WO1994024147A1 - Iodeoxycholic acid derivatives - Google Patents
Iodeoxycholic acid derivatives Download PDFInfo
- Publication number
- WO1994024147A1 WO1994024147A1 PCT/EP1994/001143 EP9401143W WO9424147A1 WO 1994024147 A1 WO1994024147 A1 WO 1994024147A1 EP 9401143 W EP9401143 W EP 9401143W WO 9424147 A1 WO9424147 A1 WO 9424147A1
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- WO
- WIPO (PCT)
- Prior art keywords
- therapy
- cooh
- compounds
- bile
- residue
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
- C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The compounds of formula (I), wherein R is the residue: (Ia) or (Ib) and the pharmaceutically acceptable salts thereof have therapeutic properties in the treatment of the hepatobiliary pathologies.
Description
IODEOXYCHOLIC ACID DERIVATIVES
The present invention relates to iodeoxycholic acid derivatives of formula (I):
I (la)
NHC0CH3 or -N-CH2-COOH
I (lb)
CH„ and pharmaceutically acceptable salts.
The invention also relates to processes for the preparation of compounds of formula (I)/ the use thereof as therapeutical agents and pharmaceutical compositions containing.
Iodeoxycholic acid (HDCA) is a natural bile salt present in pig bile. The purification of iodeoxycholic acid is described in US 2745849 and in US 3006927.
Recently, the taurine conjugated HDCA, tauroiodeoxycholic acid, (EP 0293751) proved to be
potentially useful both in dissolving human cholesterol calculi (Gastroenterology 100-.A308, 1991), and in promoting bile secretion and desaturation (Hepatology 14; 294A, 1991; Gastroenterology, May 1992). The conjugation with N-methyl-glycine of other bile acids has already been described (Hepatology, 11, 989-96 1990; J. Lipid Res. 27, 742-52, 1986), as an effective measure to obviate the problem of the deconjugation by colon bacteria; the up-to-now available experimental evidences on bile acids N- methyl-glycine conjugated, particularly of ursodeoxycholic acid, however, do not allow to draw final conclusions about the general effectiveness of said measure in order to develop novel therapeutical agents.
Now it has been found that the compounds of formula (I) have advantageous properties, which can thus be summarized.
1 - Effective intestinal absorption, mainly with an active mechanism at the level of terminal ileum.
2 - Very good uptake by liver. Absence of biotransformations and/or hepatic metabolization.
3 - Ready and effective secretion in the bile, requiring no conjugation steps, being the molecule already present in an "active" form, i.e. ready for bile secretion.
4 - Remarkable choleretic and cholagogue efficacies.
5 - Favourable hydrophilic properties.
6 - Absence of membrane-toxicity, thanks to the hydrophilic characteristics and the poor detergent power.
7 - Reduced or no intestinal deconjugation, thanks to the above cited resistance to enzyme hydrolysis. This fact prevents the compound from being 6-0- dehydroxylated and thus it is not transformed into lithocholic acid.
8 - Absence of hepatic and renal glucuronation, which is a direct consequence of the conjugation in a biologically stable form, as it happens, on the contrary, with iodeoxycholic acid in the unconjugated form (J. Lipid Res. 24:604-613,
1983).
The pharmacological tests evidenced that the compounds of the invention are capable of promoting the bile secretion of lipids, particularly cholesterol, in a stable form, due to the formation in the bile of an abundant liquid-crystal phase, which prevents any precipitations of cholesterol monohydrate in a solid crystal from.
The derivatives of the invention, moreover, have a strong membrane-protecting action, thanks to the intrinsic hydrophilicity thereof. Particularly, they are capable of protecting cells (in particular hepatocytes) from both the toxic-detergent action of hydrophobic endogenous bile salts and the one of toxic or viral agents. Further, they proved to have a longer- lasting pharmacological effect than natural bile salts.
From the above statements, it is evident that the compounds of the invention can advantageously be used in human therapy, with the following indications: 1 - Prevention and therapy of bile calculosis and bile dyspepsia.
2 - Therapy of acute and chronic hepatopathies, including those of toxic or viral origin and those of cholestatic nature, both primary and secondary.
3 - Therapy of malabsorption syndromes, both primary and secondary.
4 - Therapy of reflux gastropathies.
5 - Therapy of the dyslipidemias, both primary and secondary.
