Derivatives of glycerol, means for delivering a physiologically active substance and pharmaceutical composition

 

(57) Abstract:

The aim of the invention is the creation of a lipid funds are functionally equivalent, so-called, the cationic liposome, less toxic and contain lipid or its analogue as a component of this tool. Compounds of the invention are compounds of General formula I, where R1and R2different and each represents a group-0-Y-or group - And-(CH2)n-E, where n is an integer from 2 to 4, E is pyrrolidino, piperidino, morpholino etc. or E represents a group where R3and R4-same or different and each represents a hydrogen atom, lower1- C4-alkyl, hidrogenesse - C1- C4-alkyl; a represents a group of the formula

< / BR>
R and Y are identical and each represents oleyl, or oleoyl, or, which provided that when n = 1, And cannot be a group . Means for delivering a physiologically active substance containing a phospholipid and a modifier component, and a pharmaceutical composition comprising a means for delivery of physiologically active substances, physiologically active substance and an inert diluent. 3 S. and 9 C.p. f-crystals, 2 PL.

about

The crust is not the same and each represents OY or-A-(CH2)n-E;

n represents an integer from 0 to 4;

E represents pyrrolidino, piperidino, substituted or unsubstituted, piperazine derivatives, morpholino, substituted or unsubstituted guanidino,

or

< / BR>
where

R3and R4- same or different and each represents hydrogen, lower C1-C4-alkyl, hydroxy-lower C1-C4-alkyl, or mono - or di(lower)alkylamino-alkyl, C2-C8.

A represents the following formula

< / BR>
R and Y are the same or different, and each represents a saturated or unsaturated aliphatic hydrocarbon group of from 10 to 30 carbon atoms, or a saturated or unsaturated residue of a fatty acid of 10 to 30 carbon atoms.

(However, this excludes compounds in which A represents A or above, and n = 1).

Compounds of the present invention (hereinafter referred to as compounds of the invention have wide application as a component of DDS (drug delivery system drug delivery means. The term "tool" refers to a material whose function is to transport the physiologically active substance, i.e. the media.

It is known that the tool containing the ENES in cells (for example, JP-A-4108391, W 091/17424). It is also known that when a nucleic acid as double-strand RNA is introduced together with a tool such as a cationic liposome, is the potentiation of interferon inducer (U.S. patent 5049386). It is usually assumed that since nucleic acid, for example, the gene has a negative charge, it forms a complex with a cationic liposome, and the complex merges with the cell membrane and nucleic acid or gene, or something like that, finds its way into the cell.

The specified cationic liposome, Lipofectin (trade mark, Bethesda Research Laboratories Life Technologies Inc.), containing N-[1-/2,3-dialerace/propyl] -N, N,N-trimethylammoniumchloride (hereinafter DOTMA) and dioleoylphosphatidylcholine in the ratio of 1:1 is well known.

However, as DOTMA as a component of Lipofectin is a mixture of Quaternary ammonium compounds, and, therefore, has a high hemolytic toxicity, it is not suitable for pharmaceutical use.

An attempt was made to increase the efficiency of the liposomes due to the replacement DOTMA in Lipofectin derived cholesterol (Third International Symposium on Catalytic RNAs and Targeted Gene Therapy for theatment of HIV Infection, December 6-11, 1992).

The aim of the present invention is to provide a lipid Treponema tools.

In the process of intensive research, the authors of the present invention found that the above problem can be solved by using the compound of the present invention instead DOTMA in Lipofectin, and accomplished the present invention.

One of the major distinguishing features of the present invention is the structure of the compounds of General formula (I). The compound of the present invention is a novel compound which is not described in the literature.

The compound of the present invention is structurally characterized by the fact that glycerol is the main skeleton, one of the three hydroxyl groups of glycerol substituted group of the formula-A-(CH2)n-E, where A, n and E have the above values. Another feature of the present invention is that A in the above formula A-(CH2)n-E has the following values:

< / BR>
Among the specific compounds of the present invention not one of them has an amine group substituent E in the form of Quaternary ammonium. In JP-A-4108391 indicated that the lipid containing a Quaternary ammonium group, suitable as a lipid constituting the liposome or funds, but such compounds are not suitable for the purposes of nastiashurigina, 4 isopropylpiperazine, 4-n-butylpiperazine, 4-isobutylpyrazine, 4-(2-hydroxyethyl)-piperazine derivatives, 4-(2-hydroxypropyl)piperazine derivatives and 4-(3-hydroxypropyl)piperazine derivatives along with other.

Substituted guanidino for E includes methylguanine, ethylguanidine, n-propylaniline, N, N-dimethylguanidine, N,N-diethylaniline, N,N-di-n-propylaniline, N,N'-dimethylguanidine, N,N'-diethylaniline, N,N'-di-n-propylaniline, N, N,N'-trimethylpyridine, N,N,N'-triethylamine, N,N,N'-tri-n-propylaniline, N, N, N',N'-tetramethylguanidine, N,N,N',N'-tetramethylguanidine and N,N,N',N'-Tetra-n-propylaniline along with others.

The lower alkyl for R3, R4includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert-butyl along with others.

Hydroxy/lowest/the alkyl for R3, R4includes hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and 3-hydroxypropyl along with others.

Mono - or di-(lower)acylaminoalkyl for R3, R4includes methylaminomethyl, dimethylaminomethyl, 2-(methylamino)ethyl, 2-dimethylaminoethyl, 3-(methylamino)propyl, 3-dimethylaminopropyl, ethylaminomethyl, diethylaminomethyl, 2-(ethylamino)ethyl, 2-diethylaminoethyl, 3-(ethylamino)propyl, 3-di is propylamino)propyl, and 3-(di-n-propylamino)propyl along with others.

With regard to further differences in the General formula (I), R and Y are the same or different, and each represents a saturated or unsaturated aliphatic hydrocarbon group containing from 10 to 30 carbon atoms, or a residue of a saturated or unsaturated fatty acids containing from 10 to 30 carbon atoms, as mentioned previously.

However, the preferred case when R and Y are the same and each represents an unsaturated aliphatic hydrocarbon or a residue of an unsaturated fatty acid containing from 12 to 20 carbon atoms. The most preferred case when both R and Y represent oleyl or oleoyl, for example.

Preferably, A is represented urethane or ester bond.

Compounds of the present invention are non-toxic or very low toxicity.

The compound of General formula (I) according to the method of the present invention can be obtained, along with others, in the following ways:

(1) If R1is OY, and A represents-O-C(=O)-NH-,

< / BR>
(where B is usually imidazolyl, halogen or phenoxy. The halogen may be, for example, chlorine, bromine or iodine. R, Y, E and n have the previously indicated values).

This reaction (II) and (III) can be performed using 1-3 equivalent (III) the equivalent of (II) in the presence of a solvent at 0 - 150oC for 1-20 hours as solvent in the reaction can be used dimethylformamide, pyridine, toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform, etc. To accelerate the reaction it is possible to add such basis as triethylamine. Moreover, you can first turn (III) salt of the metal, using sodium hydride, n-utility, etc. in the above solvent, and then analyze its interaction with (II).

(2) If R1is OY, and A is-NH-C/=O/-O-,

< / BR>
(where

B, R, Y, E and n have the previously indicated values).

The compound (I) of the present invention can be obtained by subjecting the interaction (IV) (V) in accordance with the above scheme, using reaction conditions similar to those in paragraph (I).

(3) If R1is OY, and A is-NH-C(=O)-O,

< / BR>
(where

R, Y, E and n have the previously indicated values).

The compound (I) of the present invention can be obtained by the communication (VI) C (III) as shown previously, using reaction conditions similar to those specified in paragraph (1).

The compound (I) of the present invention can be obtained by interaction of (IV) to (VII) as shown in the diagram above, using reaction conditions similar to the conditions specified in paragraph (1).

(5) If R1is OY, and R2is-A-(CH2)n-E

< / BR>
(where

A, E and n have the previously indicated values).

The compound (I) of the present invention can be obtained by converting the hydroxyl group of the above compounds in the group of the substituents R and Y due to the reaction with suitable allerease agents (for example, anhydrides or acid chlorides of fatty acids). This method of obtaining preferred if R and Y represent the remains of fatty acids.

(Getting starting compounds (IV), (IV'), (V), (VI), (VII) and (VIII))

(1) preparation of starting compound (IV')

The original compound (IV') can be obtained usually in accordance with the following reaction scheme:

< / BR>
(where

Tr represents trityl, Ts represents tosyl; R and Y have the previously indicated values).

(2) obtaining the starting compound (IV)

The original compound (IV) can be obtained usually as follows, which is given as an example.

Based on the compound (IV') monr> (3) obtaining the starting compound (V)

The original compound (V) in which B represents, for example, imidazolyl, can be obtained by subjecting the interaction of the compound (III') with N,N'-carbonyl diimidazol in pyridine at room temperature.

(4) obtaining the starting compound (VI)

The original compound (VI) can be obtained by the interaction of the compound (IV) with diphosgene.

(5) obtaining the starting compound (VII)

The original compound (VII) can be easily obtained in the usual reaction of the compound (III) with diphosgene, or in the interaction of the compounds of formula HOOC-(CH2)n-E (where n and E have the above meanings) with DPPA (diphenylphosphorylacetate) in the presence of a tertiary amine such as triethylamine, at temperatures from 0 to 150oC, and in addition, in the presence of a tertiary amine such as pyridine, at a temperature of from 0 to 150oC.

(6) obtaining the starting compound (VIII)

The compound (VIII), where A represents-O-C(=O)-NH-, can be obtained in accordance with the following reaction scheme

< / BR>
(where

Im represents imidazolyl).

The compound (VIII), where A is-NH-C(=O)-O-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

Im predstava)-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

DCC is dicyclohexylcarbodiimide, and DMAP is 4-N,N-dimethylaminopyridine; E and n have the previously indicated values).

The compound (VIII), where A represents-O-C(=S)-NH-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

Im represents imidazolyl).

The compound (VIII), where A is-NH-C(=O)-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

DCC is dicyclohexylcarbodiimide; E and n have the previously indicated values).

< / BR>
The compound (VIII), where A is-OSO2-NH-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

E and n have the previously indicated values).

< / BR>
The compound (VIII), where A represents-O-P(=O)(-CH3)-O-, can be obtained in accordance with the following reaction scheme:

< / BR>
where

BT is 1-benzotriazolyl.

The following is a partial list of the compounds of the present invention.

