GB1569380A - 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 compositions Download PDFInfo
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- GB1569380A GB1569380A GB23697/77A GB2369777A GB1569380A GB 1569380 A GB1569380 A GB 1569380A GB 23697/77 A GB23697/77 A GB 23697/77A GB 2369777 A GB2369777 A GB 2369777A GB 1569380 A GB1569380 A GB 1569380A
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- United Kingdom
- Prior art keywords
- glucuronic acid
- water
- amino
- alcohol
- salt
- Prior art date
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- CKRZKMFTZCFYGB-UHFFFAOYSA-N N-phenylhydroxylamine Chemical class ONC1=CC=CC=C1 CKRZKMFTZCFYGB-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 21
- 239000000203 mixture Substances 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims abstract description 41
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims abstract description 32
- 229940097043 glucuronic acid Drugs 0.000 claims abstract description 29
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 230000010412 perfusion Effects 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 238000010253 intravenous injection Methods 0.000 claims abstract description 6
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- -1 tetradecylamino - 1 - propanol Chemical compound 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 25
- 239000007864 aqueous solution Substances 0.000 claims description 16
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 claims description 12
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 claims description 9
- 229940097042 glucuronate Drugs 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 8
- 229940044613 1-propanol Drugs 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000354 decomposition reaction Methods 0.000 claims description 5
- GZCGUPFRVQAUEE-SLPGGIOYSA-N aldehydo-D-glucose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-SLPGGIOYSA-N 0.000 claims description 4
- 229940089206 anhydrous dextrose Drugs 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 230000002349 favourable effect Effects 0.000 claims description 3
- 229960005335 propanol Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004552 water soluble powder Substances 0.000 claims description 3
- SKRMSEQRBCTDLN-UHFFFAOYSA-N 2-(hexylamino)-1-(4-propan-2-ylsulfanylphenyl)propan-1-ol Chemical compound CCCCCCNC(C)C(O)C1=CC=C(SC(C)C)C=C1 SKRMSEQRBCTDLN-UHFFFAOYSA-N 0.000 claims description 2
- APDUDRFJNCIWAG-UHFFFAOYSA-N 4-propan-2-ylbenzenethiol Chemical compound CC(C)C1=CC=C(S)C=C1 APDUDRFJNCIWAG-UHFFFAOYSA-N 0.000 claims description 2
- HNUALPPJLMYHDK-UHFFFAOYSA-N C[CH]C Chemical group C[CH]C HNUALPPJLMYHDK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052788 barium Inorganic materials 0.000 claims description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 claims description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001626 barium chloride Inorganic materials 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000007972 injectable composition Substances 0.000 claims description 2
- 231100000053 low toxicity Toxicity 0.000 claims description 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000012265 solid product Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 150000001298 alcohols Chemical class 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 3
- 239000003814 drug Substances 0.000 description 7
- BFCDFTHTSVTWOG-UHFFFAOYSA-N 2-(octylamino)-1-[4-(propan-2-ylthio)phenyl]-1-propanol Chemical compound CCCCCCCCNC(C)C(O)C1=CC=C(SC(C)C)C=C1 BFCDFTHTSVTWOG-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000010669 acid-base reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000003465 bronchodilatator Substances 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- ZEWYCNBZMPELPF-UHFFFAOYSA-J calcium;potassium;sodium;2-hydroxypropanoic acid;sodium;tetrachloride Chemical compound [Na].[Na+].[Cl-].[Cl-].[Cl-].[Cl-].[K+].[Ca+2].CC(O)C(O)=O ZEWYCNBZMPELPF-UHFFFAOYSA-J 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000003975 mesenteric artery Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Molecular Biology (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
Glucuronic acid or a salt of this acid is reacted, in a solvent, with a substituted phenylaminoalcohol of formula I, in which R1 represents an alkyl with 1 to 4 C atoms, R2 an alkyl with 1 or 2 C atoms and R3 an alkyl with 4 to 16 C atoms, or with a salt of this alcohol. The compounds obtained by this process are of great therapeutic importance and can be administered orally, parenterally and preferably by intravenous injection or perfusion. <IMAGE>
Description
(54) PHARMACEUTICAL COMPOSITIONS COMPRISING
SUBSTITUTED PHENYL-AMINO-ALCOHOL
AND PROCESS FOR PREPARING THESE
COMPOSITIONS
(71) We, CONTINENTAL PHARMA, a Belgian Body Corporate, of 135 avenue
Louise, Brussels, Belgium, do hereby declare the invention, for which we pray 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:- The invention relates to a hydrosoluble pharmaceutical composition based on phenyl-amino-alcohol.
