WO1999033787A1 - Amino acid derivatives - Google Patents

Abstract

Novel amino acid derivatives represented by the following general formula and salts thereof and chemokine receptor antagonists containing the same as the active ingredient: R?1-X1-ph-X2-A-Y-R2¿, wherein A represents an amino acid residue selected from among Arg, Lys and Orn or a peptide consisting of 2 or 3 amino acid residues selected from among Arg, Lys, Orn, Leu, Ala, Val, Ile, Gly, Glu and Asp which contains at least one of Arg, Lys and Orn; R?1 and R2¿ independently represent each alkyl, alkenyl, cholesteryl or hydrogen, provided that at least one of R?1 and R2¿ represents C¿12-30? alkyl, alkenyl or cholesteryl; X?1¿ is absent or represents -(C=O)-, -(C=O)-NH-, -(C=O)-O-, -NH-(C=O)-, -NH-(C=O)-NH-, -(S=O)-, -SO¿2?-, -NH-, -O-, -S-, etc.; X?2¿ is absent or represents -(C=O)-, -(S=O)-, -SO¿2?-, -NH-(C=O)-, etc.; Y is absent or represents -O-, -S-, -NH- or -NR?3¿; and ph is absent or present at an arbitrary substitution site of o-, m- or p-.

Description

 Description Amino acid derivative Technical field

 The present invention relates to a novel amino acid derivative and a salt thereof. Furthermore, the present invention relates to a chemokine receptor antagonist comprising this compound as an active ingredient. The compound of the present invention is used as a chemokine receptor antagonist for treating or preventing AIDS, allergic diseases, inflammatory diseases and the like. n landscape technology

 Chemokine (short for chemokine, cheraotactic cytokine) is a group of proteins having chemotactic activity on leukocytes, and is a CXC chemokine with one amino acid inserted between the first and second cystine. There is a chemokine subfamily and a CC chemokine subfamily with the first and second cysteines adjacent. The CXC chemokine has enabled the entry of T-cell lin- tropic HIV (T-HIV) into CD4-positive cells. The CC chemokine family includes RANTES, MIP-1 MCP-1, MCP-2, MCP-3, 1-309, and so on. CCR5, the second receptor of macrophage-1 ropic HIV (M-HIV), is present in CC chemokines. CC chemokines act alone, act on lymphocytes, eosinophils, basophils, and mast cells to migrate these cells, and also act to degranulate and release various inflammatory mediators. Interleukin 8 (lL-8) is also known as a chemokine.

According to a recent review (Internal Medicine ^ (2) 218-224 (1997)), Berger et al. Reported that G protein-binding receptor Yuichi CXCR4 was a CD4 of T cell lline-tropic HIV (T-HIV). That it was found to allow entry into negative cells I have. And it has been revealed that the physiological ligand of CXCR4 is a molecule belonging to the CXC chemokine (chemokine) called SDF-1.

 CXCR4 had already been found and cloned by the Matsushima group at Kanazawa University (now Tokyo University), and SDF-1 had already been cloned by the Honjo group at Kyoto University and the Kishimoto group at Osaka University.

 Furthermore, CC chemokines (^ chemokines such as RANTES, MIP-1 and others) discovered by other groups in the United States immediately before the discovery of CXCR4 have been reported to suppress HIV-1 infection.

 Ultimately, macrophages were found to have CCR5, and normal T cells were found to have CXCR4 along with CD4.

 As the chemokine receptor antagonist, a peptide consisting of 6 to 14 amino acids of Arg Arg Trp Trp Cys Xaa is used as an interleukin 8 antagonist (wo95 / 16702), and an indole derivative is used. Non-peptide interleukin-8 antagonists (JP-A-9-169729) and chemokine receptor antagonists containing piperidine derivatives (JP-A-9-249566) as active ingredients are known.

 The present inventors have conducted intensive studies to develop drugs that inhibit diseases caused by chemokines such as interleukin 8, RANTES, MIP-1 and SDF-1, and found that a novel amino acid derivative was obtained. On the other hand, they have found that they have an antagonistic effect on receptors such as RANTES, MIP-1 and SDF-1. Further, as a result of further study based on this finding, the present invention was completed.

That is, an object of the present invention is to provide a novel amino acid derivative and a chemokine receptor antagonist comprising the amino acid derivative as an active ingredient.c In the present invention, the amino acid derivative is one or more amino acid residues Means an amino acid derivative containing one amino acid residue and an amino acid derivative containing a peptide consisting of two or three amino acid residues together with a derivative consisting of two or three amino acid residues. Including the disclosure of the invention

 The present invention relates to an amino acid derivative represented by the following formula (1) or a salt thereof.

R for X ¹ — ph— X ² — A— Y— R ² ■ · · (I)

 In the formula, A is arginine containing at least one amino acid residue selected from the group consisting of arginine, lysine, and ordinine, or A or arginine, lysine, and ordinine; A peptide consisting of two or three amino acid residues selected from the group consisting of, lysine, ordinine, leucine, alanine, quinoline, isoleucine, glycine, glumic acid and aspartic acid Is shown.

X ¹ does not exist, or-(C = 0)-,-(00)-NH- '-(C = 0)-0-,-(C = 0)-S-,-NH- (C = 0) -, -NH- (C = S) -, - NH- (C = 0) -NH -, - NH- (C = S) - NH -, - (S = 0) -, - S0 2 - , NH-, -0- and -S-.

X ² is absent or - (C = 0) _, - (S = 0) -, - S0 2 -, - NH- (C = 0) - or - NH- (C = S) _ Is shown.

Y is absent, or - 0 -, - S -, - NH- or - NR ³ - shows the.

RR ² independently represents a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group. Or ^one of R ¹ and!? ^{2 represents} a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.

R ³ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.

Further, ph is not present, or when ph is present, the substitution position of the ph group may be any of ortho, meta and para. The present invention also relates to an amino acid derivative represented by the following formula (I) or a salt thereof.

R ¹ -X is ph-X ² -A-YR ² (I) In the formula, A represents an amino acid residue selected from D or L arginine, lysine and orditin.

X ¹ does not exist, or-(C = 0)-,-(C = 0)-NH-,-(C = 0)-0-,-(C = 0) -S-, -NH-( 00) -, -NH- (C = S) -, - NH- (C = 0) - NH-, -NH- (C = S) -NH -, - (S = 0) -, - S0 2 - , NH-, -0- and -S-.

X ² is absent or - (C = 0) -, - (S = 0) -, - S0 2 -, - NH- (C = 0) - or - NH- (C = S) - Is shown.

Y is absent, or - 0 -, - S-, -NH- or - NR ³ - shows the.

R′R ² is independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group. Or ^{one of} R ¹ !? ^{2 represents} a hydrogen atom, a straight-chain alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.

 R represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.

 The substitution position for the ph group may be any of ortho, meta and para.

The present invention also relates to an amino acid derivative having no ph group or X ^{2 in the} formula (I), that is, an amino acid derivative represented by the following general formula (I) or a salt thereof.

 In the formula (I), A represents an amino acid residue selected from the group consisting of arginine, lysine and ordinine;

X ¹ is absent, _ (C = 0) - , - (S = 0) -, - S0 2 -, - NH- (00) -, -NH- (c = s)-

Y is absent or represents -0-, -S- or -NR ^3- .

R ¹ and R ² are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group. Or ^one of R ¹ and R ² represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group. R ² may have an acyloxy group at the terminal.

R ³ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group. Further, the present invention relates to an amino acid derivative in which the ph group and X ² are not present in the formula (1) and ^two to three amino acids are peptide-bonded, that is, an amino acid derivative represented by the following general formula (3) Or its salts.

R ¹ -X then A- Y- R ² (I)

 Formula (wherein, A contains at least one amino acid residue selected from the group consisting of arginine, lysine and orditin, arginine, lysine, orditin, leucine, alanine, nokurin, isoleucine , Glycine, glutamic acid and aspartic acid, and a peptide consisting of two or three amino acid residues.

X ¹ is absent, - (00) -, - (S = 0) -, -S0 2 - - NH- (C = 0) -, or -NH- (C = S) - shows the.

Y is absent, - 0- '-S- or - NR ³ - shows the.

R ¹ and R ² are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group containing 1 to 5 double bonds, and a branched alkenyl group. Or ^one of R ¹ and R ² is a hydrogen atom, a straight-chain alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a straight-chain alkenyl group, or a branched alkenyl group. Show. Also R ² May have an acyloxy group at the terminal.

R ³ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a direct alkenyl group or a branched alkenyl group. Further, the present invention relates to a caffeine receptor antagonist comprising an amino acid derivative represented by the above general formula (1) or a salt thereof as an active ingredient. BEST MODE FOR CARRYING OUT THE INVENTION

 The amino acid derivative of the present invention is represented by the following general formula.

R to X ¹ -Ph-X ² -A- YR ² (I)

 In the formula, A is an arginine containing at least one amino acid residue selected from D or L arginine, lysine and orditin, or an amino acid residue selected from the group consisting of arginine, lysine and orditin. A peptide consisting of two or three amino acid residues selected from the group consisting of lysine, orthine, leucine, alanine, quinoline, isoleucine, glycine, glutamic acid and aspartic acid.

Γ does not exist, or-(00)-,-(C = 0) -NH-,-(C = 0)-0- '-(C = 0) -S-,-NH- (C = 0 ) -, -NH- (C = S ) -, -NH- (C = 0) -NH-, - NH- (C = S) - NH -, _ (S = 0) -, - S0 2 -, It represents a group selected from the group consisting of ΝΗ-, -0- and -S-.

X ² is absent or - (C = 0) -, - (S = 0) -, - S0 2 -, - NH- (C = 0) - or - NH- (C = S) - Is shown.

Y is absent, or - 0 -, - S- NH- or - NR ³ - shows the.

RR ² independently represents a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group containing 1 to 5 double bonds or a branched alkenyl group. Or ^one of R ¹ and!? ^{2 represents} a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group.

R ³ is a hydrogen atom, a linear alkyl group having 1-8 carbon atoms, a branched alkyl group, a linear It represents an alkenyl group, a branched alkenyl group or a cyclic alkyl group.