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-delwilliams,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-diminishingreturns,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-Carbamoyl-1,2-O-divinelyinspired,

3-O-/2-dimethylaminoethyl/carbarnoyl-2-O-lauryl-1-O - ministergeneral,

3-O-/2-dimethylaminoethyl/carbarnoyl-1-O-oleyl-2-O - palmitoleic,

3-O-/2-dimethylaminoethyl/carbarnoyl-1-O-linoleyl-2-O - allergycare,

3-O-/dimethylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/3-dimethylaminopropyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/4-dimethylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminopropyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-di-n-propylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diisopropylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-di-n-butylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diisobutylamine/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-di-sec.-butylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-/N-ethyl-N-methylamino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-methylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-ethylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-n-propylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-n-butylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-amino-ethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-/N-methyl-N-/2-hydroxyethyl/LineIn,

3-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-/4-methylpiperazine/ethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-morpholinoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-piperidinoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-pyrrolidinone/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/thiocarbamoyl-1,2-O-dioleoylglycerol,

3-O-/2-dimethylaminoethyl/thiocarbamoyl-1,2-0-dioleoylglycerol,

3-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/thiocarbamoyl - 1,2-0-dioleoylglycerol,

3-O-/2-pyrrolidinone/thiocarbamoyl-1,2-O-dioleoylglycerol,

3-O-/2-dimethylaminoethyl/sulfamoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/sulfamoyl-1,2-O-dioleoylglycerol,

3-O-/2-N, N-di-/2-hydroxyethyl/amino/ethyl/sulfamoyl - 1,2-O-dioleoylglycerol,

3-O-/2-pyrrolidinone/sulfamoyl-1,2-O-dioleoylglycerol,

3-O-/N,N-dimethylaminoacetyl/-1,2-O-dioleoylglycerol,

3-O-/4-dimethylaminoethanol/-1,2-O-delwilliams,

3-O-/4-Diethylaminoethanol/-1,2-O-depalletizers,

3-O-/4-dimethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-Diethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-dimethylaminoethanol butanol/-1-O-linoleyl-2-O-allergycare,

3-O-/3-dimethylaminopropionic/-1,2-O-dioleoylglycerol,

3-O-/5-dimethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-di-n-propylaminoethyl/-1,2-O-dioleoylglycerol,

3-O-/4-diisopropylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-/N-ethyl-N-methylamino/butanol/-1,2-O-dioleoylglycerol,

3-O-/4-ethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-/N-methyl-N-/2-hydroxyethyl/amino/butanol/-1,2-O - dioleoylglycerol,

3-O-/4-/N,N-di-/2-hydroxyethyl/amino/butanol/-1,2-O - dioleoylglycerol,

3-O-/4-/N-/2-diethylamino/ethyl-N-methylamino/butanol/-1,2-O - dioleoylglycerol,

3-O-/4-/4-methylpiperazine/butanol/-1,2-O-dioleoylglycerol,

3-O-/4-morpholinomethyl/-1,2-O-dioleoylglycerol,

3-O-/4-pyrrolidineethanol/-1,2-O-dioleoylglycerol,

3-O-/4-piperidinemethanol/-1,2-O-dioleoylglycerol,

O-/2-diethylaminoethyl/-O'-/2,3-valeronitrile/methylphosphonate,

O-/2-dimethylaminoethyl/-O'-/2,3-valeronitrile/methylphosphonate,

O-/2-/N, N-di/2-hydroxyethyl/amino/ethyl/-O'-/2,3 - valeronitrile/methylphosphonate,

O-/2-pyrrolidinone/-O'-/2,3-valeronitrile/methylphosphonate,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-dilauroyllecithin,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-dimyristoyl,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-d/carbarnoyl-1,2-O-tylenoltylonel,

3-O-/2-dimethylaminoethyl/carbarnoyl-1-O-oleoyl-2-O - palmitoylated,

3-O-/2-dimethylaminoethyl/carbarnoyl-1-O-linoleyl-2-O - reorgnization,

3-O-/3-dimethylaminopropyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-di-n-propylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diisopropylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O/2-/N-ethyl-N-methylamino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-ethylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-/N-methyl-N-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl/carbarnoyl-1,2-O - dioleoylglycerol,

3-O-/2-piperidinoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-pyrrolidinone/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-amino-ethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/thiocarbamoyl-1,2-O-dioleoylglycerol,

3-O-/2-dimethylaminoethyl/thiocarbamoyl-1,2-O-dioleoylglycerol,

3-O-/2-/-N, N-di-/2-hydroxyethyl/amino/ethyl/thiocarbamoyl - 1,2-O-dioleoylglycerol,

3-O-/2-pyrrolidinone/thiocarbamoyl-1,2-O - dioleoylglycerol,

3-O-/2-diethylamino-N, N-di-/2-hydroxyethyl/amino/ethyl/sulfamoyl-1,2-O - dioleoylglycerol,

3-O-/2-pyrrolidinone/sulfamoyl-1,2-O-dioleoylglycerol,

3-O-/4-dimethylaminoethanol/-1,2-O-dilauroyllecithin,

3-O-/4-dimethylaminoethanol/-1,2-O-dimyristoyl,

3-O-/4-dimethylaminoethanol/-1,2-O-dipalmitoyl,

3-O-/4-dimethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-dimethylaminoethanol/-1,2-O-tylenoltylonel,

3-O-/4-dimethylaminoethanol/-1-O-oleoyl-2-O-palmitoylated,

3-O-/4-dimethylaminoethanol/-1-O-linoleyl-2-O-reorgnization,

3-O-/3-dimethylaminopropionic/-1,2-O-dioleoylglycerol,

3-O-/5-dimethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-Diethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-di-n-propylaminoethyl/-1,2-O-dioleoylglycerol,

3-O-/4-diisopropylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-/N-ethyl-N-methylamino/butanol/-1,2-O-dioleoylglycerol,

3-O-/4-ethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/4-/N-methyl-N-/2-/hydroxyethyl/amino/butanol/- 1,2-O-dioleoylglycerol,

3-O-/4-/N,N-di-/2-hydroxyethyl/amino/butanol/1,2-O - dioleoylglycerol,

3-O-/4-/N-/2-diethylamino/ethyl-N-methylamino/butanol/- 1,2-O-dioleoylglycerol,

3-O-/4-pyrrolidineethanol/-1,2-dioleoylglycerol,

O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/-O'-/2,3 - dioleoylglycerol/methylphosphonate,

O-/2-pyrrolidinone/-O'-/2,3-dioleoylglycerol/methylphosphonate,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-delwilliams,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-diminishingreturns,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-depalletizers,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-divinelyinspired,

2-O-/2-dimethylaminoethyl/carbarnoyl-1-O-lauryl-3-O - ministergeneral,

2-O-/2-dimethylaminoethyl/carbarnoyl-1-O-oleyl-3-O - palmitoleic,

2-O-/2-dimethylaminoethyl/carbarnoyl-1-O-linoleyl-3-O - allergycare

2-O-/3-dimethylaminopropyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/4-dimethylaminomethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-di-n-propylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-diisopropylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-di-n-butylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-diisobutylamine/-carbarnoyl-1,3-dioleoylglycerol,

2-O-/2-di-sec.-butylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N-ethyl-N-methyl/aminoacyl/carbarnoyl-1,3-O - dio is ilargiaren,

2-O-/2-n-propylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-butylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-amino-ethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N-methyl-N-/2-hydroxyethyl/amino/ethyl/carbarnoyl - 1,3-O-dioleoylglycerol,

2-O-/2-/N-ethyl-N-/2-hydroxyethyl/amino/ethyl/carbarnoyl - 1,3-O-dioleoylglycerol,

2-O-/2-/N,N-di-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,3 - O-dioleoylglycerol,

2-O-/2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl/carbarnoyl-1,3 - O-dioleoylglycerol,

2-O-/2-/4-methylpiperazine/ethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-morpholinoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-piperidinoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-pyrrolidinone/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/thiocarbamoyl - 1,3-O-dioleoylglycerol,

2-O-/2-pyrrolidinone/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/sulfamoyl-1,3-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/sulfamoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/sulfamoyl - 1,3-O-dioleoylglycerol,

2-O-/2-pyrrolidinone/sulfamoyl-1,3-O is polymethylpentene,

2-O-/4-dimethylaminoethanol/-1,3-O-divinelyinspired,

2-O-/4-dimethylaminoethanol/-1-O-oleyl-3-O-palmitoleic,

2-O-/4-dimethylaminoethanol/-1-O-linoleyl-3-O-allergycare,

2-O-/3-dimethylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/5-dimethylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-di-n-propylaminoethyl/-1,3-O-dioleoylglycerol,

2-O-/4-diisopropylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-/N-ethyl-N-methyl/aminobutanol/-1,3-O-dioleoylglycerol,

2-O-/4-ethylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-/N-methyl-N-/2-hydroxyethyl/amino/butanol/-1,3-O-dioleoylglycerol,

2-O-/4-/N,N-di-/2-hydroxyethyl/amino-butanoyl/-1,3-O-dioleoylglycerol,

2-O-/4-/N-/2-diethylamino/ethyl-N-methylamino/butanol/- 1,3-O-dioleoylglycerol,

2-O-/4-/4-methylpiperazine/butanol/-1,3-O-dioleoylglycerol,

2-O-/4-morpholinomethyl/-1,3-O-dioleoylglycerol,

2-O-/4-pyrrolidineethanol/-1,3-O-dioleoylglycerol,

2-O-/4-piperidinemethanol/-1,3-O-dioleoylglycerol,

O-/2-diethylaminoethyl/-O'-/1-3-valeronitrile/methylphosphonate,

O-/2-dimethylaminoethyl/-O'-/1-3-dioperasikan-2-yl/methylphosphonate,

O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/-O'-/1-3 - dioperasikan-2-yl/methylphosphonate,

O-/2-pyrrolidinone/-O'-/1-3-valeronitrile/carbarnoyl-1,3-O-dimyristoyl,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-dipalmitoyl,

2-O-/2-diethylaminoethyl/carbarnoyl-1,3-O-dipalmitoyl,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/carbarnoyl-1,3-O-tylenoltylonel,

2-O-/2-dimethylaminoethyl/carbarnoyl-1-O-oleoyl-3-O-palmitoylated,

2-O-/2-dimethylaminoethyl/carbarnoyl-1-O-linoleyl-3-O-reorgnization,

2-O-/dimethylaminomethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/3-dimethylaminopropyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-di-n-propylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-diisopropylaminoethyl/carbarnoyl-1,3-dioleoylglycerol,

2-O-/2-/N-ethyl-N-methylamino/ethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N-methyl-N-n-butylamino/ethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-ethylaminomethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N, N-di-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,3-O - dioleoylglycerol,

2-O-/2-/N-methyl-N-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,3-O - dioleoylglycerol,

2-O-/2-/N-ethyl-N-/2-hydroxyethyl/amino/ethyl/carbarnoyl-1,3-O - dioleoylglycerol,

2-O-/2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl/carbarnoyl-1,3-O-dioleoylglycerol,

dioleoylglycerol,

2-O-/2-piperidinoethyl/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-pyrrolidinone/carbarnoyl-1,3-O-dioleoylglycerol,

2-O-/2-/4-ethylpiperazine/ethyl/-carbarnoyl-1,3-dioleoylglycerol,

2-O-/2-/4-/2-hydroxyethyl/piperazine derivatives/ethyl/-carbarnoyl-1,3-O - dioleoylglycerol,

2-O-/2-diethylaminoethyl/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-/N,N-di-/2-hydroxyethyl/amino/ethyl/thiocarbamoyl-1,3-O - dioleoylglycerol,

2-O-/2-pyrrolidinone/thiocarbamoyl-1,3-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/sulfamoyl-1,3-O-dioleoylglycerol,

2-O-/2-dimethylaminoethyl/sulfamoyl-1,3-O-dioleoylglycerol,

2-O-/2-N,N-di-/2-hydroxyethyl/aminoacyl/sulfamoyl-1,3-O - dioleoylglycerol,

2-O-/pyrrolidinyl/sulfamoyl-1,3-O-dioleoylglycerol,

2-O-/3-diethylaminopropyl/-1,3-O-dioleoylglycerol,

2-O-/4-dimethylaminoethanol/-1,3-O-dilauroyllecithin,

2-O-/4-dimethylaminoethanol/-1,3-O-dimyristoyl,

2-O-/4-dimethylaminoethanol/-1,3-O-dipalmitoyl,

2-O-/4-dimethylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-dimethylaminoethanol/-1,3-O-tylenoltylonel,

2-O-/4-dimethylaminoethanol/-1-O-oleoyl-3-O-palmitoylated,

2-O-/4-dimethylaminomethylphenol/-1,3-O-dioleoylglycerol,

2-O-/4-Diethylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-di-n-propylaminoethyl/-1,3-O-dioleoylglycerol,

2-O-/4-diisopropylaminoethanol/-1,3-O-dioleoylglycerol,

2-O-/4-/N-ethyl-N-methylamino/butanol/-1,3-O-dioleoylglycerol,

2-O-/4-/ethyl/aminobutanol/-1,3-O-dioleoylglycerol,

2-O-/4-/N-methyl-N-/2-hydroxyethyl/amino/butanol/-1,3-O - dioleoylglycerol,

2-O-/4-/N,N-di-/2-hydroxyethyl/amino/butanol/-1,3-O - dioleoylglycerol,

2-O-/4-/N-/2-diethylamino/ethyl-N-methylamino/butanol/- dioleoylglycerol 1,3-O-dioleoylglycerol,

