CA1095416A - Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions - Google Patents
Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositionsInfo
- Publication number
- CA1095416A CA1095416A CA279,790A CA279790A CA1095416A CA 1095416 A CA1095416 A CA 1095416A CA 279790 A CA279790 A CA 279790A CA 1095416 A CA1095416 A CA 1095416A
- Authority
- CA
- Canada
- Prior art keywords
- amino
- alcohol
- pharmaceutical composition
- substituted phenyl
- glucuronic acid
- 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.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Dermatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
Abstract
"Continental Pharma"
"Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions"
ABSTRACT OF THE DISCLOSURE.
A hydrosoluble pharmaceutical composition based on a substituted phenyl-amino-alcohol as active ingredient, wherein said amino-alcohol is provided in association with glucuronic acid.
"Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions"
ABSTRACT OF THE DISCLOSURE.
A hydrosoluble pharmaceutical composition based on a substituted phenyl-amino-alcohol as active ingredient, wherein said amino-alcohol is provided in association with glucuronic acid.
Description
109~416 This invention relates to a hydrosoluble pharmaceu-tical composition based on a substituted phenyl-amino-alcohol.
The advantage of having hydrosoluble forms of medi-caments is multiple. As a matter of fact, in addition to the possibility of administering such medicaments parenterally, a hydrosoluble form has several other advantages, namely to allow an optimum distribution of the medicament to be obtained surely when screening tests are made and also to allow in vitro tests to be carried out. In therapeutics, an injectable form also allows to obtain a quick medicament action.
To administer medicaments orally, it is also some-times interesting to have rather hydrosoluble compounds with the object of accelerating or modifying the active product absorption.
An object of the invention is to provide a pharma-ceutical composition based on a substituted phenyl-amino-alcohol having a substantially unlimited water solubility.
According to the invention, the substituted phenyl-amino-alcohol is provided in the pharmaceutical composition in 20 association with a glucuronic acid.~ The phenyl-amino-alcohol ~:
advantageously has the general formula:
RlS ~ - CHOH-CH-NHR3 (I) wherein Rl is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of 1 or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms.
The hydrosoluble pharmaceutical composition is prepared by reacting glucuronic acid with the substituted phenyl-amino-alcohol in a solvent.
~k ~l , 10~5416 This invention also provides a method of use of said pharmaceutical composition in which this composition is administered intravenously or orally in doses between 1 and 50 mg/day.
The invention is based on the fact that it has been found that glucuronic acid, and more particularly D-glucuronic acid, is able to give such substituted phenyl-amino-alcohols a quite remarkable hydrosolubility which is impossible to reach with other kinds of acids. Such amino-alcohols have been 10 described in Belgian Patent 799,379.
Other details and particularities of the invention will become apparent from the following description given by way of a non limitative example of several embodiments of the com-position, the process for preparing this composition and its use.
Amino-alcohols which are of a particular interest for the hydrosoluble pharmaceutical composition according to the invention are more particularly those of formula (I) wherein Rl is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon àtoms.
More particularly for compound 1-(4-isopropylthio-phenyl)-2-n-octylamino-1-propanol, the water solubility of the glùcuronate is unlimited while it is only of 1510 mg/l for hydrochloride, of 550 mg/l for succinate, of 1505 mg/l for citrate and of 4720 mg/l for lactate.
In general, it is known that these amino-alcohols have a very high therapeutical interest and have activities on cardiovascular system, as antihypertensive agent, antispas-modic agent, peripheral vasodilatator, protecting agent against myocardium anoxia, bronchodilatator, ~-lytic agent, normolipi-demient agent, normolipoproteinement agent, inhibitor of platelet aggregation and stimulator of cerebral energetic metabolism. Moreover, these compounds allow to act on the central nervous system, for example as tranquillizer.
The acute toxicity with an i.v. administration was studied on mice for l-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronate.
DL50 is 20 mg/kg (confidence limits for p = 0,95 : 18-22 mg/kg).
The oral toxicity on mice is similar to that of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol(~ 4000 mg/
kg).
The tolerance after repeated i.v. administrations (5 successive days) was studied on rabbits. No anomaly was observed till the dose of 0,03 mg/kg/ml.
