GB2051069A - Phospholipid Derivatives Useful in Therapy as Antilepaemics and Antiarteriosclerotics and Compositions Containing Them - Google Patents
Phospholipid Derivatives Useful in Therapy as Antilepaemics and Antiarteriosclerotics and Compositions Containing Them Download PDFInfo
- Publication number
- GB2051069A GB2051069A GB7921163A GB7921163A GB2051069A GB 2051069 A GB2051069 A GB 2051069A GB 7921163 A GB7921163 A GB 7921163A GB 7921163 A GB7921163 A GB 7921163A GB 2051069 A GB2051069 A GB 2051069A
- Authority
- GB
- United Kingdom
- Prior art keywords
- oleyl
- phosphatidylethanolamine
- antilipemic
- antiarteriosclerotic
- therapy
- 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.)
- Granted
Links
- 150000003904 phospholipids Chemical class 0.000 title claims description 14
- 239000000203 mixture Substances 0.000 title claims description 13
- 238000002560 therapeutic procedure Methods 0.000 title claims 4
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims abstract description 27
- 230000002402 anti-lipaemic effect Effects 0.000 claims abstract description 10
- 229940067605 phosphatidylethanolamines Drugs 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 21
- 125000001931 aliphatic group Chemical group 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims 1
- 150000002888 oleic acid derivatives Chemical class 0.000 abstract description 2
- 150000002169 ethanolamines Chemical class 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 239000002775 capsule Substances 0.000 description 8
- 150000002632 lipids Chemical class 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 6
- 244000068988 Glycine max Species 0.000 description 5
- 235000010469 Glycine max Nutrition 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 150000003626 triacylglycerols Chemical class 0.000 description 5
- MLQBTMWHIOYKKC-KTKRTIGZSA-N (z)-octadec-9-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCC(Cl)=O MLQBTMWHIOYKKC-KTKRTIGZSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 4
- 229910002012 Aerosil® Inorganic materials 0.000 description 3
- 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
- 229930003427 Vitamin E Natural products 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 description 3
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 3
- 235000019165 vitamin E Nutrition 0.000 description 3
- 239000011709 vitamin E Substances 0.000 description 3
- 229940046009 vitamin E Drugs 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 2
- 229960001214 clofibrate Drugs 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 231100000816 toxic dose Toxicity 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- HVYWMOMLDIMFJA-UHFFFAOYSA-N 3-cholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 HVYWMOMLDIMFJA-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000208818 Helianthus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013345 egg yolk Nutrition 0.000 description 1
- 210000002969 egg yolk Anatomy 0.000 description 1
- 238000002481 ethanol extraction Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical class CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- GFAUNYMRSKVDJL-UHFFFAOYSA-N formyl chloride Chemical compound ClC=O GFAUNYMRSKVDJL-UHFFFAOYSA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229930004090 phosphatidylinositide Natural products 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 231100000456 subacute toxicity Toxicity 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- MDYZKJNTKZIUSK-UHFFFAOYSA-N tyloxapol Chemical compound O=C.C1CO1.CC(C)(C)CC(C)(C)C1=CC=C(O)C=C1 MDYZKJNTKZIUSK-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
N-oleyl derivatives of natural and synthetic phosphatidylethanolamines exhibit antilipemic and antiarteriosclerotic properties and can be used in pharmaceutical compositions. They may be made by reaction of oleic acid derivatives with the corresponding ethanolamines.
Description
SPECIFICATION
Novel Phospholipid Derivatives and Their Preparation and Use
Naturally occurring phospholipids (i.e., phosphatides) consist of a mixture of chemically different phospholipids, with phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositide being the predominant components. Such phospholipids may be products from egg yolks, soya beans, rape, peanuts, or sunflowers. It has been known for some time that phosphatidylcholine, or phosphatidylcholine-enriched phospholipide fractions together with unsaturated aliphatic acids, possess an advantageous metabolic effect on the symptons of many diseases including arteriosclerosis, hyperlipemias, and diabetes. However, such properties have only been observed heretofore with respect to choline-containing glycerinephospholipides.The phosphatidylethanolamine on the other hand, does not display any antiarteriosclerotic or antilipemic effects.
