EP0422055A1 - Ursodeoxycholsäure-derivate - Google Patents
Ursodeoxycholsäure-derivateInfo
- 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- Withdrawn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
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical class 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 claims abstract description 11
- 239000003020 ursodeoxycholic acid derivative Substances 0.000 title abstract description 4
- 206010057969 Reflux gastritis Diseases 0.000 claims abstract description 4
- 208000019423 liver disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 10
- 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 claims description 9
- 229960001661 ursodiol Drugs 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 201000001883 cholelithiasis Diseases 0.000 abstract 1
- 208000001130 gallstones Diseases 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000015924 Lithiasis Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic 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-BSWAIDMHSA-N 0.000 description 1
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
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)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2113588 | 1988-06-28 | ||
| IT21135/88A IT1219733B (it) | 1988-06-28 | 1988-06-28 | Derivato dell' acido ursodesossicolico |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0422055A1 true EP0422055A1 (de) | 1991-04-17 |
Family
ID=11177269
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP89907146A Withdrawn EP0422055A1 (de) | 1988-06-28 | 1989-06-21 | Ursodeoxycholsäure-derivate |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0422055A1 (de) |
| JP (1) | JPH03505455A (de) |
| AU (1) | AU3839489A (de) |
| IT (1) | IT1219733B (de) |
| WO (1) | WO1990000175A1 (de) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112016002268B1 (pt) * | 2013-08-01 | 2022-11-01 | The Penn State Research Foundation | Uso de inibidores do receptor x farnesoide |
| IT201800009682A1 (it) * | 2018-10-22 | 2020-04-22 | Ice Spa | Coniugati di acidi biliari e loro derivati per la veicolazione di molecole attive |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1167038B (it) * | 1983-11-30 | 1987-05-06 | Prodotti Chimici & Alimentari | Procedimento per la sintesi di acido ursodesossicolico coniugato con la taurina |
-
1988
- 1988-06-28 IT IT21135/88A patent/IT1219733B/it active
-
1989
- 1989-06-21 WO PCT/EP1989/000699 patent/WO1990000175A1/en not_active Ceased
- 1989-06-21 JP JP1506976A patent/JPH03505455A/ja active Pending
- 1989-06-21 EP EP89907146A patent/EP0422055A1/de not_active Withdrawn
- 1989-06-21 AU AU38394/89A patent/AU3839489A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9000175A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1219733B (it) | 1990-05-24 |
| IT8821135A0 (it) | 1988-06-28 |
| JPH03505455A (ja) | 1991-11-28 |
| AU3839489A (en) | 1990-01-23 |
| WO1990000175A1 (en) | 1990-01-11 |
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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 |