The effects of 1-(4-isopropylthiophenyl)-2-n-octyla-mino-1-~opanolgl~curonate are atleast thesame as those of the 1-(4-isoprophylthiophenyl)-2-n-octylamino-1-propanol itself).
The antispasmodic activity was compared on guinea pig ileum (inhibition of the contractions caused by histamine) and on rat aorta (inhibition of the contactions caused by calcium on depolarized bands).
The results are at least similar for both compounds.
The activity is of the musculatrope type, comprising a 6pecific inhibition of movements of calcium ions. On guinea pig ileum, the PD~2 values (logarithm of the molar concentration reducing maximum concentration by 50%) are 6.42 (- 0.19) and 6.66 (- O.O9)respectively for glucuronate and 1-(4-isopropyl-thiophenyl)-2-n-octylamino-1-propanol. These two values are significantly different.
On rat aorta, the PA2 values in relation to calcium (logarithm of the molar concentration for which the effect of a double antagonist dose is reduced to that of a simple dose) are 7.52 ~ - 0.08) and 7.46 (- 0.19) respectively for 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol glucuronate and for l-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol.
The anti-platelet and antithrombotic activity was studied under various conditions.
The 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol was tested relating to its antithrombotic activity on thromboses induced in rats by applying ADP on mesenteric arteries having previously received a standard electric sti-mulation.
Formation of thrombus is significantly reduced (by 80%) at a dose of lmg/kg i.v. It is also found that the latency period before a thrombus appears is increased and that the formation rate is decreased. The duration of the protec-tion effect of the product is 1 hour.
By using the filter loop technique, it is remar-ked that the product, at a dose of lmg/kg i.v. inhibits the platelet aggregation induced by ADP by 70% and is ten times as active as a reference drug such as dipyridamole.
The stability of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronatein aqueous solu~ion ~asrevealed as bein~ exce~ent;a so~fn ~ lm~ does n~ shcw any detectaole varia-tion of the product content after 110 days at 20 C and 40 C.
Compatibility of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronate with the most current clini-cally used perfusion solutions (Ringer lactate and glucidic Trophysan 100 for example) has also revealed very favourable.
The hydrosoluble pharmaceutical composition accor-ding to the invention can be prepared by reacting glucuronic acid and substituted phenyl-amino-alcohol in a preferably aqueous solvent.
This reaction can be for example carried out by slowly adding an equimolecular amount of phenyl-amino-alcohol to an aqueous solution of glucuronic acid, this mixture being stirred until a clear solution is obtained.
The obtained aqueous solution can be directly used for therapeutical uses or can be brought to the desired concen-tration by concentration or dilution.
In some cases, it may be advantageous to heat the aqueous solution of glucuronic acid before addition of phenyl-amino-alcohol, preferably to a temperature of 40-60C.
A low excess of glucuronic acid may be optionally used.
lO~t~4~6 Inversely, it is possible to add the aqueous so-lution of glucuronic acid to the substituted phenyl-amino-alcohol, the latter being optionally suspended in water.
According to the invention, the eompound can also be diss~ved and suspended in water or in a mixture of water miscible organic solvent, such as alcohols, more particular-ly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran.
After addition of glucuronic acid, the solution may be still evaporated under reduced pression or lyophilised in the case of aqueous solutions.
So a water soluble powder is obtained, which can be used for preparing aqueous solutions having wished dilution (extemporaneous preparation).
In some eases, it may be useful to prepare hydroso-luble pharmaceutical compositionsaccording to the invention ^-from a phenyl-amino-aleDhol salt, sueh as for example hydro~
ehloride, by double decomposition with a glueuronie aeid salt, for example barium glucuronate, most advantageously in aqueous solution. The residual salt resulting from this double deeom-position, for example barium ehloride, is then filtered out.
Although the pharmaeeutieal eomposition aeeording to the invention may be administered orally, due to its very high water solubility, it is more pa~tieularly suitable for administration by intravenous injeetion or perfusion.
Due to the low toxieity of glueuronie aeid, it is possible to obtain eompositions having a very favourable the- 3 rapeutieal index.
The invention is still illustrated by a number of preparation examples of speeifie eompositions aeeording to the invention.
