Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
  • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • 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
  • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/06—Preparations for care of the skin for countering cellulitis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
  • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C323/11—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/12—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
  • A61K2800/92—Oral administration

Definitions

• Lipid compounds for use in cosmetic products , as food supplement or as a medicament Lipid compounds for use in cosmetic products , as food supplement or as a medicament
• the present invention relates to lipid compounds of the general formula
• R 1 is selected from a C10-C 2 1 alkyl, a C 10 -C 21 alkenyl having 1-6 double bonds, and a C 1O -CaI alkynyl having 1-6 triple bonds;
• P 1 is selected from a hydrogen, a C 10 -C 2 1 alkyl, a C 10 -C 2 i alkenyl having 1-6 double bonds, and a C 10 -C 21 alkynyl having 1-6 triple bonds, optionally substituted; or P 1 is represented by:
• P 2 , P 3 and P 4 are selected from a hydrogen, an alkyl, alkenyl, alkynyl, optionally substituted; or
• P 1 is a phosphonate or a phosphate ester, represented by
• Pi is a sulphonate or a sulphate ester, represented by
• P 5 is a hydrogen or a CrC ⁇ alkyl; or a pharmaceutically acceptable salt, complex or solvate thereof.
• the invention also relates to pharmaceutical compositions and lipid compositions comprising such compounds, and to such compounds for use as medicaments or for use in therapy, in particular for the treatment of diseases related to the cardiovascular, metabolic and inflammatory disease area.
• dietary polyunsaturated fatty acids have been shown to regulate plasma lipid levels, cardiovascular and immune functions, insulin action, and neuronal development and visual function.
• Tetradecylthioacetic acid is a modified fatty acid which has a number of powerful effects demonstrable both in vivo and in vitro on living organisms.
• TTA has properties very similar to natural fatty acids, the main difference being that it cannot be oxidised by the mitochondrial ⁇ -oxidation, but significantly increases the oxidation of other fatty acids. Despite the fact that
• TTA is not able to undergo ⁇ -oxidation, it is metabolised in most ways as a normal saturated fatty acid.
• TTA affects antioxidant status at different levels by having the potential of changing the antioxidant defence system in addition to being an antioxidant itself through its free radical scavenging capacity.
• TTA may prevent the oxidative modification of LDL particles in plasma and reduce the generation of lipid peroxides.
• One object of the present invention is to provide lipid compounds having pharmaceutical activity. This object is achieved by a lipid compound of formula
• R 1 is selected from a C1 0 -C 2 1 alky ) , a C1 0 -C 2 1 alkenyl having 1-6 double bonds, and a C1 0 -C21 alkynyl having 1-6 triple bonds;
• R 2 and R 3 are the same or different and are selected from hydrogen and a CrC ⁇ alkyl group; and X is selected from O, S, SO, SO 2 , Si or Se;
• n 1 or 3; and • Pi is selected from a hydrogen, a C10-C21 alkyl, a C 10 -C 2 I alkenyl having
• P 1 is represented by:
• P2, P 3 and P4 are selected from a hydrogen, an alkyl, alkenyl, alkynyl, which optionally may be substituted; or
• Pi is a phosphonate or a phosphate ester, represented by
• Pi is a sulphonate or a sulphate ester, represented by
• P 5 is a hydrogen or a d-C ⁇ alkyl
• Ri is a C10-C21 alkyl, e.g. a Cu alkyl, and said lipid compound is derived from a saturated fatty acid.
• Ri is a C"io-C2 2 -alkenyl with 1-6 double bonds, wherein said lipid compound is either derived from a monounsaturated fatty acid or a polyunsaturated fatty acid.
• Ri When derived from a monounsaturated fatty acid, Ri is typically a Ci 4 -C 18 alkenyl, e.g. with 1-3 double bonds. When derived from a polyunsaturated fatty acid, Ri is typically a C10-C 22 alkenyl with 3-6 double bonds, e.g. 3-6 methylene interrupted double bonds in Z configuration. For example, Ri is:
• R 1 may be a C1 0 -C 22 alkynyl, e.g. a C16-C 2 2 alkynyl, wherein said lipid compound is derived from lipids comprising 1-6 triple bonds.
• the present invention also relates to salts of the compounds according to formula (I).
• Such salts may comprise a monovalent cation such as Li + , Na + , K + , NH4 + , meglumine, tris(hydroxymethyl)aminomethane, diethylamine, arginine; a divalent ion such as Mg 2+ , Ca 2+ , ethylenediamine, piperazine; or a polyvalent cation such as chitosan.
• P2, P3, P4 are typically selected from a hydrogen, a Ci-C 6 alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, n-hexyl, optionally substituted.
• a Ci-C 6 alkyl e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, n-hexyl, optionally substituted.
• one of P 2 , P 3 , P 4 is a hydrogen, a methyl group, or an isopropyl group.
• one of P 2 , P 3 , P 4 is a CrC 6 alkyl, e.g. methyl and the other two are represented by hydrogen.
• Pi in formula (I) is represented by:
• said alkyl, alkenyl or alkynyl is substituted with a carboxy group, typically a C-i-C ⁇ carboxy group.
• a carboxy group typically a C-i-C ⁇ carboxy group.
• Pi according to formula (II) may be represented by :
• salts of the compounds according to formula (I) may be represented by
• Z + is selected from the group consisting of Li + , Na + , K + , NH 4 + ,
• Z 2+ is selected from the group consisting of Mg 2+ , Ca 2+ ,
• Pi may also be represented by:
• P 2 , P 3 , P 4 is typically a hydrogen, a C-i-C ⁇ alkyl, e.g. methyl, ethyl, n- propyl, isopropyl, n-butyl, iso-butyl, sec-butyl or an n-hexyl.
• P 2 , P 3 , P 4 is a hydrogen, a methyl group or an isopropyl group.
• P 5 is typically a hydrogen or a CrC ⁇ alkyl; preferably a hydrogen or a methyl group according to the formulas below
• (V) P 5 is typically a hydrogen or a d-C ⁇ alkyl, preferably a hydrogen or a methyl group according to the formulas below
• n 1
• R 2 and R 3 may be the same or different and may be selected from a hydrogen and a CrC ⁇ alkyl group. Typically, R 2 and R 3 are both hydrogen.
• X may be selected from O, S, SO, SO 2 , Si and Se.
• X is either S, Se or O. Typically it is S.
• the compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all optical isomers of the compounds of formula (I) and mixtures thereof, including racemates. Therefore, the present invention includes compounds of formula (I) that are racemic, either as the (S) or (R) enantiomer.
• the present invention also relates to a lipid compound according of formula (I) for use as a medicament.
• Cosmetic formulations comprising compounds of formula I form a further aspect of the invention.
• the present invention provides a food supplement, a food additive, or a neutraceutical preparation comprising a lipid compound of formula (I).
• a food supplement may be produced for administration through any route of administration.
• the food supplement may be administered as a liquid nutritional or as a beverage.
• the food supplement may be in the form of a capsule, preferably a gelatine capsule, and the capsule may be flavoured.
• the present invention provides a pharmaceutical composition comprising a compound of formula (I), preferably together with one or more pharmaceutically acceptable carriers or excipients.
• novel lipid compounds and compositions of the invention may be formulated in conventional administration forms, e.g. tablets, coated tablets, capsules, powders, granulates, solutions, dispersions, suspensions, syrups, emulsions, sprays, suppositories, pessaries, etc using conventional excipients, e.g.
• compositions may likewise be administered by conventional administration routes, e.g. orally, by injection, infusion, nasally, rectally, etc.
• orally administrable compositions e.g. tablets, coated tablets, capsules, syrups, etc is especially preferred.
• a suitable daily dosage of the compound according to formula (I) is 1 mg to 10 g of said compound; 50 mg to 1 g of said compound, or 50 mg to 200 mg of said compound.
• the pharmaceutical composition according to the invention may be used as a medicament.
• the present invention also relates to lipid composition
• lipid composition comprising a lipid compound according to formula (I).
• lipid compound according to formula (I)
• at least 60% by weight, or at least 80% by weight of the lipid composition is comprised of said compound.
• the lipid composition may further comprise a pharmaceutically acceptable antioxidant, e.g. tocopherol.
• a pharmaceutically acceptable antioxidant e.g. tocopherol.
• the present invention relates to a lipid composition for use as a medicament.
• the present invention relates to the use of a lipid compound according to formula (I) for the production of a medicament for:
• NAFLD nonalcoholic fatty liver disease
• the invention also relates lipid compounds according to formula (I) for the treatment of the above mentioned conditions, and to to methods for the treatment and/or prevention of the conditions listed above, comprising administering to a mammal in need thereof a pharmaceutically active amount of a compound according to formula (I).
• an inflammatory disease or condition e.g. a chronic inflammatory disease like psoriasis • the treatment and/or the prevention of a condition selected from the group consisting of dyslipidemia, hypertension, atherosclerosis, cancer, rheumatoid arthritis, and brain disorders, e.g. MS and Alzheimer's
• the invention also relates lipid compounds according to formula (I) for the treatment of the above mentioned conditions, and to to methods for the treatment and/or prevention of the conditions listed above, comprising administering to a mammal in need thereof a pharmaceutically active amount of a compound according to formula (I).
• the present invention encompasses methods for manufacturing lipid compounds according to formula (I).
• TTA tetradecylthioacetic acid
• lipid compound relates to fatty acid analogues derived from e.g. monounsaturated fatty acids, polyunsaturated fatty acids and lipids comprising 1-6 triple bonds.
• Pro-drugs are entities which may or may not possess pharmacological activity as such, but may be administered (such as orally or parenterally) and thereafter subjected to bioactivation (for example metabolization) in the body to form the agent of the present invention which is pharmacologically active.
• a "pharmaceutically active amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e. an amount of the combination product which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the combination product is within the skill of the art. Generally, the dosage regimen for treating a condition with the combination product of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient.
• a pharmaceutical composition is meant a lipid compound according to the invention in any form suitable to be used for a medical purpose.
• Treatment includes any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatments are within the scope of the present invention. Treatment may be in respect of an existing condition or it may be prophylactic.
• Fatty acids are straight chain hydrocarbons possessing a carboxyl (COOH) group at one end ( ⁇ ) and (usually) a methyl group at the other ( ⁇ ) end. In chemistry, the numbering of the carbon atoms starts from the ⁇ end.
• the ⁇ carbon refers to the first carbon after the carbon that attaches to the functional group, and the second carbon is the ⁇ carbon.
• methylene interrupted double bonds relates to the case when a methylene group is located between to separate double bonds in a carbon chain of a lipid compound.
• the basic idea of the present invention is a lipid compound of formula (I):
• R 1 , R 2 , R 3 , X, n, and P 1 are as defined above.
• the resulting compound is a lipid compound with a heteroatom incorporated in the lipid chain, i.e. a lipid compound with a heteroatom preferably in the ⁇ -position.
• lipid compound categories A-D are particularly preferable.
• R 1 is a Ci O -C 21 alkyl
• R 1 is a C 1O -C 21 alkenyl having 1 double bond
• R 1 is a Cio-C-22 alkenyl having 1-6 double bonds
• the unsaturated alcohols may be prepared directly from the carboxylic esters of the naturally occurring unsaturated fatty acids; alpha-linolenic acid, oleic acid, conjugated linoleic acid, linoleic acid, eicosapentaenoic acid, etc. by reduction with diisobutylaluminiumhydride.
• the alcohols can also be prepared by degradation of the polyunsaturated fatty acids EPA and DHA as described by Holmeide et al. (J.Chem. Soc, Perkin Trans. 1 , 2000, 2271). In this case one can start with purified EPA or DHA, but it is also possible to start with fish oil containing EPA and DHA in mixture.
• the saturated alcohols can be obtained from their corresponding carboxylic acids or carboxylic esters.
• 2-Tetradecylsulfanyl-ethanol (0.54 g, 1.97 mmol) was dissolved in dry THF (10 ml) and pyridine (0.16 ml, 1.97 mmol) was added followed by acetyl chloride (0.15 m, 2.16 mmol). The resulting mixture was allowed to stir at ambient temperature for 23 hours, then another portion of acetyl chloride (0.075 ml, 1.08 mmol) and pyridine (0.080 ml, 0.95 mmol) was added. The mixture was stirred at ambient temperature for a further 90 minutes and then portioned between diethyl ether (30 ml) and 10% NH 4 CI (30 ml).
• Step 1 Ethyl (5£,9Z,12Z,15Z,18Z)-3-thia-heneicosa-pentaenoate:
• Step 2 (5E,9Z,12Z,15Z,18Z)-3-thia-heneicosa-pentaen ⁇ 1- ol
• Triphenylphosphine, PPh 3 (79.11 g, 302 mmol) was dissolved in dry THF (600 ml) at 0
• Step 2 (all Z)-eicosa-5,8,11 ,14,17-pentaene-1-thiol
• Step 3 (all-Z)-2-ethyl-3-thia-tricosa-8,11,14,17,20-pentaenoic acid
• Step 4 (all-Z)-2-ethyl-3-thia-tricosa-8, 11 , 14, 17,20-pentaen-1 -ol

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• 2008
  • 2008-11-06 EP EP08846228.8A patent/EP2217224B1/en active Active
  • 2008-11-06 US US12/741,890 patent/US8741966B2/en active Active
  • 2008-11-06 WO PCT/NO2008/000391 patent/WO2009061208A1/en not_active Ceased
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