JPH08119917A - Amino acid-containing lipid compound - Google Patents

Abstract

PURPOSE: To obtain the subject new compound capable of suppressing the production of tumor necrosis factor by antagonistically acting on a lipopolysaccharide, thus useful for preventing or treating septicemic shock. CONSTITUTION: This new compound is expressed by formula I (R is an amino acid or ester thereof, R-CO represents that an amide bond has been formed; (n) and (m) are each 6-16; X is O or S; where, excepting ornithine-contg. lipid II as a natural-type optically active form and serine-contg. lipid), e.g. [3- hydroxy-2(S)-[15-methyl-3(R)-(13methyltetradecanoyloxy) hexadecanoyl]amino]propionic acid. This compound of formula I is obtained by condensation reaction between a compound of formula II (R<1> is a carboxyl- protecting group; Y is OH or SH) and a compound of formula III in the presence or absence of a condensation agent followed by, if desired, removing the carboxyl-protecting group in the resultant condensate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an amino acid-containing lipid compound and a method for producing the same. More specifically, it relates to an amino acid-containing lipid compound useful as a therapeutic agent for septic shock, which competitively suppresses tumor necrosis factor (TNF) production caused by lipopolysaccharide (LPS), and a method for producing the same. Furthermore, the present invention relates to a therapeutic agent and a preventive agent for septic shock containing the above-described amino acid-containing lipid compound as an active ingredient, and a tumor necrosis factor production inhibitor.

[0002]

It has been reported that lipoamino acid ornithine-containing lipids and serine-containing lipids are present in membrane lipids of Gram-positive bacteria such as flavobacterium, and their structures and hemagglutination have been clarified. (Eur. J. Bi
ochem., 136, pp.531-538, 1983; Eur. J. Biochem., 1
71, pp. 73-80, 1988; and Eur. J. Biochem. 175, pp.
633-641, 1988). Further, it has been suggested that these compounds may activate macrophages and have an immunopotentiating effect (Infection and Immunity, 57, pp.2086-2091,
1989).

These naturally occurring amino acid-containing lipid compounds are structurally characterized by having a 3-acyloxyacylamide moiety. In particular, Flavobacterium meningosepticum
ornithine-containing lipid II contained in the membrane lipid of icum)
(ornithine-containing lipid II) and serine-containing lipid
(serine-containing lipid) is a hydrophobic lipid moiety [
_{[(CH 3) 2 CH (} CH 2) 11] [(CH 3) 2 CH (CH 2) 11 COO] CHCH 2 CO- ] a It is known that have a common structure (Eur. J. Bio
chem., 171, pp.73-80). These two kinds of amino acid-containing lipid compounds each have one asymmetric carbon present in the lipid moiety and one asymmetric carbon derived from the amino acid, and are present as optically active compounds. However, their absolute structure is still unknown. Further, the optically active substances and diastereoisomers other than the above-mentioned naturally derived ornithine-containing lipid II and serine-containing lipid have not been separated or collected.

As a method for producing these amino acid-containing lipid compounds, a method for producing a compound in which serine is converted to substituted glycine has been reported (J. Antibiot., Pp.1476-.
1486, 1985). This production method involves a step of condensing a glycine derivative with β-hydroxy acid and then condensing a hydroxy group of the obtained condensate with a carboxyl group of another fatty acid. However, the method is complicated and the yield is low, so it cannot be said to be a practical synthetic method.

[0005]

DISCLOSURE OF THE INVENTION The present inventor diligently studied the physiological action of the above amino acid-containing lipid compounds,
These compounds have an inhibitory effect on LPS against tumor necrosis factor production promoted by lipopolysaccharide (LPS), and are useful for the treatment and prevention of septic shock. I found it. Therefore, an object of the present invention is to provide a novel use of an amino acid-containing lipid compound.

[0006] Another object of the present invention is to provide a novel amino acid-containing lipid compound that strongly suppresses tumor necrosis factor production by LPS and is useful for treating and preventing septic shock.

A further object of the present invention is to provide a method for efficiently and inexpensively producing the above-mentioned amino acid-containing lipid compound. More specifically, an object of the present invention is to provide a method for efficiently producing the above-described amino acid-containing lipid compound by a simple process using a readily available known compound as a starting material.

[0008]

Means for Solving the Problems As a result of diligent efforts to solve the above-mentioned object, the present inventor has found that an amino acid containing It has been found that the lipid compounds are produced very efficiently. In addition, a novel amino acid-containing lipid compound produced by such a method is
It was found that it has a remarkable inhibitory effect on the tumor necrosis factor production, which is enhanced by the above, and is useful for the treatment and prevention of septic shock. The present invention has been completed based on these findings.

That is, according to the present invention, the following formula:

[0010]

[Chemical 9]

(In the formula, R represents an amino acid or its ester, and R-CO- represents that an amide bond is formed by the amino group of the amino acid or its ester represented by R and the carbonyl group represented by -CO-. And n and m each independently represent an integer of 6 to 16 and X represents an oxygen atom or a sulfur atom).

According to a preferred embodiment of the present invention, n and
The above amino acid-containing lipid compound in which m independently represents an integer of 9 to 13; and the above amino acid-containing lipid compound in which n and m are 11 respectively; the above amino acid-containing lipid compound in which X is an oxygen atom; and the amino acid is an α-amino acid The above-mentioned amino acid-containing lipid compound; wherein the amino acids are alanine, arginine, asparagine, aspartic acid, cysteine,
The amino acid-containing lipid compound selected from the group consisting of glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, 2,4-diaminobutyric acid, and ornithine. Amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine,
And an amino acid-containing lipid compound selected from the group consisting of 2,4-diaminobutyric acid; an amino acid-containing lipid compound in which the amino acid is serine or ornithine; and an amino acid-containing lipid compound in which the amino acid is D- or L-amino acid. To be done.

According to another aspect of the present invention, a method for producing an amino acid-containing lipid compound represented by the above formula, and an amino acid-containing lipid compound represented by the above formula or a physiologically acceptable salt thereof is effective. A therapeutic and prophylactic agent for septic shock, which is included as a component, and a tumor necrosis factor production inhibitor are provided.

In the above formula, R represents an amino acid or its ester, and R-CO- represents that an amide bond is formed by the amino group of the amino acid or its ester represented by R and the carbonyl group represented by -CO-. Indicates. For example, when the amino acid is alanine, R-CO- is HOOC-CH (C
H ₃ ) -NH-CO-. The amino acid is not particularly limited, and any natural or unnatural α-amino acid, β-amino acid, γ-amino acid or the like may be used, but among these, it is preferable to use the α-amino acid. The amino acid may be either D-amino acid or L-amino acid.

As the amino acid, for example, alanine (Al
a), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamic acid (Gl
u), glutamine (Gln), glycine (Gly), histidine
(His), isoleucine (Ile), leucine (Leu), lysine
(Lys), methionine (Met), phenylalanine (Phe),
Proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val),
2-aminoadipic acid (Aad), 3-aminoadipic acid (bAa)
d), β-alanine (β-aminopropionic acid: bAla)
, 2-aminobutyric acid (Abu), 4-aminobutyric acid (piperidine acid:
4Abu), 6-aminocaproic acid (Acp), 2-aminoheptanoic acid (Ahe), 2-aminoisobutyric acid (Aib), 3-aminoisobutyric acid (bAib), 2-aminopimelic acid (Apm), 2,4-diaminobutyric acid (Dbu), desmosine (Des), 2,2'-diaminopimelic acid (Dpm), 2,3-diaminopropionic acid (Dpr), N-ethylglycine (EtGly), N-ethylasparagine (EtAsn),
Hydroxylysine (Hyl), Allo-hydroxylysine (aH
yl), 3-hydroxyproline (3Hyp), 4-hydroxyproline (4Hyp), isodesmosine (Ide), alloisoleucine (aIle), N-methylglycine (sarcosine: MeGl
y), N-methylisoleucine (MeIle), 6-N-methyllysine
(MeLys), N-methylvaline (MeVal), norvaline (Nv
A), norleucine (Nle), ornithine (Orn) and the like can be used.

Of these amino acids, alanine, arginine, asparagine, aspartic acid, cysteine,
It is possible to use an amino acid selected from the group consisting of glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, 2,4-diaminobutyric acid, and ornithine. Although preferred, the amino acid used in the amino acid-containing lipid compound of the present invention is not limited thereto.

The ester of an amino acid is an ester group which can be cleaved in vivo by a biological method such as hydrolysis or a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. Possible ester groups can be used. The former can form a prodrug of the amino acid-containing lipid compound of the present invention, and the latter can act as a protecting group in the reaction.

The ester acting as a protecting group in the reaction is preferably methyl, ethyl, n-propyl,
Isopropyl, n-butyl, isobutyl, s-butyl, tert
-Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-
Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, Ester of "lower alkyl group" such as 2-ethylbutyl; ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2- Methyl-2-propenyl, 2-ethyl-
2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-
Butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-
Butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl- 3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5- Esters of "alkenyl groups" such as hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2. -Butynyl, 2-methyl-2-
Butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-
Butynyl, 2-pentynyl, 1-methyl-2-pentynyl, 2-
Methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-
Esters of "alkynyl groups" such as methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; trifluoromethyl, trichloromethyl, difluoromethyl, dichloro. Methyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4 -Ester of "halogeno lower alkyl group" such as fluorobutyl, 6-iodohexyl and 2,2-dibromoethyl; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl , Esters of "hydroxy lower alkyl groups" such as 4-hydroxybutyl; of "aliphatic acyl lower alkyl groups" such as acetylmethyl Ester; 1-3 such as benzyl, phenethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, 6-phenylhexyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl Esters of "aralkyl groups" such as lower alkyl groups substituted with 4 aryl groups; 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4 -Methoxyphenyldiphenylmethyl,
Like 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis (2-nitrophenyl) methyl, piperonyl, 4-methoxycarbonylbenzyl Ester of "aralkyl group" such as lower alkyl, lower alkoxy, nitro, halogen, cyano, lower alkyl group substituted with 1 to 3 aryl groups in which aryl ring is substituted with alkoxycarbonyl group; and trimethylsilyl, triethyl Such as silyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl. Mention may be made of esters of "silyl groups".