 Further, ph is not present, or when ph is present, the substitution position of the ph group may be any of ortho, meta and para.

In the amino acid derivative of the present invention represented by the above general formula (1), when there is one amino acid residue and no ph group and X ² are present, R ¹ is a linear alkyl having 4-8 carbon atoms. Group, branched alkyl group, cyclic alkyl group, linear alkenyl group or branched alkenyl group. R ² is an amino acid derivative that is a linear alkyl group, branched alkyl group, cyclic alkyl group, cholesteryl group, or linear alkenyl group or branched alkenyl group containing 1-5 double bonds, having 12-30 carbon atoms. Or X ¹ is absent, or-(c = o)-, and Y is -0- or -NH-, or a salt thereof.

In one amino acid residue, and the compounds according to the invention no ph group and X ² may be prepared by synthetic methods known peptide. For example, 1) a protected amino acid with a protected N-terminus of a given amino acid, R ² - by condensing YH (step 1), 2) removing the amino acid N-terminal protecting group (step 2), 3) R ¹ -Condensation with XZ (Step 3) (where Z represents a halogen atom, hydrogen atom or hydroxyl group) 4) Removal of amino acid side chain protecting group (Step 4) .

At the amino acid residue is one of the present invention, and, as the § amino acid derivative ph group and X ² is absent can be exemplified the following compounds.

4-methylpentanoyl-L-arginine-n-octadecyl ester (Compound No. 1)

Acetyl-shi-arginine-n-octadecyl ester (Compound No. 2) acetyl-L-arginine-n-hexadecyl amide (Compound No. 3) Compound No. 4) n-Hexadecanoyl-shi-arginine -n-hexadecylamide (Compound No. 5)

Acetyl-L-lysine-n-octadecyl ester (Compound No. 6) In the amino acid derivative of the present invention represented by the above general formula (1), when a ph group is present and there is one amino acid residue, A is an amino acid residue selected from arginine, lysine, and olunichi; R is a linear alkyl group having 4 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group, or a branched alkylene group; Represents a group. R ² may be a compound having a linear alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group having 1 to 5 double bonds, or a branched alkenyl group. Good. χι 、 χ

² , Α and Υ have the same meaning as above.

In the present invention, among the above compounds, a compound in which X ¹ is -0-, -NH- (C = 0)-, X ² is-(O 0)-, and Y is -0- or -NH- is desirable.

In one amino acid residue, and the compounds according to the invention no ph group and X ² may be prepared by known methods. For example, 1) an amino acid with a protected N-terminal of a predetermined § amino acid, by condensation of the R ² -Y- H (step 1), 2) removing the amino acid N-terminal protecting group (step 2), 3) Condensation of R i -X ¹ -Z and X ¹ -p -X ² -0R ⁴ (Step 3) (where R ⁴ represents a protecting group such as a methyl group); 4) Deprotection of R ⁴ If there is, activate (Step 4), 5)! ? ¹ - ^ph- X ² - Z and A '- Y - R ² and condensation of (Step 5) (wherein, Z is a halogen atom or a hydroxyl group, A' represents an amino acid side chain is protected), 6) It can be produced by removing the amino acid side chain protecting group (Step 6).

 The following compounds can be exemplified as the amino acid derivative of the present invention having a Ph group and one amino acid residue.

2- (Isopropyl-caproluvamoyl) -benzoyl- ぃ arginine-n-hexadecylamide (Compound No. 9) 3- (Isopropyl rubamoyl) -benzoyl-shi-arginine-n-hexadecylamide (Compound No. 10)

 4- (Isopropyl rubamoyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 11)

 3-(Isopropyl rubamoyl) -benzoyl-shi-lysine-n-hexadecylamide (Compound No. 12)

 2-(Isopropyl rubamoyl)-benzoyl-L-lysine-n-hexadecyl amide (Compound No. 13)

Benzyl-L-arginine-n-hexadecylamide (Compound No. 14) In the amino acid derivative of the present invention represented by the above general formula (1), the amino acid residue has 2 to 3 amino acids, and the ph group and X ² are When not present, R ¹ represents a straight-chain alkyl group, branched alkyl group, cyclic alkyl group, straight-chain alkenyl group or branched alkenyl group having 1 to 8 carbon atoms, and R ² has 12 to 30 carbon atoms. It is preferable to be a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group containing 1 to 5 double bonds or a branched alkenyl group. Also, A is composed of A ¹ and A ^2, A ¹ is D or L mouth prestige, Aranin, Nokuri down, isoleucine, Amino acid residue selected from the group consisting of glutamicum phosphate and Asupara Gin acid used, a ² is preferably be peptides binding with Amino acid residue selected from the group consisting of D or L of § arginine, lysine and ol two Chin, X ¹ in the case the general formula (1) is It is desirable that it does not exist or that-(C = 0)-and Y be -0- or -NH-.

The compound of the present invention having 2 to 3 amino acid residues and having no ph group and X ² can be produced by a known peptide synthesis method. The protected amino acid whose terminal is protected is condensed with R ² -Y-H (step 1), and 2) the amino acid N-terminal protecting group is removed (step 2), 3) If necessary, amino acids are sequentially condensed (Step 3), 4) Condensed with Ri-X-Z (Step 4), where Z represents a halogen atom, a hydrogen atom or a hydroxyl group. 5) Amino acid It can be produced by removing the side chain protecting group (Step 5). The following compounds can be exemplified as amino acid derivatives (peptide derivatives) of the present invention having 2 to 3 amino acid residues and having no ph group and X ² .

Acetyl-shi-leucyl-L-arginine-n-dodecylamide (Compound No. 15)

Acetyl-shi-leucyl-L-arginine-n-tridecylamide (Compound No. 16)

Acetyl-L-leucyl-L-arginine-n-tetradecylamide (Compound No. 17)

Acetyl-L-leucyl-L-arginine-n-hexadecylamide (Compound No. 18)

Acetyl-L-leucyl-L-arginine stearyl amide (Compound No. 19)

Acetyl-L-leucyl-L-arginine nonadecyl ester (Compound No. 20)

Acetyl-releucyl-shi-arginine eicosyl ester (Compound No. 21)

Acetyl-L-leucyl-L-arginine docosyl ester (Compound No. 22)

Acetyl-L-leucyl-L-arginine hexacosyl ester (Compound No. 23)

Acetyl-reloysyl-shi-arginine triacontyl ester (Compound No. 24)

Acetyl-L-leucyl-L-arginine cholesteryl ester (compound number twenty five)

 Examples of these salts include trifluoroacetate, hydrochloride, acetate, sulfate, lactate, maleate, methanesulfonate, oxalate, malonate, succinate, and fumarate. , Propionate, butyrate and the like.

 The present invention also relates to a chemokine receptor antagonist comprising the amino acid derivative or a salt thereof as an active ingredient.

 The amino acid derivative or a salt thereof according to the present invention is used for treating or preventing diseases caused by chemokines such as IL-8, RANTES, MIP-1 and SDF-1, such as AIDS, allergic diseases, and inflammatory diseases. Can be The amino acid derivative of the present invention or a salt thereof was administered to an ICR mouse in a single oral administration (dose of 500 mg / kg), and no deaths were observed after 6 days, indicating no acute toxicity. Is determined.

 The dosage can be 0.1 to 150 mg, preferably 1 to 100 mg, per 1 kg of body weight per day, which can be administered once or in several divided doses. Oral administration is desirable, but not limited to. Parenteral administration can be appropriately selected, for example, injection, transdermal, enteral administration and the like. In addition, the dose can be appropriately changed according to the patient's condition.

In the case of oral administration, the dosage form is such that powder or tablet, granule, capsule, suppository is obtained by adding one or more pharmaceutically acceptable additives to the amino acid derivative of the present invention or a salt thereof. , Injection, or oral liquid. Additives include, for example, magnesium stearate, sugar, lactose, dextrin, starches, methylcellulose, fatty acid glycerides, water, propylene glycol, macrogol, alcohol, crystalline cellulose, hydroxypropylcellulose, low degree of substitution Hydroxypropyl cellulose, carmelloses, povidone, polyvinyl alcohol, calcium stearate and the like can be mentioned. In addition, if necessary In addition, coloring agents, stabilizers, antioxidants, preservatives, pH regulators, tonicity agents, solubilizing agents, and / or soothing agents can be added. Granules, tablets or capsules can also be coated with a coating base such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate and the like. It is desirable that the amino acid derivative of the present invention be contained in a single dose in an amount of 0.1 to 500 mg, preferably 1 to 100 mg.

 Next, the method for producing the amino acid derivative of the present invention will be specifically described with reference to examples.

 In the following description, the following abbreviations may be used.

 WSCI; 1-Ethyl-3- (3-dimethylaminopropyl) -carbodiimid HOBt; 1-Hydroxybenzotriol

 Pmc; 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl

 DMF; N, N-dimethylformamide

 Fmoc; 9-fluorene methoxycarbonyl

 Boc; tert-butoxycarbonyl

 DMAP; 4-dimethylaminoviridine

 Bz; benzoyl

 Also, in the description of the structural formula of an amino acid derivative containing two or three amino acid residues, G is Gly, P is Pro, A is Ala, L is Leu, and R is Arg. , T represents ¾r, V represents Val, K represents ys, and E represents Glu. Next, the production method of the amino acid derivative of the present invention will be specifically described with reference to examples.

 [Example 1]

Preparation of 4-methylpentanoyl-L-arginine-n-octadecyl ester (Compound No. 1) (Formula α)

^{(1) N G -2, 2} , 5, Ryo, 8-Bae pointer methyl chroman - 6-sulphonyl -L- arginine - n-O click evening Synthesis of decyl ester _{(Arg ^ m -Od 3 H 3} τ)

500 rag of Fmoc-Arg (Pmc) was dissolved in 10 ml of methanol and water iml, adjusted to pH 8 with a 20% cesium carbonate aqueous solution, and concentrated under reduced pressure. It was azeotroped with DMF, the residue obtained by concentration under reduced pressure was dissolved in D FlOml, added MsO-C ₁₈ H _3T 789mg, for 24 hours閭攪stirred at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer is washed with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained is subjected to silica gel chromatography (Shiroguchi Form Z Methanol Z Water = 7/3 / 0.5) Purified to give 136 mg of the title compound as a cream solid.

