NZ230605A - Choline salts of 5-beta-cholanic-24 acid derivatives and compositions for pharmaceutical and cosmetic uses - Google Patents
Choline salts of 5-beta-cholanic-24 acid derivatives and compositions for pharmaceutical and cosmetic usesInfo
- Publication number
- NZ230605A NZ230605A NZ230605A NZ23060589A NZ230605A NZ 230605 A NZ230605 A NZ 230605A NZ 230605 A NZ230605 A NZ 230605A NZ 23060589 A NZ23060589 A NZ 23060589A NZ 230605 A NZ230605 A NZ 230605A
- Authority
- NZ
- New Zealand
- Prior art keywords
- 5beta
- cholanic
- acid
- hydroxy
- 3alpha
- Prior art date
Links
Classifications
-
- 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
Abstract
2-Hydroxy-N,N,N-trimethylethanaminium salts of 5 beta -cholane-24-acid derivatives of general formula (I), wherein R1 and R2 as well as R3 and R4 jointly denote an oxo group, or denote two hydrogen atoms, or one hydrogen atom and one hydroxy group, and X denotes a C-O bond or a group of formula -NH-(CH2-CO- or -NH-CH2)2-SO2-, are compounds with useful pharmacological and cosmetic activity.
Description
New Zealand Paient Spedficaiion for Paient Number £30605
23 0 6 05
Priority DaMs):..^
CoropteU Specification Steel:
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NO DRAWINGS
N.Z. NO.
NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION 2-HYDROXY-N.N.N-TRIMETHYLETHANAMINIUM SALTS OF 5BETA-CHOLANIC-24 ACID DERIVATIVES
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We, DIAMALT AKTIENGESELLSCHAFT, a German company of Werk Miinchen-Allach, Georg-Reismuller-Str. 34, D-8000 Munchen 50, Germany do hereby declare the invention, for which pray we that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 - (Followed by 1A)
230605
- i A"
2—HYDROXY-N, N, N-TRIMETHYLETIIANAMINIUM SALTS OF 5BETA-CHOUVNIC—24 ACID DERIVATIVES
Summary of the Invention This invention provides 2-hydroxy-N,N,N-trimethylethanaminium salts (= choline salts) of formula I
HO
X - 0
ich3)3NCH2CH2OH
(I
wherein
R1 and R2, and R3 and R4, independently, together are an oxo group, or are two hydrogen atoms or a hydrogen atom and a hydroxy group, and
X is a C-0 bond (i.e., a single bond directly 0
II
connecting -C- and -0-) or an -NH-CH2-CO- or -NH-(CH2) 2-S02- group,
23 0 6
which are pharmacologically effective substances which can be used, for example, as active ingredients of cholagogue or biliary tract therapeutic agents, as well as pharmaceutical and cosmetic preparations containing them.
The production of 2-hydroxy-N,N,N-trimethylethanaminium salts (= choline salts) of formula I can be performed under conditions which are well known to one skilled in the art.
Thus, for example, the free carboxylic acids of formula II
wherein
R, and R2, and R3 and R;, independently, together are an oxo group, or are two hydrogen atoms or a hydrogen atom and a hydroxy group, and
X is a C-0 bond or an -NH-CH2-CO- or -NH-(CH2) 2-S02-group, and
Y represents a hydrogen or an alkali metal atom, is reacted with a compound of general formula III
Z
(ch3) 3-n-hc2-ch2-oh
23 0 6 0 5
wherein
Z represents a hydroxy group, if Y is a hydrogen atom, or means the radical of an inorganic acid, if Y is an alkali metal atom;
can be reacted in a polar inert solvent with choline.
Suitable solvents include, for example, lower alcohols (e.g., methanol, ethanol, propanol, isopropanol, etc.) or lower ketones (e.g., acetone, methyl ethyl ketone). On the other hand, dipolar aprotic solvents (e.g., dimethylformamide, hexamethylphosphoric acid triamide, etc.) are also suitable. But the latter generally do not produce any advantages. If lower alcohols and about 0.2 to 1 mol of acid per mol of choline are used, the salts can be isolated in a simple way, by the reaction mixture being concentrated by evaporation and/or the reaction products being precipitated by addition of nonpolar solvents, such as, for example, acetone.