2-O-/4-pyrrolidineethanol/-1,3-O-dioleoylglycerol,

O-/2-dimethylaminoethyl/-O'-/1,3-dioleoylglycerol-2-yl/-methylphosphonate,

O-/2-amino-ethyl-O'-/1,3-dioleoylglycerol-2-yl/methylphosphonate,

O-/2-diethylaminoethyl/-O'-/1,3-dioleoylglycerol-2-yl/-methylphosphonate,

2-dimethylaminoethyl-N-/2,3-delawarelexapro/carbamate,

2-dimethylaminoethyl-N-/2,3-demonstratsiya/carbamate,

2-dimethylaminoethyl-N-/2,3-dioleoylglycerol/carbamate,

2-dimethylaminoethyl-N-/2,3-divinelyinspired/carbamate,

2-dimethylaminoethyl-N/2-laurenoxe-3-linolelaidic/carbamate,

2-dimethylaminoethyl-N-/3-ministroke-2-oleraceae/carbamate,

3-dimethylaminopropyl-N-/2,3-valeronitrile/carbamate,

2-di-n-propylaminoethyl-N-/2,3-valeronitrile/carbamate,

2-di-n-butylaminoethyl-N-/2,3-valeronitrile/carbamate,

2-ethylmethylamino-N-/2,3-valeronitrile/carbamate,

2-/N-ethyl-N-methylamino/ethyl-N-/2,3-valeronitrile/carbamate,

2-ethylaminomethyl-N-/2,3-valeronitrile/carbamate,

2-n-propylaminoethyl-N-/2,3-valeronitrile/carbamate,

2-/N-methyl-N-/2-hydroxyethyl/amino/ethyl-N-/2,3-valeronitrile/ carbamate,

2-/N-ethyl-N-/2-hydroxyethyl/amino/ethyl-N-/2,3-valeronitrile/ carbamate,

2-/N,N-di-/2-hydroxyethyl/amino/ethyl-N-/2,3-valeronitrile/ carbamate,

2-/N-/2-diethylamino/-ethyl-N-methylamino/-ethyl-N-/2,3-valeronitrile/ carbamate,

2-/4-methylpiperidino/ethyl-N-/2,3-valeronitrile/carbamate,

2-morpholinoethyl-N-/2,3-valeronitrile/carbamate,

2-piperidinoethyl-N-/2,3-valeronitrile/carbamate,

2-pyrrolidinyl-N-/2,3-valeronitrile/carbamate,

2-dimethylaminoethyl-N-/2,3-valeronitrile/THIOCARBAMATE,

2-diethylaminoethyl-N-/2,3-valeronitrile/THIOCARBAMATE,

2-/N, N-di-/2-hydroxyethyl/amino/ethyl-N-/2,3-valeronitrile/ THIOCARBAMATE,

2-pyrrolidinyl-N-/2,3-valeronitrile/THIOCARBAMATE,

2-dimethylaminoethyl-N-/2,3-valeronitrile/sulfanilamide/sulpham,

2-pyrrolidinyl-N-/2,3-valeronitrile/sulpham,

N-/2,3-dialerace/propyl-4-dimethylaminobutyric,

N-/2,3-dialerace/propyl-4-diethylaminoethylamine,

N-/2,3-dialerace/propyl-4-/N,N,-di/2-hydroxyethyl/- amino/butylamide,

N-/2,3-dialerace/propyl-4-pyrrolidinedione,

2-dimethylaminoethyl-N-/2,3-dilauroyllecithin/carbamate,

2-dimethylaminoethyl-N-/2,3-demeritorious/carbamate,

2-dimethylaminoethyl-N-/2,3-dipalmitoylphosphatidyl/carbamate,

2-dimethylaminoethyl-N-/2,3-dioleoylglycerol/carbamate,

2-dimethylaminoethyl-N-/2,3-tylenolrisperdal/carbamate,

2-dimethylaminoethyl-N/2-oleolux-3-palmitoylation/ carbamate,

2-dimethylaminoethyl-N/2-linolenate-3-aeolotropic/ carbamate,

2-diethylaminoethyl-N-/2,3-dioleoylglycerol/carbamate,

3-dimethylaminopropyl-N-/2,3-dioleoylglycerol/carbamate,

2-diisopropylaminoethyl-N-/2,3-dioleoylglycerol/carbamate,

2-di-n-propylaminoethyl-N-/2,3-dioleoylglycerol/carbamate,

2-/N-ethyl-N-methylamino/ethyl-N-/2,3-dioleoylglycerol/carbamate,

2-ethylaminomethyl-N-/2,3-dioleoylglycerol/carbamate,

2-/-N-methyl-N-/2-hydroxyethyl/amino/ethyl-N-/2,3-dioleoylglycerol/ carbamate,

2-/N,N-di/2-HYDR shall velociprey/carbamate,

2-piperidinoethyl-N-/2,3-dioleoylglycerol/carbamate,

2-pyrrolidinyl-N-/2,3-dioleoylglycerol/carbamate,

2-amino-ethyl-N-/2,3-dioleoylglycerol/carbamate,

2-dimethylaminoethyl-N-/2,3-dioleoylglycerol/THIOCARBAMATE,

2-diethylaminoethyl-N-/2,3-dioleoylglycerol/THIOCARBAMATE,

2-/N, N-di/2-hydroxyethyl/aminoethyl-N-/2,3-dioleoylglycerol/ THIOCARBAMATE,

2-pyrrolidinyl-N-/2,3-dioleoylglycerol/THIOCARBAMATE,

2-dimethylaminoethyl-N-/2,3-dioleoylglycerol/sulpham,

2-diethylaminoethyl-N-/2,3-dioleoylglycerol/sulpham,

2-/N,N-di/2-hydroxyethyl/aminoethyl-N-/2,3-dioleoylglycerol/ sulpham,

2-pyrrolidinyl-N-/2,3-dioleoylglycerol/sulpham,

N-/2,3-tileorassi/propyl-4-dimethylaminobutyric,

N-/2,3-tileorassi/propyl-4-diethylaminoethylamine,

N-/2,3-tileorassi/propyl-4-/N,N-di-/2-hydroxyethyl/-amino/ butylamide,

N-/2,3-tileorassi/propyl-4-pyrrolidinedione,

2-dimethylaminoethyl-N-/1,3-delayedaction-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-demonstration-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-divinelyinspired-2-yl/carbamate,

2-dimethylaminoethyl-N-/1-Laurila is at,

2-dimethylaminoethyl-N-/1-oliloqui-3-palmitoylation-2 - yl/carbamate,

3-dimethylaminopropyl-N-/1,3-dioperasikan-2-yl/carbamate,

4-dimethylaminomethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-diethylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-di-n-propylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-di-n-butylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-/N-ethyl-N-methylamino/ethyl-N-/1,3-dioperasikan-2-yl/ carbamate,

2-methylaminomethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-ethylaminomethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-n-propylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-n-butylamino-N-/1,3-dioperasikan-2-yl/carbamate,

2-N-methyl-N-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-N-ethyl-N-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-/N, N-di-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioperasikan-2 - yl/carbamate,

2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl-N-/1,3 - dioperasikan-2-yl/ carbamate,

2-/4-methylpiperidino/ethyl-N-/1,3-dioperasikan-2-yl/- carbamate,

2-piperidinoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-pyrrolidinyl-N-/1,3-dioperasikan-2-yl/carbamate,
is-2-yl/THIOCARBAMATE,

2-/N,N-di-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioperasikan-2-yl/ THIOCARBAMATE,

2-pyrrolidinyl-N-/1,3-dioperasikan-2-yl/THIOCARBAMATE,

2-dimethylaminoethyl-N-/1,3-dioperasikan-2-yl/sulpham,

2-diethylaminoethyl-N-/1,3-dioperasikan-2-yl/sulpham,

2-/N, N-di-/2-hydroxyethyl, amino/ethyl-N-/1,3-dioperasikan - 2-yl/sulpham,

2-pyrrolidinyl-N-/1,3-dioperasikan-2-yl/sulpham,

N-/4-dimethylaminoethanol/-1,3-dialerace-1-amino-propane,

N-/4-dimethylaminoethanol/-1,3-dialerace-1-amino-propane,

N-/4-/N, N-di-/2-hydroxyethyl/amino/butanol/-1,3 - dialerace-1-amino-propane,

N-4-pyrrolidineethanol-1,3-dialerace-1-amino-propane,

2-diethylaminoethyl-N-/1,3-dilauroyllecithin-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-genericcollection-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-dipalmitoylphosphatidyl-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-dioperasikan-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-tylenolacetaminophen-2-yl/ carbamate,

2-dimethylaminoethyl-N-/1-oleolux-3-palmitoylation - 2-yl/carbamate,

2-dimethylaminoethyl-N-/1-linolenate-3-aeolotropy - 2-yl/carbamate,

2-diethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,
2-di-n-propylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,

2-/N-ethyl-N-methylamino/ethyl-N-/1,3-dioleoylglycerol - 2-yl/carbamate,

2-ethylaminomethyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,

2-/N-methyl-N-/-2-hydroxyethyl/amino/ethyl-N-/1,3 - dioleoylglycerol-2-yl/carbamate,

2-/N, N-di-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioleoylglycerol - 2-yl/carbamate,

2-/N-/2-diethylamino/ethyl-N-methylamino/ethyl-N-/1,3 - dioleoylglycerol-2-yl/carbamate,

2-piperidinoethyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,

2-pyrrolidinyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,

2-amino-ethyl-N-/1,3-dioleoylglycerol-2-yl/carbamate,

2-dimethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/ THIOCARBAMATE,

2-diethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/ THIOCARBAMATE,

2-/N, N-di-/2-hydroxyethyl/amino/ethyl-N-/1,3-tileorasi - propan-2-yl/THIOCARBAMATE,

2-pyrrolidinyl-N-/1,3-dioleoylglycerol-2-yl/ THIOCARBAMATE,

2-dimethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/sulpham,

2-diethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/sulpham,

2-/N, N-di-/2-hydroxyethyl/amino/ethyl-N-/1,3-dioleoylglycerol - 2-yl/sulpham,

2-pyrrolidinyl-N-/1,3-dioleoylglycerol-2-yl/sulpham,

N-/2,3-tileorassi/propyl-4-dimetilan hydroxyethyl/- amino/-butylamide/

N-/2,3-tileorassi/propyl-4-pyrrolidinedione.

Among the compounds of the present izobreteniya are preferred:

3-O-/4-dimethylaminoethanol/-1,2-O-dioleoylglycerol,

3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

3-O-/2-diethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol,

2-O-/2-diethylaminoethyl/carbarnoyl-1,3-O-dioleoylglycerol etc.

The most preferred 3-O-/2-diethylaminoethyl/carbarnoyl - 1,2-O-dioleoylglycerol.

Another another object of the invention is a preparation containing the compound (I) of the present invention and a phospholipid, and having a function DDS.

Oil containing means having a function of DDS, liposomes and lipid emulsions are known. The same tool with the function of the DDS according to the method of the present invention (hereinafter referred to as the tool of the present invention), belongs to the category of such assets.

The tool of the present invention may take various forms, such as lipid suspension, liposome, etc. only if it has the ability to transport the physiologically active substance in the cell.

The phospholipid, as a component of the tool of the present invention, may, for example, byclostridium tool of the present invention is about 0.1:9,9-9,9-0,1 (compound of the present invention: a phospholipid (molar ratio), preferably 1:9 - (9: 1) (the compound of the present invention: phospholipid/molar ratio)), and most preferably from 1: 3 to 3:1 (compound of the present invention: a phospholipid (molar ratio)).

The tool of the present invention can be obtained, for example, in the following way.

The tool of the present invention can be obtained by simply mixing the compound of the present invention with a phospholipid in the presence of water. It is possible to obtain a method which comprises dissolving the compound of the present invention and phospholipid in chloroform, careful removal of the chloroform in the atmosphere of nitrogen gas, stirring the mixture with the addition of water and processing of ultrasound in a few minutes.

