BE902888A - Ursodesoxycholic acid di:hemi:succinate - for treatment of biliary calculi and other biliary disorders - Google Patents
Ursodesoxycholic acid di:hemi:succinate - for treatment of biliary calculi and other biliary disorders Download PDFInfo
- Publication number
- BE902888A BE902888A BE0/215351A BE215351A BE902888A BE 902888 A BE902888 A BE 902888A BE 0/215351 A BE0/215351 A BE 0/215351A BE 215351 A BE215351 A BE 215351A BE 902888 A BE902888 A BE 902888A
- Authority
- BE
- Belgium
- Prior art keywords
- biliary
- hemi
- succinate
- treatment
- calculi
- Prior art date
Links
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 title abstract description 10
- 229960001661 ursodiol Drugs 0.000 title abstract description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title 1
- 208000001130 gallstones Diseases 0.000 title 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 4
- 150000001413 amino acids Chemical class 0.000 abstract description 4
- 229940014800 succinic anhydride Drugs 0.000 abstract description 4
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 150000002739 metals Chemical class 0.000 abstract 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000004472 Lysine Substances 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000002152 aqueous-organic solution Substances 0.000 description 1
- 210000000013 bile duct Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 201000001883 cholelithiasis Diseases 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Ursodesoxy cholic acid dihemisuccinate (I) and its salts with alkali(ne earth) metals and basic amino acids, are new. - (II) is treated with succinic anhydride under anhydrous conditions in the presence of an acid acceptor. (I) may be given orally or parenterally at a daily dosage of 100-1000 mg.
Description
"Composés régulateurs de la fonction biliaire" "Composés régulateurs de la fonction biliaire".
La présente invention est relative à de nouveaux dérivés de l'acide ursodésoxycholique, qui sont intéressants comme régulateurs de la fonction biliaire. Elle se rapporte plus particulièrement au dihémisuccinate de l'acide ursodésoxycholique ou acide
<EMI ID=1.1>
<EMI ID=2.1>
et à ses sels avec des métaux alcalins ou alcalino-terreux ou avec des aminoacides basiques, tels que la lysine, l'arginine, l'hystidine.
La présente invention se rapporte en outre à un procédé de préparation du composé 1 et des ses sels.
Un autre but encore de l'invention concerne les compositions pharmaceutiques contenant, à titre de principe actif, des quantités prédéterminées et efficaces du point de vue thérapeutique du composé 1 ou de ses sels.
Les compositions de l'invention trouvent application dans le traitement des calculs biliaires cholestéroliques, des dyscinésies des voies biliaires et, d'une façon générale, des altérations des fonctions biligéniques.
Le composé de l'invention présente en outre, par rapport à l'acide ursodésoxycholique déjà utilisé en thérapeutique, des avantages d'ordre pharmacocinétique et de biodisponibilité.
Le composé I, que l'on désignera ci-après, pour la brièveté, par le sigle RG 044, est préparé de façon convenable suivant l'invention par réaction entre l'acide ursodésoxycholique et l'anhydride succinique en présence d'accepteurs d'acidité et sous des conditions anhydres. On opère de préférence dans de la pyridine anhydre à la température de reflux.
Le produit peut ensuite être précipité dans de l'eau distillée, ou bien il peut être salifié avec des quantités stoechiométriques d'hydroxydes de métaux alcalins ou alcalino-terreux ou d'aminoacides basiques, comme la lysine, l'arginine, l'hystidine.
Les sels correspondants peuvent être obtenus par précipitation ou lyophilisation de solutions aqueuses ou aqueuses-organiques les contenant, suivant des procédés connus.
Les exemples suivants illustreront plus complètement encore l'invention sans pour autant limiter son cadre.
EXEMPLE 1
On chauffe au reflux pendant 4 heures une solution de 4 g d'acide ursodésoxycholique et de 2 g d'anhydride succinique dans 50 ml de pyridine anhydre redistillée. On laisse au repos pendant la nuit et on concentre ensuite sous vide d'abord avec une trompe à eau et ensuite avec une pompe à huile. On reprend le reste mielleux avec 50 ml d'acétone et la solution obtenue est versée directement dans 1000 ml d'eau sous agitation énergique, en maintenant en même temps acide (pH d'environ 3)la suspension aqueuse.