On the other hand, the alkali metal salts of cholanic-24 acid derivatives of formula II (preferably the sodium and potassium salts) can also be reacted with choline salts of inorganic acids (preferably choline chloride or choline sulfate) . This reaction can also be performed in inert polar solvents. If the reaction is performed in one of the above-named lower alcohols by use of approximately equimolar amounts of the two reactants, then the reaction product, after filtering off of the alkali metal salt of the inorganic acid, can be isolated in a simple way, by the filtrate being concentrated by evaporation and/or precipitated by addition of nonpolar solvents such as, for example, acetone.
These reaction variants can of course also be performed so that the free acids of formula II are reacted with a choline salt or an inorganic acid in an inert solvent, for example in the presence of alkali
230605
metal bicarbonates (e.g., sodium bicarbonate or potassium bicarbonate).
The 2-hydroxy-N,N,N-trimethylethanaminium salts of general formula I have the same pharmacological effect as the 5beta-cholanic-24 acid derivatives of general formula II, wherein R, and R2 are oxo, and R3, RA and Y are H. Further, they exhibit a bactericidal or virucidal effectiveness.
Furthermore, the compounds according to the invention surprisingly exhibit, among other properties, good water solubility, good stability, relatively low basicity, and relatively good resorbability.
For production of pharmaceutical agent specialties the compounds according to the invention optionally are processed with the usual additives and flavorings into tablets, dragees and capsules, which normally contain 50 to 500 mg of active ingredient per dosage unit.
If the pharmaceutical agent specialty is to be used for medicinal dissolution of cholesterol gallstones, in animals, e.g., mammals, e.g., humans, as prophylaxis against gallstone formation or as bactericidal or virucidal agents, 5 to 2 0 mg of active ingredient per kg of body weight per day is generally administered to the patient, analogously to the known compound
Z3 0 6
It will be appreciated that the actual preferred amounts of active compound in a specific case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of 5 application, and the particular situs and organism being treated. Dosages for a given host can be determined using conventional considerations, e.g., by customary comparison of the differential activities of the subject compounds and of a known agent, e.g., by means of an 10 appropriate, conventional pharmacological protocol.
The great water solubility of the substances according to the invention further also make possible the production of aqueous solutions, which, for example, are suitable for infusion or injection, which can 15 advantageously be used for treatment of primary biliary cirrhosis and primary sclerosing cholangitis as well as also for treatment of organ-caused acute disturbances of the bile flow or of intestinal absorption or which are suitable for irrigation of the bile duct or of the 20 gallbladder by percutaneous transhepatic drainage.
Further, the substances according to the invention are also suitable for making into water/oil and/or oil/water emulsions. The lotions, creams or ointments are suitable as dermatological preparations, for example, 25 for treatment of wounds or as cosmetics. Production of these lotions, creams or ointments takes place according to methods as they are well known to one skilled in the art (Dr. J. Stephen Jellinek "Kosmetologie" [Cosmetology] 2nd edition, 1967, Dr. Alfred Huethig Verlag, Heidelberg 30 (West Germany) and European patent specification 0065
929) .
2306 05
The substances according to the invention are further suitable as galenical auxiliary agents for pharmaceutical preparations of active ingredients to improve their transdermal resorption.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.
The entire texts of all applications, patents and publications, cited above and below, and of corresponding German application P 38 30 932.7, filed September 12, 1988, are hereby incorporated by reference.
23 0 6
Example 1
21.6 g of sodium salt of 3alpha,7beta-dihydroxy-5beta-cholanic-24 acid (= 0.052 mol) is dissolved in 250 ml of ethanol with warming, mixed with a solution of 7.0 g of choline chloride in 50 ml of ethanol and reacted for 2 hours. Then the reaction mixture is allowed to cool, the precipitated common salt is filtered out and the filtrate is largely concentrated by evaporation and the still flowable residue is instilled in 0.5 1 of acetone. The mixture is stirred for two hours more, the product is suctioned off and dried in a vacuum. Thus, 17.9 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,7beta-dihydroxy-5beta-cholanic-24 acid with a melting point of 185 to 190*C is obtained.