As the ester which is cleaved in vivo by a biological method such as hydrolysis to produce a free acid or a salt thereof, methoxymethyl, 1-ethoxyethyl and 1-methyl-1 are preferable. -Methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl,
1,1-dimethyl-1-methoxymethyl, ethoxymethyl,
"Lower alkoxy lower alkyl group" such as n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl; "Lower alkoxylated lower alkoxy lower alkyl group" such as 2-methoxyethoxymethyl; phenoxymethyl "Aryloxy lower alkyl group" such as; "Halogenated lower alkoxy lower alkyl group" such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; "Lower such as methoxycarbonylmethyl "Alkoxycarbonyl lower alkyl group";"cyano lower alkyl group" such as cyanomethyl, 2-cyanoethyl; "lower alkylthiomethyl group" such as methylthiomethyl, ethylthiomethyl; "aryl" such as phenylthiomethyl, naphthylthiomethyl "Luthiomethyl group"; 2-methanesulfoni Ethyl, 2-halogen-substituted "lower alkylsulfonyl-lower alkyl group" may be such as trifluoromethanesulfonyl ethyl;
"Arylsulfonyl lower alkyl group" such as 2-benzenesulfonylethyl, 2-toluenesulfonylethyl;
Formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1 -Propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2- Acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxy Propyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryl Xypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-
Isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, "Aliphatic acyloxy lower alkyl group" such as 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl; cyclopentanoyloxymethyl, cyclohexanoyloxymethyl, 1-
“Cyclopentanoyloxyethyl, 1-cyclohexanoyloxyethyl, 1-cyclopentanoyloxypropyl, 1-cyclohexanoyloxypropyl, 1-cyclopentanoyloxybutyl, 1-cyclohexanoyloxybutyl, etc. “Alkylcarbonyloxy lower alkyl group”; “acyloxy lower alkyl group” such as aromatic acyloxy lower alkyl group such as benzoyloxymethyl; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, Butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyl Oxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1-
(Methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-propoxycarbonyloxyethyl, 1- (isopropoxycarbonyloxy) ethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1- (Tert-butoxycarbonyloxy) ethyl, 1-pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl,
1-cyclopentyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxypropyl, 1-cyclohexyloxycarbonyloxypropyl, 1-cyclopentyloxycarbonyloxybutyl, 1-cyclohexyloxycarbonyloxybutyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl, 2-propoxycarbonyloxyethyl, 2-isopropoxycarbonyloxyethyl, 2-butoxycarbonyloxyethyl, 2-isobutoxycarbonyl Oxyethyl, 2-pentyloxycarbonyloxyethyl, 2-hexyloxycarbonyloxyethyl, 1-methoxycarbonyloxypropyl, 1-ethoxycarbonylo Xypropyl, 1-propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl,
1-pentyloxycarbonyloxypropyl, 1-hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl, 1-butoxycarbonyloxy "Alkoxycarbonyloxyalkyl group" such as butyl, 1-isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl, 1-ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl, 1-ethoxycarbonyloxyhexyl; (5 -
Phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4- Methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- ( 4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolene
-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) methyl,
"Carbonyloxyalkyl group" such as oxodioxolenylmethyl group such as (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; like phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl A "phthalidyl group"; an "aryl group" such as phenyl and isodanyl;
Mention may be made of esters of the above-mentioned “alkyl group”; “carboxyalkyl group” such as carboxymethyl; and “amide-forming residue of amino acid” such as phenylalanine. The fact that the ester has the desired properties described above means that
It can be easily determined by administering the ester form to an experimental animal such as rat or mouse by intravenous injection, then examining the body fluid of the animal, and detecting the original compound or its pharmacologically acceptable salt.

In the above formula, n and m each independently represent an integer of 6-16. Preferably, the lower limits of n and m are 9 or more and the upper limits are 13 or less. It is particularly preferred that both n and m are 11. X represents an oxygen atom or a sulfur atom, but X is preferably an oxygen atom. Further, the amino acid-containing lipid compound of the present invention, if necessary, a salt,
Preferably, it may be a pharmacologically acceptable salt. Such salts include, for example, hydrofluorides in the case of basic amino acids, hydrochlorides, hydrobromides, hydrohalides such as hydroiodides, nitrates, perchlorates, Inorganic acid salts such as sulfates, phosphates, carbonates; lower alkylsulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate Aryl sulfonates, fumarates, succinates, citrates, such as
Examples thereof include organic acid salts such as tartrate, oxalate and maleate, and acid addition salts which are organic acids such as amino acid salts such as glutamate and aspartate. Further, as the base addition salt, a sodium salt of a carboxyl group derived from an amino acid, a metal salt such as a potassium salt, a lithium salt, a calcium salt, an ammonium salt, a base addition salt such as an organic amine compound salt such as monomethylamine or triethylamine. Can be mentioned. Further, the amino acid-containing lipid compound of the present invention may exist as a hydrate of the free compound or a salt thereof.

Furthermore, the compound of the present invention is not limited to a specific isomer, but includes all geometric isomers, stereoisomers, optical isomers and mixtures thereof, for example, racemates. More specifically, the amino acid-containing lipid compound of the present invention has one asymmetric carbon atom in the lipid portion, and the amino acid may have an asymmetric carbon atom.
All such optical isomers based on one or more asymmetric carbons and any optically active isomers or diastereoisomers based on a plurality of asymmetric carbons are included in the amino acid-containing lipid compound of the present invention. .

However, among the various aspects of the present invention, regarding the invention relating to chemical substances, among the compounds included in the above general formula, the European Journal of Biochemistry (Eur. J. Biochem.) Volume 171, 73-8
Page 0 (1988), flavobacterium meningosepticum (Flavobacterium meningosept
The naturally-occurring optically active ornithine-containing lipid II and serine-containing lipid contained in the membrane lipid of icum) are not included in the scope of the present invention. Each of these compounds is 2
Specific enantiomers having asymmetric carbons, optical enantiomers of these specific compounds, or diastereoisomers of these specific compounds are all included in the scope of the present invention relating to chemical substances. To be done. In addition, among the aspects of the present invention, regarding each invention (invention of method and invention of use) other than the chemical substances described below, the ornithine-containing lipid II and the serine-containing lipid of the above naturally-occurring optically active substance are Also included within the scope of the invention.

The preferred amino acid-containing lipid compounds of the present invention are shown below, but the scope of the present invention is not limited to these compounds.

[0024]

[Chemical 10]

[0025]

[Table 1] Compound No. RX mn Compound No. RX mn ──────────────────────────────────── Compound 1 L-Ala O 11 11 Compound 2 D-Ala O 11 11 Compound 3 L-Arg O 11 11 Compound 4 D-Arg O 11 11 Compound 5 L-Asn O 11 11 Compound 6 D-Asn O 11 11 Compound 7 L -Asp O 11 11 Compound 8 D-Asp O 11 11 Compound 9 L-Cys O 11 11 Compound 10 D-Cys O 11 11 Compound 11 L-Glu O 11 11 Compound 12 D-Glu O 11 11 Compound 13 L-Gln O 11 11 Compound 14 D-Gln O 11 11 Compound 15 L-Gly O 11 11 Compound 16 D-Gly O 11 11 Compound 17 L-His O 11 11 Compound 18 D-His O 11 11 Compound 19 L-Ile O 11 11 Compound 20 D-Ile O 11 11 Compound 21 L-Leu O 11 11 Compound 22 D-Leu O 11 11 Compound 23 L-Lys O 11 11 Compound 24 D-Lys O 11 11 Compound 25 L-Met O 11 11 Compound 26 D-Met O 11 11 Compound 27 L-Phe O 11 11 Compound 28 D-Phe O 11 11 Compound 29 L-Pro O 11 11 Compound 30 D-Pro O 11 11 Compound 31 L-Ser O 11 11 Compound 32 D -Ser O 11 11 Compound 33 L-Thr O 11 11 Compound 34 D-Thr O 11 11 Compound 35 L-Trp O 11 11 Compound 36 D-Trp O 11 11 Compound 37 L-Tyr O 11 11 Compound 38 D-Tyr O 11 11 Compound 39 L-Val O 11 11 Compound 40 D-Val O 11 11 Compound 41 L-Orn O 11 11 Compound 42 D-Orn O 11 11 Compound 43 L-Ala O 12 12 Compound 44 L-Ala O 10 10 Compound 45 L-Arg O 12 12 Compound 46 L-Arg O 10 10 Compound 47 L-Asn O 12 12 Compound 48 L-Asn O 10 10 Compound 49 L-Asp O 12 12 Compound 50 L-Asp O 10 10 Compound 51 L-Cys O 12 12 Compound 52 L- Cys O 10 10 Compound 53 L-Glu O 12 12 Compound 54 L-Glu O 10 10 Compound 55 L-Gln O 12 12 Compound 56 L-Gln O 10 10 Compound 57 L-Gly O 12 12 Compound 58 L-Gly O 10 10 Compound 59 L-His O 12 12 Compound 60 L-His O 10 10 Compound 61 L-Ile O 12 12 Compound 62 L-Ile O 10 10 Compound 63 L-Leu O 12 12 Compound 64 L-Leu O 10 10 Compound 65 L-Lys O 12 12 Compound 66 L-Lys O 10 10 Compound 67 L-Met O 12 12 Compound 68 L-Met O 10 10 Compound 69 L-Phe O 12 12 Compound 70 L-Phe O 10 10 Compound 71 L-Pro O 12 12 compound Compound 72 L-Pro O 10 10 Compound 73 L-Ser O 12 12 Compound 74 L-Ser O 10 10 Compound 75 D-Ser O 12 12 Compound 76 D-Ser O 10 10 Compound 77 L-Thr O 12 12 Compound 78 L-Thr O 10 10 Compound 79 L-Trp O 12 12 Compound 80 L-Trp O 10 10 Compound 81 L-Tyr O 12 12 Compound 82 L-Tyr O 10 10 Compound 83 L-Val O 12 12 Compound 84 L- Val O 10 10 Compound 85 L-Orn O 12 12 Compound 86 L-Orn O 10 10 Compound 87 D-Orn O 12 12 Compound 88 D-Orn O 10 10 Compound 89 L-Ser O 13 13 Compound 90 L-Ser O 9 9 Compound 91 D-Ser O 13 13 Compound 92 D-Ser O 9 9 Compound 93 L-Orn O 13 13 Compound 94 L-Orn O 9 9 Compound 95 D-Orn O 13 13 Compound 96 D-Orn O 9 9 Compound 97 L-Ser O 11 10 Compound 98 L-Ser O 10 11 Compound 99 D-Ser O 11 10 Compound 100 D-Ser O 10 11 Compound 101 L-Ser O 11 9 Compound 102 L-Ser O 9 11 Compound 103 D-Ser O 11 9 Compound 104 D-Ser O 9 11 Compound 105 L-Ser O 11 8 Compound 106 L-Ser O 8 11 Compound 107 D-Ser O 11 8 Compound 108 D-Ser O 8 11 Compound 109 L- Ser O 11 7 Compound 110 L-Ser O 7 11 Compound 111 D-Ser O 11 7 Compound 112 D-Ser O 7 11 Compound 113 L-Ser O 11 6 Compound 114 L-Ser O 6 11 Compound 115 D-Ser O 11 6 Compound 116 D-Ser O 6 11 Compound 117 L-Ser O 11 12 Compound 118 L-Ser O 12 11 Compound 119 D-Ser O 11 12 Compound 120 D-Ser O 12 11 Compound 121 L-Orn O 11 13 Compound 122 L-Orn O 13 11 Compound 123 D- Orn O 11 13 Compound 124 D-Orn O 13 11 Compound 125 L-Ser O 11 14 Compound 126 L-Ser O 14 11 Compound 127 D-Ser O 11 14 Compound 128 D-Ser O 14 11 Compound 129 L-Ser O 11 15 Compound 130 L-Ser O 15 11 Compound 131 D-Ser O 11 15 Compound 132 D-Ser O 15 11 Compound 133 L-Ser O 11 16 Compound 134 L-Ser O 16 11 Compound 135 D-Ser O 11 16 Compound 136 D-Ser O 16 11 Compound 137 L-Ser S 11 11 Compound 138 L-Ser S 12 12 Compound 139 D-Ser S 11 11 Compound 140 D-Ser S 12 12 Compound 141 L-Orn S 11 11 Compound 142 L-Orn S 10 10 Compound 143 D-Orn S 11 11 Compound 144 D-Orn S 10 10 ───────────────────────────── ─ ────── In these amino acid-containing lipid compounds,-(C
H ₃ ) _n , X, and —CH ₂ —COR may have either the S-configuration or the R-configuration as the steric configuration with respect to the carbon atom, but a compound having the R-configuration is preferred.