For the envisaged therapeutical uses, the compounds of the invention can be formulated in suitable pharmaceutical compositions, according to known techniques and excipients, such as those described in "Remington's Pharmaceutical Sciences Handbook, Mack Pub. Co., NY. USA XVII Ed.". Preferred compositions are those suitable for oral administration, such as capsules, tablets, sugar-coated pills, granulates in sachets, solutions or suspensions for reconstitution before use, controlled and/or modified (retard) release-forms and the like. The average daily dosage will be chosen by the physician, depending on many factors (weight, sex and age of the patient, severity and phase of the disease), but in principle it will range from 100 to 1,500 mg, optionally subdivided into 2-4 administrations. The compounds of the invention are prepared by processes depending on the nature of the R group.
When R is the N-acetylcysteine residue (la), the compound of the invention is prepared through two steps: a) iodeoxycholic acid is reacted with an alkyl or phenyl chloroformate;
b) the formed anhydride is esterified with N- acetylcysteine.
In the first step, iodeoxycholic 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 triethylamine.
When triethylamine addition is over, the temperature is raised to about 29°C.
The final product is recovered from the reaction mixture and optionally purified with conventional techniques known to those skilled in the art.
When R is the sarcosine residue (lb), the compound of the invention is prepared starting from iodeoxycholic acid and N-methyl-glycine, using the conventional techniques used for the synthesis of bile acid amides. See for example Arkiv. Kemi 8, 331, 1955 and J. Lipid Res. 18:400-407, 1967. By way of examples, the methods using mixed anhydrides, those involving the formation of bile acid azides and those using various coupling substances, such as quinolone derivatives, may be cited.
If desired, N-methyl-glycine-iodeoxycholic acid can be salified with non toxic, pharmaceutically compatible cations.
The following examples further illustrate the invention.
Example 1 a) Iodeoxycholic acid anhydride
A solution of 20.2 g of iodeoxycholic acid in 80
ml of dioxane is added with 4.9 ml of phenyl chloroformate. The solution is cooled to about 8°C in an ice bath. Keeping this temperature, a 1 M triethylamine solution in dioxane (1:2,3 v/v) is slowly added.
A white precipitate forms which is not very fluid, but which becomes more fluid leaving the reaction mixture at room temperature b) The mixture is added at 20°C with 4.5 g of N- acetylcysteine.
The reaction mixture is kept at about 7°C. keeping temperature at about 10°C, 1 mol of triethylamine is slowly added and, after the addition, the reaction mixture is heated to 20°C and kept under stirring for 7-10 hours until the reaction is completed. The exothermicity of the reaction raises temperature to about 29°C. The reaction product is separated by dilution with 500 ml of aqueous HC1 and the chloroform phase is extracted. The organic extracts, after washing with H-O, are concentrated to obtain a clear oil which is subsequently purified to give a white crystal powder which begins decomposing at 57°C and is completely liquid at 95°C. The obtained product is soluble in alcohol, partially soluble in acetone and insoluble in water. The product is purified by chromatography and identified by the UV, IR and NMR spectra.
If desired, N-methyl-tauroiodeoxycholic acid can be salified with non-toxic, pharmaceutically compatible cations. Example 2
1.035 g of sarcosine in 1.8 ml of triethylamine
are added under stirring to a solution containing 2.5 g of iodeoxycholic acid and 2.5 g of ethoxycarbonyl-1,2- dihydroquinoline as the coupling agent dissolved in 15 ml of dimethylformamide. The resulting suspension is heated to 80-90°C for 40 minutes to obtain a clear solution, which is cooled to 5°C. The iodeoxycholic acid triethylammonium salt is purified by adding slowly 200 ml of ethyl ether. A precipitate is obtained, containing the HDCA-sarcosine triethylammonium salt, which is washed with anhydrous ether. HDC-Sarcosine is crystallized, in the acidic form, from ethyl acetate and methanol. The pure product is obtained in a yield higher than 80%, melting at about 199°-195°C.
Claims
1. Compounds of formula (I):
CO-R
(I)
H OH wherein R is the residue: -S-CH2_CH-COOH;
I (la)
NHCOCH, or -N-CH2-COOH
I (lb) CH, and the pharmaceutically acceptable salts thereof.
2. A process for the preparation of the compound of formula (I) :
(I)
I (la)
NHCOCH, which process comprises reacting iodeoxycholic acid and an alkyl or phenyl chloroformate, to give' the corresponding mixed anhydride, and subsequently esterificating the anhydride with N- acetyl-cysteine.
3. A process for the preparation of the compound of formula (I) :
wherein R is the residue: -N-CH2-COOH
! (lb) CH„ which process comprises reacting iodeoxycholic acid and N-methyl-glycine.
4. The use of the compounds of claim 1 as therapeutical agents.
5. The use of the compounds of claim 1 for the preparation of a medicament useful in the prevention and therapy of bile calculosis and bile dyspepsia, in the therapy of acute and chronic hepatopathies, including those of toxic and viral origin and those of cholestatic nature, both primary and secondary, in the therapy of reflux gastropathy, in the therapy of the dyslipidemias, both primary and secondary.
6. Pharmaceutical compositions comprising a compound of claim 1 as the active ingredient, in admixture with excipients pharmaceutically acceptable.
7. Compositions according to claim 5 suitable for oral administration, such as capsules, tablets, sugar- coated pills, granulates in sachets, solutions or suspensions for reconstitution before use, forms a controlled and/or modified release forms (retard) .
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU65682/94A AU6568294A (en) | 1993-04-16 | 1994-04-13 | Iodeoxycholic acid derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT93MI000749A IT1264131B1 (en) | 1993-04-16 | 1993-04-16 | DERIVED FROM IODESOXICOLIC ACID |
ITMI93A000749 | 1993-04-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994024147A1 true WO1994024147A1 (en) | 1994-10-27 |
Family
ID=11365771
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1994/001143 WO1994024147A1 (en) | 1993-04-16 | 1994-04-13 | Iodeoxycholic acid derivatives |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU6568294A (en) |
IT (1) | IT1264131B1 (en) |
WO (1) | WO1994024147A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015017813A2 (en) * | 2013-08-01 | 2015-02-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inhibitors of the farnesoid x receptor and uses in medicine |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0273188A1 (en) * | 1986-11-26 | 1988-07-06 | Jago Research AG | Process for preparing therapeutically active derivatives of ursodeoxycholic acid. |
EP0513887A1 (en) * | 1991-04-17 | 1992-11-19 | Prodotti Chimici E Alimentari Spa | N-alkyltauroursodeoxycholic acids and their therapeutically active derivatives, a process for their preparation and pharmaceutical compositions containing them |
WO1994002503A1 (en) * | 1992-07-22 | 1994-02-03 | Enosys S.A. | Bile acid derivative and use thereof in therapy |
-
1993
- 1993-04-16 IT IT93MI000749A patent/IT1264131B1/en active IP Right Grant
-
1994
- 1994-04-13 WO PCT/EP1994/001143 patent/WO1994024147A1/en active Application Filing
- 1994-04-13 AU AU65682/94A patent/AU6568294A/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0273188A1 (en) * | 1986-11-26 | 1988-07-06 | Jago Research AG | Process for preparing therapeutically active derivatives of ursodeoxycholic acid. |
EP0513887A1 (en) * | 1991-04-17 | 1992-11-19 | Prodotti Chimici E Alimentari Spa | N-alkyltauroursodeoxycholic acids and their therapeutically active derivatives, a process for their preparation and pharmaceutical compositions containing them |
WO1994002503A1 (en) * | 1992-07-22 | 1994-02-03 | Enosys S.A. | Bile acid derivative and use thereof in therapy |
Non-Patent Citations (1)
Title |
---|
E. H. MOSBACH ET AL: "Effect of Bile Acids and Bile Acid Analogs on Cholesterol Metabolism in the Hamster", FALK SYMPOSIUM, vol. 42, 1985, LANCASTER GB, pages 199 - 204 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015017813A2 (en) * | 2013-08-01 | 2015-02-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inhibitors of the farnesoid x receptor and uses in medicine |
WO2015017813A3 (en) * | 2013-08-01 | 2015-04-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inhibitors of the farnesoid x receptor and uses in medicine |
CN105593237A (en) * | 2013-08-01 | 2016-05-18 | 美国卫生和人力服务部 | Inhibitors of the farnesoid x receptor and uses in medicine |
US9540415B2 (en) | 2013-08-01 | 2017-01-10 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inhibitors of the farnesoid X receptor and uses in medicine |
US10233209B2 (en) | 2013-08-01 | 2019-03-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Inhibitors of the farnesoid x receptor and uses in medicine |
CN110437297A (en) * | 2013-08-01 | 2019-11-12 | 美国卫生和人力服务部 | The inhibitor of farnesoid X receptor and purposes in medicine |
Also Published As
Publication number | Publication date |
---|---|
ITMI930749A0 (en) | 1993-04-16 |
ITMI930749A1 (en) | 1994-10-16 |
AU6568294A (en) | 1994-11-08 |
IT1264131B1 (en) | 1996-09-16 |
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