Example 2
6.05 g of choline (=0.05 mol) is dissolved in 50 ml of ethanol, mixed with 19.6 g of 3alpha,7beta-dihydroxy-5beta-cholanic-24 acid (= 0.05 mol) and after dissolution is completed, is evaporated to dryness. The residue is taken up in acetone, the separated crystallizate is suctioned off and dried. 21.6 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,7beta-dihydroxy-5beta-cholanic-24 acid with a melting point of 186 to 190"C is obtained.
v.
23 i
Example 3
6.05 g of choline (0.05 mol) is dissolved in 50 ml of ethanol, mixed with 19.6 of 3alpha,7alpha-5beta-cholanic-24 acid (= 0.05 mol) and, after dissolution is completed, is instilled in 200 ml of acetone. It is stirred for another hour, the separated crystallizate is suctioned off and dried in a vacuum. Thus 20.0 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,7alpha-dihydroxy-5beta-cholanic-24 acid with a melting point of 70 to 75*C is obtained.
Example 4
11.7 g of 3alpha,12alpha-dihydroxy-5beta-cholanic-24 acid (= 0.030 mol) is dissolved in 30 ml of ethanol and mixed with 14.3 ml (= 0.030 mol) of a 2.1 molar solution of choline base in ethanol. Then the reaction mixture is instilled in 250 ml of acetone, the precipitate is suctioned off and dried in a vacuum. 12.8 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,12alpha-dihydroxy-5beta-cholanic-24 acid with a melting point of 253 to 255"C is obtained.
Example 5
57 g of 3alpha,12beta-dihydroxy-5beta-cholanic-24 acid (= 0.145 mol) is dissolved in 100 ml of ethanol and mixed with a solution of 17.5 g of choline base (145 mmol) in ethanol. Then the ethanol is distilled off, the residue is mixed with 200 ml of acetone, the precipitate is suctioned off and dried in a vacuum. 60 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,12beta-dihydroxy-5beta-cholanic-24 acid with a melting point of 170 to 174.5"C is obtained.
Example 6
4.6 g of N-(3alpha,7alpha-dihydroxy-24-oxo-5beta-cholan-24-yl) glycine (= 0.00832 mol) is dissolved in 10
ml of ethanol and mixed with a solution of 1.0 g of choline base (= 0.00832 mol) in 10 ml of ethanol. Then the mixture is instilled in 200 ml of acetone, stirred for some additional time, the crystals are suctioned off and dried in a vacuum.
3.6 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of N-(3alpha,7alpha-dihydroxy-24-oxo-5beta-cholan-24-yl) glycine with a melting point of 80 to 83°C is obtained.
Example 7
8.04 g of 2-[(3alpha,7beta-dihydroxy-24-oxo-5beta-24-yl)-amino]-ethane sulfonic acid (= 0.0133 mol) is dissolved in 30 ml of ethanol and mixed with a solution of 1.61 g of choline base (= 0.0133 mol) in 16 ml of ethanol. Then the mixture is instilled in 200 ml of acetone, stirred for some additional time, the crystals are suctioned off and dried in a vacuum.
Thus, 6.9 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 2-[(3alpha,7beta-dihydroxy-24-oxo-5beta-cholan-24-yl)-amino]-ethane sulfonic acid with a melting point of 80 to 85*C is obtained.
23 0 6
Example 8
g of 3alpha-hydroxy-7-oxo-5beta-cholanic-24 acid (0.1 mol) is suspended in 200 ml of ethanol and mixed with a solution of 12.1 g of choline base (0.1 mol) in 100 ml of ethanol. Then the solvent is distilled off in a vacuum, the residue is mixed with 500 ml of acetone, the precipitate is filtered off and dried in a vacuum.
Thus 37.7 g of 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha-hydroxy-7-oxo-5beta-cholanic-24 acid with an indefinite melting point is obtained.
[ ©Uo° = 11.2* (ethanol).
The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
230605
Claims (15)
1. A 2-hydroxy-N,N,N-trimethylethanaminium salt of a 5beta-cholanic-24 acid derivative, of formula I wherein R, and R2, and R3 and R4, independently, together are an oxo group, or are two hydrogen atoms or a hydrogen atom and a hydroxy group, and X is a single bond or an -NH-CH2-CO- or -NH-(CH2) 2-S02- group; with the proviso that the compounds 3alpha,12alplia-dihydroxy-5beta-cholanic-24 acid and 3alplia,7alp!ia,12alpha-trihydroxy-5beta-cholanic-24 acid are excluded.
2- A 2-hydroxy-N,N,N-trimethylethanaminium salt of a 5beta-cholanic-24 acid derivative according to claim 1, wherein at least one of the substituents R1 to R4 is not hydrogen. ''' ~ 7 MAY (992 - 12 - 730605
3. A 2-hydroxy-N,N,N-trimethylethanaminium salt of a 5beta-cholanic-24 acid derivative according to claim 1, wherein the substituents R3 and R4 together are an oxo group, or are two hydrogen atoms or a hydrogen atom and a beta-hydroxy group.
4. A 2-hydroxy-N,N,N-trimethylethanaminium salt of 3alpha,7alpha-dihydroxy-5beta-cholanic-24 acid, 3alpha,7beta-dihydroxy-5beta-cholanic-2 4 acid, 3alpha,12beta-dihydroxy-5beta-cholanic-24 acid, N-(3alpha,7alpha-dihydroxy-24-oxo-5beta-cholan-24-yl) glycine, 2-[(3alpha,7beta-dihydroxy-24-oxo-5beta-cholan-24-yl)-amino] ethane sulfonic acid, or 3alpha-hydroxy-7-oxo-5beta-cholanic-24 acid, each a compound of claim 1.
5. A pharmaceutical preparation comprising at least one 2-hydroxy-N,N,N-trimethylethanaminium salt of a 5beta-cholanic-24 acid derivative, of formula I wherein R, and R2, and R3 and R4, independently, together are an oxo group, or are two hydrogen atoms or a hydrogen atom and a hydroxy group, and X is a single bond or an -NH-CH2-CO- or -NH-(CH2) 2-S02- group; together with a pharmaceutical^ acceptable carrier. - 13 - 730605
6. A cosmetic preparation containing at least one 2-hydroxy-N,N,N-trimethylethanaminium salt as defined in claim 5, together with a cosmetically acceptable carrier.
7. A method of dissolving gallstones in non-human animals, comprising administering a compound of the formula I as defined in claim 5.
8. A method of treating primary biliary cirrhosis in non-human animals, comprising administering a compound of the formula I as defined in claim 5.
9. A method of treating primary sclerosing cholangitis in non-human animals, comprising administering a compound of the formula I as defined in claim 5.
10. A method of irrigating the bile duct or the gallbladder in non-human animals, comprising irrigating with an aqueous solution containing a compound of the formula 1 as defined in claim 5.
11. A method of treating bacterial or viral infections in non-human animals, comprising administering a compound of the formula 1 as defined in claim 5.
12- Process for the production of 2-Hydroxy-N,N,N-trimethylethanaminium salts of general formula I, according to claim 1, wherein a 5beta-cholanic-2A acid derivative of general formula II X-O-Y (II) P Y 1992 - u - 230605 in which R-, , R0, Rg, Rd and X have the meaning mentioned in claim 1 and gamma represents a hydrogen or an alkali metal atom, is reacted with a coniDound of general formula III Z 1 CCH3)3-K-HC2-CH2-OH in which 2 represents a hydroxy group, if gamma is a hydrogen atom, or means the-radical-of an inorganic acid, if gamma is an alkali metal atom- with the proviso that the compounds 3aipha. 12aipha-dihydroxy-5beta-choIanic-24 acid and 3alpha,7alpha, l2alpha-trihydroxy-5beta-cholanic-24 acid are excluded.
