WO1998018751A1 - Presentation de substances bioactives - Google Patents

Presentation de substances bioactives Download PDF

Info

Publication number
WO1998018751A1
WO1998018751A1 PCT/GB1997/002932 GB9702932W WO9818751A1 WO 1998018751 A1 WO1998018751 A1 WO 1998018751A1 GB 9702932 W GB9702932 W GB 9702932W WO 9818751 A1 WO9818751 A1 WO 9818751A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
disease
acid
disorders
set out
Prior art date
Application number
PCT/GB1997/002932
Other languages
English (en)
Inventor
David Frederick Horrobin
Mehar Manku
Austin Mcmordie
Andrea Pitt
Paul Bradley
Original Assignee
Scotia Holdings Plc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Scotia Holdings Plc filed Critical Scotia Holdings Plc
Priority to AU47174/97A priority Critical patent/AU4717497A/en
Publication of WO1998018751A1 publication Critical patent/WO1998018751A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/587—Monocarboxylic acid esters having at least two carbon-to-carbon double bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
    • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • 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
    • C07F9/113—Esters of phosphoric acids with unsaturated acyclic alcohols

Definitions

  • bioactives in which term we include a drug, essential nutrient or any other compound to be administered to the human or animal body in therapy or maintenance of health.
  • the specification relates to the presentation of such bioactives in a form in which they are lipophilic so that they can pass lipid barriers in the body readily, or to the presentation of two bioactives in the same molecule (where at least one of the bioactives is a fatty acid or fatty alcohol), or to the presentation of bioactives in a form which serves both aims. From a drug regulatory viewpoint it is a great advantage to have two bioactives presented as a single molecule rather than as two separate entities. There may also be advantages in presenting known bioactives in novel ways. Those advantages include increased lipophilicity, the additive effects of two bioactives which are not normally presented together, and the sometimes synergistic effects of such bioactives .
  • the invention concerns the linking of bioactives through a 1,2-propane diol link molecule and the usefulness of these compounds in therapy and/or the maintenance of health.
  • drugs act at the cell membrane surface by combining with cell surface receptors, or alternatively are taken into cells by specific transport systems.
  • drugs which, while they act within cells by modifying one of many different functions such as nucleic acid functions, the actions of intracellular enzymes, or the behaviour of systems like the lysosomes or the microtubules, are not able to penetrate cells effectively.
  • Equally drugs may penetrate intracellular membranes such as mitochondrial and nuclear membranes at less than optimum rates.
  • lipophilic substances are able to cross the barriers more readily without the need for any specific receptor or transport system.
  • Drugs whose pharmacokinetic behaviour may be improved by increased lipophilicity, listed by route of entry, are as follows:
  • drugs particularly likely to benefit are those that act primarily intracellularly. These include: a. All anti-inflammatory drugs, whether steroid or non-steroid;
  • drugs that have to enter cells in order to achieve optimum effects in particular drugs which act on DNA or RNA, or on enzymes located intracellularly, or on second messenger systems, or on microtubules, mitochondria, lysosomes, or any other intracellular organelle.
  • drugs which act on DNA or RNA or on enzymes located intracellularly, or on second messenger systems, or on microtubules, mitochondria, lysosomes, or any other intracellular organelle.
  • Steroid hormones and other hormones that act intracellularly such as oestrogens, progestins, androgenic hormones and dehydroepiandrosterone.
  • Blood-brain barrier all drugs acting on the central nervous systems will have their transport improved by this technique. This includes all drugs used in psychiatry, all drugs used in cerebral infections with any organism or in cerebral cancer and all other drugs acting on nerve cells such as anti-epileptic drugs and others acting on neurological disorders such as multiple sclerosis, amyotrophic lateral sclerosis, Huntington's chorea and others.
  • the approach discussed is applicable to amino acids. Of particular interest are those which seem to play roles in the regulation of cell function as well as acting as components of proteins. Examples include tryptophan (a precursor of 5- hydroxytryptamine [5-HT], a key regular of nerve and muscle function), phenylalanine (a precursor of catecholamines) and arginine (a regulator of the synthesis of nitric oxide which also plays important roles in controlling cellular activities).
  • tryptophan a precursor of 5- hydroxytryptamine [5-HT], a key regular of nerve and muscle function
  • phenylalanine a precursor of catecholamines
  • arginine a regulator of the synthesis of nitric oxide which also plays important roles in controlling cellular activities.
  • the compounds proposed herein have many advantages in addition to their lipophilicity.
  • two moieties of a given fatty acid may be delivered, in a form which is readily incorporated into the body as an oral, parenteral or topical formulation; which is very well tolerated with none of the side effects associated, for example, with free fatty acids; which is not too stable to be properly utilised; and which is much more readily synthesised than the corresponding triglyceride with three moieties of the same fatty acid attached.
  • the compounds allow drugs or other compounds to be administered in the form of relatively 1