JH NMR (500MHz, DMS0- _ds ) δ:

 6.75-6.30 (3Η, br), 4.02-3.94 (2 m), 3.26-3.21 (1Η, m), 3.07-3.00 (2Η, π, 2.58C2H, t, J = 6.5Hz), 2.50 (9H, 3s ), 2.48 (3H.s), 2.03 (3H, s), 1.77 (2H, t, J = 6.5Hz), 1.59-1.20 (36H, m), 0.85 (3H, t, J = 7.0Hz)

MS m / z (FAB); 693 (MH ⁺ )

 (2) Synthesis of 4-methylpentanoinole-L-arginine-n-octadecyl ester

18.5 mg of Arg (Pmc) -0Ci ₈ H ₃ T was dissolved in 0.37 ml of pyridine, 10.2 mg of WSCi hydrochloride and 0.51 of 4-methylpentanoic acid were added, and the mixture was stirred at room temperature for 3.5 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with a mixture of benzene / ethyl acetate = 1/2. After the organic layer was dried over anhydrous sodium sulfate, the crude product obtained by concentration under reduced pressure was dissolved in 0.2 ml of chloroform, 0.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1.5 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform / methanol = 5/1) to obtain 10.4 mg of the title compound as a colorless syrup. ^! H original (500MHz, DMSO-ds) o:

 8.17C1H, d, J = 7.5Hz), 7.57C1H, brs), 7.50-6.70 (2H, br), 4.26-4.18C1H, m), 4.07-3.99C2H, ni), 3.16-3.07 (2H, m) , 2.12 (2H 丄 J = 7.5), 1.80-1.70 (lH, m), 1.65-1.18C38H, m), 0.90-0.83 (9H, ni)

MS m / z (FAB); 525 (MH +)

 [Example 2]

 Preparation of acetyl-L-arginine-n-octadecyl ester (Compound No. 2) (Formula (2))

 AcSO ^ J (2)

(1) Asechiru ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl § arginine - II- O Kuta decyl ester (Ac-Arg (Pmc) - 0C IS H 37) Synthesis of

Arg synthesized by the method of Example _{1 (Pmc) - 0C 18 H} 37 17. was dissolved lm in pyridine lmg, acetic anhydride was added 5 \, and 2:00閭攪徉at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (chloroform / methanol-15 / 1) to obtain 16.7 mg of the title compound as a white solid. .

^J H MR (500MHz, DMS0- _ds ) δ:

 8.19C1H, J = 7.5Hz), 6.80-6.30C3H, br), 4.20-4.lKlH, m), 4.05-3.96 (2H, m), 3.08-2.98 (2H, m), 2.58 (2H, t ' J = 6,5Hz), 2.50 (9H, 3s), 2.47 (3H, s), 2.03 (3H, s), 1.78 (2H, t, J = 6.5Hz), 1.70-1.17C36H, m), 0.85 (C3H, t, J = 7.0Hz)

MS m / z (FAB); 735 (MH ⁺ )

 (2) Synthesis of acetyl-shi-arginine-π-ota decyl ester (Ac-Arg-OC I SHST)

Dissolve 15.70 mg of Ac-Arg (Pmc) -0Ci ₃ H3- in 0.16 ml of 0.16 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (form / methanol / water = 7/3 / 0.5 in quenched mouth) to obtain 8.2nig of the title compound as a white solid.

JH concealed (500MHz, DMS0- _ds ) δ:

 8.24C1 d, J = 7.5Hz), 7.52 (1H, brt), 7.47-6.50 (3H, br), 4.25-4.18 (lH 'n, 4.06-3.97 (2H, m), 3.14-3.04 (2H, m ), 1.85C3H, s), 1.75-1.6δ (1Η, m), 1.62- 1.45 (5H, m), 1.31-1.15C30H, m), 0.86 (3H, t, J = 7.0Hz)

MS m / z (FAB); 469 (H ⁺ )

 [Example 3]

Preparation of acetyl-L-arginine-n-hexadecylamide (Compound No. 3) (Formula (3))

 AcRNH ^ L-(3)

(1) N-9-Fluorenylmethoxycarbonyl--2,2,5,7,8-pentamethylchroman-6-sulfonyl-L-arginine-n-hexadecylamide (Fmoc-Arg (Pmc) NHC ₁₈ H ₃ 3) Synthesis of

 500 m of Fmoc-Arg (Pmc) 0H was dissolved in DMFlOml, 10.2 mg of WSCI hydrochloride, 203.9 mg of H0Bt, and 364 mg of n-hexadecylamine were added, and the mixture was stirred at room temperature for 5 hours. 1N Hydrochloric acid was added to the reaction solution, and extracted with a mixed solution of benzene / ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (ethyl acetate) to obtain 455 mg of the title compound as a white solid.

JH MR (500MHz, DMSO-ds) δ:

7.88C2H, d, J = 7.5Hz), 7.79 (lH, brt), 7.74-7.70 (2H, m), 7.45-7.40 (3H, m), 7.3 2H, t, J = 7.5Hz), 7.00-6.30 (3H, m), 429-4.18 (3H, m), 3.95-3.89C1H, m), 3.07-3.00 (4H, m), 2.57C2H, t, J = 6.5Hz), 2.50 (9H, 3s), 2.4 7 (3H, s), 2.02C3H, s), 1.75C2H, t, J = 6.5Hz), 1.67-1.15C32H, t, J = 7.0Hz), 0.85C3H, t, J = 7.0)

MS m / z (FAB); 886 GOT)

(2) Asechiru ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman-6-sulfonyl - L-§ arginine - II- to Kisadeshiruami de (Ac-Arg (Pmc) NHC ls H 33) Synthesis of

The Fmoc-Arg (Pmc) NHCi βΗ 33 40.7mg dissolved in DMF 0.16 ml, added Jechiruami down 16 ^ 1, and攪捽15 minutes at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was added to 0.9 ml of pyridine, 9 ul of acetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over sodium sulfate anhydride, concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (chloroform / methanol = 15/1) to give 13.4 mg of the title compound as a white syrup As obtained.

XH (500MHz, DMSO-ds) δ:

 7.91 (1Η, d, J = 8.0Hz), 7.84C1H, t, J = 5.5Hz), 6.72-6.30 (3H, br), 4.20-4.14 (lH, m), 3.07-2.98 (4H, m ), 2.59 (2H, t, J = 6.5Hz), 2.50C9H, 3s), 2.47 (3H, S), 2.03 (3H, s), 1.82 (3H, s), 1.78 (2H, t, J = 6.5Hz), 1.62-1.54 (1 H, m), 1.49-1.18 (31H, m) 0.85C3H, t, J = 7.0)

MS ni / z (FAB); 706 (MH ⁺ )

Synthesis of Kisadeshiruami de to _{n- (Ac-ArgNHC ls H 33} ) - (3) Asechiru -L- arginine

The _{Ac-Arg (Pmc) -NHC 18} H 3 3 llmg dissolved in black port Holm 0.11 ml, tri Furuoro acid o.iimi added, followed by stirring at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform / methanol / water = 7/3 / 0.5) to obtain 7.0 mg of the title compound as a white solid.

^ R (500MHz, DMSO-de) d:

8.0 (IH.br), 7.94C1H, br), 7.86-7.69 (2H, br), 7.37-6.80 (4H, br), 4. 23-4. 16C1H, m), 3.14-3. 00 (4H, m), 1.70-1.60 (1H, m), 1.57-1.19 (31H, m), 0.85C3H , t, J = 7.0Hz)

MS m / z (FAB); 440 (MT)

 [Example 4]

Preparation of n-hexadecanoyl-L-arginine-n-octadecyl ester (Compound No. 4) (Formula (4))

(1) n-to Kisade force Noiru ^{- N G - 2, 2,} 5, 7, 8- Bae pointer methylchroman-6-sul Honiru -L- arginine - n-O Kuta decyl ester (C _{1 5} H _{3 1} Synthesis of-(C = 0) -Arg (Pmc) 0C H ₃₇ )

77.3 g of Arg (Pmc) 0C _ls H3 synthesized by the method of Example 1 is dissolved in 0.35 ml of methylene chloride, and triethylamine 71 and 15 l of n-hexadecanoyl chloride are added thereto. Stirred. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform / methanol = 15: 1) to give 24.1 mg of the title compound. Was obtained as a white solid.

! H MR (500MHz, DMS0- _ds ) δ:

 8.10C1H, d, J = 7.5Hz), 6.80-6.30 (3H, br), 4.19-4.12 (1H, m), 3.98 (2H, t, J = 6.5Hz), 3 98C2H, t, J = 6.5Hz), 3.09-3.00 (2H, m), 2.58 (2H, t, J = 6.5Hz), 2.50 (9H, 3s), 2.47 (3H, s), 2 , 11-2.05 (2H, m), 2.03 (3H, s), 1.77 (2H, t, J = 6.5Hz), 1. T0-1.17C56H, m), 0.85 (6H, t, J = 7.0 Hz)

MS m / z (FAB); 930 (MT)

(2) n-hexadecanol-L-arginine-n-octadecyl ester (5

Synthesis of

20.5 ing was dissolved in 0.2 ml of form in mouth and 0.2 mi of trifluoroacetic acid was added, followed by stirring at room temperature for 4 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5/1) to obtain the title compound 4.nig as a colorless syrup.