There are several advantages in having hydrosoluble forms of medicaments. 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 automatically 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 sometimes useful to have rather hydrosoluble compounds with the object of accelerating or modifying the active product absorption.
According to the invention, there is provided a hydrosoluble pharmaceutical composition comprising a l-phenyl-2-amino alcohol or a salt thereof and glucuronic acid or a salt thereof, or the acid-base reaction product of a l-phenyl-2-amino alcohol and glucuronic acid.
The phenyl-amino-alcohols used in the invention have the general formula:
wherein R, 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 invention also relates to processes for preparing such a hydrosoluble pharmaceutical composition.
In one such process glucuronic acid is reacted with the substituted phenyl-aminoalcohol in a solvent.
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.
It has been found that glucuronic acid, preferably D-glucuronic acid, is able to give 1 - phenyl - 2 - amino - alcohols a quite remarkable hydrosolubility which has not been reached with other kinds of acids.
It has become apparent that, amongst phenyl-amino-alcohols, a quite remarkable solubilization has been obtained with amino-alcohols, such as provided for example in Belgian Patent 799,379 and having the formula (I):
wherein R, 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.
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 R, is an isopropyl radical, R2 is a methyl radical and R3 is an alkyl radical of 6 to 14 carbon atoms.
More particularly for compound 1 - (4 isopropylthio - phenyl) - 2 - n octylamino - 1 - propanol, the water solubility of the glucuronate appears to be unlimited while it is only 1510 mg/l for hydrochloride, of 550 mg/l for succinate, of 1505 mg/l for citrate and of 472 mg/l for lactate.
In general, it is known that these aminoalcohols have a very high therapeutical interest and have activities on the cardiovascular system, acting as antihypertensive agents, antispasmodic agents, peripheral vasodilators, protecting agents against myocardium anoxia, bronchodilatators, p-lytic agents, norm ol ipidemient agents, normolipoproteinemient agents, inhibitors of platelet aggregation and stimulator of cerebral energetic metabolism. Moreover, these compounds may also act on the central nervous system, for example as tranq uillizer.
The acute toxicity with an i.v.
administration was studied on mice for I (4 - isopropylthiophenyl) - 2- n octylamino - 1 - -propanol glucuronate.
DL, was 20 mg/kg (confidence limits for p=0,95: 18-22 mg/kg).
The oral toxicity on mice is similar to that ol 1 - (4 - isopropylthiophenyl) - 2 - n octylamino - I - 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 efficacy of I - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate is at least the same as that of the 1 - (4 - isopropylthiophenyl) - 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 specific 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 (+0.09) respectively for glucuronate and 1 - (4 - isopropylthiophenyl)- 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 1 - (4 isopropylthiophenyl) -2- n - octylamino - 1 - propanol.
The anti-platelet and antithrombotic
activity was studied under various
conditions.
The I - (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 stimulation.
Formation of thrombus is significantly reduced (by 80van) at a dose of Img/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 protection effect of the product is 1 hour.
By using the filter loop technique, it was noticed 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 I - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate in aqueous solution has revealed as being excellent; a solution at Img/ml does not show any detectable variation of the product content after 110 days at 200C and 40"C.
Compatibility of 1 - (4 isopropylthiophenyl) - 2 - n - octylamino 1 - propanol glucuronate with the most current clinically used perfusion solutions (Ringer lactate and glucidic Trophysan 100 for example) has also been found very favourable.
The hydrosoluble pharmaceutical composition according 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 concentration 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--60"C.
A low excess of glucuronic acid may be optionally used.
Inversely, it is possible to add the aqueous solution of glucuronic acid to the phenylamino-alcohol, the latter being optionally suspended in water.
According to the invention, the compound can also be dissolved and suspended in water or in a mixture of water miscible organic solvent, such as alcohols, more particularly methanol, ethanol, isopropanol, dioxan and tetrahydrofuran.
After addition of glucuronic acid, the solution may be still evaporated under reduced pressure or lyophilised in the case of aqueous solutions.