Another object of the present invention is a pharmaceutical composition comprising the tool of the present invention and a physiologically active substance.

As mentioned earlier, even if the substance shows a high extracellular physiological activity cannot be fully expect the same activity, if its ability to penetrate the cell is low, which requires an increase in dose. At the present state of knowledge for this reason, many of the barb, but, unfortunately, the loss from the point of view of preserving the health of the nation.

However, if you write them with the tool of the present invention, even physiologically active substance with a weak ability to penetrate into cells can penetrate into cells with remarkable ease, and to demonstrate its activity effectively. This means you can return to the use of drugs, which still remained undiluted.

Therefore, the pharmaceutical composition obtained by the method of the present invention (hereinafter referred to as the compositions of the present invention can be widely used in industry, and in terms of preserving the health of the nation.

The tool of the present invention can be applied with physiologically active substances which are effective from the standpoint of penetration into the cells. Even if physiologically active substance with good intracellular permeability injected with the tool of the present invention, is implemented to further increase penetration into the cell and, consequently, the dose can be reduced and eliminated, thereby, the risk of side effects.

Physiologically AK is nonnie connection antitumor agents, antiviral agents and antibiotics, along with others. More specifically, it may be such compounds are nucleic acids, as double-strand RNA and double-strand or Trenitalia antisense nucleic acid, such acid sugars, as heparansulfate and textresult, cytokinins, such secondary messengers like cyclic AMP, ATP and IP3the penicillins and cephalosporins, vitamins such as vitamin C and retinol, other famous containing acid groups of drugs, interferons (,,), , interleukins (IL-1, IL-2), colony-stimulating factors (CSF), tumor necrosis factor (TSF), levamisole, bestatin, retinoic acid, 5-fluorouracil inside the body (5-FU), citizenoriented (Ara-C), adrenalised (Ara-A), cisplatin (CDDP), cyclophosphamide, azidothymidine (AZT), along with others.

Double-strand RNA include, but are not limited to) the following connections:

(1) Complexes of homopolymer-homopolymer

1. Basically-modified

Polyinosine acid - policitally acid

Polyinosine acid-poly/5-branitelja acid).

Polyinosine acid-poly/2-thiocytidine acid/.

Poly/7-easeinsine acid/-policitally acid.

Complexes of homopolymer-copolymer

Polyinosine acid-poly(Citadella acid-pridelava acid).

Polyinosine acid-poly(Citadella acid-4-toritilla acid).

(3) Complexes of synthetic nucleic acid-polycation

Polyinosine acid-policitally acid-poly-L-lysine.

(4) Other

Polyinosine acid-poly(1-venicetimisoara acid).

The antisense nucleic acid include (but are not limited to) natural nucleic acids and their derivatives such as nucleic acids containing methylphosphonate phosphorothioate or phosphorodithioate group as internal communication, and their derivatives.

The weight ratio of the means of the present invention and the physiologically active substance is preferably 1:0.1 to 1:10 (the tool of the invention: a physiologically active substance).

The composition of the present invention can be obtained by adding a physiologically active substance to the tool of the present etiologichesky active substance in the process of obtaining means of the present invention.

The composition of the present invention, preferably administered in unit dosage form and can be applied to animals, including humans, by intravenous, intra-arterial, oral, interstitial, local (e.g., transdermal or rectal route of administration. The most preferred intravenous, intra-arterial and local introduction. Naturally, the composition is administered in a dose forms suitable for the appropriate route of administration, such as injections, eye drops, ointments, suppositories, etc.

Although the dosage of the compositions of the present invention as a drug, preferably, determined based on the type of active ingredient, dosage form, such patient characteristics as age and weight, route of administration, nature and severity of the disease, and so on, the usual dose for adults is 0.1 mg - 10 g /day/ person, preferably 1 mg to 500 mg /day/ person per active ingredient. In some cases, may be sufficient to lower doses, whereas in other cases the higher doses. These doses can be entered in several divided doses or with intervals of a few days.

The following example is Obtaining 1,2-O-dioleoylglycerol

(1) In 50 ml of pyridine is dissolved 4.6 g (50 mmol) of glycerol followed by the addition of 13.9 g (50 mmol) of Fritillaria, and the resulting mixture was stirred at room temperature overnight. Then the reaction mixture was concentrated under reduced pressure and the residue diluted with water and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatographic column (silica gel/chloroform-methanol) to obtain 9.5 g (59%) of 1-O-tritylglycine.

(2) In 120 ml of xylene was dissolved 3,22 g (10 mmol) 1-O-tritylglycine, then add to 3.36 g (30 mmol) of tert-butoxylate in argon atmosphere. After 5 min stirring was added dropwise 30 ml of a solution of 12.8 g (30 mmol) reipertswiller in acid, and the resulting mixture is stirred under reduced pressure (20-30 mm RT. Art.) at room temperature for 30 min and then at 50oC for 1 h Then the reaction mixture was poured into a mixture of ice and water, extracted with ether and the extract obtained was washed with water, dried and concentrated. The residue is purified through column chromatography (silica gel/n-hexane-ethyl acetate) to obtain 6,10 g (73%) of 1,2-O-dioleoyl-3-O-tritylglycine.

(2) 1,2-O-dioleoyl-3-O-tricylen/ at room temperature for 1 h Then the organic layer was washed with saturated aqueous sodium bicarbonate and water, dried and concentrated. The residue is purified through column chromatography (silica gel/chloroform) to obtain 3.75 g (87%) specified in the title compound.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz, CH3x2), 1,14-1,44 (44H, m, CH3x2), 1,48 by 1.68 (4H, m, OCH2CH2x2), 1,90-2,10 (8H, m, CH= CHCH2x4), 3,38-of 3.78 (9H, m, OCH2x4 and OCH), 5,26-of 5.45 (4H, m, CH=SNH).

Mass spectrum bombarded with fast electrons: 593(M+H)+.

Comparative example 2:

Obtain 2,3-valeronitrile

(1) To a mixture of 1.00 g (1.7 mmol) of 1,2-O-dioleoylglycerol, or 0.83 g (17 mmol) of lithium azide, 0,89 g (3.4 mmol) of triphenylphosphine and 1.13 g (3.4 mmol) chetyrehpostovye carbon add 10 ml of N,N-dimethylformamide in the bulb, and the resulting mixture was stirred at room temperature for 3 hours After completion of the reaction the solvent is distilled off and the residue is diluted with water and extracted with ether. The ether layer is washed with water, dried and concentrated, and the resulting residue is purified through column chromatography (silica gel/n-hexane-ethyl acetate) to obtain of 1.03 g (100%) of 2,3-valeronitrile in the form of butter.

IR (pure) cm-1: 2920, the suspension under ice cooling, was added dropwise to 1.03 g (1.7 mmol) of 2,3-valeronitrile, and the resulting mixture is stirred for 30 minutes and Then the resulting mixture was stirred at room temperature for another 2 hours After completion of the reaction, the reaction mixture was poured into ice water and extracted with ether and the extract washed with water, dried and concentrated. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 0,98 g (98%) specified in the title compounds as colorless oils.

1H-NMR (200 MHz, CDCl3) : 0,88/6H, t, J = 6 Hz, CH3x2), 1,17-1,45 (44H, m, CH2h), 1,48 is 1.70 (4H, m, OCH2SNH), 1,90-2,14 (8H, m, CH=CHCH2x4), 2,64-only 2.91 (2H, m, NCH2), 3,30-of 3.78 (9H, m, OCH2X3 and OCH), a 5.25-5,46 (4H, m, CH=SNH)

Mass spectrum bombarded with fast electrons): 592 (M+H)+.

Comparative example 3:

Obtaining 1,3-O-dioleoylglycerol

(1) dissolved In pyridine and 1.00 g (11 moles) of glycerol and 2,96 g /43 mmol of imidazole, and carry out azeotropic distillation. The resulting residue is dissolved in 15 ml of N, N-dimethylformamide. To this solution under ice cooling type of 3.60 g (24 mmol) of tributyltinchloride, and the resulting mixture was stirred at room temperature for 5 hours After completed the rum sodium bicarbonate. It is dried and concentrated to obtain of 3.45 g (99%) 1,3-O-di/tert-butyldimethylsilyl/glycerin.

(2) dissolved In dioxane of 3.45 g (11 mmol) of 1,3-O-di/tert-butyldimethylsilyl/glycerol followed by the addition 3.03 g /12 mmol pyridine-para-toluensulfonate. To this suspension is added to 16.5 ml (22 mmol) of dihydropyran gradually under ice cooling, and the mixture was stirred for 1 h After warming to room temperature, the mixture is left to react overnight. After completion of the reaction the solvent is distilled off and the residue is treated with methylene chloride and saturated aqueous sodium bicarbonate. Methylenchloride layer washed with water, dried and concentrated to obtain 4,25 g (100%) of 1,3-O-di/tert-butyldimethylsilyl/2-O-tetrahydrofurfurylamine.

(3) To a solution of 4.25 g (11 mmol) of 1,3-O-di/tert-butyl-dimethylsilane/2-O-tetrahydrofurfurylamine in 30 ml of tetrahydrofuran, add 30 ml of Tetra-n-butylammonium (1 mol/l in THF) dropwise and the resulting mixture was stirred at room temperature for 2 h Then the reaction mixture was concentrated, and the residue is treated on a chromatographic column /silica gel/methylene chloride-methanol to obtain 1.70 g (96%) 2-O-tetrahydrofuranyl is 1.78 g (15.9 mmol) tert-butoxylate in an argon atmosphere, and the resulting mixture stirred for 5 minutes Then added dropwise 10 ml of a solution of 6.71 g (15.9 mmol) Olaylar-toluensulfonate in xylene, and the mixture was stirred under reduced pressure (20-30 mm RT.CT.) at room temperature for 30 min, and 1 h at 50oC. the Reaction mixture was poured into a mixture of ice and water, extracted with ether, and the extract obtained was washed with water, dried and concentrated. The residue is purified through column chromatography (silica gel/chloroform) to obtain 628 mg (18%) of 1,3-O-dioleoyl-2-O-tetrahydrofurfurylamine in the form of a yellow oil.

(5) In 30 ml of tetrahydrofuran is dissolved 628 mg (0.95 mmol) of 1,3-O-dioleoyl-2-O-tetrahydrofurfurylamine, and then add 5 ml of dilute (10%) hydrochloric acid, and the resulting mixture is stirred over night. Then the reaction mixture is diluted with water, neutralized with saturated aqueous sodium bicarbonate solution and extracted with ether. The obtained extract is dried and concentrated, and the residue is treated through column chromatography (silica gel/n-hexane-ethyl acetate) to obtain 321 ml (57%) specified in the title compounds as colorless oils.

1H-NMR (200 MHz, CDCl3) : 0,88/6H, t, J = 6 Hz, CH3x2), 1,14-1,26 (44H, m, CH2h), 1,49 by 1.68 (P CLASS="ptx2">

Mass spectrum bombarded with fast electrons 593 (M+H)+.

Comparative example 4:

Obtaining 1,3-dialerace-2-Propylamine

(1) In 5 ml of pyridine was dissolved 150 mg (0.25 mmol) of 1,3-O-dioleoylglycerol followed by the addition of 77 mg (0.40 mmol) of para-toluensulfonate, and the resulting mixture is heated at 60oC, and stirred for 2 days. After completion of the reaction the solvent is distilled off and the residue is diluted with water and extracted with ether. The obtained extract is dried and concentrated to obtain 150 mg (80%) of 1,3-O-dioleoyl-2-O-(para-toluensulfonyl)of glycerol in the form of a yellow oil.

(2) a Mixture of 150 mg (80%) was obtained 1,3-O-dioleoyl-2-O-(para-toluensulfonyl)glycerol, 30 mg (0.6 mmol) of lithium azide and 5 ml of N,N-dimethylformamide was stirred at 100oC for 2 hours After cooling, the solvent is distilled off and the residue is diluted with water and extracted with ether. The extract obtained was washed with water and concentrated to obtain 125 mg (99%) 1,3-dioleoyl-hydroxy-2-propylated in the form of butter a light brown color.

(3) In 3 ml of tetrahydrofuran suspended 8 mg (0.2 mmol) of sociallyengaged. Upon cooling the slurry with ice to it was added dropwise 125 mg (0.2 mmol) of 1,3-dialerace-2-propylated, the water, and extracted with ether. The extract obtained was washed with water, dried and concentrated. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 104 mg (89%) specified in the title compounds as colorless oils.

Comparative example 5:

Obtaining 1,2-O-dioleoylglycerol

(1) In pyridine was dissolved 1 g (to 0.011 moles) of glycerol and carry out azeotropic distillation. The residue is dissolved in 30 ml of pyridine, then add of 4.05 g (0,012 mol) of dimethoxytrityl while cooling with ice. Then the resulting mixture is stirred over night at room temperature. After completion of the reaction, add 5 ml of methanol, and the mixture was stirred for 30 min, by the end of this time the solvent is distilled off. To the residue add methylene chloride, and the resulting mixture washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue is treated through column chromatography (silica gel/methylene chloride-methanol, 0.1% pyridine) to obtain 2.58 g (60,2%) of 1-O-dimethoxymethylsilane.

(2) thus Obtained 1-O-dimethoxytrityl, 290 mg (0,735 mmol) azeotropic distillation with pyridine, and the residue is dissolved in 5 ml of pyridine. Then, when the cooling ldii the solvent is distilled off under reduced pressure, and the residue is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue is treated through column chromatography (silica gel/n-hexane-methylene chloride to obtain 519 mg (76,5%) of 1-O-dimethoxytrityl-2,3-O-dioleoylglycerol.

1H-NMR (60 MHz, CDCl3) : 0,88 (6H, m), 1.27mm (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 3,10-3,30 (2H, m), with 3.79 (6H, s), 4,20-4,20 (2H, m), 5,10-5,50 (5H, m), 6,70-7,40 (13H, m).

(3) Obtained 1-O-dimethoxytrityl-2,3-O-dioleoylglycerol, 218 mg (0,236 mmol) dissolved in 10 ml of 5% formic acid-methylene chloride, and the reaction of the lead within 10 minutes the Reaction mixture is then neutralized with a saturated aqueous solution of sodium bicarbonate, and the organic layer washed with further saturated aqueous sodium bicarbonate, dried and concentrated. The residue is treated through column chromatography (silica gel/n-hexane-methylene chloride-methanol) to obtain 100 mg (68,0%) specified in the title compound.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t), J = 6.0 Hz), 1.28 (in 40H cm.with. ), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,28-to 2.40 (2H, m), and 3.72 (2H, d, J = 6 Hz), 4,10-and 4.40 (2H, m), 5,00-5,12 (1H, m), and 5.30-of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 621 (M+H)+.

Comparative example 6:

glicerina, then add 8,82 g (0,028 mole) of reorganiza while cooling with ice. The reaction is carried out at 50oC for 15 hours After completion of the reaction the solvent is distilled off and the residue is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The result is 1,3-O-dioleoyl-2-O-/tert-butyldimethylsilyl/glycerin.

(2) To 1,3-O-dioleoyl-2-O-(tert-butyldimethylsilyl/add glycerin 266 ml of 0.1 M Tetra-n-butylammonium-tetrahydrofuran, and the reaction is carried out at room temperature for 30 minutes After completion of the reaction the solvent is distilled off under reduced pressure, and the residue is diluted with methylene chloride, washed with water, dried and concentrated. The residue is treated through column chromatography (silica gel/ethyl acetate-n-hexane) to obtain of 3.97 g (48,0% based on 2-O-tert-butyldimethylsilyloxy) specified in the title compound.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 40 H, Shir. C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,34 (4H, t, J = 8 Hz), 4,10-4,22 (5H, m), and 5.30-of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 621 (M+H)+.

Comparative example 7:

Obtaining 1,3-O-dioleoyl-2-O-/2-bromacil/carbamylcholine

(1) In peritoneum in 5 ml of pyridine and, after the addition of 120 mg (0,740 mmol) of N,N'-carbonyldiimidazole the resulting mixture was stirred at room temperature for 3 hours The solvent is then distilled off under reduced pressure, and the residue is dissolved in methylene chloride, washed with 5% monopotassium phosphate in water, dried and concentrated. The residue is dissolved in 10 ml of N,N'-dimethylformamide and after the addition of 45 mg (0,737 mmol) of 2-aminoethanol the resulting mixture was stirred at room temperature overnight. After completion of the reaction the solvent is distilled off and the residue is dissolved in methylene chloride, washed with 5% solution of monopotassium phosphate in water, dried and concentrated. The residue is treated chromatography (silica gel/methylene chloride-methanol) to obtain 204 mg (79,5%) of 1,3-O-dioleoyl-2-O-(2-hydroxyethyl)-carbamylcholine.

1H-NMR (200 MHz, CDCL3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 40H cm. C.), 1,50-1,80 (4H, m), 1,90-2,10 (8H, m), 2,34 (4H, t, J = 8 Hz), 3,28 is 3.40 (2H, m), 3,64-of 3.80 (2H, m), 4,20-and 4.40 (4H, m), 5,06-5,20 (2H, m), and 5.30-of 5.50 (4H, m).

Mass spectrum bombarded with fast electrons: 690 (M-OH)+< / BR>
(2) To a mixture of 160 mg (0,226 mmol) of 1,3-O-dioleoyl-2-O-(2-hydroxyethyl)carbamylcholine, 150 ml (0,452 mmol) of carbon tetrachloride and 120 mg (0,458 mmol) of triphenylphosphine add 10 ml of N,N-dimethylformamide in the bulb, and the resulting mixture was stirred at room temperature for 2 hours After completion of R is Obtained residue is treated through column chromatography (silica gel/ethyl acetate-n-hexane) to obtain 91 mg (52.2 per cent) specified in the title compound.

1H-NMR (200 MHz, CDCl3) : 0,86 (6H, t, J = 6 Hz), 1.28 (in 40H cm. C) 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,31 (4H, t, J = 8 Hz), 3,40-to 3.52 (2H, m), 3,51-3,70 (2H, m), 4,20-of 4.44 (4H, m), 5,06-5,20 (2H, m), 5.25-in of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 770 M+H.

Example 1

Obtain 3-O-/2-dimethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol

To 25 ml of a solution of 2.00 g (3.4 mmol) of 1,2-O-dioleoylglycerol in pyridine added 0.66 g (4.1 mmol) of N,N'-carbonyldiimidazole, and the resulting mixture was stirred at room temperature for 5 hours Then the solvent is distilled off under reduced pressure, and the residue is dissolved in methylene chloride, washed with 5% solution of monopotassium phosphate in water, dried and concentrated. The residue is dissolved in 20 ml of N,N-dimethylformamide and after adding 595 mg (6.8 mmol) of N,N-dimethylethylenediamine the resulting mixture is stirred over night. After completion of the reaction the solvent is distilled off and the residue is diluted with water and extracted with methylene chloride. The extract obtained was washed with water, dried and concentrated, and the residue is treated through column chromatography (silica gel/chloroform-methanol to obtain 2,18 g (91%) indicated in the title of the compounds of the present invention.

1H-NMR (200 MHz, CDCl>the 4), of 2.20 (6H, s, N(CH3)2), 2,39 (2H, t, J = 6 Hz/ NCH2), 3,18-and 3.31 (2H, m, CONHCH2), 3,36-3,64 (7H, m, OCH2X3 and OCH), a 4.03-4.26 deaths (2H, m, CH2OCO), with 5.22 (1H, Shir.s, NHCO), 5,28-5,43 (4H, m, CH=SNH).

Mass spectrum bombarded with fast electrons: 707 (M+H)+.

Example 2

Obtain 3-O-(2-methylaminomethyl)carbarnoyl-1,2-O-dioleoylglycerol

Specified in the title compound, receive by way of example 1 except that N-methylethylenediamine used instead of N,N-dimethylethylenediamine.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm. C) 1,50-1,60 (4H, m), 1,90-2,10 (8H, m), 2,43 (3H, s), a 2.71 (2H, t, J = 6 Hz), or 3.28 (2H, q, J = 6 Hz); 3.40 in-3,70 (7H, m), of 4.05-4.26 deaths (2H, m), 5,14 (1H, Shir. C) 5,30-5,44 (4H, m).

Mass spectrum bombarded with fast electrons 693 (M+H)+.

Example 3

Obtain 3-O-/2-amino-ethyl/carbarnoyl-1,2-O-dioleoylglycerol

This connection will be received, using N-titilatingly instead of N,N-dimethylethylenediamine, in all other respects according to the method of example 1, it is treated with 5% trichloroacetic acid - methylene chloride and purified in the same way to obtain the title compound.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm. C) 1,50-1,60 (4H, m), 1,90-2,10 (8H, m), of 3.10-3.20 (2H, m), 3,40-3,70 (9H, m)BR> Example 4

Obtain 3-O-/2-diethylaminoethyl/carbarnoyl-1,2-O-dioleoylglycerol

Using N,N-diethylenediamine instead of N,N-dimethylethylenediamine, according to the method of example 1 in all other respects, receive specified in the title compound of the present invention.

1H NMR (200 MHz, CDCl3) : of 0.87 (6H, t, J = 6 Hz), a 1.01 (6H, t, J = 6 Hz), 1.27mm (44H, Shir. C) a 1.46-of 1.62 (4H, m), 1,90-2,10 (8H, m), 2,48-2,62 (6H, m), 3,18-3,30 (2H, m), 3,38-3,66 (7H, m), 4.04 the-4,24 (2H, m), 5,24-5,44 (4H, m).

Mass spectrum bombarded with fast electrons: 735 (M+H)+.

Example 5

Obtain 3-O-/4-dimethylaminomethyl/carbarnoyl-1,2-O-dioleoylglycerol

Using 4-dimethylaminobutyric instead of N, N-dimethylethylenediamine, otherwise according to the method of example 1, get mentioned in the title of a compound of the invention.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm. C), 1,46 is 1.70 (8H, m), 1,90-2,10 (8H, m), 2,39 (6H, s), 2,44-of 2.56 (2H, m), 3,10-3,24 (2H, m), 3,36-3,70 (7H, m), 4,00-4,24 (2H, m), 5,18-5,42 (5H, m).

Mass spectrum bombarded with fast electrons: 736 (M+H)+.

Example 6

Obtain 3-O-/2-dimethylaminoethyl/thiocarbamoyl-1,2-O-dioleoylglycerol

Using N, N-thiocarbonyldiimidazole instead of N,N-carbonyl-diimidazole, otherwise according to the method of example 1, receive specified in saps), 1,50-1,60 (4H, m), 1,90-2,10 (8H, m), of 2.21 (6H, d, J = 4 Hz), a 2.36-of 2.54 (2H, m), 3,30-of 3.80 (9H, m), 4,40-4,70 (2H, m), 5,26-of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 723 (M+H)+.

Example 7

Obtain 3-O-/4-dimethylaminoethanol/-1,2-O-dioleoylglycerol

In 6 ml of methylene chloride-N,N-dimethylformamide (1:2) dissolve 120 mg (0.20 mmol) of 1,2-O-dioleoylglycerol, then add 168 mg (1 mmol) 4-dimethylaminomethylene acid hydrochloride. Then added 206 mg (1 mmol) of N, N'-dicyclohexylcarbodiimide (DCC) and 25 mg (0.2 mmol) 4-methylaminopropane, and the reaction is conducted at room temperature over night. Deposited as a by-product urea is filtered off using a glass filter, and the filtrate is concentrated to dryness under reduced pressure, and treated with methylene chloride-saturated aqueous sodium bicarbonate. After separation of the phases methylenchloride layer is dried over sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is treated through column chromatography with silica gel, elwira a methylene chloride-methanol, to obtain 123 mg (87%) indicated in the title of the compounds of the present invention.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1,20-1,40 (44H, m), 1,45-to 1.60 (4H, m), 1.70 to ektr bombarded with fast electrons: 706 (M+H)+.