! H NMR (500MHz, DMS0-d _e ) δ:

 8.16C1H.d, J = 7.0Hz), 7.49 (1H, brt), 7.35-6.60 (3H, br), 4.26-4.18C1H, m), 4.0K2H, t, J = 6.0Hz), 3.13-3.06 ( 2H, m), 2.16- 2.10 (2H, m), 1.79- 1.70 (lH, m), L 65-1.46C7H, m), 1.35-1.20 (48H, m), 0.85C6H, 2t, J = 7. OH z)

 [Example 5]

n-Hexadecanoyl-L-arginine-n-hexadecylamide (Compound No. 5) Preparation of Formula (5)

(1) n - to Kisadekanoiru ^{- N G - 2, 2,} 5, 7, 8- pentamethyl chroman - 6-sul Honiru -L- arginine - n-to Kisadeshiru Ryomi de _{(C 15 H 3I - (O0} ) -Arg (Pmc) HC ₁₆ H ₃₃ )

The _{Finoc-Arg (Pmc) NHCi S} H 33 38.2mg synthesized by the method of Example 1 was dissolved in DMF0,16m 1, added Jechiru completion Min 16 i, and攪捽15 minutes at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 0.6 ml of methylene chloride, triethylamine 121 and hexadecanoyl chloride 261 were added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (form: form / methanol = 20: 1). Purification gave 29.7 mg of the title compound as a white solid.

! H NMR (500MHz, DMS0-d ₃ ) δ

 7.82C1H, d, J = 8.0Hz), 7.58C1H, t), 6.90-6.30 (3H, br), 4.22-4.14 (1H, m), 3.07-2.98 (4H, m), 2.58 (2H 丄 J = 6. OHz) '2.50 (9H, 3s), 2,47 (3H, s), 2.12-2.07C2H, m), 2.03 (3H, s), 1.77C2H, t, J = 6.5Hz), 1.70-1.18 C56H, m), 0.85C3H, t, J = 7.5Hz)

MS ln / z (FAB); 902 (volume +)

(2) Synthesis of n-hexadecanoinole-L-arginine-n-hexadecylamide (C ₁₅ H ₃ (C = 0) -Arg HC _ls H ₃₃ )

Ci ₅ H ₃

Construed dissolved the ₈ H ₃₃ 22.8 mg in black port Holm 0.23 ml, added Torifuruoro acetate 0.23 ml, and stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol = 5: 1) to obtain 9.0 mg of the title compound as a white solid.

! H NMR (500MHz, DMS0-d ₈ ) δ

 7.90C1H, d, J = 7.0Hz), 7.81 (1H, t, J-6.0Hz), 7.44 (1H, brt), 7.35-6.60 (3H, br), 4.26-4.19C1H, m), 3 11- 2.97 (4H, m), 2.16-2.09 (2H, m), 1.70-1.60C1H, m), 1.52-1.18C53H, m), 0.85C6H, 2t, J = 7.OHz)

MS m / z (FAB); 636 (MH ⁺ )

 [Example 6]

Acetyl-L-lysine-octadecyl ester (Compound No. 6) (T-273) (Preparation of formula (6)

(1) Synthesis of N-9-fluorenylmethoxycarbonyl-ε-tert-butoxycarbonyl-L-lysine-n-octadecyl ester (Synthesis of Fmoc-Lys (Boc) 0C! ₃ H ₃ 100 mg of Fmoc-Lys (Boc) was dissolved in 2 ml of DMF, and 123 mg of WSCi hydrochloride, HOBtST mg and CisH3T0H173 mg were added, and the mixture was stirred at room temperature for 8 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with a mixture of benzene / ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product obtained was purified by silica gel chromatography (chloroform / methanol) to obtain 182.5 mg of the title compound as a white solid.

] H (500MHz, DMS0-d ₈ ) δ

 7.89C2H, d, J = 7.OHz), 7.78-7.69 (3H, m), 7.41 (2H, t, J = 7.0Hz), 7.33 (2H, t, J = 7.0Hz), 6.75 (1H, brt ), 4.40-4.20 (3H, m), 4.11-3.96C2H, m), 2.93 -2.88 (2H, m), 1.70-1.10 (39H.m), 0.85C3H, t, J = 7.5Hz)

MS m / z (FAB); 721 (MH ⁺ )

(2) Asechiru -L- lysine - n-O click evening decyl ester (Ac- Lys- 0C ₁₃ H ₃₇₎ of synthetic

The resulting solution was dissolved in 8 ml, digylamine (0.08 ml) was added, and the mixture was stirred at room temperature for 1 hour. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in pyridine (0.55 ml), acetic anhydride 101 was added, and the mixture was stirred at room temperature for 15 hours. To the crude product obtained by concentrating the reaction solution under reduced pressure was added 0.28 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (chloroform / methanol = 5/1) to give 3.3 mg of the title compound as a colorless syrup.

! H (500MHz, DMSO-ds) δ:

 8.20C1H, d.J = 7.5Hz), 7.53 (2H, brs), 4.22- 4.17 (1H, m), 4.08-3.98 (2F "m), 2.75C2H, t, J = 7.5Hz), 1.84 (3H , S), 1.72-1.15 (38H, m), 0.86 (3H, t, J = 7.0Hz)

MS m / z (FAB); 441 (MH ⁺ )

 [Example 7]

4-methylpentanoyl-L-lysine-n-hexadecylamide (Compound No. No. 7) (Formula (7))

(1) N-9- full O Les methoxycarbonyl - epsilon-tert-butoxycarbonyl two Le -L- lysine - to n- Kisadeshiruami de (Fmoc-to _{ys (Boc) -NHC ls H 3} 3) Synthesis of

? 1110 (: - 1 ^ 3 (80 (:) 585 ^ dissolved in 0 ^ 11. 7 ml, WSC 〖hydrochloride 718 mg, HOBt 506 mg, a C _IS H _{3 3} NH ₂ 452mg addition, at room temperature for 15 hours 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform.The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by methanol = 20/1) gave 792 mg of the title compound as a white solid.

JH jet 500MHz, DMS0- _ds ) δ:

 7.89C2H, d, J = 7.3Hz), 7.81 (1H, brt), 7.74-7.70 (2H, m), 7.44-7.40 (3H, m), 7.32 ( 2H, t, J = 7.3Hz), 6.77 (1H, brt), 4.26-4, 18C3H, m), 3, 91-3.86 (1H, m), 3.09-2.84 ( 4H, ra), 1.60-1.10 (43H, m), 0.85 (3H, t, J = 6.8Hz)

MS ra / z (FAB); 692 (MH ⁺ )

 (2) Synthesis of 4-methylpentanoyl-ε-tert-butoxycarbonyl-lysine-n-hexadecylamide

Fmoc-Lys and _{(Boc) -NHC ls H 3 3} 50mg dissolved in DMFl. Oml, added Jechiruamin 0. 1 ml, and stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in DMFl.Oml, 4-methylpentanoic acid 14 ^ 1, 21 mg of WSCI hydrochloride and 13 mg of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with 1N hydrochloric acid, extracted with chloroform, and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (chloroform / methanol-30 / 1) to give the title compound 34. 7nig was obtained as a white solid.

JH NMR (500MHz, DMS0- _ds ) d: 7.80C1H, d, J = 8.0Hz), 7.78-7.73 (1H, brt), 6.72-6.68C1H, brt), 4.19-4.11 [1H, m), 3.09-2.93 (2H, m), 2.90-2.83 ( 2H, m), 2.16-2.07 (2H, m), 1.60-1.1 7 (37H, in), 0.90-0.83C9 m)

 (3) Synthesis of 4-methylpentanoyl-L-lysine-n-hexadecylamide

32.5 ing of 4-methylpentanoyl-s-tert-butoxycarbonyl-L-lysine-n-hexadecylamide was dissolved in 0.3 ml of chloroform, 0.3 ml of acetic acid in trifluoromethyl was added, and the mixture was stirred at room temperature for 4.5 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform / methanol = ₁₀ / O) to obtain 13.7 mg of the title compound as a white solid.

lE NMR (500 MHz, DMSO-d ₈ ) δ:

 7.86C1H.d, J = 9.0Hz), 7.81-7.77 (1H, brt), 7.53 (2H, brs), 4.21-4.13 (1H, m), 3.06-2.98 (2H, m), 2.76-2.68 (2H , m), 2, 12 (2H, t, J = 8. OHz) '1.63-1. 17 (37H, m), 0.90-0.82 (9H.m)

MS m / z (FAB); 468 (MH ^<+> )

 [Embodiment 8]

 Preparation of pentanoyl-L-lysine-n-hexadecylamide (Compound No. 8) (Formula (8))

0

(1) Synthesis of pentanoyl-ε-tert-butoxycarbonyl-L-lysine-n-hexadecylamide

The _{Fmoc-Lys (Boc) -NHC ls} H 32 50mg dissolved in DMFl.Oinl, added Jechiruamin 0. lml, and stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 0.7 ml of pyridine, and 13 l of pentanoyl chloride was added. Stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (chloroform / methanol = 30/1) to give the title compound 19.Omg. Obtained as a white solid.

^! H NMR (500MHz, DMS0-d ₈ ) δ:

7.81-7. 74 (2Η, πθ '6.71 (1Η, brt), 4.19-4. I KIH, m), 3.09-2. 94 (2H, m), 2.89- 2.82C2H, m), 2, 13-2.06C2H, m), 1.60-1.10 (38H, m), 0.88-0.82 (6H, m) MS m / z (FAB) ; 554 (MH ⁺ )

 (2) Synthesis of pentanoyl-L-lysine-n-hexadecylamide

 14 mg of pentanoyl- £ -tert-butoxycarbonyl-L-lysine-n-hexadecylamide was dissolved in 0.2 ml of chloroform, 0.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4.5 hours. . The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform / methanol = 6/1) to obtain 19.8 mg of the title compound as a white solid.

! H NMR (500 MHz, DMS0-d ₆ ) δ:-. 7.85C1H, d, J-8.5 Hz), 7.79 (1H, t, J = 6. OHz), Ί, 65 (2H, brs ), 4.23-4.15 (1 m), 3.02-(2H, dd, J = 7.OHz, 13.OHz), 2.77-2.70 (2H, m), 2.12 (2H, t, J = 7.5Hz), l, 64-1.17 (38H, m), 0.90-0.82 (6H, m)

MS m / z (FAB); 468 (MH ⁺ )

 [Embodiment 9]

 Preparation of 2- (Isopropyl-rubamoyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 9) (Formula (9))

(T-290) (1) 2- (Isopropyl rubamoyl) -benzoic acid (Synthesis of Formula (9a)

 (Process 1)

 562.6ing of monomethyl phthalate was dissolved in 11.25 ml of DMF, and 1.197 g of WSC1 hydrochloride, 0.844 g of HOBt, and 0.321 ml of 2-aminopropane were sequentially added with stirring at room temperature, and the mixture was further stirred at the same temperature for 3 hours. The reaction solution is mixed with 1N hydrochloric acid, separated and extracted with a toluene: ethyl acetate = 1: 2 solution, and the organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product obtained by silica gel chromatography. Purification with 1- (n-hexane: ethyl acetate = 1: 1) yielded 742.2 mg of methyl-2- (isopropylpropyl rubamoyl) -benzoate as a colorless transparent viscous solid.