Example 1 20 g (0.103 mole) of D-glueuronie aeid and 30.9 g ( ~.l mole) of 1-(4-isopropylthiophenyl)-2-n-hexylamino-1-propanol are mixed with 20 ml of water. A elear syrup is formed, which can be diluted with distilled water at will.
By lyophilisation of the solution, 52 g of dry product is obtained (comprising 2.1% of water).
10C~S4~6 Example 2.
24 g (0.127 mole) of D-glucuronic acid and 41.9 g (o.l mole) of 1-(4-isopropylthiophenyl)-2-n-tetradecylamino-1- propanol are mixed with 50 ml of water. Stirring is made until complete solution (a few minutes). So a clear solution, which can be diluted with distilled water at will is obtained.
Example 3.
20.4 g (0.105 mole) of D-glucuronic acid are dissol-ved in 283.5 g of water and 33.76 g(0.1 mole) of 1-(4-isopro-pylthiophenol)-2-n-octylamino-1-propanol are added to this solution with stirring . Stirring is continued until complete solution, which requires about 1/2 hour. A clear solution containing 10% of 1-(4-isopropylthiophenyl)-2-n-octhylamino-l-propanol is so obtained.
Instead of treating at room temperature, as in the present example, higher temperaturesare used according to a variant, more particularly in water heated to about 60C.
Example 4.
To 33.76 g (0.1 mole) of 1-(4-isopropylthiophenyl)-
The advantage of having hydrosoluble forms of medi-caments is multiple. As a matter of fact, in addition to the possibility of administering such medicaments parenterally, a hydrosoluble form has several other advantages, namely to allow an optimum distribution of the medicament to be obtained surely when screening tests are made and also to allow in vitro tests to be carried out. In therapeutics, an injectable form also allows to obtain a quick medicament action.
To administer medicaments orally, it is also some-times interesting to have rather hydrosoluble compounds with the object of accelerating or modifying the active product absorption.
An object of the invention is to provide a pharma-ceutical composition based on a substituted phenyl-amino-alcohol having a substantially unlimited water solubility.
According to the invention, the substituted phenyl-amino-alcohol is provided in the pharmaceutical composition in 20 association with a glucuronic acid.~ The phenyl-amino-alcohol ~:
advantageously has the general formula:
RlS ~ - CHOH-CH-NHR3 (I) wherein Rl is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of 1 or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms.
The hydrosoluble pharmaceutical composition is prepared by reacting glucuronic acid with the substituted phenyl-amino-alcohol in a solvent.
~k ~l , 10~5416 This invention also provides a method of use of said pharmaceutical composition in which this composition is administered intravenously or orally in doses between 1 and 50 mg/day.
The invention is based on the fact that it has been found that glucuronic acid, and more particularly D-glucuronic acid, is able to give such substituted phenyl-amino-alcohols a quite remarkable hydrosolubility which is impossible to reach with other kinds of acids. Such amino-alcohols have been 10 described in Belgian Patent 799,379.
Other details and particularities of the invention will become apparent from the following description given by way of a non limitative example of several embodiments of the com-position, the process for preparing this composition and its use.
Amino-alcohols which are of a particular interest for the hydrosoluble pharmaceutical composition according to the invention are more particularly those of formula (I) wherein Rl is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon àtoms.
More particularly for compound 1-(4-isopropylthio-phenyl)-2-n-octylamino-1-propanol, the water solubility of the glùcuronate is unlimited while it is only of 1510 mg/l for hydrochloride, of 550 mg/l for succinate, of 1505 mg/l for citrate and of 4720 mg/l for lactate.
In general, it is known that these amino-alcohols have a very high therapeutical interest and have activities on cardiovascular system, as antihypertensive agent, antispas-modic agent, peripheral vasodilatator, protecting agent against myocardium anoxia, bronchodilatator, ~-lytic agent, normolipi-demient agent, normolipoproteinement agent, inhibitor of platelet aggregation and stimulator of cerebral energetic metabolism. Moreover, these compounds allow to act on the central nervous system, for example as tranquillizer.
The acute toxicity with an i.v. administration was studied on mice for l-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronate.
DL50 is 20 mg/kg (confidence limits for p = 0,95 : 18-22 mg/kg).
The oral toxicity on mice is similar to that of 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol(~ 4000 mg/
kg).