Phosphatidylethanolamine, however, is a component of the phosphatides and can cause undesirable side effects if such phosphatides are medically administered.
It is known that the primary amino group of the phosphatide can be acylated by reaction with polycarboxylic acid anhydrides (see German patent 721 002) in order to improve its solubility characteristics.
The acylation of lecithin-containing mixtures is known as described in United States patent 2,791 594, and the acylation of the phosphatides with acetic acid anhydrides has been disclosed by
British patents 766,394 and 974,432 as well as by the published German patent application 1 5 43 937.
Higher n-aliphatic acid acyl compounds of phosphatidylethanolamine were detected in small quantities in naturally occurring glycerinephospholipides and especially in the phospholipide mixture derived from soya beans. Specifically, n-acylphosphatidylethanolamine was admixed with different aliphatic acids with palmitic acid predominating (i.e. comprising about 65% of the mixture).
It has been surprisingly and unexpectedly found that phosphatidylethanolamines of natural as well as synthetic origin can be converted by acylation with oleic acid to new noleylphosphatidylethanolamines which demonstrate a pronounced antiarteriosclerotic, or antilipemic effect. Such an effect has been observed even in small doses in animal tests.
It is surprising and unexpected that this property can only be clearly observed with respect to the oleic acid derivatives of the phosphatidylethanolamines. Such an effect is not observed with respect to corresponding compounds which are derived either from the highly unsaturated aliphatic acids or from the saturated aliphatic acids having widely differing chain lengths. Even the n-linolate of the phosphatidlyethanolamine only exhibits a moderate antilepemic effect, even though n-linolyl compounds of cyclic amines, such as the cyclohexyllinolamide, have been specifically known for some time for their lipid-reducing effect.
The novel n-oleyl derivatives of phosphatidylethanolamines of the present invention have the general formula:
wherein R, and R2 are saturated, unsaturated, straight-chain, or branched aliphatic acids. Preferably, the R1 and R2 substituents are naturally occurring unsaturated aliphatic acids containing 12 to 22 carbon atoms.
The n-oleyl derivatives of the present invention may be manufactured by dissolving pure phosphatidylethanolamine or a phosphatidylethanolamine-containing phospholipid fraction (e.g., raw phosphatides or phospholipid fractions) in a suitable solvent such as an aliphatic, cyclic or chlorinated hydrocarbon, or tetrahydrofuran or dioxan. The determination of which type of solvent is suitable is within the skill of the artisan. After the admixture of a basic compound, such as triethylamine, pyridine or a similar acid acceptor, the phosphatidylethanolamine is reacted with oleic acid chloride or, by use of the anhydride mechanism, with oleic acid and formic acid chloride.
The fact that cephalin-containing phosphatide fractions can be used for the n-oleyl production of phosphatidylethanolamine is economically important. Phospholipid mixtures containing the biologically valuable phosphatidylcholine together with the n-oleylphosphatidylethanolamines of the present invention having an antilipemic and antiarteriosclerotic effect can thus be simply produced.
The phospholipid derivatives of the present invention were tested on rats to observe their antilipemic effects. Such tests, carried out in accordance with the procedures described bv H. Schoen and G. Berg in Arzneimittelforschung, Vol. 7, page 307 (1957) and Schurr, P. E. et al, Lipids Vol. 7, pages 68-74 (1972) demonstrated that in the case of both healthy animals as well as in animals exhibiting a Triton-hypercholesterin condition (i.e., "aemie"), the administration of the n-oleyl derivatives provided a significant decrease in the total amount of lipids. A decrease in the cholesterin and the triglycerides were also observed in comparison to untested control animals.
The following tests were employed to determine the therapeutic effect of the n-oleyl derivatives of the present invention: a) Prophylactic Application
The n-oleyl derivative (i.e., n-oleyl cephalin) was orally administered to the test animals. Twentyfour hours later an intraperitoneal application of triton-WR 1 339 (to produce hyperlipemia) occurred.
Forty-eight hours after the triton application, serum was analyzed for lipids and compared with a control group. The results are depicted in Table I.
b) Therapeutic Application
Triton-WR 1339 was intraperitoneally administered to the test animals. One hour later the n-oleyl cephalin was orally administered. Forty-eight hours after the triton is administered, serum is analyzed for lipids and evaluated against a control group. The results are depicted in Table c) Biochemical Screening
In accordance with the procedures set forth in Fletcher, M. J., Clin. Chim. Acta., Vol. 22, page 393 (1968), the n-oleyl cephalin was orally administered to unstressed animals. Four hours later serum was analyzed for lipids and evaluated against a control group. The results are depicted in Table I.
Table I
Test N-oleylcephalin Clofibrate 1. Acute triton test Total lipids E.D.50 0.29 mg/kg BW* Dosing to 250 mg/kg BW (1 x propylactic Phospholipids E.D.50 0.62 mg/kg BW ineffective application) on Triglycerides E.D.50 0.18 mg/kg BW Dosing 500 mg(kg BW rats Total cholesterol Effect from 0.01 mg/kg BW very effective Free cholesterol Effct from 0.10 mg/kg BW 2. Acute triton test Total lipids E.D.50 8.49 mg/kg BW Drop from 250 mg/kg BW (1 x therapeutic Triglycerides E.D.50 5.63 mg/kg BW Drop from 250 mg/kg BW application) on Triglycerides E.D.50 278.86 mg/kg BW No effct up to 500 mg/kg BW rats Phospholipids Drop from 0.10 mg/kg BW Drop from 500 mg/kg BW Free cholesterol Drop from 0.10 mg/kg BW No effect up to 500 mg/kg BW 3. Biochemical Total lipids 50 mg/kg BW Drop from 100 mg/kg BW screening Phospholipids 50 mg/kg BW Not determined (unstressed rat) Triglycerids Drop from # 50 mg/kg BW Drop from 50 mg/kg BW Total cholesterol 50 mg/kg BW Drop from 50 mg/kg BW Free cholesterol 50 mg/kg BW Not determined 4. Acute toxicity LD50 mouse 4640 mg/kg BW 2960 mg/kg BW LD50 mouse 4640 mg/kg BW ~ 1470 mg/kg BW LD50 rat 5000 mg/kg BW 1100 mg/kg BW LD0rat 5000 mg/kg BW ~ 681 mg/kg BW 5. Subchronic Rat 4 weeks: Rat 13 weeks: toxicity Lowest toxic dose between Lowest toxic dose between 250 and 1250 mg/kg BW 88 and 265 mg/kg BW *BV=body weight The data contained within Table I demonstrates that the n-oleyl derivatives of the present invention have a marked hypolipemic or antihyperlipemic effect, even when administered in a low dosage. On the other hand, a higher dosage of clofibrate (1 50 to 500 times higher) is usually necessary to achieve comparable results. Furthermore, the compounds of the present invention exhibit less acute and subacute toxicity.
In order to produce a suitable oral therapeutic composition, the noleylphosphatidylethanolamines of the present invention can be placed into soft gelatin capsules after the admixture of an antioxidant, such as, for example vitamin E. In the case of the admixture of the noleylphosphatidylethanolamines with other phospholipids, the composition may be placed into capsules after the admixture of mono-, di- or triglycerides obtained from natural aliphatic acids. The noleylphosphatidylethanolamines may also be orally applied in a solid form together with a porous solid such as diatomaceous earth and silica. Suitable porous solids are marketed under the tradenames
Aerosil and Celite. Lactose, calcium cabonate and magnesium stearate can be employed as additives in the manufacture of such solid forms in addition to antioxidants such as tocopherol (i.e., Vitamin E) or ascorbic acid.The pharmaceutical preparations of the present invention may also contain pigments, aromatic additives and preservatives.
The daily oral dosage of a pharmaceutical preparation containing noleylphosphatidylethanolamine can range from 100 to 2,000 milligrams, with this amount normally being divided into periodic (i.e. 2 to 4 times per day) doses of 50 to 500 milligrams.