Thus, a water soluble powder is obtained, which can be used for preparing aqueous solutions having a desired dilution (extemporaneous preparation).
In some cases, it may be useful to prepare hydrosoluble pharmaceutical compositions according to the invention from a phenylamino-alcohol salt, such as for example hydro-chloride, by double decomposition with a glucuronic acid salt, for example barium glucuronate, most advantageously in aqueous solution. The residual salt resulting from this double decomposition, fdr example barium chloride, is then removed, e.g. filtered out.
Although the pharmaceutical composition according to the invention may be administered orally, due to its very high water solubility, it is more particularly suitable for administration by intravenous injection or perfusion.
Due to the low toxicity of glucuronic acid, it is possible to obtain compositions having a very favourable therapeutical index.
The invention is still illustrated by a number of preparation examples of specific compositions according to the invention.
Example I
20 g (0.103 mole) of D-glucuronic acid and 30.9- g (0.1 mole) of 1 - (4 - isopropylthiophenyl) - 2 - n - hexylamino 1 - propanol are mixed with 20 ml of water.
A clear 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).
Example 2
24 g (0.127 mole) of D-glucuronic acid and 41.9 g (0.1 mole) of 1-(4- isopropylthiophenyl) - 2 - n tetradecylamino - 1 - propanol are mixed with 50 ml of water. Stirring is maintained 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 dissolved in 283.5 g of water and 33.76 p (0.1 mole) of 1 - (4 - isopropylthiophenol) - 2 - n - octylamino
I - propanol are added to this solution with stirring. Stirring is continued until complete solution, which requires about 1/2 hour. A clear solution containing I 00/,, of I - (4 isopropylthiophenyl) - 2 - n octylamino - 1 - propanol is so obtained.
Instead of treating at room temperature, as in the present example, higher temperatures are used according to a variant, more particularly in water heated to about 60"C.
Example 4
To 33.76 g (0.1 mole) of I - (4 - isopropylthiophenyl) - 2 - n - octylamino 1- - propanol dissolved in 330 ml of tetrahydrofuran, 19,41 g (0.1 mole) of Dglucuronic acid and 50 ml of water are added and stirring is continued until complete solution of glucuronic acid, which requires about 2 hours. Solvents are evaporated under vacuum and 53.3 g of dry product are obtained.
The preparation of injectable solutions or of aqueous solutions for oral administration can be made directly from a solution prepared according te Example 2 or from a solid product prepared according to
Example 1 after dissolution in water.
Hereinafter two typical pharmaceutical formulations are given for injectable compositions.
1. 1 - (4 - isopropyl
thiophenyl) - 2 - n - octyl
amino - I - propanol I mg
D-glucuronic acid 0.6 mg
Anhydrous dextrose 55.1 mg Bidist. water, q.s. h I ml 2. 1 - (4 - isopropyl
thiophenyl) - 2 - n - octyl
amino - 1 - propanol 20 mg
D-glucuronic acid 12 mg
Anhydrous dextrose
Bidist, water, q.s. 1 ml
The daily doses of substituted phenylamino-alcohols in association with glucuronic acid, proposed for humans, are about 1 to 50 mg, preferably 0.001 to 1 mjkg.
Application is preferably made by intravenous injection or perfusion.
WHAT WE CLAIM IS:
1. A hydrosoluble pharmaceutical composition comprising a l-phenyl-2-amino alcohol of the general formula:
wherein R, is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of I or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms, or a salt thereof, and glucuronic acid or a salt thereof, or a reaction product of the l-phenyl-2-amino alcohol and glucuronic acid.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (18)
1. 1 - (4 - isopropyl
thiophenyl) - 2 - n - octyl
amino - I - propanol I mg
D-glucuronic acid 0.6 mg
Anhydrous dextrose 55.1 mg Bidist. water, q.s. h I ml 2. 1 - (4 - isopropyl
thiophenyl) - 2 - n - octyl
amino - 1 - propanol 20 mg
D-glucuronic acid 12 mg
Anhydrous dextrose
Bidist, water, q.s. 1 ml
The daily doses of substituted phenylamino-alcohols in association with glucuronic acid, proposed for humans, are about 1 to 50 mg, preferably 0.001 to 1 mjkg.
Application is preferably made by intravenous injection or perfusion.
WHAT WE CLAIM IS:
1. A hydrosoluble pharmaceutical composition comprising a l-phenyl-2-amino alcohol of the general formula:
wherein R, is an alkyl radical of 1 to 4 carbon atoms, R2 is an alkyl radical of I or 2 carbon atoms and R3 is an alkyl radical of 4 to 16 carbon atoms, or a salt thereof, and glucuronic acid or a salt thereof, or a reaction product of the l-phenyl-2-amino alcohol and glucuronic acid.
2. A composition as claimed in claim 1,
wherein the glucuronic acid is D-glucuronic acid.
3. A composition as claimed in claim 1 or 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.
4. A composition as claimed in claim 3, wherein the compound of formula (I) is 1 (4 - isopropylthiophenyl) - 2 - n octylamino - 1 - propanol.
5. A composition as claimed in any one of claims 1 to 4, wherein the composition is an aqueous solution of the l-phenyl-2-amino- alcohol and glucuronic acid.
6. A composition as claimed in any one of claims 1 to 4, in the form of a water soluble powder.
7. A composition as claimed in any of claims I to 5, in a form suitable for intravenous injection or perfusion.
8. A process for preparing a hydrosoluble pharmaceutical composition as claimed in any one of claims 1 to 7, wherein glucuronic acid is reacted in a solvent with a l-phenyl- 2-amino-alcohol of formula (I).
9. A process as claimed in claim 8, wherein an at least equimolecular amount of the l-phenyl-2-amino-alcohol is gradually added to an aqueous solution of glucuronic acid and the mixture is stirred until a clear solution is obtained.
10. A process as claimed in claim 8, wherein an aqueous solution of glucuronic acid is added to the l-phenyl-2-amino- alcohol in suspension or solution in a solvent.
11. A process as claimed in claim 10, wherein water or a mixture of water and one or more water miscible organic solvents, is used as solvent.
12. A process as claimed in any one of claims 8 to 11, wherein glucuronic acid is heated to a temperature of 40 to 600C before contacting it with the l-phenyl-2amino-alcohol.
13. A process as claimed in any one of claims 8 to 12, wherein solvent is removed after reaction between the glucuronic acid and the l-phenyl-2-amino-alcohol until the reaction product is obtained as a powder.
14. A process for preparing a hydrosoluble pharmaceutical composition as claimed in any one of claims 1 to 7, wherein a salt of glucuronic acid is reacted with a salt of the l-phenyl-2-amino-alcohol to form the glucuronic acid salt of the amino-alcohol and another salt by double decomposition, and then the mixture is freed of the other salt.
15. A hydrosoluble pharmaceutical composition, substantially as hereinbefore described.
16. A process for preparing a hydrosoluble composition, substantially as hereinbefore described.
17. A hydrosoluble pharmaceutical composition as substantially as hereinbefore described in any one of the specific
Examples.
18. A process for producing a hydrosoluble pharmaceutical composition substantially as hereinbefore described in any one of the specific Examples.
Applications Claiming Priority (1)
| 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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1569380A true GB1569380A (en) | 1980-06-11 |
Family
ID=9174050
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB23697/77A Expired GB1569380A (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 CA CA279,790A patent/CA1095416A/en not_active Expired
- 1977-06-03 NL NL7706177A patent/NL7706177A/en not_active Application Discontinuation
- 1977-06-03 SE SE7706481A patent/SE441183B/en not_active IP Right Cessation
- 1977-06-03 JP JP6490677A patent/JPS5318721A/en active Granted
- 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
Also Published As
| Publication number | Publication date |
|---|---|
| CH622023A5 (en) | 1981-03-13 |
| DE2724608C2 (en) | 1986-09-18 |
| SE441183B (en) | 1985-09-16 |
| SE7706481L (en) | 1977-12-05 |
| DE2724608A1 (en) | 1977-12-22 |
| NL7706177A (en) | 1977-12-06 |
| BE855320A (en) | 1977-12-02 |
| FR2353288B1 (en) | 1978-12-15 |
| JPS6126526B2 (en) | 1986-06-20 |
| JPS5318721A (en) | 1978-02-21 |
| CA1095416A (en) | 1981-02-10 |
| FR2353288A1 (en) | 1977-12-30 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |