ITMI930749A1 - DERIVED FROM IODESOXICOLIC ACID - Google Patents

Description

Description of the industrial invention having the title: "DERIVATIVE OF IODEXOXICOLIC ACID"

The present invention relates to derivatives of the iodesoxycholic acid of formula (I):

(THE)

where R represents the residue:

(Ia)

or

(Ib)

and pharmaceutically acceptable salts thereof.

The invention also relates to processes for the preparation of compounds of formula (I), and to methods of their use as therapeutic agents and pharmaceutical compositions containing them.

Ideoxic acid (HDCA)? a natural biliary scyl present in pig bile. The purification of iodesoxycholic acid? described in US 2745849 and in US 3006927.

Lately, ? it has been shown that the conjugate of HDCA with taurine, tauroiodesoxioolic acid, (EP 0293751)? of potential utility? both in the dissolution of human cholesterol stones (Gastroenterology 100: A308, 1991), and in the premozione of biliary secretion and desaturation of bile (Hepatology 14; 294A, 1991; Gastroenterology, May 1992).

The conjugation of other bile acids with N-methyl-glycine? already? has been described {Hepatology, 11, 989-961990; J. Lipid Res. 27, 742-52, 1986), as an effective device to overcome the problem of deconjugation by colon bacteria, the experimental evidence currently available on N-methyl-glycine conjugates of bile acids, in particular of ursodeoxycholic acid, 'do not, however, allow to draw definitive conclusions on the validity? general of this expedient for the development of new therapeutic agents.

It has now been found that the compounds of formula (I) are endowed with advantageous properties. cos? summarized.

1 - Effective intestinal absorption, mainly with an active mechanism at the level of the terminal ileum.

2 - Excellent uptake by the liver. Absence of biotransformations and / or liver metabolism.

3 - Prompt and efficient secretion in the bile, which does not require any phase of conjugation, being the molecule already? present in an "active" form, that is? ready for bile secretion.

4 - Remarkable choleretic and cholagogue efficacy.

5 - Good properties hydrophilic.

6 - Absence of membrane-toxicity, thanks to its hydrophilic character and low detergent power.

7 - Reduced or absent intestinal deo-conjugation, thanks to the increased resistance to bacterial enzymatic hydrolysis. There? it also prevents the compound from being 6-alpha dehydroxylated and therefore not transformed into lithocolic acid.

8 - Absence of hepatic and renal glucuronidation, a direct consequence of the conjugation in a biologically stable form, which prevents the elimination of the molecule via the kidney, while it occurs for iodesoxycholic acid in unconjugated form (J. Lipid Res. 24: 604-613, 1983).

The pharmacological tests performed have shown that the compounds of the invention are able to promote a biliary secretion of lipids, and in particular of cholesterol, in a stable form, thanks to the formation in the bile of an abundant liquid-crystalline phase, which prevents any form of solid crystalline precipitation of cholesterol monohydrate.

The derivatives of the invention are also endowed with a powerful memtarane-probative action, thanks to their intrinsic hydrophilicity. In particular they are able to protect cells (and in particular hepatocytes) both from the toxic-detergent action of hydrophobic endogenous bile salts, and from that of toxic or viral agents. They have also been shown to have a more pharmaoological effect. lasting over time compared to natural bile salts.

From the above, it is evident that the compounds of the invention can be advantageously used in human therapy, with the following indications:

1 - Prevention and therapy of gallstones and biliary dyspepsia.

2 - Treatment of acute and chronic liver diseases, including those of toxic and viral origin and those of a holestatic nature, both primary and secondary.

3 - Treatment of both primary and secondary malabsorption syndromes.

4 - Therapy of reflux gastropathy.

5 - Therapy of both primary and secondary dyslipidemias.

For the intended therapeutic uses, the compound of the invention can be formulated in suitable pharmaceutical compositions, using known techniques and excipients, as described for example in "Remin gton's Pharmaceutical Sciences Handbook, Mack Pub. Co., Ny. USA XVII ed. ". Compositions suitable for oral administration such as capsules, tablets, sugared almonds, granules in sachets, extemporaneous solutions or suspensions, controlled and / or modified release forms (retard) and the like will be preferred. The average daily dosage will be? decided by the doctor on the basis of pi? parameters (weight, sex and age of the patient, severity and stage of the disease) but will it be? in principle between 100 and 1,500 mg, possibly divided into 2-4 administrations.

The compounds of the invention are prepared by processes which are a function of the nature of the R group.

When R represents the N-acetylcysteine residue (la), the compound of the invention is prepared through two steps:

a) the iodesoxycholic acid is reacted with an alkyl or a phenyl chloroformate:

b) the anhydricte that is formed? esterified with N-acetylcysteine.

In the first step, the iodesoxycholic acid is reacted with phenyl chloroformate in the presence of triethylamine at a temperature of 6-20 ° C.

The resulting mixture is then reacted with compounds containing the N-acetylcysteine group at about 10 ° C, always in the presence of triethylaninine.

When is the addition of triethylamine? when the temperature is over it is brought to about 29 ° C.

The final product is isolated from the reaction mixture and optionally purified with conventional techniques known to those skilled in the art.

When R? the residue of sarcosine (Ib), the substance of the invention is prepared starting from iodesoxycholic acid and N-methyl-glycine, using the conventional techniques used for the synthesis of bile acid annides. See for example Arkiv. Remi 8, 331, 1955 and J. Lipid Res. 18: 400-407, 1967. Methods based on the use of mixed anhydrides, those based on the formation of azides of bile acids and those which involve the use of various coupling substances such as quinolinic derivatives.

If desired, N-methyl-glycine-iodesoxycholic acid can be salified with non-toxic and pharmaceutically compatible cations.

The following examples further illustrate the invention.

Example 1

a) Anhydride of iodesoxycholic acid

4.9 ml of phenyl chloroform are added to a solution of 20.2 g of iodesoxycholic acid in 80 ml of dioxane. The solution cools down to about 8 ° C in an ice bath. Maintaining this temperature, a 1 M solution of triethylanine in dioxane (1: 2.3 v / v) is slowly added.

A white precipitate is slowly formed, not very fluid, whose fluidity? increases leaving the reaction mixture at room temperature.

b) To this mixture are added 4.5 g of N-acetylcysteine at 20 ° C.

The reaction mixture? kept at around 7? C. Always around 10 ° C, 1 mole of triethylanine is slowly added and, after the addition, the reaction mixture? heated to 20 ° C and kept under stirring for 7-10 hours until completion of the reaction. The exothermicity of the reaction causes the temperature to reach about 29 ° C. The reaction product is separated by dilution with 500 ml of aqueous HC1. The chloroform is extracted.

The organic extracts after washing with H2O are concentrated. A clear oil is obtained which by subsequent purification d? a white crystalline powder that begins to decay at 57? C but? totally liquid at 95? C.

The product obtained? soluble in alcohol, partially soluble in acetone and insoluble in water. It is purified through chromatography and is identified through UV, IR and NMR spectra.

If desired, N-methyl-tauroiodesoxycholic acid can be used. be salified with ncn toxic and pharmaceutically carpatible cations.

Example 2

1.035 g of sarcosine in 1.8 ml of triethylamine breast added under stirring to a solution containing 2.5 g of iodesoxycholic acid and 2.5 g of ethoxycarbonyl 1,2 dihydroquinoline as capsulating agent dissolved in 15 ml of dimethylformamide.

A suspension is obtained which is heated at 80-90 ° C for 40 minutes until a clear solution is obtained. It is cooled to 5 ° C and the triethylanonium salt of the iodesoxycholic acid is purified by slowly adding 200 ml of ethyl ether.

A precipitate is obtained which contains the triethylanonium salt of HDCA-sarcosine. It is washed with anhydrous ether and HDC-sarcosine is crystallized in acid form from ethyl acetate and methanol.

The pure product obtained with a yield greater than 180% has a melting point of around 199? -195? C.

Claims (7)

CLAIM 1. Compounds of formula (I): where R represents the residue: (Ia) or <"> (Ib) and pharmaceutically acceptable salts thereof. 2 . Procedure for the preparation of the settlement of formula (I): R (I) where R represents the residue: (there) involving the reaction between iodesoxycholic acid and an alkyl or a phenyl chloroformate, to give the corresponding mixed anhydride and the subsequent esterification of the anhydride with N-acetyl cysteine. 3. Process for the preparation of the compound of formula (I): (I) where R represents the residue: (Ib) involving the reaction between iodesoxycholic acid and N-methyl-glycine. 4. Use of the compounds of claim 1 as therapeutic agents. 5. Use of the compounds of claim 1 for the preparation of a medicament useful in the prevention and therapy of gallstones and biliary dyspepsia, in the therapy of acute and chronic liver diseases, including those of toxic and viral origin and those of a cholestatic nature, both primitive that secondary, in the. therapy of reflux gastropathy and in the therapy of dyslipidemias, both primary and secondary. 6. Pharmaceutical compositions comprising a compound of claim 1, as active principle, in admixture with pharmaceutically acceptable excipients. 7. Constitutions according to claim 5 suitable for oral administration, such as capsules, tablets, sugared almonds, granules in sachets, extenporaneous solutions or suspensions, controlled and / or modified (retard) release forms and the like.