Example 8

Obtain 3-O-/N,N-dimethylaminoacetyl/-1,2-O-dioleoylglycerol

In a solvent mixture of 22 ml of N,N-dimethylformamide and 11 ml of methylene chloride are suspended 572 mg (5,547 mmol) of N,N-dimethylglycine, then add 1736 mg (8,414 mmol) N,N-dicyclohexylcarbodiimide, and the resulting mixture was stirred at room temperature overnight. The solvent is then distilled off under reduced pressure, and the residue is dissolved in 12 ml of pyridine containing 327 mg (0,551 mmol) dissolved 1,2-O-dioleoylglycerol. Then add 80 mg (0,388 mmol) N,N'-dicyclohexylcarbodiimide (DCC), and the reaction is conducted at 50oC during the night. After completion of the reaction the solvent is distilled off and the residue is dissolved in methylene chloride, washed with saturated aqueous sodium bicarbonate, dried and concentrated. The residue is treated through column chromatography (silica gel/ethyl acetate-n-hexane) to obtain 251 mg (67.2 per cent) specified in the title compounds of the present invention.

1H NMR (400 , CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm. C) 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), a 2.36 (6H, s), 3,23 (2H, s), 3,40-3,70 (7H, m), 4,00-4,20 (2H, m), 5,20-of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 678 (M+H)+.

Example 9

Palmol 1,2-O-dioleoylglycerol, then add 188 mg (1,91 mmol) of 4-bromoethylamine while cooling with ice. After the temperature allow to return to room temperature, the reaction is carried out at 50oC for 1 h Then the solvent is distilled off and the residue is treated with methylene chloride-saturated solution of sodium bicarbonate. After separation of the phases and drying over sodium sulfate, the solvent is distilled off under reduced pressure. Thus obtained residue is treated through column chromatography with silica gel, elwira a methylene chloride-methanol, to obtain 159 mg (42%) of the bromo-compounds.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.27mm (44H, Shir. C) 1,50-1,70 (4H, m), 1,90-of 2.20 (10H, m), of 2.53 (2H, t, J = 8 Hz), 3,40-3,70 (9H, m), 4,05-4,30 (2H, m), a 5.25 to 5.45 (4H, m).

(2) In 6 ml N,N-dimethylformamide-isopropyl alcohol-chloroform (1:1:1) dissolved 130 mg (0.18 mmol) of the above bromoethylene, and then add 1 ml of diethylamine and 70 mg (0.54 mmol) of N,N-diisopropylethylamine. The resulting mixture was left to react at 60oC for 20 h and then at 80oC for 6 hours, the Solvent is distilled off under reduced pressure, and the residue is treated with methylene chloride-water. Methylenchloride layer is dried over sodium sulfate and concentrated under reduced Dalnego in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), was 1.04 (6H, t, J= 6 Hz), 1.27mm (44H, Shir.C.), 1,50-1,70 (4H, m), of 1.80 (2H, m), 1,90-2,10 (8H, m), is 2.37 (2H, t, J = 6 Hz), 2,44-2,70 (6H, m), 3,40-3,70 (7H, m), 4,05-4,30 (2H, m), and 5.30-of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 734 (M+H)+.

Example 10

Obtaining N-(2,3-dialerace)propyl-4-dimethylaminobutyric

In 3 ml of anhydrous N,N-dimethylformamide was dissolved 100 mg (0,17 mmol) of 2,3-valeronitrile. To this solution was added 71 mg (0.42 mmol) of 4-dimethylaminomethylene acid hydrochloride, 105 mg (0.51 mmol) of N,N'-dicyclohexylcarbodiimide (DCC) and 4.1 mg (0,034 mmol) of 4-dimethylaminopyridine, and the reaction is conducted at room temperature over night. Then the reaction mixture is treated according to the method of example 6 to obtain 115 mg (96%) indicated in the title of the compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6.0 Hz), 1,20-1,40 (44H, m), 1,50-1,60 (4H, m), 1,70-1,90 (2H, m), m), 1,90-2,10 (8H, m), of 2.23 (6H, s), 2,24 (2H, t, J = 8 Hz), was 2.34 (2H, t, J = 8 Hz), 3,20-3,60 (9H, m), and 5.30-5,42 (4H, m).

Mass spectrum bombarded with fast electrons: 705 (M+H)+.

Example 11

Obtain 3-O-/2-dimethylaminoethyl/sulfamoyl-1,2-O - dioleoylglycerol

In 4 ml of methylene chloride-pyridine (2: 1) was dissolved 150 mg (0.25 mmol) 1 is Langlade, and the reaction is carried out at room temperature for 2 hours After completion of the reaction the solvent is distilled off under reduced pressure, and the residue is treated with methylene-chloride - saturated aqueous sodium bicarbonate. The methylene chloride layer is dried over sodium sulfate and concentrate under reduced pressure. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 34 mg/18%/ specified in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1,20-1,40 (44H, m), 1,45-of 1.65 (4H, m), 1,90-2,10 (8H, m), 2,24 (6H, s), 2,48 (2H, t, J = 6 Hz), 3,18 (2H, t, J = 6 Hz), 3,40-of 3.60 (6H, m), 3,60 of 3.75 (1H, m), 4,08-4,30 (2H, m), 5,30-of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 743 (M+H)+.

Example 12

Getting 2-dimethylaminoethyl-N-/2,3-valeronitrile/-carbamate

In 2 ml of pyridine was dissolved 45 mg (0.5 mmol) of 2-dimethylaminoethanol, and then add 97 mg (0.6 mmol) N,N-carbonyldiimidazole, and the resulting mixture was stirred for 4 h To this solution add 355 mg (0.6 mmol) of 2,3-valeronitrile dropwise, and the mixture was stirred for 24 hours After completion of the reaction the solvent is distilled off and the residue is dissolved in methylene chloride, graphic column (silica gel/methylene chloride-methanol) to obtain 383 mg (100%) specified in the title compounds of the present invention.

1H-NMR (MHz, CDCl3) : of 0.87 (6H, t, J = 6 Hz, CH3x2), 1,12-1,44 (44H, m, CH2h), 1,46-of 1.64 (4H, m, OCH2CH2x2), 1,88-2,12 (8H, m, CH=CHCH2x4), is 2.37 (6H, s, N(CH3)2), to 2.54 (2H, t, J = 6 Hz, NCH2), 3,32-3,64 (9H, m, OCH2X3, OCH and NHCH2), to 4.16 (2H, t, J = 6 Hz, COOCH2), to 5.17 (1H, Shir.s, NHCO), 5,26-5,46 (4H, m, CH=SNH).

Mass spectrum bombarded with fast electrons: 707 (M+H)+.

Example 13

Getting 1-O-/2-dimethylaminoethyl/carbarnoyl-1,3-dioleoylglycerol

To 2 ml of a solution of 150 mg (0,253 mmol) of 1,3-O-dioleoylglycerol in pyridine added 82 mg (0.51 mmol) of N,N'-carbonyldiimidazole, and the resulting mixture was stirred at room temperature for 5 hours the Solvent is distilled off under reduced pressure, and the residue is dissolved in methylene chloride, washed with 5% solution of monopotassium phosphate in water, dried and concentrated. The residue is dissolved in 1.6 ml of N,N-dimethylformamide and stirred with 45 mg (0.51 mmol) of N,N-dimethylethylenediamine during the night. After completion of the reaction the solvent is distilled off and the residue is diluted with water and extracted with methylene chloride. The extract obtained was washed with water, dried and concentrated. The residue is treated through column chromatography (silica gel/chloroform-methanol to po
) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm.C.), 1,50-of 1.65 (4H, m), 1,90-2,10 (8H, m), of 2.20 (6H, s), 2,39 (2H, t, J = 6 Hz), 3,20-3,30 (2H, m), 3,34-3,55 (4H, m), 3,55-3,70 (4H, d, J = 4 Hz), 4,99 (1H, t, J = 4 Hz), 5.25 to 5,46 (5H, m).

Mass spectrum bombarded with fast electrons: 707 (M+H)+.

Example 14

Getting 2-dimethylaminoethyl-N-/1,3-dioperasikan-2-yl/ carbamate

Using 1,3-dialerace-2-Propylamine, all the rest by way of example 12, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 44H cm.C.), 1,50-1,60 (4H, m), 1,90-2,10 (8H, m), of 2.28 (6H, s) to 2.54 (2H, t, J = 6 Hz), 3,40-3,55 (8H, m), 3,80-are 3.90 (1H, m), is 4.15 (2H, t, J = 6 Hz), 5,10-5,20 (1H, m), 5,20-of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 707 (M+H)+.

Example 15

Obtain 3-O-(2-dimethylaminoethyl)carbarnoyl-1,2-O-dioleoylglycerol

Using 1,2-O-dioleoylglycerol, in all other respects the same procedure of example 1, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 40H cm.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,22 (6H, s), 2,24-to 2.40 (4H, m), is 2.41 (2H, t, J = 6 Hz), 3,20-3,30 (2H, m), 4,10-to 4.15 (4H, m), 5,20-and 5.30 (2H, m), and 5.30-of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 735 (M+H)+

1H NMR (200 MHz, CDCl3) : : to 0.88 (6H, t, J = 6 Hz), 1.26 in (40H, Shir. C. ), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,22 (6H, s), 2,32 (4H, t, J = 8 Hz), 2,42 (2H, t, J = 6 Hz), 3,20-3,30 (2H, m), 4,12-of 4.25 (4H, m), of 5.15 (1H, t, J = 6 Hz), 5,20-of 5.45 (5H, m)

Mass spectrum bombarded with fast electrons: 735 (M+H)+< / BR>
Example 17

Getting 2-dimethylaminoethyl-N-(2,3-dioleoylglycerol)- carbamate

In 30 ml of anhydrous pyridine was dissolved 500 mg (5,61 mmol) of 2-dimethylaminoethanol, then add 1,91 g (to 11.8 mmol) of N,N'-carbonyldiimidazole, and the reaction is carried out at room temperature for 5 hours To this reaction mixture are added 197 mg (2,16 mmol) 3-amino-1,2-propane diol, and the reaction is conducted at room temperature over night. Then the pyridine is distilled off under reduced pressure and the remaining crude carbamate again dissolved in pyridine. Then, while cooling with ice, add 5,22 g a (17.4 mmol) of reorganiza, and the reaction is conducted at 50oC for 14 h and Then the pyridine is distilled off under reduced pressure, and the residue is dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate. The methylene chloride layer is dried over sodium sulfate and concentrate the data in the title compounds of the present invention.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz) 1,25 (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (4H, m), of 2.28 (6H, s), is 2.30 (4H, t, J = 8 Hz), to 2.57 (2H, t, J = 6 Hz), 3,30-3,50 (2H, m), 4,06-4,30 (4H, m), 5,04-of 5.15 (2H, m), 5.25-in of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 735 (M+H)+.

Example 18

Getting 2-dimethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl/ carbamate

Using 2-amino-1,3-propandiol instead of 3-amino-1,2-propane diol, in the rest of the way 17 receive 372 mg (2.2 mmol) specified in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : of 0.87 (6H, t, J = 7 Hz), 1,20-1,40 (40H, m), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), is 2.30 (6H, s), 2,32 (4H, t, J = 8 Hz), at 2.59 (2H, t, J = 6 Hz), 4,00-4,25 (7H, m), 5,10-5,20 (1H, m), and 5.30-of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 735 (M+H)+< / BR>
Example 19

Getting 2-O-/2-piperidinoethyl/carbarnoyl-1,3-O - dioleoylglycerol

Using 1,3-O-dioleoylglycerol and 1-/2-amino-ethyl/piperidine, all the rest by way of example 13 ,get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 40H cm.C.), the 1.44-of 1.54 (2H, m), 1,54 to 1.76 (8H, m), 1,90-2,10 (8H, m), 2,32 (4H, t, J = 8 Hz), 2,39-of 2.56 (6H, m), 3,20-3,40 (2H, m), 4,12-and 4.40 (4H, m), 5,08-5,24 (1H, m), 5,24-5,52 (5H, m).