The tolerance after repeated i.v. administrations (5 successive days) was studied on rabbits. No anomaly was observed till the dose of 0,03 mg/kg/ml.
The effects of 1-(4-isopropylthiophenyl)-2-n-octyla-mino-1-~opanolgl~curonate are atleast thesame as those of the 1-(4-isoprophylthiophenyl)-2-n-octylamino-1-propanol itself).
The antispasmodic activity was compared on guinea pig ileum (inhibition of the contractions caused by histamine) and on rat aorta (inhibition of the contactions caused by calcium on depolarized bands).
The results are at least similar for both compounds.
The activity is of the musculatrope type, comprising a 6pecific inhibition of movements of calcium ions. On guinea pig ileum, the PD~2 values (logarithm of the molar concentration reducing maximum concentration by 50%) are 6.42 (- 0.19) and 6.66 (- O.O9)respectively for glucuronate and 1-(4-isopropyl-thiophenyl)-2-n-octylamino-1-propanol. These two values are significantly different.
On rat aorta, the PA2 values in relation to calcium (logarithm of the molar concentration for which the effect of a double antagonist dose is reduced to that of a simple dose) are 7.52 ~ - 0.08) and 7.46 (- 0.19) respectively for 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol glucuronate and for l-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol.
The anti-platelet and antithrombotic activity was studied under various conditions.
The 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol was tested relating to its antithrombotic activity on thromboses induced in rats by applying ADP on mesenteric arteries having previously received a standard electric sti-mulation.
Formation of thrombus is significantly reduced (by 80%) at a dose of lmg/kg i.v. It is also found that the latency period before a thrombus appears is increased and that the formation rate is decreased. The duration of the protec-tion effect of the product is 1 hour.
By using the filter loop technique, it is remar-ked that the product, at a dose of lmg/kg i.v. inhibits the platelet aggregation induced by ADP by 70% and is ten times as active as a reference drug such as dipyridamole.
The stability of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronatein aqueous solu~ion ~asrevealed as bein~ exce~ent;a so~fn ~ lm~ does n~ shcw any detectaole varia-tion of the product content after 110 days at 20 C and 40 C.
Compatibility of 1-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol glucuronate with the most current clini-cally used perfusion solutions (Ringer lactate and glucidic Trophysan 100 for example) has also revealed very favourable.
The hydrosoluble pharmaceutical composition accor-ding to the invention can be prepared by reacting glucuronic acid and substituted phenyl-amino-alcohol in a preferably aqueous solvent.
This reaction can be for example carried out by slowly adding an equimolecular amount of phenyl-amino-alcohol to an aqueous solution of glucuronic acid, this mixture being stirred until a clear solution is obtained.
The obtained aqueous solution can be directly used for therapeutical uses or can be brought to the desired concen-tration by concentration or dilution.
In some cases, it may be advantageous to heat the aqueous solution of glucuronic acid before addition of phenyl-amino-alcohol, preferably to a temperature of 40-60C.
A low excess of glucuronic acid may be optionally used.
lO~t~4~6 Inversely, it is possible to add the aqueous so-lution of glucuronic acid to the substituted phenyl-amino-alcohol, the latter being optionally suspended in water.
According to the invention, the eompound can also be diss~ved and suspended in water or in a mixture of water miscible organic solvent, such as alcohols, more particular-ly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran.
After addition of glucuronic acid, the solution may be still evaporated under reduced pression or lyophilised in the case of aqueous solutions.
So a water soluble powder is obtained, which can be used for preparing aqueous solutions having wished dilution (extemporaneous preparation).
In some eases, it may be useful to prepare hydroso-luble pharmaceutical compositionsaccording to the invention ^-from a phenyl-amino-aleDhol salt, sueh as for example hydro~
ehloride, by double decomposition with a glueuronie aeid salt, for example barium glucuronate, most advantageously in aqueous solution. The residual salt resulting from this double deeom-position, for example barium ehloride, is then filtered out.
Although the pharmaeeutieal eomposition aeeording to the invention may be administered orally, due to its very high water solubility, it is more pa~tieularly suitable for administration by intravenous injeetion or perfusion.
Due to the low toxieity of glueuronie aeid, it is possible to obtain eompositions having a very favourable the- 3 rapeutieal index.