The invention is additionally illustrated in connection with the following Examples which are to be considered as illustrative of the present invention. It should be understood, however, that the invention is not limited to the specific details of the Examples.
Example 1
One hundred grams of chemically pure phosphatidylethanolamine are produced by columnchromatiographic separation by use of silica gel of a soya lecithin fraction having a high phosphatidylethanolamine content and being insoluble in alcohol with chloroform-methanol serving as eluant. The phosphatidylethanolamine is dissolved in 500 milliliters of toluol and the solution is treated, after an admixture of 38 milliliters of triethylamine, with a solution of 41.2 grams of oleic acid chloride in 60 milliliters of toluol while stirring. The stirring is continued for one hour at room temperature and the precipitated triethylaminehydrochloride is then filtered out and the solution is evaporated in a vacuum at 600C bath temperature and a nitrogen atmosphere. The noleylphosphatidylethanolamine remaining is in the form of a viscous oil having a yellow-brown color.
The yield of 115 grams corresponds to 96% of the theoretical yield. The Rf value of the noleylphosphatidylethanolamine is 0.72 using silica gel "G-Fertigpiatten 60 F254 (Merck)", "Laufmittel" chloroform/methanol/NH4OH (12.5%) at a volumetric ratio of 70/25/5.
Example 2
A solution containing 1 9.3 grams of oleic acid and 300 milliliters of tetrahydrofuran is formed and cooled to OOC under stirring after the admixture of 9.5 milliliters of triethylamine. The solution is treated with 6.5 milliliters of chlorinated formic acid ethyl ester, and after 5 minutes it is treated with a solution of 50 grams of phosphatidylethanolamine (produced in the manner described in Example 1) in 120 milliliters of tetrahydrofuran. After an admixture of 9.5 milliliters of triethylamine, the reaction mixture is stirred for one hour at room temperature. The precipitated triethylaminehydrochloride is filtered out and the solution is evaporated in a vacuum at bath temperature of 600 C. The noleylphosphatidylethanolamine produced remains in the form of a viscous oil having a yellow-brown color.The yield of 58 grams corresponds to 97% of the theoretical yield.
Example 3
Two hundred grams of a soya phosphatide fraction, soluble in alcohol and produced by the repeated (continuous) ethanol extraction of de-oiled raw soya bean phosphatide at 40 to 600 C, are dissolved in 800 milliliters of chloroform and are treated, after the admixture of 25 milliliters of pyridine, with a solution of 16.4 grams of oleic acid chloride under stirring. The stirring is continued for one hour at room temperature and the reaction solution is then extracted by means of shaking and the use of 800 milliliters of water. After drying with sodium sulphate, the chloroform phase is evaporated in a vacuum at a bath temperature of 600C in the presence of an inert gas. The resulting plastic phosphatide mixture contains approximately 30% of n-oleylphosphatidylethanolamine and approximately 60% of phosphatidylcholine.
Example 4
Five hundred grams of a soya phosphatide fraction, insoluble in alcohol, containing approximately 33% by weight of phosphatidylethanolamine obtained in the course of the preparation of the alcoholsoluble fraction described in Example 3, are dissolved in 2,500 milliliters of n-hexane and are treated, after the admixture of 47 milliliters of triethylamine, with a solution of 52 grams of oleic acid chloride in 75 milliliters of n-hexane under stirring. The stirring is continued for one hour at room temperature and the precipitated triethylaminehydrochloride is then filtered out and the soluti6n is evaporated in the vacuum at a bath temperature of 600C. The remaining residue is then extracted under stirring at room temperature, first by the use of 500 milliliters of acetone and then twice with the use of 250 milliliters of acetone.From the combined acetone extracts there is then obtained, after removal of the solvent in a vacuum at a bath temperature of 600 C, n-oleylphosphatidylethanolamine in a 70% concentration in the form of a viscous, yellow-brown oil having a phosphatidylcholine content of approximately 25%.
The yield of 240 grams corresponds to 90% of the theoretical yield.
