Plasmalogen compounds, pharmaceutical compositions containing them and methods of treating age-related diseases

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, wherein R1 and R2 are identical or different and specified in an alkyl or alkenyl hydrocarbon chain; the R3 group values split by lipase are specified in the patient claim. R4 and R5 are independently hydrogen or C1-C7alkyl; R6 represents hydrogen or C1-C7alkyl; and R7 and R8 are independently hydrogen or C1-C7alkyl. The invention also refers to using compounds of formulas ,

which are introduced into the mammalian biological system and increase the cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens.

EFFECT: compounds are applicable in treating or preventing the age-related disorders associated with high membrane cholesterol, high amyloids and low plasmalogens, such as neurodegeneration, cognitive disorder, dementia, cancer, osteoporosis, bipolar disorder and vascular diseases.

11 cl, 18 dwg, 7 ex

 

The technical field to which the invention relates

The present invention relates to the synthesis and application of novel chemical compounds having useful biochemical, physiochemical and clinical properties. In particular, provided a series of derivatives of 1-alkyl, 2-acylglycerides that can be used for treating or preventing the disease. The invention also relates to pharmaceutical compositions and kits containing such compounds.

The level of technology

It is known that the likelihood of many different human diseases such as cancer, dementia or low cognitive functioning increases with age. With epidemiological and statistical point of view, these diseases often look very similar. However, from a clinical point of view each of cancer, dementia and reduced cognitive functioning are very different. At present a large risk factor for these diseases is age of the subject. Moreover, it was found that most cancers, dementia and reduced cognitive functioning have a long prodromal phase (5-15 years), during which the disease is present, but subclinical. Reported age-related increase in the level of cholesterol in membranes-3 and increased content of cholesterol in the membranes of mitochondria4-6. These increase the level of cholesterol in the membrane lead to a decrease of membrane fluidity2the reduction in the function of ion channels6-8, lowering the activity of some membrane-bound enzymes such as 5'-nucleotidase9and α-secretase10and the change in diffusion properties of signaling molecules such as nitric oxide (no11.

Subjects suffering from elevated levels of cholesterol in the membrane, demonstrating an increased prevalence of neurodegenerative diseases (e.g. Alzheimer's, Parkinson's, multiple sclerosis and age-related macular degeneration), cognitive impairment, dementia, cancer (e.g., prostate, lung, breast, ovary, and kidney), osteoporosis, bipolar disorder and cardiovascular disease (atherosclerosis, hypercholesterolemia).

In relation to specific diseases, cholesterol accumulates in the membrane structures of the brain of patients with Alzheimer's disease depending on the severity of the disease12-14. It was shown that lowering the level of cholesterol in membranes reduces the activity of beta - and gamma-secretase, blocking the abnormal processing of beta-amyloid15-16. At the molecular level, cholesterol binds to transmembrane�tion domain of the precursor protein beta-amyloid (RDAs), activating the migration of ARD in cholesterol-rich membrane domains with high content of beta - and gamma-secretase that leads to the production of beta-amyloid17. Changes of synaptic membranes resulting from an increased level of cholesterol, can also be an important factor in the use of membrane phospholipids to support cholinergic neurotransmission (the concept of autocannibalism)18. It was suggested that early administration of statins to reduce the incidence or delay the start of Alzheimer's and Parkinson's19. The accumulation of cholesterol also occurs in druses associated with age-related macular degeneration20. The level of cholesterol in the membrane is also increased in cancer21and it has been hypothesized that the increased levels of cholesterol in the membranes of mitochondria is defective, leading to the Warburg effect, which is associated with most cancer cells22. The Warburg effect is a defining characteristic of cancer cells, because, unlike normal cells, which are almost entirely dependent on respiration for energy, cancer cells for energy can be used as respiration and glycolysis.

In addition to challenging the negative effects of the accumulation of cholesterol on the membrane, there is also an increased education� of oxysterol 23. These oxysterols are cytotoxic (apoptosis and necrosis), proinflammatory, Deplete glutathione GSH and induce phospholipids23-26. Diseases that can be involved these toxic oxysterol include neurodegeneration (neuronal and demyelinizing), osteoporosis, age-related macular degeneration and cardiovascular disease, in particular atherosclerosis23.

Modern clinical therapy to lower cholesterol mainly in the inhibition of cholesterol synthesis by statins or blocking the absorption of cholesterol from the gastrointestinal tract by ezetimibe. According to the authors of the invention, in currently no medications intended to mobilize the migration of cholesterol from the membranes.

Disclosure of the INVENTION

The present invention relates to compounds and methods for treating age-related diseases associated with pathological levels of cholesterol in the membrane. Described compounds include new predecessors of plasmalogens that reduce the levels of free cholesterol in the membrane and enhance the esterification of cholesterol for transport out of cell membranes. These compounds are therefore useful for reducing levels of cholesterol in the membrane of the subjects suffering from p�vesennih levels of cholesterol in the membrane. Connections can also be used to treat or prevent diseases associated with elevated levels of cholesterol in the membrane, such as neurodegenerative diseases (including, but without limitation, Alzheimer's disease, Parkinson's disease, multiple sclerosis and age-related macular degeneration), cognitive impairment, dementia, cancer (including, but without limitation, prostate cancer, lung, breast, ovary, and kidney), osteoporosis, bipolar disorders, and vascular diseases (including, but without limitation, atherosclerosis and hypercholesterolemia). In addition, these compounds are effective for the treatment of disorders resulting from abnormal gene expression of cholesterol transport proteins such as apolipoprotein E.

These predecessors of plasmalogens contain glycerol skeleton with alkyl or alkenyl lipid substitution at sn-1-position or lipid acyl substitution at sn-2-position. Polar Deputy provided in sn-3-position to improve the pharmaceutical properties (e.g., for improved stability and/or bioavailability, or to compose in the form of salt).

Without being bound to theory, it is believed that in certain embodiments, the substituent at sn-3-position split by lipase, and the resulting 1-alkyl, 2-acyl glycerol or 1-Alka�Il, 2-acyl glycerol are then transformed into plasmalogen in the endoplasmic reticulum, thus avoiding paroxysmally the compartment, which may show reduced function during aging.

Accordingly, compositions are provided compounds of the formula I:

in which:

R1and R2may be the same or different, and represent alkyl or alkenyl hydrocarbon chain selected from Table 1 or 2;

Table 1
Alkyl or alkenyl hydrocarbon group
No.The chemical structureReduction
1CH3(CH2)3-C4:0
2CH3(CH2)5-C6:0
3CH3(CH2)7-C8:0
4CH3(CH2)9-C10:0
5CH3(CH2)11-C12:0
6CH3(CH2)13-C14:0
7CH3(CH2)15-C16:0
8CH3(CH2)17-C18:0
9CH3(CH2)19-C20:0
10CH3(CH2)21-C22:0
11CH3(CH2)23-C24:0
12CH3(CH2)SN=CH(CH2)7-C14:1
13CH3(CH2)SN-CH(CH2)7-C16:1
14CH3(CH2)7CH=CH(CH2)7-C18:1
15CH3(CH2)SN=CNSNS=CH(CH2)7-C18:2
16CH3CH2CH=CHCH2CH=CH(CH2)7-C18:3
17SNSN(CH=CH)-C4:1
18CH3(CH2)3(CH -�)- C6:1
19CH3(CH2)5(CH=CH)-C8:1
20CH3(CH2)7(CH=CH)-C10:1
21CH3(CH2)9(CH=CH)-C12:1
22CH3(CH2)11(CH=CH)-C14:1

23CH3(CH2)13(CH-CH)-C16:1
24CH3(CH2)15(CH=CH)-C18:1
25CH3(CH2)17(CH=CH)-C20:1
26CH3(CH2)19(CH=CH)-C22:1
27CH3(CH2)21(CH-CH)-C24:1
28CH3(CH2)3CH=CH(CH2)5(CH=CH)-C14:2
29CH3(CH2)SN=CH(CH2)5(CH=CH)-C16:2
30 CH3(CH2)SN=CH(CH2)5(CH=CH)-C18:2
31CH3(CH2)4CH=CHCH2CH=CH(CH2)5(CH=CH)-C18:3
32CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)5(CH=CH)-C18:4

Table 2
Side chain CIS-unsaturated fatty acids
No.Name acidChemical strcuture
1Myristoleate (14:1)CH3(CH2)3CH=CH(CH2)7-
2Palmitoleic (16:1)CH3(CH2)5CH=CH(CH2)7-
3Oleic (18:1)CH3(CH2)7CH=CH(CH2)7-
4Linoleic(18:2)CH3(CH2)4(CH=CHCH2)2(CH2)6-
5 Linolenic (18:3)CH3CH2(CH=SNSN2)3(CH2)6-
6Arachidonic (20:4)CH3(CH2)4(CH=SNSN2)4(CH2)2-
7Eicosapentaenoic (20:5)CH3CH2(CH=SNSN2)5(CH2)2-
8Erucic(22:1)CH3(CH2)7CH=CH(CH2)11-
9Docosahexaenoic (22:6)CH3CH2(CH=SNSN2)6CH2-

R3is a group selected from fatty acids, carnitine, acetyl-D/L-carnitine, ticaretine, acetyl-D/L-ticaretine, creatine, nocardicin, phosphocholine, lipoic acid, dihydrolipoic acid, phosphoethanolamine, phosphoserine, N-acetylcysteine, substituted or unsubstituted amino groups and having the structure shown in Table 3 below.

Table 3

R4and R5are the same or different and may represent hydrogen or lower alkyl, e.g., methyl or ethyl;

R6represents hydrogen or lower alkyl, e.g., methyl or ethyl; and

R7and R8are the same or different and may represent hydrogen or lower alkyl, e.g. methyl or ethyl,

and also including racemate or isolated stereoisomers and their pharmaceutically acceptable salts or esters.

Another aspect of the present invention is directed to pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound as described above.

In one embodiment of the present invention R2may represent a side chain docosahexaenoic acid (DHA) or CH3CH2(CH=SNSN2)6CH2-.

In another embodiment, the compound may be a 2-acetoxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-g�xenoglossy)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine.

In other embodiments, the compound can be a (4Z,7Z,10Z,13Z,16Z,19Z)-1-(5-((R)-1,2-dithiolan-3-yl)pentanoate)-3-(hexadecylamine)propan-2-yl docosa-4,7,10,13,16,19-hexaenoic:

or (4Z,7Z,10Z,13Z,16Z,19Z)-1-(2-atsetamido-3-mercaptopropionate)-3-(hexadecylamine)propan-2-yl docosa-4,7,10,13,16,19-hexaenoic:

The invention also includes pharmaceutical compositions containing PPI-1009, PPI-1011, PPI-1014 or a combination thereof.

Without being bound to theory, it is believed that certain compounds described herein increase the levels of plasmalogens, the hydrolysis of acetyl-L-carnitine in sn-3-position, and may participate in the possible molecular mechanisms, which include: (1) acetylation functional-NH2and-Oh groups in the amino acids and the N-terminal amino acids in peptides and proteins, which alters their structure, dynamics, function, and metabolism; and/or (ii) functioning as a molecular chaperone for larger molecules, which leads to a change in the structure, molecular dynamics and functions of larger molecules.

Carnitine is important in the beta-oxidation of fatty acids, and acetyl group can be used to maintain levels of acetyl COA. The action of acetyl-L-carnitine (ALCAR) include modulation of: (i) cerebral energy and meth�of belisma phospholipids; (ii) cellular macromolecules, including neurotrophic factors and hormones; (iii) the morphology of synapses; and (iv) synaptic transmission of multiple neurotransmitters.

According to another aspect of the present invention, a method is provided of treating or preventing age-related diseases, mediated by deficiency of plasmalogens, comprising administering to a patient in need, an effective amount compound or composition as described above.

In still another aspect, the present invention is provided a method of treating age-related diseases associated with elevated levels of cholesterol in the membrane, increased levels of amyloid and reduced levels of plasmalogens, comprising administering to a patient in need, an effective amount compound or composition as described above.

The invention also relates to a method for preparing compounds according to the structure of formula II:

where R1and from R4to R8are as described above and R9is a blocking group, and includes racemate or isolated stereoisomers and pharmaceutically acceptable salts or their esters.

The method comprises interaction of a compound of formula III:

in a suitable solvent with a nucleophilic catalyst, �a base and a blocking agent under conditions suitable for the formation of the compounds of formula II and optional purification of the obtained compound.

In certain non-limiting embodiments, as a blocking agent may be used a silane, for example, tert-butyldimethylsilyl halide, which then causes the formation of R9being tert-butyldimethylsilyloxy group.

In other non-limiting embodiments, the nucleophilic catalyst DMAP may be, the base may be triethylamine, and the solvent may contain dimethylformamid (DMF) and CH2Cl2.

Without wanting to be limited, in certain embodiments it is preferable to prepare a solution, comprising a compound of formula III, the nucleophilic catalyst and base in a suitable solvent at a temperature from 0°C to 5°C before adding the blocking agent, followed by the addition of blocking agent and further conducting the reaction at a temperature of from about 15 to 25°C, for example, at 20°C. Preferably, the reaction was carried to completion for up to 20 hours.

Also provided is an intermediate compound according to the structure of formula II:

where R1and from R4to R9are as described above, including racemate or isolated stereoisomers, and the pharmaceutical industry�ski acceptable salts or their esters.

BRIEF description of the DRAWINGS

These and other features of the invention will become more apparent from the following description, in which made an appeal to the accompanying drawings, in which:

FIGURE 1 shows the overall experimental methodology preparation of PPI-1009: 2-acetoxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine according to the embodiment of the present invention.

FIGURE 2 shows that lower levels of DHA plasmalogens in N-Rel cells relative to control cells SSS are restored concentration-dependent manner with the help of PPI-1005 (R1=16:0; R2=DHA; R3=HE), 72 h of incubation, *p<0/05 depending on the media (the nose).