According to another embodiment of the present invention, wherein R is an amino acid or its ester and R-CO- is
With the amino group of the amino acid represented by R or its ester
-CO- indicates that an amide bond is formed by a carbonyl group, n and m independently represent an integer of 6 to 16, and X represents an oxygen atom or a sulfur atom). A method for producing a compound, comprising the following steps: (a) the following formula:

[0027]

[Chemical 11]

(Wherein R ¹ represents a protecting group for a carboxyl group, Y represents a hydroxyl group or a thiol group, and n represents an integer of 6 to 16), and the following formula:

[0029]

[Chemical 12]

A step of condensing the compound (II) represented by the formula (wherein m represents an integer of 6 to 16) in the presence or absence of a condensing agent; (b) if desired, the above step (a) Removing the carboxyl group protecting group of the condensate obtained in step (c) reacting the compound or reactive derivative thereof obtained in step (a) or (b) with an amino acid compound or ester thereof, And (d) optionally removing the ester group of the compound obtained in step (c).

As a preferred example of the production method of the present invention, a compound (I) in which n is 11, Y is a hydroxyl group, and R ¹ is a benzhydryl group, and a compound in which m is 11
The following scheme shows a method for producing the amino acid-containing lipid compound of the present invention in which m and n are 11, X is an oxygen atom, and R is an α-amino acid using (II) and. In the scheme, R ² represents a protecting group for a carboxyl group that can be easily deprotected by catalytic reduction, and R ³ represents an amino acid residue.

[0032]

[Chemical 13]

In the above-mentioned compound (I) used as a starting material in the above reaction, the carboxyl group of the corresponding β-hydroxy or β-thiohydroxycarboxylic acid in which n is an integer of 6 to 16 is converted into an appropriate carboxyl group. It can be easily produced by protecting with a protecting group. The β-hydroxycarboxylic acid or β-thiohydroxycarboxylic acid into which a protecting group is to be introduced is a compound known per se, or can be easily produced by a person skilled in the art by a known method from a readily available known compound. . For example, referring to the method shown in the scheme below, a person skilled in the art can appropriately produce β-hydroxycarboxylic acid or β-thiohydroxycarboxylic acid into which a protecting group is to be introduced, from a readily available starting compound. it can.

[0034]

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The protecting group for the carboxyl group represented by R ¹ is a protecting group in a reaction which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis. Suitably, an ester group capable of being cleaved by the chemical method exemplified above can be used as a protecting group for a carboxyl group. Of these, it is particularly preferable to use, for example, benzhydryl ester. This protecting group can be easily introduced by reacting diphenyldiazomethane (Ph ₂ CN ₂ ) with a carboxylic acid. An example of the method is concretely shown in the following examples. In the formula (I), Y is a hydroxyl group (OH-) or a thiol group.
Although (SH-) is shown, it is preferable to use a compound in which Y is a hydroxyl group. Compounds preferably used in the method of the present invention
Examples of (I) include optically active β-hydroxy-15-methylhexadecanoic acid benzhydryl ester (J. Antibio
t., pp.1476-1486, 1985).

Compound (I) and compound (I) shown in step (a)
The condensation with I) can be carried out in the presence or absence of a condensing agent, preferably in the presence of a condensing agent, in an inert solvent or in the absence of a solvent. When a solvent is used, it is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, and for example, aliphatic hydrocarbons such as hexane, heptane, ligrolein and petroleum ether; benzene, toluene, xylene. Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate,
Esters such as propyl acetate, butyl acetate, diethyl carbonate; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol,
Alcohols such as methyl cellosolve; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; Nitro compounds such as nitroethane and nitrobenzene; Nitriles such as acetonitrile and isobutyronitrile; Formamide, N , N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; amides such as dimethyl sulfoxide and sulfolane. it can.

As the condensing agent, a usual condensing agent can be used, and examples thereof include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide. N-hydroxy derivatives; disulfide compounds such as 2,2'-dipyridyldisulfide; succinic acid compounds such as N, N'-disuccinimidyl carbonate; N, N'-bis (2-oxo -3-phosphinic chloride compounds such as oxazolidinyl) phosphinic chloride; N, N'-disuccinimidyl oxalate (DSO), N, N'-diphthalimido oxalate (DPO), N , N'-bis (norbornenylsuccinimidyl) oxalate (BNO), 1,1'-bis (benzotriazolyl) oxalate (BBTO), 1,1'-bis (6-chlorobenzotriazolyl) Oxalate (BCT
O), oxalate derivatives such as 1,1′-bis (6-trifluoromethylbenzotriazolyl) oxalate (BTBO); triarylphosphines such as triphenylphosphine, diethyl azodicarboxylate-triphenylphosphine Triarylphosphines such as di-lower alkyl-triarylphosphines of azodicarboxylic acid; N-lower alkyl-5-arylisoxazos such as N-ethyl-5-phenylisoxazolium-3'-sulfonate Lithium-3'-sulfonates; N ', N'-dicycloalkylcarbodiimides such as N', N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC ) Etc .; diheteroaryl diselenides such as di-2-pyridyl diselenide; p-nitrobenzenesulfonyl Arylsulfonyl triazolyl de, such as azolide; 2-
Chlor-1-methylpyridinium 2-such as iodide
Halo-1-lower alkylpyridinium halides; Diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA); 1,1'-Oxalyldiimidazole, N,
Imidazole derivatives such as N'-carbonyldiimidazole; Benzotriazole derivatives such as 1-hydroxybenzotriazole (HOBT); Dicarboxyls such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) An imide derivative can be used, but preferably,
For example, dicyclohexylcarbodiimide (DCC) or the like can be used. Although the reaction temperature and the reaction time are not particularly limited, for example, at a reaction temperature of 0 to 50 ° C. for 5 minutes to
It is preferable to carry out the reaction for about 16 hours. In carrying out the condensation reaction, it is also possible to use a catalytic amount of 4- (N, N-dimethylamino) pyridine, 4-pyrrolidinopyridine or the like,
In order to carry out the reaction effectively, quaternary ammonium salts such as benzyltriethylammonium chloride and tetrabutylammonium chloride, dibenzo-18-
Crown ethers such as Crown-6 and the like can also be added.

In step (b), if desired, the protecting group for the carboxyl group of the condensate obtained above is removed. The reaction to remove the carboxyl protecting group is
Depending on the nature of the protecting group, generally known methods in the art may be used as follows.

When a lower alkyl group or an aryl group is used as the protecting group for the carboxyl group, it can be removed by treating with an acid or a base. The acid or base is not particularly limited as long as it does not affect the other parts of the compound, but for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid or the like can be used as the acid. As the base, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, concentrated ammonia-methanol solution and the like can be used. When performing hydrolysis with a base, a base that does not cause isomerization should be selected.

The solvent used is not particularly limited as long as it is used in a usual hydrolysis reaction and does not inhibit the reaction, but preferably water, methanol, ethanol,
A mixed solvent of an alcohol such as n-propanol or an organic solvent such as tetrahydrofuran or an ether such as dioxane and water can be used. The reaction temperature and the reaction time vary depending on the starting materials, the solvent, the reagents to be used and the like and are not particularly limited, but in order to suppress side reactions, it is usually carried out at 0 to 150 ° C. for about 1 to 10 hours.

When the carboxyl-protecting group is a diaryl-substituted methyl group such as diphenylmethyl, it can usually be removed by treating with an acid in a solvent.
The solvent used is preferably an aromatic hydrocarbon such as anisole, and the acid used may be a fluorinated organic acid such as trifluoroacetic acid. The reaction temperature and reaction time will differ depending on the starting materials, solvent, acid used, etc., but usually the reaction may be carried out at room temperature for about 30 minutes to 10 hours.

When the carboxy-protecting group is an aralkyl group or a halogeno lower alkyl group, it can usually be removed by reduction in a solvent. As a reduction method,
When the protecting group for the carboxyl group is a halogeno lower alkyl group, a method by chemical reduction such as zinc-acetic acid is suitable, and when it is an aralkyl group, a catalyst such as palladium carbon or platinum is used. It can be removed by a conventional catalytic reduction method or by a chemical reduction using an alkali metal sulfide such as potassium sulfide or sodium sulfide. The solvent used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; tetrahydrofuran,
Ethers such as dioxane; fatty acids such as acetic acid or a mixed solvent of these organic solvents and water are preferable.
The reaction temperature and the reaction time will differ depending on the starting materials, the solvent, the reduction method, etc., but are usually 0 ° C to room temperature for 5 minutes to 12 minutes.
It is enough to react for about time.

When the carboxy-protecting group is an alkoxymethyl group, it can usually be removed by treating with an acid in a solvent. The acid used is not particularly limited as long as it is usually used as a Bronsted acid, but preferably, an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or paratoluenesulfonic acid. Can be used. The solvent to be used is not particularly limited as long as it does not participate in the reaction, but alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane, or a mixed solvent of these organic solvents and water. It is suitable. The reaction temperature and reaction time will differ depending on the starting materials, solvent, and type of acid used, but usually the reaction may be carried out at 0 to 50 ° C. for about 10 minutes to 18 hours.

