CN100391930C - 1, 3-propane diol derivatives as bioactive compounds - Google Patents

Abstract

Compounds of 1,3-propane diol linked structure (I), when for use in therapy, where R<1> 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 R<2> is hydrogen, or an acyl or fatty alcohol group as R<1> the same or different, or any other nutrient, drug or other bioactive residue.

Description

As 1 of bioactive compounds, the ammediol derivative

Invention field

This specification sheets relates to the introduction of bioactive compounds, this term comprise medicine, must nutrition or any other compound that in treatment or maintaining healthy, will use the human or animal.

Specifically, relate in this specification sheets and introduce biologically active substance, they are lipophilic forms, thereby pass intravital lipid barrier easily, or be presented in, or can reach above-mentioned two purposes simultaneously and/or make this class not have the biologically active substance of the easy synthesized form of compound of chiral centre with two kinds of bio-active substances in a part (wherein at least a bio-active substance is lipid acid or Fatty Alcohol(C12-C14 and C12-C18)).By the viewpoint of medication management, make two kinds of bio-active substances have very big advantage as individual molecule rather than two isolating individualities.Also may be beneficial to aspect the known bio-active substance showing with novel manner.These advantages comprise that lipotropy increases, the adduction effect of the two kinds of bio-active substances existing of being not together usually, and the synergism that exists sometimes of this class bio-active substance.

The present invention relates to the connection of bio-active substance via some link molecule (back goes through), and a series of compounds is synthetic, some are arranged in them itself is brand-new, and other also are novel with regard to the purposes of its treatment and/or maintaining healthy.But, compound and direct-connected bio-active substance that other link molecule outside requiring with the application forms also have been discussed, for example disclosed in about the EPA-0 393 920 of lipid acid and antiviral agent and common unsettled EP-95301315.8 (as EPA-0675 103 announcements) about lipid acid and non-steroidal anti-inflammatory medicine.

The material of announcing

All notions as discussed above do not come into one's own in patent of having announced and general document.But relate to the nutrition of some special natural diol, derivatives and some special diol ester and the material of pharmaceutical use.A original in the general document be Bergelson etc. [Acta Biochimica et Biophysica Sinica (and Biochim., Biophys.Acta) 116(1966) 511-520] article, wherein mentioned 1 especially, the long-chain diester of ammediol.Say seldom about acid moieties, but mentioned dioleate.Aspect patent documentation, Nabisco has proposed the edible fat imitation in EPA-0 405 873 and EPA-0 405 874, and this comprises 1, linolenate of 4-butyleneglycol (not limiting this term representative " α " isomer if having in addition) and arachidonate.The british patent specification 2 161 477 of Unilever company (being equivalent to EPA-0 161 114) relates to uses 1 of linoleic acid plus linolenic acid particularly, plant-growth that ammediol ester (also being αYi Gouti undoubtedly) is realized and economical output.In the EPA-0 056 189 of SS drugmaker, introduced anti-ulcer medicament 2, the 3-butanediol ester.In the EPA-0 018 342 of Sanofi the third-1 of short chain fatty acid is disclosed, the pharmaceutical effect miscellaneous of 3-diol ester.Perhaps more early be that Terumo K.K. is connected to 5 FU 5 fluorouracil on alpha-linolenic acid, dihomo-gamma linolenic acid or the timnodonic acid as anticarcinogen by a group-CH (R)-O-(wherein R is a methyl etc.) in EPA-0 222 155.

Lipid barrier

A lot of medicines work by combining with cell surface receptor or being absorbed in the cell by special delivery system on surface of cell membrane.But, though have a lot of medicines in cell by a kind of adjusting the in a lot of different functions (nucleic acid function for example, the effect of intracellular enzyme or such as the behavior of systems such as lysosome or microtubule) worked, they can not see through cell effectively.May not have acceptor and delivery system that they can connect, or these systems may with less than the speed of optimum value with drug delivery in cell.Equally, medicine may be to pass intracellular membrane with the speed less than optimum value, as mitochondrial membrane and nuclear membrane.

Also have the barrier of other medicine motion also to be considered to important.Significant especially one is hemato encephalic barrier, and it has a lot of cytolemma characteristics.There are a lot of medicines to be difficult to the concentration that in brain, reaches enough owing to this barrier.Another is a skin: up to A few years ago also only the purposes of medicine be when on skin, working just with medicament administration on skin.But have realized that now skin can be to make medicine enter intravital suitable pathways with systemic effect, consequently increasing compound is just with patch form administration miscellaneous.

All this three classes barrier-cytolemma and intracellular membrane, hemato encephalic barrier and skins all have a common important feature, that is, they are made up of lipid basically.These medicines this means them for water miscible medicine can not be saturating basically, unless can be commanded film by acceptor or delivery system.On the contrary, lipophilic substance more easily passes film and need not any special acceptor or delivery system.Need pass all kinds of bio-active substances of lipid barrier

According to route of entry, can list as follows by increasing the medicine that lipotropy improves the pharmacokinetics behavior:

1. cell enters: the medicine that may benefit is the medicine that mainly works in cell especially.These medicines comprise:

A. all anti-inflammation drugs are no matter be steroid or on-steroidal medicine;

B. all are used for tackling the cytotoxic drug of cancer;

C. all antiviral;

D. all must enter cell so that reach the other medicines of the best use of, particularly act on DNA or RNA and go up or be positioned at medicine on intracellular enzyme or second messenger system or microtubule, plastosome, lysosome or any other born of the same parents' inner cell organ.

E. steroid hormone and other hormone of effect, for example oestrogenic hormon, progestogen, male sex hormone and dehydroepiandrosterone in the cell.

2. hemato encephalic barrier: all medicines that act on central nervous system all will improve it and transport owing to this technology.This is included in all medicines that use in the psychiatry, in any organism of big capsules of brain infects or the medicine that uses in the cancer of the brain, and act on all other medicines such as the antiepileptic drug on the neurocyte and act on the neuropathy other medicines of (as multiple sclerosis, amyotrophic lateral sclerosis, Huntington Chorea and other).

3. skin: the same with hemato encephalic barrier, might need to see through skin and all will change into the derivative of fatty acid with the medicine that reaches the whole body effect and acquire benefit from them.

For example, the method for being discussed can be used for amino acid.Special those amino acid that in regulating cell function, work and work as protein component of meaningfully it seems.Example comprises tryptophane (precursor of serotonin [5-HT], a kind of crucial conditioning agent of N﹠M function), phenylalanine (precursor of catecholamine) and arginine (at the synthetic conditioning agent of the nitrogen oxide that plays an important role aspect the control cytoactive).

Usually the character that has

In general, the compound of the application's proposition also has many good qualities except that lipotropy.Two portions of given lipid acid, even an independent part can be used as oral, parenteral or topical formulations and discharge to be attached to intravital form easily; Its tolerance is fine, the side effect that does not have free fatty acids for example to have; It is also within reason stable as can't suitably to use; It must not have chiral centre; And compare it synthetic much easier with the corresponding triglyceride level that has three identical fatty acid parts.Though the tolerance of triglyceride level is fine and use in a large number, compare with The compounds of this invention that they are not ideal, because they are difficult synthetic and a chiral centre can be arranged, thereby a plurality of possible isomer are arranged.In addition, for triglyceride level, lipid acid may relatively easily be moved to another from a position, is created in non-existent recruit in the original preparation.This obviously can throw into question, and particularly aspect the medication management regulation, this unstable may be unacceptable.

When discharging two kinds of different lipid acid, its advantage is that above-mentioned benefit is added in individual molecule and given simultaneously and two kinds of abilities with material of different biological actions.This has been avoided following during as the isolated compound administration and the medication management problem of coming when two kinds of materials, and the problem that takes place in the occasion that may have chiral centre.When two kinds of medicines discharged as isolating molecule, administration required not only will study separately every kind of medicine usually, also will combine research.If two kinds of medicines are combined in the individual molecule, only need the research individual molecule, significantly reduced development cost.

The occasion that exists at the actives that has outside the lipid acid has confers similar advantages.The compounds of this invention makes medicine or other compound form administration of relative lipophilic compound, they are achirality (unless medicine or other compound itself are chiralitys), discharge the active part ratio and be easier to, and better tolerance in oral, part or during administered parenterally.Their lipotropy can be partially absorbed it by lymphsystem, so just walked around liver, the stimulation that compares stomach and intestine with a lot of compounds is less, and helps medicine and other medicament passes the lipotropy barrier, and for example skin, cytolemma and hemato encephalic barrier transports.

Evidence suggests,, can make a lot of medicines except easily by also having special property highly significant the lipid barrier by making more lipotropy.These character comprise and prolong action time, reduce particularly gastrointestinal side-effect of side effect, have walked around the first liver metabolism effect of crossing, and might directedly discharge different materials.

Derivative of fatty acid; The effect of lipid acid

Actives passes transporting of lipid film and can be improved by they are connected to particularly on gamma-linolenic acid (GLA) or these two kinds of lipid acid of two height-gamma linolenic acid (DGLA) directly or via intermediate, and above-mentioned two kinds of lipid acid itself just have ideal role miscellaneous.Do not consider any benefit aspect transporting, these connections also make bio-active substance mass-energy discharge with regard to the lipid acid with desirable effect with itself at same intramolecularly.Other lipid acid, the 12 kinds of natural acids (Fig. 1) among for example any indispensable fatty acid (EFA), particularly n-6 and the n-3 series EFA also can use.In these 12 kinds of acid, arachidonic acid, adrenic acid, therapic acid, timnodonic acid, clupanodonic acid n-3 and docosahexenoic acid particularly important are because they itself have special ideal effect.In addition, also can use any lipid acid, with C ₁₂-C ₃₀Or C ₁₆-C ₃₀Acid is advisable, and preferably has two or more cis or trans carbon-to-carbon double bond.Can use with the form of lipid acid or corresponding Fatty Alcohol(C12-C14 and C12-C18).Conjugated linolic acid and punicic acid are the examples that itself has the lipid acid of useful quality, and be particularly useful probably.Only in the special occasion that one or another kind of chemical structure is discussed, the lipid acid of mentioning here is interpreted as two kinds of forms.But the ideal performance of GLA and DGLA makes it particularly useful.

Indispensable fatty acid in fact all is a cis-configuration, and they are the derivative of corresponding octadecanoic acid, arachic acid or docosoic acid, for example z by systematic naming method, the z-Linolenic Acid, 12-diolefinic acid or z, z, z, z, z, z-22 carbon-4,7,10,13,16, the 19-acid, but, very convenient according to the numeral that the number at the number of carbon atom, unsaturated center and the carbon atom number that begins from the end of the chain to degree of unsaturation are done, for example correspondingly represent with 18:2n-6 or 22:6n-3.The abbreviated form (for example timnodonic acid) that adopts capitalization prefix (for example EPA) and title in some cases is as being commonly called as.

Fig. 1

GLA and DGLA

GLA and DGLA itself demonstrated has antiinflammation, brings high blood pressure down, and suppresses platelet aggregation, reducing cholesterol concentration, the anticancer growth reduces the dyskinesia activity, alleviate mastalgia, improve calcium absorption and strengthen its deposition in bone, reduce the side effect of ionizing rays, treat various psychosis, cause vasorelaxation, improve renal function, the complication of treatment diabetes, vasodilator etc.Therefore, be connected to actives on GLA and the DGLA more lipophilic that not only can become, improved penetrance, but also shown the other result of treatment that makes new advances probably all various films, skin and hemato encephalic barrier.Therefore these fatty acid cpds can be prodrug (if directly connecting) that two parts are arranged or the prodrug (if connecting by link molecule) that three parts are arranged.

Useful especially probably in this respect other lipid acid is arachidonic acid and the docosahexenoic acid as all cells film main ingredient; Adrenic acid; With therapic acid and timnodonic acid with a series of ideal performances similar to GLA and DGLA.The useful especially lipid acid that is not included in Fig. 1 is conjugated linolic acid (cLA) and punicic acid (CA).CLA promotes to contain the growth of proteinaceous tissue in treatment and preventing cancer, prevents and treats cardiovascular disorder and as the antioxidant aspect a series of vital role are arranged.CA has a lot of performances of indispensable fatty acid.

All kinds of activess that have common effect with the acid of biological activity fat

All kinds of activess that are attached in the compound as described herein can be summarized as follows:

A) medicine, comprise microbiotic, antiprotozoal, antipsychotic drug, thymoleptic and NSAID (NSAID), and the compound that is used for the treatment of cardiovascular drug, respiratory system disease, tetter, psychosis, neuropathy, ephrosis, muscle disease, gastrointestinal illness, reproductive system disease and other disease and cancer.

B) hormone

C) amino acid

D) VITAMIN vitamin B group especially, and other essential nutrients.

E) cytokine and peptide

F) neurotransmitter and precursors of neurotransmitters.

G) phosphatide head base, for example inositol, choline, Serine and thanomin, they can directly connect or partly connect by phosphate.

H) aromatics lipid acid, as phenylacetic acid, phenylbutyric acid and styracin, they are particularly useful in cancer therapy.

Effect

The therapeutic action of medicine can be passed through following case expedition with combining of the therapeutic action of lipid acid:

A) medicine that influences spirit can be connected to the lipid acid that plays an important role in brain function, for example on GLA, DGLA, arachidonic acid, timnodonic acid or the docosahexenoic acid, thereby provides dual result of treatment.

B) medicine that is used for the treatment of cardiovascular disorder can be connected on the lipid acid that also has this therapeutic action, for example can triglyceride reducing concentration and suppress the timnodonic acid of platelet aggregation, perhaps can reducing cholesterol content and the GLA or the DGLA of vasodilator effect arranged, perhaps as the effective arachidonic acid of cholesterol reducing agent, the DHA that perhaps has the anti-arrhythmia performance.

C) medicine that is used for the treatment of any form inflammation can be connected to the lipid acid that also has antiinflammation, for example on gamma-linolenic acid, dihomo-gamma-linolenic acid or timnodonic acid or the docosahexenoic acid.

D) be used for the treatment of osteoporotic medicine and can be connected to and can strengthen calcium in bone on bonded GLA or the DGLA, or be connected to can reduce to urinate on the calcium EPA or DHA that discharge.

E) be used for dermopathic medicine can be connected to antiinflammation to skin GLA or DGLA.

F) medicine that is used for cancer can be connected to GLA, DGAL, arachidonic acid, EPA or DHA, and they itself just have antitumous effect, and can reverse the resistance to cancer therapy drug.

About the notion of indispensable fatty acid as bio-active substance

As mentioning with well-known, indispensable fatty acid (EFA) is made up of a series of 12 kinds of compounds.Though linolic acid (parent compound of n-6 series) and alpha-linolenic acid (parent compound of n-3 series) are main dietary fat acid, these materials effect in vivo itself is less relatively.In order to can be used for health fully, these parent compounds must be metabolized to than long-chain and the higher compound of degree of unsaturation.Say quantitatively, as by they in cytolemma and the concentration in other lipid reactant judge, dihomo-gamma linolenic acid (DGLA) and arachidonic acid (AA) are main n-6 series EFA metabolites, and timnodonic acid (EPA) and docosahexenoic acid (DHA) are the major metabolite of n-3 series.DGLA, AA, EPA and DHA are the important component of most of lipids in the body.Except the importance of itself, they also can generate oxidized derivatives-eicosanoid miscellaneous, comprise prostaglandin(PG), leukotriene and other compound.Useful especially probably lipid acid is DGLA, AA, EPA and DHA aspect treatment, and GLA, the precursor of DGLA, therapic acid (SA), the precursor of EPA and DPA (22:5n-3), the precursor of DHA and adrenic acid.

In addition, some lipid acid such as oleic acid, therapic acid and punicic acid are not EFA, but have vital role in vivo.Being subjected to most one of attention person in these lipid acid is the conjugated linolic acid, has before mentioned it and has had a series of desirable effects.