13. A compound according to claim 1 substantially as herein described or exemplified. 1 & .
A preparation according to claim 5 or 5 substantially as herein described or exemplified.
15. A process according to claim 12 substantially as herein described or exemplified. • - /' c - ,; DIAMALT AKTIENGESELLSCHAFT 1 By Their /itltprneys 7 MAY 1992' HENRY HUGHES LIMITED III I! Per: /I
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3830932A DE3830932A1 (en) | 1988-09-12 | 1988-09-12 | 2-HYDROXY-N, N, N-TRIMETHYL ETHANAMINIUM SALTS OF 5SS-CHOLAN-24-ACID DERIVATIVES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ230605A true NZ230605A (en) | 1992-06-25 |
Family
ID=6362765
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ230605A NZ230605A (en) | 1988-09-12 | 1989-09-11 | Choline salts of 5-beta-cholanic-24 acid derivatives and compositions for pharmaceutical and cosmetic uses |
Country Status (7)
| Country | Link |
|---|---|
| EP (2) | EP0387325B1 (en) |
| AT (1) | ATE118218T1 (en) |
| AU (1) | AU4131089A (en) |
| CA (1) | CA1338907C (en) |
| DE (2) | DE3830932A1 (en) |
| NZ (1) | NZ230605A (en) |
| WO (1) | WO1990002748A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942248A (en) * | 1992-06-12 | 1999-08-24 | Cortecs Limited | Pharmaceutical composition containing a low detergent effect bile salt and an active compound that undergoes biliary excretion and/or enterohepatic recycling |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112012020110B1 (en) | 2010-02-10 | 2021-06-08 | Kissei Pharmaceutical Co., Ltd. | fused heterocyclic derivative compound, pharmaceutical composition comprising the same and therapeutic use of said compound |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE593258C (en) * | 1931-09-12 | 1934-02-23 | Egon Gluecksmann | Process for the preparation of salts of bile acids |
| US2589840A (en) * | 1948-08-14 | 1952-03-18 | Fellows Medical Mfg Co Inc | Method of preparing choline salts of bile acids |
| FR2074736A1 (en) * | 1970-01-22 | 1971-10-08 | Prugnaud Robert | Choline dehydrocholate - for treating hepatic and biliary disorders |
| ATA207181A (en) | 1981-05-08 | 1983-09-15 | Schering Wien | COSMETIC AGENT AND METHOD FOR THE PRODUCTION THEREOF |
-
1988
- 1988-09-12 DE DE3830932A patent/DE3830932A1/en not_active Withdrawn
-
1989
- 1989-09-01 EP EP89909564A patent/EP0387325B1/en not_active Expired - Lifetime
- 1989-09-01 DE DE58908984T patent/DE58908984D1/en not_active Expired - Fee Related
- 1989-09-01 WO PCT/EP1989/001023 patent/WO1990002748A1/en active IP Right Grant
- 1989-09-01 AT AT89909564T patent/ATE118218T1/en not_active IP Right Cessation
- 1989-09-01 EP EP89116158A patent/EP0359058A1/en active Pending
- 1989-09-11 NZ NZ230605A patent/NZ230605A/en unknown
- 1989-09-11 CA CA000610954A patent/CA1338907C/en not_active Expired - Fee Related
- 1989-09-12 AU AU41310/89A patent/AU4131089A/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5942248A (en) * | 1992-06-12 | 1999-08-24 | Cortecs Limited | Pharmaceutical composition containing a low detergent effect bile salt and an active compound that undergoes biliary excretion and/or enterohepatic recycling |
Also Published As
| Publication number | Publication date |
|---|---|
| DE3830932A1 (en) | 1990-03-15 |
| ATE118218T1 (en) | 1995-02-15 |
| EP0359058A1 (en) | 1990-03-21 |
| EP0387325B1 (en) | 1995-02-08 |
| EP0387325A1 (en) | 1990-09-19 |
| CA1338907C (en) | 1997-02-11 |
| AU4131089A (en) | 1990-03-15 |
| WO1990002748A1 (en) | 1990-03-22 |
| DE58908984D1 (en) | 1995-03-23 |
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