Step (c) forms an amide bond with the carboxyl group of the 3-acyloxy-carboxylic acid or protected compound obtained in step (a) or (b) and the amino group derived from the amino acid compound to be bound. It is a process. This reaction is
For example, azide method, active ester method, mixed acid anhydride method,
It can be carried out by an acid halide method or a condensation method.

In the azide method, the carboxylic acid obtained in step (b) or the ester thereof obtained in step (a) is reacted with hydrazine in an inert solvent (for example, dimethylformamide) at around room temperature, Then, the produced hydrazide is reacted with a nitrite compound to convert it into an azide compound which is a reactive derivative, and then treated with an amino acid compound. Examples of the nitrite compound used include alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidone such as N-methylpyrrolidone. Can be mentioned. The two steps of this method are usually performed in one reaction,
The reaction temperature is about -50 ℃ to 0 ℃ in the first step, and -10 ℃ in the second step.
The temperature is about 10 ° C., and the time required for the reaction is about 5 minutes to 1 hour in the former stage and about 10 hours to 5 days in the latter stage.

The active ester method is carried out by reacting the carboxylic acid obtained in step (b) with an active esterifying agent to produce an active ester which is a reactive derivative, and then reacting it with an amino acid compound. Both reactions are preferably carried out in an inert solvent, and examples of the solvent to be used include methylene chloride, halogenated hydrocarbons such as chloroform, ethers, ethers such as tetrahydrofuran, dimethylformamide, Examples thereof include amides such as dimethylacetamide and nitriles such as acetonitrile. Examples of the active esterifying agent used include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy compounds such as N-hydroxy-5-norbornene-2,3-dicarboximide, and dipyridyldisulfide. Such a disulfide compound can be mentioned, and the active esterification reaction is preferably carried out in the presence of the condensing agent exemplified in the above step (a). The reaction temperature is -10 ℃ in the active esterification reaction.
The reaction temperature of the reaction is about room temperature, and the time required for the reaction is about 30 minutes to 80 hours for both reactions.

The mixed acid anhydride method is carried out by preparing a mixed acid anhydride which is a reactive derivative from the carboxylic acid obtained in step (b) and then reacting it with an amino acid compound.
The reaction to produce the mixed acid anhydride is carried out in an inert solvent (for example,
(The above-mentioned halogenated hydrocarbons, amides, ethers)
A mixed acid anhydride agent, for example, a lower carbonic acid (C ₁ -C ₄ ) alkyl halide such as ethyl chlorocarbonate, isobutyl chlorocarbonate, a lower alkanoyl halide such as pivaloyl chloride or diethyl cyanophosphoric acid, diphenyl cyano. This is achieved by reacting compound (II) with a lower alkyl or diaryl cyanophosphoric acid such as phosphoric acid. The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is about -10 ° C to 50 ° C, and the time required for the reaction is 3
It is about 0 minutes to 20 hours. The reaction between the mixed acid anhydride and the amino acid compound is preferably carried out in an inert solvent (for example, the above amides and ethers) in the presence of the above organic amine, and the reaction temperature is 0 ° C to 80 ° C. The reaction time is about 1 hour to 24 hours. Also, this reaction is
It is also carried out in the presence of the carboxylic acid obtained in step (b), an amino acid compound and a mixed acid anhydride agent.

The acid halide method was obtained in step (b) above.
It can be carried out by converting 3-acyloxy-carboxylic acid into an acid halide such as an acid chloride or acid bromide which is a reactive derivative, preferably an acid chloride, and then reacting it with an amino acid compound. The conversion of carboxylic acid to acid halide may be carried out by a method known per se,
Treatment with a halogenating agent (for example, phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.) at around room temperature for 30 minutes to 5 hours may be performed to convert to the corresponding acid halide. For example, when producing an acid chloride, methylene chloride is used. A preferred method is to react 3-acyloxy-carboxylic acid with oxalyl chloride in chloride. This reaction is, for example, 2
It only has to be done for about an hour. The reaction between the obtained acid halide and the amino acid compound is preferably carried out in an inert solvent such as methylene chloride under ice cooling for about 30 minutes.

In the condensation method, the carboxylic acid and amino acid ester obtained in step (b) are treated with dicyclohexylcarbodiimide, carbonyldiimidazole, and the like exemplified in step (a).
It is carried out by reacting directly in the presence of a condensing agent such as 1-methyl-2-chloro-pyridinium iodide-triethylamine. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

In the reaction of step (c), an amino acid compound in which the carboxyl group is protected as an ester group and the amino group to form an amide bond is not protected is used. As the ester, it is possible to use ester groups exemplified above which can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, and photolysis. It is particularly preferable to use. When the amino acid compound used in the reaction has a reactive amino group or the like other than the amino group which should form an amide bond, or when other reactive functional groups are present, those functional groups are added prior to the reaction. It is preferred that the group be protected. Such a protecting group can be appropriately selected by those skilled in the art.

In step (d), the ester group is removed from the N- (3-acyloxyacyl) amino acid ester in which the carboxyl group is protected by the ester, when a free carboxylic acid is desired. The ester group can be removed according to the conditions of the deprotection reaction exemplified above. For example, when a benzhydryl group is used as a protecting group,
It is preferable to carry out hydrogenolysis. Further, if desired, the obtained salt of the free carboxylic acid can be produced, for example, as follows.

Metal salt of carboxylic acid: hydroxide of the metal,
It is obtained by contacting a carbonate or the like with a free carboxylic acid in an aqueous solvent. As the aqueous solvent used, for example, water: alcohols such as methanol and ethanol, a mixed solvent of water and an organic solvent such as acetone is suitable. Particularly, a mixed solvent of a hydrophilic organic solvent and water is suitable. The reaction is usually carried out preferably near room temperature, but may be carried out under heating if necessary.

Amine salt of carboxylic acid: Obtained by contacting the corresponding amine with a free carboxylic acid in an aqueous solvent. As the aqueous solvent used, for example,
Water: Examples include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, a mixed solvent of nitriles such as acetonitrile and water, and the like, and water-containing acetone is preferable. The reaction is usually
The reaction is preferably completed at pH 7 to 8.5 and below room temperature, especially at 5 ° C to 10 ° C. Or, for example, above
The metal salt of the carboxylic acid obtained in (1) is dissolved in an aqueous solvent, and then a mineral acid salt of the desired amine (for example, a hydrogen halide salt such as hydrochloride) is added under the above conditions. It can also be produced by a salt exchange reaction.

Amino acid salts of carboxylic acids: Obtained by contacting the corresponding amino acid with the free carboxylic acid in an aqueous solvent. Examples of the aqueous solvent used include water: alcohols such as methanol and ethanol, a mixed solvent of ethers such as tetrahydrofuran and water, and the like.

Further, when an ester group which can be cleaved in vivo by a biological method such as hydrolysis is used as an ester of an amino acid, a free carboxylic acid or a salt thereof is used as a solvent (preferably tetrahydrofuran). Ethers or polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphorotriamide, triethylphosphate) in 2 equivalents of a base (preferably triethylamine, dicyclohexylamine) Base, alkali metal hydrides such as sodium hydride or alkali metal carbonates or bicarbonates such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate), and the like, such as acetoxymethyl chloride, propionyloxymethyl bromide. Nasty fatty acyl 1-lower alkoxycarbonyloxyethyl halides such as oxymethyl halides, 1-methoxycarbonyloxyethyl chloride, 1-ethoxycarbonyloxyethyl iodide, phthalidyl halides or (2-oxo-5-methyl-1, 3-dioxolen-4-
Yl) methyl halides may be reacted.

More specifically, in order to convert the carboxy group into an ester, the above-prepared carboxylic acid salt or free carboxylic acid is prepared by the following method: <Method 1> having the general formula R ⁴ -Y Compound (in the above formula, R ⁴ represents a carboxyl-protecting group that can be cleaved in vivo by a biological method such as hydrolysis, Y is, for example, chlorine, bromine,
Halogen atoms such as iodine; methanesulfonyloxy,
Lower alkanesulfonyloxy groups such as ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy, pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, etc. A group that leaves as a nucleophilic residue such as an arylsulfonyloxy group is shown. ] (For example,
Aliphatic acyloxymethyl halides such as acetoxymethyl chloride, pivaloyloxymethyl bromide, pivaloyloxymethyl chloride; ethoxycarbonyloxymethyl chloride, isopropoxycarbonyloxymethyl chloride, 1- (ethoxycarbonyloxy) ethyl chloride, Lower alkoxycarbonyloxyalkyl halides such as 1- (ethoxycarbonyloxy) ethyl iodide; phthalidyl halides;
Alternatively, (5-methyl-2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl halides can be mentioned. ), And in a solvent (the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and heptane; benzene , Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, Ethers such as diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide can be mentioned in the presence of a base (the base used. Are not particularly limited as long as they are used as a base in a normal reaction, but preferably, alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, Alkali metal hydrogen carbonates such as lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide Alkali metal hydroxides; Alkali metal fluorides such as sodium fluoride and potassium fluoride Inorganic bases such as; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, lithium methoxide; mercaptan alkalis such as methyl mercaptan sodium and ethyl mercaptan sodium Metals; N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6- Di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] nona-5-
Ene, 1,4-diazabicyclo [2.2.2] octane (DABCO),
Organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl)
Mention may be made of organometallic bases such as amides. ) To react with. The reaction temperature and reaction time are
Usually, at -20 to 120 ° C (preferably 0 to 80 ° C), 0.5 to
It takes about 10 hours.

<Method 2> A compound having the general formula R ⁴ —OH wherein R ⁴ has the same meaning as described above. ] In the presence of an esterifying agent and a catalytic amount of a base in a solvent, the esterifying agent used is a condensing agent; a halogenated formate ester such as methyl chloroformate or ethyl chloroformate; cyanophosphoric acid. Mention may be made of cyanophosphoric acid diesters such as diethyl. As the condensing agent, the above step (a)
Those exemplified above can be used, and diarylphosphoryl azides are preferable.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably aliphatic hydrocarbons such as hexane and heptane; benzene, Aromatic hydrocarbons such as toluene and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy Ethers such as ethane and diethylene glycol dimethyl ether; Nitriles such as acetonitrile and isobutyronitrile; Formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl
It is possible to use amides such as -2-pyrrolidone, N-methylpyrrolidinone and hexamethylphosphorotriamide. The base used is not particularly limited as long as it is used as a base in a normal reaction,
Preferably, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-
Of pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline Such organic bases can be mentioned. still,
4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine can be used in catalytic amounts in combination with other bases, and in order to carry out the reaction effectively, benzyltriethylammonium chloride can be used. It is also possible to add quaternary ammonium salts such as tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, and the like. The reaction temperature is -20 ° C to 80 ° C, preferably 0 ° C to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days, and preferably 30 minutes to 1 day.