No matter imagination once was in trophism or aspect the treatment disease, as long as supply linolic acid and alpha-linolenic acid are just enough, remaining work will be finished by the metabolism of health itself.Now common recognition this be incorrect.Different diseases has the unusual form of different EFA, and because the problem in the metabolism can not obtain correction by giving linolic acid or alpha-linolenic acid simply.Therefore under a lot of situations, the suitable practice is the amount of providing of a kind of other EFA to be provided or to give two or more EFA simultaneously.Though EFA can preferably can supply lipid acid with the form of specific molecular with various forms with as various mixture supply in trophism and pharmacological agent.Equally, may wish with amino acid, VITAMIN, medicine or itself have the form that other molecule of desirable performance combines and give EFA or other lipid acid in various different occasions.

Up to now, be to utilize specific triglyceride level about the proposal of using two kinds of lipid acid simultaneously, this is that the imitation indispensable fatty acid is to exist so that the form of triglyceride level is natural.But unless around the 2nd carbon atom symmetry, triglyceride level all is a chirality, and this fact adds the migration of acyl group between α and β position, makes that synthesizing of specific triglyceride level is very difficult.This migration may take place in synthetic back, thereby produces special problem aspect medication management.Narrow spectrum shortage when two kinds of lipid acid are present in the same triglyceride level molecule, make synthetic, pharmacology, preparation and stable aspect produce a lot of problems.In addition, triglyceride level synthetic not only slowly but also difficult.And when handling under similar condition, the preparation meeting of propanediol derivative is faster.

In order to use different lipid acid easily simultaneously or to take the single lipid acid of high quantity with the good form of tolerance, the optimal fat that is to use glycol really.

Can be according to the derive chemical nature of the bio-active substance that obtains of the disclosure of invention

Present specification has comprised lipid acid (or Fatty Alcohol(C12-C14 and C12-C18)) derivative of the bio-active substance that has available carboxyl, alcohol radical or amino, thereby has formed single, completely specified chemical entities.Become the number of several parts, this coupling can directly generate the compounds of two parts according to compound decomposition, or separated the tripartite compound of shape by suitable linking group.

Bio-active substance is by the chemical structure classification

Comprise following compound in classes of compounds, wherein n is advisable with 1-3.The material that the present invention proposes claim comprises class (a) diester (ii); N=3 also comprises class (b) phosphoric acid ester (iv); N=3.The material that the number of n is bigger or less, or linking group is not the material of ester group may be because similar reason and useful and be disclosed, but that major part does not belong to is of the presently claimed invention.

(a) have the bio-active substance of free carboxyl group-they can derive obtain as follows:

(i) with unsaturated fatty alcohol (UFA) the ester coupling takes place

(ii) with the ω-hydroxyalkyl acrylate generation ester coupling of unsaturated fatty acids

(iii) with the ω-hydroxyalkyl carboxyl ester generation ester coupling of unsaturated fatty alcohol

(b) have the bio-active substance of free hydroxyl-they can derive obtain as follows:

(i) with the coupling of unsaturated fatty acids generation ester

(ii) with the ω-carboxyalkyl carboxyl ester generation ester coupling of unsaturated fatty alcohol

(iii) with the ω-carboxyalkyl ester generation ester coupling of unsaturated fatty acids

(iv) with the ω-hydroxyalkyl acrylate generation phosphoric acid ester coupling of unsaturated fatty acids

Wherein R=H, CH ₃Or positively charged ion counter ion.

(c) band free amino group bio-active substance-they can derive obtain as follows:

(i) with the coupling of indispensable fatty acid generation acid amides

(ii) with the ω-carboxyalkyl carboxyl ester generation acid amides coupling of essential Fatty Alcohol(C12-C14 and C12-C18)

(iii) with the ω-carboxyalkyl ester generation acid amides coupling of indispensable fatty acid

All above-mentioned all kinds of in, n is advisable with 1-3, unsaturated fatty acids or alcohol carbochain be expressed as:

In all are all kinds of, many groups of lipid acid of " unsaturated fatty acids " (and deutero-" unsaturated fatty alcohol ") representative, comprise oleic acid (and oleyl alcohol) and any have two or more along or the lipid acid (or corresponding Fatty Alcohol(C12-C14 and C12-C18)) of trans double bond.But the most useful probably in this respect lipid acid is the indispensable fatty acid that is shown among Fig. 1, especially GLA, DGLA, AA, SA, EPA and DHA.For special purpose, conjugated linolic acid and punicic acid may be of great use.

About the synthetic general discussion

Each lipid acid can be by natural animal, plant or microbe-derived purifying, or can be with the well known by persons skilled in the art or method chemosynthesis of development after this.

Each Fatty Alcohol(C12-C14 and C12-C18) can make above-mentioned fatty acid chemistry reduction with method well known by persons skilled in the art or development after this.

The class (a) and (b) and (c) the deriving of bioactive compounds in [group (ii) and (iii)] need to form one or more ester bonds.This class chemical reaction can be undertaken by any suitable ester synthetic method, particularly:

(a) under 0-120 ℃ temperature, react in suitable inert solvent (as methylene dichloride) by alcohol and acyl chlorides, acid anhydrides or suitable activatory ester, can be with or without organic tert-alkali (as pyridine) and exist.

(b) in the presence of suitable acid catalyst (as the 4-toluenesulphonic acids), react with acid or with the weak point or the medium-chain alkyl ester of acid by alcohol, can be with or without inert solvent (as toluene) during reaction, temperature of reaction is 50-180 ℃, so that make the water that forms in the reaction be removed (for example under vacuum).

(c) alcohol exists down at condensing agent (as 1, the 3-dicyclohexyl carbodiimide) with acid, reacts under 0-50 ℃ temperature in inert solvent (as methylene dichloride), can be with or without suitable organic tert-alkali (as 4-(N, N-dimethyl aminopyridine)) and exist.

(d) alcohol and acid, perhaps with the weak point or the medium-chain alkyl ester of acid, perhaps Suan Acibenzolar (as vinyl ester), in the presence of lytic enzyme (as Pig Liver Esterase), under 20-80 ℃ temperature, react, can be with or without suitable solvent (as hexane) in the reaction exists, reaction conditions should make water or alcohol or aldehyde by product be removed, and for example removes under vacuum.

(e) sour and suitable alcohol derivate (as iodide) reacts under 0-180 ℃ temperature in suitable inert solvent (as dimethyl formamide), can be with or without suitable alkali (as salt of wormwood) and exist.

(f) weak point of alcohol and acid or medium-chain alkyl ester are at the M of catalytic amount ⁺OY ^-There is reaction down in the type alkoxide, wherein M is basic metal or alkaline-earth metal (as sodium), Y is the alkyl that contains 1-4 carbon atom, it can be side chain, straight chain, saturated or unsaturated, being with or without suitable solvent (as toluene) during reaction exists, temperature is 50-180 ℃, so that (for example under vacuum) removes lower alcohol HOY from reaction mixture.

The preparation of deriving of the bio-active substance in the class (c) needs to form amido linkage.This class chemical reaction can be undertaken by any suitable acid amides synthetic method, especially:

(g) amine and acyl chlorides, acid anhydrides or suitable activatory ester react under 0-120 ℃ temperature in suitable inert solvent (as methylene dichloride), can be with or without organic tert-alkali (as pyridine) and exist.

(h) amine reacts under 0-50 ℃ temperature in inert solvent (as methylene dichloride) under condensing agent (as 1, the 3-dicyclohexyl carbodiimide) exists with acid, can be with or without suitable organic tert-alkali (as 4-(N, N-Dimethylamino pyridine)) and exist.

(i) amine and acid or with the weak point or the medium-chain alkyl ester of acid, perhaps the Acibenzolar (as vinyl ester) with acid reacts in the presence of lytic enzyme (as Pig Liver Esterase), being with or without suitable solvent (as hexane) exists, temperature of reaction is 20-80 ℃, reaction conditions should make water or alcohol or aldehyde by product to be removed, and for example removes under vacuum.

Deriving of the bio-active substance of class (b) in (iv) needs to form the phosphoric acid ester bond.This class chemical reaction can be undertaken by any suitable phosphoric acid ester synthetic method, especially:

(j) alcohol (as UFA, the 3-hydroxypropyl ester) and suitable activatory phosphate derivative are (as POCl ₃) and tertiary base (as triethylamine) in suitable solvent (as tetrahydrofuran (THF)) in the thermotonus below 10 ℃, obtain rough phosphorus dichloride acid esters.Alcohol (as alpha-tocopherol) reacts under envrionment temperature in suitable solvent (as tetrahydrofuran (THF)) with rough phosphorus dichloride acid esters and tertiary base (as triethylamine) subsequently, generates rough chlorinated phosphate.Its hydrolysis (as by adding entry and triethylamine) is generated phosphodiester.Or, adding methyl alcohol and generate phosphotriester, it can generate phosphodiester with suitable nucleophilic reagent (as lithiumbromide) demethylation in appropriate solvent (as methylethylketone).

(k) phosphate monoester (as the phosphoric acid ester of UFA, 3-hydroxy-propyl ester) reacts in appropriate solvent and under the suitable temperature under condensing agent (as 1, the 3-dicyclohexyl carbodiimide) exists with alcohol (as choline).

(l) 2-deoxidation-2-lyso-phosphatidylcholine and primary alconol or secondary alcohol carry out the phosphatidyl transferance under Phospholipase D catalysis.

In general, chemical reaction depends on the essence of the compound that will connect certainly and is directly or indirectly to connect.Lipid acid be to can directly connecting into lipid acid-aliphatic alcohol ester or connect into acid anhydrides, and if use the glycol linking agent, the ehter bond that then connects Fatty Alcohol(C12-C14 and C12-C18) has substituted the ester bond that connects lipid acid itself usually more easily; In all scenario, all can connect with known chemical process itself equally.

Can directly connect or by connector, particularly 1, ammediol connect each to the actives example

What list as far as we know, is novel by actives to the examples of compounds major part that forms.So long as this situation, no matter whether propose claim at present, they all as new chemical entities with in new application aspect treatment or the preventing disease, have represented a part of the present invention.

Lipid acid

GLA-OA (OA=oleic acid), GLA-GLA, EPA-EPA, GLA-EPA, GLA-DHA, AA-DHA, AA-EPA, GLA-AA, GLA-SA, SA-DHA, AA-SA, DGLA-DGLA, DGLA-GLA, DGLA-SA, DGLA-AA, DGLA-EPA, DGLA-DHA, AA-AA, EPA-SA, EPA-DHA, DHA-DHA, cLA-cLA, 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.

VITAMIN

GLA-nicotinic acid, the GLA-vitamin A acid, the GLA-Vogan-Neu, the GLA-pyridoxal, two GLA-Benadons, two EPA-pyridoxals and in general have among GLA, DGLA, AA, SA, EPA or the DHA of any VITAMIN any one, described VITAMIN comprise vitamins C, vitamins D and derivative thereof and analogue, vitamin-E and derivative thereof and analogue, vitamin K and derivative thereof and analogue, vitamins B ₁(VitB1), vitamins B ₂(riboflavin), vitamin Bc (folic acid) and relevant petrin, vitamins B ₁₂, vitamin H (vitamin H) and pantothenic acid.

Amino acid

The GLA-tryptophane, the GLA-proline(Pro), the GLA-arginine, GLA-or DHA-phenylalanine, GLA-GABA, the GLA-amino-laevulic acid, and in general have for example any one among GLA, DGLA, AA, SA, EPA or the DHA of taurine and carnitine of any natural amino acid or allied compound.

Aromatic acid

The GLA-phenylbutyric acid, the GLA-phenylacetic acid, the GLA-trans-cinnamic acid, and in general have among GLA, DGLA, AA, SA, EPA or the DHA of any aryl-alkanoic or aryl alkenoic acid any one.

Steroide

The GLA-hydrocortisone, GLA-androstane glycol, GLA-and DHA-dehydroisoandrosterone, and in general have any natural or synthetic steroide, any one among GLA, DGLA, AA, SA, EPA or the DHA of the steroide of for example any oestrogenic hormon, any progesterone, any suprarenal gland steroide and any anti-inflammatory (particularly Betamethasone Valerate, prednisone, Prednisolone Acetate, triamcinolone, budesonide, clobetasol, beclometasone and other relevant steroide).

Antioxidant

The GLA-Thioctic Acid, the DHA-Thioctic Acid, the GLA-tocopherol, two-GLA-3,3 '-thio-2 acid, and in general have can with GLA, DGLA, AA, SA, EPA or the DHA of any natural or synthetized oxidation preventive agent of its chemical bonding in any one.This comprise phenol antioxidant (as oxymethoxyallylbenzene, Salvin, coffic acid, Yoshinox BHT (BHT), gallate, tocopherol, tocotrienols and flavonoid antioxidant are (as myricetin, Zante Fustic), polyene hydrocarbon (as retinoic acid), undersaturated sterol is (as A ⁵-avenasterol), organosulfur compound (as allicin), terpenes (as Geraniol, sylvic acid) and amino acid antioxidant (as halfcystine, carnosine).

Medicine

GLA and INDOMETHACIN, ibuprofen, fluoxetine, penbritin, penicillin v, sulindac, Whitfield's ointment, metronidazole, Fluphenazine, dapsone, Tranylcypromine, acetylcarnitine, haloperidol, Quinacrime, chloroquinoline, penicillin, tsiklomitsin, Pravastatin, bisphosphate is (as efidronic acid, ammonia hydroxyl bisphosphate and clordronic acid and sodium salt thereof), adenosyl succinate and adeninyl succinate and allied compound thereof, and as the reagent of x-ray contrast agent, and in general, have any medicine, especially for treatment transmissible disease and inflammation, comprise various forms of sacroiliitis, cancer, cardiovascular diseases, respiratory tract disease, tetter, psychosis, neuropathy, myonosus, ephrosis, gastrointestinal disorder, the GLA of any medicine of reproductive system disease and other disease, DGLA, AA, SA, among EPA or the DHA any one.

Conception is used for NSAID; The effectiveness that demonstrates

As the specific examples of the notion of being discussed, we have prepared the GLA-ester of various non-steroidal anti-inflammatory medicine (NSAID), particularly INDOMETHACIN.INDOMETHACIN is as a kind of non-steroidal anti-inflammatory medicine, and its effect it is believed that it mainly is by mechanism of action in the born of the same parents that suppress cyclooxygenase, and this enzyme can change into arachidonic acid short scorching prostaglandin metabolism thing.

Known INDOMETHACIN penetration cell poor ability, therefore must use heavy dose of, and this can produce a lot of side effects, so once INDOMETHACIN-GLA and INDOMETHACIN itself ability with regard to its penetration cell was compared, normal fibroblast, breast cancer cell line and malignant melanoma cell system are used in this research.

The result who is listed among the EPA-0 675 103 shows that behind the INDOMETHACIN incubation, the INDOMETHACIN intracellular concentration in all cells system is all very low, and detected only is trace level.On the contrary, same in all clone, be that INDOMETHACIN-GLA and the free INDOMETHACIN quantity found in cell are all very big with the result of INDOMETHACIN-GLA incubation.These results show clearly, the GLA ester of INDOMETHACIN passes cell effectively, in born of the same parents, take off esterification then, form the free INDOMETHACIN, consider that cytolemma barrier and hemato encephalic barrier and skin barrier have a lot of similarities, INDOMETHACIN-GLA quicken that INDOMETHACIN passes also can be effective aspect these barriers.Expection all compounds of statement herein can show that all this penetration and division discharge actives.

Claim of the present invention

Stated all respects of invention in the application's claim, main claim relates to compound, 1 when being used for the treatment of in the described compound, and the ammediol group is in radicals R ¹And R ²Between form connecting key, R wherein ¹Be by the C that preferably has two or more cis or trans double bond _12-30, preferred C _16-30Acyl group that fatty acid derived obtains or Fatty Alcohol(C12-C14 and C12-C18) group, R ²Be hydrogen, or and R ¹Identical or different acyl group or fatty alcohol radical, or any other nutrition, medicine or other bio-active group.Preferably, no matter pass any lipid film, R ²Be medicine, VITAMIN, amino acid, antioxidant or to R ¹Play adduction, replenish or other required actives of synergism.

Compound generally is acid-functionalized compound, has the actives of direct esterification on the glycol-based, and Fatty Alcohol(C12-C14 and C12-C18) or have other actives of hydroxy functional group for example is at R ¹And/or R ²Group and 1 can insert phosphate, Succinic Acid base or other difunctional acidic-group between the ammediol base, particularly work as R ²When being the nutrition that has hydroxyl or amido functional group, medicine or other bio-active substance.