¹ H MR (500MHz, CDCls)

δ: 7.84C1H, d, J = 7.5Hz), 7.48 (1H, d, J = 7.5Hz), 7.43 (1H, t, J = 7.5Hz), 7.41 (1H, t, J = 7.5Hz), 5.77C1H, br.s), 4.26C1H, sept, J = 6.5Hz), 3.87 (3H, s), 1.26 (6H, d, J = 6, 5Hz)

MS m / z (FAB); 222 (MH ^<+> )

 (Process 2)

69 0.9 m of methyl-2- (isopropyl rubumoyl) -benzoate obtained in step 1 was dissolved in 6.91 ml of tetrahydrofuran and 6.91 ml of methanol, and 6.91 ml of a 1N aqueous sodium hydroxide solution was added with stirring at room temperature, followed by stirring for 1 hour. . 1N hydrochloric acid was added to the reaction mixture, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was chromatographed on silica gel (form: methanol = 1: 1). ) To give 317.3 rag of the title compound (Formula 4) as a colorless transparent viscous solid. ¹ H MR [500Mfiz, DMS0- _ds ) d: 8.38 (1H, br, s), 7.77 (1H, d, J = 7.5Hz), 7.49 (1 Et, J = 7.5Hz), 7.43C1H, t, J = 7.5Hz), 7.44 (1H, i J = 7.5Hz), 5.77ClH.br, s) 3.99C1H, sept, J = 6.5Hz), 1.12 (6H, d, J- 6.5Hz)

MS ni / z (FAB); 208 (MH ⁺ )

(2) N ^a -9 - Full O Les methoxycarbonyl -2,2,5,7,8- pen evening methyl chroman - 6-sulphonyl -L- arginine - to Kisadeshiruami de _{^{CFmoc-Arg (G) - 33}} 3 Synthesis of (Formula (9b)) ynoc-ArgC mc (9b)

 H

N σ -g-fluorenylmethoxycarbonyl-2,2,5, Ί, 8_pentamethylchroman-6-sulfonyl-L-arginine (Fmoc-Arg ( ^NG Pmc) -NH-0H) 544. 8m was dissolved in 10.90nil of DMF, and stirred at room temperature, 286.8mg of TWSC1 hydrochloride, 202mg of HOBt and 232.2mg of dexadecylamine were added, and the mixture was further stirred at the same temperature for 3 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was separated and extracted with a toluene: ethyl acetate == 1: 2 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product obtained was subjected to silica gel chromatography (n -Hexane: acetone = 1: 1) to give 645.4 mg of the title compound as a white solid.

1H NMR (500ffiz, DMS0-ds)

 <5: 7.88 (2H, d, J = 7.5Hz), 7.79 (1H, t), 7.74-7.70 (2H, m), 7, 457.40 (3 m), 7.31C2H, t, J = 7.5Hz), 7.00-6.30 (3H, m), 4.29-4.18 (3H, m), 3.95-3,89 (lH, m), 3.07-3.00 (4H, m), 2.56C2H, t, J = 6.5Hz) , 2.47 (6H, Sx2), 2.02 (3H, s), 1.75C2H, t, J = 6.5Hz), 1.67-1.15 (38H, m), 0.85 (3H, t, J = 7.0Hz)

(3) Synthesis of 2- (isopropyl rubamoyl) -benbuyl-L-arginine-n-hexadecylamide (Formula (9c)) The N-9-Furuorenirume Toki obtained in (2) aryloxycarbonyl ^{-N G -2, 2, 5,} 1, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - n-to hexa Deshiruami F [Fffloc- ^{arg (N G Pmc) -NH-} n- C 1S H 33] 421. ling dissolved in DMF8.422mi were 0.25 times閭stirred at the same temperature was added at room temperature under stirring Jechiruamin 0.842Ml. The reaction solution was separated extracted organic layer was concentrated under reduced pressure distilled water was added acetic Echiru the then dried and concentrated under reduced pressure sulfuric anhydride Natoriumu ^{N G -2, 2, 5,} 7, 8- Bae pointer methyl chroman - 6 -Sulfonyl-L-arginine-n-hexadecylamide [Arg (Ns Pmc) -NH-nC _1e H ₃₃ ]. Was obtained as a pale yellow viscous solid.

Next, 98.8 mg of 2- (isopropyl rubumoyl) benzoic acid obtained in the above (1) was dissolved in DMF1.976ffll, and under stirring at room temperature, 182.2 mg of WSCI hydrochloride and 28.4 mg of H0BU were added, followed by stirring for 10 minutes. the obtained ^{Arg (Ν σ Pmc) - HnC} ls crude product H ₃₃ added thereto, dissolved in DMF0.316Ml, and stirred for 20 hours at the same temperature. Distilled water and 1N aqueous hydrochloric acid were added to the reaction mixture, and the mixture was separated and extracted with a mouth-form. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product obtained was subjected to silica gel chromatography (chloroform-form). - black port Holm: methanol = 15: 1) to give 2- (isopropyl force Rubamoiru) - Benzoiru ^{-N G -2,2, 5, 7,} 8- pentamethyl chroman - 6-sulphonyl -L- arginine 341.9 mg of -n-hexadecyl amide (Formula 7) was obtained as a white solid.

 (Process 2)

To the 2- (isopropyl rubamoyl) -benzoyl- ^NG -2,2,5,7,8-pentanomethylchroman-6-sulfonyl-s-arginine-n- obtained in step 1 341.9 rag of xadecyl amide was dissolved in 3.419 ml of chloroform, and thioanifur 93.91 and 3.419 ml of trifluoroacetic acid were added thereto at room temperature with stirring, followed by stirring for 1 hour. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (chloroform: methanol = 10: 1 to 5: 1) to obtain 119.4 mg of the title compound (Formula 6) as a white solid. Was.

JH (500MHz, DMSO-ds)

 <5: 8.50 (1H, d, 8.0Hz), 8.40 (1H, d.8.0Hz), 8.05 (1H, t, J = 5.5Hz), 7.57 (1H, d, J = 6.0Hz) .7.52-7.48 (2H, m), 7.40 (1H, d, J = 6.0Hz), 4.40-4.28 (1H, m), 4.03C1H.sept, J = 7.0Hz), 3.15-3.05 (4H, m), 1.82-1.29 C36H, d, J = 7.0Hz), l.ll (6H, d, J = 6.5Hz), 0.85C3H, t, J = 7.0Hz)

MS m / z (FAB); 587 (MH ⁺ )

 [Example 10]

 Preparation of 3- (isopropylcapillumyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 10) (Formula (10))

 (T-288)

 3- (Isopropyl rubamoyl) -benzoic acid (synthesis of formula (10a)

(Process 1) 566.4 mg of monomethyl isophthalate was dissolved in 11.33 ml of DMF, and 1.205 g of WSCI hydrochloride, 0.850 g of H0Bt, and 0.323 ml of 2-aminopropane were sequentially added with stirring at room temperature, and the mixture was further stirred at the same temperature for 3 hours. 1N hydrochloric acid was added to the reaction mixture, and the mixture was separated and extracted with a toluene: ethyl acetate = 1: 2 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product obtained by silica gel chromatography. Purification was performed using (n-hexane: ethyl acetate = 1: 1) to obtain 615.6 mg of methyl-3- (isopropyl pyruvamoyl) -benzoate as a white solid. ^J H original (500MHz, CDCi ₃ )

 5: 8.33 (lH, s), 8.15C1H, d, J = 7.5Hz), 8.04C1H, d, J = 7.5Hz), 7.53C1H, t, J = 7.5Hz), 6.00 (lH, br, s) , 4.30 (1H, sept, J = 6.5Hz), 3.95 (3H, s), 1.29C6 d, J = 6.5Hz) MS m / z (FAB); 222 (MH +)

 (Process 2)

 615.6 mg of methyl-3- (isopropylcapilluvyl) -benzoate obtained in Step 1 was dissolved in 6.16 ml of tetrahydrofuran and 6.16 ml of methanol, and 6.91 ml of 1N aqueous sodium hydroxide solution was added with stirring at room temperature, followed by stirring for 1 hour. . 1N hydrochloric acid was added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was subjected to silica gel chromatography (form: methanol = methanol = 4: 1) to give 562.9 mg of the title compound (Formula 7) as a white solid.

_{NMR (500MHz, DMS0-d 6} )

5: 8.42 (lH, s), 8.07C1H, d.J = 8.0Hz), 8.06C1H, d, J = 8.0Hz), 7.58 (1H, t, J = 8.0Hz), 4.11 (lH, sept, J = 6.5Hz), 1.18 (6H, J = 6.5Hz)

MS m / z (FAB); 208 (MH +)

 (2) Synthesis of 3- (isopropyl rubumoyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 2) (Formula (10))

 (Process 1)

Example 9 N-9-fluorenyl methoxycarbonyl obtained in (2) - 2, 2, 5, 7, 8-pentamethyl chroman - 6-sulphonyl -L- arginine - Kisadeshiruami de to ^{n--CFmoc Arg (N G Pmc} ) -NH-n-Ci S H 33) 81.5oig the DMF After dissolving in 1.63 Oml, 0.163 ml of getylamine was added under stirring at room temperature, followed by stirring at the same temperature for 0.25 hours. The reaction solution is concentrated under reduced pressure, distilled water is added, and the mixture is separated and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated, and then N ° -2,2,5,7,8-pentamethylchroman-6-sulfo cycloalkenyl - crude product of L- Aruginin to -n- Kisadeshiru Ami de ^{[Arg (N s Pmc) -NH-} nC 18 H 3 3) as a yellow sticky solid.