The invention is still illustrated by a number of preparation examples of speeifie eompositions aeeording to the invention.
Example 1 20 g (0.103 mole) of D-glueuronie aeid and 30.9 g ( ~.l mole) of 1-(4-isopropylthiophenyl)-2-n-hexylamino-1-propanol are mixed with 20 ml of water. A elear syrup is formed, which can be diluted with distilled water at will.
By lyophilisation of the solution, 52 g of dry product is obtained (comprising 2.1% of water).
10C~S4~6 Example 2.
24 g (0.127 mole) of D-glucuronic acid and 41.9 g (o.l mole) of 1-(4-isopropylthiophenyl)-2-n-tetradecylamino-1- propanol are mixed with 50 ml of water. Stirring is made until complete solution (a few minutes). So a clear solution, which can be diluted with distilled water at will is obtained.
Example 3.
20.4 g (0.105 mole) of D-glucuronic acid are dissol-ved in 283.5 g of water and 33.76 g(0.1 mole) of 1-(4-isopro-pylthiophenol)-2-n-octylamino-1-propanol are added to this solution with stirring . Stirring is continued until complete solution, which requires about 1/2 hour. A clear solution containing 10% of 1-(4-isopropylthiophenyl)-2-n-octhylamino-l-propanol is so obtained.
Instead of treating at room temperature, as in the present example, higher temperaturesare used according to a variant, more particularly in water heated to about 60C.
Example 4.
To 33.76 g (0.1 mole) of 1-(4-isopropylthiophenyl)-
2-n-octylamino-1-propanol dissolved in 330 ml of tetrahydro-furan, l9r 41 g (0.1 mole) of D-glucuronic acid and 50 ml of water are added and stirring is continued until complete solution of glucuronic a~d, which requires about 2 hours.
Solvents are evaporated under vacuum and 53.3 g of dry pro-duct are obtained.
The preparation of injectable solutions or of aque-ous solutions for oral administration can be made directly from a solution prepared according to Example 2 or from a so-lid product prepared according to Example 1 after dissolution in water.
Hereinafter two typical galenic formulations are still given for in~ectable compositions.
1 l-(4-isopropylthiophenyl)-2-n-octylamino-1-p~opanol 1 m~
D-glucuronic acid 0.6 mg Anhydrous dextrose 55.1 mg ~idist. water, q.s. 1 ml 2 l-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol 20 mg 8 1o954l6 D-glucuronic acid 12 mg Anhydrous dextrose Bidist, water, q.s. 1 ml The da~y doses of substituted phenyl-amino-alcohols in association with glucuronic acid, proposed for humans, are about 1 to 50 mg, preferably 0.001 to 1 mg/kg.
Application is preferably made by intravenous in-jection or perfusion.
Solvents are evaporated under vacuum and 53.3 g of dry pro-duct are obtained.
The preparation of injectable solutions or of aque-ous solutions for oral administration can be made directly from a solution prepared according to Example 2 or from a so-lid product prepared according to Example 1 after dissolution in water.
Hereinafter two typical galenic formulations are still given for in~ectable compositions.
1 l-(4-isopropylthiophenyl)-2-n-octylamino-1-p~opanol 1 m~
D-glucuronic acid 0.6 mg Anhydrous dextrose 55.1 mg ~idist. water, q.s. 1 ml 2 l-(4-isopropylthiophenyl)-2-n-octylamino-l-propanol 20 mg 8 1o954l6 D-glucuronic acid 12 mg Anhydrous dextrose Bidist, water, q.s. 1 ml The da~y doses of substituted phenyl-amino-alcohols in association with glucuronic acid, proposed for humans, are about 1 to 50 mg, preferably 0.001 to 1 mg/kg.
Application is preferably made by intravenous in-jection or perfusion.
Claims (22)
1. A process for preparing a hydrosoluble pharmaceutical composition based on substituted phenyl-amino-alcohol as active ingredient, comprising reacting glucuronic acid with a sub-stituted phenyl-amino-alcohol in a solvent.
2. A process according to claim 1 wherein said substituted phenyl-amino-alcohol has the formula:
wherein R1 is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of l or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms.
wherein R1 is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of l or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms.
3. A process as claimed in claim 1 wherein an at least equimolecular amount of said substituted phenyl-amino-alcohol is gradually added to an aqueous solution of glucuronic acid, and the mixture is stirred until a clear solution is obtained.
4. A process as claimed in claim 1 wherein an aqueous solution of glucuronic acid is added to said substituted phenyl-amino-alcohol in suspension or solution in a solvent.
5. A process as claimed in claim 3 wherein water or a mixture of water and water miscible organic solvents, such as alcohols, more particularly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran, is used as solvent.
6. A process as claimed in claim 1 wherein glucuronic acid is heated before contacting it with said substituted phenyl-amino-alcohol to a temperature of 40-60°C.
7. A process as claimed in claim 1 wherein the solvent is eliminated after reaction between glucuronic acid and said substituted phenyl-amino-alcohol until reaction products are obtained as a powder.
8. A process as claimed in claim 1 wherein a salt of glucuronic acid is reacted with a salt of said substituted phenyl-amino-alcohol and then the residual salt resulting from the double decomposition is eliminated.
9. A process according to claim 1 wherein glucuronic acid is D-glucuronic acid.
10. A process according to claim 2 wherein R1 is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon atoms.
11. A process according to claim 10 wherein the substituted phenyl-amino-alcohol is 1-(4-isopropylthiophenyl)-2-n-octylamino-1-propanol.
12. A hydrosoluble pharmaceutical composition based on substituted phenyl-amino-alcohol as active ingredient, wherein said amino-alcohol is provided in association with glucuronic acid, the composition having been prepared by the process of claim 1 or any obvious chemical equivalent thereof.
13. A hydrosoluble pharmaceutical composition prepared by the process of claim 2 or any obvious chemical equivalent thereof.
14. A hydrosoluble pharmaceutical composition prepared by the process of claim 3 or any obvious chemical equivalent thereof.
15. A hydrosoluble pharmaceutical composition prepared by the process of claim 4 or any obvious chemical equivalent thereof.
16. A hydrosoluble pharmaceutical composition prepared by the process of claim 5 or any obvious chemical equivalent thereof.
17. A hydrosoluble pharmaceutical composition prepared by the process of claim 6 or any obvious chemical equivalent thereof.
18. A hydrosoluble pharmaceutical composition prepared by the process of claim 7 or any obvious chemical equivalent thereof.
19. A hydrosoluble pharmaceutical composition prepared by the process of claim 8 or any obvious chemical equivalent thereof.
20. A hydrosoluble pharmaceutical composition prepared by the process of claim 9 or any obvious chemical equivalent thereof,
21. A hydrosoluble pharmaceutical composition prepared by the process of claim 10 or any obvious chemical equivalent thereof.
22. A hydrosoluble pharmaceutical composition prepared by the process of claim 11 or any obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7617110A FR2353288A1 (en) | 1976-06-04 | 1976-06-04 | HYDROSOLUBLE PHARMACEUTICAL COMPOSITION BASED ON AN AMINE COMPOUND AS ACTIVE PRODUCT |
| FR76.17.110 | 1976-06-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095416A true CA1095416A (en) | 1981-02-10 |
Family
ID=9174050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA279,790A Expired CA1095416A (en) | 1976-06-04 | 1977-06-03 | Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JPS5318721A (en) |
| BE (1) | BE855320A (en) |
| CA (1) | CA1095416A (en) |
| CH (1) | CH622023A5 (en) |
| DE (1) | DE2724608C2 (en) |
| FR (1) | FR2353288A1 (en) |
| GB (1) | GB1569380A (en) |
| NL (1) | NL7706177A (en) |
| SE (1) | SE441183B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1198386B (en) * | 1982-07-06 | 1988-12-21 | Lepetit Spa | A PROTRACTED RELEASE PRODUCT CONTAINING SULOCTIDYL |
| DE3815273A1 (en) * | 1988-05-05 | 1989-11-16 | Draegerwerk Ag | MOBILE INTENSIVE TREATMENT UNIT |
| WO1998019707A1 (en) * | 1996-11-05 | 1998-05-14 | Alcon Laboratories, Inc. | Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH52A (en) * | 1889-01-08 | Emil Zetter | New petroleum gas apparatus for heating purposes | |
| CH54A (en) * | 1889-01-08 | Emile Mertz | Device for humidifying and cooling the air in spinning rooms, malt houses, ships, theaters, etc. | |
| GB1390748A (en) * | 1973-04-09 | 1975-04-16 | Continental Pharma | Alkyl and cycloalkylthiophenylalkylaminoalkanols their salts and the preparation thereof |
-
1976
- 1976-06-04 FR FR7617110A patent/FR2353288A1/en active Granted
-
1977
- 1977-06-01 DE DE2724608A patent/DE2724608C2/en not_active Expired
- 1977-06-02 BE BE178135A patent/BE855320A/en not_active IP Right Cessation
- 1977-06-03 NL NL7706177A patent/NL7706177A/en not_active Application Discontinuation
- 1977-06-03 CA CA279,790A patent/CA1095416A/en not_active Expired
- 1977-06-03 GB GB23697/77A patent/GB1569380A/en not_active Expired
- 1977-06-03 CH CH689277A patent/CH622023A5/en not_active IP Right Cessation
- 1977-06-03 JP JP6490677A patent/JPS5318721A/en active Granted
- 1977-06-03 SE SE7706481A patent/SE441183B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2353288B1 (en) | 1978-12-15 |
| NL7706177A (en) | 1977-12-06 |
| GB1569380A (en) | 1980-06-11 |
| CH622023A5 (en) | 1981-03-13 |
| DE2724608A1 (en) | 1977-12-22 |
| BE855320A (en) | 1977-12-02 |
| JPS6126526B2 (en) | 1986-06-20 |
| FR2353288A1 (en) | 1977-12-30 |
| SE441183B (en) | 1985-09-16 |
| SE7706481L (en) | 1977-12-05 |
| DE2724608C2 (en) | 1986-09-18 |
| JPS5318721A (en) | 1978-02-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3658966A (en) | Methods of treating hypertension | |
| WO1985003507A2 (en) | Metallicenium salts and utilization thereof as cytostatic agents for combatting cancer | |
| CA1095416A (en) | Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions | |
| CA1069125A (en) | 4-imino-1,3-diazabicyclo-(3.1.0) hexan-2-one | |
| JPS6117574A (en) | Calcium-antagonistic 1-(bis-(4-fluorophenyl)-methyl)-4- (3-phenyl-2-propenyl)-hexahydro-1h-1,4-diazepine, manufacture and medicinal composition | |
| US4176193A (en) | Therapeutic isobutyramides | |
| US3422086A (en) | Rutin alkyl sulphonates | |
| DE2432392C3 (en) | Tris (2-hydroxyethyl) ammonium orthocresoxyacetate, process for its production and pharmaceuticals based on it | |
| EP0923932B1 (en) | Composition containing antitumor agent | |
| CH644596A5 (en) | 2,6-DIMETHYL-1,4-DIHYDROPYRIDINE-3,5-DICARBONIC ACID ESTER AND METHOD FOR THE PRODUCTION THEREOF. | |
| DE2008693A1 (en) | New 'pyrazolines | |
| US4100287A (en) | Pyrimidine derivative | |
| US3810986A (en) | Novel method and composition | |
| US4148898A (en) | N-oxy-ajmaline and the use thereof in treating cardiovascular disorders | |
| AT213395B (en) | Process for the preparation of the new β-hydroxybutyric acid cyclohexylamide | |
| DE2221281A1 (en) | Pyrazole derivatives and processes for their preparation | |
| JPS589119B2 (en) | Ajmaline cardenolide and bufadienolide derivatives and their production method | |
| US2766175A (en) | Mersalyl diuretic solutions stabilized with methylated glycines | |
| US3733353A (en) | Aminocyclohexanemethyl benzoates | |
| DE1919895C (en) | 2 phenyl 2 morpholinomethyl indan 1.3 dione | |
| KR890000381B1 (en) | Process for preparing acylaninophenol derivatives | |
| CA2247329C (en) | Composition containing antitumor agent | |
| KR790001523B1 (en) | Process for preparation of benzylamines | |
| GB2070004A (en) | 1-Aminoadamantane D,L-2- acetamido-3-phenylpropionate | |
| DE2215999A1 (en) | NITROIMIDAZOLYL-TRIAZOLO-PYRIDAZINE AND THE METHOD FOR THEIR PRODUCTION |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |