dehydrocholic acid in a dose of 500 mg / kg in rats, according to Choleresesteigerung J "- h hours completely subsided. Other known choleresis drugs also do not have a longer duration.

It has now been found that derivatives of 3 - <& - IIydroxy-7.12- (liketocholanic acid and their esters obtained by reacting this acid with alcohols, which are in the 3-position by a Ixono or dicarboxylic acid are esterified, an increase in choleresis cause which surprisingly is extraordinarily extended in time. Have a particularly good effect

Under ^ erM?, *! I.

-ie £. 1047

also the alkali and magnesium salts of the new compounds, In addition, these substances have the advantage that they Bile acids have largely lost their own bitter taste to have.

The new connections are established indeü ¹ . one 3 - ^ - JJydroxy-7.12-diketoeholansäure or an ester obtained by reacting this acid with an alcohol in a known iveise with a mono- or dicarboxylic acid, for example in the presence of pyridine or other bases such as quinoline, dimethylaniline, lutidine, Esterified collidine in the 3-position.

The formic acid esters are obtained by heating the starting compounds made with 98-100% formic acid.

Alternatively, the new compounds can be prepared by adding a derivative of cholic acid or a cholic acid ester, which is selectively acylated in the 3-position by a mono- or bio-carboxylic acid, with a suitable oxidizing agent, for example with chromium trioxide, oxidized in a manner known per se.

The esters obtained can then optionally be mixed with an alkali metal or magnesium compound in a manner known per se be converted into the corresponding alkali or magnesium salt »

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Example 1;

3- <fc-Succinoxy-7 »12-diketo-cholanic acid 140 g of 3- <£ -hydroxy-7.12-diketocholanic acid are dissolved in 450 ml of anhydrous pyridine, 70 g of succinic anhydride are added and the mixture is stirred at 100 for 3 hours. After the pyridine has been removed in vacuo, the lump is poured into ice water, in the course of which the 3- * £ "-Succinoxy- 7.12- diketo-cliolanic acid separates out as a highly viscous hate. The supernatant solution is decanted and the residue caused to crystallize by trituration with 50% methanol. After two recrystallization from 50% aqueous glacial acetic acid, 107 g of 3-C ^ - succinoxy-7.12-diketo-cholanic acid are obtained:
Mp. 235-236 °, / ic / _D ² ° = + 52.0 ° (methanol).

Example 2:

3- <£ -Suocinoxy-7 «12-diketo-oholanoic acid ethyl ester 80 g 3- <£ -hydroxy-7» 12-diketo-cholanoic acid ethyl ester are dissolved in 320 ml of pyridine, 40 g of succinic anhydride are added and the mixture is heated to 100 ° for 3 hours. After removal of the pyridine, the residue is poured into about 1 liter of 10% hydrochloric acid, the precipitate is filtered off with suction and recrystallized twice from 50% aqueous alcohol. 67 g of 3 - ** - succinoxy-7 «12-diketo-cholanic acid ethyl ester are obtained: mp 171-171.5 °.

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Example 3;

3 ~ wC / -formoxy-7 »12-diketo-oholanoic acid

25 g of 3-ok-hydroxy-7.12-diketo-cholanic acid are poured into 200 ml Dissolved 98-100% formic acid and heated to 100 ° for 2 hours.

It is then poured into ice water, the precipitated crystals are filtered off with suction and recrystallized from aqueous methanol.

16.4 g of 3- <£ -formoxy-712-diketo-cholanic acid are obtained:

Pp. 205-208 °.

Example 4:

3Tft-acetoxy-7 «12-diketooholanoic acid

25 g of 3-tk-hydroxy-7.12-diketo-cholanic acid are poured into 200 ml Dissolved pyridine, treated with 200 ml of acetic anhydride and heated to 100 ° for 2 hours. The solution is then cooled and poured into ice water. The crystals are filtered off with suction and recrystallized from aqueous methanol. You get 20 g 3-cC-acetoxy-7 «12-diketo-oholanoic acid: Pp. 205-207 °.

Example 5:

3- <£ -Succinoxy-7.12-diketo-cholanic acid — disodium salt 25.1 g of the 3-ck-suooinoxy-7.12-diketo-cholanic acid obtained according to Example 1 are mixed with a solution of 5.2 g of sodium carbonate in 50 ml of water added, resulting in a clear solution. Water is removed by evaporation in vacuo

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and the substance by repeated evaporation with the addition of Dried alcohol. 28 g of 3T £ -suecinoxy-7 »12-diketocholanic acid disodium salt are obtained.

The preparation of 3- * k-Sucoinoxy-7.12-diketo-cholanic acid potassium salt and -magnesiumsalζ is done in an analogous way by reaction with potassium or magnesium carbonate.

Example 6;

3-d-Succinoxy-7.12-dilceto-oholanoic acid ethyl ester 50 g of cholic acid ethyl ester are dissolved in 50 ecm of anhydrous pyridine and, after the addition of 20.9 g of succinic anhydride, heated to 100 ° for 3 hours. The batch is then diluted with 500 ml of glacial acetic acid and, after cooling to 20 °, an aqueous solution of 22 g of chromic anhydride is added dropwise. After standing overnight, 100 ecm of methanol are added to destroy the excess chromic anhydride and the mixture is heated to 50 ° for 1/2 hour. After cooling, the solution is poured into ice water.

The crystalline deposit is recrystallized from aqueous alcohol. 36 g of ethyl 3- ^ £ -succinoxy-7.12-diketocholanate are obtained:
Mp 171-171.5 °.

The product present is identical to the end product described in Example 2.

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acute toxicity

Mice, strain NMJ (inbred), per dose groups of 6 animals iu Weight of 18-22 g, kept under the same conditions and with a commercial standard dry food ad libitum have been fed. Equidistant dose interval logarithmic, evaluation on I-probability paper.

Result: The Lü ^ values of all the compounds described in Examples 1-5 are above 3 »0 g / kg per os.

Biliary activity

Test animals are sober male albino inbred slats weighing between 190 and 250 g. The experiments are carried out under urethane anesthesia - 1.75 g / kg as above. After opening the abdominal cavity, the common bile duct and the duodenum are cannulated with polyethylene catheters. The ambient temperature during the experiment remains constant at 30 C. After a previous period - after substance administration, the bile secreted in 30-minute periods is collected and peuoht and dry weight determinations are made. All animals receive a regular supply of fluid (0.5 ml 0.9% NaCl solution) intraduodenally. The changes in bile flow are assessed as a percentage of the initial value.

The results are summarized in the following table:

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Result of choletic activity in rats

Dose max. Increase in % mg / kg wet-dry weight after min. Duration of action

3- <f- succinoxy-7.12-500
diketo-cholanic acid

—Succinoxy-7.12-
ethyl xketo-cho1anoate

3-dG-formoxy-7.12-diketo-cholanic acid

3-dü-acetoxy-7.12-diketo-cholanic acid

3- <fc-Suocinoxy-7.12-diketo-cholanoic acid dinatriura salt

3-oC-Suceinoxy-7 .12-

cholanic acid di-

potassium salt

3- <i ^ -Suc c inoxy-7 .12-diketo-cholanic acid ragnesiura salt

500
250 127
116 500
250 188
96 500
250 206
170 500
250 26O
155 500
250 178
169 500
250 155
126. 500
250 85.5
74.5

165 130

120 100

210 174

200 185

250 243 180 60

150 150

60 60

60 60

90 60

90 60

60 60

14 hours 9 1/2 hours

9 hours 6 hours

10 hours 9 hours

10 hours 71/2 hours

9 hours

7 1/2 hours

11 hours 5 1/2 hours

4 hours 4 hours

"in comparison:

Dehydrocholic acid

250

362

458 30

3 1/2 hours

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Claims (2)

- 8 - Ref. 1047 claims 1. A process for the preparation of choleretically active derivatives of 3- ⁴ ^ * - hydroxy-7.12-diketo-cholanic acid, characterized in that 3 - <& - hydroxy-7.12-diketo-cholanic acid or one by reaction thereof is obtained in a manner known per se The acid obtained with an alcohol ester is esterified with a mono- or dicarboxylic acid in the 3-position or a 3- ^ k-monoacylate of cholic acid or a cholic acid ester is oxidized with a suitable oxidizing agent, in particular chromium trioxide, and the ester obtained is optionally oxidized with an alkali or magnesium compound converted into the corresponding alkali or magnesium salt. 2. Choleretic drugs, characterized in that they contain as active ingredient 3-dk-formoxy, 3-dCrAcetoxy or 3τ £ - suocinoxy-7.12-diketo-cholanic acid, its ethyl ester or its disodium, dipotassium or magnesium salt. Subjects 909825/1528