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  • 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
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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.

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