USRE40480E1 - 1,3-Propane diol esters and ethers and methods for their use in drug delivery - Google Patents

1,3-Propane diol esters and ethers and methods for their use in drug delivery Download PDF

Info

Publication number
USRE40480E1
USRE40480E1 US11/405,041 US40504196A USRE40480E US RE40480 E1 USRE40480 E1 US RE40480E1 US 40504196 A US40504196 A US 40504196A US RE40480 E USRE40480 E US RE40480E
Authority
US
United States
Prior art keywords
acid
gla
linolenic
octadeca
fatty
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US11/405,041
Other languages
English (en)
Inventor
Mehar Manku
Philip Knowles
Peter Redden
Andrea Pitt
Paul Bradley
Paul Wakefield
Austin McMordie
David B. Horrobin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Scarista Ltd
Original Assignee
Scarista Ltd
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
Priority claimed from GBGB9508823.3A external-priority patent/GB9508823D0/en
Priority claimed from GBGB9517107.0A external-priority patent/GB9517107D0/en
Priority claimed from GBGB9605440.8A external-priority patent/GB9605440D0/en
Application filed by Scarista Ltd filed Critical Scarista Ltd
Priority to US12/230,018 priority Critical patent/USRE43632E1/en
Priority to US11/405,041 priority patent/USRE40480E1/en
Application granted granted Critical
Publication of USRE40480E1 publication Critical patent/USRE40480E1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/16—Acetic acid esters of dihydroxylic compounds
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • 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
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/36—[b, e]-condensed, at least one with a further condensed benzene ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • 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
    • C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • U.S. application No. 11 / 405 , 041 (the present application) filed Apr. 14 , 2006 is a divisional reissue of U.S. application No. 11 / 119 , 495 filed Apr. 29 , 2005 which is a reissue of U.S. application No. 08 / 945 , 667 filed Jan. 28 , 1998 , now U.S. Pat. No. 6 , 555 , 700 which is a 371 of PCT/GB 96 / 01053 filed May 1 , 1996 .
  • 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 and/or the aims of ready synthesis of such compounds without a chiral centre.
  • 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 and/or the aims of ready synthesis of such compounds without a chiral centre.
  • 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.
  • the invention concerns the linking of bioactives through certain link molecules, considered in detail later herein, and the synthesis of a range of compounds some of which are entirely novel in themselves, while others are novel in the sense of their usefulness in therapy and/or the maintenance of health. Discussion is however, also given of compounds using other link molecules not currently claimed, and of directly linked bioactives, disclosed for example in EPA-0 393 920 concerning fatty acids and antivirals, and in co-pending EP-95301315.8 (published as EPA-0 675 103) concerning fatty acids and non-steroidal anti-inflammatory drugs.
  • 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.
  • barriers all three types of barriers, the cell membrane and intra-cellular membranes, the blood-brain barrier and the skin have an important feature in common, they are substantially composed of lipids. What this means is that they are impermeable to primarily water-soluble drugs unless these drugs can be carried across the membrane by a receptor or transport system. In contrast, 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:
  • 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 or even a single moiety may be delivered, in a form which is readily incorporated into the body as an oral, parenteral or topical formation; 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; which need have no chiral centre; and which is much more readily synthesised than the corresponding triglyceride with three moieties of the same fatty acid attached.
  • triglycerides are well tolerated and well utilised, they are less desirable than the proposed compounds because they are more difficult to synthesise and may have a chiral centre with multiple potential isomers. Moreover with triglycerides the fatty acids may relatively easily migrate from one position to another creating new molecules not present in the original preparation. This obviously causes problems, particularly in the context of drug regulation where such instability may be unacceptable.
  • the compounds allow drugs or other compounds to be administered in the form of relatively-lipophilic compounds which are non-chiral (unless the drugs or other compounds are themselves chiral), 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 blood-brain barrier.
  • the transport of actives across lipid membranes may be improved by linking them directly or via intermediate links to, in particular, gamma-linolenic acid (GLA) or dihomo-gamma-linolenic acid (DGLA), two fatty acids which in themselves have a range of desirable effects.
  • GLA gamma-linolenic acid
  • DGLA dihomo-gamma-linolenic acid
  • GLA gamma-linolenic acid
  • DGLA dihomo-gamma-linolenic acid
  • 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.
  • 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 C 12 -C 30 or C 16 -C 30 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 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.
  • FIG. 1 n-6 EFA's n-3 EFA's 18:2n-6 18:3n-3 (Linoleic acid, LA) ( ⁇ -Linolenic acid, ALA) ⁇ ⁇ -6-desaturase ⁇ 18:3n-6 18:4n-3 ( ⁇ -Linolenic acid, GLA) (Stearidonic acid, SA) ⁇ elongation ⁇ 20:3n-6 20:4n-3 (Dihomo- ⁇ -linolenic acid, DGLA) ⁇ ⁇ -5-desaturase ⁇ 20:4n-6 20:5n-6 (Arachidonic acid, (Eicosapentaenoic acid, AA) EPA) ⁇ elongation ⁇ 22:4n-6 22:5n-3 (Adrenic acid) ⁇ ⁇ -4-desaturase ⁇ 22:5n-6 22:6n-3 (Docosahexaenoic acid, DHA)
  • 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. Activities 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.
  • the fatty acid compounds may thus be mutual bipartate prodrugs (if linked directly) or mutual tripartate prodrugs (if connected via a link).
  • 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 FIG. 1 which are of particular interest are conjugated linoleic acid (cLA) and columbinic acid (CA).
  • cLA conjugated linoleic acid
  • CA columbinic acid
  • CA has many of the properties of essential fatty acids.
  • 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 (22:5n-3), 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 diols For purposes of convenient administration 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 diols.
  • the present specification covers fatty acid (or fatty alcohol) derivatives of bioactives with an available carboxyl, alcohol or amino group such that a single, well defined chemical entity is formed.
  • the coupling may be direct yielding bipartate compounds or spaced with an appropriate link group, yielding tripartate compounds, in terms of the number of moieties into which the compounds split.
  • n is conveniently 1 to 3.
  • Bioactives with a free carboxyl group these may be derivatised as follows: In all of the above categories where n is suitably 1 to 3, the carbon chain of the unsaturated fatty acid or alcohol is represented by: In all of these categories “unsaturated fatty acid” (and the derived “unsaturated fatty alcohol”) represents a member of a group comprising oleic acid (and oleoyl alcohol) and any fatty acid (or corresponding fatty alcohol) with two or more cis or trans double bonds.
  • the fatty acids likely to be of most value in this context are the essential fatty acids shown in FIG.1 and in particular GLA, DGLA, AA, SA, EPA and DHA. For particular purposes conjugated linoleic acid and columbinic acid may be of great interest.
  • the individual fatty acids may be purified from natural animal, vegetable or microbial sources or may be chemically synthesized by methods known to those skilled in the art or developed hereafter.
  • the individual fatty alcohols may be prepared by chemical reduction of the fatty acids outlined above by methods known to those skilled in the art or developed hereafter.
  • Fatty acid pairs may for example be linked directly as fatty acid-fatty alcohol esters or as anhydrides, and if diol linkers are used ether links to fatty alcohols are an alternative to the more generally convenient ester links to fatty acids as such; in all cases linking may again be by chemistry known in itself.
  • Pairs of Actives which may be Linked either Directly or via a Link, Particularly a 1,3-Propane Diol Link
  • 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 1 (thiamin), Vitamin B 2 (riboflavin), folic acid and related pterins, Vitamin B 12 , 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 taurine 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 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.
  • 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.
  • organosulfur compunds e.g. allicin
  • terpenes e.g. geraniol, abietic acid
  • amino acid anti-oxidants 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.
  • NAIDS non-steroidal anti-inflammatory drugs
  • GLA-ester of indomethacin a non-steroidal anti-inflammatory drug
  • Indomethacin as a non-steroidal anti-inflammatory drug is believed to have a primarily intracellular mechanism of action by inhibiting the enzyme cyclo-oxygenase, which converts arachidonic acid to pro-inflammatory prostaglandin metabolites.
  • Indomethacin is known to penetrate cells very poorly and so has to be given in relatively large doses which can produce many side effects, thus indomethacin-GLA was compared with indomethacin itself for its ability to penetrate cells, using a normal fibroblast line, a breast cancer line and a malignant melanoma line.
  • the compounds will generally be acid-function bearing actives esterified directly to the diol residue but for example with a fatty alcohol or other hydroxy-function bearing active, a phosphate, succinate or other difunctional acid group may be interposed between the R 1 and/or R 2 group and the 1,3-propane diol residue, particularly when R 2 is a nutrient, drug or other bioactive with a hydroxy or amino function.
  • the invention is also discussed broadly below, concerning a wide range of actives releasable in the body.
  • This diol may also be regarded as 2-deoxyglycerol and the corresponding diesters as 2-deoxy-1,3-diglycerides.
  • the compounds listed herein are almost all new chemical entities or at least have never previously been used in treatment of human or animal disease.
  • the diol used as a link is, broadly, disclosed in the literature among many other diols but we have seen that its use in therapy in the form of an essential fatty acid diester or as a compound with an essential fatty acid at one position and a bioactive (not being an essential fatty acid) at the other, is both undisclosed and particularly significant. Indeed it offers a favourable way to give a single fatty acid as the monoester or diester if a completely defined compound is required, as there is no chiral centre such as is present in glycerol 1(3)-monoesters and in diglycerides ( ⁇ , ⁇ and 1,3 where the fatty acid at position 1 is different from that at position 3), nor do positional isomers exist.
  • 1,3-propane diol structure is close to the glycerol of natural triglycerides and an effective and safe delivery system. Moreover it allows ready and unequivocal synthesis of defined compounds without the problems of acyl migration shown in triglycerides and without complications by optical isomers.
  • intravenous infusion and oral administration of a 1,3 propane diol GLA/EPA diester emulsion leads to rapid in vivo release of free GLA and EPA and to further metabolism of the GLA to AA and of the EPA to DHA.
  • GLA-GLA and EPA-EPA diesters, and niacin-GLA and indomethacin-GLA diesters have been shown to be absorbed following oral administration and to release their active moieties.
  • the fatty acid diesters have a wide variety of possible uses. They may be used as pharmaceuticals for the treatment or prevention of diseases in which abnormalities of fatty acids have been identified. They may be added to foods or added to or used as nutritional supplements for those who require the particular fatty acid for the treatment or prevention of diseases. They may also be used in foods or pharmaceuticals for veterinary use. They may further be used for skin care.
  • the fatty acids have a large number of desirable biological and therapeutic activities which have been detailed in numerous publications by the inventors and by others.
  • this group of fatty acids can be used in the treatment of may 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 inflammatory 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: 194-207) 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.
  • the 1,3 GLA-EPA propane diol diester was tested in the treatment of the ASPC-1 human pancreatic -cancer transplanted subcutaneously into nude mice which because they lack thymus function are able to accept foreign transplants without rejection.
  • 15 mice were each injected subcutaneously with 15 million ASPC-1 cells suspended in Matrigel and DMEM buffer.
  • Tumour size in each animal was measured twice weekly for five weeks. The animals were divided into three groups. 5 animals were used as controls and received 10 g/kg corn oil per day only.
  • mice received 10 g/kg corn oil per day but in addition received two injections per week of a dose of 1.5 g/kg of the GLA-EPA diester.
  • the diester was administered in the form of a 20% emulsion in which 2% of oat galactolipid was used as the emulsifier; the intravenous emulsion was very well tolerated and caused no haemolysis or thrombophlebitis or any other form of distress to the animals.
  • the other 5 animals instead of the corn oil received 10 g/kg/day of the GLA-EPA diester.