FIGURE 3 shows (A) the period of implementation of PPI-1009 (10 μm) in plasmalogen and lack of effect on cellular levels hemilopha alcohol or the bound alkenyl-acyl-glycerol (In) N-Rel cells(0, 6, 12, 24, 48 and 72 h). The content in the cells of plasmalogens and docosahexaenoic acid (DHA) was calculated by LC-MS/MS, whereas himaloy alcohol was estimated by the method of GC-MS.

FIGURE 4 shows (A) concentration-dependent increase (72 h) of DHA plasmalogens in Cho cells using PPI-1005 and PPI-1009. Although himaloy alcohol increased DHA-plasmalogen in cells N-Rel, effect in Cho cells was not (In). The content of plasmas�of Loginov in cells was estimated by LC-MS and expressed relative to controls SSS or controls an N-Rel.

FIGURE 5 shows the response of the concentration to reduce cholesterol in the membranes in the cells N-Rel after 48 hours of incubation with 16:0 (sn-1 alkyl/DHA(sn-2 acyl) glycerol (PLM-05). Note that cholesterol levels are significantly elevated (p<0.05) in cells NRel cells relative to Cho, and 20 µm (PLM-05) levels of free cholesterol in the membrane decreases and the levels of cholesterol esters in the membrane increased (p<0.05).

FIGURE 6 shows the structural-specific and concentration-dependent implementation (72 h) in a linked plasmalogen (R1=16:0, R2=22:6, R3= phosphoethanolamine) N-Rel cells with PPI-1005 (A; 1 or 5 μm) and PPI-1009 (B; 0.5, 1, 2, 3&10 μm). The fatty acid substituents at sn-2-position was also subjected to decelerating and reallymoving for the formation associated with plasmalogen 20:4, 18:3, 18:2 and 18:1 at the sn-2-position. The content of plasmalogens in cells was estimated by LC-MS/MS and normalized relative to cell N-Rel-treated media.

FIGURE 7 shows that the level of cholesterol in the membrane is increased in mutant cells N-Rel relative to control cells SNO. The level of cholesterol in the membrane in cells N-Rel is reduced (p<0.05) after 48 h of incubation (20 μm) with precursors of plasmalogens containing palmitic (16:0) or stearic (18:0) acid in the sn-1-position in combination with unsaturated LM�governmental acids, in particular DHA in sn-2-position. At 20 μm DHA free was ineffective to change the levels of cholesterol in the membrane. In contrast to the activity of analogues with alkyl linkage at the sn-1-position, diately analogue (16:0*:glycerin DHA) was inactive. PPI-1009 (16:0/DHA/ALCAR) caused the strongest decrease in free cholesterol and accumulation of esterified cholesterol. V, medium.

FIGURE 8 shows a decrease (p<0.04) cholesterol in the membrane in cells NECK after 48 h of incubation with 20 µm 16:0 (sn-1 alkyl)/BHA(sn-2 acyl) glycerol, 18:0/DHA glycerol or 16:0/18:3 glycerin. At 20 µm 16:0/18:1 glycerol, 16:0/18:2 glycerin, 16:0/20:4 glycerol and free DHA were ineffective to change the levels of free cholesterol in the membrane. Unlike the activity of analogues with alkyl linkage at the sn-1-position, diately analogue (16:0*:glycerin DHA) was inactive.

FIGURE 9 shows the response of the concentration to reduce cholesterol in the membrane in NEC cells after 48 h of incubation with 16:0(sn-l alkyl)/DHA (sn-2 acyl)/acetyl-L-carnitine (sn-3 acyl)glycerol (PPI-1009).

FIGURE 10 shows that PPI-1005 (5A, 20 μm) reduces basal and stimulated cholesterol (25.8 μm) Aβ42 secretion by cells NECK, (A). PPI-1009 (PLM09, 10 μm) acted similarly (In).

FIGURE 11 illustrates the effect of PPI-1011 to plasmalogen in the plasma of rabbits. PPI-1011 was introduced in ethanolamine-plasmalogen (PlsEtn) and FD�faciciliterne (PtdEtn) plasma after 1, 3, 6 and 12 hours after oral dose of 200 mg/kg in gelatin capsules. Also seen the release of DHA (free 22:6) from the sn-2 through deatils. Groups consisted of 3 to 5 rabbits.

FIGURE 12 shows a graph of the inclusion of the predecessor plasmalogens PPI-1011 in circulating Pls 16:0/22:6, DHA, Pls 18:0/22:6 and Ptd 16:0/22:6 in time. The incorporation of PPI-1011 in ethanolamine-plasmalogens (Pls) and phosphatidylethanolamine (Ptd) of plasma was measured using 1, 3, 6, 12, 18, 24 and 48 hours after oral dose of 200 mg/kg in gelatin capsules. Also seen the release of DHA from sn-2 through deatils. Groups consisted of 3 to 5 rabbits, except the 12 hour mark, which included 7 rabbits from 2 separate experiments.

FIGURE 13 illustrates the dose-dependent incorporation of PPI-1011 in plasmalogen and phosphatidylethanolamine plasma. The incorporation of PPI-1011 in ethanolamine-plasmalogens (Pls) and phosphatidylethanolamine (Ptd) of plasma was measured 6 hours after oral doses of 10, 75, 200, 500 and 1000 mg/kg in gelatin capsules. Also seen the release of DHA from sn-2 through deatils. Groups consisted of 3 to 5 rabbits.

FIGURE 14 shows the increase of plasmalogens and DHA in the tissues under the influence of PPI-1011 in the kidney of rabbits. The incorporation of PPI-1011 in ethanolamine-plasmalogen (PlsEtn) and phosphatidylethanolamine (PtdEtn) of the kidney was measured after 1, 3, 6 and 12 hours after oral administration of doses at 200 mg/kg in �latinboy capsule. Also seen the release of DHA (free 22:6) from the sn-2 through deatils. Groups consisted of 3 to 5 rabbits.

FIGURE 15 shows the time increase plasmalogens and DHA in the tissue with time under the influence of PPI-1011 in the kidneys of rabbits. The incorporation of PPI-1011 in ethanolamine-plasmalogen (16:0/22:6) was measured through the kidney 1, 3, 6, 12, 18, 24 and 48 hours after oral administration of doses at 200 mg/kg in gelatin capsules. Groups consisted of 3 to 5 rabbits.

FIGURE 16 shows the time increase plasmalogens and DHA in the tissue with time under the influence of PPI-1011 in the liver of rabbits. The incorporation of PPI-1011 in ethanolamine-plasmalogen (16:0/22:6) of the liver was measured after 12, 18, 24 and 48 hours after oral administration of doses at 200 mg/kg in gelatin capsules. Groups consisted of 3 to 5 rabbits.

FIGURE 17 shows the structural-specific and concentration-dependent incorporation of PPI-1014 in ethanolamine-plasmalogen (PlsEtn) and phosphatidylethanolamine (PtdEtn) N-Rel cells after 72 hours (5, 10 and 20 μm). The content of plasmalogens in cells was estimated by LC-MS/MS and normalized relative to cell N-Rel-treated media. The group consisted of three 10 cm plates.

FIGURE 18 shows (A) the effects of increasing concentrations of PPI-1005 membrane-resident proteins loaded in cholesterol cells NAC, (B) the effects of PPI-1005 membrane-resident proteins in the cells NECK wild type, and (C) the effects Prevost�Tina on membrane-resident proteins ADAM10 and SOAT1. β-actin was used as loading control.

The IMPLEMENTATION of the INVENTION

Described compounds according to the structure of the formula I:

where:

R1and R2are the same or different and selected from alkyl or alkenyl hydrocarbon chain selected from the group consisting of: CH3(CH2)3-, CH3(CH2)5-, CH3(CH2)7-, CH3(CH2)9-, CH3(CH2)11-, CH3(CH2)13-, CH3(CH2)15-, CH3(CH2)17-, CH3(CH2)19-, CH3(CH2)21-, CH3(CH2)23-, CH3(CH2)SN=CH(CH2)7-, CH3(CH2)SN=CH(CH2)7-, CH3(CH2)SN=CH(CH2)7-, CH3(CH2)4CH-CHCH2CH=CH(CH2)7-, SNSDS-CNSSN=CNSNS-CH(CH2)7-, SNSN(CH=CH)-, CH3(CH2)3(CH=CH)-, CH3(CH2)5(CH=CH)-, CH3(CH2)7(CH=CH)-, CH3(CH2)9(CH=CH)-, CH3(CH2)11(CH=CH)-, CH3(CH2)13(CH=CH)-, CH3(CH2)15(CH=CH)-, CH3(CH2)17(CH=CH)-, CH3(CH2)19(CH=CH)-, CH3(CH2)21(CH-CH)-, CH3(CH2)SN=CH(CH2)5(CH-CH)-, CH3(CH2)SN=CH(CH2)5(CH-CH)-, CH3(CH2)7CH=CH(CH2)5(CH=CH)-, CH3(CH2)SN=CNSNS=CH(CH2)5(CH=CH), CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)5(CH-CH)-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)SN=CH(CH2)7-, CH3(CH2)4(CH=CHCH2)2(CH2)6-, SNSN(CH=SNSN)3(CH2)6-, CH3(CH2)4(CH=SNSN)4(CH2)2-, SNSN(CH=SNSN)5(CH2)2-, CH3(CH2)SN-CH(CH2)11 and SNSN(CH=SNSN)SN is:

R3is a group selected from fatty acids, carnitine, acetyl-D/L-carnitine, ticaretine, acetyl-D/L-ticaretine, creatine, nocardicin, phosphocholine, lipoic acid, dihydrolipoic acid, phosphoethanolamine, phosphoserine, N-acetylcysteine, substituted or unsubstituted amino groups and having a structure�s, shown below:

R4and R5are independently hydrogen or lower alkyl;

R6represents hydrogen or lower alkyl; and

R7and R8independently are hydrogen or lower alkyl, and include racemate or isolated stereoisomers and pharmaceutically acceptable salts or their esters.

Such compounds are effective for treatment or prevention of age-related diseases associated with elevated levels of cholesterol in the membrane, increased levels of amyloid or reduced levels of plasmalogen.

Such compounds are also effective for the treatment or prevention of age-related diseases, mediated by deficiency of plasmalogens.

Such compounds can also be used to treat a neurodegenerative Soboleva�th (including, but without limitation, Alzheimer's disease, Parkinson's disease and age-related macular degeneration), cognitive impairment, dementia, cancer (including, but without limitation, prostate cancer, lung, breast, ovary, and kidney), osteoporosis, bipolar disorders, and vascular diseases (including, but without limitation, atherosclerosis and hypercholesterolemia).

For the purposes of the present invention, the hydroxy groups in positions sn-1, sn-2 and sn-3 glycerol backbone of the compounds of formula I are named using the generally accepted nomenclature of plasmalogens, i.e., the oxygen atom of glycerol, attached to a carbonyl group-C=O(acetyl), -C (forms an ether bond) and-R (phosphoryl) indicated in formula I.

In certain non-limiting embodiments, the compounds as described herein may contain one or more chiral centers. Typically, such compounds can be prepared as racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as enriched stereoisomer mixtures. All such stereoisomers (and enriched mixtures) compounds of formula I are included in the scope of this invention. Pure stereoisomers (or enriched mixtures) may be prepared with the IP�altanium, for example, optically active starting materials or stereoselective reagents well-known in this field. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral optical decomposing agents and the like.

Definitions:

In the description of the alkyl/acyl fatty acids (table 1, table 2) and biologically active compounds (table 3), pharmaceutical compositions and methods of this invention, the following terms have the following meanings, unless otherwise indicated.

"Fatty acids are aliphatic monocarboxylic acids, extracted, or contained in esterified form in an animal or vegetable fats, oils or wax. Natural fatty acids commonly have a chain of 4 to 28 carbons (usually unbranched and even numbered), which may be saturated or unsaturated. These acids are known as acyclic aliphatic carboxylic acids.

Within the meaning of saturated fatty acids, the term "saturated" refers to the carbon atoms (excluding the original carboxyl [-COOH] group) that contains as many hydrogen atoms as possible. In other words, the ultimate omega (ω) contains 3 atoms of hydrogen (CH3-) and the carbon atom in the chain with�holds 2 atoms of hydrogen.

Unsaturated fatty acids (including but not limited to the examples described in Table 2) are similar to saturated fatty acids, except that one or more alkenyl functional groups present along the chain, with each alkene has the substitution of a simple-CH2-CH2 - in the chain at the double bond-CH=CH- (i.e., the carbon atom connected by a double bond with another carbon atom). Such acids are called as CIS/TRANS and C:D, where C denotes the number of carbon atoms, and D denotes a double bond.

"Unsubstituted and substituted amino" refers to optionally substituted fragment of an amino acid containing an amino group, a carboxylic acid group and a variable side chain, side chain may include General side chains of amino acids, i.e. those that are used in the formation of proteins or etc., well known in this field. Proteins amino acid residues are particularly preferred and include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, Proline, series, threonine, tryptophan, tyrosine and valine. It is also possible to alternate amino acid residues comprising substituents with functional groups including, but without limited�of Iceni, low alkali, acetate, phosphate, lipids, and carbohydrates.

The term "lower alkyl" refers to a cyclic monovalent alkyl radical branched or straight chain, containing from one to seven carbon atoms (C1-C7and in certain non-limiting embodiments, from one to four carbon atoms (C1-C4). This term, in addition, represented by such radicals as methyl, ethyl, n-propyl, ISO-propyl, n-butyl, tert-butyl, ISO-butyl (or 2-methylpropyl"), cyclopropylmethyl, I-amyl, n-amyl, hexyl and heptyl. Lower alkyl groups can also be unsubstituted or substituted, specific examples of the substituted alkyl is 1,1-dimethylheptyl.