  • lipophilic compounds which release the active moieties relatively easily, and which are well tolerated on oral, topical or parenteral administration. Their lipophilicity enables them to be absorbed partially through the lymphatic system, so by-passing the liver; to cause less gastrointestinal irritation than with many compounds; and to facilitate transport of drugs and other agents across lipophilic barriers such as the skin, the cell membrane and the bloodbrain barrier.
  • the transport of actives across lipid membranes may be improved by linking them via an intermediate link to, in particular, gamma-linolenic acid (GLA) or dihomogammalinolenic acid (DGLA), two fatty acids which in themselves have a range of desirable effects.
  • GLA gamma-linolenic acid
  • DGLA dihomogammalinolenic acid
  • Linkage also enables bioactive substances to be co-delivered in the same molecule with fatty acids which in themselves have desirable actions, irrespective of any transport advantages.
  • Other fatty acids such as any of the essential fatty acids (EFAS) and in particular the twelve natural acids of the n-6 and n-3 series EFAs (fig. 1), can be used.
  • EFAS essential fatty acids
  • n-6 and n-3 series EFAs fig. 1
  • arachidonic acid, adrenic acid, stearidonic acid, eicosapentaenoic acid and docosahexaenoic acid are of particular interest because they in themselves have particularly desirable effects.
  • any fatty acid suitably C12-C30 or C16-C30 and desirably with two or more cis or trans carbon-carbon double bonds may also be of use. Use may be in the form of the fatty acid or the corresponding fatty alcohol.
  • Conjugated linoleic and columbinic acids are examples of fatty acids which in themselves have valuable properties and are likely to be of particular use. References to fatty acids are accordingly to be read herein as to both forms, except where the chemistry of one or the other specifically is under discussion. The desirable properties of GLA and DGLA however, make them especially valuable for the purpose.
  • the essential fatty acids as set out in Figure 1 which in nature are of the all -cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z-octadeca -9, 12- dienoic acid or z,z,z,z,z,z -docosa- 4, 7, 10, 13, 16, 19 hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2n-6 or 22:6n-3 are convenient.
  • Initials, e.g., EPA and shortened forms of the name e.g. eicosapentaenoic acid are used as trivial names in some of the cases.
  • FIGURE 1 The essential fatty acids as set out in Figure 1 , which
  • LA Linoleic acid
  • ALA ⁇ -linolenic acid
  • GLA Stearidonic acid
  • Adrenic acid Adrenic acid (AdrA)
  • DHA Docosahexaenoic acid
  • GLA and DGLA have been shown to have anti-inflammatory effects, to lower blood pressure, to inhibit platelet aggregation, to lower cholesterol levels, to inhibit cancer cell growth, to reduce dyskinetic movements, to relieve breast pain, to improve calcium absorption and enhance its deposition in bone, to reduce the adverse effects of ionising radiation, to treat various psychiatric disorders, to cause vasodilation, to improve renal function, to treat the complications of diabetes, to dilate blood vessels and so on. Actives linked to GLA and DGLA will therefore not only become more lipophilic, enhancing penetration across all membranes, the skin and the blood brain barrier, but are also likely to exhibit new and additional therapeutic effects.
  • fatty acids likely to be of especial value in this context are arachidonic acid and docosahexaenoic acid which are major constituents of all cell membranes; adrenic acid; and stearidonic acid and eicosapentaenoic acid which have ranges of desirable properties similar to those of GLA and DGLA.
  • Fatty acids not included in the fatty acids of Figure 1 which are of particular interest are conjugated linoleic acid (cLA) and columbinic acid (CA).
  • cLA conjugated linoleic acid
  • CA columbinic acid
  • cLA has a range of interesting effects in treating and preventing cancer, in promoting growth particularly of protein-containing tissues, in preventing and treating cardiovascular disease and as an antioxidant.
  • CA has many of the properties of essential fatty acids.
  • Psychotropic drugs may be linked to fatty acids such as GLA, DGLA, arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid which have important roles in brain function, so providing a dual therapeutic effect.
  • Drugs used for the treatment of cardiovascular disease may be linked to a fatty acid which also has value in such treatment, such as eicosapentaenoic acid which lowers triglyceride levels and inhibits platelet aggregation, or GLA or DGLA which lower cholesterol levels and have vasodilator action, or arachidonic acid which is a potent cholesterol lowering agent, or DHA which has anti-arrhythmic properties.
  • Drugs used in the treatment of any form of inflammation may be linked to a fatty acid such as gammalinolenic acid, dihomo-gammalinolenic acid or eicosapentaenoic acid or docosahexaenoic acid which also has anti inflammatory action.
  • Drugs used in the management of osteoporosis may be linked to GLA or DGLA which enhance the incorporation of calcium into bone, or to EPA or DHA which reduce urinary calcium excretion.
  • Drugs used in skin disease may be linked to GLA or DGLA which have anti inflarnmatory effects on the skin.
  • Drugs used in cancer may be linked to GLA, DGLA, arachidonic acid, EPA or DHA which have anticancer effects in their own right and which may reverse resistance to anticancer drugs.
  • the essential fatty acids consist of a series of twelve compounds. Although linoleic acid, the parent compound of the n-6 series, and alpha-linolenic acid, the parent compound of the n-3 series, are the main dietary EFAS, these substances as such have relatively minor roles in the body. In order to be fully useful to the body, the parent compounds must be metabolised to longer chain and more highly unsaturated compounds.
  • dihomogammalinolenic acid (DGLA) and arachidonic acid (AA) are the main EFA metabolites of the n-6 series while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the main metabolites of the n-3 series.
  • DGLA, AA, EPA and DHA are important constituents of most of the lipids in the body. As well as being important in themselves they can also give rise to a wide range of oxygenated derivatives, the eicosanoids, including the prostaglandins, leukotrienes and other compounds.
  • the fatty acids likely to be of particular value in therapy are DGLA, AA, EPA and DHA, together with GLA, the precursor of DGLA, stearidonic acid (SA), the precursor of EPA, and DPA (22:5n3), the precursor of DHA, and adrenic acid.
  • fatty acids such as oleic acid, parinaric acid and columbinic acid that are not EFAs but may have significant effects in the body.
  • conjugated linoleic acid which as noted earlier has a range of desirable effects.
  • esters of 1 ,2-propane diol For purposes of convenient adrninistration of different fatty acids simultaneously or indeed of a single fatty acid in high amounts in well tolerated form, use is thus desirably made of esters of 1 ,2-propane diol.
  • PLC phospholipase C
  • DAG diacylglycerol
  • PK protein kinases
  • DAG analogues of this type are thus 3-deoxy-l,2-diglycerides (alternatively named as diesters of 1.2-propane diol).
  • 1,2-propane diol esters Lin and Shaw JAOCS vol. 73 no. 11 (1995) p.1271 etc. discuss the EPA and DHA monoesters as potentially health beneficial emulsifiers in the food industry and Gattefosse catalogue has offered the palmitostearate and isostearate monoesters.
  • the present invention covers fatty acid derivatives of bioactives with an available
  • the two molecules are linked via a 1,2-propane diol link group.
  • a difunctional intermediate linking group e.g. succinate
  • a difunctional intermediate linking group e.g. succinate
  • the invention relates to compounds of the following 1,2-propane diol linked
  • R 1 or R 2 comprise an acyl group derived from a C ⁇ 2 -C 30 preferably C 16 -C 30 fatty acid
  • bioactive residue (which may be derivatised with a suitable intermediate linking group), such as
  • R 1 or R 2 comprises an acyl group as defined above, and, wherein both R 1
  • R 2 comprise acyl groups, they may be the same or different. Furthermore, the present invention covers esters of both racemic and optically active 1,2-
  • esters of the latter type may have either (R) or (S) configuration at C-2 of the
  • the compounds will generally be acid-function bearing actives esterified directly to the
  • the difunctional group is particularly
  • the amide linkage is between the bioactive with a free amino group and an intermediate
  • the ideal intermediate link group for this is succinic acid. This is
  • ester link for example that of a fatty alcohol.
  • the fatty acids likely to be of most value in this context are the essential fatty acids
  • the diol is, broadly, disclosed in the literature among many other diols
  • diesters may have value in pharmaceutical formulation as emulsifiers.
  • 1,2 -propane diol 1,2 -propane diol
  • SA, EPA, DHA, cLA and CA is present at one position and at the other position is a vitamin, amino acid, aromatic acid, steroid, antioxidant or other therapeutic drug, are new substances.
  • the fatty acid diesters have a wide variety of possible uses. They may be used as
  • GLA-OA Oleic Acid
  • GLA-GLA EPA-EPA, GLA-EPA, GLA-DHA, AA- DHA, AA-EPA, GLA-AA, GLA-SA, SA-DHA, AA-SA, DGLA-DGLA, DGLA-GLA, DGLA-SA, DGLA-AA, DGLA-EPA, DGLA-DHA, AA-AA, EPA-SA, EPA-DHA, DHA- DHA, cLA-cLA, c-LA-GLA, c-LA-DGLA, c-LA-AA, c-LA-SA, c-LA-EPA, c-LA-DHA, CA- CA, CA-GLA, CA-DGLA, CA-AA, CA-SA, CA-EPA, CA-DHA.
  • GLA-niacin GLA-retinoic acid, GLA-retinol, GLA-pyridoxal, di-GLA-pyridoxine, di- EPA-pyridoxal and in general any of e.g. GLA, DGLA, AA, SA, EPA or DHA with any vitamin including ascorbic acid, Vitamin D and its derivatives and analogues, Vitamin E and its derivatives and analogues, Vitamin K and its derivatives and analogues, Vitamin B, (thiamin), Vitamin B2 (riboflavin), folic acid and related pterins, Vitamin B12, biotin and pantothenic acid.
  • GLA-tryptophan GLA-proline, GLA-arginine, GLA- or DHA-phenylalanine GLA- GABA, GLA-aminolevulinic acid and in general any of e.g. GLA, DGLA, AA, SA, EPA or DHA with any natural amino acid or related compound such as tarurine and carnitine.
  • GLA-phenylbutyric acid GLA-phenylacetic acid
  • GLA-trans-cinnamic acid in general any of e.g. GLA, DGLA, AA, SA, EPA or DHA with any aryl alkanoic or aryl alkenoic acid.
  • GLA -hydrocortisone GLA-oestradiol
  • GLA - and DHA-dehydroepiandrosterone and in general any of e.g. GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic steroid, such as any oestrogen, any progestin, any adrenal steroid and any anti-inflammatory steroid, particularly betamethasone, prednisone, prednisolone, triamcinolone, budesonide, clobetasol, beclomethasone and other related steroids.
  • any natural or synthetic steroid such as any oestrogen, any progestin, any adrenal steroid and any anti-inflammatory steroid, particularly betamethasone, prednisone, prednisolone, triamcinolone, budesonide, clobetasol, beclomethasone and other related steroids.
  • GLA-lipoic acid DHA-lipoic acid, GLA-tocopherol, di-GLA-3,3'-thiodipropionic acid and in general any of e.g. GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic anti-oxidant with which they can be chemically linked.
  • phenolic antioxidants e.g. eugenol, carnosic acid, caffeic acid, BHT, gallic acid, tocopherols, tocotrienols and flavonoid anti-oxidants (e.g. myricetin, fisetin)
  • polyenes e.g. retinoic acid
  • unsaturated sterols e.g.
  • delta-5-avenosterol e.g. delta-5-avenosterol
  • organosulfur compounds e.g. allicin
  • terpenes e.g. geraniol, abietic acid
  • amino acid antioxidants e.g. cysteine, carnosine
  • GLA, DGLA, AA, SA, EPA or DHA with any drug, particularly any drug used in the treatment of infections, inflammatory diseases, including various forms of arthritis, cancer, cardiovascular, respiratory, dermatological, psychiatric, neurological, muscular, renal, gastrointestinal, reproductive and other diseases.
  • the non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are notorious for causing severe gastointestinal toxicity with ulceration of the stomach and intestines and bleeding into the gastointestinal tract.
  • Cardiovascular actions including vasodilatation, lowering of blood pressure inhibition of platelet aggregation, lowering of triglyceride and LDL-cholesterol levels; elevation of HDL- cholesterol levels and inhibition of smooth muscle proliferation.
  • Anti-inflammatory actions including reduction of formation of pro-inflammatory mediators such as cytokines, and of eicosanoids derived from arachidonic acid, reduction of neutrophil migration and the neutrophil respiratory burst, reduction of local inflammatory responses, inhibition of inflammation in various animal models such as uric acid induced inflammation and adjuvant arthritis, and treatment of various inflammatory disorders such as osteoarthritis and rheumatoid arthritis.
  • pro-inflammatory mediators such as cytokines, and of eicosanoids derived from arachidonic acid
  • neutrophil migration and the neutrophil respiratory burst reduction of local inflammatory responses
  • inhibition of inflammation in various animal models such as uric acid induced inflammation and adjuvant arthritis
  • treatment of various inflammatory disorders such as osteoarthritis and rheumatoid arthritis.
  • Immunomodulatory functions including the damping down of excessive immune and allergic responses in animal models such as experimental allergic encephalomyelitis and uveitis, bronchial and cutaneous hyper-reactivity in sensitised animals, leading to the concept that they are of value in human diseases where excessive immune responses play a role.
  • Respiratory actions including bronchodilatation and inhibition of bronchoconstrictor actions.
  • Actions on nerve cells including maintenance of normal nerve membrane structure and function and the normal pre- and post-synaptic actions of neurotransmitters.
  • this group of fatty acids can be used in the treatment of many different disorders including cardiovascular disorders of many types, inflammatory disorders including rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn's disease, respiratory disorders including asthma, psychiatric disorders including schizophrenia, alcoholism, attention deficit disorder, depression and Alzheimer's disease, neurological disorders including multiple sclerosis and Huntington's chorea, renal and urinary tract disorders including various types of renal iriflammatory disease and urinary calcium stones, metabolic disorders including osteoporosis and ectopic calcification, and gastrointestinal ulcerative and inflammatory diseases.
  • conjugated linoleic acid (cLA) has not been nearly as widely tested as, say GLA or EPA, it also seems to have a wide range of actions including effects valuable in the treatment of cancer, cardiovascular and metabolic diseases.
  • GLA, DGLA, AA and columbinic acid have desirable actions on the skin and are particularly valuable in the treatment of skin diseases such as atopic eczema, psoriasis, urticaria and allergic reactions.
  • AA is often regarded as a potentially harmful fatty acid. However, it is an essential constituent of all normal cell membranes and has been found to be present in low levels in various illnesses including atopic eczema, schizophrenia (Horrobin et al, Schizophrenia Res. 1994; 13: 195-207) and cardiovascular disorders (Horrobin, Prostaglandins Leukotr. EFAs 1995; 53: 385-96). AA is likely to be of particular value in these situations and also in other psychiatric disorders such as alcoholism and attention deficit disorder where levels are also often low.
  • DHA shares some of the above actions of the EFAs but is found in particularly important amounts in cell membranes and especially in the membranes of the heart, the retina and the brain. DHA also has potent anti-inflammatory and desirable cardiovascular effects. DHA is likely to be of particular value in cardiovascular disorders, in retinal and visual disorders including retinitis pigmentosa, senile macular degeneration and dyslexia, and in psychiatric and neurological disorders including schizophrenia, attention deficit disorder, depression, alcoholism, Alzheimer's disease and other forms of dementia and multiple sclerosis.
  • 1,2-propane diol as derivatives containing: two fatty acids in which one fatty acid is GLA or DGLA and the other is GLA, DGLA, SA, EPA, DHA, cLA (conjugated linoleic acid) or CA (columbinic acid) for the treatment of
  • respiratory diseases including asthma
  • psychiatric disorders including schizophrenia, Alzheimer's disease, attention deficit disorder, alcoholism and depression; (1) prostatic hypertrophy and prostatitis;
  • dermatological disorders including atopic eczema, hand eczema, psoriasis, urticaria and allergic disorders;
  • dyslexia and other learning disabilities including cancer cachexia.
  • 1,2-propane diol as derivatives containing two fatty acids in which one fatty acid is AA and the other is AA, GLA, DHA, DGLA or EPA for treatment of the disorders as at (1) above and especially (a), (g), (i),G), (k), (q) and (r).
  • 1,2 -propane diol as derivatives containing two fatty acids in which one fatty acid is EPA and the other is EPA or DHA for the treatment of any of the disorders as at (1) above but especially (b), (c), (d), (e), (f), (g), (h), (i), j), (k), (p), (r) and (s).
  • 1,2 -propane diol as derivatives in which one position is occupied by a fatty acid drawn from GLA, DGLA, AA, SA, cLA, EPA or DHA and the other position is occupied by an agent, selected from the following list, whose chemical structure is such that it can be linked to the 1,2-propane diol by one of the linkages described herein:
  • camitine or caoritine derivatives for the treatment of any disease but especially muscle weakness, cardiac failure, chronic fatigue syndrome, Alzheimer's disease, and peripheral neuropathies;
  • any other amino acid or related substance for the treatment of any disease or aminolevulinic acid or derivative thereof for the treatment of any disease but especially cancers;