The mass spectrum with the/carbarnoyl-1,3-O - dioleoylglycerol

Using 1,3-O-dioleoylglycerol and N,N-diethylethylenediamine, the rest by way of example 13, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), of 1.02 (6H, t, J = 6 Hz), 1.28 (in 40H cm.C) 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,32 (4H, t, J = 8 Hz), 2,44-of 2.66 (6H, m), 3,16-of 3.32 (2H, m), 4,22-to 4.38 (4H, m), 5,08-5,22 (1H, m), 5,26-5,52 (5H, m).

Mass spectrum bombarded with fast electrons: 763 (M+H)+.

Example 21

Getting 2-O-/2-diisopropylaminoethyl/carbarnoyl-1,3-O - dioleoylglycerol

Using 1,3-O-dioleoylglycerol and N,N-diisopropylethylamine, the rest by way of example 13 get mentioned in the title of a compound of the present invention.

1H NMR (200 MHz, CDCl3) :/ to 0.88 (6H, t, J = 6 Hz), and 1.00 (12H, t, J = 6 Hz), 1.27mm (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,30 (4H, t, J = 8 Hz), 2,48-of 2.64 (2H, m), 2,88-3,20 (4H, m), 4,10-4,32 (4H, m), 5,06 is 5.28 (2H, m), and 5.30-5,42 (4H, m).

Mass spectrum bombarded with fast electrons: 791 (M+H)+.

Example 22

Getting 2-O-/-2-pyrrolidinone/carbarnoyl-1,3-O - dioleoylglycerol

Using 1,3-O-dioleoylglycerol and 1-/2-amino-ethyl/pyrrolidin, the rest by way of example 13, get mentioned in the title of a compound of the present invention.

<-2,70 (6H, m), 3,20-3,40 (2H, m), 4,20 was 4.42 (4H, m), 5,08-5,22 (1H, m), 5,24-5,46 (5H, m).

Mass spectrum bombarded with fast electrons: 671 (M+H)+.

Example 23

Getting 2-O-/2-morpholinoethyl/carbarnoyl-1,3-O-dioleoylglycerol

Using 1,3-dioleoylglycerol and 4-/2-amino-ethyl/morpholine, the rest by way of example 13, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : : to 0.88 (6H, t, J = 6 Hz), 1.27mm (40H, Shir.C.), 1,50 - 1,70 (4H, m), 1,90 - 2,10 (8H, m), 2,31 (4H, t, J = 8 Hz), 2,40 - of 2.54 (6H, m), 3,20 - 3,40 (2H, m), 3,70 (4H, t, J = 6 Hz), 4,12 - to 4.38 (4H, m), 5.08 to 5,20 (2H, m), 5,20 - 5,46 (4H, m).

Mass spectrum bombarded with fast electrons: 777 (M+H)+.

Example 24

Getting 2-O-/3-diethylaminopropyl/carbarnoyl-1,3-O-dioleoylglycerol

Using 1,3-O-dioleoylglycerol and 3-diethylaminopropylamine, the rest by way of example 13 ,get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : : to 0.88 (6H, t, J = 6 Hz), 1,03 (6 Hz, t, 6H), 1.28 (in 40H cm.C.), 1,50 - 1,70 (4H, m), 1,90 - 2,10 (8H, m), 2,30 (4H, t, J = 8 Hz), 2,46 - of 2.58 (6H, m), 3,20 - of 3.32 (2H, m), 4,10 - 4,34 (4H, m), 5,10 - 5,20 (1H, m), and 5.30 - 5,42 (4H, m), 6,18 - 6,30 (1H, Shir.S.).

Mass spectrum bombarded with fast electrons: 777 (M+H)+.

Example 25

The floor is Aut 173 mg (0,224 mmol) of 1,3-O - dioleoyl-2-O-/2-bromacil/carbamylcholine, then add 543 mg (7,228 mmol) 2-/methylamine/ethanol and 27 mg /0,209 mmol/ diisopropylethylamine, and the resulting mixture was refluxed at 80oC during the night. Then the reaction mixture is washed with 5% monopotassium phosphate sodium water, dried and concentrated. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 128 mg (74,3%) specified in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : 0,86 (6H, t, J = 6 Hz), 1.27mm (40H, Shir.C.), 1,50 - 1,70 (4H, m), 1,90 - 2,10 (8H, m), 2.26 and - of 2.38 (7H, m), 2,50 - 2,70 (4H, m), 3,20 - 3,40 (2H, m), 3,61 (4H, t, J = 6 Hz), 4,20 - of 4.44 (4H, m), 5,06 - 5,20 (2H, m), and 5.30 - of 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 765 (M+H)+.

Example 26

Getting 2-O-/2-N-ethyl-N-/2-hydroxyethyl/amino/ethyl-carbarnoyl-1,3-O-dioleoylglycerol

Using 2-(ethylamino)ethanol, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6.0 Hz), of 1.03 (3H, t, J = 6 Hz), 1.28 (in 40H cm.C.), 1,50 - 1,70 (4H, m), 1,90 - 2,10 (8H, m), 2,32 (4H, t, J = 8 Hz), 2,54 of 2.68 (6H, m), 3,20 - 3,30 (2H, m), of 3.56 (2H, t, J = 6 Hz), 4,12 - 4,34 (4H, m), 5,06 - 5,20 (2H, m), and 5.30 - 5,44 (4H, m).

The mass spectrum of the bombing quick e is 1,3-O-dioleoylglycerol

Using diethylamine, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1.28 (in 40H cm.C.), 1,50 - 1,70 (4H, m), 1,90 - 2,10 (8H, m) 2,32 (4H, t, J = 8 Hz), 2,60 - 2,70 (6H, m), 3,20 - 3,30 (2H, m), of 3.60 (4H, t, J = 6 Hz), 4,12 - and 4.40 (4H, m), 5.08 to 5,20 (1H, m), and 5.30 - 5,42 (4H, m), the ceiling of 5.60 - 5,70 (1H, Shir.S.).

Mass spectrum bombarded with fast electrons: 795 (M+H)+.

Example 28

Getting 2-O-/2-/-N-methyl-N-n-butylamino/ethyl/carbarnoyl-1,3 - dioleoylglycerol

Using N-methylbutylamine, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : 0,82 - to 0.96 (9H, m), 1,10 - 1,50 (42H, m), 1,50 - 1,75 (6H, m), 1,90 - 2,10 (8H, m), are 2.19 (3H, s), and 2.26 - 2.40 a (6H, m), 2,46 (2H, m), 3,20 - 3,30 (2H, m), 4,10 - 4,30 (4H, m), 5.08 to 5,20 (1H, m), 5.25 - in of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 777 (M+H)+.

Example 29

Getting 2-O-/2-/4-/2-hydroxyethyl/piperazine derivatives/ethyl/carbarnoyl - 1,3-O-dioleoylglycerol

Using a 1-/2-hydroxyethyl/piperazine, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (3H, t, J = 6 Hz), 1.28 (in 40H, Shi - ,40 (4H, m).

Mass spectrum bombarded with fast electrons: 820 (M+H)+.

Example 30

Getting 1-O-/2-/N, N, N', N'-tetramethylguanidine/ethyl/carbarnoyl-1,3-O-dioleoylglycerol

Using N, N, N', N'-tetramethylguanidine, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (3H, t, J = 6 Hz), 1.27mm (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,30 (4H, t, J = 8 Hz), 2,96 (3H, s), 3,10 (3H, s), 3,35 is 3.40 (2H, m), 3,60-3,70 (2H, m), 4.04 the-4,34 (4H, m), 4,98-5,08 (1H, m), and 5.30-of 5.40 (4H, m), 6.30-in-6,40 (1H, m).

Mass spectrum bombarded with fast electrons: 805 (M+H)+.

Example 31

Getting 2--O-/2-/N-/2-diethylamino/ethyl-N-methylamino/ethylcarbitol-1,3-O - dioleoylglycerol

Using N, N-diethyl-N'-methylethylenediamine, otherwise according to the method of example 25, get mentioned in the title of a compound of the present invention.

1H NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), was 1.04 (6H, t, J = Hz), 126 (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2.26 and-2,36 (7H, m), 2,44-2,64 (10H, m), 3.15 and is 3.25 (2H, m), 4,16-4.26 deaths (4H, m), 5.08 to by 5.18 (1H, m), and 5.30-of 5.40 (4H, m), 6,46-6,60 (1H, Shir.S.).

Mass spectrum bombarded with fast electrons: 820 (M+H)+.

Example 32

Getting 2-O-/2-/4-ethylpiperazine/ethyl/carbarnoyl - connection of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 1,10 (3H, t, J = 6 Hz), 1.26 in (40H, Shir.C) 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,32 (4H, t, J = 8 Hz), 2,38-2,60 (12H, m), 3,22-to 3.34 (2H, m), 4,12-4,34 (4H, m), 5,10-and 5.30 (2H, m), and 5.30-5,42 (4H, m)

Mass spectrum bombarded with fast electrons: 802 (M+H)+.

Example 33

Getting 2-/2-/N-ethyl-N-methylamino/ethyl/carbarnoyl-1,3-O-dioleoylglycerol

In 3 ml of chloroform is dissolved 131 mg (0,170 mmol) 1.3-0-dioleoyl-2-O-/2-bromacil/carbamylcholine, and then add 470 mg (7,951 mmol) of N-ethylmethylamine, and reaction are in a sealed vial at 80oC during the night. The reaction mixture is washed with 5% solution of monopotassium phosphate in water, dried and concentrated. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 104 mg (81,5%) specified in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), was 1.04 (3H, t, J = 6 Hz), 1.26 in (40H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), of 2.20 (3H, s), 2,32 (4H, t, J = 8 Hz), 2,38-2,52 (4H, m), 3,20-3,30 (2H, m), 4,12-4,32 (4H, m), 5,10-5,20 (1H, m), 5.25 to 5,42 (5H, m)

Mass spectrum bombarded with fast electrons: 749 (M+H)+.

Example 34

Getting 2-On/2-diethylaminoethyl/carbarnoyl-1,3-O-dipalmitoyl

Using 1,3-O-di is Obedinenie of the present invention.

1H-NMR (200 MHz, CDCl3, : of 0.87 (6H, t, J = 6 Hz), and 1.00 (6H, t, J = 6 Hz), 1,25 (48H, Shir.C.), 1,50-1,70 (4H, m), 2,30 (4H, t, J = 8 Hz), 2,46-2,60 (6H, m), 3,10-3,30 (2H, m), 4,12-4,32 (4H, m), 5,10-5,20 (1H, m), 5,20 to 5.35 (1H, m)

Mass spectrum bombarded with fast electrons: 711 (M+H)+.

Example 35

Getting 2-diethylaminoethyl-N-/1,3-dioleoylglycerol-2-yl)-carbamate

The methylene chloride is dissolved 470 mg (4 mmol) 2-Diethylaminoethanol. After adding 633 mg (8 mmol) of pyridine, 690 mg (4.4 mmol) of phenylcarbamate add further while cooling with ice and the reaction is carried out at room temperature for 2 hours After completion of the reaction the solvent is distilled off and the residue is transferred to the ethyl acetate-1% aqueous solution of sodium bicarbonate. An ethyl acetate layer emit, dried over sodium sulfate and concentrated under reduced pressure to obtain 705 mg (74%) of the crude carbonate compound. This crude carbonate was dissolved in anhydrous pyridine, then added 134 mg (1,47 mmol) 2-amino-1.3-propane diol and the reaction is carried out at 80oC during the night. Then add 972 mg (3.2 mmol) of reorganize, and reaction are another 24 h at room temperature. After completion of the reaction the solvent is distilled off, under reduced pressure, and the residue is transferred into a methylene chloride-the lower the pressure, and the residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 250 mg (22%) indicated in the title of the compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : of 0.87 (6H, t, J = 6 Hz), was 1.04 (6H, t, J = 6 Hz), 1.28 (in 40 H, Shir.C.), 1,50-1,70 (4H, m), 1,90-2,10 (8H, m), 2,30 (4H, t, J = 8 Hz), 2,50-2,70 (6H, m), 4,00-4,30 (7H, m), of 5.05-5,20 (1H, m), a 5.25 to 5.45 (4H, m).

Mass spectrum bombarded with fast electrons: 763 (M+H)+.

Example 36

Getting 2-Oh/3-diethylaminopropyl/-1,3-O-geologicaly

In a solvent mixture of 3 mg of N,N-dimethylformamide and 6 ml of methylene chloride is dissolved 172 mg (0,277 mmol) of 1,3-dioleoylglycerol, and then added 101 mg (0,556 mmol) of N,N-diethyl-alanine (as hydrochloride), 114 mg (0,553 mmol) N, N-dicyclohexylcarbodiimide and 7 mg (0,057 mmol) of 4-dimethylaminopyridine, and the resulting mixture is stirred over night. Then the reaction mixture was filtered, and the filtrate concentrated under reduced pressure. The residue is dissolved in methylene chloride and washed with water. The washed solution is dried and concentrated, and the residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 129 mg (62%) indicated in the title of the compounds of the present invention.

Mass spectrum bombarded with fast electrons: 707 (M+H)+.

Example 37

Receiving O-/2-dimethylaminoethyl/-O-(1,3-dioleoylglycerol/- methylphosphonate

To 310 mg (0.50 mmol) of 1,3-dioleoylglycerol, dried through azeotrope distillation with pyridine, add to 9.1 ml (1 mmol) of 0.11 M methyl-bis-O, O-(1-benzotriazolyl)phosphonate-dioxane, and the reaction is carried out at room temperature for 3 hours To the reaction mixture 446 mg (5 mmol)of 2-dimethylaminoethanol and 411 mg /5 mmol/ 1-methyl-imidazole, and conduct further reaction at room temperature over night. Then the reaction mixture is treated with methylene chloride-5% solution of monopotassium phosphate, and methylenechloride layer is dried over sodium sulfate and concentrate under reduced pressure. The residue is treated through column chromatography (silica gel/methylene chloride-methanol) to obtain 272 (59%) indicated in the title of the compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : 0,86 (6H, t, J = 6 Hz), 1,25 (40H, Shir.C.), and 1.54 (3H, d, J = 20 Hz), 1,50-1,70 (4H, m), 2,32 (4H, t, J = 8 Hz), to 2.35 (6H, s), 2,68 (2H, t, J = 6 Hz), 4,05-of 4.25 (4H m), 4,25 is 4.35 (2H, m), 4,70-of 4.90 (1H, m), 5.25-in of 5.40 (4H, m).

The mass spectrum of the bombing quick elecdata

Using tert-butyl N-/2-hydroxyethyl/carbamate instead of 2-dimethylaminoethanol, the rest by way of example 37 get a connection that process triperoxonane acid (methylene chloride) (1:2) to obtain the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : to 0.88 (6H, t, J = 6 Hz), 2,25 (40H, Shir.C.), 1,50-1,90 (7H, m), 1,90-2,10 (8H, m), 2,34 (4H, t, J = 8 Hz), 3,30 is 3.40 (2H, s), 4,10-4,50 (6H, m), 4.75 V-the 4.90 (1H, m), and 5.30-of 5.40 (4H, m).

Mass spectrum bombarded with fast electrons: 770 (M+H)+.

Example 39

Receiving O-/2-diethylaminoethyl/-O-/1,3-dioleoylglycerol/- methylphosphonate

Use 2-Diethylaminoethanol, by way of example 37 get 166 mg (70,7%) specified in the title compounds of the present invention.

1H-NMR (200 MHz, CDCl3) : of 0.87 (6H, t, J = 6 Hz), a 1.01 (6H, t, J = 6 Hz), 1.26 in (40H, Shir.C.), 1,48 is 1.70 (7H, m), 1,90-2,10 (8H, m), 2,32 (4H, t, J = 8 Hz), 2.57 m (4H, square, J = 6 Hz), 2,80 (2H, t, J = 6 Hz), 3,90-and 4.40 (6H, m), 4,70-of 4.90 (1H, m), and 5.30-5,42 (4H, m).

Mass spectrum bombarded with fast electrons: 798 (M+H)+.

Example 40

200 ál of chloroform in the ampoule is dissolved with 5 ml of the compounds of the present invention according to example 4 and 5 mg of egg yolk phosphatidylethanolamine. Then, nitrogen gas purge is. the ATEM ampoule left overnight under reduced pressure and after adding 2 ml of sterile distilled water is stirred in a vortex mixer for exfoliation of the film. After blowing nitrogen gas vials hermetically closed and left to stand at 4oC for 3 hours and Then for 10 min spend sonication using the disintegrator to obtain a lipid tool of the present invention. The ratio of connections to phospholipid is 1:1.

Example 41

Using the compound of the present invention in example 7, receive the lipid vehicle of the present invention by way of example 40. The ratio of connections to the phospholipid is 1.03:1.

Example 42

Using the compound of the present invention according to example 20, receive the lipid vehicle of the present invention by way of example 40. The ratio of connections to the phospholipid is of 0.96:1.

Example 43

Using phosphatidylcholine from egg yolk instead of egg yolk phosphatidylethanolamine, get the tool of the present invention according to example 20, receive the lipid vehicle of the present invention by way of example 40. The ratio of connections to the phospholipid extending t is the tool of the present invention in the rest by way of example 43. The ratio of connections to the phospholipid is 1.10:1.

Example 45

Using the compound of the invention according to example 20, in the rest by way of example 43, receive the lipid vehicle of the present invention. The ratio of connections to the phospholipid is 1.10:1.

Example 46

Composition for injection

To 60 μl of the means of the present invention according to example 40 add 0.9 ml of physiological saline. To this mixture is added 0.1 ml of 100 µg/ml of saline solution incorrectly paired double-strand RNA (double-strand RNA consisting of a copolymer polyinosinic acid and cititravel acid containing one link 4-toritillas acid is replaced by 20 parts of cititravel acid, with the full distribution of molecular sizes controlled in the range of about 50-10000 grounds) (hereinafter referred to as the study medication), and the resulting mixture is stirred to obtain a composition for injection.

Example 47

Composition for injection

Using the tools of the present invention obtained by the method of examples 41-45, all the rest by way of example 46 receive a composition for injection.

Example 48

Composition for injection

Ispot composition for injection.

Test example 1

Hemolytic action

To 0.9 ml of a suspension of rat erythrocytes, washed with isotonic solution, add 0.1 ml of aqueous suspensions of the compounds of the present invention, and the resulting mixture is incubated at 37oC under stirring for 45 minutes the mixture centrophorus with the speed of 3000 rpm for 2 min, and determine the absorption of the supernatant at 540 nm. If we take the absorption of the sample obtained by adding 0.1 ml of isotonic for 0% (no hemolysis) and the absorbance of the sample obtained by the addition of 0.1 ml of 0.1% Triton X-100 for 100% (complete hemolysis), then the degree of hemolysis for the tool of the present invention can be calculated. The results are shown in table. 1. Suspension of erythrocytes prepared so that the absorption at 540 nm after complete hemolysis would be 1,2.

From the data table. 1 shows that compared to commercial lipid tool, gemoliticheskie action tools of the present invention, which causes hemolysis 30% of erythrocytes is approximately 1/10.

Therefore, assume that the tool of the present invention has very low toxicity.

Test note what Amnesty 104cells/cell (90 μl). The next day add 10 µg/cell Lipofectin (trade mark) or the tool of the present invention, the concentration of each lipid is 30 µg/ml, and concentrations of the studied drugs are different. Plateau incubated for 72 h after the addition, and then add 10 ál/well 5 mg/ml MTT/3-/4,5-dimethylthiazol-2-yl/-2,5-diphenyltetrazolium. After 2-4 h, the reaction is stopped by adding isopropyl alcohol /0,04 N. hydrochloric acid. After receipt of the suspension of each cell determine the absorption at 540 nm using a reader (Corona) and calculate the degree of inhibition of cell growth in HeLa S3 (%). The calculation result on the basis of the following formula. As a control using the degree of inhibition of cell growth investigational medication in the absence of Lipofectin, and in the absence of the means of the present invention.

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The results are shown in table. 2

Notes to the table. 2:

Exp = example

The test drug is a substance: polyinosine acid - poly(Citadella acid-4-toritilla acid).

The values in the table represent the degree of inhibition (%).

However, it was cooked lipid medium containing 3-/N-/-N',N'-dimethylaminoethyl/-carbarnoyl/cholesterol (DC-chol) and the egg yolk phosphatidylethanolamine (1:1), the method described in the literature (Biochemical and Biophysical Research Communication, 280-285, Vol. 179, No. 1 (1991) and compares with the tool of the present invention (examples 40 and 43) on the activity of inhibiting the growth of cells Hela S3. It was found that when using 0.1 µg/ml of the investigated tools when the lipid concentration of 30 μg/ml, the tool of the present invention is about 6 times more efficient than DC-chol lipid tool from the point of view of the activity of inhibiting the growth of cells.

1. Derivatives of glycerol General formula I

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R1and R2- different and each represents a group-O-Y, or a group-A-(CH2)n-E, where n is an integer from 1 to 4, E is pyrrolidino, piperidino, morpholino, piperazinone, substituted hydrokinesis C1-C4-alkyl, guanidinium, substituted lower alkitab hydrogen, lower-C1-C4-alkyl, hidrogenesse-C1-C4-alkyl,

A represents a group of the formula

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< / BR>
< / BR>
< / BR>
R and Y are identical and each represents oleyl, or oleoyl, or Palmitoyl provided that when n = 1, then A cannot be a group of 3 or 5.

2. Derivatives of glycerol General formula I' under item 1

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where R11and R21the same and each represents oleyl or oleoyl;

D represents-CH2- or-NH-;

R30and R40the same and each represents methyl or ethyl.

3. Connection on p. 1, characterized in that it is chosen from the group consisting of 3-0-(4-dimethylaminoethanol)-(1,2-0-dioleoylglycerol, 3-0-(2-dimethylaminoethyl)-carbarnoyl-1,2-0-dioleoylglycerol, 3-0-(2-diethylaminoethyl)carbarnoyl-1,2-0-dioleoylglycerol and 2-0-(2-diethylaminoethyl)-carbarnoyl-1,3-0-dioleoylglycerol.

4. Means for delivering a physiologically active substance containing a phospholipid and a modifier component, characterized in that the modifying component it contains a derivative of glycerol General formula I on p. 1, where the ratio derived glycerin and phospholipid is from 1 : 9 to 9 : 1.

5. Means on p. 4, characterized in that the

6. Means on p. 4, characterized in that it contains a compound selected from the group consisting of 3-0-(4-dimethylaminoethanol)-(1,2-0-dioleoylglycerol, 3-0-(2-dimethylaminoethyl)-carbarnoyl-1,2-0-dioleoylglycerol, 3-0-(2-diethylaminoethyl)carbarnoyl-1,2-0-dioleoylglycerol and 2-0-(2-diethylaminoethyl)carbarnoyl-1,3-0-dioleoylglycerol, and a phospholipid as main components.

7. Means on p. 4, characterized in that the phospholipid is a phosphatidylethanolamine or phosphatidylcholine.

8. Means on p. 5, characterized in that the phospholipid is a phosphatidylethanolamine or phosphatidylcholine.

9. Means on p. 6, characterized in that the phospholipid is a phosphatidylethanolamine or phosphatidylcholine.

10. A pharmaceutical composition comprising a means for delivery of physiologically active substances, physiologically active substance and an inert diluent, characterized in that as a means for delivery of physiologically active substances it contains a tool for PP.4 to 9, when the mass ratio of the means of physiologically active substance is 1 : 0.1 to 1 : 10.

11. The composition according to p. 10, characterized in that the physiologically aksjologiczny active ingredient is a double-strand RNA, consisting of a copolymer polyinosinic acid and cititravel acid containing one link 4-toritillas acid for every 20 parts of cititravel acid and the total size distribution of molecules in the range of about 50 to 10,000 bases.

 

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