Par des décantations répétées de la matière surnageante aqueuse, reprise chaque fois avec une quantité égale d'eau redistillée, on arrive à obtenir la transformation complète des gommes blanches en solide cristallin; on filtre, on lave à fond à l'eau et on sèche à l'air.
Le composé obtenu (4 g) se présente sous forme d'une poudre blanche cristalline d'un point de fusion de 100-102[deg.]C, insoluble dans l'eau et soluble dans le méthanol et l'éthanol. Analyse élémentaire
<EMI ID=3.1>
EXEMPLE 2
Sel de lysine.
On met en suspension dans de l'eau bidistillée 3 g du composé I, obtenu suivant l'Exemple 1. A la suspension, maintenue sous une forte agitation, on ajoute 1,5 g de lysine. On agite jusqu'à dissolution totale, on filtre et on verse le filtrat dans des bacs en acier inoxydable, de manière à avoir un niveau de liquide d'environ 1 cm. Après congélation à -45[deg.]C, on procède à la lyophilisation . dans un appareil approprié de lyophilisation de laboratoire. On obtient 4,34 g de sel de lysine de l'hémisuccinate d'acide ursodésoxycholique.
Analyse élémentaire
<EMI ID=4.1>
La présente invention concerne également tous les aspects industriellement applicables liés à l'emploi de RG 044 et de ses sels en thérapeutique.
Un aspect essentiel de l'invention est par conséquent constitué par les compositions pharmaceutiques pouvant être administrées par voie orale ou parentérale du RG 044 ou de ses sels, par exemple sous la forme de capsules, de dragées, de comprimés, de sirops, d'ampoules, etc.
La posologie moyenne journalière est comprise entre
100 et 1000 mg du composé 1 par jour.
REVENDICATIONS.
1. Dihémisuccinate d'acide ursodésoxycholique (acide
<EMI ID=5.1>
<EMI ID=6.1>
et ses sels avec des métaux alcalins ou alcalino-terreux ou avec des aminoacides basiques, comme la lysine, l'arginine, l'hystidine.
2. Procédé de préparation du composé de la revendication 1, caractérisé en ce que l'acide ursodésoxycholique est mis en réaction avec de l'anhydride succinique en présence d'accepteurs d'acidité.
3. Compositions pharmaceutiques ayant une activité régulatrice de la fonction biliaire et contenant, comme principe actif, des quantités prédéterminées et thérapeutiquement efficaces
"Biliary function regulating compounds" "Biliary function regulating compounds".
The present invention relates to new derivatives of ursodeoxycholic acid, which are of interest as regulators of bile function. It relates more particularly to the dihemisuccinate of ursodeoxycholic acid or acid
<EMI ID = 1.1>
<EMI ID = 2.1>
and to its salts with alkali or alkaline-earth metals or with basic amino acids, such as lysine, arginine, hystidine.
The present invention further relates to a process for the preparation of compound 1 and its salts.
Yet another object of the invention relates to pharmaceutical compositions containing, as active principle, predetermined and therapeutically effective amounts of compound 1 or its salts.
The compositions of the invention find application in the treatment of cholesterol gallstones, dyscinesias of the bile ducts and, in general, alterations in biligenic functions.
The compound of the invention also has, compared to ursodeoxycholic acid already used in therapy, advantages of pharmacokinetics and bioavailability.
Compound I, which will be designated below, for brevity, by the acronym RG 044, is suitably prepared according to the invention by reaction between ursodeoxycholic acid and succinic anhydride in the presence of d acceptors acidity and under anhydrous conditions. It is preferably carried out in anhydrous pyridine at the reflux temperature.
The product can then be precipitated in distilled water, or it can be salified with stoichiometric amounts of alkali or alkaline earth metal hydroxides or basic amino acids, such as lysine, arginine, hystidine .
The corresponding salts can be obtained by precipitation or lyophilization of aqueous or aqueous-organic solutions containing them, according to known methods.
The following examples will illustrate the invention even more completely without limiting its scope.
