WO1988003019A1 - Hydrosoluble ubidecarenones derivatives and their preparation - Google Patents
Hydrosoluble ubidecarenones derivatives and their preparation Download PDFInfo
- Publication number
- WO1988003019A1 WO1988003019A1 PCT/EP1987/000613 EP8700613W WO8803019A1 WO 1988003019 A1 WO1988003019 A1 WO 1988003019A1 EP 8700613 W EP8700613 W EP 8700613W WO 8803019 A1 WO8803019 A1 WO 8803019A1
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- WIPO (PCT)
- Prior art keywords
- ubidecarenones
- acyl
- amino
- derivatives
- hydrosoluble
- Prior art date
Links
- 235000017471 coenzyme Q10 Nutrition 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims description 7
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 8
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 claims description 7
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
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- 229960004747 ubidecarenone Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 3
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- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 238000000527 sonication Methods 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims 1
- 239000012736 aqueous medium Substances 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 5
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- XXWWMPQBFKPUSO-KTKRTIGZSA-N 2-[[(z)-octadec-9-enyl]amino]ethanesulfonic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCNCCS(O)(=O)=O XXWWMPQBFKPUSO-KTKRTIGZSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- DXLKPVHZKBSMFP-HZJYTTRNSA-N 2-[[(9z,12z)-octadeca-9,12-dienyl]amino]ethanesulfonic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCNCCS(O)(=O)=O DXLKPVHZKBSMFP-HZJYTTRNSA-N 0.000 description 1
- GWSHTUIRQSLJOC-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[4.1.0]hept-1(6)-en-5-one Chemical compound O=C1C(C)CCC2=C1C2(C)C GWSHTUIRQSLJOC-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- OCNZHGHKKQOQCZ-CLFAGFIQSA-N [(z)-octadec-9-enoyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(=O)CCCCCCC\C=C/CCCCCCCC OCNZHGHKKQOQCZ-CLFAGFIQSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 208000037849 arterial hypertension Diseases 0.000 description 1
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- 230000003683 cardiac damage Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000003413 degradative effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000036450 inotropism Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000027756 respiratory electron transport chain Effects 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- 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
- A61K31/12—Ketones
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
- A61K8/355—Quinones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
- A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
Definitions
- Hydrosoluble ubidecarenones derivates and their preparation.
- the present invention relates to pharmaceutica preparations containing soluble ubidecarenones prepared b disperding in acqueous media mixtures having differen ratios of ubidecarenones and acyl derivatives of 2-amino- ethansulphonic acid.
- the ubidecarenones form an important class of lipo- soluble vitaminic principles, particularly 2,3-dimethoxy- 5-methyl-8-decaprenyl-l,4-benzoquinone, known as ubideca- renone-10, localized at the mitochondrial level, plays a key-role in mammals in the electron-transfer system and more generally in the energy production.
- the ubiquinone-10 is widely used in a large number of cardiac pathologies, protecting the myocardium from ischemic phe- nomena and preserving the functions thereof.
- the drug is generally administered by the oral route in form of franules, tablets and soft capsules, generally at a dosage of 10 mg.
- the experiments carried out show a critical role of the administration form in the drug's absorption, which is usually slight.
- biocompatible hydrosoluble formulation is therefore particularly desired.
- the development of biocompatible, hydrosoluble formulations is of particular interest for a better bio- availability of ubidecarenone-10 both in the pharmaceuti ⁇ cal and cosmetic use.
- the present invention concerns the development of a sys.tem able to carry in aqueous media the ubidecarenones, thanks to the interaction with amphipatic ions of general formula RNH-CH -CH -SO , wherein R is an acyl radical having more than 5 carbon atoms, preferably a natural fatty acid of the normal, iso, an eiso series or cycloal- kyl, saturated or unsaturated having from 8 to 26 carbon atoms.
- This class of amphipatic molecules is surprisingly able to carry the ubidecarenones in water, in form of micellar and/or liposomial aggregates, even using an equi- molar ratio of the two compounds.
- a molar excess of the amphipatic solubilizing spe- cies is preferably used, from 2 to 4 times higher than the vitamin, said conditions granting a better and faster solubilization.
- hydrosoluble ubidecarenones may be carried out in different ways, for instance by sonica- ting an acqueous solution of the amphipatic species, to which the ubidecarenone is added or preferably by dispers ⁇ ing in water, under vigorous stirring, a mixture of ubide ⁇ carenone and N-acyl-2-amino-ethanesulphonate, prepared by evaporation of a solution of the two compounds in an orga- nic solvent, in which both are soluble.
- micellar and/or liposomial systems so prepared are stable over long periods of time, even at extremely low or high environmental temperatures, that may be more ⁇ over lyophilized, yielding generally materials of waxy consistency, easily soluble in water by simple stirring.
- Important characteristics of the invention, under the pharmaceutical profile are: a) the stability in time of the micellar and/or liposomial aggregates, formed by combining in aqueous solution ubidecarenones and N-acyl-2-amino-ethanesulphonates; b) the low toxicity of the solubilizing agent, which is biodegradable and metabolizable, because derived from the formation of an amide bond, which may be cleaved by amidases present in the body, said bond linking a fatty acid to 2-amino-ethanesulphonic acid, both naturally present metabolites in man; c) an improved bioavailability of ubidecarenone both by the oral and injection route; d) an improved stability of ubi
- compositions containing as the active principle compounds of ubidecarenone and N-acyl-2-amino-ethanesulphonates optionally in admixture with conventional excipients.
- composition of the invention may be used in the pharmacological use in many fields and particularly as myocardioenergetics, indicated in the alterations of the myocardium characterized by reduced inotropism: senile myocardiosclerosis, congestive heart failure, chronic pulmonary heart, in combination with digitalis and other cardiotonics; as adjuvant in the treatment of acute and chronic ischemic cardiopathies and of the arterial hyper- tension, prevention of cardiac damages due to the use of some cardiotoxic antitumoral agents (adriamycin and dauno- mycin) .
- compositions of the inven ⁇ tion may moreover comprise other active principles having complementary activity.
- T Thhee HH--NNMMRR ssppectrum in CDC1 shows the signal of the acyl moiety, in the correct integration ratio, at o 5.3; 2.4; 1.9; I.r.: 1.3 and 0.9 and those of 2-amino- ethanesulphonate at S 3.7 and 4.6.
- the obtained biphasic system after sonication, yields an homogeneous phase of micellar and/or liposomial kind, stable in time and to the environmental parameters. For instance, freezing of the solution or its heating do not change the chemico-physical state of the dispersed supermolecular aggregates.
- EXAMPLE 2 87.5 g of 2-amino-ethanesulphonate, suspended in 500 ml of anhydrous pyridine, were reacted at 50°C for 10 hours with 311 g of linolenic acid chloride.
- EXAMPLE 3 43.1 g of ubidecarenone-10 and 64.2 g of arachido- nyl-2-amino-ethanesulphonate were dissolved in 1 1 of CHC1 .
- micellar and/or liposomial system After removal of the solvent, 2 1 of water were added under vigorous stirring, till the formation of a stable micellar and/or liposomial system. After freezing and lyophilization of the solution a waxy compound orange in colour, readily soluble in the presence of water, was obtained.
Abstract
Ubidecarenones are effectively dissolved in aqueous media by means of N-acyl-2-amino-ethanesulphonates, wherein the acyl residues have more than 5 carbon atoms. Pharmaceutical compositions containing ubidecarenones so solubilized are particularly effective as moycardioenergetics.
Description
Λ-
Hydrosoluble ubidecarenones derivates and their preparation.
The present invention relates to pharmaceutica preparations containing soluble ubidecarenones prepared b disperding in acqueous media mixtures having differen ratios of ubidecarenones and acyl derivatives of 2-amino- ethansulphonic acid.