Example 5
Several types of capsules containing the n-oleylphosphatidylethanolamine of this invention are suitable for oral administration and may be prepared as follows: a) Capsules Filled With a Liquid Composition
Capsules suitable for oral dispensation can be produced in a conventional manner by filling soft gelatin capsules with the n-oleylphosphatidylethanolamines prepared in accordance with the invention, optionally admixed with vitamin E. An exemplary dosage would be 500 milligrams of noleylphosphatidylethanolamine per capsule.
b) Capsules Filled With a Dry Composition
It is also possible to produce a pourable powdery material which is suitable for filling hard-gelatin capsules by mixing and grinding n-oleylphosphatidylethanolamine together with Aerosil in the following exemplary proportion:
n-oleylphosphatidylethanolamine 250 mg.
Aerosil 250 mg.
The capsules manufactured in such manner can be used for treating hyperlipemia and arteriosclerosis, with 1 to 2 capsules to be given 2 to 4 times daily.
Claims (6)
1. N-oleyl derivatives of natural and synthetic phosphatidylethanolamines of the formula:
wherein R1 and R2 are saturated or unsaturated, straight-chain or branched aliphatic acid residues.
2. The N-oleyl derivatives of Claim 1 wherein R1 and R2 are each residues of aliphatic acids containing 1 2 to 22 carbon atoms each.
3. N-Oleyl-cephalin.
4. A method for the production of n-oleyl derivatives of phosphatidylethanolamines comprising dissolving a phosphatidylethanolamine or a phosphatidylethanolamine-containing fraction in a suitable solvent and reacting said phosphatidylethanolamine with an acid chloride or anhydride of oleic acid in the presence of a weak base.
5. A composition as claimed in Claim 4, substantially as described in Example 5 (2) or (b).
5. A method according to Claim 4 wherein the reaction occurs in the presence of other phospholipids.
6. A method according to Claim 4 substantially as described in any one of Example 1 to 4.
7. An n-oleyl derivative of phosphatidylethanolamine as claimed in any of Claims 1 to 3 when produced by a process as claimed in any of Claims 4 to
6.
8. An n-oleyl derivative of phosphatidylethanolamine as claimed in any of Claims 1 to 3 or 7 for use in therapy as an antilipemic or antiarteriosclerotic.
9. A pharmaceutical composition having antilipemic and antiarteriosclerotic properties comprising a n-oleyl derivative of a phosphatidylethanolamine as claimed in any of Claims 1 to 3 or 7 in association with a compatible pharmaceutical carrier.
10. A composition as claimed in Claim 9 substantially as described in Example 5 (2) or (b).
New Claims or Amendments to Claims filed on 18-4-80
Superseded Claims 1-10 New or Amended Claims:
1. An N-oleyl derivative of a natural and synthetic phosphatidylethanolamine of the formula:
wherein R1 and R2 are saturated or unsaturated, straight-chain or branched aliphatic acid residues, for use in therapy as an antilipemic or antiarteriosclerotic.
2. The N-oleyl derivatives of Claim 1 wherein R1 and R2 are each residues of aliphatic acids containing 12 to 22 carbon atoms each.