EXAMPLE 1
A solution of 4 g of ursodeoxycholic acid and 2 g of succinic anhydride in 50 ml of redistilled anhydrous pyridine is heated at reflux for 4 hours. It is left to stand overnight and then concentrated in vacuo first with a water pump and then with an oil pump. The honey residue is taken up with 50 ml of acetone and the solution obtained is poured directly into 1000 ml of water with vigorous stirring, while at the same time keeping the aqueous suspension acidic (pH approximately 3).
By repeated decantations of the aqueous supernatant, taken up each time with an equal amount of redistilled water, it is possible to obtain the complete transformation of the white gums into a crystalline solid; filter, wash thoroughly with water and air dry.
The compound obtained (4 g) is in the form of a white crystalline powder with a melting point of 100-102 [deg.] C, insoluble in water and soluble in methanol and ethanol. Elementary analysis
<EMI ID = 3.1>
EXAMPLE 2
Lysine salt.
3 g of compound I, obtained according to Example 1, are suspended in bidistilled water. To the suspension, maintained under vigorous stirring, 1.5 g of lysine are added. Stir until completely dissolved, filter and pour the filtrate into stainless steel tanks, so as to have a liquid level of approximately 1 cm. After freezing at -45 [deg.] C, lyophilization is carried out. in a suitable laboratory freeze-drying device. 4.34 g of lysine salt of ursodeoxycholic acid hemisuccinate are obtained.
Elementary analysis
<EMI ID = 4.1>
The present invention also relates to all the industrially applicable aspects linked to the use of RG 044 and its salts in therapy.
An essential aspect of the invention therefore consists of pharmaceutical compositions which can be administered orally or parenterally of RG 044 or its salts, for example in the form of capsules, dragees, tablets, syrups, bulbs, etc.
The average daily dosage is between
100 and 1000 mg of compound 1 per day.
CLAIMS.
1. Ursodeoxycholic acid dihemisuccinate (acid
<EMI ID = 5.1>
<EMI ID = 6.1>
and its salts with alkali or alkaline earth metals or with basic amino acids, such as lysine, arginine, hystidine.
2. Process for the preparation of the compound of claim 1, characterized in that the ursodeoxycholic acid is reacted with succinic anhydride in the presence of acid acceptors.
3. Pharmaceutical compositions having an activity regulating bile function and containing, as active principle, predetermined and therapeutically effective amounts
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE0/215351A BE902888A (en) | 1985-07-12 | 1985-07-12 | Ursodesoxycholic acid di:hemi:succinate - for treatment of biliary calculi and other biliary disorders |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE902888 | 1985-07-12 | ||
| BE0/215351A BE902888A (en) | 1985-07-12 | 1985-07-12 | Ursodesoxycholic acid di:hemi:succinate - for treatment of biliary calculi and other biliary disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BE902888A true BE902888A (en) | 1985-11-04 |
Family
ID=25654659
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BE0/215351A BE902888A (en) | 1985-07-12 | 1985-07-12 | Ursodesoxycholic acid di:hemi:succinate - for treatment of biliary calculi and other biliary disorders |
Country Status (1)
| Country | Link |
|---|---|
| BE (1) | BE902888A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2630649A1 (en) * | 1988-04-30 | 1989-11-03 | Sandoz Sa | ACID ADDITION SALTS OF TAURINE OR GLYCINE N-ACYLATED DERIVATIVES, THEIR PREPARATION AND THEIR USE |
-
1985
- 1985-07-12 BE BE0/215351A patent/BE902888A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2630649A1 (en) * | 1988-04-30 | 1989-11-03 | Sandoz Sa | ACID ADDITION SALTS OF TAURINE OR GLYCINE N-ACYLATED DERIVATIVES, THEIR PREPARATION AND THEIR USE |
| BE1003817A3 (en) * | 1988-04-30 | 1992-06-23 | Sandoz Sa | Acid addition salts of derivatives of n-acylated taurine or glycine, preparation and use. |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| RE | Patent lapsed |
Owner name: RIPARI GERO ISTITUTO FARMACO BIOLOGICO S.R.L. Effective date: 19950731 |