  • adenylosuccinate or related substances for the treatment of any disease but especially muscular dystrophy, cardiac failure, chronic fatigue and Alzheimer's disease and other dementias;
  • any antibiotic for the treatment of any appropriate infectious disease but especially tetracycline, clindamycin, minocycline, chlortetracycline and erythromycin for the treatment of acne;
  • any anti-malarial or anti-protozoal drug for the treatment of any disease but especially chloroquine, mepacrine, quinacrine and mefloquine for the treatment of malaria, protozoal disorders, inflammatory disorders and schizophrenia;
  • any antifungal drug for the treatment of any disease but especially metronidazole and antifungal imidazoles and nitroimidazoles and amphotericin for the treatment of fungal infections of various types;
  • any anti-inflammatory steroid for the treatment of any disease but especially hydrocortisone and betamethasone for the treatment of skin disorders and beclomethasone and budesonide for the treatment of asthma.
  • any gonadal steroid for the treatment of any disease but especially oestrogens and progestogens for the treatment of ovarian deficiency and osteoporosis and androgens for the treatment of testicular deficiency;
  • any adrenal steroid for the treatment of any disease, but especially dehydroepiandrosterone for the treatment of disorders associated with ageing
  • any retinoid for the treatment of any disease but especially tretinoin and isotretinoin for the treatment of dermatological disorders and for use in skin care
  • any anticancer agent for the treatment of cancer
  • any antipsychotic agent for the treatment of schizophrenia and other psychoses any antidepressive agent for the treatment of any disease but especially for the treatment of depression;
  • any anti-anxiety agent for the treatment of any disease, but especially for the treatment of anxiety and panic attacks any immunosuppressive agent for the treatment of any disease but especially cyclosporine and tacrolimus for the control of immunity after organ transplantation and for the treatment of autoimmune and inflammatory disorders including psoriasis, eczema, asthma, rheumatoid arthritis and inflammatory bowel disease;
  • any proton pump inhibitor or H2 antagonist for the treatment of any disease but especially diseases associated with excess gastric acid production or reduced defences against gastric acidity;
  • any diuretic for any disease, but especially for diseases associated with fluid retention and hypertension;
  • any calcium antagonist used for any disease but especially for cardiovascular diseases any angiotensin converting-enzyme inhibitor or angiotensin antagonist used for any disease but especially
  • any contrast agents used in radiology including diatrizoate compounds iodipamide, ioglycamates, iopanoates, iophendylate, iothalamate, ioxaglate, metrizamide and related compounds;
  • any antioxidant used in the management of any disease but especially for those diseases in which antioxidants may be especially beneficial including cardiovascular diseases, cancer and inflammatory disorders and any antioxidant used as a food or other preservative or as a component of a food, food additive or nutritional supplement,
  • the present invention covers esters of both racemic and optically active 1,2-
  • Derivatisation of a bioactive having a free hydroxyl group requires the formation of either a carboxylic ester bond or a phosphate ester bond.
  • Formation of an ester bond may be achieved by any reasonable method for such
  • a suitable inert solvent e.g. dichloromethane
  • organic tertiary base e.g. 4-(N,N-dimethylamino)pyridine, in an inert
  • solvent e.g. dichloromethane
  • a suitable solvent e.g. hexane
  • inert solvent e.g. dimethylformamide
  • alkali or alkaline earth metal e.g. sodium
  • Y is an alkyl group
  • Formation of an amide bond may be achieved by any reasonable method for such chemistry
  • a suitable inert solvent e.g. dichloromethane
  • organic tertiary base e.g. 4-(N,N-dimethylamino)pyridine, in an inert
  • solvent e.g. dichloromethane
  • a suitable solvent e.g. hexane
  • alcohol or aldehyde by-product is removed, e.g. under vacuum.
  • Formation of a phosphate ester bond may be achieved by any reasonable method for such chemistry and especially: (m) by reaction of alcohol, e.g. UFA 1,2-propane diol monoester, with a
  • phosphate derivative e.g. phosphorus oxychloride
  • a tertiary base e.g. triethylamine
  • a suitable solvent e.g. tetrahydrofuran
  • tocopherol with the crude phosphorodichloridate with a tertiary base, e.g.
  • the individual fatty acids may be purified from natural animal, vegetable or microbial
  • the compounds may be formulated in any way appropriate and which is known to those skilled in the art of preparing pharmaceuticals, skin care products or foods. They may be administered orally, enterally, topically, parenterally (subcutaneously, intramuscularly, intravenously), rectally, vaginally or by any other appropriate route.
  • the 1,2-propane diol diesters may be readily emulsified using phospholipid or particularly galactolipid emulsifiers. Such emulsions are particularly useful for administration via oral, enteral and intravenous routes.
  • fatty acid (UFA) diesters occur as free flowing oils and therefore can be formulated as follows :-
  • Oral emulsions were prepared by high-pressure homogenisation.
  • the particle size distributions and the zeta potential of the resulting emulsions were determined by dynamic light scattering at room temperature.
  • the particle size measurements were carried out at room temperature (Zetasizer 4 Malvern Instruments Limited).
  • An oil-in-water emulsion (batch size 200g) was prepared containing the following ingredients:-
  • Emulsifier (Galactolipid) 1 2.00
  • the emulsifier-galactolipid as disclosed in Ontario Lipidteknik patent PCT SE95/00115 (WO 95/20943), was dispersed in the diester and, Vitamin E, AP and water were mixed.