Dissolve 19.lmg of 3- (isopropyl rubumoyl) -benzoic acid obtained in the above (1) in 0.382ml of DMF, add 35.2mg of WSC 〖hydrochloride, 24.9mg of H0Bt under stirring at room temperature, and stir for 30 minutes. ^Arg (Ν σ Pmc) obtained in - H- nC _iS H of crude product ₃₃ was added what was DMF0.122mU this dissolved, and stirred for 1.5 hours at the same temperature. Distilled water and 1N hydrochloric acid were added to the reaction solution, and the mixture was separated and extracted with a toluene: ethyl acetate = 1: 2 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purified by chromatography (black form to black form: methanol = 15: 1-10: 1), and 3- (isopropylcarbamoyl) -benzoyl- ^NG -2., 5,7,8-pentamethyl 35.2 mg of chroman-6-sulfonyl-L-arginine-n-hexadecylamide was obtained as a white solid.

 (Process 2)

Obtained in Step 1 3- (isopropyl force Rubamoiru) - Benzoiru ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - black and Kisadeshiruami de 35.2mg to n- The solution was dissolved in 0.352 ml of mouth form, and 0.352 ml of trifluoroacetic acid was added thereto with stirring at room temperature, followed by stirring for 3 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (form: methanol = _{10: 1} -5: ι) to give 10.0 mg of the title compound (Compound No. 10) as a white solid. Obtained. Ή 圆 (500MHz, DMS0-d ₅ )

 <5: 8.53 (lH, d, J = 8.0 Hz), 8.34 (1H, dr, s), 8.32 (lH, s), 7.99C2H, d, J = 9.5 Hz), 7,96 (lH, br , T), 7.54 (1H, t, J = 7.5Hz), 7.52 (1H, br, t), 7.30-6.8 0 (3H, m), 4.48-4.40 (1H, m), 4.12 (1H, sept, J = 7. OHz), 3.12-3.05 (4H, m), 1.82-1.29 (32H, d, J = 7. OHz), 1.18 (6H, d, J = 6. OHz), 0.85C3H, t, J = 7.OH z)

MS m / z (FAB); 587 (MH ⁺ )

 [Example 11]

 Preparation of 4- (isopropyl-powered rubamoyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 11) (Formula (11))

 (T-232)

 (1) 4- (Isopropyl rubamoyl) -benzoic acid (synthesis of formula (11a)

 (Process 1)

Dissolve 5 mg Llmg of monomethyl terephthalate in 11.42 ml of DMF, add 1.125 g of WSCi hydrochloride, 0.85 g of H0Bt, 0.326 ml of 2-aminopropane sequentially with stirring at room temperature, and stir at the same temperature for another 3 hours. . Add 1N aqueous hydrochloric acid to the reaction solution. Separation and extraction with a toluene: ethyl acetate = 1: 2 solution, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was subjected to silica gel chromatography (n-hexane: Purification was performed with ethyl acetate (1.5: 1) to obtain 592.4 mg of methyl- (4-isopropyl rubamoyl) benzoate as a white solid.

^J H NMR (500MHz, CDCU)

 δ: 8.08 (2Η, d, J = 8.0Hz), 7.80C2 d, J = 8.0Hz), 5.99 (1H, br, s), 4.29 (1H, sept, J = 7.0Hz), 3.94 (3H, s), 1.29C6H, J = 7. OHz)

MS m / z (FAB); 222 (H +)

 (Process 2)

 592.4 mg of methyl-4- (isopropylcapilluvyl) -benzoate obtained in Step 1 was dissolved in 5.92 ml of tetrahydrofuran and 5.92 ml of methanol, and 5.92 ml of a 1N aqueous sodium hydroxide solution was added with stirring at room temperature, followed by stirring for 1 hour. 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (cloform: methanol = 4: 1) to give 534. Omg of the title compound (Formula 11a) as a white solid.

! H anonymous (500MHz, DMS0-d ₆₎

 (5: 8. S5 (1H, d, J = 8.0Hz), 7.99 (2H, d, J = 8.2Hz), 7.90 (2H, d, J = 8.2Hz), 4.14-4.07C1H, m) , 1.17 (6H, d, J = 7. OHz)

MS ra / z (FAB); 208 (H +)

 (2) Synthesis of 4- (isopropyl rubamoyl) -benzoyl-L-arginine-n-hexadecylamide (Compound No. 11)

 (Process 1)

Example 9 (2) obtained in Furuorenirume Tokishikarubo nil ^{- Ν σ -2, 1, 5} , Ί, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - .eta. to hexa Deshiruami de [Fmoc-Arg ( ^σ Pm -NH-nd ₈ Η ₃₃ ) 57.2mg to DMF1.145ml After dissolving, 0.115 ml of getylamine was added under stirring at room temperature, and the mixture was stirred at the same temperature for 0.25 hours. The reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was separated and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain ^NG- 2, 2, 5, 7, 8-pentamethylchroman- 6-Sulfonyl-L-arginine-n-hexadecylamide [ArgO Pmc) -Hn-Ci6H ₃₃ was obtained as a pale yellow viscous solid.

Dissolve 13.4 mg of 4- (isopropyl lubamoyl) -benzoic acid obtained in (1) above in 0.536 ml of DMF, add 24.8 mg of WSCI hydrochloride and 7.5 mg of H0Btl under stirring at room temperature, and stir for 1 hour. obtained Arg (N ^G Pmc) - HnC the耝product _ls H ₃₃ added those obtained by MF0 .086MU this dissolution, the mixture was stirred for 2 hours at the same temperature. Distilled water and 1N hydrochloric acid were added to the reaction mixture, and the mixture was separated and extracted with a toluene: ethyl acetate = 1: 2 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Purified by i- (form-form-form-form: methanol = 10: 1), 4- (isopropyl-rubamoyl) -benzoyl--2.2,5,7,8-pentamethylchroman-6-sulfonyl -S-Arginine-n-hexadecylamide (Formula llb) (40.1 mg) was obtained as a white solid.

0 Arg (N ^G pmc) -N

(lib)

H

 (Process 2)

The obtained in Step 1 4- (Isopuropiru force Rubamoiru) - Benzoiru -N ^G -2, 2,5,7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - Kisadeshiruami de 40. lmg to n- Was dissolved in 0.401 ml of chloroform and stirred at room temperature, 0.401 nil of trifluoroacetic acid was added, and the mixture was stirred for 3.5 hours. Reaction solution The S product obtained by concentrating under reduced pressure was purified by silica gel chromatography (chloroform: methanol = 10: 1 to 5: 1) to obtain 36.4iiig of the title compound as a pale yellow solid.

! H MR (500MHz, DMS0- d 3)

 d: 8.53C1H, d, J = 8.0Hz), 8.32QH, d, J = 7.0Hz), 7.96C2H, d, J = 8.0Hz), 7.92C2K d, J = 8.5Hz), 7.50 (lH, br, t), 7.30-6.80 (3H, in), 4.48-4.40 (IE m), 4.12 (lH, sept, J = R, 0 Hz), 3.12-3.05 (4H, m), 1.82-1.29 (33H, d, J = 7.0Hz), 1.22C6H, d, J = 6.0Hz) 0.85C3H, t, J = 7.0Hz)

 [Example 12]

 Preparation of 3- (isopropylcarbamoyl) -benzoyl-L-lysine-n-hexadecyl amide (Compound No. 12) (Formula (12))

0

(12) people

(1) Synthesis of N-9-fluorenylmethoxycarbonyl-ε-tert-butoxycarbonyl-L-lysine-Q-hexyldecylamide Fmoc-Lys (Boc) -NH-n-Ci ₈ H33]

585 mg of Fnioc-Lys (Boc) -0H was dissolved in 12 ml of F, 720 mg of WSCI salt, 510 mg of H0Bt, and 450 mg of n-hexadecylamine were added, and the mixture was stirred at room temperature for 15 hours. Hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel chromatography (form: methanol = 20: 1) to give the title compound 792nig in white. Obtained as a solid. (2) Method for preparing 3- (isopropyl-potamoyl) -benzoyl-ε-tert-butoxycalponyl-L-lysine-n-hexadecylamide

The Fmoc-Lys (Boc) -NH- nC 1e H 33 45.5mg dissolved in DMFlml, added Jechiruami down O.Lmi, and撹捽15 minutes at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 6 ml of DMFO, and 25 mg of WSCI hydrochloride, 16 mg of DMAP, and 15 mg of 3-isopropyl rubamoyl-benzoic acid obtained in (1) of Example 2 were added. The mixture was stirred at room temperature for 2 minutes. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained product was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title compound 31. lnig as a white solid. As obtained.

Ή NMR (500MHz, DMS0- _ds )

d: 8.44 (lH, d, J = 7.5Hz), 8.32 (1H, d, J = 8.0Hz), 8.30 (lH, s), 7.99 (1H, d, J = 8.0Hz), 7.96C1H, d, J = 8.0Hz), 7.92 (lH, brt), 7.53C1H, dd, J = 8.0Hz), 6.73C1H, brt), 4.43-4.37 (1H, m), 4.15-4.08 (IE m), 3.11-2.98 (2H, m), 2.93-2.87C2H, m), 1.75_1, 68 (2H, m), 1.42- 1.16 (38H, m), 0.85C3H, t, J = 7.0Hz)

 MS m / z (FAB); 659 (MT)

 (3) Synthesis of 3- (isopropylcapilluvyl) -benzoyl-L-lysine-n-hexadecylamide (Formula 12)

 Dissolve 26.4 mg of 3- (isopropylcapilluvyl) benzoyl-s-tert-butoxycarbonyl-L-lysine-n-hexadecylamide in 0.3 ml of chloroform, add 0.3 ml of trifluoroacetic acid and stir at room temperature for 45 minutes. I did. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography- (form: methanol = 5: 1) to obtain 28.1 mg (formula 12) of the title compound as a white solid.