The ubidecarenones form an important class of lipo- soluble vitaminic principles, particularly 2,3-dimethoxy- 5-methyl-8-decaprenyl-l,4-benzoquinone, known as ubideca- renone-10, localized at the mitochondrial level, plays a key-role in mammals in the electron-transfer system and more generally in the energy production.
Because of said important metabolic roles, the ubiquinone-10 is widely used in a large number of cardiac pathologies, protecting the myocardium from ischemic phe- nomena and preserving the functions thereof.
Because of its complete insolubility in aqueous media the drug is generally administered by the oral route in form of franules, tablets and soft capsules, generally at a dosage of 10 mg. The experiments carried out show a critical role of the administration form in the drug's absorption, which is usually slight.
The availability of biocompatible hydrosoluble formulation is therefore particularly desired. The development of biocompatible, hydrosoluble formulations is of particular interest for a better bio-
availability of ubidecarenone-10 both in the pharmaceuti¬ cal and cosmetic use.
The present invention concerns the development of a sys.tem able to carry in aqueous media the ubidecarenones, thanks to the interaction with amphipatic ions of general formula RNH-CH -CH -SO , wherein R is an acyl radical having more than 5 carbon atoms, preferably a natural fatty acid of the normal, iso, an eiso series or cycloal- kyl, saturated or unsaturated having from 8 to 26 carbon atoms. This class of amphipatic molecules is surprisingly able to carry the ubidecarenones in water, in form of micellar and/or liposomial aggregates, even using an equi- molar ratio of the two compounds.
A molar excess of the amphipatic solubilizing spe- cies is preferably used, from 2 to 4 times higher than the vitamin, said conditions granting a better and faster solubilization.
The preparation of hydrosoluble ubidecarenones may be carried out in different ways, for instance by sonica- ting an acqueous solution of the amphipatic species, to which the ubidecarenone is added or preferably by dispers¬ ing in water, under vigorous stirring, a mixture of ubide¬ carenone and N-acyl-2-amino-ethanesulphonate, prepared by evaporation of a solution of the two compounds in an orga- nic solvent, in which both are soluble.
The micellar and/or liposomial systems so prepared are stable over long periods of time, even at extremely low or high environmental temperatures, that may be more¬ over lyophilized, yielding generally materials of waxy consistency, easily soluble in water by simple stirring.
Important characteristics of the invention, under the pharmaceutical profile, are: a) the stability in time of the micellar and/or liposomial aggregates, formed by combining in aqueous solution ubidecarenones and N-acyl-2-amino-ethanesulphonates; b) the low toxicity of the solubilizing agent, which is biodegradable and metabolizable, because derived from the formation of an amide bond, which may be cleaved by amidases present in the body, said bond linking a fatty acid to 2-amino-ethanesulphonic acid, both naturally present metabolites in man; c) an improved bioavailability of ubidecarenone both by the oral and injection route; d) an improved stability of ubidecarenones towards undesi- red degradative processes; e) a more effective therapeutic action in comparison to the formulations presently marketed.
The invention provides therefore pharmaceutical compositions containing as the active principle compounds of ubidecarenone and N-acyl-2-amino-ethanesulphonates optionally in admixture with conventional excipients.
The composition of the invention may be used in the pharmacological use in many fields and particularly as myocardioenergetics, indicated in the alterations of the myocardium characterized by reduced inotropism: senile myocardiosclerosis, congestive heart failure, chronic pulmonary heart, in combination with digitalis and other cardiotonics; as adjuvant in the treatment of acute and chronic ischemic cardiopathies and of the arterial hyper- tension, prevention of cardiac damages due to the use of
some cardiotoxic antitumoral agents (adriamycin and dauno- mycin) .