<Method 3> A compound having the general formula R ⁴ —OH [in the above formula, R ⁴ has the same meaning as described above]. ] And a halogenated phosphoric acid diester such as diethyl chlorophosphate and a base in a solvent.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and heptane; benzene and toluene. , Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Such ethers; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
Ethers such as dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as pyrrolidinone and hexamethylphosphorotriamide can be used. As the base to be used, the same base as described in the above <Method 2> can be used.
The reaction temperature is 0 ° C to the reflux temperature of the solvent used, and preferably room temperature to 50 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 3 days,
It is preferably 30 minutes to 1 day.

<Method 4> In the case of a lower alkyl ester, there is no particular limitation in a solvent (so long as it does not inhibit the reaction and dissolves the starting material to some extent, preferably the same alcohol as the reagent; hexane , Aliphatic hydrocarbons such as heptane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; formic acid ethyl,
Ethers such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone Ketones such as; acetonitrile, nitriles such as isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-
Pyrrolidone, N-methylpyrrolidinone, amides such as hexamethylphosphorotriamide can be mentioned,
It is preferably the same alcohol as the reagent. ), In the presence of an acid catalyst (which is not particularly limited as long as it is used as an acid catalyst in a normal reaction, preferably, hydrochloric acid, chlorobromic acid, sulfuric acid, perchloric acid, phosphoric acid such as Inorganic acid or Bronsted acid such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, organic acid such as trifluoromethanesulfonic acid, or boron trichloride, boron trifluoride, boron tribromide Such as a Lewis acid or an acidic ion exchange resin), a corresponding lower alcohol such as methanol, ethanol, propanol or butanol, and 0 ° C to 100 ° C (preferably 20 ° C to 60 ° C). Then, the reaction is carried out for 1 to 24 hours. <Method 5> The carboxylic acid is added to (i) a halogenating agent (for example,
Phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.) at about room temperature for 30 minutes to 5 hours to convert to the corresponding acid halide; or (ii) chloroformic acid in the presence of an organic base such as triethylamine. After treatment with a methyl formate or a chloroformate such as ethyl chloroformate and conversion into a corresponding acid anhydride, an inert solvent (not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent Preferable but not preferred are aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; esters such as ethyl acetate and propyl acetate; ethers, tetrahydrofuran and dioxane. , Ethers such as dimethoxyethane or nitriles such as acetonitrile), bases (eg triethylamine) Presence of) alcohol form the corresponding (e.g. when producing tert- butyl ester,
Potassium tert-butoxide is preferred. ) Method of reacting with. The reaction temperature and the reaction time are -10 ° C to 150 ° C (preferably around room temperature) and about 10 minutes to 15 hours (preferably 30 minutes to 10 hours).

<Method 6> A method of bringing a free carboxylic acid into contact with a diazoalkane such as diazomethane or diazoethane (usually an ether solution of diazoalkane). The reaction is performed near room temperature (may be performed under heating depending on the type of reaction system).

<Method 7> In the case of lower alkylation, it can be produced, for example, by a method of reacting with a dialkyl sulfuric acid such as dimethyl sulfuric acid or diethyl sulfuric acid according to a conventional method.

When an ester of a carboxylic acid is used as a starting material, a compound having the general formula R ⁴ —OH [wherein R ⁴ has the same meaning as described above]. ], And an object compound can also be manufactured by performing a transesterification reaction according to a conventional method.

It is achieved by any one of the methods described below.

After completion of the reaction, the compound of the present invention can be collected from the reaction mixture by a conventional method. For example, it can be obtained by distilling the solvent from the reaction mixture, or by pouring the reaction mixture into water, extracting with a water-insoluble organic solvent, and distilling the solvent from the extract. further,
If desired, it can be further purified by means well known to those skilled in the art, such as recrystallization, reprecipitation or chromatography.

Furthermore, according to another aspect of the present invention, a method comprising the above step (c) and optionally (d),
A method for producing an amino acid-containing lipid compound represented by the above formula, comprising the following formula:

[0068]

[Chemical 15]

(Wherein n, m, and X are as defined above) or a reactive derivative thereof with an amino acid compound or an ester thereof, and optionally removing the ester group of the amino acid. The method of doing is also provided. The method for producing a reactive derivative, the method for forming an amide bond, and the reaction for removing an ester group in the above method can be performed under the same conditions as above.

The amino acid-containing lipid compound of the present invention, a physiologically acceptable salt thereof, or any hydrate thereof, inhibits the lipopolysaccharide (LPS) -enhanced tumor necrosis factor production from LPS. When administered orally or parenterally, septic shock can be prevented or treated. Therefore, according to still another aspect of the present invention, a prophylactic and therapeutic agent for sepsis containing an amino acid-containing lipid compound represented by the above general formula or a physiologically acceptable salt thereof or any hydrate thereof as an active ingredient. Will be provided. The medicament of the present invention is useful as a therapeutic or prophylactic agent for mammals including humans.

Examples of the administration form of the compound of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections. These formulations include excipients (eg lactose, mannitol, corn starch, crystalline cellulose etc.), binders (eg cellulose derivatives, gum arabic, gelatin etc.), disintegrants (eg carboxymethyl cellulose calcium etc.), Lubricants (eg,
It is produced by a known method using additives such as talc, magnesium stearate), stabilizers, flavoring agents, solvents for injections (eg, water, ethanol, glycerin, etc.). The dose varies depending on symptoms, age, etc., but the lower limit of the daily dose is 0.1 mg / kg, preferably 1 mg / kg
The maximum daily dose is 1,000 mg / k
g, preferably about 100 mg / kg. Such a dose of the compound can be administered to an adult once a day or in several divided doses.

[0072]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0073]

[Example 1] Diphenylmethyl 15-methyl-3 (R) -hydroxyhexade
Canoate (1) 15-Methyl-3 (R) -hydroxyhexadecanoic acid crude crystal
(1.65 g, 5.77 mmol) was dissolved in ethyl acetate (50 ml),
Diphenyldiazomethane (1.86 g, 9.58 mmol) was added. After stirring at 50 ° C. for 45 minutes, the solvent was removed and the product was purified by silica gel column chromatography. Elute with cyclohexane-ethyl acetate (10: 1) to obtain the desired compound 1.2.
6 g was obtained as an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (6H,
d, J = 7.0Hz), 1.14-1.55 (23H, m), 2.58-2.61 (3H, m), 4.01
(1H, m), 6.91 (1H, s), 7.33-7.34 (10H, m) IR spectrum, ν _max cm ^-1 (Film): 2926,2853,17
36,1165,699 Elemental analysis C ₃₀ H ₄₄ O ₃・ 0.24 H ₂ O = 457.00 Calcd. C: 78.85, H: 9.81 Found C: 78.97, H: 9.61 MS spectrum, m / z: 452

[0074]

[Example 2] Diphenylmethyl 15-methyl-3 (R)-(13-methyltetrade
(Canoyloxy) -hexadecanoate (2) Compound (1) obtained in Example 1 (336 mg, 0.74 mmol) and 13-
Methyltetradecanoic acid (213 mg, 0.88 mmol) was dissolved in methylene chloride (20 ml), N, N'-dicyclohexylcarbodiimide (DCC, 460 mg, 2.23 mmol) and 4-dimethylaminopyridine (DMAP, 90.4 mg, 0.74 mmol) ) Was added. After stirring at room temperature for 1 hour, dilute with ethyl acetate,
It was washed with sodium bicarbonate solution and brine. Dried over magnesium sulfate,
After filtration and concentration, the product was purified by silica gel chromatography. Elution with cyclohexane-ethyl acetate (20: 1) gave the desired product (449 mg, 89%) as an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12
H, d, J = 7.0Hz), 1.13-1.55 (44H, m), 2.10 (2H, m), 2.66 (2H,
m), 5.26 (1H, m), 6.89 (1H, s), 7.29-7.34 (10H, m) IR spectrum, ν _max cm ^-1 (film): 292
6,2855,1740,1466,1167,699 Elemental analysis _{C 45 H 72 O 4 = 677.06} Calcd. C: 79.83, H: 10.7
2 Found C: 79.52, H: 11.0
2 MS spectrum, m / z: 676

[0075]

[Example 3] 15-methyl-3 (R)-(13-methyltetradecanoyloxy)-
Hexadecanoic acid (3) The compound (2) (446.2 mg, 0.66 mmol) obtained in Example 2 was dissolved in ethanol (10 ml), and palladium hydroxide (50 mg) was added. It was hydrolyzed at room temperature for 1.5 hours in a hydrogen gas stream. The catalyst was filtered, concentrated under reduced pressure, and then purified by silica gel chromatography. Elution with cyclohexane-ethyl acetate (10: 1) gave the desired product (404.5 mg, crude) as an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12
H, d, J = 7.0Hz), 1.11-1.63 (43H, m), 2.28 (2H, m), 2.60 (2H,
m), 3.99 (1H, s), 5.21 (1H, m) IR spectrum, ν _max cm ^-1 (film): 2926,2855,174
0,1713,1466,1123,699 Elemental analysis C ₃₂ H ₆₂ O ₄・ 0.16 Ethyl acetate = 523.02 Calcd. C: 75.24, H: 12.23 Found C: 74.68, H: 12.15 MS spectrum, m / z: 511 (M ⁺ +1)

[0076]

Example 4 [3-Hydroxy-2 (S)-[15-methyl-3 (R)-(13-methylteto
Radecanoyloxy) hexadecanoyl] amino] pro
Pionate (4) The compound (3) (50.1 mg, 0.1 mmol) obtained in Example 3 was dissolved in methylene chloride (2 ml), oxalyl chloride (43.6 μl, 0.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. did. The mixture is concentrated, dried and then methylene chloride
It was dissolved in (1 ml). L-serine-benzyl ester hydrochloride (34.1 mg, 0.15 mmol) was added to methylene chloride (1 m
l) and was added dropwise to the acid chloride solution, and triethylamine (70 μl, 0.5 mmol) was added under ice cooling. The mixture was stirred for 30 minutes, the solvent was removed, and the product was purified by silica gel chromatography. Elution with cyclohexane-ethyl acetate (3: 1) gave the desired product (42.8 mg, 63%) as an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12
H, d, J = 7.0Hz), 1.11-1.62 (45H, m), 2.30 (2H, m), 2.50 (2H,
d, J = 6.0Hz), 4.00 (2H, br), 4.66 (1H, m), 5.17 (1H, m), 5.22
(2H, s), 6.57 (1H, d, J = 7.0Hz), 7.36 (5H, s) IR spectrum, ν _max cm ^-1 (Film): 3312,2922,285
1,1732,1543,1531,1466,1234,699 Elemental analysis C ₄₂ H ₇₃ NO ₆・ 0.4 H ₂ O = 695.25 Calcd. C: 73.32, H: 10.69, N: 2.04 Found C: 72.56, H: 10.70, N: 2.01 MS spectrum, m / z: 688 (M ⁺ +1)

[0077]

Example 5 [3-Hydroxy-2 (S)-[15-methyl-3 (R)-(13-methylteto
Radecanoyloxy) hexadecanoyl] amino] pro
Pionic acid (5) The compound (4) (38.9 mg, 0.057 mmol) obtained in Example 4 was dissolved in ethyl acetate (2 ml) to give a 10% palladium carbon catalyst.
(5 mg) was added, and the mixture was stirred in a hydrogen gas stream at room temperature for 4 hours. The catalyst was filtered and concentrated under reduced pressure to obtain 29.6 mg (88
%) As an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12H,
d, J = 7.0Hz), 1.11-1.62 (46H, m), 2.30 (2H, m), 2.55 (2H, d, J
= 6.0Hz), 3.90 (1H, dd, J = 4.0Hz), 4.09 (1H, dd, J = 4.0Hz), 4.
56 (1H, m), 5.22 (1H, m), 6.90 (1H, d, J = 7.0Hz) IR spectrum, ν _max cm ^-1 (film): 3312,2924,285
3,1734,1655,1545,1466,1383,1365,1184,1076,721 Elemental analysis C ₃₅ H ₆₇ O ₆ N = 597.92 Calcd. C: 70.31 H: 11.30 N: 2.34 Found C: 70.19, H: 11.45 N : 2.17 FAB-MS spectrum, m / z: 620.4889
(M ⁺ +1) [α] _D = 12.0 ° (c = 1.0, solvent: chloroform)

[0078]

Example 6 [3-Hydroxy-2 (R)-[15-methyl-3 (R)-(13-methylteto
Radecanoyloxy) hexadecanoyl] amino] pro
Pionate (6) The compound (3) (43.5 mg, 0.09 mmol) obtained in Example 3 was dissolved in methylene chloride (2 ml), oxalyl chloride (25 μl, 0.13 mmol) was added, and the mixture was stirred at room temperature for 2 hours. . The mixture is concentrated, dried and then methylene chloride
It was dissolved in (2 ml). D-serine-diphenylmethyl ester (152.3 mg, 0.37 mmol) was added to methylene chloride (2
ml)), the solution was added dropwise to the acid chloride solution, and triethylamine (18 μl, 0.13 mmol) was added under ice cooling. The mixture was stirred for 30 minutes, the solvent was removed, and the product was purified by silica gel chromatography. Elution with cyclohexane-ethyl acetate (20: 1) gave the desired product (65 mg, 100%) as an oil. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12H,
d, J = 7.0Hz), 1.11-1.58 (45H, m), 2.19 (2H, m), 2.50 (2H, m),
3.68 (1H, m), 3.97 (1H, m), 4.88 (1H, m), 5.14 (1H, m), 5.24 (1
H, s), 6.66 (1H, m), 7.26 (10H, m)

[0079]

Example 7 [3-Hydroxy-2 (R)-[15-methyl-3 (R)-(13-methylteto
Radecanoyloxy) hexadecanoyl] amino] pro
Pionic acid (7) The compound (6) (65 mg, 0.09 mmol) obtained in Example 6 was dissolved in ethyl acetate (3 ml), and 10% palladium carbon catalyst (10 m
g) was added, and the mixture was stirred at room temperature for 4 hours in a hydrogen gas stream.
The catalyst was filtered, concentrated under reduced pressure, and purified by silica gel chromatography. It was eluted with ethyl acetate: methanol (2: 1), concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated to obtain 37 mg (72%) of the desired product as a colorless transparent solid. 270MHz ¹ H-NMR spectrum, δppm (CDCl ₃ ): 0.86 (12H,
d, J = 7.0Hz), 1.14-1.60 (44H, m), 1.91-2.10 (2H, br), 2.24-
2.31 (2H, m), 2.50-2.52 (2H, m), 3.62-3.74 (1H, m), 3.86-3.
94 (1H, m), 4.24-4.32 (1H, m), 5.14-5.22 (1H, m) IR spectrum, ν _max cm ^-1 (film): 2953,2921,28
51,1728,1468,1366,1171,1109,722 [α] _D = −15.8 ° (c = 0.85, chloroform)

[0080]

Example 8 5-O-benzyl-3-deoxy-1,2-O-isopropylidene-
α-D-ribose (8) 3-deoxy-1,2-O-isopropylidene-α-D
-Ribose (7.24 g, 0.42 mmol) was dissolved in dimethylformamide (80 ml), and sodium hydride (1.05 g, 43.75 mmol) suspended in dimethylformamide (20 ml) in a nitrogen stream was cooled with ice. And added dropwise, and the mixture was stirred until it reached room temperature. Benzyl bromide (5.2 ml, 43.72 mmol) was added dropwise thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography. Elute with cyclohexane-ethyl acetate (9: 1) to obtain the desired product (8) 8.81 g.
(80%) was obtained as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.32 (3H, s), 1.51 (3H, s), 1.71-1.82 (1
H, m), 2.06 (1H, d, d, J = 13.3,4.5Hz), 3.55 (1H, d, d, J = 10.6,
4.8Hz), 3.65 (1H, d, d, J = 10.6,3.5Hz), 4.36-4.44 (1H, m),
4.59 (2H, s), 4.73 (1H, t, J = 4.2Hz), 5.84 (1H, d, J = 3.6Hz),
7.26-7.40 (5H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
2992,2937,2866,1496,1454,1384,1375,1325,1164,1092,
1064,1027,851 Elemental analysis C ₁₅ H ₂₀ O ₄ = 264.32 calcd C: 68.16 H: 7.63 Found 68.15 7.62 Mass spectrum: (m / z): 264

[0082]

Example 9 5-O-benzyl-3-deoxy-D-ribose (9) Compound (8) obtained in Example 8 (8.94 g, 33.8)
2 mmol) was dissolved in 1,4-dioxane (200 ml), water (20 ml) 1N-hydrochloric acid (10 ml) was added,
The mixture was stirred at 70 ° C for 3 hours. The mixture was neutralized with 1N-sodium hydroxide aqueous solution, concentrated, diluted with water and extracted with chloroform. After drying over anhydrous magnesium sulfate and concentration, the residue was purified by silica gel column chromatography. Elution with cyclohexane-ethyl acetate (3: 1 to ethyl acetate) gave 4.55 g (60%) of the target compound (9).
%) As an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.87-2.54 (3H, m), 3.41-3.77 (3H, m), 4.
20-4.32 (1H, m), 4.46-4.67 (3H, m), 5.17-5.40 (1H, m), 7.26
-7.34 (5H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3417,3086,2936,2867,1717,1496,1454,1409,1361,1114,
1054,1001,961,944,912,867 Elemental analysis _{C 12 H 16 O 4 · 0.32mol} EtOAc = 252.45
1 calcd C: 63.18 H: 7.41 Found 63.17 7.56 Mass spectrum: (m / z): 224, 225 [M + H] ⁺

[0084]

Example 10 (2S, 4R) -1-Benzyloxy-2,4,5-trihydroxypep
(10) Compound (9) obtained in Example 9 (336 mg, 1.5 m
(mol) was dissolved in ethanol (5 ml), sodium borohydride (57 mg) was added under ice cooling, and the mixture was stirred for 1.5 hours. It was quenched with 0.1 N-hydrochloric acid, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
After concentration, the residue was purified by silica gel column chromatography. Dichloromethane-methanol (20: 1)
The target compound (10) (318 mg, 94%) was obtained as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.59-1.65 (2H, m), 2.30 (1H, broad), 3.0
3 (1H, broad), 3.35-3.66 (5H, m), 3.96-4.12 (2H, m), 4.56 (2
H, s), 7.26-7.36 (5H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3584,3474,2927,2867,1496,1454,1391,1365,1297,1097,
1061,1028,909,843 Elemental analysis _{C 12 H 18 O 4 · 0.48} molH 2 O = 234.92 calcd C: 61.35 H: 8.14 Found 61.16 8.15 Mass Spectrum: (m / z): 227 [M + H] +

[0086]

Example 11 (2 R , 4S) -5-benzyloxy-1-tert-butyldiphenyloxy
Ryloxy-2,4, -dihydroxypentane (11) Compound (10) obtained in Example 10 (300 mg, 1.3
3 mmol) was dissolved in dimethylformamide (5 ml), and tert-butylchlorodiphenylsilane (383 μl) and triethylamine (19.5 μm) in a nitrogen stream.
1) was added, and the mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with ethyl acetate, washed with 0.1N-hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography. Elute with n-hexane-ethyl acetate (3: 1) to obtain 488 mg (7%) of the desired product.
9%) as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.06 (9H, s), 1.51-1.70 (2H, m), 3.09 (1
H, d, J = 2.5Hz), 3.22 (1H, d, J = 1.9Hz), 3.43 (2H, d, J = 5.4H
z), 3.55-3.63 (2H, m), 3.97-4.06 (2H, m), 4.55 (2H, s), 7.26
-7.67 (15H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3583,3517,2933,2861,1472,1454,1428,1392,1363,1280,
1113,1029,1006,999,846 Mass spectrum: (FAB) ⁺ m / z C ₂₈ H ₃₆ O ₄ SiNa observed: 487.2254 calcd for: 487.2280 503 [M + K] ⁺ , 487 [M + Na] ⁺

[0088]

Example 12 (2R, 4S) -2,4-benzylideneoxy-5-benzyloxy-1
-tert-Butyldiphenylsilyloxypentane (12) Compound (11) obtained in Example 11 (480 mg, 1.0
3 mmol) was dissolved in dimethylformamide (5 ml), benzaldehyde dimethyl acetal (5 ml) and pyridinium paratoluenesulfonic acid (1 g) dissolved in dimethylformamide (5 ml) were added in a nitrogen stream, and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography. By eluting with n-hexane-ethyl acetate (20: 1), 448 mg (78%) of the objective compound (12) was obtained as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.05 (9H, s), 1.51-1.60 (1H, m), 1.76 (1
H, t, d, J = 13.0,2.5Hz), 3.54 (1H, d, d, J = 10.3,4.6Hz), 3.64
-3.72 (2H, m), 3.85 (1H, d, d, J = 10.4,5.3Hz), 3.99-4.16 (2
H, m), 4.61 (2H, d, d, J = 15.9,12.2Hz), 5.56 (1H, s), 7.27-7.
70 (20H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3073,2961,2932,2861,1472,1455,1428,1391,1363,1342,
1312,1113,1056,1028,1007

[0090]

Example 13 (2S, 4R) -2,4-benzylideneoxy-1-benzyloxy-5
-Hydroxypentane (13) Compound (12) obtained in Example 12 (440 mg, 0.8
mmol) in tetrahydrofuran (5 ml),
Tetra-n-butylammonium fluoride 1 mol tetrahydrofuran solution in a nitrogen stream (1 ml)
Was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Water was added and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After concentration, the residue was purified by silica gel column chromatography. n-hexane-ethyl acetate (2: 1)
The target compound (13) (246 mg, 98%) was obtained as white crystals (mp 53-55 ° C).

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 1.57-1.62 (2H, m), 1.98-2.03 (1H, broa)
d), 3.52-3.57 (1H, m), 3.62-3.75 (3H, m), 3.99-4.19 (2H,
m), 4.60 (2H, d, d, J = 13.9,12.2Hz), 5.60 (1H, s), 7.28-7.53
(10H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3601,2924,2869,1496,1454,1393,1363,1342,1139,1112,
1097,1055,1027,1013,968,838 Elemental analysis C ₁₉ H ₂₂ O ₄ · 0.48 molH ₂ O = 323.03 calcd C: 70.65 H: 7.16 Found 70.84 6.97 Mass spectrum: (m / z): 314

[0092]

Example 14 (2R, 4S) -2,4-benzylidenedioxy-5-benzyloxy
Dimethylsulfoxide (135 μl) was added to a solution of pentanal (14) oxalyl chloride (75 μl) in dichloromethane (1 ml) at −78 ° C., and 5 minutes later, the compound (13) obtained in Example 13 (100 mg, 0. A solution of 32 mmol) in dichloromethane (1 ml) was added. Stir at −78 ° C. for 15 minutes, add triethylamine (600 μl) and add 5
After stirring for 1 minute, the temperature was returned to room temperature. Water was added, the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography. n-hexane-
Elute with ethyl acetate (2: 1) to obtain the target compound (14) 93
Obtained mg (93%) as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δ ppm: 1.67 (1 H, d, tJ = 13.3, 11.9 Hz), 1.95 (1
H, t, d, J = 13.3,2.8Hz), 3.57 (1H, d, d, J = 9.9,5.3Hz), 3.69
(1H, d, d, J = 9.9,5.3Hz), 4.11-4.21 (1H, m), 4.36 (1H, d, d, J
= 11.9,2.8Hz), 4.60 (2H, s), 5.65 (1H, s), 7.29-7.57 (10H,
m), 9.74 (1H, s) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
2868,1740,1496,1454,1393,1364,1334,1103,1028,1001,
909 Elemental analysis C ₁₉ H ₂₀ O ₄ = 312.365 calcd C: 73.06 H: 6.45 Found 73.00 6.66 Mass spectrum: (m / z): 311 [MH] ⁺

[0094]

Example 15 (2S, 4R) -2,4-benzylidenedioxy-5-benzyloxy
-16-Methylheptade-5-cene (15) 11- methyldodecyltriphenylphosphonium salt (1.6 g) was dissolved in tetrahydrofuran (10 ml), and n-butyllithium (2.0 ml) was slowly added at -78 ° C. It was The mixture was stirred for 30 minutes at the same temperature, then returned to room temperature and further stirred for 30 minutes.

The compound (14) (100) obtained in Example 14 was used.
(mg, 0.33 mmol) was dissolved in tetrahydrofuran, a tetrahydrofuran solution of phosphorane was added at room temperature, and the mixture was stirred for 1 hour. After concentration, water was added and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography. Elution with n-hexane-ethyl acetate (20: 1) gave the desired compound (15) 88.
Obtained 4 mg (58%) as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 0.86 (6H, d, J = 6.6Hz), 1.13-1.65 (19H, 19H,
m), 2.07-2.17 (2H, m), 3.51-3.56 (1H, m), 3.65-3.71 (1H,
m), 4.11-4.20 (1H, m), 4.61 (2H, d, J = 2.23), 4.64-4.72 (1H,
m), 5.44-5.59 (2H, m), 5.62 (1H, s), 7.28-7.53 (10H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
2955,2928,2856,1467,1454,1386,1366,1336,1306,1300,
1120,1094,1028,1006,907 Mass spectrum: (FAB) ⁺ m / z C ₃₂ H ₄₆ O ₃ Na calcd for ： 501.3345 observed ： 501.3336 517 [M + K] ⁺ , 479 [M + H] ⁺ , 477 [MH] ⁺

[0097]

Example 16 (2S, 4S) -16-methyl-1,2,4-trihydroxyheptadeca
(16) Compound (15) obtained in Example 15 (86 mg, 0.18
mmol) in tetrahydrofuran (3 ml),
A 5% palladium carbon catalyst (10 mg) was added, and the mixture was stirred overnight at room temperature in a hydrogen stream. After filtering the catalyst, the filtrate was concentrated and purified by silica gel column chromatography. Dichloromethane-methanol (50: 1-20:
The product was eluted with 1) to obtain 31 mg (36%) of the desired product (16) as a white powder (mp 70 ° C.).

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 0.86 (6H, d, J = 6.6Hz), 1.10-1.69 (27H,
m), 2.46-2.58 (1H, broad), 3.49 (1H, d, d, J = 11.3,6.6Hz),
3.65 (1H, d, d, J = 13.3,3.3Hz), 3.87-3.98 (2H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3307,2953,2920,2850,2465,1471,1366,1336,1127,1101,
1068,1030,1012,843,720 Elemental analysis _{C 18 H 38 O 3 Na =} 325.488 calcd for: C: 66.42 H: 11.77 O: 21.81 Found: 66.21 11.87 21.92 Mass Spectrum: (m / z): 302 [MH] +

[0099]

Example 17 Diphenylmethyl 15-methyl-3 (S) -hydroxyhexa
Decanoate (17) Compound (16) obtained in Example 16 (31.4 mg, 0.
1 mmol) in dioxane (2 ml) and water (0.4 ml) dissolved in sodium metaperiodate (1
11 mg, 0.52 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was dissolved in water and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. 28 mg of the obtained oily aldehyde was dissolved in chloroform (5 ml), metachloroperbenzoic acid (28 mg) was added to shield the light, and the mixture was stirred at 50 ° C. for 1 hour. 56 mg of the obtained oily carboxylic acid was dissolved in ethyl acetate (5 ml), and diphenyldiazomethane (78 mg) was added.
The mixture was protected from light, stirred at 50 ° C. for 45 minutes and then concentrated, and the residue was purified by silica gel column chromatography.
Elute with benzene-ethyl acetate (19: 1) to obtain the desired product
(17) 40 mg (86%) was obtained as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 0.86 (6H, d, J = 7.0Hz), 1.14-1.55 (23H, 23H,
m), 2.58-2.61 (3H, m), 4.01 (1H, m), 6.91 (1H, s), 7.33-7.34
(10H, m). Infrared absorption spectrum (film): ν _max cm ^-1 : 292
6,2853,1736,1165,699 Elemental analysis C ₃₀ H ₄₄ O ₃ · 0.24 mmol H ₂ O = 45
7.00 calcd for: C: 78.85 H: 9.81 Found: 78.97 9.61 Mass spectrum: (m / z): 452

[0101]

Example 18 Diphenylmethyl 15-methyl-3 (S)-(13-methylteto
Radecanoyloxy) -hexadecanoate (18) The compound (17) obtained in Example 17 (40.0 mg, 0.
09 mmol) in the same manner as in Example 2 to give the target compound (1
8) 47 mg (79%) was obtained.

[0102]

Example 19 15-Methyl-3- (S)-(13-methyltetradecanoyloxy
Si) Hexadecanoic acid (19) Compound (18) obtained in Example 18 (47.0 mg,
07 mmol) by the same operation as in Example 3 (1
9) 33 mg (92%) was obtained.

[0103]

Example 20 [3-Hydroxy-2 (S)-{15-methyl-3 (S)-(13-methyl te
[Tradecanoyloxy) hexadecanoyl} amino] pre
Ropionate (20) Compound (19) obtained in Example 19 (16.0 mg, 0.
(03 mmol) by the same procedure as in Example 4
0) 12 mg (55%) was obtained.

[0104]

[Example 21] [3-hydroxy-2 (S)-{15-methyl-3 (S)-(13-methyl te
[Tradecanoyloxy) hexadecanoyl} amino] pre
Ropionic acid (21) Compound (20) obtained in Example 20 (10.0 mg, 0.
014 mmol) by the same procedure as in Example 5
(21) 9.0 mg (100%) was obtained. 270MHz¹H-NMR (deuterated chloroform): δpp
m: 0.86 (12H, d, J = 6.6Hz), 1.12-1.69 (44H, m), 2.30 (2H,
t, J = 7.5Hz), 2.52-2.56 (2H, m), 2.59-2.79 (2H, br), 3.84-
3.86 (1H, m), 4.06 (1H, dd, J = 7.3Hz, 2.1Hz), 4.52 (1H, s), 5.
20-5.23 (1H, m), 6.95 (1H, br, NH) Mass spectrum: FAB⁺ 620 [M + Na]⁺, 598 [M + H]⁺ [Α]_D= + 12.8 (C = 0.125, CHCl₃)

[0105]

Example 22 [3-Hydroxy-2 (R)-{15-methyl-3 (S)-(13-methyl te
[Tradecanoyloxy) hexadecanoyl} amino] pre
Ropionate (20) Compound (19) obtained in Example 19 (16.0 mg, 0.
03 mmol) and D-serine benzyl ester in Example 4
17 mg (77%) of the desired product (22) was obtained by the same procedure as described above.