: Η new (500MHz, DMSO-ds)

<5: 8.50 (lH'd, J = 8.5Hz), 8.33C1H, d, J = 6.5Hz), 8.32 (lH, s), 8.00 (lH, d , J = 8, 0Hz), 7.97C1 d, J = 8.0Hz), 7.93 (1H, t), 7.63 (2H, brs), 4.47-4.39 (lH, ni), 4.16-4.08 (lH, m), 3.09-3.03C2H, m), 2.82-2.73 (2H, m), 1.8

1-1.70 (2H, m), 1.45-1. 16 (36H, m), 0.85 (3 t, J = 7.5Hz)

MS m / z (FAB); 559 (MH ⁺ )

 [Example 13]

 Preparation of 2- (isopropyl rubamoyl) benzoyl-L-lysine-n-hexadecyl amide (Compound No. 13) (Formula (13))

The resulting Fmoc- Lys (Boc) -NH-nC ls H 33 41mg (1) of Example 12 was dissolved in D F0.8 ml, added Jechiruamin 0.08 ml, was stirred for 25 minutes at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 3 ml of DFO, and 23 mg of WSCI hydrochloride, 15 mg of DMAP, and 14 mg of 2-isopropyl rubamoylbenzoic acid obtained in (1) of Example 1 were added. The mixture was stirred at room temperature for 20 hours. 1N Hydrochloric acid was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in 0.5 ml of chloroform, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (form: methanol = 5: 1) to obtain 33.lmg of the title compound (Formula 13) as a white solid.

JH NMR (500MHz, DMSO-ds)

(5: 8.47 (1H, d, J = 7.5Hz), 8.40C1H, d, J = 7.5Hz), 8.04 (1H, t, J = 5.5Hz), 7.7K2H, brs, 7.58-7.40 (4H , m), 4.26-4.21 (1H, m), 4.07-4.00 (1H, m), 3.14-3. 07C2H, ra), 2.87-2.73 (2H, m), 1. 96-1.83C1E m), 1.65-1.35 (4H, m), 1.28 (28H, brs), 1.15 (3H, d, J = 6.5Hz), 1.14C3H, d, J = 6.5Hz), 0.86C 3H, t, J = 7.5Hz)

MS m / z (FAB); 559 (MT)

 [Example 14]

Preparation of Benbuyl-L-arginine-n-hexadecylamide (Compound No. 14) (Formula (14))

W- Benzoiru ^{-N G - / 2,2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - n-to Kisadeshiruami de Synthesis of

Example 9 (3) Arg obtained in step 1 (N Pmc.) -. The _S H ₃₃ 15. Ryo mg was dissolved in pyridine 0.3 ml, Benzoiruku chloride de 3.3 l was added, stirred for 1 hour at room temperature did. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (form: methanol = 20: 1) to give 12.5 mg of the title compound as a colorless syrup Obtained.

: H MR (500MHz, DMS0- _ds )

δ: 8.34C1H, d, J = 7.5Hz), 7.89C2H, d'J = 7.OHz), 7.61 (2H, t'J = 7.OHz), 7.58-7.45 (3H, m), 6.80 -6.30 (3H, br), 4.42-4.35C1H, m), 3, 10-3.00 (4H, m), 2.56C2H, t, J = OK.OHz), 2.46 (6H, 2s), 2.01 (3H , s), 1.76 (2 t, J = 7. OHz), 1.73 -1. 13 (38H, m), 0.85C3H, t, J = 7. OHz)

MS m / z (FAB); 767 (MT)

^{Bz-Arg (N G Pmc)} - the HNC _ls H ₃₃ 10.0 mg dissolved in black port Holm 0. 1 mi, added Torifuruoro acetate 0. 1 ml, was擾律2 hours at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol = 5: 1) to give the title compound. 3 completed

^: H 囊 (500MHz, DMS0-d _s )

 δ: 8.40C1H, d 'J-8.0Hz), 7.97-7.89 (3H,), 7.60 (1H, brt), 7.54 (1H, t, J = 7.5Hz), 7.46C2H, t J-7.5Hz), 7.40-6.80 (3H, br), 4.45-4.37C1H, m), 3.17 -3.04 (4H, m), 1, 88-1.20 (32H, m), 0.85 (3H, t, J-7.0Hz)

MS inA (FAB); 502 (MH ⁺ )

 [Example 15]

Acetyl-L-leucyl-L-arginine-n-dodecylamide (Compound No. 15) Preparation of Formula ₍₁₅₎

(1) Asechiru port Isil ^{- N G -2, 2, 5} , 7, 8- pentamethyl chroman - 6- scan Ruhoniru -L- arginine - n-Dodeshiruami de (Ac-Leu-Arg (Pmc ) - HC 12 H ₂₅ )

124.4 mg of n-dodecylamine, 90.7 mg of HOBt, and 200 mg of Ac-Leu-Arg (pmc) were dissolved in 2 ml of black-mouthed form and cooled to 0 ° C. A solution prepared by dissolving 128.7 mg of WSCI hydrochloride in 1.2 ml of black mouth form was added thereto, and water was added to the reaction solution _c which had been left overnight at step 2, followed by extraction with black mouth form. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 15: 1) to give 250.7 mg of the title compound as a colorless syrup As obtained.

! H ((500MHz 'DMS0- _ds ) δ

7.97C1 d, J = 7.5Hz), 7.83 (1H, d, J = 8.0Hz), .18 (1H, t, J-5.0Hz), 6.78-6.2i (3H, br), 4.24 (lH, dt, J = 7.5,8.0Hz), 4.16-4.13 (1H, m), 3.08-2.9 4 (4H, m), 2.59C2H, t, J = 7.0Hz), 2.47 (6H, 2s), 2.03 (3H , s), 1.83 (3H, s), 1.78C2H, t, J = 6.0Hz), 1.68-1.51 (1H, m), 1.49-1.15 (32H, m), 0.88-0. 82 (9H, m)

 MS ni / z (FAB); 763 GOT)

 (2) Synthesis of acetyl-L-leucyl-L-arginine-n-dodecylamide

Ac-Leu-Arg (Pmc) -HCi ₂ H25 lOOmg was dissolved in black-mouthed form lnil, trifluoroα-acetic acid lml was added, and the mixture was allowed to stand at room temperature overnight. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 8: 1) to obtain 50.3 mg of the title compound as a colorless syrup.

^J Hatsu (500MHz, DMS0- _ds ) δ:

 8.00 (1H, d, J = 8.0Hz), 7.93 (1H, d, J = 8.5Hz), 7.74 (1H, t, J = 5.5Hz), 7.48 (1H, t, J = 5.5Hz), 7.38- 6.51 (3H, br), 4.26-4.19 (3H, m), 4.18-4.11 (1H, m), 3.12-2.94 (4H, m), 1.84 (3H, s), 1.71-1.15 (25H, m), L10 (2H, t, J = 7.0Hz), 0.90-0.83 (9H, m)

MS m / z (FAB); 497 (MH ⁺ )

 [Example 16]

 Preparation of acetyl-L-leucyl-L-arginine-n-tridecylamide (Compound No. 16) (Formula (16))

 AcLW- ^ '-' (16)

 ノ 1.2

(1) Asechiru -L- mouth Isil -N ^G -2,2,5, Ryo, 8-pentamethyl chroman - 6-sulphonyl -L- arginine - n-Torideshiruami de (Ac- Leu-Arg (Pmc) -NH Synthesis of C13H2T)

133.8 mg of n-tridecylamine, 90.7 mg of HOBt, 200 mg of Ac- and eu-Arg (Prac) were dissolved in 2 mi of porcine form. Cooled to C. A solution prepared by dissolving 128.7 mg of WSCI hydrochloride in 1.2 ml of black-mouthed form was added thereto, and allowed to stand at 2 ° C overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Purification by chromatography (form: methanol = 15: 1) gave 255 mg of the title compound as a colorless syrup.

lE Note (500MHz, D S0-d _e ) δ:

 7.98C1H, ά, J = 7.5Hz), 7.83 (1H, d, J = 8.0Hz), 7.72C1 brt), 7.11-6.22C 3H, br), 4.24 (lH, m), 4.19-4.10 (1H, m), 3.09-2.92 (4H, m), 2.59C2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.03C3 s), 1.83 (3H, s), 1.78 (2H, t, J = 6.5Hz) '1.68-1.52C2 m), 1.51-1.09C33H, m), 0.88-0.82C9H, in)

MS m / z (FAB); 777 (MT)

 (2) Synthesis of acetyl-L-leucyl-L-arginine-n-tridecylamide

The Ac-Leu-Arg (Pmc) -NHC 1 3H 2 7 150mg was dissolved in black port Holm L 5 ml, the door Rifuruoro acetate 1.5mi was added, and allowed to stand overnight at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 11.5ing of the title compound as a colorless syrup.

^! H NMR (500MHz, DMS0- _ds ) δ:

8,00 (lH, d, J-7.0Hz), 7.94 (1H, d, J = 7.5Hz) .7.56 (1H, t, J = 5.5Hz), 7.50 (lH'brt), 7.41-6.52 (3H , br), 4.29—4.21 (1H, m), 4.20-4. IKIH 'm), 3.11-2.98C4H, m), 1.84 (3H, s), 1.71-1.11 (29H, m), 0.88- 0.83 (9 m) MS m / z (FAB); 511 (MH ⁺ )

 [Example 17]

Acetyl-L-leucyl-L-arginine-n-tetradecyl amide (Compound No. 17) (Formula 1 (17))

AcL NIH ^ (17) Asechiru -L- leucyl ^{-N c -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - n-tetradecyl amine de (Ac-Leu-Arg ( Pnic) -N HC ₁₄ H ₂₉ ) 143.3 mg of n-tetradecylamine, 90.7 mg of HOBt, 200 nig of Ac-Leu-ArgCPmc) were dissolved in 2 ml of chloroform and cooled to 0 ° C. To this was added a solution prepared by dissolving 28.7 mg of WSCi hydrochloride in 2 ml of black-mouthed form, and allowed to stand at 2 ° C for 2 days. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 15: 1) to give 256.5 mg of the title compound as a colorless syrup. Was.