The daily theraperutic dose, the administration route and frequency depend on various factors (diagnosis, patient's conditions, etc.), but they will be anyhow easi¬ ly determined, case by case, absolutely in non-critical way as a consequence, inter alia, of the very low toxicity of the system components. The compositions of the inven¬ tion may moreover comprise other active principles having complementary activity.
The procedures generally described in the present invention, because of their simplicity or limited cost, are easily suited to the development of preparative pro¬ cesses on the industrial scale. The following examples illustrate the preparation of different kinds of soluble ubidecarenones. They necessarily concern only some of the numerous possibilities which can be envisaged and, without any limitative character, they only define the scope of the invention. EXAMPLE 1
62.5 g of 2-amino-ethansulphonate, suspended in 500 ml of anhydrous dimethylformamide, were reacted at 70°C for 10 hours with 410 g of oleic anhydride, in the presen¬ ce of 0.5 g of dimethylami opyridine as a catalyst. After evaporation of the solvent under vacuo, the oily residue was repeatedly triturated in ethyl ether. 190 g of N-oleyl-2-amino-ethansulphonate as a waxy, white solid, were obtained.
2 2
T Thhee HH--NNMMRR ssppectrum in CDC1 shows the signal of the acyl moiety, in the correct integration ratio, at o
5.3; 2.4; 1.9; I.r.: 1.3 and 0.9 and those of 2-amino- ethanesulphonate at S 3.7 and 4.6.
86.2 g of ubidecarenone-10 were added to 81 g of N-oleyl-2-aminoethansulphonate, dissolved in 2.8 liters of water.
The obtained biphasic system, after sonication, yields an homogeneous phase of micellar and/or liposomial kind, stable in time and to the environmental parameters. For instance, freezing of the solution or its heating do not change the chemico-physical state of the dispersed supermolecular aggregates.
EXAMPLE 2 87.5 g of 2-amino-ethanesulphonate, suspended in 500 ml of anhydrous pyridine, were reacted at 50°C for 10 hours with 311 g of linolenic acid chloride.
After evaporation of the solvent under vacuo, the oily residue was first triturated in ethyl ether and then, dissolved in water, was dialyzed against water. After lyophilization 255 g of N-linoleyl-2-amino-ethanesulphona- te as a white, waxy solid, were obtained. The H -NMR spectrum recorded in CDC1 shows, in the correct integra¬ tion ratios the signals of the acyl moiety at S 5.3; 2.8; 2.4; 1.9;1.6;1.3;0.9 and those of 2-amino-ethanesulphonate at S 3.7 and 4.6. 172 g of ubidecarenone-10 and 321 g of N-linoleyl- 2-amino-ethanesulphonate were dissolved in 2 1 of 1 CHC1 . After evaporation of the solvent under vacuum, 3.4 liters of water were added under vigorous stirring. An homogeneous system, yellow-orange in colour, of micellar and/or liposomial kind, stable in time and to the environ-
mental parameters was obtained.
EXAMPLE 3 43.1 g of ubidecarenone-10 and 64.2 g of arachido- nyl-2-amino-ethanesulphonate were dissolved in 1 1 of CHC1 .
After removal of the solvent, 2 1 of water were added under vigorous stirring, till the formation of a stable micellar and/or liposomial system. After freezing and lyophilization of the solution a waxy compound orange in colour, readily soluble in the presence of water, was obtained.
Claims
1. Hydrosoluble ubidecarenones derivatives obtained by addition to the ubidecarenones of N-acyl-2-amino-ethane- sulphonate wherein the acyl residue has more than 5 carbon atoms and is preferably a natural fatty acid, saturated or unsaturated of the normal, iso, anteiso or cycloalkyl series, having from 8 to 26 carbon atoms.
2. A process for the preparation of the derivatives of claim 1, characterized in that ubidecarenones are subjected to sonication in acqueous solutions of N-acyl-2-amino- ethanesulphonates, generally used in a stoichiometric ratio with respect to the ubidecarenone higher than 1:1 (moles of ubidecarenones/moles of N-acyl-2-amino-ethane- sulphonate), preferably 1:2-4.