"Hydroxyl" refers to-IT.

"Pharmaceutically acceptable salt" refers to any salt of the compounds of this invention which retains its biological properties and which is not biologically or otherwise undesirable. Such salts can be derived from various organic and inorganic counterions, well known in this field and include, for example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and when the molecule contains an alkaline functional group, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesilate, acetate, maleate,�salad and such. The term "pharmaceutically acceptable cation" refers to pharmaceutically acceptable the cationic counterion of the acid functional groups. Examples of such cations are the cations of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and such.

"Pharmaceutically acceptable ester" refers to commonly used esterified compound of Formula I containing a carboxyl group, wherein the ester retains the biological effectiveness and properties of the compounds of Formula I and are cleaved in vivo (in the organism) to the corresponding active carboxylic acid. Information concerning esters and the use of esters for the delivery of pharmaceutical compounds is available in Design of Products. Bundgaard H ed. (Elsevier 1985). See also H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6thEd. 1995) at pp. 108-109; Krogsgaard-Larsen, et al. Textbook of Drug Design and Development (2d Ed. 1996) pp. 152-191.

"Pharmaceutical agent" or "drug" refers to a chemical compound or composition capable of causing the desired therapeutic or prophylactic effect in a relevant introduction to the subject.

The term "effective amount" means that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is determined, for example, a researcher �whether Clinician. Moreover, the term "therapeutically effective amount" means any amount which, as compared with a corresponding subject who has not received such amount, results in improved treatment, alleviation, prevention or suppression of disease, disorder or side effects or a decrease in the rate of development of disease or disorders. The term also includes, within its scope, amount, effective to enhance normal physiological function.

All chemical compounds include both (+) and (-) stereoisomers, as well as one of the (+) or (-) stereoisomers.

Others mentioned herein chemical terms are used in accordance with traditional use in this area, as shown in The McGraw-Hill Dictionary of Chemical Terms (1985) and The Condensed Chemical Dictionary (1981).

Compounds described herein that include precursors of plasmalogen extracted from the glycerol backbone by substitution at sn-1 and sn-2-position fatty acids and sn-3-position fatty acids or endogenous metabolic intermediate compounds can be prepared from readily available starting materials using the following General methods and techniques, illustrated in Figure 1. Preferably, for a given typical or preferred process conditions (i.e. reaction temperature, time, they say�rye ratio of reagents, solvents, pressures, etc.), it is also possible to use other terms, unless otherwise indicated. Optimum reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be identified skilled in this field specialist using conventional optimization methods.

In addition, experienced in this field specialists will be obvious that the commonly used protecting groups may be necessary to protect certain functional groups from undesired reactions. The choice of suitable protective groups for specific functional groups as well as suitable conditions for protection and of deprotection are well known in this field. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and listed here in the links.

In a preferred method of synthesis, compounds described herein containing a substitution of glycerol in sn-1 and sn-2-positions in fatty acids and sn-3-position fatty acids or endogenous metabolic intermediates, as described herein, prepared using the protection deprotection hydroxyl groups of the glycerol backbone of suitable protective groups, with subsequent O-alkylation and O-acylation of the compound; for example PPI1009, PPI-1011 and PPI-1014.

When used as pharmaceuticals, the compounds as described herein, are usually introduced in the form of pharmaceutical compositions. Such compositions can be prepared using techniques well known in the pharmaceutical field, and include at least one active connection.

In General, the compounds of this invention are injected in pharmaceutically effective amounts. The actual number of input connections is usually determined by the physician taking into account the relevant circumstances including the condition to be treated, the chosen mode of administration, the specific input connection, age, weight, individual characteristics of the patient, the severity of the symptoms and such.

The compounds and compositions described herein can be administered to a subject, preferably a mammal, more preferably human, for the treatment and/or prevention of disease in any acceptable manner, including, for example, oral, topical, rectal, transdermal, subcutaneous, intravenous, intramuscular, intranasal, and the like. Depending on the intended method of delivery, the compounds of this invention are preferably formulated for oral, topical or injectable compositions.

Pharmaceutical compositions for oral administration can be � the form of liquid solutions, suspensions or powders. In General, however, such compositions are presented in the form of single dosage forms to facilitate accurate dosing. The term "single dosage form" refers to physically discrete units suitable for use as one-time doses for human subjects and other mammals, each unit contains a predetermined quantity of active material calculated for the desired therapeutic effect, in combination with suitable pharmaceutically acceptable auxiliary substance. Single dosage forms include pre-filled, pre-measured ampoules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.

Liquid forms suitable for oral administration may include suitable aqueous and nonaqueous carriers with buffers, suspendresume and dispersing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose, dezintegriruetsja agents, such as alginic acid, primogel or corn starch; lubr�edges, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavoring.

Compositions for topical application are usually prepared in the form of ointments or creams that contain active(e) ingredient(s) in an amount which varies from about 0.01 to 20% by weight, preferably from about 0.1 to 10% by mass, and more preferably from about 0.5 to 15% by weight. In the preparation in the form of an ointment, the active ingredients usually combined with paraffin or water-miscible oil base. Alternatively, the active ingredients can be formulated into a cream, for example, water-in-oil base. Local compositions are well known in this field, and generally include additional ingredients to enhance penetration into the skin, or stability of active ingredients or composition. All such known compositions for local use and the ingredients included in the scope of this invention.

Compounds of the present invention may also be administered using the device for transdermal administration. Thus, topical administration can be made using plaster, porous or tank of the membrane type or range of solid matrices.

Injecting �oppozitsii usually is based upon injectable sterile saline or phosphate-buffered saline, or other injectable carriers known in this field. As previously reported, alkyl nitrone compound in such compositions is typically a minor component, often constituting from about 0.05 to 10% by weight with the remainder being the injectable carrier and etc.

The above components for oral, topical or injectable compositions are merely by way of example. Other materials and processing techniques, etc. are set forth in Part 8 Of Remington's Pharmaceutical Sciences, 18thedition, 1990, Mack Publishing Company, Easton, Pennsylvania, 18042, which is incorporated here by reference.

Compounds of the present invention may also be administered in form with a slow release or by using the delivery systems of drugs with a slow release. Description of representative materials with a slow release can be found in the materials included in Remington's Pharmaceutical Sciences.

Pharmaceutical compositions of this invention can be prepared in the form of tablets, capsules, liquids, injectable composition, or as an ointment. The present invention, however, is not limited to the following pharmaceutical compositions. For example, without wanting to be limited in any way, the compound of formula I may be dissolved in a buffered sterile saline solution, inyecci�the auditors aqueous medium to an appropriate concentration, of approximately 5 mg/ml.

The invention also includes kits that can simplify the introduction of pharmaceutically active agent to an animal. A typical kit of the invention contains a unit dosage form of the pharmaceutical compositions according to the invention. In one embodiment, the unit dosage form is a container (such as a flask, a bag, a vial, syringe, etc.), which are preferably sterile, containing pharmaceutical composition of the invention. The kit may also contain a label or printed instructions for use of pharmaceutically active agent for treatment or prevention of disease. In another embodiment, the kit contains a unit dosage form of the pharmaceutical composition of the invention and a pipette, syringe or other applicator for the introduction of the pharmaceutical composition. Usually, the components are set, for example, a unit dosage form and instructions are contained within suitable packaging material.

It is shown that bioavailable precursor plasmalogens with replacement of docosahexaenoic acid (22:6) at the sn-2-position have lowered levels of cholesterol in the membrane. In contrast, stearic acid (18:0), oleic acid (18:1), Linova acid (18:2), arachidonic acid (20:4) or linolenova acid (18:3) in sn-2-position were Zn�significantly less active and free DHA was inactive. The substitution of the fatty acid at the sn-1-position showed the need alkenyl communication, and acyl bond completely eliminated lowering cholesterol activity. Alkenyl communication can be generated in the endoplasmic reticulum of the alkyl precursor (e.g., PPI-1009); however, the synthesized alkenyl shape can also be a potential therapeutic molecule. Pharmaceutical properties of the target data predecessors of plasmalogens can also be improved by addition of a polar substituent at sn-3 position. This substitution provides improved pharmaceutical properties, including: 1) the stabilization of the sn-2 replacement migration in sn-327-28; (ii) the ability to generate pharmaceutically acceptable salts for improving the composition and dissolution of drug and absorption; and (iii) the ability of sn-3 substituents to be easily removable lipase29thus, the precursor can be transformed into the corresponding endogenous plasmalogen.

Thus, the introduction of the compounds of the present invention in the biological system of a mammal causes an increase in cell concentrations of specific sn-2 substituted ethanolamine-plasmalogens, whatever the ability of the system to the synthesis of ether lipids. Elevated levels of specific data sn-2 �ameenah groups help to lower cholesterol levels in the membrane and a decrease in the secretion of amyloid, making these compounds useful for treatment or prevention of age-related diseases associated with elevated levels of cholesterol in the membrane, increased levels of amyloid and reduced levels of plasmalogens.

Without being bound by theory, believe that the compounds described herein can be obtained, bypassing paroxysmally the path of the biosynthesis of the lipid with an ether bond, ensuring the recovery of plasmalogens in subjects with deficiency of plasmalogens, while also delivering a pharmaceutically effective specific lowering of cholesterol plasmalogens. Thus, these molecules can be used to treat or prevent diseases associated with reduced levels of plasmalogens, elevated levels of cholesterol in the membrane or elevated levels of amyloid. I believe that these factors can be the cause of many human diseases such as neurodegeneration (including, but without limitation, Alzheimer's disease, Parkinson's disease and age-related macular degeneration), cognitive disturbance, dementia, cancer (including, but without limitation, prostate cancer, lung, breast, ovary, and kidney), osteoporosis, bipolar violation, and vascular diseases (including, but without limitation, atherosclerosis and hipercolesterolemia). Thus,the present invention relates to the treatment of these diseases with the use of the described precursors plasmalogens. In addition, these derivatives are effective in the treatment of disorders resulting from abnormal gene expression of cholesterol transport proteins such as apolipoprotein E.

It is also shown that the introduction of 1-alkyl-2-alkyl glycerine leads to stereoselective increase PlsEtn levels in PlsEtn normal and PlsEtn deficient systems. These data also demonstrate for the first time that 1-alkyl, 2-acyl the glycerol lowers the levels of cholesterol in the membrane and the levels of amyloid, and that these effects require specific overrides fatty acids at the sn-2-position.

The inventors also showed that:

1) ether bond at the sn-1-position is stable and, in addition, processaway Desaturate (endoplasmic reticulum) to generate the main alkenyl communication sn-1-position characterizing plasmalogen, but this desaturation occurs after you add phosphoethanolamine via the CDP-ethanolamine transferase (endoplasmic reticulum);

2) a charged substitution at sn-3-position substitution stabilizes the fatty acid in sn-2-position of migration27-28in sn-3;

3) a charged substitution at sn-3-position easily cleaved by cellular lipases and provides the formation of the free hydroxyl group to add phosphoethanolamine via the CDP-ethanolamine transferase (ahd�plazmaticeski retical);

4) substituted fatty acid at the sn-2-position may be decelerating and reallymoving other fatty acids in the cells;

5) DHA substitution in sn-2-position is optimal for lowering cholesterol in the membrane, and

6) a charged substitution at sn-3-position improves the pharmaceutical properties (stability, bioavailability and cooking in the form of salt) presents new predecessors of plasmalogens.

Compounds of the present invention effectively transformed into compounds of PlsEtn in cells with a damaged ability to biosynthesis of plasmalogens, and in cells with an intact ability to biosynthesis of plasmalogens. These results contradict the results available in this field, in relation to other predecessors of plasmalogens. 1-alkyl, 2-hydroxy glycerol (hemeroby, batrawy, selfirony alcohols) have shown that they can raise the levels of PlsEtn in PlsEtn deficient systems to control levels, but not above control levels, as in PlsEtn deficient systems in PlsEtn sufficient systems. Thus, the compounds of the present invention can be effective in preventing age-related diseases, mediated by deficiency of plasmalogens, but to increase the PlsEtn levels above control levels in PlsEtn deficient systems and PlsEtn sufficient systems.

Learning�waiting above, these compounds are suitable for use in different systems of drug delivery; however, without wanting to be limited, the compounds are particularly effective for oral delivery in a capsule or tablet. It is assumed that in such cases the maximum total dose does not exceed 2 g/day for a human patient weighing 40 or 80 kg.

In the following examples, the following abbreviations have the following meanings. Abbreviations that are not defined below have in common the value.

bd = broad doublet

bs = broad singlet

d = doublet

dd = deplet doublets

dec = decomposed

dH2O = distilled water

ELISA = enzyme-linked immunosorbent assays

EtOAc = ethyl acetate;

EtOH = ethanol

g = grams

h = hours

Hz = Hertz

ip = intraperitoneally

L = liters

m = multiplet

min = minutes

M = molar

MeOH = methanol;

mg = milligrams

MHz = megahertz

ml = milliliters

mmol = millimoles

m.p. = melting point

N = normal

po = per os, orally

q = Quartet

quint. = quintet

s = singlet

t = triplet

THF = tetrahydrofuran;

tlc = thin layer chromatography

µg = micrograms

µL = microliter

UV = ultraviolet

In the examples below, all temperatures are presented in degrees Celsius, unless the decree�about otherwise. The following examples of synthesis and biological examples are presented to illustrate this invention and are not considered as limiting the scope of this invention.

EXAMPLES

EXAMPLE 1: Chemical synthesis

PPI-1009: 2-acetoxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine prepared in accordance with the following General experimental methods.

