TW546138B - Compounds with 1,3-propane diol linked structure and 1,3-propane diol derivatives - Google Patents

Abstract

Compounds of the following 1,3-propane diol linked structure, when for use in therapy: where R1 is an acyl or fatty alcohol group derived from a C12-30 preferably C16-30 fatty acid desirably with two or more cis or trans double bonds, and R2 is hydrogen, or an acyl or fatty alcohol group as R1 the same or different, or any other nutrient, drug or other bioactive residue.

Description

Employees' Cooperative Printing Bag of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 —_________ B7 V. Description of the Invention (1) ~~ —- Scope This description refers to the preparation of biologically active substances, including drugs, essential nutrients or any other given to humans or animals. To treat or maintain healthy compounds. In particular, this note relates to bioactive preparations in lipophilic forms that can easily pass through dyslipidemia in the body, or to preparations with two bioactives in the same molecule (wherein at least one of the bioactives is a fatty acid or Fatty alcohols), or bioactive preparations that can accomplish both of these goals and / or can easily synthesize compounds without palm centers. From the perspective of drug management, it is better to have two biologically active substances in a single molecule than to separate the two biologically active substances. It is also beneficial to supply known bioactives in novel ways. These benefits include an increase in lipophilicity, and the simultaneous supply of two bioactives can produce additive effects, and sometimes these bioactives can produce synergistic effects. The present invention relates to the bonding of biologically active substances through specific bonding molecules, which will be described in detail later, and related to the synthesis of novel compounds. Some compounds are also novel in terms of their use in the treatment and / or maintenance of health. However, this description also discusses and uses other compounds that are not patented here for bonding molecules, and also discusses and directly binds biologically active substances such as the fatty acids and antivirins disclosed in epa_0 393 920, and Ep-95301315 8 ( Published as EpA-0 675 103) fatty acids and non-steroidal anti-inflammatory drugs. References The published concepts and general literature do not pay attention to the above concepts, but some literatures discuss the specific natural diol derivatives and diol esters for nutritional and medical uses. In general literature, BergelSon, etc. (Biochim, this paper size applies Chinese national standard specifications (iioxw7 mm) (Please read the precautions on the back before filling out this page) · «Clothes · Order 546138 Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs Preparation of A7 B7 V. Description of the invention (2) Biophys. Acta (1966) 511-520) has mentioned 1,3-propanediol. It does not mention acid groups, only dioleate. Nabisco in the EPA-0 405 873 and EPA-0 405 874 patent documents describe edible fat mimetics and include linolenates (the term is specifically noted to mean `` α, 'isomers) and arachidene Acid esters, and obviously the 1,4-butanediol esters of these acids. Unilever's UK Patent 2 161 477 (equivalent to EPA-0-0 161 114) describes the effects of the use of 1,3 · propanediol esters of linoleic acid and linolenic acid (also referred to as alpha isomers) on plant growth and economics . EPA-0 056 189 from SS Pharmaceutical Co. describes an anti-ulcer drug for 2,3-butanediol. Sanofi at EPA-0 018 342 showed various pharmaceutical effects of propane-1,3-diol esters. A more different possibility is that Terumo K · K · in EPA-0 222 155 revealed that -CH (R) -0- (where R = methyl, etc.) was bonded to 5-urethane deposited on π-linolenic acid, dijunca Maleic acid or eicosapentaenoic acid acts as an anticancer agent. Ester disorders Many drugs act on the surface of cell membranes by binding to cell surface receptors, or enter cells by specific transport systems. Many drugs work by changing one or more functions within the cell (such as nucleic acid functions), changing the role of enzymes in the cell, or changing the behavior of the lysosome or microtubule system, but they do not enter the cell effectively. These drugs may not have binding receptors and delivery systems, or such delivery systems can only deliver drugs into cells at a slower rate. The same drugs may penetrate the inner membranes of cells, such as the mitochondrial membrane and the nuclear membrane, at a lower rate. There are other obstacles that are also important for drug movement. One of the most important obstacles is the blood-brain disorder, which has many cell membrane characteristics. Many drugs-5- This paper is in accordance with the Chinese National Standard (CNS) A · 4 size (210 × 297 mm) (Please read the precautions on the back before filling out this page) 546138 A7 B7 5. Description of the invention (5 private Other sites, forming new molecules that were not present in the original preparation. This will obviously cause problems, especially in terms of drug management, which is tolerant of this instability. When two different fatty acids are delivered In addition to the foregoing, its advantages are that it can simultaneously administer substances with two different biological effects in a single molecule. This can avoid management problems, which occur when the two compounds are administered separately, And it may happen when the center of the palm is matched. When two drugs are delivered as separate molecules, the regulatory authority generally requires each compound to be studied and the two compounds to be used in combination. If two molecules are synthesized For one molecule, only a single molecule needs to be studied, which can greatly reduce the development cost. In addition to fatty acids, there are similar advantages in the presence of actives. These compounds allow Drugs or other compounds are given in the form of more lipophilic compounds 'these compounds are non-palladium (unless the drug or other compound is anti-peptide)' are also more likely to release active ingredients and are given orally It is also more tolerated when given topically or parenterally. Its lipophilicity allows it to be partially absorbed through the lymphatic system, which bypasses the liver; reduces the gastrointestinal irritation like many compounds; it is also easy to make drugs And other agents are transported through lipophilic disorders, such as skin, cell membranes, and blood-brain disorders. They are all lipophilic disorders. It has been proven that in addition to being easy to pass through lipid disorders, there are other specific properties that make drugs more lipophilic. This Other properties include prolonged action time, reduced side effects (especially gastrointestinal side effects), bypassing the liver's metabolism, and allowing different substances to be delivered to specific locations. -8 This paper size applies Chinese National Standards (CNS) A4 specification (210X297mm) .II-i-I- ------- (Please read the notes on the back before filling out this page] Staff Consumer Cooperatives, Central Bureau of Standards, Ministry of Economic Affairs Print 546138 A7 ---- B7 V. Description of the invention (6) —— 'A fatty acid derivative; the effect of fatty acid The active substance can be transported through the lipid membrane directly or through an intermediate, especially Yes, it is improved on Gamma linolenic acid (GLA) or Dijungamaric linolenic acid (DGLA), while Gamma linolenic acid and dijungalma linolenic acid itself have various desired effects. This bonding can also By co-delivering the biologically active substance with the same fat fe, these fatty acids have the required effect in addition to any transport advantages. Other fatty acids, such as any essential fatty acids (EFAs), especially η · 6, can also be used. And twelve natural fatty acids of the n-3 series (Figure 1). Among these twelve fatty acids, arachidonic acid, adrenal 'stearic acid, icosatepentarate, and twenty-two Hexanoic acid is particularly preferred because it has the desired effect. Also, any fatty acid may be used, preferably CirC30 or CfCso and having two or more cis or trans carbon-carbon double bonds. It can be used in the form of a fatty acid or the corresponding fatty alcohol. Co-linoleic acid and columbinic acid are examples of fatty acids, and these fatty acids, by themselves, have valuable properties and seem to be particularly useful. As such, references to lipoic acid refer to both forms, with the exception that the chemical nature of one or the other form is unknown. However, the properties of GLA and DGLA make them particularly suitable for this purpose. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs! (Please read the notes on the back before filling out this page) Essential fatty acids are all cis configuration in nature, which are called corresponding derivatives of octadecanoic acid, behenic acid or behenic acid in the system. For example, z, z_stearyl 9,12-dienoic acid or z, z, z, z, z, z_twenty-two_4,7,10,13,16,19-hexadecanoic acid, but its The numerical indication is based on the number of carbon atoms, the number of unsaturated centers, and the number of carbon atoms counted from the end of the chain at the beginning of chain unsaturation. For example, it is more convenient to use 18: 2n_6 or 22: 6n_3. Abbreviations of names such as EPA and abbreviations such as -9-This paper size applies to Chinese National Standard (CNS) A4 specifications (210X 297 mm) 546138 A7 B7 V. Description of the invention (Eicosapentaenoic acid is arbitrary in some cases Figure 1 used n-6 EFA's 18: 2n-6 (linoleic acid, LA) 4 18: 3η · 6 (plant linolenic acid, GLA) i 20: 3n-6 (di-m-r-linolenic acid, DGLA) 1 20 : 4n-6 (arachidonic acid, AA) 1 22: 4n-6 (adrenal acid) 22: 5n-6 d -6-desaturase growth β-5-desaturase growth-4-desaturase n -3 EFA-s 18: 3η-3 (α-linolenic acid, ALA) 1 18: 4n-3 (stearyltetraenoic acid, SA) 4 20: 4n-3 20: 5n-6 (20 carbon five associations Acid, EPA) I 22: 5n-3 22: 6n-3 (Docosahexaenoic acid, DHA) (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs GLA and DGLA GLA and DGLA itself have anti-inflammatory effects, lower blood pressure, inhibit platelet coagulation, reduce cholesterol content, inhibit cancer cell growth, reduce movement disorders, relieve chest pain, improve calcium absorption and enhance fixation in bones, reduce ions Side effects of radiation to treat various mental illnesses It can dilate blood vessels, improve renal function, treat diabetic complications, relax blood vessels, etc. Therefore, the bonding of active substances to GLA and DGLA will not only become more lipophilic, but also enhance the passage through various membranes, skin and cardio-brain disorders. It can show new and other therapeutic effects. Therefore, fatty acids can be symbiotic prodrugs (direct bonding-10- This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 546138 A7 B7, invention Note (at time 8)) or a symbiotic three-pronged prodrug (if linked via a bond). Other fatty acids with special valences in this regard are arachidonic acid and docosahexaenoic acid. These acids are cell membranes. The main constituents of adrenaline; stearic tetraenoic acid and eicosapentaic acid also have properties similar to GLA and DGLA. The fatty acids that are not included in Figure 1 but also have a special valence fluorene are cLA And galenic acid (CA). CLA has special properties in the treatment and prevention of cancer, in the promotion of growth, especially in protein synthesis, in the prevention and treatment of cardiovascular disease, and as an antioxidant. Effects. CA also has various properties of essential fatty acids. The types of actives that have a symbiotic effect with bioactive fatty acids can be broadly divided into the types of actives added to the compounds described here:-a) including antibiotics, antiprotozoal drugs, Antipsychotics, antidepressants, and NS AIDs, as well as drugs used to treat cardiovascular disease, respiratory disease, skin disease, mental illness, neuropathy, kidney disease, and muscle disease. Cancer compounds. b) hormones c) amino acids d) vitamins, especially B vitamins, and other essential nutrients. e) cytokines and peptides f) neurotransmitters and neurotransmitter precursors. g) Phospholipid compounds, such as inositol, bile test, serine and ethanolamine. These compounds can be directly bonded or hindered by acid radical bonding. h) Aromatic fatty acids, such as phenylacetic acid, phenylbutyric acid, and cinnamic acid. These acids are of particular value in the treatment of cancer. -11-This paper size applies to Chinese National Standard (CNS) Α4 specification (210 × 297 mm) —--------- 丨 (Please read the precautions on the back before filling this page

1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (9) The combination of the efficacy of therapeutic drugs with fatty acids can be considered from the following examples : A) Drugs that affect mental conditions can be bonded to fatty acids such as GLA, DGLA, arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. These acids have important effects on brain function. , Can produce dual treatment effects. b) Drugs used to treat cardiovascular diseases can be bonded to fatty acids that also have such therapeutic value, such as eicosapentaenoic acid that reduces triglyceride content and inhibits platelet aggregation, which can reduce cholesterol content and have Vasodilatory GLA or DGLA, or arachidonic acid such as an effective cholesterol lowering agent, or DHA with antiarrhythmic properties. c) Drugs used to treat any form of inflammation can be bound to classes such as Gamma Linolenic Acid, Dijungamaric Acid or Eicosapentaenoic Acid or Docosahexaenoic Acid. These fatty acids are resistant to Inflammatory effect. d) Drugs used to treat osteoporosis can be bonded to GLA or DGLA, which enhances calcium deposition in bone, or to EPA or DHA, which reduces calcium excretion from urine. e) Drugs for skin diseases can be bonded to GLA or DGLA with anti-inflammatory effects on the skin. f) Drugs for cancer can be bonded to GLA, DGLA, arachidonic acid, EPA, or DHA, which have anticancer effects and reduce resistance to anticancer drugs. (Please read the precautions on the back before filling this page) -12- This paper size applies to Chinese National Standard (CNS) A4 (2lOX 297 mm) 546138 Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Explanation (10) The concept of using essential fatty acids as an active substance The aforementioned essential fatty acids (EFAs) are well known and are composed of a series of twelve compounds. Although linoleic acid (the parent compound of the n-6 series) and [linolenic acid (the parent compound of the n-3 series) are the main food essential fatty acids, these substances themselves have little effect in the body. To be fully utilized in the body, these parent compounds must be metabolized into longer chain and more unsaturated compounds. In terms of quantity, judging from the content of the cell membrane and other lipids, dijungamalin (DGLA) arachidonic acid (AA) is the main EFA metabolite of the n-6 series, and eicosapentaenoic acid (EPA) And docosahexahexanoic acid (DHA) is the main metabolite of the n-3 series. DGLA, AA, EPA and DHA are important components of most lipids in the body. In addition to being important in its own right, it can also generate a variety of oxidative derivatives, twenty kinds of burners, including prostaglandins, white scutellaria and other compounds. Specially treated fatty acids are DGLA, AA, EPA and DHA, and GLA (DGLA precursor) stearate (SA), EPA and DPA (22: 5n-3) precursors, DHA precursors, and Adrenaline. Some fatty acids, such as oleic acid, octadecatenoic acid, and galanthine, are not essential fatty acids, but they play an important role in the body. The most interesting of these is linoleic acid, which, as mentioned earlier, has several desired effects. It has been thought that in nutrition and disease treatment, supplementing with linoleic acid and ^ -linolenic acid is sufficient, and the body's metabolism will complete the rest of the work. It is now known that this is not true. Different diseases have different forms of abnormal essential fatty acids, and due to metabolic problems, only the supply of linoleic acid or cardiolenic acid cannot be easily corrected. Therefore, in most cases, one extra EFA or two or more EFAs must be given at the same time. As EFA can be in various forms-13-This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X 297 mm) (Please read the precautions on the back before filling this page) Road 4461 A7 B7 V. Description of Invention (12 Substances include (a) (ii) diesters; n = 3. Another patent pending substance is (b) (iv) phosphate esters; n = 3. Η is larger or smaller than this, Or the bond is not ester-bonded. For similar reasons, it may also be valuable. It is only disclosed here, but most of them have not yet been applied for patents. (A) Biological actives with free-state defect groups can be divided into: ⑴ Esters coupled with unsaturated fatty alcohols (UFA) (ii) Esters coupled with unsaturated fatty acid ω-alkylene esters: II-蜷! (Please read the precautions on the back before filling this page)

Production cooperation between employees of the Central Bureau of Standards of the Ministry of Economic Affairs, Du Printing (iii) Esters coupled with unsaturated ethyl esters of unsaturated fatty alcohols

(b) Biologically active compounds with free hydroxyl groups-can also be divided into: (i) Esters coupled with unsaturated fatty acids

— -15- This paper size applies to Chinese National Standards (CNs) A4 specification (210X 297 mm) 546138 A7 _________ B7 V. Description of the invention (13) (ii) Esters coupled with carboxyalkylcarboxylates of unsaturated fatty alcohols

(iii) Esters coupled with carboxyalkyl esters of unsaturated fatty acids 0

(Please read the notes on the back before filling this page) -II ^ 衣. (Iv) ω-based alkyl esters coupled with unsaturated fatty acids

R = H, CH3, or cation counter ion (c) Biological actives with free amine groups-· They can also be divided into: (i) Amidoamine coupled with essential fatty acids

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (ii) Amidine-16 coupled with the ω-carboxyalkylcarboxylate of an essential fatty alcohol-16- (%) Α7 Β7 V. Description of the invention (14