  • the oil phase was added to the aqueous phase under a high shear mix (Ulfraturrax) at speed 4, for a few minutes.
  • This pre-emulsion was then homogemsed at 80 MPA and at 50'C for 6 cycles (mini-Lab 8.30 H; APV Rannie AS, Denmark).
  • the emulsion formed has an average droplet size of 230 nm.
  • Anti-microbial preservatives - potassium sorbate, and flavour can also be added to the above oral emulsion.
  • the above emulsion, homeginised for 6 minutes in a high pressure homogeniser had an average droplet size of 211 nm, a zeta potential of -40mV.
  • These IV. emulsions can be either filtered through a membrane with a pore size of 0.22 microns or can be autoclaved with change in droplet size.
  • the doses of the actives to be administered largely range from lmg to 200g per day, preferably lOmg to lOg and very preferably lOmg to 3g, according to their kind.
  • preferable doses may be in the 2-150g/day range. They may be administered topically where appropriate in preparations where the actives form from 0.001 ) to 50%) of the topical preparation, preferably 0.05%> and very preferably 0.1%) to 10%>.
  • Example 2 In a similar manner to Example 1 but replacing z,z,z-octadeca-6,9,12-trienoic acid with z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid was prepared ( ⁇ )-l,2-di(z,z,z,z,z,z-docosa- 4,7,10,13,16,19-hexaenoyloxy)propane as a pale yellow oil.
  • reaction mixture was diluted with hexane, filtered, concentrated and purified by silica gel chromatography to yield ( ⁇ )-l,2- di(z,z,z,z,z-eicosa-5,8,l l,14,17-pentaenoyloxy)propane as a pale yellow oil.
  • Example 7 In a similar manner to Example 5 but replacing l,2(R)-propane diol with l,2(S)-propane diol was prepared l,2(S)-di(z,z,z-octadeca-6,9,12-trienoyloxy)propane as an almost colourless oil.
  • Example 7 In a similar manner to Example 5 but replacing l,2(R)-propane diol with l,2(S)-propane diol was prepared l,2(S)-di(z,z,z-octadeca-6,9,12-trienoyloxy)propane as an almost colourless oil.
  • the residual oil was filtered to remove Amberlyst-15, diluted with diethyl ether (600mL) and washed with water (2x75 OmL). The organic layer was dried (magnesium sulfate) and concentrated under reduced pressure.
  • the residual oil was dissolved in acetonitrile (250mL) and extracted with 2,2,4-trimethylpentane (3xl00mL). The acetonitrile solution was concentrated to dryness, redissolved in ethyl acetate(250mL), washed with water (250mL) and dilute brine (250mL), dried (magnesium sulfate) and concentrated under reduced pressure to leave a mixture of 1 - and 2- monoesters as a yellow oil.
  • reaction mixture was diluted with hexane, filtered, concentrated and purified by silica gel chromatography to yield ( ⁇ )-l-(z,z,z-octadeca-6,9,12- trienoyloxy)-2-(z,z,z,z,z-eicosa-5,8,l l,14,17-pentaenoyloxy)propane and ( ⁇ )-l-(z,z,z,z,z- eicosa-5,8,1 l,14,17-pentaenoyloxy)-2-(z,z,z-octadeca-6,9,12-trienoyloxy)propane as a colourless oil.
  • Part 3 Part 3 - 1 -(4-methylphenyl)sulfonyloxy-2(S)-(z,z,z,z,z,z-docosa-4,7, 10,13,16,19- hexaenoyloxy)propane.
  • Example 9 In a similar manner to Example 9 but replacing z,z,z,z-eicosa-5,8,l 1,14-tetraenoic acid in Part 3 with z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid yielded l-(z,z,z-octadeca-6,9,12- trienoyloxy)-2(S)-(z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoyloxy) propane and ⁇ -(z,z,z,z,z,z- docosa-4,7, 10,13,16,19-hexaenoyloxy)-2(S)-(z,z,z-octadeca-6,9, 12-trienoyloxy)propane as a colourless oil.
  • reaction mixture was diluted with hexane, filtered, concentrated and purified by silica gel chromatography to yield ( ⁇ )-l-(z,z,z-octadeca-6,9,12-trienoyloxy)-2- (nicotinyloxy)propane and ( ⁇ )- 1 -(nicotinyloxy)-2-(z,z,z-octadeca-6,9, 12-trienoyloxy)propane as a pale yellow oil.
  • reaction mixture was diluted with diethyl ether (250mL) and washed with 2M hydrochloric acid (2x250mL), water (250mL) and brine (250mL), dried (sodium sulfate) and concentrated to dryness.
  • 2M hydrochloric acid 2x250mL
  • water 250mL
  • brine 250mL
  • succinate monoester 1 -(z,z,z-octadeca-6,9, 12-trienoyloxy)propan-2(S)-ol and 2(S)- (z,z,z-octadeca-6,9,12-trienoyloxy)propan-l-ol which was used without any further purification.
  • reaction mixture was diluted with hexane, filtered, concentrated and purified by silica gel chromatography to yield tr ⁇ , -l-(l-(z,z,z-octadeca-6,9,12-trienoyloxy)-2- propyloxycarbonylpropanoylamino)-2-phenylcyclopropane and trans- 1 -(2-(z,z,z-octadeca- 6,9,12-trienoyloxy)-l-propyloxy carbonylpropanoylamino)-2-phenylcyclopropane as a pale yellow oil.
  • Example 16 l-(z,z,z-octadeca-6,9,12-trienoyloxy)-2(S)-(2(S)-amino-3-phenylpropionyloxy)propane and 1- (2(S)-amino-3-phenylpropionyloxy)-2(S)-( z,z,z-octadeca-6,9,12-trienoyloxy)propane. (Enantiopure diester of GLA and phenylalanine with 1,2-propane diol - mixture of positional isomers)
  • Triethylamine (7.5mL) was added to a solution of freshly distilled phosphorus oxychloride (1.26g) in anhydrous THF (7.5ml) at 0°C. After 15 min. a solution of l-(z,z,z-octadeca- 6,9,12-trienoyloxy)-2-propanol and 2-(z,z,z-octadeca-6,9,12-trienoyloxy)-l -propanol (2.5g) in anhydrous THF (7.5mL) was added dropwiseover a period of 30 min. at 0°C. Stirring at this temperature was continued for 30 min. after the end of addition.
  • z,z,z-octadeca-6,9,12 trienol (1.98g) in anhydrous THF (5mL) was added dropwise at 10°C and the resultant mixture was stirred at 10°C for 1 h and then overnight, warming up to room temperature.
  • Triethylamine (8mL) and water (20mL) were added. The mixture was stirred under nitrogen in an ice bath for lh. acidified to pHl with 2M hydrochloric acid and extracted into ethyl acetate (80mL) and methanol (20mL).
  • the extract was dried, concentrated and purified by silica gel chromatography to yield (l-(z,z,z-octadeca-6,9,12-trienoyloxy)-2-propyl)-(z,z,z- octadeca 6,9,12-trienyl)phosphate and (2-(z-z-z-octadeca 6-9-12-trienoxyloxy)-l-propyl)-(z-z- z-octadeca-6,9- 12 trienyl)phosphate.