Stage - 1

At 0°C to a solution of unlabeled PPI-1001 (50 g, 158 mmol) in dry DMF (20 ml) was added imidazole (21.5 g, 316 mmol), the resulting mixture was stirred for 10 min. dropwise added a solution of TBDMS-Cl (26,2 g, 174 mmol) in DMF (50 ml) and the resulting solution was stirred at room temperature for 4 h. the Reaction mixture was diluted with water (50 ml), was extracted with EtOAc (2×250 ml). The organic layer was washed with ice water (2×100 ml), brine (50 ml), dried (Na2SO4) and evaporated to obtain crude compound 4, which was purified by column chromatography (neutral alumina, EtOAc - petroleum ether (0,5:9,5) to obtain compound 3 (45 g, 66%). Rf=0.65 (EtOAc - petroleum ether (1-9)).

Stage - 2

At 0°C a solution of compound 3 (75 g, 174 mmol) in DMF (750 ml) portions was added NaH (60% dispersion in oil, 5 g, 209 mmol), stirred for 30 min, was added dropwise to the bromide (44.8 g, 262 mmol)for 1 h, left to establish room temperature and stirred overnight until complete consumption of compound 3, which was confirmed by TLC. The reaction mixture was cooled to 0°C, was added methanol (5 ml), ice water (50 ml), was extracted with Et2O (2×250 ml), the organic layer was washed with water (2×50 ml), brine (50 ml), dried (Na2SO4) and evaporated to obtain crude compound 4 (90 g) as a yellow oil (Rf=0.7; EtOAc - petroleum ether [5-95]), which was used for next step without further purification.

Stage - 3

At -15°C solution of compound 4 (1.7 g, 3,26 mmol) in dry THF (15 ml) was added a solution of TBAF (1.7 g, a 6.53 mmol) in dry THF (5 ml) and the reaction mixture was allowed to warm to room temperature and stirred overnight until complete consumption of compound 4 was confirmed by TLC. The reaction mixture was precipitated with water (10 ml) and was extracted with EtOAc (2×50 ml), the organic layer was washed with brine (20 ml), dried (Na2SO4) and evaporated to obtain crude compound 6, which was purified by flash column chromatography (100-200 mesh silica gel, EtOAc - petroleum ether (3:7)) to obtain compound 5 (850 mg, 65%) as a light yellow oil. Rf=0.54 (EtOAc - petroleum ether (3:7).

Stage - 4

At 0°C a solution of compound 7 (8 g, 39 mmol) in dry CH2Cl2 (50 ml) - DMF (3 drops) was added oxalicacid (4,2 ml, 40 mmol) and the resulting mixture was slowly warmed to room temperature and stirred for 5 h. an Excess amount of oxalicacid evaporated, the residue was dissolved in toluene and the solvent was evaporated to obtain compound 6. A solution of compound 6 in dry CH2Cl2(25 ml) was added dropwise to a solution of compound 5 (11 g, 20 mmol) in dry CH2Cl2(50 ml) and the resulting solution was purged with argon until complete consumption of compound 5, which was confirmed by TLC. The reaction mixture was concentrated to obtain crude compound 8 (14 g), which was used for next step without further purification. Rf=0.45 (MeOH-CHCl3(1:4)).

Stage - 5

A solution of compound 8 (14 g, crude) in EtOH (50 ml) were hydrogenosomal over 10% Pd/C at 40 psi until complete consumption of compound 8, which was confirmed by TLC. The reaction mixture was filtered and evaporated to obtain crude compound 9, which was purified column chromatography on neutral aluminum oxide to obtain compound 9 (6 g, 6 g, 61% over two steps) as a light brown oil. Rf=0.25 (MeOH-CHCl3(2:3)).

Stage - 6

At 0°C a solution of compound 9 (8.2 mg, 16 mmol) in THF (150 ml) was added catalytic amount of DMAP (1.9 g, 20 mmol), pyridine (7,6 ml, 90 mmol) and stirred at room tempera�ur within the hour. To this solution was dropwise added a solution of DHA-Cl (prepared by adding a solution of oxalicacid (2.5 ml, 28 mmol) in dry CH2Cl2at 0°C in DHA acid (7.7 g, 20 mmol), evaporation of excess oxalicacid to obtain DHA-Cl) in CH2Cl2(50 ml) at 0°C and stirred for 0.5 h. the Reaction mixture was slowly warmed to room temperature and stirred for 24 h. the Reaction mixture was diluted with water (50 ml), was extracted with EtOAc (2×200 ml), washed with brine (50 ml), dried (Na2SO4) and evaporated to obtain crude product, which was purified by column chromatography (neutral alumina, MeOH-CHCl3(5:95)) to obtain PPI-1009 (1.2 g, ~10%, HPLC purity 97% together with 1.7 g of impurities) as a light brown semi-solid substance. Rf=0.45 (MeOH-CHCl3(15:85)).

EXAMPLE 2: Biological testing

The ovarian cells of Chinese hamster (line Cho), N-Rel30(a mutant cell line Cho deficit peroxisomal enzyme dihydroxyacetonephosphate of acyltransferase) cells and human embryonic kidney (NEC) were grown in cups 10 cm2in DMEM/Ham's F12 (1:1) containing 10% FBS. Cells were incubated with precursors of plasmalogens dissolved in ethanol (final concentration of ethanol is 0.1%), and collected for analysis plasmalogens with �via LC-MS/MS 31and cholesterol and ester cholesterol were analyzed using a commercial colorimetric kit (BioVision#K613).

1-alkyl, 2-acyl the glycerol with palmitic acid (16:0) at sn-1-position of DHA in sn-2-position, and HE or acetyl-L-carnitine in sn-3-position, PPI-1005 or PPI-1009, respectively, were effectively converted into compounds of PlsEtn in cells with damaged ability plasmalogen biosynthesis (N-Rel, Figures 2, 3A) and in cells with an intact ability plasmalogen biosynthesis (SSS, Figure 4A). These results are contrary to the scientific data in relation to other predecessors of plasmalogens. It was shown that 1-alkyl, 2-hydroxy glycerol (hemeroby, batrawy, selfirony alcohols) increase the levels of PlsEtn in PlsEtn deficient systems to control levels, but not above control levels in PlsEtn deficient and in PlsEtn sufficient systems (Figure 4B). In addition, Bioperine 1-alkyl, 2-acyl glycerine described in this invention, did not lead to increased levels hemilopha alcohol or 1-alkenyl, 2-acyl glycerine (Figure 3B), which indicates that neither himaloy alcohol or 1-alkenyl, 2-acyl the glycerol are not intermediates in the pathways of biotransformation molecules described in PlsEtn.

Compound PPI-005 described in the pending application PCT/SA/001472 and shown below:

Treatment cells 1-alkyl, 2-acyl a glycerol with palmitic acid (16:0) at sn-1-position of DHA in sn-2-position, and HE or acetyl-L-carnitine in sn-3-position led to a structurally-specific enrichment of PlsEtn DHA in sn-2-position (Figure 6). This is the first description of the structural-specific enrichment of PlsEtn.

PPI-1009 is a precursor of plasmalogens with improved pharmaceutical properties. This molecule exists at room temperature in the form of salt and is the first predecessor of plasmalogens on non-oil based, which have ever been reported.

Biological system with an existing deficiency in the synthesis of plasmalogens and, consequently, low levels of plasmalogens (N-Rel compared to SSS) (Figure 1) have elevated levels of cholesterol in the membrane (Figure 5). Increasing DHA-PlsEtn up to 80% of control values using the PPI-1005 (Figure 2) resulted in a significant reduction of cholesterol in the membrane (Figure 5).

It has been discovered that lowering cholesterol effect of high levels of PlsEtn depends on the sn-2 substituent (Figures 7 and 8). It was observed that only polyunsaturated fatty acids (DHA, 18:3) have lower cholesterol activity in NAC cells, while saturated, mono - and Dimensione fatty acids have no effect. Only the restoration of DHA-PlsEtn levels drive�t to a strong reduction of elevated levels of cholesterol in the membrane, observed in N-Rel cells as a result of low levels of plasmalogens (Figure 7). These results indicate that polyunsaturated fatty acids containing PlsEtn, is selectively involved in the homeostasis of cholesterol in the membrane. It was also shown that PPI-1009 reduces the levels of cholesterol in the membrane concentration-dependent manner in NRel (Figure 7) and NC cells (Figure 9). These results indicate that lowering cholesterol effect of high levels of PlsEtn requires the introduction of the predecessor of plasmalogens, can effectively increase the levels of PlsEtn-specific sn-2 substituents.

Processing NEC cells PPI-1005 or PPI-1009 led to low levels of both, the AB-40 and AB-42, in normal cells and loaded with cholesterol cells (Figure 10). These results also illustrate the functional utility of the predecessors of plasmalogens lies in their ability to positively modulate the function of membrane protein. In this respect, it is known that decreased levels of cholesterol in the membrane negatively modulate production of amyloid peptide15. In addition to the reduction of cholesterol in the membrane in NEC cells, it was observed that PPI-1005 and PPI-1009-also lowers the secretion of amyloid peptides (Figure 10).

Structural-specific and concentration-dependent implementation of PPI-1014 in ethanolamine-p�amelogenin (PlsEtn) and phosphatidylethanolamine (PtdEtn) N-Rel cells was also observed after 72 hours using concentrations of 5, 10 and 20 μm PPI-1014 (Figure 17).

EXAMPLE 3: Preparation of PPI-1011

The scheme of synthesis:

The scheme of synthesis for PPI-1011

Phase response:

Brief methodology: a Solution of compound 1 (2.0 kg, 15,15 mol) in 10% NaOH solution (10,0 l) was stirred at 80°C for 1 h, added TAV (992,0 g, 3.03 mol) and stirred for 15 minutes was Slowly added celibrated (5.5 kg, 18,18 mol) and the reaction mixture was stirred at 80°C for 20 h. (the Development of the reaction was monitored by diluting small aliquots with water, extracting with ethyl acetate, drawing on analytical silica gel TLC plate (30% ethyl acetate in petroleum ether) and visualization of relevant spots using Mo staining and a solution of KMnO4). Below is RfSthe components of the mixture: compound 1 (0.1), compound 2 (0.7).

Isolation and purification: the Reaction mixture was cooled to room temperature, was extracted with CH2Cl2(3×3.0 l). United CH2Cl2layer was washed with a solution of NaHCO3(1.0 l), water (2×2.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated to obtain crude compound 2 (2.9 kg, crude) as a pale yellow liquid, which was used for next� stage.

Phase response:

Brief methodology: a Solution of compound 2 (2.9 kg, 81,23 mol) in 20% water. HCl (14.5 l) was stirred at 85°C for 16 hours (the Development of the reaction was monitored by diluting small aliquots with water, extracting with ethyl acetate, drawing on analytical silica gel TLC plates (40% ethyl acetate in petroleum ether) and visualizing spots using Mo staining). The following is RfSthe components of the mixture: compound 2 (0.8), compound 3 (0.2).

Isolation and purification: the Reaction mixture was cooled to room temperature, was extracted with CH2Cl2(3×4.0 l). The combined organic layer was washed with a solution of NaHCO3(1.0 l), water (2×2.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was triturated with 5% ethyl acetate in petroleum ether (2×1.0 l) and then dried to obtain compound 3 (2.0 kg, 42% from 2 stages) as off-white solids.

Phase response:

Brief methodology: the cooled solution of compound 3 (1.0 kg 3,16 mol) in DMF (640.0 ml) and CH2Cl2(400 ml) at 0°C was added DMAP (38,6 g 0,32 mol) followed by triethylamine (735,0 g, 7,27 mol). After the addition the reaction mixture was stirred at 0°C for 30 min and added to�and TBSCI (572,0 g, 3,79 mol) in equal portions (3 portions) for 1 h, after which the reaction mixture was stirred for 20 h at room temperature. (Progress of the reaction was controlled by depositing small aliquots with water, extracting the CH2Cl2, drawing on analytical silica gel TLC plate (20% ethyl acetate in petroleum ether) and visualizing spots using Mo staining and KMnO4). The following is RfSthe components of the mixture: compound 3 (0,15), compound 4 (0.7).

Isolation and purification: the Reaction mixture was diluted with CH2Cl2(2.0 l), washed with water (3×3.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated. The resulting crude compound was purified by column chromatography (silica gel 100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to obtain compound 4 (850 g, 90%) as a pale yellow oil.

Phase response:

Brief methodology: In a chilled solution of compound 5 (160,0 g, 0,487 mol), DMF (1.0 ml) in CH2Cl2(500 ml) at 0°C was slowly added oxalicacid (105,0 g, 0,828 mol) for 30 min. After the addition the reaction mixture was stirred at 26°C for 4 h (progress of the reaction was controlled by depositing small aliquots of MeOH, drawing on analytical silica gel TLC plate(10% ethyl acetate in petroleum ether) and visualizing spots using a solution of KMnO 4). The following is RfSthe components of the mixture: compound 5 (0,3), compound 6 (0,8).

Isolation and purification: the Reaction mixture was concentrated in atmosphere of N2to obtain crude compound 6 (175 g, crude).

Phase response:

Brief procedure: To a cooled solution of compound 4 (150.0 g, 0,348 mol) in toluene (1.25 l) at 0°C was added pyridine (110.0 g, of 1.39 mol) followed by DMAP (122 2 g, 0,348 mol) and stirred for 10 min. was Added a solution of crude compound 6 (175,0 g, 0,504 mol) in toluene (250,0 ml) within 15 min. After the addition the reaction mixture was stirred at room temperature for 20 h. (the reaction Course was controlled by depositing small aliquots with water, extracting EtOAc, drawing on an analytical silica gel TLC plate (5% ethyl acetate in petroleum ether) and visualizing spots using a solution of KMnO4). The following is RfSthe components of the mixture: compound 4 (0.2), compound 7 (0.5).