In all the above ranges, the carbon chain of 3 to 3, unsaturated fatty acids or alcohols is represented by the following formula: ^ λ) In all the above ranges, "unsaturated fatty acids" (and derived, unsaturated fatty alcohols "represent Including two or more cis or trans double bonds of oleic acid (and oleic alcohol) and any fatty acid (or corresponding fatty alcohol). But the most expensive fatty acid in this is shown in Figure 1 The essential fatty acids shown, especially GLA, DGLA, AA, SA, EPA and DHA. For specific purposes, conjugated linoleic acid and gallbentamic acid are the best. Synthesis of individual fatty acids can be purified from natural animals and plants Or from mineral sources, can also be synthesized by methods known to those skilled in the art or later developed. Individual fatty alcohols can be prepared by the chemical reduction of the above fatty acids by methods known to those skilled in the art or later developed. -17-! 蜷 丨 丨 (Please read the notes on the back before filling out this page), 1T Consumer Cooperation with Central Standards Bureau of the Ministry of Economic Affairs Du printed paper sizes are applicable to China National Standard (CNS) Α4 specifications (210X ^ 97 (B)) • Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 — -----—- ----— --_. ._____ V. Description of the Invention c) [(ii) and (iii) sub-class] biological actives need one or more ester bonds. Such chemical properties can be accomplished by any reasonable method of ester synthesis, in particular: (a) Alcohol and hydrazone The reaction is based on chloride, acid anhydride or suitable activated ester, with or without organic tertiary test such as pyridine. The reaction is performed in a suitable inert solvent such as dichloromethane at a temperature between 0 ° and 120 ° C. (B) Alcohol and acid, or acid, short or medium chain alkyl ester, in the presence of a suitable acid catalyst, such as 4-toluenesulfonic acid, the reaction may or may not use a suitable inert solvent such as toluene, It is carried out at a temperature between 50 ° and 180 ° C, so that the water generated in the reaction can be removed under the air. (C) The reaction is carried out with an alcohol and an acid in the presence of a condensing agent such as 如, dicyclohexylcarbomide The reaction can be performed with or without a suitable organic tertiary base, such as 4- (N, N-monomethylaminopyridine), in an inert solvent such as dichloro The roasting is carried out at a temperature of 0 ° to 50 ° C. (D) Alcohol and acid, or acid, short or medium chain alkyl ester, or acid, activated vinegar such as vinyl vinegar in the presence of hydrolase such as porcine liver esterase In the presence of the reaction, the reaction can be carried out with or without a suitable solvent, such as hexane, at a temperature between 20 ° and 80 ° C: the reaction conditions must be such that the water or alcohol or aldehyde by-products produced during the reaction can (E) Reaction with an acid with a suitable alcohol derivative, such as a decomposed compound, with or without a suitable test such as the presence of carbonic acid, the reaction is in a suitable inert solvent such as monomethylformamide. To 180 ° C. (), Alcohol "version" short or medium bond ester ester in the presence of a catalytic amount of M; + 〇γ_ soil in the presence of k oxide, in the formula M + 〇γ_ , Μ is the inspection or inspection (please read the notes on the back before filling out this page). Order printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. A7 B7 V. Description of the invention (16) '^ Metals such as sodium, γ丨 _4 carbon atom alkyl group, this alkyl group can be knife branched, unbranched, saturated or unsaturated, the reaction can be With or without a suitable solvent such as toluene is present at 5〇. It can be carried out at a temperature between 18 and rc, so that the low alcohol and H0Y can be removed from the reaction mixture in the air. (C) The formation of bioactive compounds requires the formation of amido bonds. This chemical property can be synthesized by any reasonable amidine. The method is completed, in particular: (g) amine with acid chloride, acid anhydride or a suitable activated ester in the presence or absence of an organic secondary base such as pyridine in a suitable inert solvent such as methylene chloride. To 120X: temperature reaction. (H) Reaction with amine and acid in the presence of a condensing agent such as 13-dicyclohexylcarbodiimide. The reaction may be with or without a suitable organic tertiary base, such as 4- (N, N-dimethylaminopyridine), in an inert solvent such as dichloromethane at 0 ° to 50X: temperature. (1) amine and acid, or acid, short or medium chain alkyl ester, or Acids, activated esters such as vinyl esters are reacted in the presence of hydrolytic enzymes such as porcine liver esterase. The reaction can be carried out at a temperature between 20 ° and 80 ° C with or without a suitable solvent such as hexane. The reaction conditions must be such that The water or alcohol or aldehyde by-products produced during the reaction can be removed, for example, in the air. (B) (IV) The formation of actives requires the formation of phosphate ester linkages. This chemical property can be accomplished by any reasonable phosphate synthesis method, in particular: ⑴ Alcohols (such as UFA, 3 · hydroxypropyl esters) and suitable activated phosphate derivatives ( Such as POCI3) and a tertiary base (such as Shiyan) in a suitable solvent (such as THF) at a temperature below 10 C to produce crude digas phosphate ester. Then use alcohol (such as "Shengtong® 7") and crude A three-level test (such as Et3N) is used to convert vinegar to __ -19-

The paper size is suitable for financial and financial counties (CNS) 10X I 丨 丨 · 丨 蜷 丨 丨 (Please read the notes on the back before filling out this page) Order 546138 Printed by the Consumers Cooperative of the Central Standard Bureau of the Ministry of Economic Affairs A7 B7 V. Invention It is shown that the solvent (such as THF) in (17) reacts at a temperature lower than the surrounding temperature to make a crude chlorophosphate. This chlorophosphoric acid vinegar is hydrolyzed (for example, by adding water and Et3N) to form a phosphoric diester. Or add methanol to make phosphorus triester, and then use a suitable nucleophile (such as lithium bromide) in a suitable solvent (such as methyl ethyl ketone) to demethylate, to make scaly diazepam. (k) Phosphorus monoesters (such as phosphate esters of UFA, 3-hydroxypropyl esters) and alcohols (such as choline) in the presence of a condensing agent (such as 1,3-dicyclohexylcarbodiimide) A suitable solvent reacts at a suitable temperature. (1) 2-deoxy-2-lysophospholipid phosphocholine is transferred with a primary or secondary alcohol to phospholipid phosphonium, and the reaction is catalyzed by phospholipase D. In general, chemical properties naturally depend on the nature of the compound to be bonded and whether the bonding is direct or indirect. For example, a fatty acid couple can be directly bonded with a fatty acid-fatty alcohol ester or directly with an anhydride. If a diol bonding agent is used, an ether can be bonded to a fatty alcohol instead of the ester generally bonded to a fatty acid; all cases In the following, bonding is performed by known chemical methods. Can be directly bonded or via a bonding agent, especially 1,3-propanediol bond, examples of active couples that are bonded, examples of active couples, and the following compounds are, according to the inventors' knowledge, mostly novel of. Therefore, part of the present invention is a novel chemical entity and is also novel in the treatment or prevention of diseases, regardless of whether a patent application is filed here. 0 fatty acids GLA-OA (0A = oleic acid), GLA-GLA, EPA-EPA, GLA-EPA , GLA-DHA, AA-DHA, AA-EPA, GLA-AA, GLA-SA, SA · -20- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the back (Please fill in this page again)

1T 546138 Μ B7 V. Description of the invention (18) DHA, AA-SA, DGLA-DGLA, DGLA-GLA, DGLA-SA, DGLA-AA, DGLA-EPA, DGLA-DHA, AA-AA, EPA-SA, EPA-DHA, DHA-DHA, cLA-cLA, cLA_GLA, cLA_DGLA, cLA-AA, cLA_SA, cLA-EPA, cLA-DHA, CA-CA, CA-GLA, CA-DGLA, CA-AA, CA_SA, CA- EPA, CA_DHA 〇Vitamins GLA · niacin, GLA-retinoic acid, GLA-retinol, GLA-pyridoxal, di-GLA_p bilinol, di-EPA-bibinolic acid, and, for example, 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, and vitamin 31 (thiamine) , Vitamin B2 (nuclides), folic acid and related pterinates, vitamin B12, biotin and pantothenic acid. Amino acids GLA-tryptophan, GLA-peptamine, GLA-arginine, GLA- or DHA-phenylalanine, GLA-GABA, GLA-aminoacetamidine, and, for example, any GLA, DGLA, AA, SA, EPA or DHA with any natural amino acids or related compounds such as taurine and botulinum toxicity. Printed by the Consumers' Cooperative of the Central Bureau of Quasi-Agency of the Ministry of Aromatic Acids (please read the notes on the back before filling this page) GLA-phenylbutyric acid, GLA-phenylacetic acid, GLA · trans-cinnamic acid and any GLA, DGLA, AA, SA, EPA or DHA with any arylalkanoic acid or arylenoic acid. Steroids GLA-hydrocortisone, GLA_estradiol, GLA- and DHA-dehydroepiandroster-21-a paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 546138 Central Bureau of Standards, Ministry of Economic Affairs Printed by employees' consumer cooperatives A7 B7 V. Description of invention (19) Sterolone and generally any GLA, DGLA, AA, SA, EPA or DHA with any natural or synthetic steroid, such as any estrogen, any progestin, any adrenal gland Steroids and any anti-inflammatory steroids, especially Θ-misone, prednisone, prednisolone, triamcinolone, budesonide, crobe Clobetasol, beclomethasone, and other related steroids. Antioxidants GLA-lipoic acid, DHA-lipoic acid, GLA-tocopherol, di-GLA-3,3'-thiodipropionic acid, and generally any GLA, DGLA, AA, SA, EPA or DHA with any natural Or made into a feasible chemically bonded antioxidant. These antioxidants include various antioxidants (such as citronella, carnosic acid, caffeic acid, BHT, gallic acid, tocopherols, tocotrienols, and flavonoid antioxidants (such as bayberry flavonoids) , Featherone)), Polyammoniums (such as retinoic acid), Unsaturated sterols (such as Λ5-oatosterol), Organic sulfur compounds (such as allicin), Theophylline (such as geraniol, abietic acid) ) And amino acid antioxidants (such as cysteine, carnosine). Drugs GLA and indomethacin, indomethacin, fluphenoxamine, ampicillin, penicillin V, sulindac, salicylic acid, metronidazole, fluphenazine, flubenazine Maple (dapsone), tranylcypromine, ethyl alcohol-based botulinum test, fluphene, mepacrine, chloroquine, penicillin, tetracycline, pravastin, bisphosphonates Such as efidronic acid, pamidronic acid-22- This paper size is applicable to Chinese national standard i (—CNS —) — 1 ^ Geding ^^ 97mm) ~~ — (Please read the back first Please pay attention to this page, please fill out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ~~ -—— ~ B7 ___ V. Description of the invention (20) (pamidromc acid) and clodronic acid (clOrdr 〇nic aci sentence and its sodium salt, adenyl succinate and adenylate succinate and related compounds and agents used as x-ray developing medium, and generally any gla, DGLA, ΑΑ, SA, EPA or DHA with any drug, especially for the treatment of infectious, inflammatory diseases (including all forms of arthritis , Cancer, cardiovascular disease, respiratory disease, dermatological disease, mental disease, neurological disease, muscle disease, kidney disease, gastrointestinal disease, reproductive system disease. Concepts used in NSAIDs; show their effects to discuss this with specific examples Concept, the inventors have prepared various non-steroidal anti-inflammatory drugs (NSAIDs), especially GLA-S for indomethacin. As non-steroidal anti-inflammatory drugs, it is generally believed that the main intracellular mechanism of indomethacin is to inhibit cyclooxygenase. The cyclooxygenase converts arachidonic acid into a pro-inflammatory prostaglandin metabolite. It is known that indomethacin does not easily penetrate cells, so large doses must be given, and large doses produce many side effects, so indomethacin is used. -GLA compares its ability to permeate cells with indomethacin alone. This comparison uses normal fibroblast lines, breast cancer lines, and malignant melanoma lines.

This result is described in EPA-0 675 103. This result shows that the indomethacin content in the cells is very low after incubation with indomethacin in all cell lines, and only a small amount can be measured. In contrast, in these cell lines, after incubation with indomethacin-GLA, a large amount of indomethacin-GLA and free form indomethacin were detected in the cells. This result clearly shows that the GLA ester of indomethacin can effectively pass through the cells and deesterify in the cells, resulting in free-form indomethacin. It is also found that cell membrane disorders are similar to blood, brain, and skin disorders in many places, indomethacin- GLA • 23- This paper size applies Chinese National Standard (CNS) A4 specification (X 297 mm) --------- Clothing-(Please read the precautions on the back before filling this page) Order the Ministry of Economic Affairs Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 546138 A7 B7 V. Invention Description (21) must also effectively pass through these obstacles. Actives that penetrate and decompose into free states are also found in all compounds described herein. The aspects of the invention claimed in the patent are explained here in the patent application park. The main patent is about compounds, in which 1,3-propanediol residues form a bond between 111 and 1 ^ 2 residues. R1 is a fluorenyl or fatty alcohol group derived from a C12-30, preferably a Ci6_30 fatty acid, and must have two or more cis or trans double bonds, R2 is hydrogen or the same or different from R1 Fluorenyl or fatty alcohol, or residues about other nutrients, drugs or other biologically active substances. These compounds are generally actives with acid functions and are esterified directly on the diol residues. However, for example, with fatty alcohols or other actives with hydroxyl functions, the Ri and / or r2 groups and propane Diol residues can be inserted with phosphoric acid, succinic acid, or other difunctional acid groups, especially when R2 is a nutrient, drug, or other bioactive agent with a protecting or amine functional group. In the following, the present invention is discussed extensively with a variety of active substances that can be released in vivo. Although the biological actives and fatty acids ((a) [i], (b) [i], and ⑷⑴-type bonds have been discussed previously, The present invention mainly relates to the dehydration of a fatty acid that becomes a diester of 1,3-propanediol by bonding to a fatty acid] class n = 3 biologically active substance, and the biologically active substance itself may be a fatty acid, and is bonded through a phosphate bond Si 3-propane, a fatty acid monoester of a diol) (a bioactive species of n = 3 ', these bioactive species may themselves be fatty alcohols or fatty acid-resistant 3-hydroxypropyl vinegars. Diols can also be regarded as 2_deoxyglycerin and the corresponding 2 · deoxy_U_diacidyl acetate. (B) (iv), n = 3 compounds are also based on 13-propanediol ____________-24 _ This paper ruler is transferred to the house ~-(Please read the precautions on the back before filling out this page) Clothing. Order 5. Invention Description (22 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 丄The action is 2 · deoxy_2_ hemolysis, lipids. The diseases of the compounds listed here. Time to) have not been used in the past to treat humans or act as compounds. The diol used as a bond has been discussed in the literature together with many other dioxins, but the inventors have not seen it used in the form of essential lipid antacid dihydrazone: for treatment, nor has it been seen as a Disclosure of essential fatty acid and other-biologically active (non-essential fatty acid) compounds in position. The present invention does provide an advantageous method to generate a single fatty acid if a complete compound is needed Monoesters or diesters, because unlike glycerol 1 (3) -monoesters and diglycerides (from, Lu and 丨, 3-diglycerides, where the fatty acid at the 1st position is different from the fatty acid at the 3rd position) On the palm center, there are no positional JL isomers. Moreover, in addition to the individual acids, these mono- and diesters also have the value of emulsifiers for pharmaceutical formulations. The structure of 1% propanediol and the natural three The structure of glycerol is similar to that of glycerol, and it is an effective and safe delivery system. In addition, it is easy to synthesize the required compounds. Problems. The inventors have shown that the use of 13-propanediol GLA / EPA diluent as an intravenous infusion or oral administration results in the rapid release of gLa and EPA in the living body, further metabolizing gLa to AA, and metabolizing EPA to DHA. Similarly, GLA-GLA and EPA_EPA diesters, as well as niacin · GLA and indomethacin-GLA diesters were also absorbed and released their sexual parts after oral administration. In addition, 'as known by the inventors, on 17, The compounds derived from 1,3-propanediol described on pages 18 and 19 are novel and have never been described before. White House I—I—Small! (Please read the notes on the back before filling out this page ) -Order_ -25-

This paper size applies to Chinese National Standard (CNS) A4 ^ (21〇xl97 ^ F 546138 Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (23) Lists the specific diols of the two fatty acids and the The fatty acids of GLA, DGLA, AA, SA, EPA, DHA, cLA, and CA are located in one position and the other positions are vitamins, amino acids, aromatic acids, steroids, antioxidants or glycols of other drugs, which are novel substances Fatty acid diesters have various uses. Can be used as medicine to treat or prevent diseases that have been proven to have abnormal fatty acids. It can also be added to food, or used in nutritional supplements to give specific fatty acids to treat or prevent diseases It can also be used for veterinary use by food or medicine. It can also be used for skin care. From the advantages and specific aspects included in the patent application, the present invention provides (i) for therapeutic or nutritional purposes, giving one or two kinds Convenient and safe method for unsaturated fatty acid group, or an unsaturated fatty acid and a biologically active substance which is not a fatty acid. (Ii) A biologically active substance has a 1,3-propanediol bond Derived from natural n-6 or η-3 series fatty acids and in particular derivatives on GLA or DGLA, AA, SA, EPA or DHA or related fatty acids cLA or CA, where the biologically active substance needs to pass through the lipid membrane in the body Into cells or through the skin, blood-brain disorders or other disorders to exert its effect 0 (iii) fatty acid derivatives of a drug with which the drugs or fatty acids are synergistic. (Iv)-a drug that enhances The method of transporting through the lipid membrane in vivo is characterized by administering the drug in the above-mentioned form. (V)-a method of manufacturing including transporting the drug through the lipid membrane in the body to improve the treatment-26- This paper applies Chinese National Standards (CNS) A4 size, 210X297 mm) (Please read the precautions on the back before filling out this page) • Sample order 546138 A7 B7 printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economy It is characterized in that the medicine in the medicament is in the above-mentioned form. (vi) A method for manufacturing one or two fatty acids of (ii) in the above table or a method for delivering one of the aforementioned fatty acids and an active agent. Examples of specific compounds have been described above; synthetic examples are described later. General efficacy and use The specific use of specific compounds has been mentioned throughout this article. The use of 13-propanediol esters is described as follows: 1. Improved fatty acid tolerance: In addition to triglycerides, most can be given Fatty acid forms include free-state acids, salts, ethyl esters, and other glycerides that can cause some degree of gastrointestinal discomfort, such as nausea, P-vomiting, and abdominal dissection. Animals such as rats and mice have found that propylene glycol diesters are extremely well tolerated. For example, GLA-GLA and GLA-EPA diesters were administered to rats and mice at a dose of 10 g / kg, and diarrhea was found. This indicates that diesters are a very acceptable method of administering biologically active fatty acids. 2. Reduction of drug toxicity: Non-steroidal anti-inflammatory drugs such as aspirin and indomethacin are well-known drugs that cause stomach and intestinal ulcers and cause gastrointestinal bleeding. Fasting rats were given indomethacin (5-30 mg / kg) in a dose that caused gastrointestinal ulcers, in the form of free indomethacin and 1,3 · propanedi with GLA at another site Alcohol diester. After 24 hours, the animals were sacrificed and examined for ulcers throughout the gastrointestinal tract. Severe ulcers were found in animals given indomethacin alone, while only minimal or no ulcers were found in animals given gLA-indomethacin. Effective delivery of biologically active forms of fatty acids: GLA is based on GLA_ -—_ -27- This paper size is based on Chinese national standards (CNS 一 _ --- (Please read the precautions on the back before filling this page) Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 B7 V. Description of Invention (25) GLA or GLA-EPA is given, and EPA is given in the form of GLA-EPA or EPA · EPA. These diesters are Gavage is given orally or intravenously. It is given as a 20% emulsion, made with 2% oat galactolipid as an emulsifier, and given at a dose of about 0.1 to 2.0 g / kg. Animals were killed at 4, 8, and 24 hours, and plasma, red blood cells, and liver were collected. High-performance liquid chromatography was used to determine unmetabolized diesters. Fatty acids derived from diesters and metabolites of these fatty acids were examined as follows: Extraction of lipids from plasma, red blood cells, and lipids. Triglycerides, phospholipids, and cholesterol esters are separated by thin-layer chromatography, and methylated with the partially-derived fatty acids isolated from these. Analysis of fatty acids by gas chromatography All methods are described in the standard monograph. These experiments show that after oral administration, about 10% of the diester administered is confirmed to be in the form of a diester. Most GLA or EPA are found to be free fatty acids or phospholipids Only a small amount is found in cholesterol esters and triglycerides. In addition, especially in the phospholipid part, metabolites of GLA, DGLA and arachidonic acid were found, as well as metabolites of EPA, eicosapentazone and DHA. These phenomena indicate that fatty acids are easily released from diesters and are further metabolized into biologically active substances. Similar results have been found after intravenous administration of diesters, but at about one hour, about 40% of The diester remains in its original form, and fatty acids are released, metabolized, and enter other lipid moieties after 24 hours. This unchanged diester form is likely to be biologically active by itself. The 1,3-diglyceride form has now been discovered Linoleic acid has anticancer effects, and is only resistant to cancer. It is not resistant to normal cells, and other forms of linoleic acid are not available (A. Matsuzaki et al, Cancer Res. 1989 49: 5702-7). This is because this can make -28- This paper scales applicable Chinese National Standard (CNS) A4 size (210X 297 mm) (Please read the back of the precautions to fill out this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the 1T A7 B7 V. Description of the invention (26) The role of his needs to be the relationship of fatty acids with 1,3-diglyceride as the interval between two knives. Similar intervals can also be achieved with 13-propanediol, so intravenous administration of certain propanediol derivatives to ensure that they circulate for some time in the form of diols before complete metabolism can be particularly costly. In the writings of the inventor and others, there are detailed descriptions of various biological and oral treatments of fatty acids. The four kinds of fatty acids, GLA, DGLA, SA and EPA, have a wide range of effects. These effects include: 1 · Cardiovascular effects include vasodilation, lowering blood pressure, inhibiting platelet aggregation, reducing triglyceride and LDL_cholesterol content, increasing HDL · cholesterol content, and inhibiting smooth muscle proliferation. 2 · Fire resistance 'includes reduction of proinflammatory mediators such as cytokine formation, and reduction of eicosanoids derived from arachidonic acid, reduction of neutrophil migration, and reduction of neutrophil sudden respiration Reduction of local inflammatory response, inhibition of inflammation in various animal models, such as inhibition of uric acid-induced inflammation and arthritis, treatment of various inflammatory diseases such as osteoarthritis and rheumatoid arthritis. 3. Immune adjustment function, including preventing immune and allergic overreactions in animal models, such as experimental allergic encephalomyelitis and uveitis, overreaction in the trachea and skin of sensitized animals, which results in Diseases caused by excessive immune responses can have a pricey notion. 4 · Respiratory effects, including tracheal dilatation and inhibition of tracheal contraction. 05. Improving calcium balance due to increased calcium absorption, reducing calcium excretion, increasing calcium deposition in bones, and reducing calcium in tissues such as arteries and kidneys. Ectopic calm. -29- ___________________ _ This paper size applies to Chinese National Standards (CNS) M specifications (210 '^ 7mm) ~' (Please read the precautions on the back before filling this page)

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 f____ — Β7 V. Description of the invention (27) ^ ~ — 6 · Three types of anti-cancer effects' selective cytotoxic damage to cancer cells (abnormal cells) and cause 呑 嗤Effect, by reducing the activity of growth factors and interfering with the second messenger system required for growth, inhibiting growth, inhibiting cell division by a variety of effects, including increased expression of E-calcium-dependent proteins and effects on proteolytic enzymes such as urokinase, Inhibition of lipoxygenase and matrix metalloproteinase, and inhibition of cachexia associated with cancer. 7. Effects on nerve cells, including maintenance of normal nerve membrane structure and function and maintenance of normal neurotransmitter pre-ganglion- and post-ganglion_ effects. These required effects mean that this group of fatty acids can be used to treat a variety of diseases, including many types of cardiovascular diseases, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn's disease ( Crohn, s disease), respiratory diseases including asthma, mental illness including schizophrenia, alcoholism 'inattention disease, depression and AIDS, and neurological diseases including multiple sclerosis and Hantington's dance Disease, kidney and urethral diseases include various nephritis and urethral calculi, metabolic diseases include osteoporosis and ectopic calcification, and gastrointestinal ulcers and inflammatory diseases. Although conjugated linoleic acid (cLA) has not been universally tested like GLA or EPA, it also appears to have a wide range of effects, including treatment costs for cancer, cardiovascular disease, and metabolic diseases. GLA, DGLA, AA, and galenbinic acid have the required effect on the skin, and are particularly valuable in the treatment of atopic eczema, psoriasis, measles and allergic reactions. AA is often considered a harmful fatty acid. However, AA is an essential component of all normal cell membranes. It is found in a variety of diseases, including atopic hygrotherapy, schizophrenia, and is often found to increase slightly (Horrobin et al, Schizophrenia Res 1994 · -30- " i " paper scales are applicable to China Country $ (A4 Regulations && 297 mm) ^ '~~ ---- (Please read the precautions on the back before filling out this page)

1T 546138 Α7 Β7 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (28) l3: l95-2〇7) There is also a slight increase in cardiovascular disease (Horrbin,

Prostaglandins Leukotr. EFAs 1995; 53: 385-96). AA seems to have special value in these diseases, and it also has value in other mental diseases such as alcoholism and reduced concentration of AA. DHA also has the effects of the above-mentioned EFA, but it is particularly abundant in the cell membrane, especially in the heart membrane, retina, and meninges. DHA also has potent anti-inflammatory and cardiovascular effects. DHA seems to be effective for cardiovascular disease, retina and visual diseases including pigmented retinitis, degenerative changes in senile plaques and dyslexia, and for psychiatric and neurological diseases including schizophrenia, inattention 'depression, alcoholism, AIDS Hemeri Diseases and other forms of mental disorders and multiple sclerosis are of particular value. Closer confirmation has confirmed that the infection also appears to be responsive to lipids, particularly to Gla and DGLA, and EPA and DHA. Many bacteria can be killed by these fatty acids, including bacteria that are resistant to dysbiotics. Recent reports from some laboratories have shown that these highly unsaturated fatty acids are important for successful treatments such as dysentery and protozoal diseases. It is clear that various fatty acids seem to increase the effect of drugs and almost any other biologically active substance in the treatment and prevention of diseases, as well as in skin care and nutrition. In the form of diols, a single fatty acid or the same molecule is given. There are also therapeutic effects when two different fatty acids are administered internally. The special therapeutic value is that fatty acids are non-toxic in most cases and can be given in large doses without the risk of significant side effects. As a specific example of the efficacy of monoester treatment, 1,3 GLA-EPA propanediacetate was used to test ASPC-1 human pancreatic cancer, and this cancer was subcutaneously transplanted at __- 31-^ 张 值 适 ^^ ( (Please read the notes on the back before filling out this page), 1T

ί 1-I—I Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 V. Description of the invention (29) Nude mice, which lack thymus function and can accept foreign grafts without rejection. Each of 15 mice was injected subcutaneously with five million ASPC-1 cells suspended in Matrigel and DMEM buffer. All animals develop tumors internally. The size of the tumor can be measured with a caliper, and the volume of the tumor can be calculated from a linear vector. The tumors of each mouse were measured twice a week for five consecutive weeks. The animals were divided into three groups. Five animals served as controls and received only 10 g / kg corn oil per day. Five rats received 10 g / kg of corn oil per day, and received another injection of GLA-EPA diester at a dose of 1.5 g / kg twice a week. This diester is given in the form of a 20% emulsion with 2% oat galactolipid as an emulsifier in the emulsion; this intravenous emulsion is well tolerated and does not cause hemolysis or thrombophlebitis or any other Inhibition of animals. In addition to corn oil, the other 5 rats received 10 g / kg / day of GLA-EPA diester. This treatment lasted three weeks, the tumors were allowed to grow for another two weeks, then the animals were sacrificed and the tumors were removed to determine their weight. The average tumor weight was: control group, 1240 ± 290 mg; intravenous GLA-EPA group, 820 ± 180 mg; oral GLA-EPA group, 490 ± 160 mg. It can be seen that the tumor growth of the animals administered the GLA-EPA diesters orally and intravenously is substantially suppressed without any side effects or pain. This shows that GLA-EPA diesters can be effectively used to treat cancer, which is consistent with the expectation that using GLA and EPA in the laboratory to kill cultured human cancer cells, respectively. So diesters are a biologically active method for administering various fatty acids. Therefore, it is reasonable to expect that diesters can exert a variety of desired effects of fatty acids, which are found in many published literature (for example: Horrobin DF, ed.? Omega-6 Essential Fatty Acids: Pathophysiology and Roles in Clinical Medicine: Wiley_Liss, New York, 1990 o -32- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm): II—41— (Please read the notes on the back before filling this page) Order 546138 A7 B7 V. Invention description (30)

Simopoulos AP et al? Eds, Health Efects of Omega-3 Polyunsaturated Fatty Acids in Seafoods, Karger, Basel, 1991. Fats and Oils in Human Nutrition, World Health Organization, Rome, 1994 o Unsaturated Fatty Acids: Nutritional and Physiological Significance o British Nutrition Foundation, Chapman and Hall, London, 1992) 0 Specific uses of specific 1,3-propanediol compounds1 1,3-propanediol derivatives contain: two fatty acids, one of which is GLA or DGLA, the other is GLA, DGLA, SA, EPA, DHA, cLA (co-linoleic acid) or CA (plus (Lingbinic acid) for the treatment of:-(a) complications of diabetes, especially neuropathy and retinopathy; improved response to insulin during and before diabetes; (b) cancer; (c) osteoarthritis; (d) rheumatoid arthritis; (e) other inflammatory and autoimmune diseases, including Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, and uveitis; (f) respiratory diseases , Including asthma; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) (g) neurological diseases include multiple sclerosis, Parkinson's disease, Huntington's disease; (h) Renal and urethral diseases; ⑴ Cardiovascular disease; (j) Degenerative diseases of the eye, including pigmented retinitis and senile plaque regression -33-This paper is in accordance with China's national standard (21 〇 ：) 40 丄 A7 -------- B7 V. Explanation of the invention (31) ~~ —————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————————— B7 V. Inconcentration, alcoholism, and depression; (l) Prostatic hypertrophy and prostatitis; (m) Impotence and male infertility; (n) Breast pain; (〇) Male baldness; (P) Osteoporosis; ⑷ Skin Diseases, including atopic eczema, hand eczema, psoriasis, ramie therapy, and allergic diseases; (0 dyslexia and other learning disabilities; (S) cancer cachexia. 2. M-propanedi containing two fatty acids Alcohol derivatives in which one fatty acid is AA and the other is AA, GLA, DHA, base eight or muscle, and is used for the treatment of the diseases mentioned above, especially ⑴, (g), ⑴, ⑴, (k), Diseases described in items (q) and (r). Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Propanediol derivatives, one of which is EPA and the other is EPA or DHA, is used to treat the diseases described in (1) before, especially (b), (c), (d), (e), (f ), (G), ⑻, ⑴, ⑴, (k), (p), (r) and (S). 4. M-propanediol derivatives, in which one position is a fatty acid selected from GLA, DGLA, AA, SA, cLA, EPA or DHA, and at another position is an agent selected from the following, the chemical structure of these agents It can be bonded to 1,3-propanediol by the following bonds: -34- This paper size applies Chinese National Standard (CNS) A4 specification (210: < 297 mm) Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative 546138 A7 ---_ B7 ______ V. Description of the invention (32) (a) Tryptophan is used to treat any disease, but it is especially suitable for mental illness, neurological illness, behavioral illness, pain and Other diseases, especially depression, sleep and migraine; (b) Phenylalanine for the treatment of any disease, but particularly suitable for depression, multiple sclerosis, and chronic fatigue syndrome; (c) Arginine for the treatment Any disease, but especially for diseases with deficiencies in nitric oxide production; (d) Carnitine or carnitine derivatives, for the treatment of any disease, but especially for muscle weakness, heart failure, chronic fatigue syndrome, love Zheimer's disease and peripheral neuropathy (E) any other amino acid or related substance for the treatment of any disease; aminoacetic acid or its derivatives for the treatment of any disease, but especially for cancer; (f) adenine Acid salts or related substances for the treatment of any disease, but especially for muscular atrophy, heart failure, chronic fatigue syndrome, AIDS, and other dementias; (g) aspirin, salicylic acid, Indomethacin, ibuprofen, or other non-steroidal anti-inflammatory drugs, used to treat any disease, but especially suitable for painful inflammatory diseases, inflammatory diseases of AIDS and other dementias Disease, and any other inflammatory disease that should inhibit platelet aggregation; (h) any antibiotic for the treatment of any suitable infection, particularly tetracycline, clindamycin, minocycline , Chlorotetracycline and erythromycin for the treatment of acne -35- ~ This paper is suitable for Chinese National Standards (CNS) mm ~ ~ ~-^ —-疃 | 丨 (Please read the notes on the back before filling (This page) Order 546138 A7 B7 V. Description of the invention (33), (i) Any antimalarial and antiprotozoal drug used to treat any disease, but in particular, J is chloroquine, mepacrine, pquinacrine (Quinacrine) and mefloquine are used to treat dysentery, protozoan, inflammatory and schizophrenia; (j) any anti-bacillus drug used to treat any disease, especially metronidazole ) And anti-mycobacteria mijun and nitromizon and amphotericin (amphotericin), for the treatment of various types of bacillus infections; (k) any anti-inflammatory steroid for the treatment of any disease, especially hydrocodone Body pine and Θ · Mison, used to treat skin diseases, and beclomethasone and budesonide, used to treat asthma; (l) Any gonadal steroid, used to treat any disease, especially females Hormones and progestins for the treatment of ovarian insufficiency and osteoporosis, and androgens for the treatment of testicular insufficiency; (m) any adrenal steroids for the treatment of any disease, especially DHEA And aging Related diseases; Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs: -IΙΦΤ, (Please read the precautions on the back before filling this page) (η) Any retinoid used to treat any disease, especially vitamin A Acid and isovitamin A acid for treating skin diseases and protecting the skin; (〇) any anticancer agent for treating cancer; (P) any antipsychotic agent for treating schizophrenia and other mental illnesses -36- This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7-^^ 一 _ B7 V. Description of the invention (34) (q) Any antidepressant For the treatment of any disease, especially for the treatment of antiseptics; (r) any anxiolytic agent for the treatment of any disease, especially for the treatment of anxiety and panic attacks; (S) any immunosuppressive agent for the treatment Any disease, especially cyclotoxin and tacrolimus, to control immunity after organ transplantation and to treat autoimmune and inflammatory diseases, including psoriasis, eczema, asthma, and similar Wet arthritis and inflammatory bowel disease: Any proton pump inhibitor or H2 antagonist for the treatment of any disease, especially for diseases related to hyperacidity or diseases with reduced defense against gastric acid; (u) any diuresis Agents for the treatment of any disease, especially for the treatment of fluid retention-related diseases and hypertension; (v) any # 5 antagonist for the treatment of any disease, especially for the treatment of cardiovascular disease; (w) Any angiotensin-converting enzyme inhibitor or angiotensin antagonist, for the treatment of any disease, especially for the treatment of cardiovascular disease (X) Any Lu-blocker, for the treatment of any disease, especially for the treatment Cardiovascular diseases; (y) Any antiepileptic drug for the treatment of any disease, especially phenytoin, carbamazepine, valproate, ethosuximide, Vig Bachun-37- This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) ~~ '----------- Cloth-C Please read the notes on the back before filling This Page}-Order _ Ministry of Economy Printed by the Consumer Standards Cooperative of the Central Bureau of Standards 546138 A7 B7 V. Description of Invention (35) (vigabatrin) or Lamotrigine (lamotrigine) for the treatment of epilepsy 9 (Z) Any hypolipidemic agent for the treatment of any disease, especially It is a lipid-lowering fibrates and statins for lowering cholesterol and cholesterol upgrading; (aa) any oral hypoglycemic agent or insulin sensitizer for treating diabetes; (bb) any bisphosphine Acid salts for the treatment of osteoporosis, Paget's disease, or cancer; (cc) any radiographic developer, including diatrizoate compounds, iodipamide, glycine Ioglycamates, iopanoates, iophendylate, iothalamate, ioxaglate, metrizamide and related compounds; (dd) any peptide Or protein for the treatment of diseases using the peptide or protein, including insulin, noretin # 5, erythropoietin, and other peptides; (ee) any vitamin for the treatment of any disease, or for food or nutrition Make up Supplements or food supplements that are effective vitamin supplements 9 (ff) Any antioxidant used to treat any disease, especially diseases where antioxidants are particularly useful, including cardiovascular disease, cancer or inflammation, and anything used as Antioxidants of food or other preservatives, or as ingredients of food, food additives or nutritional supplements; -38-This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm)!: I-Γ Locust — 丨 (Please read the notes on the back before filling this page)

1. 1T Consumer Insurance Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs prints 546138 A7 _ B7 V. Description of the invention (36) a ~ (gg) Any drug mainly composed of porphyrin chlorin or bacteriochlorin, In particular, its derivatives (hydroxyphenyl) are used for photodynamic therapy of cancer. Synthetic simple synthesis of glycerides Compared with the purpose of glycerol, the use of 1,3-propanediol has the following advantages. In particular, in terms of esterified fatty acids, it is recommended to replace glycerol with i,% propanediol, especially when only one fatty acid (such as r_linolenic acid) is to be attached to the three-carbon bond scaffold. Although the chemical characteristics of bisphenol and triglyceride are very similar, the manufacture of monoester can be carried out under very mild conditions, and it can be 7D in a few hours. Strong conditions are required to make diglycerides, or fatty fluorenyl chloride is required, or a biocatalyst is required (this process takes several days). An outline of the synthesis method of acid glyceride: 1. The chemical reaction uses metal, metal vapor, or organic acid as catalyst. 2. Use fatty ammonium chloride. 3 · Use immobilized enzymes. All methods use acids, metals, metal chlorides, or organic acids as catalysts " very similar " The advantages and disadvantages are the same. Many problems are inherent to these methods, namely acidic conditions and high temperatures (140 ° C to i80 ° c). The TSA method may have the fewest problems, because this method is performed under the most mild conditions (U (rc)). The reaction of glycerol with fatty methyl chloride is completed under "cold" conditions, but it will emit toxic gases, and if you are not careful Surveillance and response will not be controlled. _-39- This paper size applies to China National Standards (CNS) A4 ^ 11 ^ 297 mm): —I 疃 — (Please read the precautions on the back before filling this page), 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 V. Description of the invention (37) There is also a disadvantage of this method, that is, it must be made into fatty amidyl chloride itself; this extra step reduces the overall efficiency of this method The esterification reaction can be catalyzed under mild conditions (such as 60 ° C) with a specific enzyme system, lipid-preventing enzymes. This enzyme may be the best catalyst for the use of polyunsaturated fatty acids. However, most of the -And 3-position reactions are the most effective. Adding fatty acids to the 2-position is slow, and often depends on "quoting", that is, the fatty acids must first be attached to the 1- or 3-position, and then transferred to the 2-digit on. Therefore, it takes several days for the synthesis of the triglyceride to be catalyzed by the enzyme to complete the reaction. In theory, the same esterification method used for glycerol can also be used for the esterification of 13-propanediol. However, when considering that it is easier to add fatty acids to the 1_ and 3_ positions of glycerol, it is clear that these enzymes can be effectively used to make diesters. This is indeed the case. Compared to the synthesis of triglycerides, this reaction can be completed between several hours and even at low temperatures (e.g. 45 ° C to 60 ° C). After four hours, there is no fatty acid, and after eight hours, the yield of the di-ester is more than 95%, and the remaining is the mono-ester. Another complication of the synthesis of specific triglycerides is the presence of primary and primary mesogens in the glycerol and the presence of a front palm center on the central carbon. These problems can be solved with carefully chosen protecting groups and with palm synthesis. However, this increases the number of synthetic steps, reduces the yield, and reduces the purity of each step. In contrast, 1,3-propanediol has only a primary hydroxyl group and does not have a pro palmar center. This synthesis can be reduced to a maximum of two steps, the total yield is increased, and the purity is reduced. In short, compared with the corresponding triglyceride synthesis, polyunsaturated fatty acids and 1,3-propanediol are used. The reaction to prepare the diester is fast, and it can be used in mild strips. ________ -40- This paper size is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm): -I— 疃 II (Please read the back (Please fill in this page again)

1T 546138 A7 B7 V. Description of the invention (under 38 pieces. This leads to a more economical and less wasteful production method and minimizes the risk of reactants or products spoiling during production. Formulations These compounds can Specialized in pharmaceuticals, skin care products or any suitable method known to food manufacturers. These formulations can be administered orally, enterally, topically, parenterally (subcutaneously, intramuscularly, intravenously) ' Straight-line administration 'is given by vaginal administration, or by any suitable route. Like glyceryl diacid, 1,3-propanediol diesters, especially those containing two fatty acids, can be phospholipids or especially galactose Fatty emulsifier. This emulsion is especially suitable for oral, enteral, and intravenous administration. For example, fatty acid (UFA) diesters like free-flowing oils can be formulated as follows:-L with EPA and 1, Preparation of 3-propanediol diester emulsions Oral emulsions were prepared by high-pressure homogenization. The particle size distribution and the ~ potential of the prepared emulsions were determined at room temperature using dynamic light scattering. Foot measurement of size was performed at room temperature (Zetasizer 4 Malvern Instruments Limited). 〇Oil-in-water emulsion (200 g batch) was prepared with the following ingredients: Ingredient emulsifier (galactose) * diester (GLA-EPA) Palm Acid Ascorbic Acid @ Purpose (AP) Vitamin E Water -41-This paper is suitable for financial standards (CNS) M specifications (21QX297 public director) (Please read the precautions on the back before filling this page), the central standard of the Ministry of Economic Affairs Printed by the Bureau ’s Consumer Cooperatives% 2.00 20.00 0.02 0.5 100.00 ^ 67 _________ ^ 67 _________ Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 V. Description of Invention (39) * Scotia LipidTeknik Patent " Oil-in-water emulsion ''. PCT / SE95 / 00115 (WO95 / 20943) Disperse the emulsifier galactose in the diester, mix vitamin E, AP and water. Add the oil phase to the water phase at 4 speeds under Ultraturrax And mix for several minutes. The previous emulsion was homogenized at 80 MPA at 50 ° C for 6 cycles (mini-Lab 8.30 H; APV Rannie As, Denmark). The average droplet size of the prepared emulsion was 230 nm. Antimicrobial Prevent Potassium sorbate and flavoring agent can be added to the above oral administration emulsion. 2. An intravenously administered 20% emulsion of a diester of GLA and EPA with 1,3-propanediol is prepared in a similar manner. 200 grams of oil-in-water emulsion containing the following ingredients: Ingredient% Emulsifier 2.0 diester (GLA-EPA) 20.0 Glycerin 2.0 water, added to 100.00 above emulsion, made by high pressure homogenization for 6 minutes, the average droplet size is 211 nm, / 9 potential -40 mV. These intravenously administered emulsions can be filtered with a membrane having a pore size of 0.22 micron, or they can be autoclaved, and the droplet size may vary. The amount of the active to be administered may be from 1 g to 200 g per day, preferably 10 mg to 10 g, more preferably 10 mg to 3 g, depending on the kind. When treating cancer, the preferred dose may be 2-150 g / day. It can also be used as a local preparation when the formulation is suitable. -42- This paper size is applicable to China National Standard (CNS) A4 regulation ^ (27 ^ 297mm) ~---------- ^^ clothing-(please first (Read the notes on the back and fill out this page)

1T 546138 Consumption Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperative Association A7 B7 V. Description of the invention (40) The active substance of this preparation accounts for 0.0001% to 50/0 of the locally administered preparation, preferably 0.05 % To 20%, more preferably 0.1% to 100/0. For the synthesis of example NSAIDs linked to fatty acids, see the aforementioned EPA-0 675 103. An illustrative synthesis of fatty acids via 1,3-propanediol residues on other general illustrative materials is as follows. Example 1 1,3 · (di · ζ, ζ, ζ · octadecyl-6,9,12 · trimethylamino) propane (GLA and 1,3-propanediol diester) will be 1 A solution of 1,3-dicyclohexylcarbodiimideamine (1.07 g) and 4- (N, N-dimethylamino) pyridine (0.59 g) in dichloromethane (5 ml) was added to 1,3 -A solution of dihydroxypropane (0.152 g) and 2,2,2-octadecyl-6,9,12-trienoic acid (95%, 1.36 g) in dichloromethane (15 ml). The reaction was stirred at room temperature under nitrogen until the reaction was complete as determined by tic (thin layer chromatography). To the reaction was added hexane (80 ml). The precipitate was removed by filtration and washed thoroughly with hexane. The combined filtrates were concentrated and 'purified by flash chromatography' to obtain 1,3_ (di-z, z, z-octadecyl-6,9,12-trienyloxy) propene as a grayish yellow. Free flowing oil body. Example 2 l- (z, z, z-octadecyl-6,9,12-trienyloxy) -3_ (ζ · octadecyl-9-alkenyloxy) propane (GLA and oil Diesters of acids and 1,3-propanediol) Part 1: Put ζ, ζ, ζ-octadecyl-6,9,12-trienoic acid (150 g) in dichloromethane (500 mmol-43 -This paper size applies CNS standard A4 (21 (3X 297 mm)): IIΓ_ΐ (Please read the precautions on the back before filling out this page), 1T Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 B7 ____ V. Description of the invention (41 liters) Dissolved in room temperature under nitrogen and added dropwise to 丨, 3-dimethyacryl (205g), 1,3 · dicyclohexylcarbodiimide (130 g) and 4- (N, N-dimethylamino) pyridine (87 g) in a mixture of dichloromethane (2500 ml). After tlc showed that the reaction was complete, the reaction mixture was filtered. The filtrate Wash with dilute hydrochloric acid 'water and saturated sodium chloride solution. The solution was dried, concentrated, and purified by dry column chromatography to obtain l_ (z, z, z-octadecyl-6,9,12-difluorene Si Alkoxy) -3- via propane, as a gray-yellow oil. Fraction 2: Place 1,3-dicyclohexylcarbodiimide (23.7 g) and 4- (Team> 1-dimethylamino) pyridine (15.9 g) in dichloromethane (200 ml). The solution was added at room temperature under nitrogen to l- (z, z, z-octadecyl-6,9,12-triamyloxy) -3-propanylpropane (3 3.6 g) and z-deca Octyl-9-enoic acid (30 g) in dichloromethane (400 ml). After the reaction was determined by tic, the solution was diluted with hexane, filtered, concentrated, and purified by dry column chromatography. L_ (z, z, z-octadecyl-6,9,12-trienyloxy) -3- (z-octadecyl-9-alkenyloxy) propane was obtained, which was free flowing Gray-yellow oil. Example 3 l- (z, z, z_octadecyl-6,9,12-trimethyloxy) _3_ (z, z, z, z, z_icosyl- 5,8,11,14,17-pentaenyloxy) propane (the diester of GLA with EPA and 1,3-propanediol) was prepared as in Example 2, part 2, but using ζ, ζ, ζ, ζ , Ζ eicosyl enoic acid instead of z-octadecyl-9_fluorenic acid. 1_ (ζ, ζ, ζ octadecyl-6,9, 12 · trienyloxy) was prepared by chromatographic analysis. ) _3- (z, z, z, z, z_: + S-5,8,11,14,17 · pentaenyloxy) propane, a gray-yellow oil body. -44-This paper size is applicable to Chinese National Standard (CNS) Λ4 specification (210X297 mm 1 ~~一 " I !: IIΓ 疃 — 丨 (Please read the precautions on the back before filling this page)

1T 546138 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the Invention (42) Example 4 1,3-Dioxo, octadecyl-6,9,12_trienyloxy) propane ( GLA and 1,3-propanediol diester) Prepared as in Example 2, Part 2, but replacing z-octadecyl-9- with z, z, z-octadecyl-6,9,12-trienoic acid Enoic acid. Chromatographic analysis yielded 13-bis (z, z, z-octadecyl · 6,9,12-trienyloxy) propane as a gray-yellow oil. Example 5 (+)-1- (1,2-monothiol-3-pentyloxy) _3 _ (; 2,2;, 2; -octadecyl-6,9,12-trienefluorenyl Oxy) propane (lipoic acid and the diester of GLA and 1,3-propanediol) 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) and 4- (Ν, Ν A solution of dimethylamino) pyridine (480 mg, 3.98 mmol) in tert-butyl methyl ether (15 ml) was added to lipoic acid (645 mg, 3.12 mmol) and 1. (ζ, ζ , Zeta-octadecyl-6,9,12-trienyloxy) -3-hydroxypropane (1 g, 3 mmol) in a mixture of tertiary butyl methyl ether (30 ml). The mixture was stirred at room temperature under nitrogen for 5 hours, and the progress of the reaction was monitored by tic (40% ethyl acetate / hexane). After the reaction was completed, the mixture was filtered, concentrated, and purified by flash chromatography (hexane, 2% ethyl acetate / hexane, 5% ethyl acetate / hexane, and finally 100/0 ethyl acetate / hexane ) To obtain (±) 4- (1,2-disulfane-3_pentamyloxy) _3_ (z, z, z_octadecyl_6,9,12_trienyloxy) ) The appearance of C is a yellow oily body. Example 6 1 _ ([Z] · 5-fluoromethyl · fluorene_ [4- (methylsulfinylfluorenyl) fluorenyl] manganyl-3-ethylethoxy) -3- (z, z, z _18 octadecyl, 6,9,12_trienyloxy) propane-45- This paper size applies to China National Standard (CNS) A4 specification (210 × 297 mm): I-Γ Zhong! (Please read the precautions on the back before filling this page) 、 Printed by the staffing cooperation agreement of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ B7 V. Description of the invention (43) (Su Lingda and GLA with 1,3_propane II Alcohol diester) A solution of 1,3-dicyclohexylcarbodiimide (720 mg, 3.45 mmol) in tertiary butyl methyl ether (30 ml) was added to Sulinda (1.12 g, 3.15 Millimoles), 4- (N, N-dimethylamino) pyridine (480 mg, 3.9 millimoles) and l- (z, z, z-octadecyl-6,9,12-triene Fluorenyloxy) -3-hydroxypropane (1 g, 3 mmol) in a mixture of tertiary butyl methyl ether (i 5 ml). The mixture was stirred at room temperature under nitrogen for 5 hours, and the progress of the reaction was monitored with tic (40% ethyl acetate / hexane). After the reaction was completed, the mixture was filtered, concentrated, and purified by flash chromatography (40% ethyl acetate / hexane, 50% ethyl acetate / hexane, and finally 60% ethyl acetate / hexane) to obtain 1- ([Z] -5-Fluoro-2-methyl-1- [4 · (methylsulfinamilide) fluorenyl] indene-3-ethylethynyloxy) _3- (ζ, ζ, ζ -Stearyl, 6,9,12-trienyloxy) propane, as a pyrene-like yellow solid. Example 7 l _ ([R) -3 · Ethyloxy-4 · [trimethylamino] butyryloxy) -3_ (ζ, ζ, ζ_ + octyl-6,9,12-trienefluorenyl (Oxy) propane (Ethyl Carnitine and GLA and 1,3-propanediol diester) Slowly add freshly distilled thionyl chloride (1.5 ml) to the (R) · in a pear-shaped flask Acetylcarnitine (0 g). Note that each reagent should be at the bottom of the flask before becoming a clear solution. After 4 hours at room temperature, excess sulfur was removed under reduced pressure and the chlorine test was maintained (maintain the flask temperature below 30 ° C). The fluorenyl chloride produced was a highly hygroscopic white solid, and this product was used immediately without purification. Into this flask were added l- (z, z, z-octadecyl-6,9,12_trienyloxy) -3 propionyl Q (4 g, 4.17 mmol) and anhydrous thf ( 4 ml). Let the mixture stand at room temperature __ ___ -46- This paper size is applicable to China National Standard (CNS) A4 Regulation 2] 〇 > < 297 meals) (Please read the precautions on the back before filling this page ) _ 、 · Ιτ Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ___ B7 V. Invention Description (44) Overnight. Tic analysis (40% ethyl acetate / hexane) showed that the reaction was complete. The reaction mixture was added dropwise into hexane (250 ml) with vigorous stirring. A fine off-white precipitate formed and was collected by centrifugation. The float was removed and the solid was resuspended in hexane and centrifuged. Then washed with hexane to obtain ethoxyl · ··························································································································· (Oxy) propane. Example 8 1- (3,3-Dimethyl-7-oxy-6-([phenoxyethylfluorenyl) amino] -4-17 plug-; [> _nitrobicyclo [3.2.0] heptane · 2 · fluorenyloxy) -3 · (ζ, ζ, ζ-octadecyl_6,9,12_trifluorenyloxy) propane (penicillin V and GLA with 1,3 · propane) Alcohol diesters) Penicillin V (1 g, 2.9 mmol), 1_ (ζ, ζ, ζoctadecyl-6,9,12_trienyloxy) -3-ylpropane ( 860 mg, 2.6 mmol), 1,3-dicyclohexylcarbodiimide (620 mg, 3 mmol) and 4- (N, N-dimethylamino) pyridine (catalyst) The mixture in methyl chloride (30 ml) was stirred at room temperature overnight. The reaction mixture was diluted with hexane (50 ml), filtered and concentrated to dryness. The residue was washed with hexane (3x50 ml) to remove unreacted octadecyl-6,9,12-trienyloxy) -3-hydroxypropane. The semi-solid residue was dissolved in ether (150 ml), washed with water (100 ml) and dried. The acid solution was diluted with hexane (125 ml) and the solution was filtered through a bed of dioxide (4 cm x 4 cm). The filtrate was concentrated to obtain 1- (3,3_dimethyl-7 · oxy_6 · ([phenoxyethylamyl) amino] -4-pyrim-1-azabicyclo [3.2.0 ] Heptan-2-yloxy (z, z, z_octadecyl-6,9,12_di-methyl-s-stilyloxy) propylene, a bleached colorless oil body 0 -47- This paper Standards are applicable to Chinese National Standards (CNS) Α · 4 specifications (210X 297 mm) I: IIι # τ, (Please read the precautions on the back before filling out this page), 11 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ________ B7 V. Explanation of the invention (45) — ~ Example 9 1- (2,2,2_octadecyl-6,9,12-trienyloxy) -3_ (1- (4-chlorobenzene Methenyl) -5 -methoxy-2_methyl-whistle-3 -acetoxy) propane (indomethacin and the diester of GLA and 1,3-propanediol) 1,3- Dicyclohexylcarbodiimide (58 mg, 0.28 mmol) and 4- (N, N-dimethylamino) pyridine (37.9 g, 0.31 mole) in dichloromethane (800 ml) Stir under nitrogen at room temperature: add to 1- (z, z, z-octadecyl-6,9,12-trienyloxy) -3-hydroxypropane (79.5 g, 0.24 mo Ear) and indomethacin 93.2 g '0.26 mole) in dichloromethane (400 ml). Stirring was continued for 3 hours. The mixture was filtered, concentrated, and purified by dry column chromatography (ethyl acetate / hexane). The product was collected And concentrated to obtain i_ (z, z, z-octadecyl-6,9,12_trimethylamino) -3- (1- (4-chlorobenzoate) -5_methoxy -2-methyl 丨 Noise-3 -ethenyloxy) propane is a pale yellow cumulant oil body. Example 10 1- (ζ, ζ, ζ Octadecyl-6, 9, 12_trifluorene Fluorenyloxy) -3- (2- ^ Lomaline carboxyl) propanone (proline and diesters of GLA and 1,3-propanediol) Part 1: Carbodiimide of 1,3-dicyclohexyl A solution of amidine (674 mg, .3.3 mmol) and 4- (N, N-dimethylamino) pyridine (472 mg, 3.9 mmol) in dichloromethane (20 ml) in a chamber Under stirring under nitrogen, add octadecyl-6,9,12-trimethyloxy) -3-¾propane (1 g, 2.97 mmol) and N-tBOC-proline (671 mg, 3.12 mmol) in dichloromethane (20 mmol-48-this paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 ^^ 7 a " ~ ----- ---- Cloth-(Please read the precautions on the back before filling this page), 11 546138 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 (5, Invention Description (46 liters)). Stirring was continued for 7 hours, and the mixture was stored at 0 ° C overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain 1 · (ζ, ζ, ζ-octadecyl-6,9,12 · trienyloxy) -3- (N_tBOC -2-Pyrrolidine carboxy) propane, as a yellow oil. Part 2: The protected product was dissolved in 10% vol / vol anisole / trifluoroacetic acid (10 ml) and placed at room temperature under nitrogen for 30 minutes. After tic analysis showed that deprotection was complete, the mixture was purified by column chromatography (80/0 methanol / 42% dichloromethane / 50% ethyl acetate) to obtain i- (z, z, z-eighteen The group _6,9,12 · trisanoic acidoxy group) -3- (2-ρ bilocarbon carboxyl) propanone is a fuming orange oil body. Example 11 1- (2,2,2_octadecyl-6,9,12-trienyloxy)) 3 < 2-amino_3_oxolinylpropanyloxy) propane (color Amino acids and diesters of GLA and 1,3-propanediol) Part 1: 1,3-Dicyclohexylcarbodiimide (674 mg, .3.3 mmol) and 4- (N, N-di Methylamino) pyridine (472 mg, 3.9 mmol) in dichloromethane (20¾ liters): Valley fluid at A temperature under nitrogen and added to ι · (ζ, ζ, ζ_ + eight -6,9,12-trienyloxy) -3-hydroxypropane (1 g, 2.97 mmol) and N-tBOC-tryptophan (950 mg, 3.12 mmol) Methyl chloride (20 ml) in solution. Stirring was continued for 7 hours, and the mixture was stored at 00C overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain l- (z, z, z-octadecyl-6,9,12-trienyloxy) small (N_tBocc_2 Amino-3 (indolylpropionyloxy) propane is a yellow oil. -49- This paper size is applicable to China National Standard (CNS) A4 specification (210X297mm) I: 丨 丨 Γ 疃 丨 丨 (Please read the precautions on the back before filling this page) Order 546138 Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the cooperative A7 ___________ B7 V. Description of the invention (47) Part 2: Dissolve the protected product in 10% volume / volume anisole / trifluoroacetic acid (61 ml) and place it at room temperature under nitrogen for 15 minutes. After tic analysis showed that the deprotection was complete, the mixture was purified by column chromatography (8% methanol / 42% dichloromethane / 50% ethyl acetate) to obtain (2,2,2_octadecyl_ 6,9,12-trienyloxy) -3- (2-amino-3-indolylpropionyloxy) propane, a viscous red waxy substance. Example 12 l- (z, z, z-octadecyl-6,9,12 · trienefluorenyloxy) -3- (from · amino-lu · phenylpropionyloxy) propane (amphetamine Acid and the diester of GLA and 1,3-propanediol) Part 1: 1,3 · Dicyclohexylcarbodiimide (ι · 77 g, 8.57 mmol) and 4- (N, N_monomethylamino group) (1.24 g '10 .13 monmor) solution in digas methylbenzene (30 ml) at room temperature under nitrogen with stirring under octadecyl-6,9, 12-Difluorenyloxy) _3_ Zynyl Propionate (2.62 g, 7.79 mmol) and N-tBOC-phenylalanine (2.17 g, 8.18 mmol) in dichloromethane ( 30¾: liter). Stirring was continued for 7 hours, and the mixture was stored at 0. ^ Overnight. The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain l- (z, z, z-octadecyl · 6,9,12-trienyloxy) _3_ (N_tBOC_ α-Amino-yS-phenylpropanoyloxy) propane is yellow oil. Part 2: Dissolve the protected product in 10% vol / vol anisole / trifluoroacetic acid (7 ml) and place at room temperature under nitrogen for 30 minutes. Analysis at tlc shows that deprotection -50 · _ This paper is suitable for China National Standard ([NS) A4 size (210X297 mm ^-'-----:! Γ_τ— (Please read the precautions on the back before filling (This page) Order printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 B7-^ 一 ~ " " '—-~ — 丨 1 ——-5. When the description of the invention (48) is complete, the mixture is used as Purification by column chromatography (8% methanol / 42% dichloromethane / 50% ethyl acetate) to obtain l- (z, z, z-octadecyl-6,9,12_trimethylamino) 3- (Amino-L-phenyl-propionyloxy) propane is a flaky yellow oil. Example 13 l- (z, z, z-octadecyl · 6,9,12_ Trienyloxy) _3- (4 · amino-butyryloxy) propane (GABA and GLA and the diester of 1,3 · propanediol) Part 1: Carbide 1,3-dicyclohexyl Solution of iminomine (0.84 g, 4.06 mmol) and 4- (N, N-dimethylamino) pyridine (0.59 g, 4.79 mmol) in dichloromethane (10 ml) Add 1- (ζ, ζ, ζ-octadecyl-6,9,12-diamidinooxy) -3-¾yl under stirring at room temperature under nitrogen. Propylene (1.24 g, 3.69 mmol) and N-tBOC-GABA (0.75 g, 3.69 mmol) in dichloromethane (15 ml). Stirring was continued for 7 hours and the mixture was stored overnight The mixture was filtered and purified by column chromatography (methanol / dichloromethane) to obtain 1- (ζ, ζ, ζ octadecyl_6,9, 12_trienyloxy) _3_ (N -tB〇c_4-Amine-butyryloxy) propane, a colorless oil. Part 2 ·· Dissolve the protected product in 10% volume / volume anisole / trifluoroacetic acid (105 ml) under nitrogen The mixture was left at room temperature for 30 minutes. After tic analysis showed that deprotection was complete, the mixture was purified by column chromatography (8% methanol / 42% digasmethane / 50% ethyl acetate) to obtain l- (z, z, z-octadecyl_6,9,12_trifluorenyloxy) -3- (4-amino-butylfluorenyloxy) propane gauge is a yellow oil body. -51-This paper size applies to China National Standard (CNS) Α4ϋ 2ί〇Τΐ97mm) — ~~ '— ·; ——— 4II (Please read the precautions on the back before filling out this page), 11 Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ B7 Explanation of the invention (49) One ~ ^ ~ Example 14 3,3'-thiodi- (bupropenyloxy) · (3_ (ζ, ζ, ζ_octadecyl α α-trisyloxy) propane) ) (GLA with 1,3-propanediol and 3,3'-thiodipropionic acid bisdiacetate) Dicyclohexylcarbodiimide (660 mg, 3.22 mol) and 4_ (N Of N-dimethylaminopyridine (5 mg, 3.64 mol) in dichloromethane (10 ml) at room temperature under nitrogen and added to 2 _ (ζ, ζ , Ζ-octadecyl · 6,9,12 · trisyloxy) -3-¾propylpropane (940 mg, 2.8 mmol) and 3,3 ·· thiopropionic acid (250 mg, 1.4 Mol) in a solution in methylene chloride (30 ml). Stirring was continued for 4 hours. The mixture was diluted with hexane (50 ml), filtered, concentrated, and purified by flash chromatography (ethyl acetate / hexane). The product fractions were collected and concentrated to obtain 3,3, _thio-di_ (1-propanyloxy)-(3- (z, z, z-octadecyl-6,9,12-trifluorene) Bake based oxy) propylene)), is a colorless oil body. Example 15 l- (l- (z, z, z-octadecyl · 6,9,12_trienefluorenyloxy > 3.propylM_ (ζ ζ, ζ_octadecyl-6,9, 12-trienyl) butane- 丨 'diester ((GLA monoester and 1,3-propanediol) and GLA alcohol and succinic acid) diester) Part 1: Put 1_ (ζ, ζ, ζ_octadecyl_6,9,12-trienyloxy) _3-hydroxypropane (10 g, 30 mmol) and succinic anhydride (3 g, 30 mmol) The mixture in anhydrous THF (100 ml) was stirred at room temperature until a clear solution was obtained. This solution was cooled to 0 ° C, and u-diazabicyclo [5 · 4.0] undecene (45 ml, 30 mmol) was added dropwise. Moore) solution in anhydrous THF (50 ml). After 3 hours ^ show _ ^ -52- This paper size applies to China National Standards (CNS) A4 specifications (21〇χ 297 public envy) I: ί— 蔑| 丨 (Please read the precautions on the back before filling this page), 1546 printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs, 546138 A7 -___ B7______ 5. The invention description (50) shows that most of the monoesters have reacted. Add a little succinic anhydride to crystallize and continue stirring for 30 minutes. The reaction mixture was treated with ether (250 ml) Dilute, wash with 2M hydrochloric acid (2x250 ml), water (250 ml), and brine (250 ml). Then dry (sodium sulfate) and concentrate to dryness. This material is used directly without purification. Part 2: The grasshopper Chlorine (3.9 ml, 45 mmol) was added to a solution of Part 1 product (13 g, 30 mmol) in dichloromethane (75 ml). The mixture was stirred at room temperature under nitrogen for 2 hours and concentrated. Add to dryness. Add hexane (75 ml), and concentrate the mixture to dryness. Repeat this process with two portions (75 liters each). This material is used directly without purification. Part 3: Prepare part 2 A solution of the obtained hydrazone gas (1 g, 2.2 mmol) in dichloromethane (10 ml) was added dropwise to z, z, z_octadecyl_6,9,12_trifluorene at room temperature. Alcohol (635 mg, 2.4 mmol), triethylamine (1 liter, 7.2 mmol) and 4- (N, N-dimethylamino) p ratio (catalytic amount) in chloroform溶液 (20 ml) in solution. After the reaction was completed, the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 1_ (ζ, ζ, ζ · 18 _6,9,12-trienyloxy) _3_propyl) _4 · (ζ, ζ, ζ-octadecyl-6,9,12_trimethyl) butyrate], 4_diacid Purpose is a colorless oil body. Example 16 1- (2,3,5 · Trispobenzyloxy) -3_ (ζ, ζ, ζ_octadecyl-6,9,12-trienyloxy) propane (2, 3,5-triiodobenzoic acid and GLA with 1,3-propanediol diacetate) 2,3,5-tribenzyl chloride (1.54 g '3.08 mol) added to the cloth (ζ, ζ ζ_ -53- P-sheet I degree is applicable to Chinese National Standard (CNS ~) A4 specification (27 ^ 77 mm ~~ -----: ——— 疃 | 丨 (Please read the note on the back first) Please fill in this page again for the matters) Order the consumer cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs, printed 546138 A7 B7 V. Description of the invention (51) ~ octadecyl-6,9,12-trienyloxy) -3- A solution of light propylene (J g, 297 mmol) and triethylamine (1 ml) in dichloromethane (80 ml), the mixture was stirred at room temperature under nitrogen overnight. The mixture was stirred. Concentrate and purify by flash chromatography (ethyl acetate / hexane) to obtain 1- (2,3,5-trispobenzyloxy) -3- (z, z, z-octadecyl- 6,9,12-trienyloxy) propane. Example 17 (Earth) -1- (1,2-disulfane · 3_pentamyloxy) _3_ (z, z, z, z, z , Z-twenty-two base one 4,7,10,1 3,16,19-Hexenyloxy) propane (DHA and the diester of lipoic acid and 1,3-propanediol) Part 1: Put 2,2,2,2,2,2-2.2 A solution of phenyl 4,7,10,13,16,19-hexaenoic acid (64 g, 19.5 mmol) in dichloromethane (225 ml) was added dropwise at -1 ° C to 1,3 -Propanediol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.65 g, 20 mmol) and 4- (N, N · dimethylamino) pyridine (21 g, 17 mmol) in dichloromethane (225 ml). The reaction mixture was stirred overnight and warmed to room temperature. The mixture was filtered, concentrated, and analyzed by flash chromatography (ethyl acetate / hexane). Alkane) purification to obtain 1- (ζ, ζ, ζ, ζ, ζ, ζ docosyl_4,7,10,13,16,19-hexaenyloxy) -3-mer It is sintered as a gray-yellow oil. Part 2: Carrying 1,3-dicyclohexylcarbodiimide (720 mg, 3-45 mmol) and 4- (N, N_dimethylamino) Edo (4 80 mg, 3.9¾ mol) in dichloromethane (30 ml) was added to 1 · (ζ, ζ, ζ, ζ, ζ, ζ_tcosyl_4, 7, 1〇 , 13 16, 19-Hexadecyloxy) -3-¾-propane (1.16 g, 3¾ mol) and lipoic acid_ -54- This paper size applies to Chinese National Standard (CNS) mm 1 '一 ~ " 一 "-!: Ί ι # τ — (Please read the notes on the back before filling this page) -Order

Printed by the Consumers' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs I 546138 A7 ------ _B7 V. Description of the invention (52) a ^ ~ --- Γ: = νΛ12mmol) and dichloromethane (05ml) . … After 2.5 hours under nitrogen rolling, the mixture was filtered, concentrated, and purified by flash color 4 analysis (ethyl acetate / hexane) to obtain (soil), disulfanyl) _3_ (ζ, ζ, ζ, ζ, ζ, ζ Twenty-two bases · WWW,:; · Dimethyloxy) propionate is a yellow oil body. Methyl-bis (ζ, ζ, ζ_octadecyl_6 9,12_trienyloxypropyl) phosphate (2 molecules of 3-hydroxypropyl ester of GLA and! Molecule of phosphorus formed by methanol Triester part 1: 1 Triethylamine (3.74 liters, 26.8 mol) was added dropwise to freshly distilled squid chloride (2.74 mg, 17.9 mmol) in anhydrous THF (15 liters) To a cold (0 C) solution, to this mixture was added dropwise octadecyl · 6,9, ΐ2_ hydrazone oxy) · 3 · ^ propylpropane (5 g, 14.9 ml) in anhydrous thF (15 ml) In solution. Maintain the temperature at 10. (Under, the reaction was carried out under nitrogen. After 15 minutes, the starting material was completely free from tlc measurement. The mixture was purged and concentrated. Toluene (50 ml) was added and the mixture was concentrated. Add another portion Toluene (50 ml) and remove again. Part 2: Put 1 · (ζ, ζ, ζ-octadecyl · 6,9,12 · trienyloxy) _3-hydroxypropane (3 g, 9 mmol) Moore) solution in anhydrous THF (10 ml) was added dropwise at room temperature under nitrogen to crude phosphonium chloride (7.5 mmol) (half of the amount prepared in Part 2) and triethylamine (3.2 (12.5 liters, 22.5 mmol) in a solution of anhydrous THF (20 ml). The reactant was stored at less than 10 ° C for 3 days. Add methanol (15 ml) and store the reactant at room temperature until tic determination. Phosphonium chloride has completely reacted to produce the required phosphorus • 55- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm): ί Γ! (Please read the precautions on the back before filling this page)- Order 546138 A7 B7 53 V. Description of the invention (------------ (Please read the precautions on the back before filling in this page) Triester. For flash chromatography analysis (acetic acid Ethyl ester / hexane) was purified to obtain methyl-bis (z, z, z-octadecyl-6,9,12-trienyloxypropyl) phosphonate as a colorless oil. 19 Bis (z, z, z-octadecyl-6,9,12-trisyloxypropyl) ridine acid (Phosphonium diphosphonate of 2-¾-propylpropyl acetate of 2 molecules of GLA) Add methyl ethyl ketone (1 ml) to desertification (104 mg, 1.13 mmol) and add methyl di (z, z, z_octadecyl_6,9,12 · triene 醯The solution of alkoxypropyl) phosphonium phosphate (0.85 g, 1.13¾ mole) (prepared in Example 18) in methyl ethyl ketone (1 liter) was heated under reflux for 1 hour. After cooling, the mixture was dissolved in ether (3 ml) and extracted with water (3 ml). A few drops of methanol were added to destroy the emulsion formed. The organic layer was separated, dried (sodium sulfate), concentrated, and analyzed by flash chromatography (methanol / Chloroform) was purified to obtain bis (z, z, z_octadecyl-6,9,12-dienyloxypropyl) phosphonate as a white solid. Example 20 (2-amino Ethyl)-(ζ, ζ, ζ · octadecyl-6,9,12-trienyloxypropyl Hong acid 酉 § (Phosphodiesters of ethanolamine and 3-hydroxypropyl esters of GLA) Part 1: Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, ethanolamine (0.5 ml, 8 25 mmol) and triethylamine (42 ml, 30 millimoles) was added to a solution of crude phosphorous chloride (7.5 millimoles X half of the amount prepared in Example 8 part i) in anhydrous THF (20 milliliters), maintaining the temperature below i 〇 ° C. The reaction was carried out with a tic supervise and a plate. This mixture was stored at less than 5 C for 3 days. Then 遽, concentrated, diluted with hexane ⑼ml), and then -56-

'The paper size applies to the Chinese national standard (CNsI A4 specification (21 〇χ297 public shame •!--! Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 ____ — ___ B7 V. Description of the invention (54)) Condensed. Part 2: The product obtained from Shaofen 1 was dissolved in isopropanol (100 ml), acetic acid (10 ml) and water (40 ml). The solution was left at room temperature under nitrogen. When tic showed that the reaction was complete The mixture was concentrated and separated between acetonitrile (50 ml) and hexane (50 ml). The hexane layer was separated, concentrated, and purified by flash chromatography (methanol / chloroform / water). The purified portion was collected and concentrated. Acetic acid was added Ethyl vinegar was crushed to obtain (2 · aminoethyl) · (ζ, ζ, ζ-octadecyl-6,9,12_trienyloxypropyl) phosphate, which was a soil-like milk color. Solid, recovered by centrifugation. Example 21 (ζ, ζ, ζ_octadecyl_6,9,12-trienyloxypropyl) _ (2- (N, N, N-trimethylammonium) Ethyl) phosphate ester (choline diester of choline and 3-hydroxypropyl ester of GLA) Part 1 ··· 2-Chloro-1,3,2_dioxophosphate · 2_ oxide (430 mg, 3.4 mo ) The solution in toluene (5 ml) was added to l- (z, z, z-octadecyl-6,9,12-trienyloxy) -3 · hydroxypropane (1 g, 2.98 Mmol) and triethylamine (0.57 ml, 4.1 mmol) in a cold (0 ° C) solution in toluene (45 ml). This mixture was stirred overnight while warming to room temperature. Tl c. The analysis shows that the reaction is complete. Add triethylamine (0.3 ml) and 2-chloro-1,3,2_dioxophane-2-oxidation (200 mg) (toluene (5 ml) in solution ), And then allowed to react overnight. At this time tic showed that the reaction was complete, the mixture was concentrated. Part 2: The crude product of Part 1 was dissolved in acetonitrile (60 ml). A quarter of this -57-paper Standards are applicable to China National Standard (CNS) A4 specifications (2⑴X 297 mm) (Please read the precautions on the back before filling out this page). Order printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 __— 一 ___ B7 5. Description of the invention (55) The solution (15 ml) and triethylamine (10 ml) were heated in a closed tube at 60 ° C for 5 hours (beware). The reaction was cooled and the reaction mixture was cooled under nitrogen. Concentrated under gas to obtain (z, z, z-octadecyl-6,9,12-trienyloxypropyl) · (2- (N, N, N_5methylammonium) ethyl) phosphate Example 22 (ζ, ζ, ζ-octadecyl-6,9,12 · trienyloxypropyl) phosphonate (phosphoric monoester of 3-hydroxypropyl ester of GLA) 1- ( ζ, ζ, ζ_octadecyl · 6,9,12_trienyloxy) · 3-hydroxypropane (1.95 g, 5.8 mmol), pyridine (1.4 mg, 17.3 mmol) and A solution of anhydrous THF (15 ml) was added dropwise to a solution of squama chloride (1.02 g, 6.6 mmol) in a cold (0 ° C) solution in water THF (5 ml). Store at 0 ° C for 3 hours. To the reaction mixture was added an aqueous sodium hydrogen carbonate solution (10% w / w, 10 ml). After stirring for 20 minutes, the mixture was poured into ice / water (30 ml), and the solution was acidified to pH 1 with 2M hydrochloric acid dropwise. This mixture was extracted with ether (2 X 30 ml). The combined ether extracts were dried and concentrated. The obtained oil body was azeotroped with anhydrous 1 " Bide Lake to obtain (z, z, z-octadecyl-6,9,12-trisyldonyloxypropyl) phosphate as a viscous yellow solid. Example 23 Methyl- (z, z, z-octadecyl-6,9,12-triammonyloxypropyl)-(α-tocopheryl radical) Phosphotriester of 3-hydroxypropyl esters of methanol and GLA) Part 1: Triethylamine (7.5 ml) was added to freshly distilled phosphorous chloride (1.26 g, 8.25 mmol) in anhydrous THF ( 7.5 ml). 15minutes-58- Chinese National Standard (CRS) Ί ^ ϋΤ2] 〇κ 297 mm) (Please read the notes on the back before filling out this page)-1T Printed by the Central Consumers Bureau of the Ministry of Economic Affairs Consumer Cooperative 546138 A7 __________ B7__ V. After description of the invention (56), add (z, z, z-octadecyl-6,9,12-trienyloxy) -3 · at 30 ° C for more than 30 minutes. A solution of hydroxypropane (2.5 g, 7.5 mmol) in anhydrous THF (7.5 ml). After the addition of alkane, stirring was continued at this temperature for 30 minutes. Then, a solution of π-tocopherol (3.23 g, 7.5 mmol) in anhydrous THF (5 ml) was added dropwise at 10 ° C, and the resulting mixture was stirred at 10 ° C for 1 hour, and then raised to room temperature and stirred overnight. Part 2 · Part 2 of a quarter mixture of triethylamine (0.8 ml, 6 mmol) and methanol (10 ml) was stirred at room temperature under nitrogen overnight. The reaction mixture was concentrated and separated between ethyl acetate (30 ml) and water (20 ml), and the emulsion was broken by adding sodium chloride and methanol at the same time. The ethyl acetate layer was dried, concentrated, and purified by flash chromatography (chloroform) to obtain methyl- (z, z, z-octadecyl-6,9,12-trienyloxypropyl)- (Cardiotocopheryl) phosphate. Example 24 (z, z, z-octadecyl-6,9,12-trisyloxypropyl) (yi-tocopheryl) phosphonate (cardiol tocopherol and GLA 3-hydroxypropyl Phosphodiesters of the ester) Triethylamine (2 ml) and water (5 ml) were added to a quarter of the reaction mixture prepared in Example 23, Part 1. The mixture was stirred in an ice bath under nitrogen for 1 hour, 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 obtain (z, z, z-octadecyl-6,9,12-trienyloxypropylsulfonyl tocopheryl) phosphate ester. Example 25 -59- This paper size applies the Chinese National Standard (CNS) Α4 size (210X29? Mm) (Please read the notes on the back before filling this page) Printing 546138 A7 _B7 __________ V. Description of the invention (57) 1- (2,2,2-octadecyl_6,9,12-trienyloxy) _5_ (2,2,2,2,2 -Eicosyl- 5,8,11,14,17-pentaenyloxy) pentane (GLA and EPA diester with 1,5-pentanediol) Part 1: z, z, z Octadecyl_6,9,12-trienephosphonium chloride (2 g) was added dropwise to 1,5-dihydroxypentane (3.5 g), triethylamine (0.94 ml) and 4- (N , N-dimethylamino) pyridine (0.2 g) in a solution of dichloromethane (50 ml), while stirring at 0 ° C under nitrogen: drop. After tic showed that the reaction was complete, the reaction mixture was washed with dilute hydrochloric acid and water, dried, and purified by column chromatography to obtain l- (z, z, z_octadecyl_ 6,9,12-trienyloxy). -5-Light pentyl pit, a gray-yellow oil body. Part 2: The method of Example 2 is used, but l_ (z, z, z_octadecyl-6,9,12 · trienyloxy) -5-¾ylpentanyl is used instead of ΐ- (ζ , Ζ, ζ-octadecyl-6,9,12 · trisyloxy) -3-hydroxypropane, using ζ, ζ, ζ, ζ, ζ eicosyl_5, 8, 11, 14 , 17-pentapic acid replaces z-octadecyl-9-enoic acid. Chromatographic analysis yields h (z, z, z_octadecyl · 6,9,12 · trienyloxy) -5_ (z, z, z, z, z-eicosyl_5,8, 11,14,17-pentaenyloxy) pentane as a gray-yellow oil. Example 26 l- (z, z, z-octadecyl-6,9,12 · trienyloxy) _4- (z, z, z, z, z_eicosyl_ 5,8,11 , 14,17-pentaenyloxy) benzene (GLA and EPA diesters with 1,4-dihydroxybenzene) Example 25 Part 1 and 2 method, but υ-disuperylbenzene in part j In place of 1,5-dimeric pentane, tetrahydrofuran was used in place of methylene chloride as the solvent in part i. Chromatographic analysis yields l- (z, z, z_octadecyl_6,9,12 • trienefluorenyl _______ _60_ This paper is suitable for the standard (---__ (Please read the precautions on the back before (Fill in this page)

、 1T 546138 A7 B7 printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economy 17-pentaenyloxy) benzene as a gray-yellow oil. Example 27 1,4-bis (2;, 2,2-octadecyl-6,9,12_dioxyl) _butan-1,4- ^ monocarboxylic acid (GLA alcohol and succinic acid Diester) Part 1: Add a solution of 1,8-diazabicyclo [5.4.0] undec-7_ene (0.54 ml) in anhydrous tetrahydrocran (10 ml) to z, z, z_octadecyl_6,9,12-trienol (1 g) and succinic anhydride (0.3 6 g) in a cold (0 ° C) solution in anhydrous tetrahydrofuran (20 ml). After tic showed that the reaction was completed, the reaction mixture was diluted with ether 'and washed with dilute hydrochloric acid, water and brine. The organic layer was dried, concentrated and used directly in Part 2 reaction. Part 2: 1,3-Dicyclohexylcarbodiimide (0.83 g) and 4- (N, N-dimethylamino) pyridine (0.55 g) in dichloromethane (20 ml) The solution was added to (z, z, z-octadecyl-6,9,12-trienyl) -butane-1,4-diester (1.32 g) and z, z, z-octadecyl A solution of stilbene-6,9,12-trienol (0.98 g) in dichloromethane (40 ml). After the tic measurement reaction was completed, the reaction mixture was diluted with hexane, filtered, concentrated, and purified by column chromatography to obtain 1,4-bis (z, z, z-octadecyl-6,9,12-trienyl ) -Butane-1,4-diester 'is a gray-yellow oil. Example 28 2- (2-methyl-5-nitroimidazolyl) ethyl-z, z, z_octadecyl-6,9,12_trienoate (ester of metronidazole and GL A) -61-This paper size applies Chinese National Standard (CNS) Α4 size (21〇 × 297 mm)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 546138 A7 _______ B7 V. Description of the Invention (59) Method A: In metronidazole (206 g) in anhydrous acetonitrile (2300 ml) and anhydrous pyridine (107 ml) To this suspension was added z, z, z-octadecyl-6,9,12-trienephosphonium chloride (373 g) under stirring at room temperature under nitrogen for 30 minutes. A short period of time after the addition of fluorenyl chloride formed a clear solution, and stirring was continued for 2 hours. The mixture was allowed to stand at room temperature overnight, and the solvent was removed by evacuating (50 ° C / 20 mmHg). Ethyl acetate (1000 ml) was added to the residue, and any precipitated solid was filtered off. The ethyl acetate solution was washed successively with brine, 2M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and finally with brine. After drying (sodium sulfate), the solvent was removed to obtain an orange oil. Using this material for dry chromatography analysis, 2- (2-methyl-5_nitroimidazolyl) ethyl-z, z, z-octadecyl-6,9,12-trienoate was obtained as Grayish yellow non-distilled 1 crude oil body. Method B: Suspend metronidazole (1.9g) in toluene (30ml), and heat the mixture under reflux with Dean and Stark head for 20 minutes under stirring to remove possible moisture. In this boiling solution, z, z, z-octadecyl-6,9,12-trienephosphonium chloride (2.96 g) was added dropwise under nitrogen for 20 minutes. This mixture was stirred and heated under reflux for 2 hours to obtain a dark reaction mixture. After cooling, the mixture was subjected to dry column chromatography to obtain 2- (2-methyl-5-nitroimidazolyl) ethyl-ζ, ζ, ζ octadecyl-6,9,12-trienoate, It is a gray-yellow non-distillable oil body. Example 29 2_ (2-methyl-5-nitroimidazolyl) ethyl_z, z_octadecyl-9,12-dienoate (metronidazole Ester with LA) I —__ -62- This paper size is applicable to Chinese National Standard (CNS) Regulation 8 "1" 2 "0 ^ 7 mm_ (Please read the precautions on the back before filling this page}

1,1T printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 546138 A7 _____ B7 V. Description of the invention (60) --- Suspension of metronidazole (1.9 g) in anhydrous dichloromethane (20 ml) Add 4- (N, N-dimethylamino) xanthene (1.22 g), cyclohexylcarbodidonylamine (2.2 g) and linoleic acid (2.8 g). This mixture was allowed to fall overnight. To this reaction was added 2M hydrochloric acid (20 ml), and teaching was continued. The organic layer was separated after washing, washed with 50% saturated brine, and then with a saturated aqueous sodium hydrogen carbonate solution. This dichloromethane solution was dried (sodium sulfate) and evaporated in vacuo (30 ° C / 20 mmHg). To this residue was added gasoline (boiling point 30-6 (rc, 20 ml)), and the mixture was left at room temperature for 2 hours to precipitate the remaining intestines. The veins were removed by filtration, and the filtrate was applied to a dry column to obtain 2- (2-Methyl_5_acidimidyl) ethyl-z, z-octadecyl-9,12-diphosphonate, a grayish yellow non-steamed oil body. Example 30 2 · (2-methyl-5-nitroimidyl) ethyl-z, z, z-icosyl-8,11,14-triassociate (ester of metronidazole and DGLA) in a similar manner However, the required amount of z, z, z-icosyl-8,11,14_trisuccinic acid was used instead of linolein 'to obtain 2- (2-methyl-5-nitroamido) ethyl-z , Z, z-icosyl_8,11,14-tris (triacetate). Example 31 2_ (2_methyl_5_nitroamido) ethyl_2:, 2,2,2,2 , 2-Doccosyl-4,7,10,13,16,19-hexaenoate (ester of metronidazole and DHA) in a similar manner but with the required amount of z, z, z, z , Z, z_docosalyl_4,7,10,13,16,19-hexaenoic acid instead of linoleic acid to obtain 2- (2-methyl-5-nitroimidazolyl) -63 -This paper size is applicable to China National Standard (CNS) A4 (210X 297mm) ^ '(Please read the back first (Please fill out this page again)

546138 A7 ------- B7 ___ V. Description of the Invention (ei) Ethyl_2,2,2,2, Redundant, 2_Ocosyl-4,7,10,13,16,19- Hexanoate. 4- [3- [2_ (trifluoromethyl) 1〇11_pheno-sepogen_ι〇_yl]] · 1 · hexahydropyridine p-ethyl · ζ, ζ, ζ-octadecyl-Hu · Trienoates (the purpose of fluphenazine and GL Α) in a similar manner but with the required amount of 4- [3- [2- (trifluoromethyl) 10H-phenpyrimidine • 10-yl]] _1_ The free state test of hexahydroecohol ethanol (fluphenazine) replaced metronidazole, and the required amount of GLA was used instead of linoleic acid to obtain 4_ [3_ [2_ (trifluoromethyl) 10H- Phenomenone_10_yl]]-1-hexahydropyroxyethyl_z, z, z-octadecyl-6,9,12-trihydrate. 4,4, (bis-z, z, z-octadecyl-6,9,12-trienylamidoamino) diphenylphosphonium (diphenylphosphonium and bisphosphoniumamine of GLA) in a similar manner but with the need The amount of 4,4, -diaminodiphenylphosphonium (aminophenylhydrazone) was used in place of metronidazole and the required amount of GLA was used in place of linoleic acid to obtain 4,4 ·-(bisζ, ζ, ζ -Octadecyl-6,9,12-trienylaminoamino) diphenylsulfone. 34 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) N-methyl-3-phenyltrifluoro-para-tolyl] propyl; ζ, ζ, ζ Octadecyl 6,9,12-trisaminol (fluorophenoxypropylamine and glutamidine GLA) in a similar manner but with the required amount of N-methyl-3-phenyl-3 [from, ~ from -Trifluoro-p-tolyl] propylamine (fluorophenoxypropylamine) in place of metronidazole and the required amount of GLA in place of linoleic acid to prepare N-methyl-3-phenyltrifluoro- Para-tolyl] propyl; ζ, ζ, ζ-octadecyl-6,9,12-trienylamine. -64- This paper size applies Chinese National Standard (CNS) A4 specification (210 × 297 mm) 546138 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (62) trans-l_ (z, z, z-octadecyl-6,9,12 · trienylamidoamino) -2 · phenylcyclopropane (transphenylcyclopropylamine and glutamine of GLA) in a similar manner but with the required amount of trans-i- Amino-2-phenylcyclopropane was used in place of metronidazole, and linoleic acid was replaced by the required amount of gla to obtain trans-1- (z, z, z_octadecyl-6,9,12 · Trimethylamino) -2-phenylcyclopropane. 6-[(Aminophenylethylaceto) amino] _3,3, · dimethyl · 7_oxy_4_thia-pyrazinebicyclo [3.2.0] heptane_2_carboxylic acid_z , Z, z-octadecyl-HU-trienamidine (Ampicillin and GLA amidine) Triethylamine (0.3 ml) was added to ampicillin (0.7 g) under anhydrous nitrogen in anhydrous DMF (120 ml) in a stirred suspension. To this clear solution was added ζ, ζ, ζ octadecyl 6,9, 12-diene, N-hydroxysuccinimide (0.75 g), while maintaining the reaction at 0-10X :. The reaction was stirred at this temperature for another hour 'and then left at room temperature overnight. At this time tlc analysis (40% THF / hexane) showed that almost all of the succinimide ester had reacted. Water (40 ml) was added to the flask 'and the contents were stirred. This solution was then neutralized and extracted with ethyl acetate. The extract was washed with water, dried (sodium sulfate), and concentrated to dryness to give the crude product as a yellow glass. Trituration with hexane yielded 6-[(aminophenylethylethyl) amino] -3,3 · -dimethyl-7-oxy-4-thia-1-azabicyclo [3.2.0] heptane Alkan-2-carboxylic acid-ζ, ζ, ζ-octadecyl-6,9,12-trimethylamine is a yellow powder. Example 37 ζ, ζ, ζ_octadecyl_6,9,12-diamidyl_ζ, ζ, ζ_octadecyl_6,9,12 · trisuccinate (GLA and GLA alcohol ester ) -65- This paper size applies Chinese National Standard (CNS) Α4 size (27 ^ 297mm) ----- IIM4Ⅰ. (Please read the precautions on the back before filling this page) Order 546138 Central Bureau of Standards, Ministry of Economic Affairs Printed by employee consumer cooperative A7 B7 V. Description of the invention (63) 1,3-Dicyclohexylcarbodiimide (0.82 g) and 4- (N, N-dimethylamino) pyridine (0.48 G) A solution in dichloromethane (5 liters) was added to z, z, z-octadecyl-6,9,12-trienol (0.95 g) and ζ, ζ at room temperature under nitrogen. Zetadecyl-6,9,12-trienoic acid (1 g) in a solution of dichloromethane (10 ml) while stirring. After tic proved that the reaction was complete, hexane was added to the reaction mixture, and then filtered and purified by column chromatography to obtain z, z, z-octadecyl-6,9,12-trienyl_ζ, ζ, ζ -Octadecyl-6,9,12-trimethyl ester, a grayish yellow oily body. Example 38 z, z, z-octadecyl-6,9,12 · trienyl-z, zz, z zicocosyl-5,8,11,14,17-pentaenoate (EPA and GLA alcohol ester) was prepared as described in Example 37, but using z, z, z, z, z-eicosyl-5,8,11,14,17-pentaenoic acid instead of z, z, z-deca Octyl-6,9,12-trienoic acid. Example 39 2-methyl-3- (2,2,2,2,2-eicosyl-5,8,11,14,17-pentaenyloxy) -4-methylamidino-5- , ^ 2-Eicosyl_5,8,11,14,17-pentaenyloxy) methyl eodolide (dipyridoxal diEPA) in diacetate) in dichloride To the suspension in methane (20 ml) was added triethylamine (2.0 ml). A clear yellow solution formed. Add 2,2,2,2,2-eicosyl-5,8,11,14,17-pentafluorene gas (1_73g) under cooling in ice. Prepared in methane). This mixture was stirred under nitrogen overnight while warming to room temperature. After diluting with an equal volume of dichloromethane, the mixture was extracted with 2M hydrochloric acid (20 ml), washed with water (3 x 20 ml), and dried ___ -66 · This paper is suitable for ^ mm · —— ( Please read the precautions on the back before filling out this page.) Order 546138 Consumption Cooperation between Employees of the Central Bureau of the Ministry of Economic Affairs, print A7, B7 5. Description of Invention (64) and condensed. Purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3- (2,2,2,2,2-icosyl-5,8,11,14,17_pentene Fluorenyloxy) -4_methylfluorenyl-5- (2,2,2,2 3-eicosyl_5,8,11,14,17_pentaenyloxy) methyleridine, To clarify the oil body. Example 40 2 · methyl_3_hydroxy · 4_methylamidino-5- (z, z, z-octadecyl-6,9,12_trienyloxy) methylpyridine (pyridoxal GLA ester) A solution of z, z, z_octadecyl-6,9,12_trienephosphonium chloride (800 mg, 2.7 mmol) in dichloromethane (10 ml) at 0 ° C at Slowly add pyridinium hydrochloride (500 mg, 2.45 mmol), triethylamine (1 ml, 7.2 mmol), and 4- (N, N · dimethylamino) pyridine under nitrogen. (A few mg, catalytic amount) in a mixture of dichloromethane (20 ml). After the reaction was determined to be complete by tic, the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3-¾yl-4-methylfluorenyl-5 · (ζ, ζ, ζ-octadecyl-6,9,12-trimethyloxy) methylpyridine is a colorless oil body, and this oil body is further cured. Example 41 '------- 2_methyl_3_hydroxy-4,5 · bis (ζ, ζ, ζ · octadecyl-6,9,12_trienyloxy) methyl Ebbitate (bis-GLA ester of pyridoxine) ζ, ζ, ζ-octadecyl-6,9,12-triene tritium (650 mg, 2.2 mmol) in dichloromethane (10 ml) The solution was at 0. (: Slowly added pimerolol hydrochloride (206 mg, 1 mmol), triethylamine (0.7 ml, 5 mmol) and 4- (N, N-dimethyl) under nitrogen. Amine) ρ Bidian (a few milligrams, catalytic amount) in two gases _ -67- This paper size applies Chinese National Standard (CNS) grid (210X 297 cm) " '~: II—41— (Please read first Note on the back, please fill out this page again) Order printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 —--------------- B7 V. Description of Invention (65) “Methane (20 Ml). After measuring the reaction to completion (4 hours), the mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain 2-methyl-3 · hydroxy · 4,5. _Bis (ζ, ζ, ζ · octadecyl-6, 9, 12 trienylfluorenyloxy) methylpyridine is a colorless oil body. Example 42 1_ (2- (2 • methylnitroimidazolyl) Ethyl) _4_ (ζ, ζ, ζ_octadecyl_6,9,12_trienyl) butane_1,4 · diester (Metronidazole and GLA alcohol and succinic acid) ) 1,3-Dicyclohexylcarbodiimide (780 g, 3.8 mmol) A solution of 4- (N, N-dimethylamino) pyridine (530 mg, 4.3 mmol) in dichloromethane (15¾ liters) was added to succinic acid under nitrogen at room temperature under nitrogen. Acid monoester (1.25 g, 3.3 mmol) (as prepared in Example 27, Part 1) and metronidazole (620 mg, 3.6 mmol) in dichloromethane (30 mL) .tic After the reaction was proved to be complete, the mixture was diluted with hexane, filtered, and concentrated to be purified by flash color analysis (ethyl acetate / hexane). The product portion was collected and concentrated to obtain 1- (2_ (2-methyl_5) _Nitroimidino) ethyl) 4- (z, z, z-octadecyl-6,9,12-trimethyl) butan-1,4 · dicarboxylic acid, which is a colorless oily body. Example 43 trans-1- (ζ, ζ, ζ-octadecyl-6,9,12-trienyloxycarbonylbutyloxyamino) -2-phenylcyclopropane (succinic acid, 1 -GLA alcohol ester, 4-transphenylcyclopropylamine sulfonamide) 1,3-dicyclohexylcarbodiimide (315 mg, L52 mmol) and 4- (N, N-dimethylamino) A solution of the precipitate (210 mg, 1.72 mol) in dichloromethane (10 ml) was stirred at room temperature under nitrogen. For GLA Alcohol-68- This paper size applies Chinese National Standard (CNS) A4 $ (210X 297 mm) ~~~~ ~ —: IIΓΓ— 丨 (Please read the notes on the back before filling this page) Order Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 546138 A7 ______ B7 V. Description of the invention (66) ~~ ^ — Succinic acid monoester _ mg, m millimoles (as prepared in Example 27 part ι) and transphenyl ring A solution of propylamine (225 mg, i.32 mmol) in dichloromethane (20 ml). After tic proved that the reaction was complete, the mixture was diluted with hexane, filtered, concentrated, and purified by flash chromatography (ethyl acetate / hexane). The product portion was collected and concentrated to obtain trans-HZ, Z, Z-octadecyl · 6,912-trienyloxycarboxybutyloxyamino) -2-phenylcyclopropanefluorene as a colorless oil. Example 44 (Earth) -2,5,7,8_tetramethyl-2 · (4,8,12, _trimethyldecyl) _6_oxanaphthyl_2,2,18 -6,9,12-trienyl ester GLA ester of tocopherol) Put 2,2 octadecyl-6,9,12-trienephosphonium chloride (2.96 g, 10 mmol) in nitrogen Below 5 ° (: add 2-3 minutes to (±) _from_tocopherol (4.3g, 10 亳 mol) and pyridine (0 885ml, ηmmol)) while stirring. In a solution in methyl chloride (35 ml). The mixture was stirred overnight while warming to room temperature. The tic showed that the reaction was substantially complete. The reaction mixture was water (100 ml), 2M hydrochloric acid (10 ml in 100 ml). Wash with water (4 ml) and water (4 × 100 ml). The organic layer was dried (sodium sulfate) and concentrated. Purified by flash chromatography (ethyl acetate / hexane) to obtain (±) _2,5,7 , 8-tetramethyl-2- (4 ', 8,12, -trimethyldecyl) -6-oxapyridinyl_ζ, ζ, ζ-octadecyl 4,932-trienyl ester, as Gray-yellow oil. Example 45 Androsta-5-ene-17 · one · 3- (ζ, ζ, ζ, ζ, ζ, ζ-docosalyl-4, 7, 10, 13, 16, 19- Saturday Ethyl acrylate) (DHA ester of dehydroepiandrosterone) -69- This paper size applies to Chinese National Standard (CNS) A4 specification (21 ^ 97 public ΪΤ (Please read the precautions on the back before filling this page) • 噃· Order 546138 Printed by A7 B7, Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (67) in dehydroepiandrosterone (1 g) and triethylamine (1 ml) in dichloromethane (20 ml) To the cold (0C) mixture, add z, z, z, z, z, z_: dodecyl_ 4,7,10,13,16,19_hexamethyl chloride (1.33 g) (to Prepared by reacting DHA with chloramphenicol in dichloromethane). The mixture was stirred overnight while warming to room temperature. Diluted with dichloromethane (20 mL), extracted with 2M hydrochloric acid (20 mL), and water (2 X 20 Ml), washed, dried and concentrated. Purified by flash chromatography (ethyl acetate / hexane) to obtain dehydroepiandrosterene-5 · ene-17-one · 3 (ζ, ζ, ζ, ζ, ζ, ζ -: +: -4,7,10,13,16,19-hexaenoate), which is a clear oil body. Example 46 ζ, ζ, ζ Octadecyl-6,9,12-trienyl _ (2_ (ζ, ζ, ζ-octadecyl_6,9,12_trienyl Base) Acetate) (GLA and GLA alcohols and glycolic acid two purposes) Part 1: Drop chloroacetamyl chloride (0.4 ml, 5 mmol) in dichloromethane (10 ml) at 0 C drop Add ζ, ζ, ζ-octadecyl · 6,9,12 · trienol (1 g, 3.8 mmol) and triethylamine (1.4 ml, 10 mmol) to methane ( 20 ml). Monitor the progress of the reaction with tic. Add a few more drops of chloroacetam. Within 5 minutes tic showed that the reaction was complete. The mixture was washed with water (2 x 50 ml) and brine (50 ml), dried (sodium sulfate), and concentrated. Add toluene (l) and azeotropically remove the last trace of water. The chloroethenyl ester of GLA alcohol was obtained as a dark brown oil body and used without purification. Part 2: Stir z, z, z-octadecyl-6,9,12-trienoic acid (700 mg, 2.5 mmol) and cesium carbonate (410 mg, 1-25 mmol) in methanol To a clear solution. _____-70-This paper rule i is applicable: IIΓ 蔑 — 丨 (Please read the precautions on the back before filling this page), 11 Printed by the Ministry of Economic Affairs Central Standards Bureau Employees' Cooperatives 546138 A7 B7 _ _ .... ......... —; —-1 — 一 -----— -----————____ 5. Description of the invention (68) Then the solution was concentrated and placed under high air Maintain at 40 ° C for 1 hour. The cesium salt of GLA was prepared and used without purification. Part 3: A flask containing the cesium salt of GLA prepared in Part 2 was charged with the chloroethenyl ester of GLA alcohol (Part 1) (500 mg, 1.5 mmol) and DMF in water (15 L). The reaction was stirred at room temperature under nitrogen. After 90 minutes, tic analysis showed that the reaction was complete. The reaction mixture was extracted with hexane (2 X 40 ml). The hexane extract was washed with brine (2 X 50 ml) and water (50 ml), dried (sodium sulphate), and concentrated to give z, z, z. -Octadecyl-6,9,12_trienyl- (2 ((ζ, ζ, ζ-octadecyl · 6,9,12 · tridiyloxy) acetate)) is a colorless oil body. Example 47 Hydrocortisone-21- (ζ, ζ, ζ_octadecyl · 6,9,12-trienoate) (GLA ester of hydrocortisone) ζ, ζ, ζ-octadecyl A solution of -6,9,12 · trienephosphonium chloride (450 mg, 1.52 mmol) in dichloromethane (10 ml) was slowly added dropwise to hydrocortisone (500 mg, 1.38 mmol), triethylamine (420 μl, 3 mmol) and 4_ (N, N-dimethylamino) pyridine (several mg, catalytic amount) in dichloromethane (20 μl) Inside the mixture. After 4 hours, tic analysis showed that the reaction was complete. The mixture was concentrated and purified by flash chromatography (ethyl acetate / hexane) to obtain hydrocortisone-21 · (ζ, ζ, ζ-octadecyl-6,9,12_trienoate), It is a colorless oil body. Example 48 ζ, ζ, ζ · octadecyl-6,9,12-trimethyl- (2- (1- (4-chlorobenzyl) -5-methoxy-2-methylpyridine -3-Ethyloxy) acetate) -71-I Paper size applies to China National Standards (CNS) Millimeter Factory I ~ One: IIΓ Read! (Please read the precautions on the back before filling this page]-Order printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Α7 ______ Β7 V. Description of the invention (69 ~~ — ― 一 ^ ~ G Xiao Yantong and GLA and glycolic acid Diester) Part 1: A mixture of Guzhi indomethacin (895 mg, 2.5 mmol) and cesium carbonate (41 mg, 125 mmol) was stirred in methanol until a clear solution was obtained. Then this solution was used; 'And maintained at 40 ° C for 1 hour under high altitude. An indomethacin absolute salt was obtained as a pale yellow solid. Shaofen 2: In a flask containing the indomethacin cesium salt prepared in Part 1, gla alcohol was added. Preparation of Gas Ethyl Ester Example 46 Part 1) (500 mg, 1.5 mol) and DMF (15 liter) in water. The reaction was stirred at room temperature under nitrogen, and the progress of the reaction was monitored by tlc knife analysis. After overnight in the refrigerator, tlc analysis showed that the reaction was complete. The reaction mixture was separated between water (50 ml) and ethyl acetate (50 ml). Add a few milliliters of saline to destroy the emulsion. The ethyl acetate layer was washed with water (3 × 50 ml), dried (sodium sulfate), filtered through a silica pad, and concentrated to obtain z, z, z_octadecyl-6,9,12_trienyl. -(2_ (1_ (4-Gasbenzylidene) _5_methoxy-2-methylpyridin-3-ethenyloxy) acetate) is a pale yellow oil. Example 49 l- (z, z, z-octadecyl-6,9,12-trifluorenyloxy) -3- (4-phenylbutylfluorenyloxy) propanyl (4-phenylbutanoic acid and Diester of GLA and 1,3-propanediol) 1,3-Dicyclohexylcarbodiimide (710 mg, 3.45 mmol) and 4- (N, N · dimethylamino) pyridine (475 g, 3.9 mmol) in dichloromethane (10 ml) was added to 1_ (ζ, ζ, ζ-octadecyl · 6,9,12-trisyloxy) -3 -Hydroxypropane (1g, 3mmol) and 4-phenylbutanoic acid (520mg, -72-) This paper size applies to China National Standard (CNS) A4 (2! 0 × 297mm) 丨 丨 1 -丨 (Please read the notes on the back before filling in this page)

Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs, 1T 546138 A7 _ — ___ B7 V. Description of the invention (70) 3.15 mol) in a solution in methylene chloride (15 ml). This mixture was stirred at room temperature under nitrogen until the reaction was complete as determined by tic. The mixture was filtered and concentrated, and purified by flash chromatography to obtain l- (z, z, z-octadecyl-6,9,12_trienyloxy) -3- (4-phenylbutyryloxy) ) Propane. Example 50 --- l- (z, z, z_octadecyl_6,9,12_trienyloxy) _3_ (phenylethoxy) propane (phenylacetic acid and GLA Diester with 1,3-propanediol) In a manner similar to Example 49, but using phenylacetic acid (430 mg, 3.15 mmol) in place of 4-phenylbutyric acid, ΐ- (ζ, ζ, ζ · octadecyl_6,9,12 · trisynyloxy) -3- (phenylethynyloxy) propanone D Example 51 l_ (z, z, z_octadecyl_6,9 , 12_trienyloxyl, trans-cinnamonyloxy) propane (trans-cinnamic acid and the diester of GL A and 1,3-propanediol) In a similar manner to Example 49, but using Trans-cinnamic acid (470 mg, 3.15 mmol) instead of 4 · phenylbutyric acid to obtain i- (z, z, z_octadecyl_6,9,12_trienyloxy)- 3- (trans-cinnamonyloxy) propane. The scope of patent application for a compound containing nicotinic acid is not proposed here, which is the subject of another application filed on the same day. The present invention is not subject to the foregoing general restrictions except for the scope of the above-mentioned patent applications, and states that the scope of patent application for the present invention is as follows. -73- This paper size applies Chinese National Standard (CNS) M specifications (210x57 mm) 丨 _. .—— Μ4Ι— (Please read the precautions on the back before filling this page) Order application date 85. 6. 13 Case No. 085107127 Category (the above columns are filled out by the Bureau) Chinese, "Name English A4 C4 Chinese Manual Replacement Page (for 92 · year 5) 546138 Compounds with 1,3-propanediol bonding structure and 1,3 -Propanediol derivatives '丨 COMPOUNDS WITH 1,3-PR0PANE DI〇L LINKED STRUCTURE AND 1,3-PROPANE DIOL DERIVATIVES' Name 1. David Frederick Harobin 2. Moha Bangkok nationality 3. Austin McMurdie 5. Andreas Pitt 7. Paul Wakefield 1. to 7. Both British 8. Canada 4. Philip North 6. Paul Bra Deli 8. Living and residence of Peter Ryden 1. Shigudi Building, Shigudi Building, Cassow Commercial Park, Stirling, Scotland, UK 2-7. Both are Kingston, Calisso, UK Research and Development Center of Scottie Pharmaceutical Co., Ltd., Kingston Road, Industrial Zone! Zheng Zhengxin, Yingying Scotty Pharmaceuticals (Josie) Limited Nationality UK Applicant f Matters Name Name British Marshall De Fagredo No. 22 Cogbirry District, Haile Street, Jersey, British Channel Islands National Standard (CNS) A4 Specification (210 X 297 mm) 546138 Patent Application for Patent No. 0851〇7 丨 27 Replacement Page (March 1992)

Therefore, it is difficult to reach a suitable concentration in the brain. Another obstacle is the skin ... Until a few years ago, drugs could only be used to act on the skin = skin. However, it is now known that the skin can also be administered with drugs to exert a systemic effect, and now more and more drugs are controlled by various patch technologies. All three types of barriers, cell membranes and inner cell membranes, blood and brain barriers, and skin have common important characteristics. They are all composed of lipids. This means that water-soluble drugs are impermeable unless they pass through the membrane via a receptor or delivery system. In contrast, lipophilic substances can pass through these obstacles without any specific receptors or delivery systems. Types of biologically active substances that need to pass through the lipid barrier pathway. Drugs whose pharmacokinetic changes can be improved by increasing lipophilicity, are classified according to their pathway of entry, and are: 1. Entering the cell: Drugs that specifically benefit are mainly acting in the cell Drug. Including: a. All anti-inflammatory drugs, including steroids or non-steroids; b. All cytotoxic drugs used to treat cancer; c. All antiviral drugs; d. All other drugs that need to enter the cell to exert appropriate effects, especially Drugs that act on DNA or RNA, drugs that act on enzymes located in cells, drugs that act on the second messenger system, or drugs that act on microtubules, mitochondria, lysosomes, or any other small organ in the cell; e. Steroid hormones or other hormones acting intracellularly, such as estrogen, progesterone, androgens and dehydroepiandrosterone. -6 ·

Η

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 public love) 546138 No. 085107127 Patent Application Chinese Specification Replacement Page (March 1992) 4 V. Description of the invention (: Improvement:; Γ acting on the center Drugs for the nervous system can improve their transport with this technology. This includes all drugs used in psychiatry, all drugs used in microbial-induced brain infections, or drugs used in brain cancer, and all other drugs that act on nerve cells Drugs, such as anti-epileptic drugs, and other drugs that act on neurological diseases such as multiple sclerosis, transsclerosis, Hantington's chorea, etc. 3. Skin ^ Like blood _ brain ^ obstacles, all need to pass through the skin Drugs that achieve systemic effects all benefit from conversion to fatty acid derivatives. For example, the aforementioned advances can be applied to amino acids. Particularly beneficial drugs are those that work to regulate cell function, as well as those that have a protein component. Drugs. Examples include tryptophan (5-hydroxytryptamine [5_ΤΗ] precursor, a key regulator of nerve and muscle function), phenylalanine (catecholamine precursor), and essence Acid (a regulator of nitric oxide synthesis that also plays an important role in controlling cell activity). Properties generally imparted In general, the compounds presented here have many advantages in addition to their lipophilic properties. Two or even one bases are given to fatty acids The base can be delivered 'as an oral' formulation for non-oral or topical use in the following form, easy to enter the body; well tolerated, without side effects, such as the side effects of free-state fatty acids; not too stable or effective Utilization; no need for palm center; easier to synthesize the corresponding triglyceride with three identical fatty acids. Although triglyceride is also well tolerated and commonly used, it is inferior to the compounds proposed here because Glycerides are difficult to synthesize and may have multiple isomers at the center of the palm. In addition, the fatty acids of triglycerides are easier to adapt to the paper size g @ 家 standard (CNS) Μ specifications (referred to as χ Norwegian public treasure) 546138 No. 085107127 Patent Application Chinese Specification Replacement Page (March 1992) A7 B7 32 years, Vi

5. Description of the invention (11)-or various mixtures, preferably fatty acids that can supply specific molecules in nutrition and therapy. In most cases, amino acids, vitamins, drugs or other molecules with the desired properties are also given when EFA or other fatty acids are given. It has now been suggested that specific triglycerides can be substituted when two fatty acids are given at the same time, based on the theory that essential fatty acids often appear in the form of triglycerides. However, triglycerides, unless symmetrical to the 2-carbon, are palm-like, and the coupled fluorenyl groups will move between the α and / 3 positions, making it difficult to synthesize specific triglycerides. Such movements also occur after synthesis and are also a problem in drug management. When two fatty acids are present in the same triglyceride molecule, the lack of specificity also poses problems in terms of synthesis, pharmacology, formulation, and stability. In addition, the synthesis of triglycerides is slow and difficult. Under the same conditions, propanediol derivatives can be easily synthesized. In order to conveniently administer different fatty acids simultaneously or to administer one fatty acid in large amounts with good tolerance, esters of diols must be used. Chemical properties of actives produced according to the present disclosure The present invention includes fatty acid (or fatty alcohol) derivatives of biologically active materials. The biologically active materials have carboxyl, alcohol, or amine groups and can form a single chemical entity with a clear meaning. This coupling can directly generate bipartate compounds, or separate them with suitable bonding groups to generate tripartate compounds. This refers to the number of parts into which the compound is split. Chemical classification of biologically active compounds The classification of compounds is shown below, where η is 1 to 3. Apply for a patent here The paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

546138 A B c D No. 085107127 Patent Application Chinese Application for Patent Scope Replacement (May 1992) 6. Scope of Patent Application 1. A compound with the following 1,3-propanediol bond structure: • O ^ OR!. CI ^ OR2 Among them, R1 is coded linolenic acid (GLA), two high coded linolenic acid (GGLA), stearic acid (SA), eicosapentacardic acid (EPA), and docosahexaenoic acid (DHA). Linoleic acid (cLA), or columbinic acid (CA), and R2 is a nutrient, drug or other biologically active residue selected from oleic acid, lipoic acid, and sulindac, Acetate-based botulinum test, penicillin v, indomethacin, proline, tryptophan, phenylalanine, GABA, succinic acid, 2,3, 5-triiodobenzoic acid, 4-phenylbutyric acid, Phenylacetic acid, cinnamic acid, choline, alpha-tocopherol, metronidazole. Seated, amine benzene reduced, fluphenazine, fluphenazine, tranylcypromine, amine penicillin, pyridoxal, pyridoxine, dehydroepiandrosterone, hydrocortisone, gama linen Group of acids (GLA) and eicosapentapentanoic acid (EPA). 2. The compound according to item 1 of the scope of patent application, wherein the phosphate, succinate or other difunctional acid radical is located between the R1 and / or R2 group and the 1,3-propanediol residue, specifically R2 is a nutrient, drug or other biologically active substance with hydroxyl or amine functionality. 3. The compound according to item 1 or 2 of the scope of patent application, which is used to improve the delivery of drugs or other actives through the lipid membrane in the body, or to obtain the paper standard applicable to China National Standard (CNS) A4 specifications ( 210 X 297 mm) 546138 Additive, complementary or synergistic effects between R1 and R2. 4. The compound according to item 1 or 2 of the scope of the patent application, which is used for preparing formulations for skin care or skin disease treatment. 5. The compound according to item 1 or 2 of the scope of patent application, which is used for preparing food, food supplement or food supplement. 6 A 丨, 3-propanediol derivative, which contains two fatty acid-derived groups, one of which is Gama linolenic acid (GLA) or dihomoma linolenic acid (DGLA), and the other is Gama linolenic acid ( GLA), dihomomaline linolenic acid (DGLA), stearic acid (s A), eicosapentapentanoic acid (epa), docosahexahexanoic acid (DHA), conjugated linoleic acid ( cLA), or columbinic acid (CA), is used to treat: (a) complications of diabetes, particularly neuropathy and retinopathy; and to improve insulin response to diabetes during and before diabetes; ( b) cancer; (c) osteoarthritis; (d) rheumatoid arthritis; (e) other inflammatory and autoimmune diseases, including the jjogren's syndrome, systemic lupus erythematosus Ulcerative colitis, Crohn's disease, and uveitis; (f) respiratory diseases, including asthma; (g) neurological diseases, including multiple sclerosis, Parkinson's disease, and Hanting's disease ( Huntington's) disease; (h) Renal and urinary tract diseases; -2- This paper size applies to China National Standard (CNS) A4 (210 X 297 male) (Centimeters) 546 138 A8 B8 C8 心血管 Cardiovascular diseases; ⑴ Degenerative diseases of the eyes, including pigmented retinitis and senile degenerative lesions; ㈨ Mental diseases, including schizophrenia, AIDS, Heymer's disease, insufficient insound, alcoholism and depression; (l) Bele hypertrophy and prostatitis; (m) Impotence and male infertility; (η) Breast pain; (〇) Male baldness; (Ρ) osteoporosis #; (q) Skin diseases, including abnormal Orthostatic eczema, hand eczema, psoriasis, ramie treatment, and allergic diseases; '(r) Dyslexia and other learning disabilities; (S) Cancer cachexia. 7 According to the u_propanediol derivative of the 6th scope of the patent application, one of the fatty acids is arachidonic acid (AA), and the other is aa, DHA 'DGLA or EPA, which is used to treat the painful sister, Zhijie, "Watt ..." according to the diseases described in the scope of the patent application, in particular, (a) ,, n), m / 1,,, ,, (J), (k), (q) and （ Institute & 1,3-propanediol derivatives according to item 6 of the scope of patent application, wherein one of the fatty acids is EPA and the other is EPA, or is used for the treatment of any Diseases, especially (b), (^ ⑷, (eWfWg),) '⑴'⑴' (k), (2 and 2 diseases. -3- This paper size applies to China National Standard (CNS) A4 specifications ( (210X297 mm) M6138 A8 B8 C8 Patent application scope • According to any of the 6 to 8 patent applications, 1,3-propanediol derivatives, where the diol is used as a food ingredient, especially Functional food or health-promoting food ingredient, used as a nutritional supplement or as a food supplement. 10. According to patent application No. 6 In any one of 8 items, a 3-propanediol derivative, wherein the diol is used for enteral administration or parenteral administration in a product for clinical nutrition. 11. According to the scope of application for patents Nos. 6 to 6 The i, 3-propanediol derivative according to any one of 8 items, wherein the diol is used as an ingredient in cosmetics or other preparations for skin or hair care. -4- This paper size applies Chinese National Standards (CNS) A4 size (210X 297 mm)