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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention a pour objet des composés de structure (I) à liaison 1, 2-propanediol lorsqu'ils sont utilisés à des fins thérapeutiques, dans laquelle R1 ou R2 comprennent un groupe d'alcools gras ou acyle, dérivé d'un acide gras C¿12-30?, de préférence C16-30, de préférence avec deux ou plusieurs liaisons doubles cis ou trans, ou tout autre substance nutritive, médicament ou résidu bioactif, de sorte que R?1 ou R2 ou R1 et R2¿ comprennent un groupe d'alcools gras ou acyle tel que définit ci-dessus, et dans laquelle R1 et R2 contiennent des groupes d'alcools gras ou acyle qui peuvent être les mêmes ou différents.
PCT/GB1997/002932 1996-10-30 1997-10-23 Presentation de substances bioactives WO1998018751A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47174/97A AU4717497A (en) 1996-10-30 1997-10-23 Presentation of bioactives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9622636.0A GB9622636D0 (en) 1996-10-30 1996-10-30 Presentation of bioactives
GB9622636.0 1996-10-30

Publications (1)

Publication Number Publication Date
WO1998018751A1 true WO1998018751A1 (fr) 1998-05-07

Family

ID=10802200

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/002932 WO1998018751A1 (fr) 1996-10-30 1997-10-23 Presentation de substances bioactives

Country Status (4)

Country Link
AU (1) AU4717497A (fr)
GB (1) GB9622636D0 (fr)
WO (1) WO1998018751A1 (fr)
ZA (1) ZA979656B (fr)

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004014359A1 (fr) * 2001-03-16 2004-02-19 Thomas Jefferson University Regulation d'apob permettant le traitement et le criblage de medicaments pour des troubles ou des syndromes cardiovasculaires et metaboliques
US6927239B1 (en) * 2000-08-02 2005-08-09 Pharmanutrients Methods and compositions for the attenuation and/or prevention of stress/catabolic responses
WO2008063772A2 (fr) * 2006-10-13 2008-05-29 The Brigham And Women's Hospital Inc. La résolvine de série d et la protectine d1 pallient à une lésion aiguë des reins
WO2010072738A1 (fr) 2008-12-22 2010-07-01 Pierre Fabre Dermo-Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
US8173831B2 (en) 2008-07-08 2012-05-08 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
EP2654744A1 (fr) * 2010-12-21 2013-10-30 Nestec S.A. Procédés et compositions pour la prévention et le traitement de l'arthrose
US8703725B2 (en) 2002-09-20 2014-04-22 Nestec S.A. Nutritional compositions
US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
US9216224B2 (en) 2010-03-05 2015-12-22 Catabasis Pharmaceuticals, Inc. Fatty acid COX inhibitor derivatives and their uses
US9238077B2 (en) 2009-09-01 2016-01-19 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
WO2016190280A1 (fr) * 2015-05-22 2016-12-01 日産化学工業株式会社 Procédé de production d'un composé o-[1-(2-hydroxypropyl)]oxime
CN107205397A (zh) * 2014-12-30 2017-09-26 美国陶氏益农公司 具有杀真菌活性的吡啶酰胺化合物的用途
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
US10172354B2 (en) 2012-12-28 2019-01-08 Dow Agrosciences Llc Synergistic fungicidal mixtures for fungal control in cereals
US10173971B2 (en) 2014-12-30 2019-01-08 Dow Agrosciences Llc Picolinamides with fungicidal activity
US10173981B2 (en) 2014-12-30 2019-01-08 Dow Agrosciences Llc Picolinamides as fungicides
US10182568B2 (en) 2014-12-30 2019-01-22 Dow Agrosciences Llc Use of picolinamide compounds as fungicides
US10433555B2 (en) 2014-12-30 2019-10-08 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
US11147293B2 (en) * 2001-01-12 2021-10-19 Fundacao De Amparo A Pesquisa Do Estado De Sao Paulo Nutritional composition for increasing milk protein in mammals
US11155520B2 (en) 2018-03-08 2021-10-26 Dow Agrosciences Llc Picolinamides as fungicides
US11191269B2 (en) 2017-05-02 2021-12-07 Dow Agrosciences Llc Use of an acyclic picolinamide compound as a fungicide for fungal diseases on turfgrasses
US11206828B2 (en) 2017-05-02 2021-12-28 Corteva Agriscience Llc Synergistic mixtures for fungal controls in cereals
US11639334B2 (en) 2018-10-15 2023-05-02 Corteva Agriscience Llc Methods for synthesis of oxypicolinamides
US11771085B2 (en) 2017-05-02 2023-10-03 Corteva Agriscience Llc Synergistic mixtures for fungal control in cereals

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407959A2 (fr) * 1989-07-11 1991-01-16 Lion Corporation Procédé de production de monoesters d'un polyol et d'un acide gras
EP0611569A2 (fr) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglycérides
WO1996034855A1 (fr) * 1995-05-01 1996-11-07 Scotia Holdings Plc Esters d'acides gras utilises comme composes bioactifs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407959A2 (fr) * 1989-07-11 1991-01-16 Lion Corporation Procédé de production de monoesters d'un polyol et d'un acide gras
EP0611569A2 (fr) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglycérides
WO1996034855A1 (fr) * 1995-05-01 1996-11-07 Scotia Holdings Plc Esters d'acides gras utilises comme composes bioactifs
WO1996034846A1 (fr) * 1995-05-01 1996-11-07 Scotia Holdings Plc Derives de 1,3-propanediol utilises comme composes bioactifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EMIL ALBERHALDEN ET AL.: "Versuche über die Darstellung optisch-aktiver Fette.I.Synthese optisch-aktiver Halogenhydrine.", BERICHTE DER DEUTSCHEN CHEMISCHEN GESELLSCHAFT., 1914, WEINHEIM DE, pages 1856 - 1866, XP002053371 *