3. N-oelyl-cephalin, for use in therapy as an antilipemic or antiarteriosclerotic.
4. A pharmaceutical composition having antilipemic and antiarteriosclerotic properties comprising a N-oleyl derivative of a phosphatidylethanolamine of the formula:
wherein R1 and R2 are saturated or unsaturated, straight-chain or branched aliphatic acid residues, in association with a compatible pharmaceutical carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7921163A GB2051069B (en) | 1979-06-18 | 1979-06-18 | Phospholipid derivatives useful in therapy as antilepaemics and antiarteriosclerotics and compositions containing them |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7921163A GB2051069B (en) | 1979-06-18 | 1979-06-18 | Phospholipid derivatives useful in therapy as antilepaemics and antiarteriosclerotics and compositions containing them |
Publications (2)
Publication Number | Publication Date |
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GB2051069A true GB2051069A (en) | 1981-01-14 |
GB2051069B GB2051069B (en) | 1983-08-24 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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GB7921163A Expired GB2051069B (en) | 1979-06-18 | 1979-06-18 | Phospholipid derivatives useful in therapy as antilepaemics and antiarteriosclerotics and compositions containing them |
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GB (1) | GB2051069B (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0072111A1 (en) * | 1981-07-20 | 1983-02-16 | Lipid Specialties, Inc. | Synthetic phospholipid compounds and their preparation |
US4788182A (en) * | 1984-07-25 | 1988-11-29 | Ciba-Geigy Corporation | Phosphatidyl compounds, processes for their manufacture, and their use |
US4873322A (en) * | 1986-01-24 | 1989-10-10 | Ciba-Geigy Corporation | Saccharide derivatives and processes for their manufacture |
US5189017A (en) * | 1982-07-23 | 1993-02-23 | Ciba-Geigy Corporation | Use of sugar derivatives for the prophylaxis and treatment of virus infections |
US5334583A (en) * | 1982-07-23 | 1994-08-02 | Ciba-Geigy Corp. | Use of sugar derivatives for the prophylaxis and treatment of virus infections |
WO2003068210A1 (en) | 2002-02-12 | 2003-08-21 | Hunza Di Pistolesi Elvira & C. S.A.S. | N-acyl-phosphatidyl-ethanolamines and/or mixtures of n-acyl-ethanolamines with phosphatidic acids or lysophosphatidic acids |
EP1609461A1 (en) * | 2004-06-24 | 2005-12-28 | Hunza di Pistolesi Elvira & C. S.a.S. | Cosmetic compositions comprising a mixture of N-acyl-phosphatidylethanolamines and cosmetic treatments thereof. |
US8377662B2 (en) | 2008-07-08 | 2013-02-19 | Chemi S.P.A. | Process for the production of N-acyl-phosphatidyl-ethanolamine |
-
1979
- 1979-06-18 GB GB7921163A patent/GB2051069B/en not_active Expired
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0072111A1 (en) * | 1981-07-20 | 1983-02-16 | Lipid Specialties, Inc. | Synthetic phospholipid compounds and their preparation |
US5189017A (en) * | 1982-07-23 | 1993-02-23 | Ciba-Geigy Corporation | Use of sugar derivatives for the prophylaxis and treatment of virus infections |
US5334583A (en) * | 1982-07-23 | 1994-08-02 | Ciba-Geigy Corp. | Use of sugar derivatives for the prophylaxis and treatment of virus infections |
US4788182A (en) * | 1984-07-25 | 1988-11-29 | Ciba-Geigy Corporation | Phosphatidyl compounds, processes for their manufacture, and their use |
US4873322A (en) * | 1986-01-24 | 1989-10-10 | Ciba-Geigy Corporation | Saccharide derivatives and processes for their manufacture |
WO2003068210A1 (en) | 2002-02-12 | 2003-08-21 | Hunza Di Pistolesi Elvira & C. S.A.S. | N-acyl-phosphatidyl-ethanolamines and/or mixtures of n-acyl-ethanolamines with phosphatidic acids or lysophosphatidic acids |
JP2005525335A (en) * | 2002-02-12 | 2005-08-25 | ウンザー ディ ピストレージ エルヴィラ エ チ. エッセ.ア.エッセ. | N-acyl-phosphatidyl-ethanolamines and / or mixtures of N-acyl-ethanolamines with phosphatidic acids or lysophosphatidic acids |
US9789127B2 (en) | 2002-02-12 | 2017-10-17 | Hunza Di Pistolesi Elvira & C. S.A.S. | N-acyl-phosphatidyl-ethanolamines and/or mixtures of N-acyl-ethanolamines with phosphatidic acids or lysophosphatidic acids |
EP1609461A1 (en) * | 2004-06-24 | 2005-12-28 | Hunza di Pistolesi Elvira & C. S.a.S. | Cosmetic compositions comprising a mixture of N-acyl-phosphatidylethanolamines and cosmetic treatments thereof. |
US8377662B2 (en) | 2008-07-08 | 2013-02-19 | Chemi S.P.A. | Process for the production of N-acyl-phosphatidyl-ethanolamine |
Also Published As
Publication number | Publication date |
---|---|
GB2051069B (en) | 1983-08-24 |
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