The present invention also briefly is discussed below, relates to the actives that many kinds can discharge in vivo.

Though the Direct Bonding (class (a) [i], (b) [i] and (c) [i]) of bio-active substance and lipid acid has been discussed above, but the present invention relates generally to class (a) [ii], n=3, the bio-active substance that itself can be lipid acid in this compounds is connected to as 1, on the lipid acid of the diester of ammediol, and class (b) (iv), n=3, the bio-active substance that in this compound itself can be Fatty Alcohol(C12-C14 and C12-C18) or lipid acid 3-hydroxypropyl ester is bonded to 1 by phosphoric acid ester, on the fatty acid monoester of ammediol.This glycol also can be regarded as 2-deoxidation glycerine, and corresponding diester is then regarded 2-deoxidation-1 as, the 3-triglyceride.Class (b) (iv), the compound among the n=3 is also with 1, ammediol is the basis, can be regarded as 2-deoxidation-2-lysophospholipid.The compound that is listed in here almost is new chemical entities entirely, perhaps at least before never is used for the treatment of human or animal's disease.

As a kind of compound, in the document with other a lot of glycol glycol as connector is disclosed briefly, but we see, it with the form of indispensable fatty acid diester or with indispensable fatty acid wherein at a place, bio-active substance (not being indispensable fatty acid) is used for the treatment of in the form of the compound at another place, but be both not disclose, and significant especially.It provides the favourable approach that obtains single fat acid for the situation of the completely specified compound of needs really, because both do not resembled glycerine 1 (3) monoesters and triglyceride (α, β and 1,3, wherein the lipid acid on 1 with 3 on different) in that class chiral centre of existing, also location isomer not.In addition, with using one acid different, this class monoesters and dibasic acid esters may can be used as emulsifying agent in pharmaceutical preparation.1, the ammediol structure is a kind of effective and safe systems that transport near the glycerine of natural glycerin three esters.Moreover it makes might synthesize the compound of determining easily and clearly, and the acyl migration problem that does not exist in triglyceride level does not exist because the complicacy that optically active isomer causes yet.For example we show, intravenous infusion and oral 1, and ammediol GLA/EPA diester emulsion causes discharging free GLA and EPA in the body rapidly, and GLA further is metabolized to AA, and EPA is metabolized to DHA.Equally, GLA-GLA and EPA-EPA diester, and nicotinic acid-GLA and INDOMETHACIN-GLA diester show after oral and be absorbed, and discharge their active part.

In addition, as far as we know, the 17th, 18 and 19 page of all that list 1, the ammediol derived compounds all is the new compound of never mentioning before this.The special glycol of two kinds of lipid acid listing, and lipid acid that is selected from GLA, DGLA, AA, SA, EPA, DHA, cLA and CA of existence on one of them position, the glycol that has VITAMIN, amino acid, aromatic acid, steroide, antioxidant or other medicine on the another location all is a novel substance.

The lipid acid diester has miscellaneous may the application.They can be used as medicine and are used for the treatment of or prevent the unusual disease of fixed lipid acid.They can add in the food or be added to or as nutriment, need to be used to the patient of special fatty acid with treatment or preventing disease.They also can be used in the food or medicine for animals.They also can be used for skin care.

The invention provides each particular aspects of claim of the present invention as advantage or comprising:

(i) be used for the treatment of or a kind of convenience of nutritional purpos and the application method of safety is used for giving one or two unsaturated fatty acids acid moieties, or unsaturated fatty acids and one are not the bio-active substances of lipid acid.

(ii) a kind of derivative of bio-active substance, this bio-active substance need enter in the body through lipid film when entering cell or pass skin, hemato encephalic barrier or other barrier and play a role, it is by 1, ammediol is bonded on natural n-6 or the n-3 series indispensable fatty acid, especially GLA or DGLA, AA, SA, EPA or DHA or relevant lipid acid cLA or CA.

The (iii) derivative of fatty acid of medicine, it makes medicine and lipid acid effective jointly.

(iv) a kind of medicine that improves passes the method that lipid film transports in vivo, it is characterized in that taking the medicine of above-mentioned form.

(v) a kind of method of making medicine is used to improve and passes lipid film with medicine and transport relevant curative effect in vivo, the method is characterized in that, medicine is attached in the medicament with above-mentioned form.

(vi) a kind of method of making medicament, a kind of or two kinds of lipid acid that this medicament is (ii) listed above being used for supplying with, or supply with a kind of and another kind of promoting agent in these lipid acid.

The present invention also provide with The compounds of this invention preparation be used for oral, parenteral medication, through the method for the medicine of intestines medication, local application or other purposes.

The example of particular compound provides in front; Provide below the synthetic embodiment.

General effectiveness and purposes

The concrete purposes of each specific groupization thing has explanation in addition, but 1, the purposes of ammediol diester generally can be described as follows:

1. improve the tolerance of lipid acid.Except that triglyceride level, most of forms that lipid acid can be used comprise free acid, salt, ethyl ester and other glyceryl ester, can cause gi tract intolerance to a certain degree, show as nauseating, the vomiting and diarrhoea.Find that in zooscopy propylene glycol diesters tolerance in rat and mouse is fabulous.For example, give GLA-GLA and GLA-EPA with dosage, do not find any symptom of diarrhea up to 10 gram/kilograms to rat and mouse.This illustrates that this diester is the complete acceptable approach of delivery of biologically active lipid acid.

2. reduce the toxicity of medicine.Non-steroidal anti-inflammatory medicine such as Asprin and INDOMETHACIN notorious because can cause serious gastrointestinal toxicity, caused gastroenteritic ulcer and gastrointestinal hemorrhage.With free INDOMETHACIN form or the INDOMETHACIN of quantity is with 1 equally, in the ammediol diester and another location is the rat administration of the form of GLA to fasting with the known INDOMETHACIN (5-30 milligram/kilogram) that can introduce gastroenteritic ulcer dosage.With sacrifice of animal, check whole GI ulcer after 24 hours.In the animal of only handling, finding ulcer widely with INDOMETHACIN, but in the animal of GLA-INDOMETHACIN processing seldom or do not find ulcer.

3. the lipid acid of delivery of biologically active form effectively.GLA is with GLA-GLA or GLA-EPA form administration, and EPA is with GLA-EPA or EPA-EPA form administration.Diester is with the oral or intravenous administration of form tube feed of 20% emulsion made as emulsifying agent with 2% galactolipid, and dosage is about 0.1-2.0 gram/kilogram.1, puts to death animal after 2,4,8 and 24 hours, collect blood plasma, red blood corpuscle and liver.Identify the not existence of metabolic diester with high pressure liquid chromatography.Derive the existence of the lipid acid that forms and these fatty acid metabolism things in order to method check down by diester: liver, blood plasma or red blood corpuscle are carried out the fat extraction, with tlc this fat extraction cut is separated into triglyceride level, phosphatide, cholesteryl ester and free fatty acids, the fatty acid methylization that to be derived and be formed by these isolated cuts adopts the method gas chromatographic analysis lipid acid that elaborates in standard textbook.These test-results show that after oral administration, about 10% diester of taking can be identified out with diester form.Most of GLA or EPA are free fatty acids or phospholipid form, and sub-fraction is cholesteryl ester and triglyceride fraction.In addition, particularly in phospholipid fraction, can find that the metabolite quantity of GLA, DGLA and arachidonic metabolite and EPA, clupanodonic acid and DHA increases.These observations show that lipid acid is discharged and further be metabolized to subsequently biologically active substance easily by diester form.Diester by intravenously administrable obtains similar result, and difference is that in the time of 1 hour, about 40% diester keeps its original form and discharges free fatty acids, at subsequently 24 hours intracellular metabolites and be attached in other the lipid cut.Unchanged diester form itself can biologically active be possible.Found linoleicly 1, the 3-triglyceride form has antitumous effect, and it is optionally to anticancer and do not injure normal cell, and the linolic acid of other form does not have this effect (A.Matsuzaki etc., cancer research (Cancer Res.) 1989; 49:5702-5707).Probably this effect and perhaps other effect need to discharge as 1 separated two kinds of fatty acid molecules in the 3-triglyceride.With 1, ammediol can be realized similar separation, therefore may be particularly useful in some propanediol derivative intravenously medication, and it can guarantee this glycol form certain hour that circulated before metabolism fully.

Lipid acid has a lot of ideal biologies and therapeutic activity, and these are existing detailed description the in detail in the inventor and other people many publications.Four kinds of lipid acid GLA, DGLA, SA and EPA have quite wide action spectrum jointly, comprising:

1. cardiovascular effect comprises vasorelaxation, brings high blood pressure down, and suppresses platelet aggregation, and triglyceride reducing and LDL-cholesterol level improve the HDL-cholesterol level, and suppresses proliferation of smooth muscle.

2. antiinflammation, comprise and reduce preceding inflammatory mediators (as cytokine) and forming by arachidonic acid deutero-eicosanoid, reduce neutrophil migration and the effect of neutrophil respiratory burst, reduce partial Inflammatory response, be suppressed at inflammation and adjuvant arthritis that inflammation in the various animal models such as uric acid bring out, and treat various inflammation such as osteoarthritis and rheumatoid arthritis.

3. immunoloregulation function, be included in and restrain excessive immunne response and allergic response in the animal pattern, for example test allergic encephalitis and uveitis, segmental bronchus and skin reaction in the sensitized animal are excessive, and this has caused them to can be used for imagination in the human diseases that excessive immunne response works.

4. respiration comprises bronchiectasis and suppresses the bronchoconstriction effect.

5. improve calcium balance, comprise the increase calcium absorption, reduce CaE, improve deposition and minimizing calcium the dystopy deposition in tissue (as artery and kidney) of calcium in bone.

6. three class antitumous effects, selecting cell toxic damages and in cancer cells and in normal cell, do not bring out apoptosis, suppress growth by effect and the essential second messenger system of interference growth that reduces somatomedin, suppress to shift by various effects, comprise the expression and arrestin lytic enzyme such as urokinase, lipoxygenase and the matrix metalloproteinase that improve the E-cadherin, and inhibition and Cancer-Related emaciation.

7. to the effect of neurocyte, comprise and keep normal neu 26S Proteasome Structure and Function, and the presynaptic of neurotransmitter and postsynaptic effect.

These desirable effects mean that this group lipid acid can be used for treating different diseases, comprise the cardiovascular diseases of a lot of types, and inflammation comprises rheumatoid arthritis, osteoarthritis, ulcerative colitis and Crohn disease; Respiratory disease comprises asthma; Psychosis comprises that schizophrenia, alcoholism, attention lax disease, dysthymia disorders and Alzheimer's disease; Neuropathy comprises multiple sclerosis and Huntington Chorea; Kidney and urethra disease comprise all kinds of ephritis and urine calcium calculus; Metabolic disease comprises that osteoporosis and dystopy sink calcium; And gastrointestinal ulceration disease and inflammation.Though conjugated linolic acid (cLA) does not for example also resemble extensive experimentation GLA or the EPA, it seems that it also has very wide sphere of action, comprises the effect that can be used for treating cancer, cardiovascular diseases and metabolic disease.

GLA, DGLA, AA and punicic acid have desirable effect to skin, and be particularly useful aspect treatment such as tetter such as atopic eczema, psoriasis, urticaria and anaphylaxis.

AA often is counted as the deleterious lipid acid of a kind of possibility.But it is a kind of basal component of all human cell membranes, has found in various diseases, for example atopic eczema, schizophrenia (Horrobin etc., schizophrenia research (Schizophrenia Res.) 1994; 13:195-207) and cardiovascular disorder (Horrobin, prostaglandin(PG), leukotriene and indispensable fatty acid (Prostaglandins Leukotr.EFAs) 1995; Exist with low levels 53:385-96).AA laxes in the disease particularly useful probably at usually also low other psychosis of these situations and AA content such as alcoholism and attention.

DHA also has some above-mentioned effect of EFA, but finds it in cytolemma, and especially quantity is great in heart film, retina and meninx.DHA also has strong anti-inflammatory and desirable cardiovascular effect.DHA is particularly useful in cardiovascular diseases, retinopathy and visual disease (comprising retinitis pigmentosa, senile macular degeneration SMD and dislexia), spirit and neuropathy (comprising that schizophrenia, attention lax the dementia and the multiple sclerosis of disease, dysthymia disorders, alcoholism, Alzheimer's disease and other form) probably.

Recently also determine transmissible disease probably to lipid acid, especially GLA and DGLA, EPA and DHA are also responded.These lipid acid kill a variety of bacteriums, comprise the bacterial strain that antibiosis is have the height resistibility.Some breadboard nearest work also show, these highly undersaturated lipid acid have important value aspect malaria and Protozoosis and so on the disease successfully replying to resemble.

Therefore obviously, various special lipid acid increase nearly all various kinds of drug and the effectiveness of other biologically active substance aspect treatment and preventing disease and skin care and nutrition possibly, and have important therapeutic action as single lipid acid or when using with two kinds of different lipid acid in a part with the glycol form.Valuable especially to treatment is that lipid acid is significantly nontoxic in most of situations, can be heavy dose of safety clothes with and do not have the danger of great side effect.

As the specific examples that the treatment of this class diester is renderd a service, test is with 1, and the 3GLA-EPA propylene glycol ester is treated the ASPC-1 human pancreatic adenocarcinoma in the subcutaneous implantation nude mice, and nude mice thymus function event for want of can be accepted external implantation and rejection does not take place.15 each subcutaneous injections of mouse are suspended in 500 ten thousand ASPC-1 cells in Matrigel and the DMEM damping fluid.All formed tumour in all animals, its big or small available kind of calliper, volume can be estimated by its linear dimension.Measure twice of the tumour size of each animal in 5 weeks weekly.Animal is divided into three groups.5 animals are only accepted 10g/kg Semen Maydis oil every day in contrast.5 animals are accepted 10g/kg Semen Maydis oil and inject the GLA-EPA diester that two doses is 1.5g/kg weekly every day.Diester wherein uses 2% oat galactolipid as emulsifying agent with the form administration of 20% emulsion; The tolerance of the emulsion that intravenously is used is fine, can not cause the disease of haemolysis, thrombophlebitis or any other form of animal.Other 5 animals are without Semen Maydis oil but accept 10g/kg/ days GLA-EPA diester.Treat continuous three weeks, and then make two weeks of tumor growth, slaughter subsequently, tumor resection is also weighed.Exemplary embodiment lock is: control group, 1240 ± 290mg; Intravenously GLA-EPA group, 820 ± 180mg; Oral GLA-EPA group, 490 ± 160mg.So oral and intravenously is used GLA-EPA and has all significantly been suppressed tumor growth, and does not cause any side effect or misery in animal.This has confirmed that the GLA-EPA diester can be used for the treatment of cancer effectively, and optionally to kill in the substratum effect of human cancer cell desired the same as having when giving GLA with EPA respectively in the laboratory.Therefore, diester is a biological activity approach of using various lipid acid.Can rationally expect thus, diester can be brought into play a lot of attracting effect [Horribin.DF etc. for example of the lipid acid of having mentioned in a lot of documents, Ω-6 indispensable fatty acid: physiopathology and the effect in clinical medicine (Omega-6 Essential Fatty Acids:Pathophysiology andRoles in Clinical Medicine): Wiley-Liss, New York, 1990; Volumes such as Simopoulos AP, the health-care effect of Ω in the food of ocean-3 polyunsaturated fatty acid (Health Effects of Omega-3 Polyunsaturated Fatty Acids inSeafoods), Karger, Basel, 1991; Fat in the human nutrition and oil (Fats andOils in Human Nutrition), the World Health Organization, Rome, 1994; Unsaturated fatty acids: nutrition and physiological significance (Unsaturated Fatty Acids:Nutritional andPhysiological Significance), BNF, Chapman and Hall, London, 1992].