Cited By (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6927239B1 (en) * 2000-08-02 2005-08-09 Pharmanutrients Methods and compositions for the attenuation and/or prevention of stress/catabolic responses
US11147293B2 (en) * 2001-01-12 2021-10-19 Fundacao De Amparo A Pesquisa Do Estado De Sao Paulo Nutritional composition for increasing milk protein in mammals
WO2004014359A1 (fr) * 2001-03-16 2004-02-19 Thomas Jefferson University Regulation d'apob permettant le traitement et le criblage de medicaments pour des troubles ou des syndromes cardiovasculaires et metaboliques
US8703725B2 (en) 2002-09-20 2014-04-22 Nestec S.A. Nutritional compositions
WO2008063772A2 (fr) * 2006-10-13 2008-05-29 The Brigham And Women's Hospital Inc. La résolvine de série d et la protectine d1 pallient à une lésion aiguë des reins
WO2008063772A3 (fr) * 2006-10-13 2008-10-23 Brigham & Womens Hospital La résolvine de série d et la protectine d1 pallient à une lésion aiguë des reins
US9708245B2 (en) 2008-07-08 2017-07-18 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
US9272984B2 (en) 2008-07-08 2016-03-01 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US8173831B2 (en) 2008-07-08 2012-05-08 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US8729293B2 (en) 2008-07-08 2014-05-20 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US8735379B2 (en) 2008-07-08 2014-05-27 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US8735378B2 (en) 2008-07-08 2014-05-27 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US9458094B2 (en) 2008-07-08 2016-10-04 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
US9139516B2 (en) 2008-07-08 2015-09-22 Catabasis Pharmaceuticals, Inc. Fatty acid acetylated salicylates and their uses
WO2010072738A1 (fr) 2008-12-22 2010-07-01 Pierre Fabre Dermo-Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
US8623916B2 (en) 2008-12-22 2014-01-07 Pierre Fabre Dermo-Cosmetique Polyunsaturated fatty acid and diol ester as an anti-acne agent
JP2012513380A (ja) * 2008-12-22 2012-06-14 ピエール、ファブレ、デルモ‐コスメティーク 抗アクネ剤としての多価不飽和脂肪酸およびジオールエステル
USRE46605E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
US9486534B2 (en) 2009-09-01 2016-11-08 Catabasis Pharmaceuticals, Inc. Niacin conjugated fatty acid mixtures and their uses
US9238077B2 (en) 2009-09-01 2016-01-19 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
US9216224B2 (en) 2010-03-05 2015-12-22 Catabasis Pharmaceuticals, Inc. Fatty acid COX inhibitor derivatives and their uses
EP2654744A4 (fr) * 2010-12-21 2014-07-02 Nestec Sa Procédés et compositions pour la prévention et le traitement de l'arthrose
CN103384521A (zh) * 2010-12-21 2013-11-06 雀巢产品技术援助有限公司 用于预防和治疗骨关节炎的方法和组合物
JP2014505679A (ja) * 2010-12-21 2014-03-06 ネステク ソシエテ アノニム 変形性関節症の予防及び治療のための方法及び組成物
EP2654744A1 (fr) * 2010-12-21 2013-10-30 Nestec S.A. Procédés et compositions pour la prévention et le traitement de l'arthrose
US10172354B2 (en) 2012-12-28 2019-01-08 Dow Agrosciences Llc Synergistic fungicidal mixtures for fungal control in cereals
CN107205398A (zh) * 2014-12-30 2017-09-26 美国陶氏益农公司 具有杀真菌活性的吡啶酰胺化合物
US10588318B2 (en) 2014-12-30 2020-03-17 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
CN107205397A (zh) * 2014-12-30 2017-09-26 美国陶氏益农公司 具有杀真菌活性的吡啶酰胺化合物的用途
US10173971B2 (en) 2014-12-30 2019-01-08 Dow Agrosciences Llc Picolinamides with fungicidal activity
US10173981B2 (en) 2014-12-30 2019-01-08 Dow Agrosciences Llc Picolinamides as fungicides
US10182568B2 (en) 2014-12-30 2019-01-22 Dow Agrosciences Llc Use of picolinamide compounds as fungicides
US10188109B2 (en) 2014-12-30 2019-01-29 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
US10252989B2 (en) 2014-12-30 2019-04-09 Dow Agrosciences Llc Picolinamides with fungicidal activity
US10433555B2 (en) 2014-12-30 2019-10-08 Dow Agrosciences Llc Picolinamide compounds with fungicidal activity
JP2018502104A (ja) * 2014-12-30 2018-01-25 ダウ アグロサイエンシィズ エルエルシー 殺真菌活性を有するピコリンアミド化合物
US10595531B2 (en) 2014-12-30 2020-03-24 Dow Agrosciences Llc Use of picolinamide compounds as fungicides
CN107205398B (zh) * 2014-12-30 2020-08-21 美国陶氏益农公司 具有杀真菌活性的吡啶酰胺化合物
US12114660B2 (en) 2014-12-30 2024-10-15 Corteva Agriscience Llc Picolinamide compounds with fungicidal activity
US11751568B2 (en) 2014-12-30 2023-09-12 Corteva Agriscience Llc Picolinamide compounds with fungicidal activity
WO2016190280A1 (fr) * 2015-05-22 2016-12-01 日産化学工業株式会社 Procédé de production d'un composé o-[1-(2-hydroxypropyl)]oxime
US11191269B2 (en) 2017-05-02 2021-12-07 Dow Agrosciences Llc Use of an acyclic picolinamide compound as a fungicide for fungal diseases on turfgrasses
US11206828B2 (en) 2017-05-02 2021-12-28 Corteva Agriscience Llc Synergistic mixtures for fungal controls in cereals
US11771085B2 (en) 2017-05-02 2023-10-03 Corteva Agriscience Llc Synergistic mixtures for fungal control in cereals
US11155520B2 (en) 2018-03-08 2021-10-26 Dow Agrosciences Llc Picolinamides as fungicides
US11639334B2 (en) 2018-10-15 2023-05-02 Corteva Agriscience Llc Methods for synthesis of oxypicolinamides

Also Published As

Publication number Publication date
GB9622636D0 (en) 1997-01-08
AU4717497A (en) 1998-05-22
ZA979656B (en) 1998-04-30

Similar Documents

Publication Publication Date Title
USRE40480E1 (en) 1,3-Propane diol esters and ethers and methods for their use in drug delivery
WO1998018751A1 (fr) Presentation de substances bioactives
ES2726765T3 (es) Acidos grasos poliinsaturados para el tratamiento de enfermedades relacionadas con el campo de enfermedades cardiovasculares, metabólicas e inflamatorias
RU2509071C2 (ru) Новые липидные соединения
JP5552314B2 (ja) 新規脂質化合物
US20100267828A1 (en) dha derivatives and their use as medicaments
CN100391930C (zh) 作为生物活性化合物的1,3-丙二醇衍生物
USRE40546E1 (en) 1,3-Propane diol esters and ethers and methods for their use in drug delivery
TW546138B (en) Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives
US20150344402A1 (en) Omefibrates for Treating Dyslipidemia and Cardiovascular Disease
MXPA97008382A (en) Fatty acid esters as bioacti compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA