EP0422055A1 - Novel ursodeoxycholic acid derivative - Google Patents
Novel ursodeoxycholic acid derivativeInfo
- Publication number
- EP0422055A1 EP0422055A1 EP89907146A EP89907146A EP0422055A1 EP 0422055 A1 EP0422055 A1 EP 0422055A1 EP 89907146 A EP89907146 A EP 89907146A EP 89907146 A EP89907146 A EP 89907146A EP 0422055 A1 EP0422055 A1 EP 0422055A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ursodeoxycholic acid
- compound
- biliary
- acid derivative
- novel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Definitions
- the present invention relates to a novel ursodeoxycholic acid derivative, namely ursodeoxycholic acid L-e ⁇ i-glycerophosphorylethanolamide of formula I:
- cholesterol solubility i ⁇ known to derive from a proper cholesterol/biliary acids/phospholipides ratio.
- compound I has been found to have surprising pharmacological activities, together with an extremely poor or no toxicity.
- a further advantage of the compound of the invention is provided by the watersolubility of said molecule, which makes it easier to be administered and therefore suited to various pharmaceutical formulations.
- compositions for the treatment of biliary calculosis, biliary dyscinesias, of some hepatopathies and of reflux gastritis containing as the active ingredient the ursodeoxycholic acid L-° -gl cerophosphorylethanolamide.
- a further object of the present invention is provided by the use of amide I for the treatment of biliary calculosis, biliary dyscinesias, reflux gastritis and some hepatopathies.
- use in the present invention means all the procedures related to the preparation of the compound of the invention, including the purification as well as the formulation into pharmaceutical compositions suited for the administration and/or the confections suited for the administration itself.
- the invention relates to a process for the preparation of amide I, which process consists in the condensation of ursodeoxycholic acid and L-c**/ -glycero- phosphorylethanola ine by means of the condensing agent EEDQ (i.e., N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoli- ne), which is a known reactant for the preparation of polypeptides under mild not racemizing conditions (Bellau, et al. , JACS, 90_, 1652, 1968).
- EEDQ condensing agent
- EXAMPLE 1 Triethylamine (21,33 ml; 153,06 mmoles) are added to a solution obtained dissolving L- o.-glycerophosphoryl- ethanolamine (21,39 g; 99,49 mmoles) in water (2,0 M; 49,3 mmoles) at room temperature. Thereafter, a solution obtained dissolving ursodeoxycholic acid (30 g; 76,53 mmoles) and EEDQ (28,39 g; 114,79 mmoles) in dimethylformamide (0,57 M; 134 ml) is added thereto at room temperature.
- the mixture is left to react for about 72 hours at r.t., under strong stirring, then DMF and water are evaporated under 0,1 mm Hg, till obtaining an oil which is taken up into about 800 ml of water and 100 ml of methanol, adjusting pH of the resulting solution to about 3 with diluted hydrochloric acid 1:1.
- Example 2 The procedure of Example 1 is repeated till evaporation under 0,1 mm Hg of the DMF/water mixture.
- compound I or a pharmaceutically acceptable salt thereof is administered to the patient either in the pure form or as a pharmaceutical composition, preferably by the oral or parenteral routes.
- the pharmaceutical compositions used are the conventional ones, prepared according to the techniques described, for example, in "Remington's Pharmaceutical Sciences Handbook”hack Pub. Co., N.Y. USA.
- the dosage will depend on various factors, such as the severity of the pathology to be treated, the patient conditions (weight, sex, age): generally, it will be 200 to 700 mg/die for compound I or the equivalent of a salt thereof, possibly divided in more administration ⁇ .
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
Le dérivé d'acide ursodésoxycholique décrit, qui est représenté par la formule (I), présente une activité thérapeutique contre les calculs biliaires, contre les diskynésies biliaires, contre les gastrites par reflux et contre certaines hépatopathies.The ursodeoxycholic acid derivative described, which is represented by the formula (I), has therapeutic activity against gallstones, against biliary diskynesias, against reflux gastritis and against certain hepatopathies.
Description
NOVEL URSODEOXYCHOLIC ACID DERIVATIVE
The present invention relates to a novel ursodeoxycholic acid derivative, namely ursodeoxycholic acid L-e^i-glycerophosphorylethanolamide of formula I:
as well as to the pharmaceutically acceptable salts thereof, such as those in which the acid hydroxy residue of phosphorus is salified with alkali or alkali-earth metals.
Therapy with ursodeoxycholic acid in the field of biliary calculosis has been known for a long time (Nakagawa, et al., Lancet, 2_ , 367, 1977). The metabolic pathway of said acid also has widely been studied; particularly ursodeoxycholic acid proved to be more effective than the 7- position epi er thereof, i.e. chenodeoxycholic acid, possibly due to the lower liability of the hydroxy group at the 7-position to undergo inactivation (Ferrari et al. , Febε. Lett., 75, 176, 1977).
Moreover, cholesterol solubility iε known to derive from a proper cholesterol/biliary acids/phospholipides ratio.
Now, compound I has been found to have surprising pharmacological activities, together with an extremely poor or no toxicity.
Said activities, which have been evidenced by pharmacokinetic tests on Wistar rats, are remarkably' higher than those of ursodeoxycholic acid, used as the control drug.
A further advantage of the compound of the invention is provided by the watersolubility of said molecule, which makes it easier to be administered and therefore suited to various pharmaceutical formulations.
Therefore, another object of the present invention is provided by pharmaceutical compositions for the treatment of biliary calculosis, biliary dyscinesias, of some hepatopathies and of reflux gastritis, containing as the active ingredient the ursodeoxycholic acid L-° -gl cerophosphorylethanolamide.
A further object of the present invention is provided by the use of amide I for the treatment of biliary calculosis, biliary dyscinesias, reflux gastritis and some hepatopathies.
The word "use" in the present invention means all the procedures related to the preparation of the compound of the invention, including the purification as well as the formulation into pharmaceutical compositions suited for the administration and/or the confections suited for the administration itself.
Finally, the invention relates to a process for the preparation of amide I, which process consists in the condensation of ursodeoxycholic acid and L-c**/ -glycero-
phosphorylethanola ine by means of the condensing agent EEDQ (i.e., N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoli- ne), which is a known reactant for the preparation of polypeptides under mild not racemizing conditions (Bellau, et al. , JACS, 90_, 1652, 1968).
The following non limiting examples illustrate the invention in more detail.
EXAMPLE 1 Triethylamine (21,33 ml; 153,06 mmoles) are added to a solution obtained dissolving L- o.-glycerophosphoryl- ethanolamine (21,39 g; 99,49 mmoles) in water (2,0 M; 49,3 mmoles) at room temperature. Thereafter, a solution obtained dissolving ursodeoxycholic acid (30 g; 76,53 mmoles) and EEDQ (28,39 g; 114,79 mmoles) in dimethylformamide (0,57 M; 134 ml) is added thereto at room temperature. The mixture is left to react for about 72 hours at r.t., under strong stirring, then DMF and water are evaporated under 0,1 mm Hg, till obtaining an oil which is taken up into about 800 ml of water and 100 ml of methanol, adjusting pH of the resulting solution to about 3 with diluted hydrochloric acid 1:1.
After that, impurities are extracted more times with chloroform, finally the solution is concentrated to obtain such a volume as to be directly loaded on an Amberlite IR-120 (Na+) column (about 300 ml of wet resin; column diameter 4 cm; flow rate = 10' /min.). The column is eluted with water (about 1,5 1) and the eluate is extracted directly with n-butanol (4 x 200 ml).
The butanol extracts are then dried over Na„SO„ and
2 4 evaporated to dryness under vacuum.
After drying under 0,1 mm Hg, about 32 g of a white crystalline slightly hygroscopic product are obtained. Yield: 68%.
EXAMPLE 2 The procedure of Example 1 is repeated till evaporation under 0,1 mm Hg of the DMF/water mixture.
Then the resulting oil is taken up into water and purified by continuous extraction with ethyl acetate. After that, the aqueous εolution iε concentrated to such a volume aε to be directly loaded on an A berlite IR-120 (Na ) column. From this moment, the procedure of Example 1 is followed, to obtain a product having the following characteristicε: 1H-NMR (80 MHz) (CD OD) : pp . 0,75-2,40 ; 3,40-4,10. Elemental analysis: C = 56,85% (theory = 56,96%) H = 8,40% (theory = 8,35%) N = 2,24% (theory = 2,29% tD = + 36,8 Cl in ethanol m.p. = 120°C.
The above disclosed data clearly show that the compounds of the invention can effectively be used for the therapy of biliary calculosiε, biliary dyεcineεias, reflux gastritiε and some hepatopathieε.
To this purpose, compound I or a pharmaceutically acceptable salt thereof is administered to the patient either in the pure form or as a pharmaceutical composition, preferably by the oral or parenteral routes. The pharmaceutical compositions used are the
conventional ones, prepared according to the techniques described, for example, in "Remington's Pharmaceutical Sciences Handbook" Hack Pub. Co., N.Y. USA.
The dosage will depend on various factors, such as the severity of the pathology to be treated, the patient conditions (weight, sex, age): generally, it will be 200 to 700 mg/die for compound I or the equivalent of a salt thereof, possibly divided in more administrationε.
Claims
1. The compound of formula I
and the pharmaceutically acceptable saltε thereof.
2. A proceεs for the preparation of compound I, in which process ursodeoxycholic acid is reacted with
L-o -glycerophosphorylethanolamine in the presence of a condensing agent.
3. A procesε as claimed in claim 2 , in which N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline is used as the condensing agent.
4. Pharmaceutical compositionε containing aε the active ingredient the compound of claim 1 in admixture with an appropriate carrier or excipient.
5. The use of the compound of claim 1 for the preparation of a medicament useful for the therapy of biliary calculosiε, biliary dyscinesias, reflux gastritis and hepatopathies.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT21135/88A IT1219733B (en) | 1988-06-28 | 1988-06-28 | URSODESOXYOLIC ACID DERIVATIVE |
| IT2113588 | 1988-06-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0422055A1 true EP0422055A1 (en) | 1991-04-17 |
Family
ID=11177269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89907146A Withdrawn EP0422055A1 (en) | 1988-06-28 | 1989-06-21 | Novel ursodeoxycholic acid derivative |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0422055A1 (en) |
| JP (1) | JPH03505455A (en) |
| AU (1) | AU3839489A (en) |
| IT (1) | IT1219733B (en) |
| WO (1) | WO1990000175A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2920017C (en) | 2013-08-01 | 2021-11-23 | Frank J. Gonzalez | Inhibitors of the farnesoid x receptor and uses in medicine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1167038B (en) * | 1983-11-30 | 1987-05-06 | Prodotti Chimici & Alimentari | Taurourso-deoxycholic acid prodn. from urso-deoxycholic acid |
-
1988
- 1988-06-28 IT IT21135/88A patent/IT1219733B/en active
-
1989
- 1989-06-21 WO PCT/EP1989/000699 patent/WO1990000175A1/en not_active Application Discontinuation
- 1989-06-21 EP EP89907146A patent/EP0422055A1/en not_active Withdrawn
- 1989-06-21 AU AU38394/89A patent/AU3839489A/en not_active Abandoned
- 1989-06-21 JP JP1506976A patent/JPH03505455A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9000175A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8821135A0 (en) | 1988-06-28 |
| JPH03505455A (en) | 1991-11-28 |
| IT1219733B (en) | 1990-05-24 |
| WO1990000175A1 (en) | 1990-01-11 |
| AU3839489A (en) | 1990-01-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 19901220 |
|
| AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
| 17Q | First examination report despatched |
Effective date: 19911028 |
|
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 19921006 |