Isolation and purification: the Reaction mixture was diluted with ethyl acetate (3.0 l), washed with water (1.0 l), and 0.05 N HCl (500,0 ml), water (2×1.0 l), brine (500,0 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound 7, which was purified by column chromatography (silica gel 100-200 mesh) using 2% ethyl acetate in petroleum ether� as eluent to obtain compound 7 (162 g, 62,7%) as a pale yellow oil.

Phase response:

Brief methodology: the cooled solution of compound 7 (160,0 g, 216,21 mmol) in THF (10.0 ml) and acetic acid (52.0 g) at 0°C was added TBAF (226,0 g, 864,86 mmol) in equal portions within 30 min. After the addition the reaction mixture was stirred at room temperature for 6 h (the Progress of the reaction was monitored by drawing on analytical silica gel TLC plate (20% ethyl acetate in petroleum ether) and visualizing spots using Mo staining and a solution of KMnO4). The following is RfSthe components of the mixture: compound 7 (0,9), compound PPI-1005 (0,4).

Isolation and purification: the Reaction mixture was diluted with ethyl acetate (3.0 l), washed with water (2×2.0 l), brine (500,0 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (silica gel 100-200 mesh) using 7% ethyl acetate in petroleum ether as eluent to obtain compound PPI-1005 (72 g, 53%) as a pale yellow oil.

Phase response:

Brief methodology: the cooled solution of α-lipoic acid 1 (12.0 g, 58.25 mmol) in THF (500,0 ml) at 0°C slowly over 10 min was added triethylamine (8,1 ml 58,25 mmol) followed by 2,4,6-trichlorobenzaldehyde (4.2 g, 58,25 mmol). After the addition the reaction mixture was allowed to warm to room temperature and stirred for 18 hours (the Progress of the reaction was monitored by drawing on analytical silica gel TLC plate (20% EtOAc in petroleum ether) and visualizing spots using 254 nm UV light and staining by Hanessian). The following is RfSthe components of the mixture: compound 1 (0,2), intermediate compound (0,6).

The reaction mixture was filtered, the solid phase was washed with THF (25.0 ml), the combined filtrate was concentrated using reduced pressure in an atmosphere of N2to obtain the crude anhydride, which was dissolved in benzene (500,0 ml), cooled to 0°C was added DMAP (7.1 g, 58,25 mmol) and stirred for 10 min In the reaction mixture at 0°C was slowly added a solution of PPI-1005 (40,1 g, 64,07 mmol) in benzene (100.0 ml). After the addition the reaction mixture was allowed to warm to room temperature and stirred for 24 h. (the reaction Course was controlled by the deposition of small aliquots of N2Oh, by the extraction with ethyl acetate, drawing on analytical silica gel TLC plate (15% THF in petroleum ether) and visualizing spots using 254 nm UV light and staining by Hanessian). The following is Rfsthe components of the mixture: PPI-1005 (0.3), PPI-1011 (0.5).

Isolation and purification: the Reaction mixture was diluted with e�ilaclama (2000 ml), were washed with saturated solution of NaHCO3(1×400 ml), 0.05 N HCl (1×400 ml), water (1×400 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (neutral silica gel 100-200 mesh) using 2.5 to 5% THF in petroleum ether as eluent.

The connection specified PPI-1011 (28.0 g, 54%) was obtained as pale brown oil.

EXAMPLE 4: Alternative method of preparation of PPI-1009

The scheme of synthesis:

Stage reaction

Methodology: a Solution of compound 1 (2.0 kg, 15,15 mol, Alfa Aesar) in 10% NaOH solution (10,0 l) was stirred at 80°C for 1 h, added TAV (992,0 g, 3.03 mol, Rajdhani scientific) and stirred for 15 minutes was Slowly added celibrated (5.5 kg, 18,18 mol, Alfa Aesar) and the reaction mixture was stirred at 80°C for 20 hours (the Progress of the reaction was monitored by dilution of small aliquots with water, extracting with ethyl acetate, drawing on analytical silica gel TLC plate (30% ethyl acetate in petroleum ether) and visualizing the appropriate spots using Mo staining and a solution of KMnO4). The following is RfSthe components of the mixture: compound 1 (0,1), compound 2 (0,7). The reaction mixture was cooled to room temperature, ek�was tragically CH 2Cl2(3×3.0 l). Layer CH2Cl2was washed with a solution of NaHCO3(1.0 l), water (2×2.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated to obtain the crude compound 2 (2.9 kg, crude) as a pale yellow liquid, which was used in the next step.

Phase response:

Methodology: a Solution of compound 2 (2.9 kg, 81,23 mol) in 20% water. HCl (14.5 l) was stirred at 85°C for 16 hours (the Development of the reaction was monitored by dilution of small aliquots with water, extracting with ethyl acetate, drawing on analytical silica gel TLC plate (40% ethyl acetate in petroleum ether) and visualizing spots using Mo staining). The following is RfSthe components of the mixture: compound 2 (0.,8), compound 3 (0,2). The reaction mixture was cooled to room temperature, was extracted with CH2Cl2(3×4.0 l). The combined organic layer was washed with a solution of NaHCO3(1.0 l), water (2×2.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was triturated with 5% ethyl acetate in petroleum ether (2×1.0 l) and dried to obtain compound 3 (2.0 kg, 42% from 2 stages) as off-white solids.

Phase response:

Method: In a chilled solution of compound 3 (1.0 kg 3,16 mol) in DMF (640,0 ml) and CH2Cl2(400.0 ml) at 0°C was added DMAP (38,6 g 0,32 mol) followed by triethylamine (735,0 g, 7,27 mol, Rankem). After the addition the reaction mixture was stirred at 0°C for 30 min and was added TBSCI (572,0 g, with 3.79 mol, Fluoro chem., 3.0 kg) in equal portions (3 portions) for 1 h, and the reaction mixture was stirred for 20 h at room temperature. (Progress of the reaction was controlled by deposition of small aliquots with water, extracting CH2Cl2, drawing on analytical silica gel TLC plate (20% ethyl acetate in petroleum ether) and visualizing spots using Mo staining and KMnO4). The following is RfSthe components of the mixture: compound 3 (0,15), compound 4 (0,7). The reaction mixture was diluted with CH2Cl2(2.0 l), washed with water (3×3.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated. The resulting crude compound was purified by column chromatography (silica gel 100-200 mesh) using 5% ethyl acetate in petroleum ether as eluent to obtain compound 4 (850,0 g, 90%) as a pale yellow oil.

Phase response:

Method: In a chilled solution of compound 4 (734 g, 1,706 mol) in DMF (2.5 l) at 0°C was added 60% NaH (204,0 g, 5,12 mol) in portions over 3 min. After the addition the reaction mixture was stirred at 0°C for 30 h and was added the bromide (438,0 g, 2.56 mol, S. D fine chemicals) dropwise for 1 h. the Reaction mixture was allowed to warm to room temperature and stirred for 20 h. (the reaction Course was controlled by the deposition of small aliquots with water, extracting EtOAc, drawing on analytical silica gel TLC plate (5% ethyl acetate in petroleum ether) and visualizing spots using Mo staining and KMnO4). The following is KD components of the mixture: compound 4 (0,2), compound 5 (0,5). The reaction mixture was precipitated with methanol (250 ml), cold water (1500 ml) and was extracted with ethyl acetate (2×2.0 l). The combined ethyl acetate layer was washed with water (3×1.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated. The resulting crude compound 5 (887 g) was used for next step without further purification.

Phase response:

Methods: In a cold solution of crude compound 5 (887,0 g, 1,702 mol) in THF (2.0 l) at 0°C was slowly added a solution of TBAF (1.3 kg, 5,107 mol, Chemrich fine chemicals) in THF (1.0 l) for 1 h. After the addition the reaction mixture was stirred at room temperature for 16 hours (the Progress of the reaction was monitored by deposition of small aliquots with water, extracting EtOAc, drawing on the analytical�die of silica-gel TLC plate (30% ethyl acetate in petroleum ether) and visualizing spots using Mo staining and KMnO 4). The following is RfSthe components of the mixture: compound 5 (0,9), compound 6 (0,3). The reaction mixture was diluted with ethyl acetate (2.5 l), washed with water (2×1.0 l), brine (1.0 l), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (silica gel 100-200 mesh) using 7% ethyl acetate in petroleum ether as eluent to obtain compound 6 (330 g, 48% from 2 stages) as a pale yellow oil.

Phase response:

Methods: In a cold solution of N-acetylcarnitine 8 (239,0 g, 1,177 mol, Molecula life Science) in CH2Cl2(500,0 ml) and DMF (5.0 l) at 0°C was slowly added oxalicacid (179,4 g, 1,412 mol) for 30 min and stirred at room temperature for 4 h. the Solvent from the reaction mixture were removed by distillation under reduced pressure and identified trace amounts of oxalicacid by codistillation with CH2Cl2. The resulting crude compound 9 (250 g) was dissolved in CH2Cl2(500,0 ml) and slowly added to a cold solution of compound 6 (334,0 g, 0,823 mol) in CH2Cl2(500,0 ml) at 0°C by passing bubbles N2. After the addition the reaction mixture was stirred for 20 h continuous transmission of bubbles N2at room temperature. (Response, which will move�and controlled deposition of small aliquots with water, the extraction of CH2Cl2, drawing on analytical silica gel TLC plate (25% MeOH in chloroform) and visualizing spots using Mo staining and KMnO4). The following is RfSthe components of the mixture: compound 6 (0,8), compound 10 (0,3). The reaction mixture was diluted with CH2Cl2(2.0 l), washed with brine (250 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (silica gel 100-200 mesh) using 5% MeOH in chloroform as eluent to obtain compound 10 (153,0 g, 31.5 per cent) in the form of a pale yellow oil.

Phase response:

Brief methodology: In suspensie 10% Pd/C (40,0 g, 25 wt.%, AlfaAesar) in ethanol (1.2 l) was added compound 10 (150.0 g, 0,298 mol) and hydrogenosomal (N2pressure 40 psi) at room temperature for 20 hours (the Progress of the reaction was monitored by drawing on analytical silica gel TLC plate (25% MeOH in chloroform) and visualizing spots using Mo staining and Ninhydrin solution). The following is RfSthe components of the mixture: compound 10 (0,4), compound 11 (0,2). The reaction mixture was filtered through a layer of cellite, the cake was washed with ethanol (2×200 ml), the combined filtrate was concentrated to obtain the crude compound was purified by column chro�ecografia (silica gel 100-200 mesh) using 10% methanol in chloroform as eluent to obtain compound 11 (75,0 g, 60%) as a pale yellow oil.

Phase response:

Brief methodology: In a chilled solution of compound 5 (48,0 g, of 0.146 mol, Nu-Chek-Prep Inc), DMF (1.0 ml) in CH2Cl2(300,0 ml) at 0°C was slowly added oxalicacid (22,3 g, 0,175 mol, Molecula Lifesciences) for 30 min. After the addition the reaction mixture was stirred at 26°C for 4 h (the Progress of the reaction was monitored by deposition of small aliquots of MeOH, drawing on analytical silica gel TLC plate tasting (10% ethyl acetate in petroleum ether) and visualizing spots using a solution of KMnO4). The following is RfSthe components of the mixture: compound 12 (0,3), compound 13 (0,8). The reaction mixture was concentrated in atmosphere of N2to obtain crude compound 6 (57 g, crude).

Stage of the reaction.

Brief methodology: In a chilled solution of compound 11 (50.0 g, is 0.102 mol) in THF (1.0 l) at 0°C was added pyridine (32,3 g, 0,409 mol) followed by DMAP (12.5 g, is 0.102 mol) and stirred for 10 min. was Added a solution of crude compound 13 (57,0 g, 0,163 mol) in toluene (1.0 ml) for 15 min. After the addition the reaction mixture was stirred at room temperature for 20 h. (the reaction Course was controlled by the deposition of small aliquots with water, extracting EtOAc, drawing on an analytical silica gel TLC plate (20% methane�La in chloroform) and visualizing spots using Mo staining and Ninhydrin solution). The following is RfSthe components of the mixture: compound 11 (0.2) and PPI-1009 (0,5). The reaction mixture was diluted with ethyl acetate (2.0 l), washed with 0.5 N HCl (250 ml), brine (250,0 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (silica gel 100-200 mesh) using 20% methanol in chloroform as eluent to obtain compound PPI-1009 (27 g, 33.3%) and in the form of a pale yellow oil.

EXAMPLE 5: Preparation of PPI-1014

Target molecule

The scheme of synthesis:

Phase response:

Reaction time: 17 h. reaction Temperature: from 0°C to 26°C. brief methodology: the cooled solution PPI-1005 (12.0 g, 19,16 mmol) in THF (600 ml) was added triphenylphosphine (7.7 g, of 28.75 mmol) and stirred at 0°C for 10 min followed by the slow addition DIEAD (5.8 g, of 28.75 mmol). After stirring at 0°C for 30 min in the reaction mixture was added N-acetylcystein (4.6 g, of 28.75 mmol) and was allowed to stir at room temperature for 16 hours (the Progress of the reaction was monitored by extraction with ethyl acetate, drawing on analytical silica gel TLC plate (30% ethyl acetate in petroleum ether) and visualizing spots using Mo staining). The following is RfS mixture components: PPI-1005 (0,8) and PPI-1014 (0,4).

Isolation and purification: the Reaction mixture was diluted with water (75 ml) and was extracted with ethyl acetate (3×200 ml). The combined ethyl acetate layer was washed with brine (50 ml), dried over anhydrous Na2SO4and concentrated to obtain crude compound which was purified by column chromatography (100-200 mesh silica gel) using 0 to 13% ethyl acetate in petroleum ether as eluent.