[0106]

[Example 23] [3-hydroxy-2 (R)-{15-methyl-3 (S)-(13-methyl te
[Tradecanoyloxy) hexadecanoyl} amino] pre
Ropionic acid (21) Compound (22) obtained in Example 22 (17.0 mg, 0.
024 mmol) by the same operation as in Example 5.
(23) 14.0 mg (97%) was obtained. 270MHz¹H-NMR (deuterated chloroform): δpp
m: 0.86 (12H, d, J = 6.6Hz), 1.12-1.63 (44H, m), 2.31 (2H,
t, J = 7.5Hz), 2.55 (2H, d, J = 5.6Hz), 2.59-2.70 (2H, br), 3.8
8 (1H, d, J = 10.7Hz), 4.10 (1H, t, J = 10.3Hz), 4.56 (1H, s), 5.
18 (1H, t, J = 6.1Hz), 6.83 (1H, d, J = 5.8Hz, NH) Mass spectrum: FAB⁺ 620 [M + Na]⁺, 598 [M + H]⁺ [Α]_D＝ -13.7 (C = 0.175, CHCl₃)

[0107]

Example 24 [3-Hydroxy-2 (S)-{15-methyl-3 (R)-
(13-Methyltetradecanoyloxy) hexadecano
Il} amino] butanoate (24) Compound 3 obtained in Example 3 [15-methyl-3 (R)-
(13-Methyltetradecanoyloxy) hexadecanoic acid] (51.5 mg, 0.1 mmol) was dissolved in methylene chloride (2 ml), and oxalyl chloride (4
3.6 μl, 0.5 mmol) was added and the mixture was stirred at room temperature for 2 hours. The mixture was triturated, dried and dissolved in methylene chloride (1 ml).

L-Threonine-benzyl ester hemi-oxalate (39 mg, 0.15 mmol) was dissolved in methylene chloride and triethylamine (70 μl, 0.5
(mmol) and added dropwise to the acid chloride solution under ice cooling. The mixture was stirred for 30 minutes, the solvent was removed, and the product was purified by silica gel chromatography. Elute with cyclohexane-ethyl acetate (3: 1) to obtain 42 mg (59%) of the desired product.
Was obtained as an oil. 270 MHz ¹ H-NMR (deuterated chloroform): δppm: 0.86 (12H, d, J = 6.6Hz), 1.10-
1.63 (48H, m), 2.28 (2H, t, J = 7.5Hz), 2.54-2.57 (2H, m), 4.3
4 (1H, dd, J = 6.6Hz), 4.62-4.66 (1H, m), 5.20 (3H, d, J = 3.7H
z), 6.43 (1H, d, J = 8.6Hz), 7.33-7.36 (5H, m) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3435,2928,2855,1733,1679,1510,1467,1384,1265,1115 Elemental analysis _{C 43 H 75 NO 6 = 702.07} calcd C: 73.56 H: 10.77 N: 2.00 Found 73.31 10.97 2.02 Mass Spectrum: (m / z ): 702

[0109]

Example 25 [3-Hydroxy-2 (S)-{15-methyl-3 (R)-
(13-Methyltetradecanoyloxy) hexadecano
Il} amino] butanoic acid Compound (24) obtained in Example 24 (32.8 mg, 0.
05 mmol) was dissolved in ethyl acetate (2 ml),
% Palladium carbon catalyst (10 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen gas stream. The catalyst was filtered and concentrated under reduced pressure to obtain 3.6 mg (83%) of the desired product (18) as an oil.

270 MHz ¹ H-NMR (deuterated chloroform): δppm: 0.86 (12H, d, J = 6.6Hz), 1.12-1.64 (47H,
m), 2.28-2.32 (2H, m), 2.53-2.63 (2H, m, containeng 1H, br
oad, OH, at δ2.35-2.81), 4.47 (2H, t, J = 7.9Hz), 5.16-5.2
2 (1H, m), 6.80 (1H, d, J = 7.5Hz) Infrared absorption spectrum (chloroform): ν _max cm ^-1 ：
3418,2928,2855,1729,1676,1151,1468,1403,1384,1366,
1170,1117 Elemental analysis _{C 36 H 69 NO 6 · 0.32mmolH} 2 O = 617.712 calcd C: 70.00 H: 11.36 N: 2.27 Found 70.05 11.46 2.22 Mass ^{Spectrum: FAB + 634 [M + Na} ] +, 612 [M + H ] ⁺ [Α] _D = 1.4 (C = 0.94, CHCl ₃ )

[0111]

[Test Example 1] TNFα production inhibition activity of the amino acid-containing lipid compound of the present invention
Human monocyte U937 cells for use in Daniel-Isakani (Daniel
-Issakani) et al. (J. Biol. Chem., 264, pp. 20240-
20247, 1989), and cultured for 72 hours in a culture medium supplemented with 30 ng / ml of TPA to induce differentiation. Next, the culture supernatant was removed and LPS (lipopolysaccharide) 10 ng / ml was added.
Was added (hereinafter, referred to as LPS-treated cells). The same volume of culture medium was added to LPS-untreated cells. Furthermore, to the LPS-treated cells, a predetermined concentration of the test compound (the compound of Example 5 above) was dissolved in the culture medium and added at the same time as LPS (hereinafter referred to as test compound-treated cells). The same volume of culture medium was added to the control cells of the test compound-treated cells (hereinafter referred to as LPS-treated control cells). The amount of TNFα produced 6 hours after the addition of LPS was measured by ELISA kit.
(Manufactured by Endogen). The inhibition rate is defined as the value obtained by subtracting the production amount of LPS-untreated cells from the production amount of test compound-treated control cells, and the inhibition rate is defined as 0%. It was calculated from the numerical value minus the production amount. Table 2 shows the results.

[0112]

[Table 2] Cell TNFα (per 10 ⁵ pg cells) Suppression rate ────────────────────────────────── ─ LPS untreated cells 47.8 Test compound treated control cells 807 0% Test compound treated cells (0.1 μM) 597 26% Test compound treated cells (1.0 μM) 202 75% Test compound treated cells (10 μM) 64.6 92 % ────────────────────────────────── As is clear from Table 2, the amino acid-containing lipid compound of the present invention is shown. Reduces TNFα production by LPS treatment. Therefore, the amino acid-containing lipid compound of the present invention is
It is clear that it has an antagonism against erythrocyte and has a palliative effect on septic shock caused by infection by Gram-negative bacteria.

[0113]

INDUSTRIAL APPLICABILITY The present invention provides a novel amino acid-containing lipid compound, and further an efficient method for producing an amino acid-containing lipid compound. The amino acid-containing lipid compounds of the present invention act antagonistically on LPS to suppress the production of tumor necrosis factor, and are therefore useful for the prevention and treatment of septic shock.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 327/22 7106-4H C07D 207/16 233/64 106 (72) Inventor Junko Ogawa Shinagawa, Tokyo 1-2-58, Hiromachi, San-ku Incorporated company

Claims (16)

[Claims] 1. The following formula: (In the formula, R represents an amino acid or its ester, and R-CO
-Represents that an amide bond is formed by the amino group of the amino acid represented by R or its ester and the carbonyl group represented by -CO-, n and m independently represent an integer of 6 to 16, and X represents Indicates an oxygen atom or a sulfur atom. However, an amino acid-containing lipid compound or a salt thereof represented by the naturally-occurring optically active ornithine-containing lipid II and serine-containing lipid). 2. The amino acid-containing lipid compound or a salt thereof according to claim 1, wherein n and m each independently represent an integer of 9 to 13. 3. The amino acid-containing lipid compound or a salt thereof according to claim 1, wherein n and m are 11, respectively. 4. The amino acid-containing lipid compound or a salt thereof according to claim 1, wherein X is an oxygen atom. 5. The amino acid is an α-amino acid, according to claim 1.
5. The amino acid-containing lipid compound or salt thereof according to any one of items 1 to 4. 6. The amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan,
The amino acid-containing lipid compound or a salt thereof according to any one of claims 1 to 5, which is selected from the group consisting of tyrosine, valine, 2,4-diaminobutyric acid, and ornithine. 7. The amino acids are alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, threonine, tryptophan, tyrosine, valine, and 2,4. -The amino acid-containing lipid compound or a salt thereof according to any one of claims 1 to 5, which is selected from the group consisting of diaminobutyric acid. 8. The lipid compound containing an amino acid or the salt thereof according to claim 1, wherein the amino acid is serine or ornithine. 9. The amino acid-containing lipid compound or a salt thereof according to any one of claims 1 to 8, wherein the amino acid is either a D-amino acid or an L-amino acid. 10. The following formula: (In the formula, R represents an amino acid or its ester, and R-CO
-Represents that an amide bond is formed by the amino group of the amino acid represented by R or its ester and the carbonyl group represented by -CO-, n and m independently represent an integer of 6 to 16, and X represents A method for producing an amino acid-containing lipid compound represented by an oxygen atom or a sulfur atom),
The following steps: (a) The following formula: (Wherein R ¹ represents a protective group for a carboxyl group, Y represents a hydroxyl group or a thiol group, and n represents an integer of 6 to 16), and a compound represented by the following formula: (In the formula, m represents an integer of 6 to 16) and a step of condensing the compound in the presence or absence of a condensing agent; (b) if desired, the condensate obtained in the step (a) (C) reacting the compound or reactive derivative thereof obtained in the above step (a) or (b) with an amino acid compound or its ester, and (d) if desired A method comprising removing the ester group of the compound obtained in step (c). 11. The method for producing an amino acid-containing lipid compound according to claim 10, wherein X is an oxygen atom and Y is a hydroxyl group. 12. The reactive derivative is an azide compound, an active ester, a mixed acid anhydride, or an acid halide.
12. The method for producing the amino acid-containing lipid compound according to 10 or 11. 13. The following formula: (In the formula, R represents an amino acid or its ester, and R-CO
-Represents that an amide bond is formed by the amino group of the amino acid represented by R or its ester and the carbonyl group represented by -CO-, n and m independently represent an integer of 6 to 16, and X represents A method for producing an amino acid-containing lipid compound represented by an oxygen atom or a sulfur atom),
The following formula: (Wherein R, R-CO-, n, m, and X have the same meanings as defined above) or a reactive derivative thereof and an amino acid compound or ester thereof are reacted to obtain a compound obtained as desired. A step of removing an ester group from the method. 14. The following formula: (In the formula, R represents an amino acid or its ester, and R-CO
-Indicates that an amide bond is formed by the amino group of the amino acid represented by R or the ester thereof and the carbonyl group represented by -CO-, n and m independently represent an integer of 6 to 16, and X represents A therapeutic and prophylactic agent for septic shock comprising an amino acid-containing lipid compound represented by an oxygen atom or a sulfur atom) or a physiologically acceptable salt thereof as an active ingredient. 15. The therapeutic and prophylactic agent for septic shock according to claim 14, wherein the ester is an ester which is cleaved in vivo by a biological method such as hydrolysis to produce a free acid or a salt thereof. 16. The following formula: (In the formula, R represents an amino acid or its ester, and R-CO
-Represents that an amide bond is formed by the amino group of the amino acid represented by R or its ester and the carbonyl group represented by -CO-, n and m independently represent an integer of 6 to 16, and X represents A tumor necrosis factor production inhibitor comprising an amino acid-containing lipid compound represented by oxygen atom or sulfur atom) or a physiologically acceptable salt thereof as an active ingredient.