  • the treatments were continued for three weeks and then the tumours were allowed to grow for a further two weeks before the animals were sacrificed and the tumours excised and weighed.
  • tumour weights were: control group, 1240 ⁇ 290 mg; intravenous GLA-EPA group, 820 ⁇ 180 mg; oral GLA-EPA group, 490 ⁇ 160 mg. Tumour growth was thus substantially inhibited by both oral and intravenous administration of the GLA-EPA diester without causing any side effects or distress in the animals.
  • the diesters are biologically active ways of administering the various fatty acids. The diesters can therefore be reasonably expected to exert the many desirable effects of the fatty acids which have been noted in many publications in the literature (e.g.
  • Horrobin D F ed., Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine: Wiley-Liss, New York, 1990. Simopoulos A P et al, eds, Health Effects of Omega-3 Polyunsaturated Fatty Acids in Seafoods, Karger, Basel, 1991. Fats and Oils in Human Nutrition, World Health Organization, Rome, 1994. Unsaturated Fatty Acids: Nutritional and Physiological Significance. British Nutrition Foundation, Chapman and Hall, London, 1992).
  • 1,3-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:
  • 1,3-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), (k), (q) and (r).
  • 1,3-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).
  • 1,3-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 1,3-propane diol by one of the linkages described herein:
  • 1,3-propane diol be used in place of glycerol in the esterification of fatty acids, especially where only one type of fatty acid (e.g. gamma-linolenic acid) is to be attached to the three-carbon chain “backbone”.
  • fatty acid e.g. gamma-linolenic acid
  • diesters and triglycerides are chemically very similar, the manufacture of di-esters can be carried out under very mild conditions, and in a matter of hours. To manufacture triglycerides, either harsh conditions are required, or fatty acid chlorides must be used, or bio-catalysts (which require reaction times of several days) are necessary.
  • a summary of triglyceride synthesis methods is: chemical reaction with metals, metal-chlorides, or organic acids as catalyst; use of fatty-acid chlorides; use of immobilised enzymes.
  • a particular family of enzymes can be used to catalyse the esterification reaction under very mild conditions (e.g. at 60° C.), and are probably the catalysts of choice when polyunsaturated fatty acids are being used.
  • most enzymes interact most effectively with the 1- and 3-positions of glycerol. Addition of fatty acid to the 2-position is slow, and often dependant upon “acyl migration”, i.e. a fatty acid must first be attached to the 1- or 3-position, and then migrate to the 2-position, where it remains attached.
  • acyl migration i.e. a fatty acid must first be attached to the 1- or 3-position, and then migrate to the 2-position, where it remains attached.
  • triglyceride synthesis reactions which are catalysed by enzymes can take days to approach completion.
  • a further complexity with specific triglyceride syntheses is the presence within glycerol of both primary and secondary hydroxyl groups and a prochiral centre at the central carbon atoms.
  • reaction which prepares diesters from polyunsaturated fatty acids and 1,3-propane diol is faster, and can be carried out under much milder conditions, than can the corresponding triglyceride synthesis. This leads to a more economical and less wasteful production process and minimises the risk of reactants or products becoming altered or degraded during processing.
  • 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 1,3-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 200 g) was prepared containing the following ingredients:
  • the emulsifier-galactolipid 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 (Ultraturrax) at speed 4, for a few minutes.
  • This pre-emulsion was then homogenised 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 can also be added to the above oral emulsion.
  • the above emulsion, homogenised for 6 minutes in a high pressure homogeniser had an average droplet size of 211 nm, a zeta potential of ⁇ 40 mV.
  • These I.V. 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 1 mg to 200 g per day, preferably 10 mg to 10 g and very preferably 10 mg to 3 g, according to their kind. In the treatment of cancer preferable doses may be in the 2-150 g/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% to 20% and very preferably 0.1% to 10%.
  • Example 2 Prepared as in Example 2, Part 2 but replacing z-octadeca-9-enoic acid with z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoic acid. Chromatography yielded 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-(z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoyloxy)propane as a pale yellow oil.
  • Example 2 Prepared as in Example 2, Part 2 but replacing z-octadeca-9-enoic acid with z,z,z-octadeca-6,9,12-trienoic acid. Chromatography yielded 1,3-(di-z,z,z-octadeca-6,9,12-trienoyloxy)propane as a pale yellow oil.
  • the residue was washed with hexane (3 ⁇ 50 ml) to remove unreacted 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane.
  • the semisolid residue was disolved in diethyl ether (150 ml), washed with water (100 ml) and dried.
  • the ether solution was diluted with hexane (125 ml) and the solution filtered through a bed of silica (4 cm ⁇ 4 cm).
  • the protected product was dissolved in 10% v/v anisole/trifluoroacetic acid (10 ml) and left at room temperature under nitrogen for 30 minutes. After tlc analysis indicated that deprotection was complete, the mixture was purified by column chromatography (8% methanol/42% methylene chloride/50% ethyl acetate) to yield 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-(2-pyrrolidine carboxy)propane as a viscous orange oil.
  • the protected product was dissolved in 10% v/v anisole/trifluoroacetic acid (6.1 ml) and left at room temperature under nitrogen for 15 minutes. After tlc analysis indicated that deprotection was complete, the mixture was purified by column chromatography (8% methanol/42% methylene chloride/50% ethyl acetate) to yield 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-(2-amino-3-indolylpropanoyloxy)propane as a viscous red wax.
  • the protected product was dissolved in 10% v/v anisole/trifluoroacetic acid (17 ml) and left at room temperature under nitrogen for 30 minutes. After tlc analysis indicated that deprotection was complete, the mixture was purified by column chromatography (8% methanol/42% methylene chloride/50% ethyl acetate) to yield 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-( ⁇ -amino- ⁇ -phenyl-propionyloxy)propane as a viscous yellow oil.
  • the protected product was dissolved in 10% v/v anisole/trifluoroacetic acid (10.5 ml) and left at room temperature under nitrogen for 30 minutes. After tlc analysis indicated that deprotection was complete, the mixture was purified by column chromatography (8% methanol/42% methylene chloride/50% ethyl acetate) to yield 1-(z,z,z-octadeca-6,9,12-trienyloxy)-3-(4-amino butanoyloxy)propane as a yellow oil.
  • Oxalyl chloride (3.9 ml, 45 mmol) was added to a solution of the product from part 1 (13 g, 30 mmol) in methylene chloride (75 ml). The mixture was stirred at room temperature under nitrogen for 2 h and concentrated to dryness. Hexane (75 ml) was added and the mixture concentrated to dryness. This process was repeated with two further portions of hexane (75 ml ea.). The material was used without any further purification.
  • 2,3,5-Triiodobenzoyl chloride (1.54 g, 3.08 mmol) was added to a mixture of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (1 g, 2.97 mmol) and triethylamine (1 ml) in methylene chloride (80 ml) and the resulting mixture stirred overnight at room temperature under nitrogen. The mixture was concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(2,3,5-triiodobenzoyloxy)-3-(z,z,z-octadeca-6,9,12-trienoyloxy)propane.
  • Triethylamine (3.74 ml, 26.8 mmol) was added dropwise to a cooled (0° C.) solution of freshly distilled phosphorus oxychloride (2.74 g, 17.9 mmol) in anhydrous THF (15 ml).
  • a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (5 g, 14.9 mmol) in anhydrous THF (15 ml).
  • the temperature was kept at less than 10° C. throughout and the reaction kept under an atmosphere of nitrogen. Tlc analysis after 15 min. indicated complete disappearance of starting material.
  • the mixture was filtered and concentrated. Toluene (50 ml) was added and the mixture concentrated. A further portion of toluene (50 ml) was added and removed.
  • Lithium bromide (104 mg, 1.13 mmol) in methyl ethyl ketone (1 ml) was added to a solution of methyl-di(z,z,z-octadeca-6,9,12-trienoyloxypropyl)-phosphate (0.85 g, 1.13 mmol) (prepared as in example 18) in methyl ethyl ketone (1 ml) and the mixture was heated under reflux for 1 h. After cooling, the mixture was dissolved in diethyl ether (3 ml) and extracted with water (3 ml). Emulsions formed were broken by the addition of a few drops of methanol.
  • the product obtained from part 1 was dissolved in isopropanol (100 ml), acetic acid (10 ml) and water (40 ml) and the solution allowed to stand under nitrogen at room temperature. When tic indicated that the reaction had gone to completion the mixture was concentrated and partitioned between acetonitrile (50 ml) and hexane (50 ml). The hexane layer was separated, concentrated and purified by flash chromatography (methanol/chloroform 1 water). The pure fractions were pooled and concentrated.
  • Triethylamine (7.5 ml) was added to a solution of freshly distilled phosphorus oxychloride (1.26 g, 8.25 mmol) in anhydrous THF (7.5m) at 0° C. After 15 min. a solution of 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane (2.5 g, 7.5 mmol) in anhydrous THF (7.5 ml) was added dropwise over a period of 30 min. at 0° C. Stirring at this temperature was continued for 30 min. after the end of addition.
  • ⁇ -Tocopherol (3.23 g, 7.5 mmol) in anhydrous THF (5 ml) was added dropwise at 10° C. and the resultant mixture was then stirred at 10° C. for 1 h and then overnight, warming up to room temperature.
  • Triethylamine (2 ml) and water (5 ml) were added to one quarter of the reaction mixture as prepared in example 23, part 1.
  • the mixture was stirred under nitrogen in an ice bath for 1 h, acidified to pH 1 with 2M hydrochloric acid and extracted into ethyl acetate (20 ml) and methanol (5 ml).
  • the extract was dried concentrated and purified by flash chromatography (chloroform) to yield (z,z,z-octadeca-6,9,12-trienoyloxypropyl)-( ⁇ -tocopheryl)phosphate.
  • z,z,z-Octadeca-6,9,12-trienoyl chloride (2 g) was added dropwise to a solution of 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 ml) and 4-(N,N-dimethylamino)pyridine (0.2 g) in methylene chloride (50 ml) with stirring at 0° C. under nitrogen.
  • the reaction mixture was washed with dilute hydrochloric acid and water, dried and purified by column chromatography yielding 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane as a pale yellow oil.
  • Example 2 Part 2 but replacing 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane with 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-5-hydroxypentane and z-octadeca-9-enoic acid with z,z,z,z,z-eicosa-5,8,11,14,17-pentaenoic acid.
  • reaction mixture was diluted with hexane, filtered, concentrated and purified by chromatography to yield 1,4-di(z,z,z-octadeca-6,9,12-trienyl)-butane-1,4-dioate as a pale yellow oil.
  • Metronidazole (1.9 g) was suspended in toluene (30 ml) and with stirring the mixture was heated under reflux with a Dean and Stark head for 20 mins. to remove any water present. To the boiling solution was added, under nitrogen, z,z,z-octadeca-6,9,12-trienoyl chloride (2.96 g) dropwise over a period of 20 mins. The mixture was stirred and heated under reflux for a further 2 hours, giving a dark reaction mixture.
  • trans-1-(z,z,z-octadeca-6,9,12-trienoylamino)-2-phenyl cyclopropane is prepared in a similar manner but replacing the metronidazole with the requisite amount of trans-1-amino-2-phenylcyclopropane (tranylcypromine) and the linoleic acid with the requisite amount of GLA there is prepared trans-1-(z,z,z-octadeca-6,9,12-trienoylamino)-2-phenyl cyclopropane.
  • Triethylamine (0.3 ml) was added to a stirred suspension of ampicillin (0.7 g) in anhydrous DMF (120 ml) under a nitrogen atmosphere.
  • z,z,z-octadeca-6,9,12-trienoic acid, N-hydroxysuccinimide ester (0.75 g) while maintaining the reaction at 0-10° C.
  • the reaction was stirred at this temperature for an additional hour before allowing the mixture to stand at room temperature overnight.
  • Tlc analysis (40% THF/hexane) at this point indicated that most of the succinimide ester had reacted.
  • Water 40 ml was added to the reaction flask and the contents stirred.
  • 1,3-dicyclohexylcarbodiimide (0.82 g) and 4-(N,N-dimethylamino)pyridine (0.48 g) in methylene chloride (5 ml) were added to a solution of z,z,z-octadeca-6,9,12-trienol (0.95 g) and z,z,z-octadeca-6,9,12-trienoic acid (1 g) in methylene chloride (10 ml) with stirring at room temperature under nitrogen.
  • reaction mixture was extracted with hexane (2 ⁇ 40 ml) and the hexane extract washed with brine (2 ⁇ 50 ml) and water (50 ml), dried (sodium sulfate) and concentrated to yield z,z,z-octadeca-6,9,12-trienyl-(2-(z,z,z-octadeca-6,9,12-trienyloxy)acetate) as a colourless oil.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Diabetes (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Oncology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Communicable Diseases (AREA)
  • Reproductive Health (AREA)
  • Nutrition Science (AREA)
  • Rheumatology (AREA)
  • Virology (AREA)
US11/405,041 1995-05-01 1996-05-01 1,3-Propane diol esters and ethers and methods for their use in drug delivery Expired - Lifetime USRE40480E1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/230,018 USRE43632E1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery
US11/405,041 USRE40480E1 (en) 1995-05-01 1996-05-01 1,3-Propane diol esters and ethers and methods for their use in drug delivery

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB9508823.3A GB9508823D0 (en) 1995-05-01 1995-05-01 Drug Derivatives
GBGB9517107.0A GB9517107D0 (en) 1995-08-21 1995-08-21 Fatty acid esters
GBGB9605440.8A GB9605440D0 (en) 1996-03-15 1996-03-15 Presentaion of bioactives
PCT/GB1996/001053 WO1996034846A1 (en) 1995-05-01 1996-05-01 1,3-propane diol derivatives as bioactive compounds
US11/405,041 USRE40480E1 (en) 1995-05-01 1996-05-01 1,3-Propane diol esters and ethers and methods for their use in drug delivery

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/945,667 Reissue US6555700B1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery

Publications (1)

Publication Number Publication Date
USRE40480E1 true USRE40480E1 (en) 2008-09-02

Family

ID=27267691

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/230,018 Expired - Fee Related USRE43632E1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery
US11/405,041 Expired - Lifetime USRE40480E1 (en) 1995-05-01 1996-05-01 1,3-Propane diol esters and ethers and methods for their use in drug delivery
US08/945,667 Ceased US6555700B1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery
US09/376,617 Expired - Fee Related US6245811B1 (en) 1995-05-01 1999-08-18 Fatty acid esters as bioactive compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US12/230,018 Expired - Fee Related USRE43632E1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery

Family Applications After (2)

Application Number Title Priority Date Filing Date
US08/945,667 Ceased US6555700B1 (en) 1995-05-01 1996-05-01 1,3-propane diol esters and ethers and methods for their use in drug delivery
US09/376,617 Expired - Fee Related US6245811B1 (en) 1995-05-01 1999-08-18 Fatty acid esters as bioactive compounds

Country Status (29)

Country Link
US (4) USRE43632E1 (de)
EP (2) EP0823895B1 (de)
JP (3) JP3960481B2 (de)
KR (2) KR19990008244A (de)
AR (1) AR004483A1 (de)
AT (2) ATE272053T1 (de)
AU (2) AU713858B2 (de)
BG (2) BG102012A (de)
BR (2) BR9606607A (de)
CA (2) CA2218699C (de)
CZ (2) CZ297646B6 (de)
DE (2) DE69623764T2 (de)
DK (2) DK0823889T3 (de)
EE (2) EE04462B1 (de)
ES (2) ES2185772T3 (de)
HK (1) HK1003882A1 (de)
HU (2) HUP9802384A3 (de)
IL (1) IL118061A (de)
IS (2) IS4604A (de)
MY (2) MY118354A (de)
NO (2) NO975035L (de)
NZ (2) NZ306509A (de)
PL (2) PL323176A1 (de)
PT (2) PT823895E (de)
RU (1) RU2215733C2 (de)
SI (2) SI0823895T1 (de)
SK (2) SK285135B6 (de)
TR (2) TR199701277T1 (de)
WO (2) WO1996034846A1 (de)

Families Citing this family (187)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2328155B (en) * 1996-04-12 2000-08-02 Peptide Technology Pty Limited Methods of treating immunopathologies using polyunsaturated fattyacids
US6576636B2 (en) * 1996-05-22 2003-06-10 Protarga, Inc. Method of treating a liver disorder with fatty acid-antiviral agent conjugates
US5795909A (en) * 1996-05-22 1998-08-18 Neuromedica, Inc. DHA-pharmaceutical agent conjugates of taxanes
US5804210A (en) * 1996-08-07 1998-09-08 Wisconsin Alumni Research Foundation Methods of treating animals to maintain or enhance bone mineral content and compositions for use therein
US5760083A (en) * 1996-08-07 1998-06-02 Wisconsin Alumni Research Foundation Use of CLA to reduce the incidence of valgus and varus leg deforomities in poultry
GB9622636D0 (en) * 1996-10-30 1997-01-08 Scotia Holdings Plc Presentation of bioactives
CZ326896A3 (cs) * 1996-11-07 1998-05-13 Milo Olomouc, A. S. Tuk se specifickými protisklerotickými účinky
GB9705102D0 (en) * 1997-03-12 1997-04-30 Scotia Holdings Inc Presentation of fatty acids
WO1998048788A1 (en) * 1997-04-29 1998-11-05 Scotia Holdings Plc Treatment of depression and anxiety using docosahexaenoic acid or natural antioxidants
DE19718245C5 (de) * 1997-04-30 2004-11-11 Cognis Deutschland Gmbh & Co. Kg Synthetische Triglyceride auf Basis konjugierter Linolsäure, Verfahren zu deren Herstellung und deren Verwendung
GB9715444D0 (en) 1997-07-22 1997-09-24 Scotia Holdings Plc Therapeutic and dietary compositions
US6019990A (en) * 1997-11-21 2000-02-01 Natural Nutrition Ltd. As Conjugated linoleic acid delivery system in cosmetic preparations
US6136985A (en) * 1997-12-23 2000-10-24 Dcv, Inc. CLA esters and uses thereof
JPH11209279A (ja) * 1998-01-05 1999-08-03 Natural Ltd As 体重減少および肥満処置の方法
US20020002154A1 (en) * 1998-02-11 2002-01-03 Pol-Henri Guivarc'h Method and composition for treatment of inflammatory conditions
WO1999040906A2 (en) * 1998-02-11 1999-08-19 Research Triangle Pharmaceuticals Method and composition for treatment of inflammatory conditions
GB9804361D0 (en) * 1998-03-02 1998-04-22 Scotia Holdings Plc Cancer treatment
JP2000516480A (ja) 1998-03-17 2000-12-12 コンリンコ，インコーポレイテッド 共役リノール酸組成物
US7776353B1 (en) 1998-03-17 2010-08-17 Aker Biomarine Asa Conjugated linoleic acid compositions
US6015833A (en) 1998-03-17 2000-01-18 Conlinco., Inc. Conjugated linoleic acid compositions
US6177580B1 (en) 1998-04-21 2001-01-23 Henkel Kommanditgesellschaft Auf Aktien Conjugated linolenic acid-based synthetic triglycerides
US6060514A (en) 1998-05-04 2000-05-09 Conlin Co., Inc. Isomer enriched conjugated linoleic acid compositions
US6214372B1 (en) 1998-05-04 2001-04-10 Con Lin Co., Inc. Method of using isomer enriched conjugated linoleic acid compositions
US6696584B2 (en) 1998-05-04 2004-02-24 Natural Asa Isomer enriched conjugated linoleic acid compositions
US7101914B2 (en) 1998-05-04 2006-09-05 Natural Asa Isomer enriched conjugated linoleic acid compositions
US6777388B1 (en) * 1998-08-21 2004-08-17 Clf Medical Technology Acceleration Program, Inc. Leptin-related peptides
US6132582A (en) 1998-09-14 2000-10-17 The Perkin-Elmer Corporation Sample handling system for a multi-channel capillary electrophoresis device
GB9901809D0 (en) * 1999-01-27 1999-03-17 Scarista Limited Highly purified ethgyl epa and other epa derivatives for psychiatric and neurological disorderes
IT1308613B1 (it) 1999-02-17 2002-01-09 Pharmacia & Upjohn Spa Acidi grassi essenziali nella prevenzione di eventi cardiovascolari.
US7235583B1 (en) 1999-03-09 2007-06-26 Luitpold Pharmaceuticals, Inc., Fatty acid-anticancer conjugates and uses thereof
US6245800B1 (en) * 1999-06-08 2001-06-12 Sigma-Tau Method of preventing or treating statin-induced toxic effects using L-carnitine or an alkanoyl L-carnitine
GB9918028D0 (en) * 1999-07-30 1999-09-29 Unilever Plc Skin care composition
GB9927629D0 (en) 1999-11-24 2000-01-19 Croda Int Plc Compounds
AU2001251449B2 (en) 2000-04-06 2005-04-07 Conlinco, Inc. Conjugated linoleic acid compositions
JP5258134B2 (ja) 2000-04-18 2013-08-07 エイカー バイオマリン アーエスアー 共役リノール酸粉末
US6380409B1 (en) 2000-04-24 2002-04-30 Conlin Co., Inc. Methods for preparing CLA isomers
US6927239B1 (en) * 2000-08-02 2005-08-09 Pharmanutrients Methods and compositions for the attenuation and/or prevention of stress/catabolic responses
US6506412B2 (en) * 2000-11-29 2003-01-14 Sciencebased Health Treatment of dry eye syndrome
ITMI20010129A1 (it) 2001-01-25 2002-07-25 Pharmacia & Upjohn Spa Acidi grassi essenziali nella terapia di insufficienza cardiaca e scompenso cardiaco
WO2002076402A2 (en) * 2001-03-23 2002-10-03 Protarga, Inc. Fatty amine drug conjugates
JP4634694B2 (ja) * 2001-03-23 2011-02-16 ルイトポルド・ファーマシューティカルズ・インコーポレーテッド 脂肪アルコール薬物複合体
CN1259044C (zh) 2001-03-30 2006-06-14 日清奥利友集团株式会社 骨代谢改善剂
CA2372450A1 (en) * 2001-05-10 2001-09-19 Pharmaceutical Partners Of Canada Inc. Liquid injectable formulation of disodium pamidronate
US6838074B2 (en) 2001-08-08 2005-01-04 Bristol-Myers Squibb Company Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent
CA2508907A1 (en) * 2001-11-08 2003-05-15 Atrium Medical Corporation Intraluminal device with a coating containing a therapeutic agent
ITMI20012384A1 (it) * 2001-11-12 2003-05-12 Quatex Nv Uso di acidi grassi poliinsaturi per la prevenzione primaria di eventi cardiovascolari maggiori
US6677470B2 (en) 2001-11-20 2004-01-13 Natural Asa Functional acylglycerides
US6743931B2 (en) 2002-09-24 2004-06-01 Natural Asa Conjugated linoleic acid compositions
NZ569868A (en) * 2002-09-27 2010-01-29 Martek Biosciences Corp Prophylactic docosahexaenoic acid therapy for patients with subclinical inflammation
US7074418B2 (en) * 2002-11-18 2006-07-11 Changaris David G Conjugated fatty acid based emulsion and methods for preparing and using same
US20050123500A1 (en) * 2003-01-31 2005-06-09 The Procter & Gamble Company Means for improving the appearance of mammalian hair and nails
JP2006524187A (ja) * 2003-01-31 2006-10-26 ザ プロクター アンド ギャンブル カンパニー 哺乳類のケラチン組織の外観を改善する手段
WO2004091603A1 (fr) * 2003-04-07 2004-10-28 Clinigenetics Utilisation d’un ester de dha pour le traitement des malades cardiovasculaires
US7091369B2 (en) * 2003-07-15 2006-08-15 Board Of Trustees Operating Michigan State University Synthesis of polyconjugated fatty acids
US7041286B2 (en) * 2003-07-23 2006-05-09 Nerenberg Arnold P Composition for mitigating a pernicious thrombotic event
AU2004263164A1 (en) * 2003-08-05 2005-02-17 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Neuroprotection protects against cellular apoptosis, neural stroke damage, alzheimer's disease and retinal degeneration
CA2436650A1 (en) * 2003-08-06 2005-02-06 Naturia Inc. Conjugated linolenic acid (clnatm) compositions: synthesis, purification and uses
US20050074443A1 (en) * 2003-10-03 2005-04-07 Treadwell Benjamin V. Methods of attenuating autoimmune disease and compositions useful therefor
US20050154059A1 (en) * 2004-01-13 2005-07-14 Cook Mark E. Method of treating type III hypersensitive reaction-related diseases and conditions by using conjugated linoleic acid
US9000040B2 (en) 2004-09-28 2015-04-07 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
US8263102B2 (en) 2004-09-28 2012-09-11 Atrium Medical Corporation Drug delivery coating for use with a stent
US9801982B2 (en) 2004-09-28 2017-10-31 Atrium Medical Corporation Implantable barrier device
US20060083768A1 (en) * 2004-09-28 2006-04-20 Atrium Medical Corporation Method of thickening a coating using a drug
US8312836B2 (en) 2004-09-28 2012-11-20 Atrium Medical Corporation Method and apparatus for application of a fresh coating on a medical device
US9801913B2 (en) 2004-09-28 2017-10-31 Atrium Medical Corporation Barrier layer
US8367099B2 (en) 2004-09-28 2013-02-05 Atrium Medical Corporation Perforated fatty acid films
US9012506B2 (en) 2004-09-28 2015-04-21 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
BRPI0518426A2 (pt) * 2004-12-06 2008-11-25 Reliant Pharmaceuticals Inc composiÇÕes farmacÊuticas compreendendo fenofibratos e sistemas solventes
US20060211762A1 (en) * 2004-12-06 2006-09-21 Rongen Roelof M Omega-3 fatty acids and dyslipidemic agent for lipid therapy
CN101098690A (zh) * 2004-12-06 2008-01-02 瑞莱恩特医药品有限公司 用于血脂治疗的ω-3脂肪酸和脂血异常剂
US20060135610A1 (en) * 2004-12-22 2006-06-22 Bortz Jonathan D Cardiovascular compositions
KR20070108945A (ko) * 2005-03-08 2007-11-13 릴라이언트 파마슈티컬스 인코퍼레이티드 스타틴과 오메가-3 지방산 및 그 조합물을 이용한 치료
US20060229366A1 (en) * 2005-04-07 2006-10-12 Lifschitz Carlos H Method for preventing or treating respiratory infections in infants
US9278161B2 (en) 2005-09-28 2016-03-08 Atrium Medical Corporation Tissue-separating fatty acid adhesion barrier
US9427423B2 (en) 2009-03-10 2016-08-30 Atrium Medical Corporation Fatty-acid based particles
CA2626030A1 (en) 2005-10-15 2007-04-26 Atrium Medical Corporation Hydrophobic cross-linked gels for bioabsorbable drug carrier coatings
US8470861B2 (en) 2005-11-22 2013-06-25 University Of Rochester Mitochondria-targeted antioxidant prodrugs and methods of use
AU2006318248A1 (en) * 2005-11-22 2007-05-31 University Of Rochester Mitochondria-targeted antioxidant prodrugs and methods of use
RU2437583C2 (ru) * 2005-12-21 2011-12-27 Бруди Текнолоджи, С.Л. Применение дгк (dha), эпк (epa) или эпк, полученных из дгк, для лечения патологии, связанной с окислительным повреждением клетки, a также их нетерапевтические применения
ES2277557B1 (es) 2005-12-21 2008-07-01 Proyecto Empresarial Brudy, S.L. Utilizacion de acido docosahexaenoico para el tratamiento del daño celular oxidativo.
EP1973536A2 (de) * 2006-01-05 2008-10-01 Reliant Pharmaceuticals, Inc. Behandlung von fettleber
CA2641815C (en) * 2006-02-03 2015-06-09 Giulio Cossu Method of treatment for muscular dystrophy
JP5622359B2 (ja) * 2006-02-10 2014-11-12 デユポン・テイト・アンド・ライル・バイオ・プロダクツ・カンパニー・エルエルシー バイオマス誘導された抽出物、フレグランス濃縮物、およびオイル用の天然非刺激性溶剤としての生物誘導された１，３−プロパンジオールおよびその共役エステル
US20070275139A1 (en) * 2006-02-10 2007-11-29 Melissa Joerger Food compositions comprising renewably-based, biodegradable1,3-propanediol
JP2009532506A (ja) * 2006-02-10 2009-09-10 デユポン・テイト・アンド・ライル・バイオ・プロダクツ・カンパニー・エルエルシー 生物学的ベースの１，３−プロパンジオールのモノエステルおよびジエステルを含む組成物
WO2007103557A2 (en) 2006-03-09 2007-09-13 Reliant Pharmaceuticals, Inc. Coating capsules with active pharmaceutical ingredients
JP5099808B2 (ja) * 2006-05-29 2012-12-19 独立行政法人農業・食品産業技術総合研究機構 脂質代謝改善用組成物
US9492596B2 (en) 2006-11-06 2016-11-15 Atrium Medical Corporation Barrier layer with underlying medical device and one or more reinforcing support structures
WO2008057344A2 (en) 2006-11-06 2008-05-15 Atrium Medical Corporation Coated surgical mesh
WO2008061187A1 (en) * 2006-11-15 2008-05-22 Dupont Tate & Lyle Bio Products Company, Llc Preservative compositions comprising renewably-based, biodegradable 1,3-propanediol
US20090029944A1 (en) * 2007-06-19 2009-01-29 Skinner Keith K Methods for adding fatty acids to agents in aqueous solution to improve bioavailability
US9085527B2 (en) 2008-07-08 2015-07-21 Catabasis Pharmaceuticals, Inc. Fatty acid acylated salicylates and their uses
ES2656903T3 (es) 2008-07-08 2018-02-28 Catabasis Pharmaceuticals, Inc. Salicilatos acetilados de ácidos grasos y sus usos
US20110070154A1 (en) * 2008-08-13 2011-03-24 Hyde Roderick A Artificial cells
EP3578177A1 (de) 2008-09-02 2019-12-11 Amarin Pharmaceuticals Ireland Limited Pharmazeutische zusammensetzungen mit eicosapentaensäure und nikotinsäure und verfahren zur verwendung davon
US20100062057A1 (en) * 2008-09-10 2010-03-11 Pronova BioPharma Norge AS. Formulation
FR2940281B1 (fr) 2008-12-22 2011-04-01 Fabre Pierre Dermo Cosmetique Ester de diol et d'acide gras polyinsature comme agent anti-acne
EP2596786B1 (de) 2009-02-10 2019-11-27 Amarin Pharmaceuticals Ireland Limited Verwendung von eicosapentaensäureethylester zur behandlung von hypertriglyceridämie
CN110538148A (zh) 2009-03-09 2019-12-06 巴斯夫股份公司 含有脂肪酸油混合物和表面活性剂的组合物及其方法和用途
EP3563842A1 (de) 2009-04-29 2019-11-06 Amarin Pharmaceuticals Ireland Limited Pharmazeutische zusammensetzungen mit epa und einem kardiovaskulären mittel sowie verfahren zur verwendung davon
RU2538691C2 (ru) 2009-04-29 2015-01-10 Амарин Фарма, Инк. Стабильные фармацевтические композиции и способы их применения
LT3318255T (lt) 2009-06-15 2021-05-25 Amarin Pharmaceuticals Ireland Limited Kompozicijos ir būdai, skirti insulto gydymui pacientui kartu su statinų terapija
US20110038910A1 (en) 2009-08-11 2011-02-17 Atrium Medical Corporation Anti-infective antimicrobial-containing biomaterials
USRE46608E1 (en) 2009-09-01 2017-11-14 Catabasis Pharmaceuticals, Inc. Fatty acid niacin conjugates and their uses
MY158504A (en) 2009-09-01 2016-10-14 Catabasis Pharmaceuticals Inc Fatty acid niacin conjugates and their uses
CA2775339C (en) 2009-09-23 2017-03-28 Amarin Corporation Plc Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
WO2011044138A1 (en) 2009-10-05 2011-04-14 Catabasis Pharmaceuticals, Inc. Lipoic acid acylated salicylate derivatives and their uses
WO2011048493A1 (en) 2009-10-23 2011-04-28 Pronova Biopharma Norge As Coated capsules and tablets of a fatty acid oil mixture
US20110212958A1 (en) * 2010-02-26 2011-09-01 Catabasis Pharmaceuticals, Inc. Fatty acid raloxifene derivatives and their uses
EP3583849A1 (de) * 2010-03-04 2019-12-25 Amarin Pharmaceuticals Ireland Limited Zusammensetzungen und verfahren zur behandlung und/oder prävention von herz-kreislauf-erkrankungen
US9216224B2 (en) 2010-03-05 2015-12-22 Catabasis Pharmaceuticals, Inc. Fatty acid COX inhibitor derivatives and their uses
JP2013526865A (ja) 2010-05-13 2013-06-27 ニトロメガ コーポレーション ニトロ脂肪酸、神経保護および／または認識減退の抑制
WO2012009707A2 (en) 2010-07-16 2012-01-19 Atrium Medical Corporation Composition and methods for altering the rate of hydrolysis of cured oil-based materials
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
NZ744990A (en) 2010-11-29 2019-10-25 Amarin Pharmaceuticals Ie Ltd Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US8951514B2 (en) 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Statin and omega 3 fatty acids for reduction of apolipoprotein-B levels
US8715648B2 (en) 2011-02-16 2014-05-06 Pivotal Therapeutics Inc. Method for treating obesity with anti-obesity formulations and omega 3 fatty acids for the reduction of body weight in cardiovascular disease patients (CVD) and diabetics
US8952000B2 (en) 2011-02-16 2015-02-10 Pivotal Therapeutics Inc. Cholesterol absorption inhibitor and omega 3 fatty acids for the reduction of cholesterol and for the prevention or reduction of cardiovascular, cardiac and vascular events
US9119826B2 (en) 2011-02-16 2015-09-01 Pivotal Therapeutics, Inc. Omega 3 fatty acid for use as a prescription medical food and omega 3 fatty acid diagniostic assay for the dietary management of cardiovascular patients with cardiovascular disease (CVD) who are deficient in blood EPA and DHA levels
WO2012142170A2 (en) 2011-04-13 2012-10-18 Elc Management Llc Conditioning agents for personal care compositions
US9242930B2 (en) 2011-04-13 2016-01-26 Elc Management Llc Mild anionic surfactants suitable for personal care compositions
US8809560B2 (en) 2011-05-17 2014-08-19 Board Of Trustees Of The University Of Arkansas Trans-, trans-conjugated linoleic acid compositions and use thereof
EP2775837A4 (de) 2011-11-07 2015-10-28 Amarin Pharmaceuticals Ie Ltd Verfahren zur behandlung von hypertriglyceridämie
US11291643B2 (en) 2011-11-07 2022-04-05 Amarin Pharmaceuticals Ireland Limited Methods of treating hypertriglyceridemia
RU2014123063A (ru) 2011-11-09 2015-12-20 Эвоник Мембрейн Экстрекшн Текнолоджи Лтд. Мембранный способ снижения по меньшей мере одной примеси и получения концентрата, содержащего по меньшей мере один природный компонент из смеси масел неморских жирных кислот, и получаемые композиции
WO2013072767A1 (en) 2011-11-18 2013-05-23 Pronova Biopharma Norge As Compositions and preconcentrates comprising at least one salicylate and omega-3 fatty acid oil mixture
LT2782584T (lt) 2011-11-23 2021-09-10 Therapeuticsmd, Inc. Natūralios kombinuotos pakaitinės hormonų terapijos kompozicijos ir gydymas
US9301920B2 (en) 2012-06-18 2016-04-05 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
WO2013093630A2 (en) 2011-12-22 2013-06-27 Pronova Biopharma Norge As Gelatin/alginate delayed release capsules comprising omega-3 fatty acids, and methods and uses thereof
EP2800469B1 (de) 2012-01-06 2021-08-25 Amarin Pharmaceuticals Ireland Limited Zusammensetzungen und verfahren zur senkung der konzentration an hochsensitivem c-reaktiven protein (hs-crp) bei einer person
EP2822403B1 (de) 2012-03-07 2022-05-04 Children's Medical Center Corporation Verfahren und verwendungen zur verstärkung, verbesserung oder steigerung einer fertilität oder reproduktionsfunktion
WO2013150386A2 (en) 2012-04-04 2013-10-10 Pronova Biopharma Norge As Compositions comprising omega-3 fatty acids and vitamin d for acne vulgaris and/or eczema, and methods and uses thereof
US9585896B2 (en) 2012-04-04 2017-03-07 Pronova Biopharma Norge As Compositions comprising omega-3 fatty acids and vitamin D for psoriasis, and methods and uses thereof
AU2013257710B2 (en) * 2012-05-08 2016-10-20 Cellixbio Private Limited Compositions and methods for the treatment of neurological disorders
US9867880B2 (en) 2012-06-13 2018-01-16 Atrium Medical Corporation Cured oil-hydrogel biomaterial compositions for controlled drug delivery
EP2861227A4 (de) 2012-06-17 2016-01-27 Matinas Biopharma Inc Omega-3 pentaensäurezusammensetzungen und verfahren zur verwendung
US10806697B2 (en) 2012-12-21 2020-10-20 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US20130338122A1 (en) 2012-06-18 2013-12-19 Therapeuticsmd, Inc. Transdermal hormone replacement therapies
US20150196640A1 (en) 2012-06-18 2015-07-16 Therapeuticsmd, Inc. Progesterone formulations having a desirable pk profile
US10806740B2 (en) 2012-06-18 2020-10-20 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
EP4342546A3 (de) 2012-06-29 2024-05-22 Amarin Pharmaceuticals Ireland Limited Verfahren zur verringerung des risikos von herz-kreislauf-ereignissen bei einem patienten in einer statintherapie
JP2015527309A (ja) * 2012-07-03 2015-09-17 セリックスビオ プライヴェート リミテッド 中等度から重度の疼痛の治療のための組成物及び方法
JP2014050781A (ja) * 2012-09-06 2014-03-20 Shiko Actec Kk 油煙含有排気用脱臭フィルタ
US20150265566A1 (en) 2012-11-06 2015-09-24 Amarin Pharmaceuticals Ireland Limited Compositions and Methods for Lowering Triglycerides without Raising LDL-C Levels in a Subject on Concomitant Statin Therapy
US9062276B2 (en) 2012-12-03 2015-06-23 Board Of Trustees Of The University Of Arkansas Conjugated linoleic acid rich vegetable oil production from linoleic rich oils by heterogeneous catalysis
US10471072B2 (en) 2012-12-21 2019-11-12 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9180091B2 (en) 2012-12-21 2015-11-10 Therapeuticsmd, Inc. Soluble estradiol capsule for vaginal insertion
US10568891B2 (en) 2012-12-21 2020-02-25 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US10537581B2 (en) 2012-12-21 2020-01-21 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11246875B2 (en) 2012-12-21 2022-02-15 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US11266661B2 (en) 2012-12-21 2022-03-08 Therapeuticsmd, Inc. Vaginal inserted estradiol pharmaceutical compositions and methods
US9814733B2 (en) 2012-12-31 2017-11-14 A,arin Pharmaceuticals Ireland Limited Compositions comprising EPA and obeticholic acid and methods of use thereof
US20140187633A1 (en) 2012-12-31 2014-07-03 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
US9452151B2 (en) 2013-02-06 2016-09-27 Amarin Pharmaceuticals Ireland Limited Methods of reducing apolipoprotein C-III
US9624492B2 (en) 2013-02-13 2017-04-18 Amarin Pharmaceuticals Ireland Limited Compositions comprising eicosapentaenoic acid and mipomersen and methods of use thereof
US9662307B2 (en) 2013-02-19 2017-05-30 The Regents Of The University Of Colorado Compositions comprising eicosapentaenoic acid and a hydroxyl compound and methods of use thereof
US9283201B2 (en) 2013-03-14 2016-03-15 Amarin Pharmaceuticals Ireland Limited Compositions and methods for treating or preventing obesity in a subject in need thereof
US20140271841A1 (en) 2013-03-15 2014-09-18 Amarin Pharmaceuticals Ireland Limited Pharmaceutical composition comprising eicosapentaenoic acid and derivatives thereof and a statin
US20150182546A1 (en) * 2013-03-15 2015-07-02 Mitochondrial Concepts Llc Therapeutic agent for enhancing mitochondrial function
US10966968B2 (en) 2013-06-06 2021-04-06 Amarin Pharmaceuticals Ireland Limited Co-administration of rosiglitazone and eicosapentaenoic acid or a derivative thereof
WO2015011724A2 (en) 2013-07-22 2015-01-29 Kms Health Center Pvt Ltd A novel omega -3 fatty acid composition with a plant extract
CN103417507B (zh) * 2013-08-23 2015-12-02 王显著 布地奈德药物组合物
US20150065572A1 (en) 2013-09-04 2015-03-05 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing prostate cancer
US9585859B2 (en) 2013-10-10 2017-03-07 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides without raising LDL-C levels in a subject on concomitant statin therapy
CA2927675A1 (en) * 2013-10-18 2015-04-23 Blanchette Rockefeller Neurosciences Institute Halogenated esters of cyclopropanated unsaturated fatty acids for use in the treatment of neurodegenerative diseases
EP3065731B1 (de) 2013-11-05 2018-10-24 Hill's Pet Nutrition, Inc. Methoden und zubereitungen zur verbesserung der nierenfunktion
AU2015264003A1 (en) 2014-05-22 2016-11-17 Therapeuticsmd, Inc. Natural combination hormone replacement formulations and therapies
US10561631B2 (en) 2014-06-11 2020-02-18 Amarin Pharmaceuticals Ireland Limited Methods of reducing RLP-C
WO2015195662A1 (en) 2014-06-16 2015-12-23 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense ldl or membrane polyunsaturated fatty acids
US10208014B2 (en) * 2014-11-05 2019-02-19 Cellix Bio Private Limited Compositions and methods for the treatment of neurological disorders
US10328087B2 (en) 2015-07-23 2019-06-25 Therapeuticsmd, Inc. Formulations for solubilizing hormones
US10669504B2 (en) 2015-07-28 2020-06-02 The Lubrizol Corporation Seal swell agents for lubrication compositions
US9968531B2 (en) 2015-08-05 2018-05-15 Dupont Tate & Lyle Bio Products Company, Llc Deodorants containing 1,3-propanediol
KR101835860B1 (ko) 2015-10-30 2018-03-09 순천향대학교 산학협력단 난소암 또는 경계성 난소종양의 예방 또는 치료용 조성물 및 진단용 마커 조성물
US10406130B2 (en) 2016-03-15 2019-09-10 Amarin Pharmaceuticals Ireland Limited Methods of reducing or preventing oxidation of small dense LDL or membrane polyunsaturated fatty acids
WO2017173071A1 (en) 2016-04-01 2017-10-05 Therapeuticsmd, Inc. Steroid hormone pharmaceutical composition
US10286077B2 (en) 2016-04-01 2019-05-14 Therapeuticsmd, Inc. Steroid hormone compositions in medium chain oils
KR20190020774A (ko) * 2016-06-20 2019-03-04 더 스크립스 리서치 인스티튜트 항말라리아 조성물 및 이의 용도
FR3053252B1 (fr) * 2016-06-29 2020-04-24 Laboratoires Carilene Produit, ou agent actif, ou composition pour le soin des seins en periode pre-mensuelle ou menstruelle ou pour le soin de la symptomatologie des mastodynies
TW201900160A (zh) 2017-05-19 2019-01-01 愛爾蘭商艾瑪琳製藥愛爾蘭有限公司 用於降低腎功能下降之個體中的三酸甘油酯之組合物及方法
US10052300B1 (en) * 2017-10-19 2018-08-21 David G. Changaris Methods and composition for suppression of deep seated fungal growth on skin
US11058661B2 (en) 2018-03-02 2021-07-13 Amarin Pharmaceuticals Ireland Limited Compositions and methods for lowering triglycerides in a subject on concomitant statin therapy and having hsCRP levels of at least about 2 mg/L
KR102076314B1 (ko) * 2018-07-16 2020-02-11 (주) 에프엔지리서치 녹용에서 분리한 신규 화합물 및 이의 약학적 용도
FI4056176T3 (fi) 2018-09-24 2024-05-30 Amarin Pharmaceuticals Ie Ltd Menetelmät kardiovaskulaaristen tapahtumien riskin pienentämiseksi tutkittavassa
US11633405B2 (en) 2020-02-07 2023-04-25 Therapeuticsmd, Inc. Steroid hormone pharmaceutical formulations
AU2022263358A1 (en) 2021-04-21 2023-11-30 Amarin Pharmaceuticals Ireland Limited Methods of reducing the risk of heart failure
EP4306101A1 (de) 2022-07-14 2024-01-17 Gat Therapeutics S.L. Zusammensetzungen mit amarouciaxanthin-a-estern und verwendungen davon

Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2924528A (en) * 1955-08-22 1960-02-09 Drew & Co Inc E F Synthetic hard butter
US2993063A (en) * 1956-12-17 1961-07-18 Colgate Palmolive Co Cocoa butter substitute and process of making same
GB888162A (en) * 1957-10-10 1962-01-24 Montedison Spa Preparation of ª--ª-, ª--ª+-unsaturated carboxylic derivatives
FR1782M (fr) * 1966-12-21 1963-04-22 Rech S Pharmacotechniques Soc Le nicotinate de cétyle comme antalgique et révulsif et les compositions pharmaceutiques pour son administration, notamment par voie percutanée.
US3291816A (en) * 1963-10-02 1966-12-13 Leo A Goldblatt Dehydration of lesquerolates
GB1135647A (en) * 1965-06-29 1968-12-04 Grace W R & Co New esters
GB1293277A (en) * 1969-03-12 1972-10-18 Ruhrchemie Ag Mixed esters of 2,2-dimethylpropane-1,3-diol and lubricant compositions
GB1493098A (en) * 1975-07-31 1977-11-23 Mitsubishi Chem Ind Production of alkylene glycol esters
GB1529762A (en) * 1975-02-12 1978-10-25 Procter & Gamble Process for synthesizing specific complete polyol mixed esters
GB1556197A (en) * 1975-07-07 1979-11-21 Ciba Geigy Ag Bromoalkyl bromoalkanoates their manufacture and use as flameproofing agents
US4268426A (en) * 1979-05-07 1981-05-19 Textron, Inc. Water-dispersible urethane polymers, aqueous polymer dispersions and half-esters useful therein
JPS5767511A (en) * 1980-10-15 1982-04-24 Lion Corp Agent for imparting iridescent luster to cosmetic
EP0018342B1 (de) * 1979-03-06 1983-02-16 Sanofi S.A. Neue Glyzerinverbindungen, ihre Herstellung und diese Verbindungen enthaltende Arzneimittel
EP0087864A2 (de) * 1982-03-01 1983-09-07 Efamol Limited Pharmazeutische Zusammensetzung
EP0139480A2 (de) * 1983-09-29 1985-05-02 Efamol Holdings Plc Topische Zubereitungen mit Gehalt an Teer und Fettsäuren
EP0139780A1 (de) * 1983-10-28 1985-05-08 Alfred Bolz Vorrichtung zum Transport von Körpern mittels einer in einer Rohrleitung strömenden Flüssigkeit
EP0161114A2 (de) * 1984-05-11 1985-11-13 Unilever N.V. Verbindungen und Zusammensetzungen mit Beeinflussung des Wachstums und der Ausbeute von Pflanzen
EP0173478A1 (de) * 1984-08-15 1986-03-05 Scotia Holdings Plc Behandlung von Hautkrankheiten
EP0184058A2 (de) * 1984-12-01 1986-06-11 Bayer Ag Verfahren zur Herstellung von neuen Indolderivaten und deren Verwendung
JPS61129190A (ja) * 1984-11-27 1986-06-17 Nippon Oil & Fats Co Ltd 重合性グリセロリン脂質
EP0057797B1 (de) * 1981-02-03 1986-06-25 Imperial Chemical Industries Plc Verfahren zur Extrahierung von Metallwerten und Metallextrahierungsmittel
EP0056189B1 (de) * 1980-12-26 1986-08-20 Ss Pharmaceutical Co., Ltd. 2,3-Butandioldiesterderivate, Verfahren zu ihrer Herstellung und sie enthaltendes Mittel gegen Geschwüre
EP0222155A1 (de) * 1985-10-11 1987-05-20 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION 5-Fluoruracilderivate
US4668664A (en) * 1985-05-14 1987-05-26 L'oreal Bi- or tri-enic fatty esters of erythromycin A; pharmaceutical and cosmetic compositions containing them
GB2161477B (en) * 1984-03-30 1987-09-16 Unilever Plc Aliphatic esters of diols and compositions containing them
EP0246540A2 (de) * 1986-05-20 1987-11-25 Paul Y. Wang Implantate zur Abgabe biologisch aktiver Makromoleküle
EP0161422B1 (de) * 1984-03-21 1989-03-01 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Alkanolamin-Derivate und diese als aktive Bestandteile enthaltende Blutplättchen-Aggregationshemmer
EP0319126A2 (de) * 1987-10-14 1989-06-07 Kao Corporation Verfahren zur Herstellung eines Polyol-Fettsäureesters und dadurch erhaltene Glyceridmischung
EP0321128A1 (de) * 1987-12-14 1989-06-21 Efamol Holdings Plc Fettsäure-Zusammensetzungen
US4851426A (en) * 1982-12-09 1989-07-25 Teva Pharmaceutical Industries, Ltd. Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
JPH02129119A (ja) * 1988-11-07 1990-05-17 Nippon Oil & Fats Co Ltd リポソーム製剤
EP0393920A2 (de) * 1989-04-17 1990-10-24 Efamol Holdings Plc Antivirale Nukleosid-Derivate
EP0405873A1 (de) * 1989-06-27 1991-01-02 Nabisco, Inc. Langkettige Dioldiester als Fettersatz mit niedrigem Kaloriengehalt
EP0405874A1 (de) * 1989-06-27 1991-01-02 Nabisco, Inc. Diol-Lipid-Analoge als essbarer Fettersatz
WO1991009831A1 (en) * 1989-12-26 1991-07-11 Nova Pharmaceutical Corporation Prodrug anhydrides of asprin, indomethacin and ibuprofen, their preparation, compositions, and anti-inflammatory method of use
JPH0499784A (ja) * 1990-08-17 1992-03-31 Miyoshi Oil & Fat Co Ltd ホスファチジルコリンの製造法
JPH0551355A (ja) * 1991-11-21 1993-03-02 Sekimoto Hiroshi ポリエン酸誘導体
EP0574312A1 (de) * 1992-06-10 1993-12-15 Adir Et Compagnie Diacylglycerol-Nicotinate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen
US5321145A (en) * 1990-10-31 1994-06-14 A. Nattermann & Cie. Gmbh Process of producing phosphatidylcholine derivatives
EP0611569A2 (de) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglyzeride
WO1994026262A1 (en) * 1993-05-13 1994-11-24 Public Health Research Institute Inhibition of expression of beta-lactamase using esters of fatty acid alcohols
WO1995004030A1 (en) * 1993-08-02 1995-02-09 Commonwealth Scientific And Industrial Research Organisation Therapeutic compound - fatty acid conjugates
EP0675103A2 (de) * 1994-03-01 1995-10-04 Scotia Holdings Plc Derivaten von essentiellen Fettsäuren und nicht-steroidischen entzündungshemmenden Mitteln
WO1996033155A1 (en) * 1995-04-20 1996-10-24 Scotia Holdings Plc Fatty acid derivatives

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3686238A (en) * 1970-01-19 1972-08-22 Syntex Corp Glycerol esterified with 2-naphthyl-acetic acids and fatty acids
GR82658B (de) * 1983-08-01 1985-02-07 Mclean Hospital Corp
EP0351897A3 (de) * 1988-06-17 1990-03-21 The Procter & Gamble Company Hautpenetrierendes System für aminfunktionelle Anrzneistoffsalze
JPH06253997A (ja) * 1992-09-18 1994-09-13 Fumio Tsukasaki 止水弁付きハンドシャワー装置
DK0823897T3 (da) * 1995-05-01 2004-12-06 Scarista Ltd Nicotinsyreestere og farmaceutiske præparater indeholdende disse

Patent Citations (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2924528A (en) * 1955-08-22 1960-02-09 Drew & Co Inc E F Synthetic hard butter
US2993063A (en) * 1956-12-17 1961-07-18 Colgate Palmolive Co Cocoa butter substitute and process of making same
GB888162A (en) * 1957-10-10 1962-01-24 Montedison Spa Preparation of ª--ª-, ª--ª+-unsaturated carboxylic derivatives
US3291816A (en) * 1963-10-02 1966-12-13 Leo A Goldblatt Dehydration of lesquerolates
GB1135647A (en) * 1965-06-29 1968-12-04 Grace W R & Co New esters
FR1782M (fr) * 1966-12-21 1963-04-22 Rech S Pharmacotechniques Soc Le nicotinate de cétyle comme antalgique et révulsif et les compositions pharmaceutiques pour son administration, notamment par voie percutanée.
GB1293277A (en) * 1969-03-12 1972-10-18 Ruhrchemie Ag Mixed esters of 2,2-dimethylpropane-1,3-diol and lubricant compositions
GB1529762A (en) * 1975-02-12 1978-10-25 Procter & Gamble Process for synthesizing specific complete polyol mixed esters
GB1556197A (en) * 1975-07-07 1979-11-21 Ciba Geigy Ag Bromoalkyl bromoalkanoates their manufacture and use as flameproofing agents
GB1493098A (en) * 1975-07-31 1977-11-23 Mitsubishi Chem Ind Production of alkylene glycol esters
EP0018342B1 (de) * 1979-03-06 1983-02-16 Sanofi S.A. Neue Glyzerinverbindungen, ihre Herstellung und diese Verbindungen enthaltende Arzneimittel
US4268426A (en) * 1979-05-07 1981-05-19 Textron, Inc. Water-dispersible urethane polymers, aqueous polymer dispersions and half-esters useful therein
JPS5767511A (en) * 1980-10-15 1982-04-24 Lion Corp Agent for imparting iridescent luster to cosmetic
EP0056189B1 (de) * 1980-12-26 1986-08-20 Ss Pharmaceutical Co., Ltd. 2,3-Butandioldiesterderivate, Verfahren zu ihrer Herstellung und sie enthaltendes Mittel gegen Geschwüre
EP0057797B1 (de) * 1981-02-03 1986-06-25 Imperial Chemical Industries Plc Verfahren zur Extrahierung von Metallwerten und Metallextrahierungsmittel
EP0087864A2 (de) * 1982-03-01 1983-09-07 Efamol Limited Pharmazeutische Zusammensetzung
US4851426A (en) * 1982-12-09 1989-07-25 Teva Pharmaceutical Industries, Ltd. Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
EP0139480A2 (de) * 1983-09-29 1985-05-02 Efamol Holdings Plc Topische Zubereitungen mit Gehalt an Teer und Fettsäuren
EP0139780A1 (de) * 1983-10-28 1985-05-08 Alfred Bolz Vorrichtung zum Transport von Körpern mittels einer in einer Rohrleitung strömenden Flüssigkeit
EP0161422B1 (de) * 1984-03-21 1989-03-01 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION Alkanolamin-Derivate und diese als aktive Bestandteile enthaltende Blutplättchen-Aggregationshemmer
GB2161477B (en) * 1984-03-30 1987-09-16 Unilever Plc Aliphatic esters of diols and compositions containing them
EP0161114A2 (de) * 1984-05-11 1985-11-13 Unilever N.V. Verbindungen und Zusammensetzungen mit Beeinflussung des Wachstums und der Ausbeute von Pflanzen
EP0173478A1 (de) * 1984-08-15 1986-03-05 Scotia Holdings Plc Behandlung von Hautkrankheiten
JPS61129190A (ja) * 1984-11-27 1986-06-17 Nippon Oil & Fats Co Ltd 重合性グリセロリン脂質
EP0184058A2 (de) * 1984-12-01 1986-06-11 Bayer Ag Verfahren zur Herstellung von neuen Indolderivaten und deren Verwendung
US4668664A (en) * 1985-05-14 1987-05-26 L'oreal Bi- or tri-enic fatty esters of erythromycin A; pharmaceutical and cosmetic compositions containing them
EP0222155A1 (de) * 1985-10-11 1987-05-20 TERUMO KABUSHIKI KAISHA trading as TERUMO CORPORATION 5-Fluoruracilderivate
EP0246540A2 (de) * 1986-05-20 1987-11-25 Paul Y. Wang Implantate zur Abgabe biologisch aktiver Makromoleküle
EP0319126A2 (de) * 1987-10-14 1989-06-07 Kao Corporation Verfahren zur Herstellung eines Polyol-Fettsäureesters und dadurch erhaltene Glyceridmischung
EP0321128A1 (de) * 1987-12-14 1989-06-21 Efamol Holdings Plc Fettsäure-Zusammensetzungen
JPH02129119A (ja) * 1988-11-07 1990-05-17 Nippon Oil & Fats Co Ltd リポソーム製剤
EP0393920A2 (de) * 1989-04-17 1990-10-24 Efamol Holdings Plc Antivirale Nukleosid-Derivate
US5286512A (en) * 1989-06-27 1994-02-15 Nabisco, Inc. Diol lipid analogues as edible fat replacements
EP0405873A1 (de) * 1989-06-27 1991-01-02 Nabisco, Inc. Langkettige Dioldiester als Fettersatz mit niedrigem Kaloriengehalt
EP0405874A1 (de) * 1989-06-27 1991-01-02 Nabisco, Inc. Diol-Lipid-Analoge als essbarer Fettersatz
WO1991009831A1 (en) * 1989-12-26 1991-07-11 Nova Pharmaceutical Corporation Prodrug anhydrides of asprin, indomethacin and ibuprofen, their preparation, compositions, and anti-inflammatory method of use
JPH0499784A (ja) * 1990-08-17 1992-03-31 Miyoshi Oil & Fat Co Ltd ホスファチジルコリンの製造法
US5321145A (en) * 1990-10-31 1994-06-14 A. Nattermann & Cie. Gmbh Process of producing phosphatidylcholine derivatives
JPH0551355A (ja) * 1991-11-21 1993-03-02 Sekimoto Hiroshi ポリエン酸誘導体
EP0574312A1 (de) * 1992-06-10 1993-12-15 Adir Et Compagnie Diacylglycerol-Nicotinate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Zubereitungen
EP0611569A2 (de) * 1993-01-27 1994-08-24 Scotia Holdings Plc Triglyzeride
WO1994026262A1 (en) * 1993-05-13 1994-11-24 Public Health Research Institute Inhibition of expression of beta-lactamase using esters of fatty acid alcohols
WO1995004030A1 (en) * 1993-08-02 1995-02-09 Commonwealth Scientific And Industrial Research Organisation Therapeutic compound - fatty acid conjugates
EP0675103A2 (de) * 1994-03-01 1995-10-04 Scotia Holdings Plc Derivaten von essentiellen Fettsäuren und nicht-steroidischen entzündungshemmenden Mitteln
WO1996033155A1 (en) * 1995-04-20 1996-10-24 Scotia Holdings Plc Fatty acid derivatives

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
Bertelsen, O. et al., "Structural Elucidation of Alkyl-Branched Chain Aliphatic Alcohols and Fatty Acids by Mass Spectrometry of their Respective Alkyl Nicotinate and Picolinylcarboxylate Derivatives," Chemical Abstracts, 104:108841 (1986). *
Breusch et al., Chemische Berichte, vol. 88, pp. 1511-1519, 1955. *
Christie, W.W., et al., "Mass Spectra of the Picolinyl Ester Derivatives of Some Isomeric Dimethylene-Interrupted Octadecadiynoic Acids," Chemical Abstracts, 109:210389(1988). *
Christie, W.W., et al., "Mass Spectra of the Picolinyl Esters of Isomeric Mono-and Dienoic Fatty Acids," Chemical Abstracts 107:55235 (1987). *
Deterding, L. et al., "Fast-Atom-Bombardment and Tandem Mass Spectrometry for Determining Structures of Fatty Acids and Their Picolyl Ester Derivatives," Chemical Abstracts, VI. 110:38801 (1989). *
Deterding, L., et al., "Tandem Mass Spectrometry for Identifying Fatty Acid Derivatives that Undergo Charge-Remote Fragmentations," Chemical Abstracts 110:56917 (1989). *
Harvey, D.J., "Pyridine-Containing Derivatives for the Structural Elucidationof the Alkyl Chains of Lipids by Mass Spectrometry and a Comparison with the Spectra of Related Heterocyclic Derivatives," Chemical Abstracts, 114:206360 (1991). *
Harvey, D.J., Picolinyl Derivatives for the structural Determination of Fatty Acids by Chemical Abstracts 101:166564 (1984). *
Hounsom et al., Oxidative Stress and Disease (2000), 4(Antioxidants in Diabetes Management), 155-172. *
Jie, et al., "Mass Spectra of Picolinyl Ester Derivatives of Some Conjugated Diacetylenic Fatty Acids," Chemical Abstracts, 118:191384 (1993). *
Kimura, K. et al., Higher Unsaturated Fatty Alcohol Esters Having Antiucler Activity, Chemical Abstracts, vol. 87, 1997 Abstract No. 53462e. *
Koori, S., "Unsaturated Higher Akuogatuc Esters of Nicotinic Acid," Chemical Abstracts, vol. 77, Abstract No. 164488f (1972). *
Kumokawa, Y. et al. gamma-Linolenic Acid Derivatives As Platelet Aggregation Inhibitors, Chemical Abstracts, vol. 105, 1986, Abstract No. 78532f. *
Kumokawa, Y. et al. γ-Linolenic Acid Derivatives As Platelet Aggregation Inhibitors, Chemical Abstracts, vol. 105, 1986, Abstract No. 78532f. *
Langen et al., Chemical Abstracts, vol. 92, No. 1, #461a, 1980. *
Lion Corp., Patent Abstracts of Japan, vol. 6, No. 143(C-117), 1982. *
Spitzer, V. et al., "Curupira Tefeensis II: Occurrence of Acetylenic Fatty Acids," Fat Sci. Technol., No. 5, (1991) pp. 169-174. *
Terumo Corp., "Trienoic Fatty Acid Pyridylmethyl Esters," Chemical Abstracts, vol. 101, 1984 Abstract No. 171104v. *
Vajdi et al., Chemical Abstracts, vol. 95, No. 5, #41676e, 1981. *
Watanabe et al, Chemical Abstracts, vol. 107, No. 3, #23659p, 1987. *

Also Published As

Publication number Publication date
BG63892B1 (bg) 2003-05-30
TR199701277T1 (xx) 1998-02-21
AU5507996A (en) 1996-11-21
EP0823889B1 (de) 2002-09-18
EP0823895A1 (de) 1998-02-18
ES2185772T3 (es) 2003-05-01
NO975035L (no) 1997-12-22
BR9606607A (pt) 1998-12-15
CA2218699C (en) 2009-09-15
CA2218702C (en) 2008-07-29
WO1996034855A1 (en) 1996-11-07
EE04462B1 (et) 2005-04-15
EP0823889A1 (de) 1998-02-18
JPH11504914A (ja) 1999-05-11
CZ341497A3 (cs) 1998-08-12
NZ306509A (en) 1999-06-29
SK146997A3 (en) 1998-10-07
USRE43632E1 (en) 2012-09-04
PL323176A1 (en) 1998-03-16
DK0823889T3 (da) 2003-01-27
DE69633008D1 (de) 2004-09-02
JP4213205B2 (ja) 2009-01-21
NO975035D0 (no) 1997-10-31
AU707600B2 (en) 1999-07-15
DK0823895T3 (da) 2004-12-06
BG102012A (en) 1998-05-29
HUP9802384A3 (en) 1999-06-28
CA2218702A1 (en) 1996-11-07
KR19990008243A (ko) 1999-01-25
NZ306508A (en) 2001-01-26
JP2007231020A (ja) 2007-09-13
RU2215733C2 (ru) 2003-11-10
ATE224353T1 (de) 2002-10-15
AR004483A1 (es) 1998-12-16
EP0823895B1 (de) 2004-07-28
IL118061A0 (en) 1996-08-04
HK1003882A1 (en) 1998-11-13
US6245811B1 (en) 2001-06-12
IS4603A (is) 1997-10-30
NO975036L (no) 1997-12-17
IS4604A (is) 1997-10-30
ATE272053T1 (de) 2004-08-15
BG102011A (en) 1998-05-29
DE69623764D1 (de) 2002-10-24
DE69633008T2 (de) 2005-08-11
PT823889E (pt) 2003-02-28
HUP9802308A3 (en) 1999-12-28
EE9700281A (et) 1998-04-15
ES2224166T3 (es) 2005-03-01
MY117596A (en) 2004-07-31
SI0823895T1 (en) 2005-02-28
PT823895E (pt) 2004-11-30
JPH11504339A (ja) 1999-04-20
PL187172B1 (pl) 2004-05-31
TR199701276T1 (xx) 1998-02-21
DE69623764T2 (de) 2003-05-28
AU5508096A (en) 1996-11-21
JP3960481B2 (ja) 2007-08-15
SI0823889T1 (en) 2003-04-30
KR19990008244A (ko) 1999-01-25
BR9606604A (pt) 1997-09-16
CA2218699A1 (en) 1996-11-07
PL323152A1 (en) 1998-03-16
EE9700275A (et) 1998-04-15
MY118354A (en) 2004-10-30
SK147097A3 (en) 1998-06-03
CZ341397A3 (cs) 1998-07-15
WO1996034846A1 (en) 1996-11-07
AU713858B2 (en) 1999-12-09
SK285135B6 (sk) 2006-07-07
NO975036D0 (no) 1997-10-31
IL118061A (en) 2002-05-23
CZ297646B6 (cs) 2007-02-21
HUP9802308A2 (hu) 1999-02-01
US6555700B1 (en) 2003-04-29
HUP9802384A2 (hu) 1999-03-29

Similar Documents

Publication Publication Date Title
USRE40480E1 (en) 1,3-Propane diol esters and ethers and methods for their use in drug delivery
WO1998018751A1 (en) Presentation of bioactives
EP0606012B1 (de) Zusammensetzungen, die Cholesterin Ester von ungesättigten Fettsäure enthalten
US20220016251A1 (en) Lymphatic mediated transport-based triglyceride prodrug, and preparation method therefor
JP5552314B2 (ja) 新規脂質化合物
KR19990007849A (ko) 지방산 유도체
UA61884C2 (en) 1,3-propane diol derivatives as biologically active compounds
USRE40546E1 (en) 1,3-Propane diol esters and ethers and methods for their use in drug delivery
WO1998013330A1 (en) Esters of unsaturated fatty acids
TW546138B (en) Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives
MXPA97008382A (en) Fatty acid esters as bioacti compounds

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

FEPP Fee payment procedure

Free format text: PAT HOLDER CLAIMS SMALL ENTITY STATUS, ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: LTOS); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

REMI Maintenance fee reminder mailed
FPAY Fee payment

Year of fee payment: 8

SULP Surcharge for late payment

Year of fee payment: 7

LAPS Lapse for failure to pay maintenance fees