The connection specified PPI-1014 (3.2 g, 22%) was obtained as a pale yellow oil, having the following properties.1H NMR (300 MHz, CDCl3): δ 6.35 (bs, 1H), 5.39-5.22 (m, 13H), 4.92-4.88 (m, 1H), 4.55-4.22 (m, 3H), 3.55-3.41 (m, 5H), 3.02-2.97 (m, 2H), 2.85-2.77 (m, 10H), 2.40 (s, 5H), 2.11-2.04 (m, 5H), 1.57-1.52 (m, 2H), 1.36-1.25 (m, N), 0.97 (t, J=7.66 Hz, 3H), 0.88 (t, J=6.63 Hz, 3H). Mass (M+H): 772.3, UREH purity ~93.68%.

EXAMPLE 6: animal Studies

Male new Zealand rabbits (1.8 to 2.5 kg) was administered orally PPI-1011, clean in hard gelatin capsules (size 3). During the course of the study rats were administered doses of 200 mg/kg PPI-1011 and dogs were killed by cordozo of eutanol through 1, 3, 6, 12, 18, 24 and 48 h. Blood was collected via heart puncture and plasma was frozen at -70°C for further analyses. The kidneys and liver were also collected and stored at -70°C for further analyses. These studies were performed in 2 experiments with overlapping groups after 12 h (Experiment 1: 1, 3, 6 and 12 h; Experiment 2: 2, 18, 24 and 48 h). Control samples were collected at each time point. Plasmalogen and lipids were extracted and analyzed by LC-MS/MS, as previously reported (Goodenowe et al., 2007).

As can be seen in Figure 11, with the use of oral doses of 200 mg/kg predecessor of plasmalogens PPI-1011 was included in the circulating plasmalogen. Also watched diallylamine in sn-2-position, releasing docosahexaenoic acid (DHA). The biggest was the inclusion in 16:0/22:6, 18:0/22:6 and 18:1/22:6 ethanolamine-plasmalogen and phosphatidylethanolamine. No changes were observed in phosphatidylethanolamine comparison 16:0/18:0.

Further study of the temporal dynamics of inclusion (Figure 12) showed that the maximum inclusion was 12 hours, and that the level of implementation was maintained throughout the remaining observation period (48 h). This served as an argument in favor of phosphatidylethanolamine and ethanolamine-plasmalogens. In contrast, the levels of circulating DHA reached a maximum after 6 hours and fell to less stable state to 18 hours.

Study dose-dependent inclusions (Figure 13) PPI-1011 in plasmalogen and phosphatidylethanolamine plasma showed that the new stable level in these circulating phospholipids was achieved dose-dependent manner from 10 to 200 mg/kg. However, further increase of the dose did not increase the steady state levels of plasmalogens and phosphate�of diethanolamine higher levels obtained at 200 mg/kg. in contrast, the highest stable levels of circulating DHA were obtained at 500 mg/kg and more not increased at the dose of 1000 mg/kg.

The increase plasmalogens and DHA in the tissues was also observed in the tissues of the kidney (Figures 4 and 5) and liver (Figure 6).

These results indicate that PPI-1011 is orally bioavailable in rabbits and converted to DHA-containing ethanolamine-plasmalogen and phosphatidylethanolamine using the responses of diallylamine/reanimirovany. Moreover, the results suggest that endogenous metabolic system can limit the maximum boost that can be enhanced pharmacologically.

EXAMPLE 7: Modulation of in vitro excess membrane protein precursors of plasmalogens

The following studies showed the effectiveness of the predecessor plasmalogens (1-alkyl-2-acyl glycerol) in the changes excess amount of membrane-resident proteins. The cellular effects of the compounds shown in the wild-type cells, as well as in artificially increased content of cholesterol in membranes.

In wild-type cells increased content of modulating protein-amyloid precursor (APP) of the enzyme ADAM10, and esterifying cholesterol SOAT1 protein was observed by increasing the concentration of precursor plasmalogens. Anal�similar effects are observed in cholesterol-loaded models. Besides, the other involved in the processing of RDA enzyme VASE, showed a reduction of excess only loaded in cholesterol cells. Without being bound to theory, these data support a method of reducing amyloid deposits in the context of Alzheimer's disease and at the same time re-balancing of cholesterol in the membrane in the system, thereby offering potential benefits in the treatment of diseases such as atherosclerosis and hypercholesterolemia, in addition to Alzheimer's disease.

RDA mainly processinputs traditional by incorporating a sequential cleavage of γ-secretase (encoded genes 1/2 presenilin) and α-secretases (encoded ADAM 10). This nematologicheskiy processing of APP leads to the formation of neurotrophic peptide (sAPPα), which shows the protection against toxicity of glutamate and hypoglycemia (Araki et al., 1991; Mattson et al., 1993; Postina et al., 2004; Fahrenholz, 2007). An alternative way of processing the RDA is manifested in Alzheimer's disease, when APP is cleaved γ - and β-secretase in cholesterol rich lipid rafts. This "unconventional" way leads to the formation of β peptides with a length 38-43 amino acid residues, which tend to aggregate into plaques in the extracellular matrix, which is a symptom of AD (Selkoe, 2002; Walsh et al., 2002; Selkoe, 2003; Meyer-Luehmann et al., 2008). At the time Cochrane-family AD is due to genetic damage in the RDA or processorsa RDAs enzymes (PSEN1/2, BOB, ADAM), the underlying cause of sporadic late AD (switching non-pathogenic processing of APP pathogenic) remains unclear.

Of particular importance to the homeostasis of cholesterol in the etiology of AD has been studied in humans (Corder et al., 1993; Saunders et al., 1993; Blacker et al., 1997; Hofman et al., 1997) and in animal models (Joyce et al., 2002; Naya et al., 2002; Van Eck al., 2006; Wahrle et al., 2008). It was shown that the change in the content of cholesterol in the plasma membrane affects the function of membrane-resident proteins (Scanlon et al., 2001; Lange et al., 2004). The high content of cholesterol in the brain has been shown in subjects with AD (Mori et al., 2001), while the rabbits that were fed cholesterol-enriched diet, showed the development of plaques in the brain (Ghribi et al., 2006). In vitro data showed that cells deficient plasmalogen contain elevated levels of free cholesterol in the membrane, however, it has been shown that in humans, the deficiency of plasmalogens in serum is consistent with the deterioration of cognitive functions (Goodenowe et al., 2007). Based on these observations, we studied the relationship between cholesterol and plasmalogen, as well as determining the impact of their balance on pathological manifestations of AD, measured in terms of the secreted β.

The proposed mechanism of action: the Shift in the processing of APP through the modulation of membrane lipids

Cladembrasil of human kidney (NEC) Express the RDA and processing ARR requires a mechanism of binding to the membrane, making it a good model for studying the processing of APP. The present in vitro study contradicts previous studies in which the modulation of membrane fluidity by loads of cholesterol and/or add a predecessor of plasmalogen cheated on intracellular Aβ42 content. Load NEC cells cholesterol increases the amount of free cholesterol by 17% (compared to Control) in cells after 48 hours of incubation period. This increase is accompanied by a parallel and significant increase (p<0.05) content β42 in air-conditioned environment compared to control. The increase in amyloid by 65% in the first place is due to increase by 22% in the concentration of β-secretase (Figure 18A, line 2); basal levels RDAs remain unchanged under the load of cholesterol. Treatment loaded with cholesterol NEC precursor cells of plasmalogens PPI-1005 significantly reduces the amount of free cholesterol in the cell membrane (p<0.05). The content β42 in conditioned medium falls 70% below loaded with cholesterol levels at a concentration of 20 μm (p=0.0001), while the content of sAPPα in the conditioned medium is increased. Impact on the processing of APP occurs not due to a change in the expression of APP, but rather due to the shift in the way of processing of ARR for treason�ia an excess amount of enzymes processorsa RDAs. Although β-secretase was restored to normal levels at a concentration of 20 μm PPI-1005, a 73% increase in sAPPα species was detected in conditioned medium. This increase was due to a 63% increase in ADAM10 (Figure 18A, lane 3), the enzyme responsible for the formation of sAPPα.

The change in lipid profile of cells after adding plasmalogen can be explained by the fact that SOAT1, the enzyme responsible for the esterification of free cholesterol, increases by about 25% (compared with the conditions loaded with cholesterol) while increasing the concentration of plasmalogen (Figure 18A, lane 5).

Separately the effects of PPI-1005 were studied on cells NECK wild type, not loaded with cholesterol. Figure 18B shows a concentration-dependent increase of the excess amount of ADAM10 (35%) and SOAT1 (50%). Changes in the content of VASE or RDAs were observed. Although, when NEC cells were depleted of cholesterol by inhibiting HMGCoA reductase the pravastatine, the levels of ADAM10 and SOAT1 remained constant (Figure 18C). While processing plasmalogens and pravastatine significantly decreased fraction of free cholesterol in the cells, only the processing plasmalogens changed the levels of ADAM10 and SOAT1 in the cage. This indicates that the effect on excessive amounts of ADAM10 and SOAT1 largely OK�fixes contained in the membrane of plasmalogen, than those contained in membrane cholesterol.

Thus, an excessive amount of membrane-resident proteins can be modified in vitro by simulating the content of plasmalogen in cells, which is achieved by treating the cells precursors of plasmalogens as described herein.

Materials and methods

Load of cholesterol

Cells NEC grown in DMEM, 10% FBS at 37°C, 5% CO2seeded the day before treatment. The next day the cell membrane loaded with exogenous cholesterol at a concentration of 10 μg/ml of medium using methyl-β-cyclodextrin as a carrier for the delivery of cholesterol as described (Rong et al., 2003).

Analysis of cholesterol

Cells were treated with a precursor of plasmalogens PPI-1005 or ethanol as a control. Cells were collected after 48 hours using a cocktail of Versene: TryPLe Express, washed with PBS. Lipids were extracted containing chloroform with 1% Triton X-100. The organic fraction was recovered and dried in a stream of nitrogen. The dried lipids were resuspended in cholesterol reaction buffer (Biovision, Mountain View, CA) and total free and verified the fraction of cholesterol was calculated using the kit to count cholesterol (Biovision, Mountain View, CA) according to manufacturer's recommendations. Cholesterol is first calculated as µg/million cells and was determined in the wee�e percent of the control conditions for each experiment.

Analysis of amyloid

NEC cells were loaded with exogenous cholesterol, as described, and treated with PPI-1005 or ethanol as a control. Conditioned medium from treated cells were collected after 48 hour incubation period. For content analysis β1-42conditioned medium was enriched with the use of the centrifuge ultrafilter Amicon (Millipore, Billerica, MA) before loading into the microplates. ELISA was performed according to manufacturer's recommendations (Covance Labs, Princeton, NJ). The reaction was stopped after 25 minutes after adding the substrate and the absorbance read at 495 nm. The experiment was conducted three times. Values were calculated as μg/ml of conditioned medium and normalized to the number β detected in conditioned medium from untreated, loaded with cholesterol control NC cells.

Immunoblotting and immunoprecipitation

Cells NECK were processed as described in the analysis of amyloid. Pellets of cells were washed in PBS and literally in RIPA buffer containing protease inhibitory cocktail (Sigma, St. Louis, MI). Protein in the cell lysate was estimated using Bio-Rad Protein Assay (Bio-Rad, Hercules, CA). The following antibodies were used for Western blot analyses: RDA (Calbiochem, Darmstadt, Germany), BACE1 and ADAM10 (Millipore, Temecula, CA), sAPPα (IBL, Gunma, Japan), SOAT1 (Santa Cruz Biotechnology Inc., CA) and β-actin (Sigma, St. Louis, MI). Immunoassay conducted to set�ing sAPPα in the conditioned medium. Briefly, antibody to sAPPα was added to the conditioned medium and incubated for 16 hours at 4°C. Immunosurgery was performed by incubation with protein A/G-agarose beads for 6 hours at 4°C. the Beads were washed with PBS and-eluted proteins were detected using immunoblotting using anti-sAPPα antibody. Band intensity was calculated using Image Processing and Analysis in Java (ImageJ) software (National Instituyes of Health, Bethesda, MD).

Statistical analysis

Statistical analysis of data was performed using Microsoft™ Office Excel 2007, and tests of Dunnett JMP version & Multiple was used to examine differences between treated and control groups.

Experienced in this field specialists will be understood that many variations and modifications may be made without departing from the scope of the invention as defined in the formula.

The following references, and references described above are incorporated herein by reference.

Sources

1. Calderini G, Bonetti AC, Battistella A, Crews FT, Toffano G (1983) Biochemical changes of rat brain membranes with aging. Neurochem Res. 8:483-92.

2. Hashimoto M, Hossain S, Masumura S (1999) Effect of aging on plasma membrane fluidity of rat aortic endothelial cells. Exp Gerontol. 34:687-98.

3. Kessler AR, Kessler B, Yehuda S (1985) Changes in the cholesterol level, cholesterol-to-phospholipid mole ratio, and membrane lipid microviscosity in rat brain induced by age and a plant oil mixture. Biochem Pharmacol. 34:1120-1.

4. Lewin MB, Timiras PS (1984) Lipid changes with aging in cardiac mitochondrial membranes. Mech Ageing Dev. 24:343-51.

5. Modi HR, KatyareSS, Patel MA (2008) Ageing-induced alterations in lipid/phospholipid profiles of rat brain and liver mitochondria: implications for mitochondrial energy-linked functions. J Membr Biol. 221:51-60.

6. Wu CC, Su MJ, Chi JF, Wu MH, Lee YT (1997) Comparison of aging and hypercholesterolemic effects on the sodium inward currents in cardiac myocytes. Life Sci, 61:1539-51.

7. Guo J, Chi S, Xu H, Jin G, Qi Z (2008) Effects of cholesterol levels on the excitability of rat hippocampal neurons. Mol Membr Biol. 25:216-23.

8. Santiago J, Guzmàn GR, Rojas LV, Marti R, Asmar-Rovira GA, Santana LF, M McNamee, Lasalde-Dominicci JA (2001) Probing the effects of membrane cholesterol in the Torpedo californica acetylcholine receptor and the novel lipid-exposed mutation alpha C418W in Xenopus oocytes. J Biol Chem. 276:46523-32.

9. Hashimoto M, Hossain S, Tanabe Y, Shido O (2005) Effects of aging on the relation of adenyl purine release with plasma membrane fluidity of arterial endothelial cells. Prostoglandins Leukot. Essent. Fatty Acids. 73:475-83.

10. Xiu J, Nordberg A, Qi X, Guan ZZ (2006) Influence of cholesterol and lovastatin on alpha-form of secreted amyloid precursor protein and expression of alpha7 nicotinic receptor on astrocytes. Newochem Int. 49:459-65.

11. Miersch S, Espey MG, Chaube R, Akarca A, R Tweten, Ananvoranich S, Mutus B (2008) Plasma membrane cholesterol content affects nitric oxide diffusion dynamics and signaling. J Biol Chem. 283:18513-21.

12. Cultler RG, Kelly J, Stone K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci USA. 101:2070-5.

13. Corrigan FM, Horrobin DF, Skinner ER, Besson JA, Cooper MB (1998) Abnormal content of n-6 and n-3 long-chain unsaturated fatty acids in the phosphoglycerides and cholesterol esters of parahippocampal cortex from Alzheimer's disease patients and its relationship to acetyl CoA content. Int J Biochem Cell Biol. 30:197-207.

14. Distl R, Meske V, Ohm TG (2001) Tangle-bearing neurons contain more free cholesterol than adjacent tangle-free neurons. Acta Neuropathol. 101:547-54.

15. Grimm MO, Grimm HS, Tomic I, Beyreuther K, Hartmann T, Bergmann C (2008) Independent inhibition o of Alzheimer's disease beta - and gamma-secretase cleavage by lowered cholesterol levels. J Biol Chem. 283:11302-11.

16. Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K (1998) Cholesterol {false inhibits the generation of beta-amyloid in hippocampal neurons. Proc Nati Acad Sci USA. 95:6460-4.

17. Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, press event JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry. 47:9428-46.

18. Sigle JP, Zander J, Ehret A, Honegger J, Jackisch R, Feuerstein TJ (2003) High potassium-induced activation of choline-acetyltransferase in human neocortex: implications and species differences. Brain Res Bull. 60:255-62.

19. Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE (2007) Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 5:20.

20. Li CM, dark ME, Rudolf M, Curcio CA (2007) Distribution and composition of esterified and unesterified cholesterol in extra-macular drusen. Exp Eye Res. 85:192-201.

21. Hager MH, Solomon KR, Freeman MR (2006) The role of cholesterol in prostate cancer. Curr Opin Clin Nutr Metab Care; 9:379-85.

22. Campbell AM, Chan SH (2008) Mitochondrial membrane cholesterol, the voltage dependent anion channel (VDAC), and the Warburg effect. J Bioenerg Biomembr.

23. Vejux A, Malvitte L, Lizard G (2008) Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis. Braz J Med Biol Res. 41:545-56.

24. Streit WJ, Sparks DL (1997) Activation of microglia in the brains of humans with heart disease and hypercholesterolemic rabbits. J Mol Med. 75:130-8.

25. Diestel A, Aktas O, Hackel D, Hake I, Meier S, Raine CS, Nitsch R, Zipp F, Ullrich O (2003) Activation of microglial poly(ADP-ribose)-polymerase-l by cholesterol breakdown products during neuroinflammation: a link between demyelination and neuronal damage. J Exp Med. 198:1729-40.

26. Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, Sambamurti K, Kindy MS, Bhat NR (2008) High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. J Neurochem. 106:475-85.

27. Shin J, Thompson DH (2003) Direct synthesis of plasmenylcholine from allyl-substituted glycerols. Org Chem. 68:6760-6.

28. Gupta CM, Radhakrishnan R, Khorana HG (1977) Glycerophospholipid synthesis: improved general method and new analogs containing photoactivable groups. Proc Natl Acad Sci USA. 74:4315-9.

29. Watt MJ, Steinberg GR (2008) Regulation and function of triacylglycerol lipases in cellular metabolism. Biochem J. 414:313-25.

30. Nagan N, Hajra AK, Larkins LK, Lazarow P, Purdue PE, Rizzo WB, Zoeller RA (1998) Isolation of a Chinese hamster fibroblast variant defective in dihydroxyacetonephosphate acyltransterase activity and plasmalogen biosynthesis: use of a novel two-step selection protocol. Biochem J. 332:273-9.

31. Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, Morihara T, Takeda M, Wood PL (2007) Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia. J Lipid Res. 48:2485-98.

32. Araki W, Kitaguchi N, Tokushima Y, Ishii K, Aratake H, Shimohama S, Nakamura S and Kimura J (1991) Trophic effect of beta-amyloid precursor protein on cerebral cortical neurons in culture. Biochem Biophys Res Commun 181:265-271.

33. Blacker D, Haines JL, Rodes L, Terwedow H, Go RC, Harrell LE, Perry RT, Bassett SS, Chase G, Meyers D, Albert MS and Tanzi R (1997) ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology 48:139-147.

34. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL and Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923.

35. Fahrenholz F (2007) Alpha-secretase as a therapeutic target. Curr Alzheimer Res 4:412-417.

36. Ghribi O, Larsen B, Schrag M and Herman MM (2006) High cholesterol content in neurons increases BACE, beta-amyloid, and phosphorylated tau levels in rabbit hippocampus. Exp Neurol 200:460-467.

37. Hofman A, Ott A, Breteler MM, Bots ML, Slooter AJ, van Harskamp F, van Duijn CN, Van Broeckhoven With and Grobbee DE (1997) Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 349:151-154.

38. Joyce CW, Amar MJ, Lambert G, Vaisman BL, Paigen B, Najib-Fruchart J, Hot RF, Jr., Neufeld ED, Remaley AT, Fredrickson DS, Brewer HB, Jr. and Santamarina-Fojo S (2002) The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci USA 99:407-412.

39. Lange Y, Ye J and Steck TL (2004) How cholesterol homeostasis is regulated by plasma membrane cholesterol in excess of phospholipids. Proc Natl Acad Sci USA 101:11664-11667.

40. Mattson MP, Cheng B, Culwell AR, Esch FS, Lieberburg I and Rydel RE (1993) Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 10:243-254.

41. Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman and WATTS (2008) Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 451:720-724.

42. Mori T, Paris D, Town T, Rojiani AM, Sparks DL, Delledonne A, Crawford F, Abdullah LI, Humphrey JA, Dickson DW and Mullan MJ (2001) Cholesterol accumulates in senile plaques of Alzheimer disease patients and in transgenic APP(SW) mice. J Neuropathol Exp Neurol 60:778-785.

43. Postina R, Schroeder A, Dewachter I, Bohl J, Schmitt U, Kojro E, Prinzen C, Endres K, Hiemke C, Blessing M, Flamez P, Dequenne A, Godaux E, van Leuven F and Fahrenholz F (2004) A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model. J Clin Invest 113:1456-1464.

44. Rong JX, Shapiro M, Trogan E and Fisher EA (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci USA 100:13531-13536.

45. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ and et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43:1467-1472.

46. Scanlon SM, Williams DC and Schloss P (2001) Membrane cholesterol modulates serotonin transporter activity. Biochemistry 40:10507-10513.

47. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298:789-791.

48. Selkoe DJ (2003) Foldin proteins in fatal ways. Nature 426:900-904.

49. Singaraja RR, Fievet C, Castro G, James ER, Hennuyer N, Clee SM, Bissada N, Choy JC, Fruchart JC, McManus BM, Staels In and Hayden MR (2002) Increased ABCA1 activity protects against atherosclerosis. J Clin Invest 110:35-42.

50. Van Eck M, Singaraja RR, Ye D, Hildebrand RB, James ER, MR Hayden and Van Berkel TJ (2006) Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Score Biol 26:929-934.

51. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM and Holtzman DM (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer's disease. J Clin Invest 118:671-682.

52. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ and Selkoe DJ (2002) Naturally secreted oligomers of amyloid beta protein are potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535-539.

1. The compound according to the structure of formula I:

where:
R1and R2are the same or different and selected from alkyl or alkenyl hydrocarbon chain selected from the group consisting of: CH3(CH2)3-, CH3(CH2)5-, CH3(CH2)7-, CH3(CH2)9-, CH3(CH2)11-, CH3(CH2)13-, CH3(CH2)15-, CH3(CH2)17-, CH3(CH2)19-, CH3(CH2)21-, CH3(CH2)23-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2) 7-, CH3(CH2)4SN=SSN2CH=CH(CH2)7-, CH3CH2SN=SSN2SN=SSN2CH=CH(CH2)7-, CH3CH2(CH=CH)-, CH3(CH2)3(CH=CH)-, CH3(CH2)5(CH=CH)-, CH3(CH2)7(CH=CH)-, CH3(CH2)9(CH=CH)-, CH3(CH2)11(CH=CH)-, CH3(CH2)13(CH=CH)-, CH3(CH2)15(CH=CH)-, CH3(CH2)17(CH=CH)-, CH3(CH2)19(CH=CH)-, CH3(CH2)21(CH=CH)-, CH3(CH2)3CH=CH(CH2)5(CH=CH)-, CH3(CH2)5CH=CH(CH2)5(CH=CH)-, CH3(CH2)7CH=CH(CH2)5(CH=CH)-, CH3(CH2)4SN=SSN2CH=CH(CH2)5(CH=CH), CH3CH2SN=SSN2SN=SSN2CH=CH(CH2)5(CH=CH)-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)4(CH=SNSN2)2(CH2)6-, CH3CH2(CH=SNSN2)3(CH2)6-, CH3(CH2)4(CH=SNSN2)4(CH2)2-, CH3CH2(CH=SNSN2)5(CH2)2-, CH3 (CH2)7CH=CH(CH2)11and CH3CH2(CH=SNSN2)6CH2-;
R3is a group, contain no cleavable lipase from compounds according to the structure of formula I, selected from the group consisting of carnitine, acetyl-D/L-carnitine, ticaretine, acetyl-D/L-ticaretine, creatine, nocardicin, lipoic acid, dihydrolipoic acid, N-acetylcysteine, substituted or unsubstituted amino groups, and groups having the structure shown below:


R4and R5are independently hydrogen or C1-C7by alkyl;
R6represents hydrogen or C1-C7alkyl; and
R7and R8independently are hydrogen or C1-C7the alkyl,
including its pharmaceutically acceptable salts or esters.

2. The compound according to claim 1, wherein R2represents CH3CH2(CH=SNSN2)6CH2- and which is preferably selected from the group consisting of 2-ACO�hydroxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine (PPI-1009),
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(5-((R)-1,2-dithiolan-3-yl)pentanoate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1011) and
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(2-atsetamido-3-mercaptopropionate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1014).

3. Pharmaceutical composition for treating or preventing age-related diseases, mediated by deficiency of plasmalogens containing a pharmaceutically acceptable carrier and an effective amount of a compound according to claim 1 or 2.

4. Use of a compound according to claim 1 or 2 for treating or preventing age-related diseases associated with elevated levels of cholesterol in the membrane, increased levels of amyloid or low plasmalogen.

5. The use according to claim 4, in which age-related disease is selected from the group consisting of: neurodegenerative diseases, cognitive impairment, dementia, cancer and vascular diseases.

6. The use according to claim 5, in which the neurodegenerative disease is selected from the group consisting of: Alzheimer's disease, Parkinson's disease and age-related macular degeneration, the cancer is selected from the group consisting of: cancer of the prostate, lung, breast, ovary and kidney, and the vascular disease is selected from the group consisting of: atherosclerosis and hypercholesterolemia.

7. Use of a compound of formula I:

in which
R3is a group, contain no cleavable lipase from compounds according to the structure of formula I, selected from the group consisting of fatty acids, carnitine, acetyl-D/L-carnitine, ticaretine, acetyl-D/L-ticaretine, creatine, nocardicin, phosphocholine, lipoic acid, dihydrolipoic acid, phosphoethanolamine, phosphoserine, N-acetylcysteine, substituted or unsubstituted amino groups, and groups having the structure shown below:


and R1, R2and from R4to R8are as defined according to claim 1, including pharmaceutically acceptable salts or esters for the treatment or prevention of age-related diseases, mediated by deficiency of plasmalogens by increasing the levels of PlsEtn above control levels in PlsEtn deficient or PlsEtn sufficient systems, or diseases caused by abnormal gene expression of cholesterol transport proteins.

8. The use according to claim 7, �de R 2represents CH3CH2(CH=SNSN2)6CH2-, preferably selected from the group consisting of 2-acetoxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine (PPI-1009),
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(5-((R)-1,2-dithiolan-3-yl)pentanoate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1011) and
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(2-atsetamido-3-mercaptopropionate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1014).