Specific 1, the concrete application of ammediol compound

1. contain 1 of two kinds of lipid acid, the ammediol derivative, wherein a kind of lipid acid is GLA or DGLA, another kind is GLA, DGLA, SA, EPA, DHA, cLA (conjugated linolic acid) or CA (punicic acid), is used for the treatment of:

(a) complication of diabetes, particularly neuropathy and retinopathy; Improve in diabetes and the prediabetes response to Regular Insulin;

(b) cancer;

(c) osteoarthritis;

(d) rheumatoid arthritis;

(e) other inflammation and autoimmune disease comprise Si Yegelun syndromes, systemic lupus, ulcerative colitis, Crohn disease and uveitis;

(f) respiratory system disease comprises asthma;

(g) neuropathy comprises multiple sclerosis, Parkinson's disease and Huntington Chorea;

(h) kidney and urethral disease;

(i) cardiovascular diseases;

(j) degenerative disease of eye comprises retinitis pigmentosa and senile macular degeneration SMD;

(k) psychosis comprises that schizophrenia, Alzheimer's disease, attention lax disease, alcoholism and dysthymia disorders;

(l) prostatomegaly and prostatitis;

(m) impotence and male infertility;

(n) mazalgia;

(o) male sex's alopecia areata;

(p) osteoporosis;

(q) tetter comprises atopic eczema, hand eczema, psoriasis, urticaria and anaphylaxis dermatosis;

(r) dislexia and other learning capacity forfeiture;

(s) carcinemia.

2. contain 1 of two kinds of lipid acid, the ammediol derivative, wherein a kind of lipid acid is AA, another kind is AA, GLA, DHA, DGLA or EPA, is used for the treatment of the disease in above-mentioned (1), particularly (a), (g), (i), (j), (k), (q) and (r).

3. contain 1 of two kinds of lipid acid, the ammediol derivative, wherein a kind of lipid acid is EPA, another kind is EPA or DHA, be used for the treatment of any disease in (1), especially (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (p), (r) and (s).

4.1, the ammediol derivative, the lipid acid that one of them position is selected from GLA, DGLA, AA, SA, cLA, EPA or DHA occupies, the another location is selected from a kind of reagent of listing below and is occupied, its chemical structure makes it to be connected to 1 by a kind of bonding mode as herein described, on the ammediol:

(a) tryptophane is used for the treatment of any disease, especially psychosis, neuropathy, behavior disorders, pain and other disease, particularly dysthymia disorders, lethargic sleep disease and migraine;

(b) phenylalanine is used for the treatment of any disease, especially dysthymia disorders, multiple sclerosis and chronic fatigue syndrome;

(c) arginine is used for the treatment of any disease, especially wherein the disease of the generation shortage of nitrogen oxide;

(d) carnitine or carnitine derivative are used for the treatment of any disease, especially gravis, heart failure, chronic fatigue syndrome, Alzheimer's disease and peripheral neurophaty;

(e) any amino acid or related substance are used for the treatment of any disease, and perhaps the amino-laevulic acid or derivatives thereof is used for the treatment of any disease, especially cancer;

(f) adenylosuccinate ester or related substance are used for the treatment of any disease, especially muscular dystrophy, heart failure, chronic fatigue syndrome and Alzheimer's disease and other dementia;

(g) Asprin, Whitfield's ointment, INDOMETHACIN, ibuprofen or any other non-steroidal anti-inflammatory medicine are used for the treatment of any disease, especially inflammatory pain, Alzheimer's disease and other dementia, and any disease that should suppress platelet aggregation;

(h) be used for the treatment of any microbiotic, especially tsiklomitsin, clindamycin, minocyline, duomycin and the erythromycin of any suitable transmissible disease, be used for the treatment of acne;

(i) any antimalarial and antiprotozoal are used for the treatment of any disease, and especially chloroquine, quinacrine hydrochloride, Quinacrime and Mefloquine hydrochloride are used for the treatment of malaria, Protozoosis, inflammation and schizophrenia;

(j) any antifungal drug is used for the treatment of any disease, and especially metronidazole and antimycotic imidazoles and nitro glyoxaline and amphotericin are used for the treatment of all kinds of fungi infestations;

(k) steroide of any anti-inflammatory is used for the treatment of any disease, and especially hydrocortisone and Betamethasone Valerate are used for the treatment of tetter, and beclometasone and budesonide, is used for the treatment of asthma;

(l) any property steroide is used for the treatment of any disease, and especially oestrogenic hormon and progestogen are used for the treatment of ovary defective and osteoporosis, and male sex hormone is used for the treatment of the testis defective;

(m) any suprarenal gland steroide is used for the treatment of any disease, and especially trans-dehydroandrosterone is used for the treatment of and aging diseases associated;

(n) any retinoid is used for the treatment of any disease, and especially retinoic acid and accutane are used for the treatment of tetter, and is used for skin care;

(o) any anticarcinogen is used for the treatment of cancer;

(p) any inhibition spirit medicine is used for the treatment of schizophrenia and other psychosis;

(q) any thymoleptic are used for the treatment of any disease, especially treat dysthymia disorders;

(r) any anxiolytic is used for the treatment of any disease, especially treats anxiety and panic attack;

(s) any immunosuppressive drug, be used for the treatment of any disease, especially S-Neoral and tacrolimus are used for immunizing power control and treatment auto-immune disease and inflammation after the organ transplantation, comprise psoriasis, eczema, asthma, rheumatoid arthritis and inflammatory bowel disease;

(t) any proton pump inhibitor or H2 antagonist are used for the treatment of any disease, especially produce excessive with hydrochloric acid in gastric juice or the hydrochloric acid in gastric juice resistibility is reduced diseases associated;

(u) any hydragog(ue) is used for any disease, in particular for uroschesis and hypertension diseases associated;

(v) any calcium antagonist is used for any disease, in particular for cardiovascular diseases;

(w) any angiotensin converting enzyme inhibitor or vasotonia peptide antagonists are used for any disease, especially cardiovascular diseases;

(x) any beta blocker is used for any disease, in particular for cardiovascular diseases;

(y) any antiepileptic drug is used for any disease, especially Phenytoin Sodium Salt, carboxamide nitrogen

, Sodium Valproate, ethosuximide, vigabatrin or lamotrigine, be used for the treatment of epilepsy;

(z) any hypolipidemic is used for the treatment of any disease, and especially fibrates and statin are used for decreasing cholesterol and cholesterol regulating;

(aa) any oral hypoglycemic or the insulin sensitivity agent of in the treatment diabetes, using;

(bb) any diphosphonate that in treatment osteoporosis, Pei Jiteshi disease or cancer, uses;

(cc) any contrast medium that uses in radiology comprises Diatrizoate, Iodipamide, ioglycamic acid salt, iodopanoic acid salt, iofendylate, iothalamate, Ioxaglic Acid salt, metrizamide and allied compound;

(dd) any peptide or the protein that itself can use in the treatment disease comprises Regular Insulin, thyrocalcitonin, erythropoietin and other peptide;

(ee) any VITAMIN of in treating any disease or in food, nutriment or foodstuff additive, using as a kind of mode that VITAMIN is provided effectively;

(ff) any antioxidant that in tackling any disease, uses, especially wherein those diseases that antioxidant may be useful especially, comprise cardiovascular diseases, cancer and inflammation, and use or as antioxidant that component is used in food, foodstuff additive or the nutrition additive as food preservatives or other sanitas;

(gg) any medicine based on porphyrin chlorin or bacterium chlorin, their four (hydroxy phenyl) derivative in the cancer optical dynamic therapy.

Synthetic easily

Synthesizing of triglyceride level

Do concrete the comparison with triglyceride level below, discussed and used 1, the advantage of ammediol

Specifically, proposed in the esterification of lipid acid with 1, ammediol replaces glycerine, is especially having only a kind of lipid acid (as gamma-linolenic acid) will be bonded to situation on three carbochains " skeleton ".Though diester is chemically very similar with triglyceride level, the preparation of diester can be carried out under very gentle condition, and finishes in several hours.And to make triglyceride level, or need harsh condition, perhaps must use fat acyl chloride, or need biocatalysis (reaction times is taken several days).

The main points of triglyceride level synthetic method are: chemical reaction with metal, metal chloride or organic acid as catalyzer; Use fat acyl chloride; Use immobilized enzyme.

It is all very similar to use acid, metal or metal chloride to respond as the institute of catalyzer, and they all have the common merits and demerits.A lot of problems are method inherent problems, that is, and and acidic conditions and high temperature (140 ℃-180 ℃).Tosic acid method possibility problem minimum is because it is in the gentleest condition (140 ℃) reaction down.The reaction of glycerine and aliphatic acyl chlorides is to carry out under " cold " condition, but emits poisonous gas, if careless monitoring, reaction can be out of hand.This method also runs into the problem that must make fat oxime acyl chlorides itself earlier; This additional step has reduced the total efficiency of method.Can be with specific gang's enzyme-lipase at the following catalytic esterification of very gentle condition (for example 60 ℃), this catalyzer that the chances are will select when using polyunsaturated fatty acid.But the 1-position of most of enzymes and glycerine and the reaction of 3-position are the most effective.The addition of lipid acid on the 2-position is very slow, usually depends on " acyl migration ", that is, lipid acid must be connected to earlier on 1-or the 3-position, moves to the 2-position then, keeps there connecting.Therefore, take several days and just can finish by enzymatic triglyceride level is synthetic.

In theory, for 1, the esterification of ammediol can be adopted the same procedure that glycerine is used.But, consider of the addition of enzyme preferred catalytic lipid acid to the 1-position and the 3-position of glycerine, obviously they should be effective especially when being used for preparing diester.Situation is like this really, is reflected at approximately to finish in several hours temperature of reaction even synthetic also low (as 45-60 ℃) that requires of comparison triglyceride level.May not have free fatty acids after four hours, the productive rate of diester can surpass 95% after 8 hours, and all the other are monoesters.

Specific another problem of triglyceride level synthetic is to have primary hydroxyl and secondary hydroxyl in glycerine simultaneously, and at the central carbon atom place prochiral center is arranged.These problems can be by using careful selection blocking group and chirality is synthetic solves.But this has caused multistep synthetic, and each step all reduces productive rate and increases foreign matter content.On the contrary, 1, ammediol has only primary hydroxyl and does not have prochiral center.Therefore building-up process also reduces to maximum two steps, and overall yield improves and foreign matter content reduces.

In a word, by polyunsaturated fatty acid and 1, the reaction that ammediol prepares diester is faster than corresponding triglyceride level building-up reactions, and can gentleness carry out under the many condition.This has just formed a kind of more economical and refuse and has produced less method, and has reduced reactant or product and change or the danger of degraded at production period.

Preparation

Compound can be prepared with any suitable mode, and this is that the technician who prepares medicine, skin-protection product or field of food understands.They can be oral, (subcutaneous, intramuscular, intravenously), per rectum, transvaginal or utilize any other suitable pathways administration outside intestines, part, enteron aisle.

As triglyceride level, 1, the ammediol diester especially contains the diester of two kinds of lipid acid, uses phosphatide, the particularly emulsification of galactolipid emulsifying agent easily.This emulsion is specially adapted to oral administration, enteron aisle and intravenous route administration.

For example, lipid acid (UFA) diester exists as free-pouring oil, therefore can be formulated as follows:

1.GLA with EPA and 1, the preparation of 20% emulsion of the diester of ammediol

Oral latex emulsion can prepare with high pressure homogenizing method.The size-grade distribution of formed emulsion and zeta-potential are at room temperature used dynamic light scattering determination.(Zetasizer 4, Malvern Instr Ltd.) are at room temperature carried out in particle size measurement.

Prepared the emulsion oil-in-water (200g in batches) that contains following composition:

Composition %

Emulsifying agent (galactolipid) * 2.00

Diester (GLA-EPA) 20.00

Ascorbyl palmitate (AP) 0.02

Vitamin-E 0.5

Water 100.00

The emulsifying agent galactolipid is dispersed in the diester, vitamin-E, AP and water are mixed.In high speed shear mixing machine (Ultraturrax), oil phase is added to aqueous phase, lasts several minutes in the 4th retaining speed.Then with this pre-emulsion at 80MPA and 6 (mini-Lab 8.30H of 50 ℃ of following homogenizing; APV Rannie AS, Denmark).The average droplet size of the emulsion that forms is 230nm.

Can also add antimicrobial sanitas-potassium sorbate and correctives in the above-mentioned oral latex emulsion.

2. GLA and EPA and 1 used of intravenously, the preparation of 20% emulsion of the diester of ammediol

Use similar mode, preparation contains the 200g emulsion oil-in-water of following composition:

Composition %

Emulsifying agent 2.0

Diester (GLA-EPA) 20.0

Glycerine 2.0

Water is added to 100.0

Above-mentioned emulsion in high-pressure homogenizer homogenizing after 6 minutes average droplet size be 211nm, ζDian Shi is-40mV.The emulsion that these intravenouslys are used can be via the membrane filtration of aperture 0.22 μ m, also can autoclaving, and the drop size changes simultaneously.

The dosage of the actives of using is essentially 1mg to 200g every day, preferred 10mg to * Scotia LipidTeknik house journal " emulsion oil-in-water ", and PCT/SE 95/00115 (WO 95/20943) 10g, preferably 10mg to 3g decides according to its kind.When the treatment cancer, preferred dosage can be 2-150g every day.They can topical in due course, and this moment, actives accounted for the 0.001-50% of topical formulations, preferred 0.05-20%, preferably 0.1-10%.

Embodiment

The example that has provided the non-steroidal anti-inflammatory medicine that is connected with lipid acid among the EPA-0675103 that has announced that formerly mentions is synthetic.Provide below through 1, ammediol base and fatty acid bonded example are synthetic, and the material of other general example explanation.

Embodiment 1

1,3-(two-z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane (GLA and 1, the diester of ammediol)

With 1,3-dicyclohexyl carbodiimide (1.07g) and 4-(N, the N-dimethylamino) solution of pyridine (0.59g) in methylene dichloride (5ml) is added to 1,3-dihydroxypropane (0.152ml) and z, z, z-18 carbon-6,9, the 12-trienic acid (95%, 1.36g) in the solution in methylene dichloride (15ml).Stirred reaction mixture under room temperature and nitrogen reacts completely until measuring with thin-layer chromatography (TLC).In reaction mixture, add hexane (80ml).Remove by filter precipitation and fully wash with hexane.The filtrate that merges is concentrated and use purified by flash chromatography, obtain 1,3-(two-z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane is light yellow free-pouring oily matter.

Embodiment 2

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(z-Linolenic Acid-alkene acyloxy) propane

(GLA and oleic acid and 1, the diester of ammediol)

Part 1:

Under room temperature and nitrogen with z, z, z-18 carbon-6,9, the solution of 12-trienic acid (150g) in methylene dichloride (500ml) dropwise is added to 1,3-dihydroxypropane (205g), 1 is in the mixture of 3-dicyclohexyl carbodiimide (130g) and 4-(N, N-dimethylamino) pyridine (87g) in methylene dichloride (2500ml).When the TLC Indicator Reaction has carried out reaction mixture being filtered when complete.Filtrate is washed with dilute hydrochloric acid, water and saturated NaCl solution.With the solution drying, concentrate, use the dry-column chromatography purifying, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane, be light yellow oil.

Part 2:

Under room temperature and nitrogen with 1,3-dicyclohexyl carbodiimide (23.7g) and 4-(N, the N-dimethylamino) solution of pyridine (15.9g) in methylene dichloride (200ml) is added to 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (33.6g) and the solution of z-Octadec-9-enoic Acid (30g) in methylene dichloride (400ml) in.After the TLC analysis confirms to react completely, solution is diluted with hexane, filter, concentrate, use the dry-column chromatography purifying, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(z-Linolenic Acid-alkene acyloxy) propane, be free-pouring light yellow oil.

Embodiment 3

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) propane

(GLA and EPA and 1, the diester of ammediol)

Prepare in 2 parts 2 as embodiment, but use z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acid substitution z-Octadec-9-enoic Acid.Chromatographic separation obtains 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) propane, is light yellow oil.

Embodiment 4

1,3-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane

(GLA and 1, the diester of ammediol)

Prepare in 2 parts 2 as embodiment, but use z, z, z-18 carbon-6,9, the 12-trienic acid replaces the z-Octadec-9-enoic Acid.Chromatographic separation obtains 1, and 3-(two-z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane is light yellow oil.

Embodiment 5

(±)-1-(1,2-dithiolane-3-penta acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane

(Thioctic Acid and GLA and 1, the diester of ammediol)

With 1,3-dicyclohexyl carbodiimide (720mg, 3.45mmol) and 4-(N, N-dimethylamino) pyridine (480mg, 3.98mmol) mixture in t-butyl methyl ether (15ml) is added to Thioctic Acid (645mg, 3.12mmol) and 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-(1g is 3mmol) in the mixture in t-butyl methyl ether (30ml) for the 3-hydroxy propane.Stirred reaction mixture is 5 hours under room temperature and nitrogen, with the carrying out of TLC (40% ethyl acetate/hexane) monitoring reaction.After reaction is finished mixture is filtered, concentrate, with purified by flash chromatography (hexane, 2% ethyl acetate/hexane, 5% ethyl acetate/hexane is used 10% ethyl acetate/hexane at last), obtain (±)-1-(1,2-dithiolane-3-penta acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane is the heavy-gravity yellow oil.

Embodiment 6

1-([Z]-5-fluoro-2-methyl isophthalic acid-[and the 4-{ methylsulfinyl } benzylidene] indenes-3-acetoxyl group)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane (sulindac and GLA and 1, the diester of ammediol)

With 1,3-dicyclohexyl carbodiimide (720mg, 3.45mmol) solution in t-butyl methyl ether (30ml) be added to sulindac (1.12g, 3.15mmol), 4-(N, N-dimethylamino) pyridine (480mg, 3.9mmol) and 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-(1g is 3mmol) in the mixture in t-butyl methyl ether (15ml) for the 3-hydroxy propane.Under room temperature and nitrogen, stirred the mixture 5 hours, with the progress (40% ethyl acetate/hexane) of TLC monitoring reaction.After reaction is finished mixture is filtered; concentrate; and with purified by flash chromatography (40% ethyl acetate/hexane is used 50% ethyl acetate/hexane subsequently, uses 60% ethyl acetate/hexane at last); obtain 1-([Z]-5-fluoro-2-methyl isophthalic acid-[4-{ methylsulfinyl } benzylidene] indenes-3-acetoxyl group)-3-(z; z, z-18 carbon-6,9; 12-triolefin acyloxy) propane is yellow waxy solid.

Embodiment 7

1-([R]-3-acetoxyl group-4-[trimethylammonium ammonium] butyryl acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane

(acetylcarnitine and GLA and 1, the diester of ammediol)

The thionyl chloride (1.5ml) that distillation is newly obtained is added in (the R)-acetylcarnitine (1g) that is contained in the pyriform flask lentamente.Carefully reagent is added to drag, up to forming clear solution.Unnecessary thionyl chloride (keeping the flask temperature to be lower than 30 ℃) is removed in decompression after at room temperature 4 hours.This has formed the chloride of acid of the white solid of high-hygroscopicity, not purified use immediately.In flask, add 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (1.4g, 4.17mmol) and anhydrous tetrahydro furan (4ml) at room temperature place mixture overnight.TLC analyzes (40% ethyl acetate/hexane) and shows that reaction carried out fully.Reaction mixture is added under vigorous stirring in the hexane (250ml).The tiny precipitation of canescence that centrifugal collection forms.Again be suspended in the hexane solid also centrifugal after removing supernatant liquid.Carry out the hexane wash step once again, obtain 1-([R]-3-acetoxyl group-4-[trimethylammonium ammonium] butyryl acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane.

Embodiment 8

1-(3,3-dimethyl-7-oxo-6-([benzene oxygen ethanoyl) amino]-4-thia-1-azabicyclo [3.2.0] heptan-2-acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane

(penicillin v and GLA and 1, the diester of ammediol)

With penicillin v (1g, 29mmol), 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (860mg, 2.6mmol), 1, the 3-dicyclohexyl carbodiimide (620mg, 3mmol) and the mixture of 4-(N, N-dimethylamino) pyridine (catalytic amount) in methylene dichloride (30ml) at room temperature stir and spend the night., filter the reaction mixture dilution with hexane (50ml), be concentrated into dried.(3 * 50ml) wash resistates, to remove unreacted 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane with hexane.Semi-solid resistates is dissolved in the 150ml ether, with 100ml washing and dry.This ethereal solution is washed with the 125ml hexane, and solution is through silica gel bed (4cm * 4cm) filter.Filtrate is concentrated, obtain 1-(3,3-dimethyl-7-oxo-6-([benzene oxygen ethanoyl) amino]-4-thia-1-azabicyclo [3.20] heptan-2-acyloxy)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane, be colourless thickness oily matter.

Embodiment 9

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(1-(4-chlorobenzene formacyl)-5-methoxyl group-2 methyl indole-3-acetoxyl group) propane

(INDOMETHACIN and GLA and 1, the diester of ammediol)

Under room temperature and nitrogen with 1,3-dicyclohexyl carbodiimide (58g, 0.28mol) and 4-(N, N-dimethylamino) pyridine (37.9g, 0.31mol) solution in methylene dichloride (800ml) is added to 1-(z under stirring, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (79.5g, 0.24mol) and INDOMETHACIN (93.2g is 0.26mol) in the solution in methylene dichloride (400ml).Continue to stir 3 hours.Mixture is filtered, concentrate, be used for column chromatography (ethyl acetate/hexane) purifying.Collect the product cut, concentrate, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(1-(4-chlorobenzene formacyl)-5-methoxyl group-2 methyl indole-3-acetoxyl group) propane, be glassy yellow thickness oily matter.

Embodiment 10

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(2-tetramethyleneimine carboxyl) propane

(proline(Pro) and GLA and 1, the diester of ammediol)

Part 1:

Under room temperature and nitrogen with 1,3-dicyclohexyl carbodiimide (674mg, 3.3mmol) and 4-(N, N-dimethylamino) pyridine (472mg, 3.9mmol) solution in methylene dichloride (20ml) is added to 1-(z under stirring, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (1g, 2.97mmol) and N-tertbutyloxycarbonyl proline(Pro) (671mg is 3.12mmol) in the solution in methylene dichloride (20ml).Continue to stir 7 hours, mixture is deposited under 0 ℃ spent the night.Mixture is filtered,, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(N-tertbutyloxycarbonyl-2-tetramethyleneimine carboxyl) propane, be yellow oil with column chromatography (ethanol/methylene) purifying.

Part 2:

Protected product is dissolved in the methyl-phenoxide/trifluoroacetic acid (10ml) of 10% (v/v), under room temperature and nitrogen, placed 30 minutes.Analyzing indication at TLC goes mixture with column chromatography (8% methyl alcohol/42% methylene dichloride/50% ethyl acetate) purifying, to be obtained 1-(z after protection finished; z, z-18 carbon-6,9; 12-triolefin acyloxy)-and 3-(2-tetramethyleneimine carboxyl) propane, be the heavy-gravity orange.

Embodiment 11

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(2-amino-3-indyl propionyloxy) propane

(tryptophane and GLA and 1, the diester of ammediol)

Part 1:

Under room temperature and nitrogen with 1,3-dicyclohexyl carbodiimide (674mg, 3.3mmol) and 4-(N, N-dimethylamino) pyridine (472mg, 3.9mmol) solution in methylene dichloride (20ml) is added to 1-(z under stirring, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (1g, 2.97mmol) and N-tertbutyloxycarbonyl tryptophane (950mg is 3.12mmol) in the solution in methylene dichloride (20ml).Continue to stir 7 hours, mixture is deposited under 0 ℃ and is spent the night.With the mixture filtration and with column chromatography purifying (ethanol/methylene), obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(N-tertbutyloxycarbonyl-2-amino-3-indyl propionyloxy) propane, be yellow oil.

Part 2:

Protected product is dissolved in the methyl-phenoxide/trifluoroacetic acid (6.1ml) of 10% (v/v), under nitrogen and room temperature, placed 15 minutes.Analyzing indication at TLC goes after protection finished; mixture column chromatography (8% methyl alcohol/42% methylene dichloride/50% ethyl acetate) purifying; obtain 1-(z; z; z-18 carbon-6; 9,12-triolefin acyloxy)-3-(2-amino-3-indyl propionyloxy) propane, be the red wax of heavy-gravity.

Embodiment 12

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3 (pantonine-phenyl propionyloxy) propane

(phenylalanine and GLA and 1, the diester of ammediol)

Part 1:

With 1,3-dicyclohexyl carbodiimide (1.77g, 8.57mmol) and 4-(N, N-dimethylamino) pyridine (1.24g, 10.13mmol) solution in methylene dichloride (30ml) is added to the 1-(z that is stirring under room temperature and nitrogen, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (2.62g, 7.79mmol) and N-tertbutyloxycarbonyl phenylalanine (2.17g is 8.18mmol) in the solution in methylene dichloride (30ml).Continue to stir 7 hours, mixture is deposited under 0 ℃ and is spent the night.Mixture is filtered,, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(N-tertbutyloxycarbonyl-pantonine-phenyl propionyloxy) propane, be yellow oil with column chromatography (ethanol/methylene) purifying.

Part 2:

Protected product is dissolved in the methyl-phenoxide/trifluoroacetic acid (17ml) of 10% (v/v), under room temperature and nitrogen, placed 30 minutes.Analyzing indication at TLC goes after protection finished; with mixture column chromatography (8% methyl alcohol/42% methylene dichloride/50% ethyl acetate) purifying; obtain 1-(z; z; z-18 carbon-6; 9,12-triolefin acyloxy) 3-(pantonine-phenyl propionyloxy) propane, be the heavy-gravity yellow oil.

Embodiment 13

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(the amino butyryl acyloxy of 4-) propane

(γ-An Jidingsuan (GABA) and GLA and 1, the diester of ammediol)

Part 1:

Under room temperature and nitrogen, with 1, and the 3-dicyclohexyl carbodiimide (0.84g, 4.06mmol) and 4-(N, the N-dimethylamino) pyridine (0.59g, 4.79mmol) solution in methylene dichloride (10ml) under agitation adds 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-(1.24g, 3.69mmol) (0.75g is 3.69mmol) in the solution in methylene dichloride (15ml) with N-tertbutyloxycarbonyl-γ-An Jidingsuan for the 3-hydroxy propane.Continue to stir 7 hours, mixture is placed down at 0 ℃ and is spent the night.Mixture is filtered,, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(the amino butyryl acyloxy of N-tertbutyloxycarbonyl-4-) propane, be colourless oily matter with column chromatography (ethyl acetate/hexane) purifying.

Part 2:

Protected product is dissolved in the methyl-phenoxide/trifluoroacetic acid (10.5ml) of 10% (v/v), under room temperature and nitrogen, placed 30 minutes.Analyzing indication at TLC goes mixture with column chromatography (8% methyl alcohol/42% methylene dichloride/50% ethyl acetate) purifying, to be obtained 1-(z after protection finished; z, z-18 carbon-6,9; 12-triolefin acyloxy)-and 3-(the amino butyryl acyloxy of 4-) propane, be yellow oil.

Embodiment 14

3,3 '-sulfo--two (1-propionyloxy-(3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane))

(GLA and 1, ammediol and 3,3 '-diester of thio-2 acid)

Under room temperature and nitrogen with 1, the 3-dicyclohexyl carbodiimide (660mg, 3.22mmol) and 4-(N, N-dimethylamino) pyridine (445mg, 3.64mmol) solution in methylene dichloride (10ml) is added to the 1-(z that is stirring, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (940mg, 2.8mmol) and 3,3 '-(250mg is 1.4mmol) in the solution in methylene dichloride (30ml) for thio-2 acid.Continue to stir 4 hours.Mixture filters with hexane (50ml) dilution, concentrates, with flash chromatography (ethyl acetate/hexane) purifying.Collect the product cut, concentrate, obtain 3,3 '-sulfo-two (1-propionyloxy-(3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane)), be colorless oil.

Embodiment 15

1-(1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-propyl group)-4-(z, z, z-18 carbon-6,9,12-trialkenyl) butane-1,4-two acid esters (diester of (GLA and 1, the monoesters of ammediol) and GLA alcohol and Succinic Acid)

With 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (10g, 30mmol) and Succinic anhydried (3g, 30mmol) mixture in anhydrous tetrahydro furan (100ml) at room temperature stirs, up to forming transparent solution.This solution is cooled to 0 ℃, to wherein dripping 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (4.5ml, 30mmol) solution in anhydrous tetrahydro furan (50ml).After 3 hours, TLC analyzes the most of monoesters of indication and reacts.Add some Succinic anhydried crystal again, continue to stir 30 minutes.Reaction mixture is with ether (250ml) dilution, with 2M hydrochloric acid (2 * 250ml), water (250ml) and salt solution (250ml) washes.Use dried over sodium sulfate, be concentrated into dried.This material directly uses without being further purified.

Part 2:

To part 1 product (13g, add in methylene dichloride 30mmol) (75ml) solution oxalyl chloride (3.9ml, 45mmol).At room temperature stirred this mixture 2 hours down, be concentrated into dried with nitrogen.Add the 75ml hexane, mixture is concentrated into dried.Use two parts of hexanes (every part of 75ml) to repeat this process again.The not purified direct use of this material.

Part 3:

At room temperature with the chloride of acid (1g that makes in the part 2; 2.2mmol) methylene dichloride (10ml) solution dropwise be added to z; z; z-18 carbon-6; 9, and 12-three enols (635mg, 2.4mmol), triethylamine (1ml; 7.2mmol) and the solution of 4-(N, N-dimethylamino) pyridine (catalytic amount) in methylene dichloride (20ml) in.After reaction is finished, mixture is concentrated and, obtain 1-(1-(z, z, z-18 carbon-6 with flash chromatography (ethyl acetate/hexane) purifying, 9,12-triolefin acyloxy)-the 3-propyl group)-4-(z, z, z-18 carbon-6,9, the 12-trialkenyl) butane-1,4-two acid esters are colorless oil.

Embodiment 16

1-(2,3,5-phenyl triiodide methanoyl)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane

(2,3,5 triiodobenzoic acid and GLA and 1, the diester of ammediol)

With 2,3,5-trisulphur benzene formyl chloride (1.54g, 3.08mmol) be added to 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-(1g, 2.97mmol) and in the mixture of triethylamine (1ml) in methylene dichloride (80ml), formed mixture stirs under nitrogen and room temperature and spends the night the 3-hydroxy propane.Mixture is concentrated,, obtain 1-(2,3,5-phenyl triiodide methanoyl)-3-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) propane with purified by flash chromatography (ethyl acetate/hexane).

Embodiment 17

(±)-1-(1,2-dithiolane-3-penta acyloxy)-3-(z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-six alkene acyloxy) propane

(DHA and Thioctic Acid and 1, the diester of ammediol)

Part 1:

Under-10 ℃ with z, z, z, z, z, z-22 carbon-4,7,10,13,16, and the 19-acid (6.4g, methylene dichloride 19.5mmol) (225ml) solution dropwise is added to 1, ammediol (7.5g, 99mmol), 1,3-dicyclohexyl carbodiimide (4.65g, 20mmol) and 4-(N, N-dimethylamino) pyridine (2.1g is 17mmol) in the solution in methylene dichloride (225ml).The reaction mixture stirring is spent the night, be warmed to room temperature.Filter, concentrate and, obtain 1-(z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-six alkene acyloxy)-3-hydroxy propane, be light yellow oil with flash chromatography (ethyl acetate/hexane) purifying.

Part 2:

With 1, and the 3-dicyclohexyl carbodiimide (720mg, 3.45mmol) and 4-(N, the N-dimethylamino) pyridine (480mg, 3.9mmol) solution in methylene dichloride (30ml) is added to 1-(z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-six alkene acyloxy)-3-hydroxy propane (1.16g, 3mmol), (645mg is 3.12mmol) and in the mixture of methylene dichloride (15ml) for Thioctic Acid.After under room temperature and the nitrogen 25 hours, mixture is filtered, concentrate, and, obtain (±)-1-(1,2-dithiolane-3-penta acyloxy)-3-(z with flash chromatography (ethyl acetate/hexane) purifying, z, z, z, z, z-22 carbon-4,7,10,13,16,19-six alkene acyloxy) propane is yellow oil.

Embodiment 18

Methyl-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester (the GLA 3-hydroxy propyl ester of 2 molecules and the phosphotriester of 1 molecule methyl alcohol)

Part 1:

(3.74ml, (2.74g is 17.9mmol) in the solution in anhydrous tetrahydro furan (15ml) 26.8mmol) dropwise to be added to the new distillatory phosphoryl chloride that is cooled to 0 ℃ with triethylamine.(5g is 14.9mmol) in the solution in anhydrous tetrahydro furan (15ml) dropwise to add 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane in this mixture.Remaining on during the entire reaction under the nitrogen atmosphere and temperature is lower than 10 ℃.TLC analyzes the completely dissolve of indication initiator after 15 minutes.Mixture is filtered and concentrates.Add toluene (50ml) and mixture is concentrated.Add another part toluene (50ml), remove again.

Part 2:

Under room temperature and nitrogen atmosphere with 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (3g, anhydrous tetrahydro furan 9mmol) (10ml) solution dropwise is added to rough chlorinated phosphate (7.5mmol, half of the batch that makes in the upper section 1) and triethylamine, and (3.2ml is 22.5mmol) in the solution in anhydrous tetrahydro furan.Deposited reaction mixture 3 days being lower than under 10 ℃ the temperature.Add 15ml methyl alcohol, make reaction mixture keep room temperature, be completed into desired phosphotriester up to TLC indication chlorinated phosphate.With flash chromatography (ethyl acetate/hexane) purifying, obtain methyl-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester, be colorless oil.

Embodiment 19

Two (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester

(phosphodiester of the GLA 3-hydroxy propyl ester of 2 molecules)

With lithiumbromide (104mg, methylethylketone 1.13mmol) (1ml) solution is added to methyl-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester (0.85g, 1.13mmol, as making among the embodiment 18) in the solution in methylethylketone (1ml), mixture heating up was refluxed 1 hour.After the cooling mixture is dissolved in the 3ml ether, with the extraction of 3ml water.The emulsion that forms is destroyed by adding several methyl alcohol.Tell organic layer, use dried over sodium sulfate, concentrate,, generate two (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester, be white waxy solid with flash chromatography (methyl alcohol/chloroform) purifying.

Embodiment 20

(2-aminoethyl)-(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester

(phosphodiester of the 3-hydroxy propyl ester of thanomin and GLA)

Part 1:

With thanomin (0.5ml, 8.25mmol) and triethylamine (4.2ml, 30mmol) mixture in anhydrous tetrahydro furan (20ml) is added to rough chlorinated phosphate (7.5mmol, half of the batch that makes in top embodiment 18 parts 1) in the solution in anhydrous tetrahydro furan (20ml), keep temperature to be lower than 10 ℃.Progress with the TLC monitoring reaction.Mixture was deposited under 5 ℃ 3 days being lower than.Subsequently with its filtration, concentrated, with 50ml hexane dilution and concentrated again.

Part 2:

The product that obtains in the part 1 is dissolved in Virahol (100ml), acetate (10ml) and the water (40ml), and solution is placed under nitrogen atmosphere and room temperature.When TLC Indicator Reaction fully the time, mixture is concentrated and is distributed among acetonitrile (50ml) and the hexane (50ml).Tell hexane layer, concentrate, with flash chromatography (methyl alcohol/chloroform/water) purifying.Collect pure fraction and concentrated.Add ethyl acetate, (2-aminoethyl)-(z, z, z-18 carbon-6,9, the 12-triolefin acyloxy propyl group) phosphoric acid ester that centrifugal collection is pulverized is creamy waxy solid.

Embodiment 21

(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(2-(N, N, N-TMA (TriMethylAmine)) ethyl) phosphoric acid ester

(phosphodiester of the 3-hydroxy propyl ester of choline and GLA)

Part 1:

With 2-chloro-1,3,2-two oxa-s phospholane-2-oxide compound (430mg, 3.4mmol) toluene (5ml) solution be added to 1-(z, z, z-18 carbon-6 that are cooled to 0 ℃, 9,12-triolefin acyloxy)-the 3-hydroxy propane (1g, 2.98mmol) and triethylamine (0.57ml is 4.1mmol) in the solution in toluene (45ml).The mixture stirring is spent the night, be warmed to room temperature.The reaction of TLC analysis revealed is incomplete as yet.Add triethylamine (0.3ml) and 2-chloro-1,3 again, the 2-two oxa-s phospholane-solution of 2-oxide compound (200mg) in 5ml toluene continues to react a night.This moment, the TLC Indicator Reaction was complete, and mixture is concentrated.

Part 2:

The crude product of part 1 is dissolved in the 60ml acetonitrile.1/4 (15ml) and the Trimethylamine 99 (10ml) of this solution are heated 5 hours (carefully in 60 ℃ in tube sealing! ).With the reaction mixture cooling, at N ₂Air-flow concentrates down, obtains (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(2-(N, N, N-TMA (TriMethylAmine)) ethyl) phosphoric acid ester.

Embodiment 22

(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester (phosphate monoester of GLA 3-hydroxy propyl ester)

Under agitation with 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-the 3-hydroxy propane (1.95g, 5.8mmol), pyridine (1.4ml, 17.3mmol) and the solution of anhydrous tetrahydro furan (15ml) dropwise be added to the phosphoryl chloride (1.02g that is cooled to 0 ℃, 6.6mmol) in the solution in anhydrous tetrahydro furan (5ml), formed mixture was kept 3 hours down at 0 ℃.In reaction mixture, add sodium bicarbonate aqueous solution (10%w/w, 10ml).Stir and after 20 minutes mixture is poured in ice/water (30ml), dropwise add 2M hydrochloric acid and make solution be acidified to pH 1.(2 * 30ml) extract mixture with ether.The ether extraction liquid is merged, dry and concentrated.Formed oily matter and anhydrous pyridine component distillation obtain (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group) phosphoric acid ester, are the heavy-gravity yellow oil.

Embodiment 23

Methyl-(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(alpha-tocopherol base) phosphoric acid ester

(alpha-tocopherol, the phosphotriester of the 3-hydroxy-propyl ester of methyl alcohol and GLA)

Part 1:

(1.26g is 8.25mmol) in the solution in anhydrous tetrahydro furan (7.5ml) triethylamine (7.5ml) to be added to the phosphoryl chloride that new distillation obtains under 0 ℃.After 15 minutes, in 30 minutes, dropwise adding 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (2.5g, 7.5mmol) solution in anhydrous tetrahydro furan (7.5ml) under 0 ℃.Adding the back continues to stir 30 minutes under this temperature.(3.23g, the 7.5mmol) solution in anhydrous tetrahydro furan (5ml) stir formed mixture 1 hour down at 10 ℃ then, are warmed to ambient temperature overnight subsequently dropwise to add alpha-tocopherol under 10 ℃.

Part 2:

With 1/4 mixture in the upper section 1, triethylamine (0.8ml, 6mmol) and methyl alcohol (10ml) stir under nitrogen in room temperature and spend the night.Reaction mixture is concentrated, be distributed among ethyl acetate (30ml) and the water (20ml), add sodium-chlor and methyl alcohol to destroy milk sap.With the ethyl acetate layer drying, concentrate, with flash chromatography (chloroform) purifying, obtain methyl-(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(alpha-tocopherol base) phosphoric acid ester.

Embodiment 24

(z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(alpha-tocopherol base) phosphoric acid ester

(phosphodiester of the 3-hydroxy-propyl ester of alpha-tocopherol and GLA)

Triethylamine (2ml) and water (5ml) are added in 1/4 reaction mixture that makes in embodiment 23 parts 1.Under nitrogen, reaction mixture was stirred in ice bath 1 hour, to pH 1, be extracted in ethyl acetate (20ml) and the methyl alcohol (5ml) with the 2M hcl acidifying.With the extraction liquid drying, concentrate, with flash chromatography (chloroform) purifying, obtain (z, z, z-18 carbon-6,9,12-triolefin acyloxy propyl group)-(alpha-tocopherol base) phosphoric acid ester.

Embodiment 25

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-5-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) pentane

(GLA and EPA and 1, the diester of 5-pentanediol)

Part 1:

Under 0 ℃ and nitrogen with z, z, z-18 carbon-6,9,12-triolefin acyl chlorides (2g) dropwise be added to stirring 1, in the solution of 5-dihydroxyl pentane (3.5g), triethylamine (0.94ml) and 4-(N, N-dimethylamino) pyridine (0.2g) in methylene dichloride (50ml).After TLC confirms to react completely, reaction mixture dilute hydrochloric acid and washing, drying is used the column chromatography purifying, obtains 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-5-hydroxyl pentane, is light yellow oil.

Part 2:

As embodiment 2 parts 2, but use 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-5-hydroxyl pentane replacement 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-the 3-hydroxy propane, use z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acid substitution z-Octadec-9-enoic Acid.Chromatographic separation obtains 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-5-(z, z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) pentane, is light yellow oil.

Embodiment 26

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-4-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) benzene

(GLA and EPA and 1, the diester of 4-dihydroxy-benzene)

As embodiment 25 parts 1 and 2 preparations, but in part 1 with 1, the 4-dihydroxy-benzene replaces 1,5-dihydroxyl pentane, with tetrahydrofuran (THF) replacement methylene dichloride as the solvent in the part 1.Chromatographic separation obtains 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-4-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) benzene, is light yellow oil.

Embodiment 27

1,4-two (z, z, z-18 carbon-6,9,12-trialkenyl) fourth-1,4-two acid esters

(diester of GLA alcohol and Succinic Acid)

Part 1:

With 1,8-diazabicyclo [5.4.0] the 11 carbon-solution of 7-alkene (0.54ml) in anhydrous tetrahydro furan (10ml) dropwise is added to the z that is cooled to 0 ℃, z, z-18 carbon-6,9, in 12-three enols (1g) and the solution of Succinic anhydried (0.36g) in anhydrous tetrahydro furan (20ml).TLC dilutes reaction mixture after confirming to react completely with ether, with dilute hydrochloric acid, water and salt washing.With organic layer drying, concentrated, be directly used in the second section reaction.

Part 2:

With 1, the solution of 3-dicyclohexyl carbodiimide (0.83g) and 4-(N, N-dimethylamino) pyridine (0.55g) in methylene dichloride (20ml) is added to 1-(z, z, z-18 carbon-6,9, the 12-trialkenyl)-Ding-1,4-two acid esters (1.32g) and z, z, z-18 carbon-6,9 are in the solution of 12-three enols (0.98g) in methylene dichloride (40ml).Analyze the afterreaction mixture that confirms to react completely at TLC and dilute, filter, concentrate, use chromatography purification, obtain 1 with hexane, 4-two (z, z, z-18 carbon-6,9,12-trialkenyl)-Ding-1,4-two acid esters are light yellow oil.

Embodiment 28

2-(2-methyl-5-nitro imidazolyl) ethyl-z, z, z-18 carbon-6,9,12-triolefin acid esters

(ester of metronidazole and GLA)

Method A:

In the suspension of metronidazole (206g) in anhydrous acetonitrile (2300ml) and anhydrous pyridine (107ml), under agitation in 30 minutes, adding z under room temperature and the nitrogen atmosphere, z, z-18 carbon-6,9,12-triolefin acyl chlorides (373g).Soon promptly form transparent solution after adding acyl chlorides, continue to stir 2 hours.The mixture placement is spent the night, solvent removed in vacuo (50 ℃/20mmHg).In resistates, add ethyl acetate (1000ml), the sedimentary any solid of filtering.Ethyl acetate solution is successively with salt solution, 2M hydrochloric acid, saturated aqueous solution of sodium bicarbonate and salt washing.Drying (is used Na ₂SO ₄) after solvent is removed, obtain orange.This material is used for the column chromatography purifying, obtains 2-(2-methyl-5-nitro imidazolyl) ethyl-z, z, and z-18 carbon-6,9,12-triolefin acid esters is light yellow not distillable oily matter.

Method B:

Metronidazole (1.9g) is suspended in the toluene (30ml), with this mixture with Dean-Stark still head under agitation reflux 20 minutes to remove any moisture that exists.Under nitrogen, in ebullient solution, in 20 minutes, dropwise add 2.96g z, z, z-18 carbon-6,9,12-triolefin acyl chlorides.Mixture is stirred, and reflux is 2 hours again, obtains the black reaction mixture.With this mixture dry-column chromatography purifying, obtain 2-(2-methyl-5-nitro imidazolyl) ethyl-z after the cooling, z, z-18 carbon-6,9,12-triolefin acid esters is light yellow not distillable oily matter.

Embodiment 29

2-(2-methyl-5-nitro imidazolyl) ethyl-z, z ,-Linolenic Acid, 12-diene acid esters

(ester of metronidazole and LA)

In the suspension of metronidazole (1.9g) in anhydrous methylene chloride (20ml), add 4-(N, N-dimethylamino) pyridine (1.22g), 1,3-dicyclohexyl carbodiimide (2.2g) and linolic acid (2.8g) successively.Mixture at room temperature stirs and spends the night.In reaction mixture, add 20ml 2M hydrochloric acid, continue to stir.Tell organic layer after the filtration, wash with 50% saturated brine and saturated aqueous solution of sodium bicarbonate successively.With the dichloromethane solution dried over sodium sulfate, vacuum-evaporation (30 ℃/20mmHg).(boiling point 30-60 ℃, 20ml), mixture was at room temperature placed 2 hours, made remaining urea precipitation to add gasoline in formed resistates.Filtration is removed it, and filtrate is used the dry-column chromatography purifying, obtains 2-(2-methyl-5-nitro imidazolyl) ethyl-z, z, and-Linolenic Acid, 12-diene acid esters is light yellow not distillable oily matter.

Embodiment 30

2-(2-methyl-5-nitro imidazoles acyl group) ethyl-z, z, z-Er Shitan-8,11,14-triolefin acid esters

(ester of metronidazole and DGLA)

In a similar fashion, still use the z of aequum, z, the z-Er Shitan-8,11, the 14-trienic acid replaces linolic acid, makes 2-(2-methyl-5-nitro imidazoles acyl group) ethyl-z, z, z-Er Shitan-8,11,14-triolefin acid esters.

Embodiment 31

2-(2-methyl-5-nitro imidazoles acyl group) ethyl-z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-acid ester

(ester of metronidazole and DHA).

Use similar mode, but use the z of aequum, z, z, z, z, z-22 carbon-4,7; 10,13,16, the 19-acid replaces linolic acid, makes 2-(2-methyl-5-nitro imidazoles acyl group) ethyl-z, z, z, z; z, z-22 carbon-4,7,10,13,16,19-acid ester.

Embodiment 32

4-[3-[2-(trifluoromethyl) 10H-thiodiphenylamine-10-yl]]-1-piperazine ethyl-z, z, z-18 carbon-6,9,12-triolefin acid esters

(ester of Fluphenazine and GLA)

Use similar mode, but 4-[3-[2-(trifluoromethyl)-10H-thiodiphenylamine-10-yl with aequum]]-1-piperazine ethanol (Fluphenazine) free alkali replacement metronidazole, GLA with aequum replaces linolic acid, obtain 4-[3-[2-(trifluoromethyl)-10H-thiodiphenylamine-10-yl]]-1-piperazine ethyl-z, z, z-18 carbon-6,9,12-triolefin acid esters.

Embodiment 33

4,4 '-(two z, z, z-18 carbon-6,9,12-triolefin amido) sulfobenzide

(bisamide of dapsone and GLA)

Use similar mode, but replace metronidazole, replace linolic acid with the GLA of aequum with the 4,4 (dapsone) of aequum, make 4,4 '-(two z, z, z-18 carbon-6,9,12-triolefin amido) sulfobenzide.

Embodiment 34

N-methyl-3-phenyl-3[α, α, α-three fluoro-p-methylphenyl] propyl group; Z, z, z-18 carbon-6,9,12-triolefin acid amides

(acid amides of fluoxetine and GLA)

Use similar mode, but with the N-methyl-3-phenyl-3-[α of aequum, α, α-three fluoro-p-methylphenyl] propylamine (fluoxetine) replacement metronidazole, GLA with aequum replaces linolic acid, make N-methyl-3-phenyl-3-[α, α, α-trifluoro p-methylphenyl] propyl group-z, z, z-18 carbon-6,9,12-triolefin acid amides.

Embodiment 35

Instead-1-(z, z, z-18 carbon-6,9,12-triolefin amido)-2-benzyl ring propane

(acid amides of Tranylcypromine and GLA)

By similar mode, still anti--1-amino-2-benzyl ring the propane (Tranylcypromine) with aequum replaces metronidazole, and the GLA replacement linolic acid with aequum makes anti--1-(z, z, z-18 carbon-6,9,12-triolefin amido)-2-benzyl ring propane.

Embodiment 36

6-[(aminophenyl ethanoyl) amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-z, z, z-18 carbon-6,9,12-triolefin acid amides

(acid amides of penbritin and GLA)

In nitrogen atmosphere with under stirring triethylamine (0.3ml) is added in the suspension of penbritin (0.7g) in anhydrous dimethyl formamide (120ml).In formed clear solution, add z, z, z-18 carbon-6,9, the 12-trienic acid, N-maloyl imines ester (0.75g), keeping temperature of reaction simultaneously is 0-10 ℃.The restir reaction mixture is one hour under this temperature, at room temperature places then and spends the night.The most of succimide ester of TLC analysis this moment (40% tetrahydrofuran (THF) hexane) indication reacts.In the reactant flask, add 40ml water, stir content.With the solution neutralization, use ethyl acetate extraction then.Extraction liquid washes with water, uses dried over sodium sulfate, is concentrated into dried.Stay the crude product of yellow glass shape.With the hexane development, obtain 6-[(aminophenyl ethanoyl) amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid-z, z, z-18 carbon-6,9,12-triolefin acid amides is yellow powder.

Embodiment 37

Z, z, z-18 carbon-6,9,12-trialkenyl-z, z, z-18 carbon-6,9,12-triolefin acid esters

(ester of GLA and GLA alcohol)

Under room temperature and nitrogen with 1,3-dicyclohexyl carbodiimide (0.82g) and 4-(N, the N-dimethylamino) solution of pyridine (0.48g) in methylene dichloride (5ml) is added to the z that is stirring, z, z-18 carbon-6,9,12-three enols (0.95g) and z, z, z-18 carbon-6,9, in the solution of 12-trienic acid (1g) in methylene dichloride (10ml).When the TLC Indicator Reaction has been finished, in reaction mixture, add hexane, filter immediately, use the column chromatography purifying, obtain z, z, z-18 carbon-6,9,12-trialkenyl-z, z, z-18 carbon-6,9,12-triolefin acid esters is light yellow oil.

Embodiment 38

Z, z, z-18 carbon-6,9,12-trialkenyl-z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acid esters

(ester of EPA and GLA alcohol)

As embodiment 37 preparations, but use z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acid substitution z, z, z-18 carbon-6,9,12-trienic acid.

Embodiment 39

2-methyl-3-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy)-4-formyl radical-5-(z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyloxy) picoline

(two EPA esters of pyridoxal)

In the suspension of pyridoxal hydrochloride (1.0g) in methylene dichloride (20ml), add triethylamine (2.0ml), formed yellow transparent solution.Ice-cooled following to wherein adding z, z, z, z, z-20 carbon-5,8,11,14,17-pentaene acyl chlorides (1.73g) (prepared in reaction in methylene dichloride) by EPA and oxalyl chloride.With mixture at N ₂Gas stirs down and spends the night, and is warmed to room temperature.After the dilution of isopyknic methylene dichloride, mixture is with 2M hydrochloric acid (20ml) extraction, wash with water (3 * 20ml), dry and concentrate.With purified by flash chromatography (ethyl acetate/hexane), obtain 2-methyl-3-z, z, z, z, z-20 carbon-5,8; 11,14,17-pentaene acyloxy-4-formyl radical-5-(z, z, z, z; z-20 carbon-5,8,11,14,17-pentaene acyloxy) picoline, be transparent oily matter.

Embodiment 40

2-methyl-3-hydroxyl-4-formyl radical-5-(z, z, z-18 carbon-6,9,12-triolefin acyloxy) picoline

(the GLA ester of pyridoxal)

Under 0 ℃ and nitrogen with z, z, z-18 carbon-6,9, and 12-triolefin acyl chlorides (800mg, 2.7mmol) solution in methylene dichloride slowly is added to pyridoxal hydrochloride (500mg, 2.45mmol), triethylamine (1ml, 7.2mmol) and the mixture of 4-(N, N-dimethylamino) pyridine (several mg, catalytic amount) in methylene dichloride (20ml) in.After TLC confirms to react completely, mixture is concentrated and, obtain 2-methyl-3-hydroxyl-4-formyl radical-5-(z with purified by flash chromatography (ethyl acetate/hexane); z, z-18 carbon-6,9; 12-triolefin acyloxy) picoline is colorless oil, solidifies immediately.

Embodiment 41

2-methyl-3-hydroxyl-4,5-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy) picoline

(two GLA esters of Benadon)

Under 0 ℃ and nitrogen with z, z, z-18 carbon-6,9, and 12-triolefin acyl chlorides (650mg, 2.2mmol) solution in methylene dichloride (10ml) slowly is added to Benadon hydrochloride (206mg, 1mmol), triethylamine (0.7ml, 5mmol) and in the mixture of 4-(N, N-dimethylamino) pyridine (several milligrams, catalytic amount) in methylene dichloride (20ml).In the complete back (4 hours) of TLC Indicator Reaction, reaction mixture concentrated and with purified by flash chromatography (ethyl acetate/hexane), obtain the 2-methyl-3-hydroxyl-4 of colorless oil, 5-two (z, z, z-18 carbon-6,9,12-triolefin acyloxy) picoline.

Embodiment 42

1-(2-(2-methyl-5-nitro imidazoles acyl group) ethyl)-4-(z, z, z-18 carbon-6,9,12-trialkenyl) fourth-1,4-two acid esters

(diester of metronidazole and GLA and Succinic Acid)

Under room temperature and nitrogen, with 1,3-dicyclohexyl carbodiimide (780mg, 3.8mmol) and 4-(N, the N-dimethylamino) pyridine (530mg, 4.3mmol) solution in methylene dichloride (15ml) under agitation is added to GLA alcohol succinate monoester (1.25g, 3.3mmol, press the preparation of embodiment 27 parts 1) and metronidazole (620mg is 3.6mmol) in the solution in methylene dichloride (30ml).After the TLC Indicator Reaction is complete, mixture is diluted with hexane, filter, concentrate, with purified by flash chromatography (ethyl acetate/hexane).Collect product cut and concentrated, obtain 1-(2-(2-methyl-5-nitro imidazoles acyl group) the ethyl)-4-(z, z, z-18 carbon-6,9,12-trialkenyl)-1 of colorless oil, the 4-succinate.

Embodiment 43

Instead-1-(z, z, z-18 carbon-6,9,12-three allyloxycarbonyl fourth oxygen amino)-2-benzyl ring propane

(Succinic Acid, 1-GLA alcohol ester, 4-Tranylcypromine acid amides)

Under room temperature and nitrogen with 1,3-cyclohexyl carbodiimide (315mg, 1.52mmol) and 4-(N, the N-dimethylamino) pyridine (210mg, 1.72mmol) solution in methylene dichloride (10ml) is added to the pure succinate monoester (500mg of GLA down in stirring, 1.32mmol) (as in embodiment 27 parts 1 preparation) and Tranylcypromine (225mg is 1.32mmol) in the solution in methylene dichloride (20ml).The TLC Indicator Reaction fully after, dilute this mixture with hexane, filter, concentrate, with purified by flash chromatography (ethyl acetate/hexane).Collect product cut and concentrated, obtain anti--1-(z, z, z-18 carbon-6,9,12-three allyloxycarbonyl fourth oxygen amino)-2-benzyl ring propane, be colorless oil.

Embodiment 44

(±)-2,5,7,8-tetramethyl--2-(4 ', 8 ', 12 '-the trimethylammonium decyl)-6-chromanyl-z, z, z-18 carbon-6,9,12-triolefin acid esters

(the GLA ester of alpha-tocopherol)

Under nitrogen and-5 ℃ with z, z, z-18 carbon-6,9, (2.96g 10mmol) dropwise was added to (±)-alpha-tocopherol (4.3g down in stirring to 12-triolefin acyl chlorides in 2-3 minute, 10mmol) and pyridine (0.885ml is 11mmol) in the solution in methylene dichloride (35ml).Subsequently reaction mixture is stirred and spend the night, be warmed to room temperature.The reaction of TLC analysis revealed is carried out fully basically.(4 * 100ml) wash with reaction mixture water (100ml), 2M hydrochloric acid (10ml is in 100ml water) and water.With organic layer drying (sodium sulfate) and concentrated.With purified by flash chromatography (ether/hexane), obtain (±)-2,5,7,8-tetramethyl--2-(4 ', 8 ', 12 '-the trimethylammonium decyl)-6-chromanyl-z, z, z-18 carbon-6,9,12-triolefin acid esters is light yellow oil.

Embodiment 45

Androst-5-ene-17-ketone-3-(z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-acid ester)

(the DHA ester of dehydroepiandrosterone)

To being cooled to add z, z, z, z in 0 ℃ dehydroepiandrosterone (1g) and the mixture of triethylamine (1ml) in methylene dichloride (20ml), z, z-22 carbon-4,7,10,13,16,19-six alkene acyl chlorides (1.33g, prepared in reaction in methylene dichloride) by DHA and oxalyl chloride.The mixture stirring is spent the night, be warmed to room temperature.With methylene dichloride (20ml) dilution, with 2M hydrochloric acid (20ml) extraction, (2 * 20ml) wash water, and drying also concentrates with it.With purified by flash chromatography (ethyl acetate/hexane), obtain dehydrogenation table androst-5-ene-17-ketone-3 (z, z, z, z, z, z-22 carbon-4,7,10,13,16,19-acid ester), be transparent oily matter.

Embodiment 46

Z, z, z-18 carbon-6,9,12-trialkenyl-(2-(z, z, z-18 carbon-6,9,12-triolefin oxygen base) acetic ester).

(diester of GLA and GLA alcohol and oxyacetic acid)

Part 1:

With chloroacetyl chloride (0.4ml, 5mmol) solution in methylene dichloride (10ml) dropwise is added to z under 0 ℃, z, z-18 carbon-6,9,12-three enols (1g, 3.8mmol) and triethylamine (1.4ml is 10mmol) in the solution in methylene dichloride (20ml).Progress with the TLC monitoring reaction.3 hours afterreactions are finished substantially but are not carried out fully.Add several chloroacetyl chlorides again.TLC analyzes and shows that reaction is complete in 5 minutes.The mixture water (2 * 50ml) and salt solution (50ml) wash, use dried over sodium sulfate, concentrate.Add toluene (50ml) so that azeotropic is removed last trace water.This obtains chocolate buttery GLA alcohol chloracetyl ester, not purified direct use.

Part 2:

With z, z, z-18 carbon-6,9, the 12-trienic acid (700mg, 2.5mmol) and cesium carbonate (410mg, the turn in methyl alcohol of mixture 1.25mmol) is up to forming transparent solution.Mixture concentrates subsequently and kept 1 hour in 40 ℃ under high vacuum.This forms the cesium salt of GLA, its not purified direct use.

Part 3:

In part 2 is housed, add in the flask of GLA cesium salt of preparation GLA alcohol the chloracetyl ester (part 1,500mg, 1.5mmol) and anhydrous dimethyl formamide (15ml).Stirred reaction mixture under nitrogen and room temperature.After 90 minutes, the reaction of TLC analysis revealed is complete.Reaction mixture with hexane (2 * 40ml) extractions, hexane extract with salt solution (2 * 50ml) and water (50ml) wash, use dried over sodium sulfate, concentrated, obtain z, z, z-18 carbon-6,9,12-trialkenyl-(2-(z, z, z-18 carbon-6,9,12-triolefin oxygen base) acetic ester), be colorless oil.

Embodiment 47

Hydrocortisone-21-(z, z, z-18 carbon-6,9,12-triolefin acid esters)

(the GLA ester of hydrocortisone)

Under 0 ℃ and nitrogen with z, z, z-18 carbon-6,9, and 12-triolefin acyl chlorides (450mg, 1.52mmol) solution in methylene dichloride (10ml) slowly is added drop-wise to hydrocortisone (500mg, 1.38mmol), triethylamine (420 μ l, 3mmol) and in the mixture of 4-(N, N-dimethylamino) pyridine (several milligrams, catalytic amount) in methylene dichloride (20ml).TLC analysis Indicator Reaction has been carried out fully after 4 hours.Mixture is concentrated,, obtain hydrocortisone-21-(z, z, z-18 carbon-6,9,12-triolefin acid esters), be colorless oil with purified by flash chromatography (ethyl acetate/hexane).

Embodiment 48

Z, z, z-18 carbon-6,9,12-trialkenyl-(2-(1-(4-chlorobenzene formacyl)-5-methoxyl group-2 methyl indole-3-acetoxyl group) acetic ester)

(diester of INDOMETHACIN and GLA alcohol and oxyacetic acid)

Part 1:

With INDOMETHACIN (895mg, 2.5mmol) and cesium carbonate (410mg, the turn in methyl alcohol of mixture 1.25mmol) is up to forming transparent solution.Concentrated solution kept 1 hour in 40 ℃ under high vacuum subsequently.This forms the cesium salt of the INDOMETHACIN of glassy yellow solid state.

Part 2:

In part 1 is housed, add in the flask of INDOMETHACIN cesium salt of preparation GLA alcohol the chloracetyl ester (as preparation in embodiment 46 parts 1,500mg, 1.5mmol) and anhydrous dimethyl formamide (15ml).Reaction stirred under nitrogen and room temperature is with the carrying out of TLC salt measured reaction.After refrigerator overnight, the reaction of TLC analysis revealed is complete.Mixture is distributed among water (50ml) and the ethyl acetate (50ml).Add several mL of saline so that destroy milk sap.(3 * 50ml) wash the ethyl acetate layer water, use dried over sodium sulfate, filter through silicagel pad, concentrate; obtain z, z, z-18 carbon-6; 9,12-trialkenyl-(2-(1-(4-chlorobenzene formacyl)-5-methoxyl group-2 methyl indole-3-acetoxyl group) acetic ester) is glassy yellow oily matter.

Embodiment 49

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(4-phenyl butyryl acyloxy) propane

(4-phenylbutyric acid and GLA and 1, the diester of ammediol)

With 1,3-dicyclohexyl carbodiimide (710mg, 3.45mmol) and 4-(N, N-dimethylamino) pyridine (475mg, 3.9mmol) solution in methylene dichloride (10ml) is added to 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-hydroxy propane (1g, 3mmol) (520mg is 3.15mmol) in the solution in methylene dichloride (15ml) with the 4-phenylbutyric acid.Under room temperature and nitrogen, stir formed mixture, complete up to the TLC Indicator Reaction.Mixture is filtered, concentrate, use purified by flash chromatography, obtain 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(4-phenyl butyryl acyloxy) propane.

Embodiment 50

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(phenyl acetoxyl group) propane

(phenylacetic acid and GLA and 1, the diester of ammediol)

According to the mode similar to embodiment 49, but (430mg 3.15mmol) replaces the 4-phenylbutyric acid, makes 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(phenyl acetoxyl group) propane with phenylacetic acid.

Embodiment 51

1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(anti--cinnamoyloxy group) propane

(trans cinnamic acid and GLA and 1, the diester of ammediol)

According to the mode similar to embodiment 49, but (470mg 3.15mmol) replaces the 4-phenylbutyric acid, makes 1-(z, z, z-18 carbon-6,9,12-triolefin acyloxy)-3-(anti--cinnamoyloxy group) propane with trans cinnamic acid.

Claims (18)

1. what be used for the treatment of is following 1, the compound of ammediol syndeton

R wherein ¹Comprise acyl group or fatty alcohol radical, by the C that contains two or more cis or trans double bond _12-30Fatty acid derived forms, R ²Be hydrogen, perhaps comprise and R ¹Identical or different acyl group or fatty alcohol radical, or be selected from the following R that removes ¹Shown in nutrition, medicine or bio-active group beyond acyl group or the fatty alcohol radical:

VITAMIN

GLA-nicotinic acid, the GLA-vitamin A acid, the GLA-Vogan-Neu, the GLA-pyridoxal, two GLA-Benadons, two EPA-pyridoxals and have among GLA, DGLA, AA, SA, EPA or the DHA of any VITAMIN any one, described VITAMIN comprises vitamins C, vitamins D and derivative thereof, vitamin-E and derivative thereof, vitamin K and derivative thereof, vitamins B ₁, vitamins B ₂, vitamin Bc, vitamins B ₁₂, vitamin H and pantothenic acid;

Amino acid

The GLA-tryptophane, the GLA-proline(Pro), the GLA-arginine, GLA-or DHA-phenylalanine, GLA-GABA, the GLA-amino-laevulic acid, and have among GLA, DGLA, AA, SA, EPA or the DHA of other natural amino acids any one;

Aromatic acid

The GLA-phenylbutyric acid, the GLA-phenylacetic acid, the GLA-trans-cinnamic acid, and have among GLA, DGLA, AA, SA, EPA or the DHA of other aryl-alkanoics or aryl alkenoic acid any one;

Steroide

The GLA-hydrocortisone, GLA-androstane glycol, GLA-and DHA-dehydroisoandrosterone, and have among other GLA, DGLA, AA, SA, EPA or DHA natural or the synthetic steroide any one;

Antioxidant

The GLA-Thioctic Acid, the DHA-Thioctic Acid, the GLA-tocopherol, two-GLA-3,3 '-thio-2 acid, and have other can with GLA, DGLA, AA, SA, EPA or the DHA of the natural or synthetized oxidation preventive agent of its chemical bonding in any one;

Medicine

GLA and INDOMETHACIN, ibuprofen, fluoxetine, penbritin, penicillin v, sulindac, acetylsalicylic acid, Whitfield's ointment, metronidazole, Fluphenazine, dapsone, Tranylcypromine, acetylcarnitine, haloperidol, Quinacrime, quinacrine hydrochloride, Mefloquine hydrochloride, chloroquinoline, penicillin, tsiklomitsin, clindamycin, minocyline, erythromycin, Pravastatin, antimycotic imidazoles, nitroimidazole, amphotericin, male sex hormone, accutane, S-Neoral, tacrolimus, Phenytoin Sodium Salt, carboxamide nitrogen

Sodium Valproate, ethosuximide, vigabatrin, lamotrigine, fibrates, statin, Diatrizoate, Iodipamide, ioglycamic acid salt, iodopanoic acid salt, iofendylate, iothalamate, Ioxaglic Acid salt, metrizamide, Regular Insulin, thyrocalcitonin, erythropoietin, medicine based on porphyrin chlorin or bacterium chlorin or their four (hydroxy phenyl) derivative, bisphosphate, the adenosyl succinate, the adeninyl succinate, as the reagent of x-ray contrast agent, and have other and be used for the treatment of transmissible disease, inflammation, cancer, cardiovascular diseases, respiratory tract disease, tetter, psychosis, neuropathy, myonosus, ephrosis, gastrointestinal disorder, the GLA of the medicine of reproductive system diseases, DGLA, AA, SA, among EPA or the DHA any one.

2. the compound of claim 1, wherein said acyl group or fatty alcohol radical are by the C that contains two or more cis or trans double bond _16-30Fatty acid derived forms.

3. the compound of claim 1 is wherein at R ¹And/or R ²Group and 1 between the ammediol base, inserts phosphate, Succinic Acid base or other difunctionality acidic groups.

4. the compound of claim 3, wherein R ²Be to have the following nutrition of being selected from of hydroxyl or amido functional group, medicine or bio-active substance group:

VITAMIN

GLA-nicotinic acid, the GLA-vitamin A acid, the GLA-Vogan-Neu, the GLA-pyridoxal, two GLA-Benadons, two EPA-pyridoxals and have among GLA, DGLA, AA, SA, EPA or the DHA of any VITAMIN any one, described VITAMIN comprises vitamins C, vitamins D and derivative thereof, vitamin-E and derivative thereof, vitamin K and derivative thereof, vitamins B ₁, vitamins B ₂, vitamin Bc, vitamins B ₁₂, vitamin H and pantothenic acid;

Amino acid

The GLA-tryptophane, the GLA-proline(Pro), the GLA-arginine, GLA-or DHA-phenylalanine, GLA-GABA, the GLA-amino-laevulic acid, and have among GLA, DGLA, AA, SA, EPA or the DHA of other natural amino acids any one;

Aromatic acid

The GLA-phenylbutyric acid, the GLA-phenylacetic acid, the GLA-trans-cinnamic acid, and have among GLA, DGLA, AA, SA, EPA or the DHA of other aryl-alkanoics or aryl alkenoic acid any one;

Steroide

The GLA-hydrocortisone, GLA-androstane glycol, GLA-and DHA-dehydroisoandrosterone, and have among other GLA, DGLA, AA, SA, EPA or DHA natural or the synthetic steroide any one;

Antioxidant

The GLA-Thioctic Acid, the DHA-Thioctic Acid, the GLA-tocopherol, two-GLA-3,3 '-thio-2 acid, and have other can with GLA, DGLA, AA, SA, EPA or the DHA of the natural or synthetized oxidation preventive agent of its chemical bonding in any one;

Medicine

GLA and INDOMETHACIN, ibuprofen, fluoxetine, penbritin, penicillin v, sulindac, acetylsalicylic acid, Whitfield's ointment, metronidazole, Fluphenazine, dapsone, Tranylcypromine, acetylcarnitine, haloperidol, Quinacrime, quinacrine hydrochloride, Mefloquine hydrochloride, chloroquinoline, penicillin, tsiklomitsin, clindamycin, minocyline, erythromycin, Pravastatin, antimycotic imidazoles, nitroimidazole, amphotericin, male sex hormone, accutane, S-Neoral, tacrolimus, Phenytoin Sodium Salt, carboxamide nitrogen

Sodium Valproate, ethosuximide, vigabatrin, lamotrigine, fibrates, statin, Diatrizoate, Iodipamide, ioglycamic acid salt, iodopanoic acid salt, iofendylate, iothalamate, Ioxaglic Acid salt, metrizamide, Regular Insulin, thyrocalcitonin, erythropoietin, medicine based on porphyrin chlorin or bacterium chlorin or their four (hydroxy phenyl) derivative, bisphosphate, the adenosyl succinate, the adeninyl succinate, as the reagent of x-ray contrast agent, and have other and be used for the treatment of transmissible disease, inflammation, cancer, cardiovascular diseases, respiratory tract disease, tetter, psychosis, neuropathy, myonosus, ephrosis, gastrointestinal disorder, the GLA of the medicine of reproductive system disease, DGLA, AA, SA, among EPA or the DHA any one.

5. according to each compound among the claim 1-4, wherein lipid acid is n-6 or n-3 series indispensable fatty acid or oleic acid or punicic acid or therapic acid or conjugated linolic acid.

6. according to the compound of claim 5, wherein lipid acid is gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, adrenic acid, therapic acid, timnodonic acid, clupanodonic acid n-3, docosahexenoic acid or conjugated linolic acid.

7. according to each compound among the claim 1-4, no matter wherein pass any lipid film, R ²Be medicine, VITAMIN, amino acid or antioxidant, it is to R ¹Play adduction, replenish or synergism required.

8. one kind is improved the method that transports that medicine passes the body lipid film, it is characterized in that, uses actives with the form of the compound in aforementioned any claim.

9. each described any or one group of compound itself, wherein R among the claim 1-4 ¹With R ²Identical and derive from except the compound of oleic acid, linolic acid or alpha-linolenic acid.

10. in the application of compound in preparation skin care or treatment dermatological formulation that claim 1-7 and 9 mentions in any one.

11. the application of the compound that claim 1-7 and 9 mentions in any one aspect preparation food, foodstuff additive or food supplement.

12. the compound of mentioning in any one with claim 1-7 and 9 is used for oral, parenteral medication, through the method for the medicine of intestines medication, local application.

13. following 1, the compound of ammediol syndeton

R wherein ¹Comprise acyl group, being derived by gamma-linolenic acid or dihomo-gamma-linolenic acid forms; R ²Be acyl group, being derived by gamma-linolenic acid, dihomo-gamma-linolenic acid, therapic acid, timnodonic acid, docosahexenoic acid, conjugated linolic acid or punicic acid forms,

Be used for the treatment of purposes in the medicine of following disease in preparation:

(a) complication of diabetes; And improve in diabetes and the prediabetes response to Regular Insulin;

(b) cancer;

(c) osteoarthritis;

(d) rheumatoid arthritis;

(e) inflammation and autoimmune disease are selected from Si Yegelun syndromes, systemic lupus, ulcerative colitis, Crohn disease and uveitis;

(f) respiratory system disease;

(g) neuropathy is selected from multiple sclerosis, Parkinson's disease and Huntington Chorea;

(h) kidney and urethral disease;

(i) cardiovascular diseases;

(j) eye degenerative disease is selected from retinitis pigmentosa and senile macular degeneration SMD;

(k) psychosis is selected from schizophrenia, Alzheimer's disease, attention and laxes disease, alcoholism and dysthymia disorders;

(l) prostatomegaly and prostatitis;

(m) impotence and male infertility;

(n) mazalgia;

(o) male sex's alopecia areata;

(p) osteoporosis;

(q) tetter is selected from atopic eczema, hand eczema, psoriasis, urticaria and anaphylaxis dermatosis;

(r) dislexia and other learning capacity forfeiture;

(s) carcinemia.

14. following 1, the compound of ammediol syndeton

R wherein ¹Comprise acyl group, being derived by arachidonic acid forms; R ²Be acyl group, being derived by arachidonic acid, gamma-linolenic acid, docosahexenoic acid, dihomo-gamma-linolenic acid or timnodonic acid forms, and is used for the treatment of purposes in the medicine of disease described in the claim 13 in preparation.

15. the purposes of claim 14, wherein said disease are (a), (g), (i), (j), (k), (q) and (r).

16. following 1, the compound of ammediol syndeton

R wherein ¹Comprise acyl group, being derived by timnodonic acid forms; R ²Be acyl group, being derived by timnodonic acid or docosahexenoic acid forms,

Be used for the treatment of purposes in the medicine of any disease described in the claim 13 in preparation.

17. the purposes of claim 16, wherein said disease are (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (p), (r) and (s).

18. following 1, the compound of ammediol syndeton

R wherein ¹Comprise acyl group, being derived by gamma-linolenic acid, dihomo-gamma-linolenic acid, arachidonic acid, therapic acid, conjugated linolic acid, timnodonic acid or docosahexenoic acid forms; R ²Be to be selected from following group:

(a) tryptophane is used for the treatment of purposes in the medicine of psychosis, neuropathy, behavior disorders, pain, dysthymia disorders, lethargic sleep disease and migraine in preparation;

(b) phenylalanine is used for the treatment of purposes in the medicine of dysthymia disorders, multiple sclerosis and chronic fatigue syndrome in preparation;

(c) arginine is used for the treatment of purposes in the medicine of the insufficient disease of generation of any wherein nitrogen oxide in preparation;

(d) carnitine or carnitine derivative are used for the treatment of purposes in the medicine of gravis, heart failure, chronic fatigue syndrome, Alzheimer's disease and peripheral neurophaty in preparation;

(e) amino acid, perhaps amino-laevulic acid or derivatives thereof is used for the treatment of purposes in the medicine of cancer in preparation;

(f) the adenylosuccinate ester is used for the treatment of purposes in the medicine of muscular dystrophy, heart failure, chronic fatigue syndrome and Alzheimer's disease and other dementia in preparation;

(g) Asprin, Whitfield's ointment, INDOMETHACIN, ibuprofen or non-steroidal anti-inflammatory medicine are used for the treatment of inflammatory pain, Alzheimer's disease and dementia in preparation, and should suppress the purposes in the medicine of any disease of platelet aggregation;

(h) be selected from the microbiotic of tsiklomitsin, clindamycin, minocyline, duomycin and erythromycin, be used for the treatment of purposes in the medicine of transmissible disease in preparation;

(i) be selected from the antimalarial and the antiprotozoal of chloroquine, quinacrine hydrochloride, Quinacrime and Mefloquine hydrochloride, be used for the treatment of purposes in malaria, Protozoosis, inflammation and the schizoid medicine in preparation;

(j) be selected from the antifungal drug of metronidazole and antimycotic imidazoles and nitro glyoxaline and amphotericin, be used for the treatment of purposes in the medicine of all kinds of fungi infestations in preparation;

(k) hydrocortisone and Betamethasone Valerate are used for the treatment of purposes in the dermopathic medicine in preparation, and beclometasone and budesonide, are used for the treatment of purposes in the medicine of asthma in preparation;

(l) oestrogenic hormon and progestogen are used for the treatment of purposes in ovary defective and the osteoporotic medicine in preparation, and male sex hormone, are used for the treatment of purposes in the medicine of testis defective in preparation;

(m) retinoic acid and accutane are used for the treatment of tetter in preparation, and the purposes that is used for the medicine of skin care;

(n) any anticarcinogen is used for the treatment of purposes in the medicine of cancer in preparation;

(o) any inhibition spirit medicine is used for the treatment of purposes in schizophrenia and the psychotic medicine in preparation;

(p) any thymoleptic are used for the treatment of purposes in the medicine of dysthymia disorders in preparation;

(q) any anxiolytic is used for the treatment of purposes in the medicine of anxiety and panic attack in preparation;

(r) S-Neoral and tacrolimus, the control of immunizing power after preparation is used for organ transplantation and treatment auto-immune disease and inflammation are selected from the purposes in the medicine of psoriasis, eczema, asthma, rheumatoid arthritis and inflammatory bowel disease;

(s) any hydragog(ue) is used for the treatment of purposes in the medicine of any and uroschesis and hypertension diseases associated in preparation;

(t) any calcium antagonist is used for the treatment of purposes in the medicine of cardiovascular diseases in preparation;

(u) any angiotensin converting enzyme inhibitor or vasotonia peptide antagonists are used for the treatment of purposes in the medicine of cardiovascular diseases in preparation;

(v) any beta blocker is used for the treatment of purposes in the medicine of cardiovascular diseases in preparation;

(w) Phenytoin Sodium Salt, carboxamide nitrogen

Sodium Valproate, ethosuximide, vigabatrin or lamotrigine,

Be used for the treatment of purposes in the medicine of epilepsy in preparation;

(x) fibrates and statin are used for reducing purposes with the medicine of cholesterol regulating in preparation.

(y) any oral hypoglycemic or insulin sensitivity agent are used for the treatment of purposes in the medicine of diabetes in preparation;

(z) any diphosphonate is used for the treatment of purposes in the medicine of osteoporosis, Pei Jiteshi disease and cancer in preparation;

(aa) any contrast medium is selected from Diatrizoate, Iodipamide, ioglycamic acid salt, iodopanoic acid salt, iofendylate, iothalamate, Ioxaglic Acid salt and metrizamide, the purposes in the medicine that uses in the preparation radiology;

(bb) peptide or protein are selected from Regular Insulin, thyrocalcitonin and erythropoietin, are used for the treatment of purposes in the medicine of the disease that described peptide or protein itself can use in preparation;

(cc) any VITAMIN, be used for the treatment of purposes or the purposes in food, nutrition additive or foodstuff additive in the medicine of any disease in preparation, in described disease treatment or in VITAMIN described in food, nutrition additive or the foodstuff additive, provided effectively;

(dd) any antioxidant is used for the treatment of purposes in the medicine of cardiovascular diseases, cancer and inflammation in preparation, and as food preservatives or sanitas or as the purposes of a component in food, foodstuff additive or the nutrition additive;

(ee) any medicine based on porphyrin chlorin or bacterium chlorin or their four (hydroxy phenyl) derivative is used for the purposes of the medicine of cancer optical dynamic therapy in preparation.