3. A process for the preparation of the derivatives of claim 1, characterized in that a mixture of ubidecarenone and N-acyl-2-amino-ethanesulphonate (molar ratio from 1:1 to 1:4), obtained by evaporation of a solution of the two compounds in an organic solvent in which both are soluble, is subjected to mechanical dispersion.
4. Pharmaceutical compositions containing as the acti¬ ve principle an hydrosoluble ubidecarenone derivative according to claim 1, in admixture with the usual exci- pients and vehicles.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22105A/86 | 1986-10-23 | ||
| IT8622105A IT1214540B (en) | 1986-10-23 | 1986-10-23 | WATER SOLUBLE FORMULATIONS OF UBIDECARENONES, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT COMPOSE THEM. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1988003019A1 true WO1988003019A1 (en) | 1988-05-05 |
Family
ID=11191567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1987/000613 WO1988003019A1 (en) | 1986-10-23 | 1987-10-19 | Hydrosoluble ubidecarenones derivatives and their preparation |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0330665A1 (en) |
| AU (1) | AU8174887A (en) |
| IT (1) | IT1214540B (en) |
| WO (1) | WO1988003019A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0493441A1 (en) * | 1989-09-21 | 1992-07-08 | Micro Vesicular Systems | Paucilamellar lipid vesicles using charge-localized, single chain, nonphospholipid surfactants. |
| WO2011112900A2 (en) | 2010-03-12 | 2011-09-15 | Cytotech Labs, Llc | Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2322133A1 (en) * | 1975-08-26 | 1977-03-25 | Bayer Ag | PROCESS FOR PRODUCING ACYL-TAURIDS |
| EP0069399A2 (en) * | 1981-07-08 | 1983-01-12 | Eisai Co., Ltd. | Pharmaceutical composition containing ubidecarenone containing liposomes |
| EP0211647A1 (en) * | 1985-08-07 | 1987-02-25 | Smithkline Beecham Corporation | Method and composition for making liposomes |
-
1986
- 1986-10-23 IT IT8622105A patent/IT1214540B/en active
-
1987
- 1987-10-19 AU AU81748/87A patent/AU8174887A/en not_active Abandoned
- 1987-10-19 WO PCT/EP1987/000613 patent/WO1988003019A1/en not_active Application Discontinuation
- 1987-10-19 EP EP87907217A patent/EP0330665A1/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2322133A1 (en) * | 1975-08-26 | 1977-03-25 | Bayer Ag | PROCESS FOR PRODUCING ACYL-TAURIDS |
| EP0069399A2 (en) * | 1981-07-08 | 1983-01-12 | Eisai Co., Ltd. | Pharmaceutical composition containing ubidecarenone containing liposomes |
| EP0211647A1 (en) * | 1985-08-07 | 1987-02-25 | Smithkline Beecham Corporation | Method and composition for making liposomes |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0493441A1 (en) * | 1989-09-21 | 1992-07-08 | Micro Vesicular Systems | Paucilamellar lipid vesicles using charge-localized, single chain, nonphospholipid surfactants. |
| EP0493441A4 (en) * | 1989-09-21 | 1992-07-22 | Micro Vesicular Systems, Inc. | Paucilamellar lipid vesicles using charge-localized, single chain, nonphospholipid surfactants |
| WO2011112900A2 (en) | 2010-03-12 | 2011-09-15 | Cytotech Labs, Llc | Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof |
| EP3366280A1 (en) | 2010-03-12 | 2018-08-29 | Berg LLC | Intravenous formulations of coenzyme q10 (coq10) and methods of use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1214540B (en) | 1990-01-18 |
| IT8622105A0 (en) | 1986-10-23 |
| EP0330665A1 (en) | 1989-09-06 |
| AU8174887A (en) | 1988-05-25 |
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