9. The use according to claim 7 or 8, in which the transport protein cholesterol is apoliprotein E.

10. Use of a compound of formula I:

for the treatment or prevention of neurodegenerative disease selected from the group consisting of: Alzheimer's disease, Parkinson's disease and age-related macular degeneration; vascular diseases selected from the group consisting of: atherosclerosis and hypercholesterolemia, where
R1and R2are the same or different and selected from alkyl or alkenyl hydrocarbon chain selected from the group consisting of: CH3(CH2)3-, CH3(CH2)5-, CH3(CH2)7-, CH3(CH2)9-, CH3(CH2)11-, CH3(CH2)13-, CH3(CH2)15-, �N 3(CH2)17-, CH3(CH2)19-, CH3(CH2)21-, CH3(CH2)23-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2)7-, CH3(CH2)4SN=SSN2CH=CH(CH2)7-, CH3CH2SN=SSN2SN=SSN2CH=CH(CH2)7-, CH3CH2(CH=CH)-, CH3(CH2)3(CH=CH)-, CH3(CH2)5(CH=CH)-, CH3(CH2)7(CH=CH)-, CH3(CH2)9(CH=CH)-, CH3(CH2)11(CH=CH)-, CH3(CH2)13(CH=CH)-, CH3(CH2)15(CH=CH)-, CH3(CH2)17(CH=CH)-, CH3(CH2)19(CH=CH)-, CH3(CH2)21(CH=CH)-, CH3(CH2)3CH=CH(CH2)5(CH=CH)-, CH3(CH2)5CH=CH(CH2)5(CH=CH)-, CH3(CH2)7CH=CH(CH2)5(CH=CH)-, CH3(CH2)4SN=SSN2CH=CH(CH2)5(CH=CH)-, CH3CH2SN=SSN2SN=SSN2CH=CH(CH2)5(CH=CH)-, CH3(CH2)3CH=CH(CH2)7-, CH3(CH2)5CH=CH(CH2)7-, CH3(CH2)7CH=CH(CH2)7-, CH3/sub> (CH2)4(CH=SNSN2)2(CH2)6-, CH3CH2(CH=SNSN2)3(CH2)6-, CH3(CH2)4(CH=SNSN2)4(CH2)2-, CH3CH2(CH=SNSN2)5(CH2)2-, CH3(CH2)7CH=CH(CH2)11and CH3CH2(CH=SNSN2)6CH2-;
R3is a group, contain no cleavable lipase from compounds according to the structure of formula I, selected from the group consisting of fatty acids, carnitine, acetyl-D/L-carnitine, ticaretine, acetyl-D/L-ticaretine, creatine, nocardicin, phosphocholine, lipoic acid, dihydrolipoic acid, phosphoethanolamine, phosphoserine, N-acetylcysteine, substituted or unsubstituted amino groups, and groups having the structure shown below:


R4and R5are independently hydrogen or C1-C7by alkyl;
R6represents hydrogen silt� 1-C7alkyl; and
R7and R8independently are hydrogen or C1-C7the alkyl,
including its pharmaceutically acceptable salts or esters.

11. The use according to claim 10, where R2represents CH3CH2(CH=SNSN2)6CH2-, in this case, preferably, a compound selected from the group consisting of 2-acetoxy-4-(2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic)-3-(hexadecylamine)propoxy)-N,N,N-trimethyl-4-oxobutyl-1-amine (PPI-1009),
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(5-((R)-1,2-dithiolan-3-yl)pentanoate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1011) and
(4Z,7Z,10Z,13Z,16Z,19Z)-1-(2-atsetamido-3-mercaptopropionate)-3-(hexadecylamine)propane-2-aldaketa-4,7,10,13,16,19-hexaenoic (PPI-1014).



 

Same patents:

FIELD: biotechnology.

SUBSTANCE: invention relates to glycosidic derivatives of 1,2-dithiole-3-thione or 1,2-dithiol-3-one of formula 1 , where R1=S or O; R2 is a residue of per-O-acetyl D-glucose, per-O-acetyl D-galactose, per-O-acetyl D-mannose, per-O-acetyl D-xylose, per-O-acetyl L-arabinose, per-O-acetyl-D-maltose or D-glucose, which can be used against cancerous diseases.

EFFECT: new bioactive compounds with cancerous preventive action and pharmaceutical products based on them are proposed, which display the cancerous preventive effect in non-cytotoxic concentrations.

2 cl, 4 ex, 5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of non-steroid anti-inflammatory drugs (NSAID) of general formula: A-Y-X (Formula I), where A represents NSAID radical, selected from group, consisting of acetylsalicylic acid (ASA), diclofenac, naproxen, indomethacin, flurbiprofen, ibuprofen, ketoprofen and lumoracoxib, Y represents -C(O)O-, and X is selected from group, consisting of: and , which have improved anti-inflammatory properties, suitable for treatment of inflammation, pain and fever.

EFFECT: obtained are NSAID derivatives with hydrosulfide (H2S)-releasing fragment, for obtaining novel anti-inflammatory compounds, which have weakened side effects.

23 cl, 16 dwg, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a 1-(1-adamantyl)ethylamine derivative (remantadin) of general formula: wherein R is a functional group of the amino acid residue (I-IV) or the lipoic acid residue (V). (I), (II), (III), (IV), (V) which possess selective antiviral activity in relation to the influenza A strains, including the viral strains resistant to action of remantadin. The compounds wherein R means the groups (l),(ll),(lll) and (V) are novel.

EFFECT: prepared compounds may be promising as substances as a part of the antiviral drugs and applicable for creating new antiviral drugs.

2 cl, 2 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: in embodiments of the invention, specific compounds are used to prepare a medicinal agent for treating, relieving and preventing conditions associated with dysfunction of monoamine transmission. The compounds have general formula (1) , where: R1 and R2 are identical or different and denote hydrogen, alkyl, alkenyl, alkynyl, aryl, thio or alkylthio, or R1 and R2 may have extra substitutes which are selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkyloxy, morpholin-4-ylalkoxy, piperidin-1-ylalkyloxy, alkylamino, dialkylamino, arylamino.

EFFECT: more efficient use of compounds in preparing medicinal agents.

8 cl, 3 tbl, 4 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new lipoic acid derivatives of general formula Ia

1, wherein n = 0-4, integer; -X-Y represents -O(CH2)r-, -CO-N(R3)-(CH2)r-, -N(R4)-CO-(CH2)r; -X'-Y' represents -(CH2)r-, -(CH2)r-N(R3)-(CH2)r-, -(CH2)r-CO-N(R3)-(CH2)2-; R3 and R4 are the same or different and represent hydrogen or alkoxycarbonyl; r = 0-4, integer; Ω represents piperazinyl, piperidyl or phenyl. Also disclosed are method for production the claimed derivatives and pharmaceutical composition, containing the same. Compounds are useful as NO-syntase inhibitors and/or reagents mediating redox state of thiol groups.

EFFECT: new lipoic acid derivatives.

7 cl, 17 ex

The invention relates to a series of new dithiolane derivatives, possessing an excellent ability to enhance the activity of glutathione reductase

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the chemical-pharmaceutical and food industries. What is presented is a catalytic method for synthesis of a recovered form of coenzyme Q10 (ubiquinol) which can be used for the rapid preparation of ubiquinol and various based pharmaceutical compositions and biologically active food additives possessing antioxidant and antihypoxant activity. The method for preparing ubiquinol of an oxidised form of coenzyme Q10 is based on the catalytic recovery of Q10 in the presence of a chemical reducing agent, a solvent and trace amounts of a Cu2+ copper catalyst for the pharmaceutical and food applications. In addition to the substantial reduction of the time for preparing ubiquinol, using the catalyst enables reducing the consumption of the chemical reducing agent and energy. Prepared ubiquinol can be used, e.g. for preparing various compositions, including ones in the liquid form and in the form of water-soluble powders containing inclusion complexes.

EFFECT: method for the synthesis of the recovered form of coenzyme Q10 (ubiquinol).

10 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula , where R1=Cl, R2, R3, R4, R5=H O-(2,3-dihydroxyprop-1-yl)-2-chlorophenol; R3=Cl, R1, R2, R4, R5=H O-(2,3-dihydroxyprop-1-yl)-4-chlorophenol; R1, R4=Cl, R2, R3, R5=H O-(2,3-dihydroxyprop-1-yl)-2,5-dichlorophenol; R1=CH3, R3=Cl, R2, R4, R5=H O-(2,3-dihydroxyprop-1-yl)-2-methyl-4-chlorophenol; R1, R3 ,R5=Cl, R2, R4=H O-(2,3-dihydroxyprop-1-yl)-2,4,6-trichlorophenol; R1, R3, R4=Cl, R2, R5=H O-(2,3-dihydroxyprop-1-yl)-2,4,5-trichlorophenol, used against weeds of the grass family.

EFFECT: high activity of the compounds.

2 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: claimed are compounds of general formula I , where values of radicals are given in description, possessing inhibiting action on sodium-dependent cotransporter of glucose SGLT. Present invention also claims pharmaceutical compositions, possessing inhibiting effect with respect to SGLT, and methods of obtaining said compounds and synthetic intermediates, as well as methods of obtaining said compounds per se or in combination with other therapeutic agents for treatment of diseases or states, subjected to impact of SGLT inhibition, for instance such disease as type 1 and 2 diabetes mellitus, hyperglucemia, diabetic complications, insulin resistance, metabolic syndrome, hyperinsulinemia, hypertension, hyperuricemia, obesity, edemas, dislipidemia, chronic heart failure and atherosclerosis.

EFFECT: increasing efficiency of application of derivatives.

21 cl, 23 ex, 1 tbl, 8 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing bis-2-hydroxethyl ether of 4,4'-dioxydiphenyl-2,2-propane, which can be used to modify polyester fibres, as well as in production of polycarbonates. The method involves reaction of 4,4'-dioxydiphenyl-2,2-propane with 2-oxo-1,3-dioxolane in an inert medium in the presence of a catalyst at temperature of 150±5°C until carbon dioxide release stops. The catalyst used is a tetramethylammonium salt of monomethyl ether of carbonic acid of formula [N(CH3)4][CO3CH3], and the end product is separated by washing with water.

EFFECT: invention enables to obtain the end product with high output using a simple and environmentally safe method.

4 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 1,5-bis(2-hydroxyphenoxy)-3-oxapentane monohydrate, which is an intermediate product during synthesis of crown ethers which have complexing and solvating properties and are widely used in different fields of chemistry, engineering, biology and medicine. The method involves reaction of β,β'-dichloroethyl ether with pyrocatechol, the reaction being carried out using an excess amount of pyrocatechol in a medium of glycerol and in the presence of sodium carbonate, as well as in the current of an inert gas, at high temperature and while stirring, followed by separation of the end product. The starting pyrocatechol, which is taken in 6-10% stoichiometric excess, is first treated with sodium carbonate in glycerol medium with intense stirring and at temperature of 60-80°C, after which the formed solution is heated to 145-150°C and β,β'-dichloroethyl ether is added, stirred at the same temperature, cooled and the end product is deposited from the reaction solution using ice water and the filter cake is washed with water to neutral reaction.

EFFECT: disclosed method enables to obtain the end product with high output.

4 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of bis-[β-(2-oxyphenoxyethyl)]oxide which can be used as a semi-product in synthesis of pharmaceutical drugs. The invention proposes the synthesis of bis-[β-(2-oxyphenoxyethyl)]oxide by reacting catechol, sodium hydroxide and bis(2-chloroethyl)ether in the presence of water using ethyl alcohol as a solvent and an N,N,N-triethylbenzylammonium chloride catalyst.

EFFECT: increase in output of the desired compound of more than 51%, wherein the desired compound has purity of 97%.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel individual diarylalkanes, to method of preventing treatment of diseases and states, associated with tyrosinases, method of preventing treatment of diseases and states, associated with overproduction or uneven distribution of melamine, method of inhibiting tyrosinase activity and method of melamine synthesis suppression, in which claimed diarylalkanes, as well as compositions for local application based on novel diarylalkanes, are applied.

EFFECT: increased efficiency of composition application.

30 cl, 5 tbl, 14 dwg, 18 ex

Antioxidants // 2454394

FIELD: chemistry.

SUBSTANCE: present invention relates to use of compounds of formula Ia, Ib or Ic or cosmetically acceptable salts thereof as antioxidants, for preparing cosmetic compositions and for controlling pigmentation, particularly for clearing areas on the skin, to certain specific compounds of formula Ia, Ib or Ic or cosmetically acceptable salts thereof, a method of producing compounds of formula Ia, Ib or Ic, a cosmetic composition based on compounds of formula Ia, Ib or Ic and preparation method thereof or . In formulae la, lb or Ic, each of R2-R6 and R9-R13 is independently selected from H, OH, straight or branched C1-C20-alkoxy groups, straight or branched C1-C20-alkyl groups.

EFFECT: obtaining compounds used as antioxidants.

14 cl, 9 ex, 3 tbl, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new etoxicombretastatines with formula (I) possessing anti-cancer activity, to a pharmaceutical composition containing the proposed compounds as well as to methods for production of some of the proposed compounds where R is a hydroxyl group, an amino group, a phosphate group selected from among disodiumphosphate or ammonium phosphate or inner salt of phosphorylcholine, -NH(COCHR'NH)m-H where R' is hydrogen, a natural amino acid side chain or a phenyl group, while m is an integer from 1 to 3.

EFFECT: production of new etoxicombretastatines possessing anti-cancer activity.

5 cl, 3 tbl, 2 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: method involves alkylation of monohydric or dihydric phenols with camphene in the presence of heterogeneous acid catalysts of sulphocationite fiban K-1 in amount of 0.1-100 wt % of the initial phenol while heating to 40-70°C for 2 hours or zeolite Z-100 in amount of 0.1-100 wt % of the initial phenol at 20°C for 48 hours, molar ratio of phenol to camphene equal to 1:1-2, respectively.

EFFECT: high output of end product.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: reaction of dichlorocarbenation of (2Z)-1,4-dialkoxybutane-2 is performed at temperature 30°C for 5 hours in presence of catamine phase transfer catalyst AB. As a rule, reaction with (2Z)-1,4-dialkoxybutane-2 is performed with the following component ratio, wt %: (2Z)-1,4-dialkoxybutane-2 2.55; chloroform 57; catamine AB 0.025; sodium hydroxide 40.425.

EFFECT: method makes it possible to obtain target products with high output with reduction of reaction time.

2 cl, 1 tbl, 2 ex

Up!