^ NMR (500MHz, DMSO-d5) δ:

 7.98 (1Η, d, J = 7.5 Hz), 7.83 (1H, d, J = 8.0 Hz), 7.72 (1H, brt), 6.95-6.20 (3H, br), 4.24-4.22 (lH , m), 3.09-2.95 (4H, m), 2.86 (2H, t, J = 7.0Hz), 2.47 (6H, 2s), 2.03C3H, s), 1.83 (3H, s), 1.78 (2H, t, J = 6. OHz), 1.68-1.51 (2H, m), 1.50-1.02C36H, m), 0.88-0.82C9H, m)

MS m / z (FAB); 791 (MH ⁺ )

(2) Synthesis of acetyl-L-leucyl_L-arginine-n-tetradecylamide Ac-Leu-Arg (Pmc) -NHC i 4H2 ₉ Dissolve 150 mg in 1,5 ml of chloroform and add trifluoroacetic acid 1 5π was added and left at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (chloroform: methanol = 8: 1) to give 6.7 mg of the title compound as a colorless syrup.

 H NMR (500MHz, DMSO-de) δ

8.00C1H, d, J = 8.0Hz), 7.94 (1H, d, J = 8.0Hz), 7.75 (1H, t, J = 5.5Hz), R.45 (lH, brt), 7.38-6.47 C3H, br), 4.26-4.24 (1H, m), 4.23-4.18 (1H, m), 3.09-3.01C4H, m), 1.84 (3H, s), 1.72-1.10 (31H , M), 0.90-0.83 (9H, m) MS m / z (FAB); 526 (MH ⁺ )

 [Example 18]

Acetyl-shi-leucyl-L-arginine-n-hexadecylamide (Compound No. 18) (Formula 1 (18)) Ac-

(18)

(1) Asechiru -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pen evening methyl chroman - 6-sulphonyl -L- arginine - _n - to Kisadeshiruami de (Ac-Leu-Arg (Pmc ) - synthesis of N HC _{1 S} H ₃₃₎

 143.3 mg of n-hexadecylamine, 90.7 mg of HOBt, and 200 mg of Ac-Leu-Arg (Pmc) were dissolved in 2 ml of n-form and cooled to zero. A solution of 28.7 mg of WSCI hydrochloride in 1.2 ml of black-mouthed form was added thereto, and left at 2 C for 2 days. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate anhydride and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 15: 1) to obtain 272.9 mg of the title compound as a colorless syrup. Was.

_{NMR (500MHz, DMS0-d 8} ) δ

7.98C1H, d, J = 7.5Hz), 7.83 (1H, d, J = 8.0Hz), 7.72 (1H, fart), 6.94-6.19 (3H, br), 4.24C1H, dt , J = 8.0, 7.5Hz), 4.18-4.10 (1H, m), 3.05-2.94 (4H, m), 2.58 (2H, t, J = 6.5Hz), 2.47 (6H, 2s ), 2.03C3H, s), 1.83 (3H, s), 1.77 (2H, t, J-6.5Hz), 1.64-1.51 (2H, m), L50-1.07C39H, m), 0.88 -0.82 (9H, m)

MS m / z (FAB); 819 (MH ⁺ )

(2) Synthesis of acetyl-L-leucyl-L-arginine-n-hexadecylamide Ac-Leu-Arg (Pmc) -NHC _ls H3 150 mg was dissolved in 1.5 ml of chloroform and 1.5 ml of trifluoroacetic acid. In addition, it was left overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel gel chromatography (chloroform: methanol = 8: 1) to obtain 29.8 mg of the title compound as a colorless syrup.

^: H NMR (500MHz, DMS0- _ds ) o:

8.00 (lH, d, J = 7.5Hz), 7.94C1H, d, J = 8.0Hz), 7.54 (lH, brt), 7.45C1H, br t), 7.41-6.59 (3H, br), 4.29-4.11 (2H, m), 3.16-2.98C4H, m), 1.84C3H, s), 1.73-1.14C35H.m), 0.88-0.83 (9H.m )

MS m / z (FAB); 553 (MH +)

 [Example 19]

Preparation of acetyl-shi-leucyl-L-arginine stearyl amide (Compound No. 19) (Formula (19))

 AcL H-^-(19)

(1) Asechiru -L- leucyl - N ^G -2,2,5,7, 8- pentamethyl chroman - 6- scan Ruhoniru -L- arginine stearyl § mi de (Ac- by eu-Arg (Pmc) - HC ₁₃ synthesis of H _3T)

 181 mg of stearylamine, 90.7 mg of HOBt, and 200 mg of Ac-Leu-Arg (Pmc) were dissolved in 2 ml of chloroform and cooled to 0 ° C. A solution prepared by dissolving 128.7 mg of WSCI hydrochloride in 1.2 ml of black mouth form was added thereto, and the mixture was allowed to stand overnight at step 2. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give 284. ling of the title compound. Obtained as a colorless syrup.

! H MR (500MHz, DMS0- _ds ) δ:

 7.98 (IH, d, J = 7.5Hz), 7.83C1H, d, J = 8.0Hz), 7.72C1H, brt), 7.12-6.20 (3H, br), 4.24ClH, dt, J = 8.0, 7.5Hz) , 4.18-4.09 (1H, m), 3.07-2.92 (4H, m), 2.59C2H, t, J = 7.0Hz), 2.47 (6H, 2s), 2.03 (3H, s), 1.83C3H, s), 1.78 (2H, t'J = 6.0Hz), 1.68-1.51 (2H, m), 1.50-1.08C43H, m), 0.88-0.82 (9H, m)

 MS m / z (FAB): 848 (MH +)

 (2) Synthesis of acetyl-L-leucyl-shi-arginine stearyl amide

The Ac-Leu-Arg (Pmc) -NHCi8H 3 7 150mg was dissolved in black port Holm 1.5 ml ', DOO 1.5 ml of trifluoroacetic acid was added and left at room temperature overnight. The reaction mixture was reduced and concentrated to give a crude product, which was purified by silica gel column chromatography (macroform: methanol = 15: 1) to obtain 15.8nig of the title compound as a colorless syrup.

Kasumi _{(500MHz, DMS0-d 8)} δ

8.0K1H, d, J = 8.0Hz), 7.94 (lfl, d, J = 8.OHz), 7.76 (1H, brt), 7.53 (lrt), 7.43-6.55 (3H, br), 4.28-4.11 (2H , M), 3.13-2.96 (4H, m), 1.84 (3H, s), 1.72-1.08 (37H, m), 0.88-0.83 (9H, m)

MS m / z (FAB); 581 (MH +)

 [Example 20]

Preparation of acetyl-L-leucyl-L-arginine nonadecyl ester (Compound No. 20) (Formula (20))

 AcL 0- ^-(20)

 \ ノ 13

(1) Asechiru -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6- scan Ruhoniru -L- arginine nonadecyl ester (Ac- Leu-Arg (Pmc) -0C 13 H ₃₉ ) Synthesis of

300 mg of 1-nonadenol was dissolved in 6 ml of black-mouthed form, and triethylamine 294 ^ 1 and methanesulfonyl chloride 1631 were added, followed by stirring at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfate Natoriumu to give the crude product concentrated in vacuo MsO- C ₁₃ H _33.

On the other hand, 200fflg of Ac-Leu-Arg (Pmc) was dissolved in 4ml of methanol and 0.4ml of water, adjusted to pH 7 with a 20% aqueous cesium carbonate solution, and concentrated under reduced pressure. Azeotropic Ri by the DMF, dried under reduced pressure to give the residue was dissolved in 2 ml of DMF, those added to dissolve the crude product of the MsO-C ₁₃ H ₃₉ previously obtained in 4 ml of DMF, stirred 10 days at room temperature The reaction solution was added with water, and extracted with benzene Z ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (Black-mouthed form—Black-mouthed form: methanol

= 5: 1) to give 16.8 mg of the title compound as a colorless chip. iH N MR (500MHz, DMSO-ds) δ:

 8.26C1H, J = 7.0Hz), 7.93 (1H, d, J = 8.0Hz), 6.80-6.30 (3H, br), 4.33-4.29 (1H, m), 4.20-4.ΙΟ (ΙΗ'πι ), 4.05-3.91 (2H, m), 3.03-3.02 (2H, m), 2.58C2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.03 (3H, s), 1.81 (3H, m s), 1.77C2H, t, J = 6.0Hz), 1.68―1.40 (47H, m), 0.89-0.84 (9H, m)

MS m / z (FAB); 862 (MH ⁺ )

(2) Asechiru -L- mouth Isil - Synthesis of Les arginine nonadecyl ester (Ac-Leu-Ar g- 0Ci 9 H 3 9)

157.7 nig of Ac-Leu-Arg (Pmc) -0C ₁₃ H ₃₃ was dissolved in 1.5 ml of chloroform, 1.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 57.7 mg of the title compound (formula (20)) as a white solid. Was.

! H (500MHz. DMS0- _ds ) δ:

 8.31 (lH, d, J = 7.5Hz), 7.98 (1H, d, J = 7.5Hz), 7.56 (1H, brt), 7.40-6.88 (3H.br), 4.31-4.28 (lH, m), 4.23 -4.14 (1H, m), 4.05-3.96 (2H, m), 3.14-3.02C2H, m), 1.82 (3H, s), 1.81-1.68C1H, m), 1.64-1.38 (8H, m), 1.32 -1 .18 (32H, m), 0.89-0.83 (9H, m)

MS m / z (FAB); 596 (MH ⁺ )

 [Example 21]

Preparation of acetyl-L-leucyl-L-arginine eicosyl ester (Compound No. 21) (Formula (21))

AcL O ^ J- (21) ( 1) Asechiru - teeth - mouth Isil -N ^G -2,2,5,7,8- pentamethyl chroman - 6- scan Synthesis of Ruphonyl-L-Arginine Eicosyl Ester (Ac-Leu-Arg (Pmc) -OC ₂ .H ₄ !)

1-Eicosanol (300 mg) was dissolved in chloroform (3 ml), triethylamine (280 / l) and methanesulfonyl chloride (156 l) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfate Natoriumu to obtain a crude product of MSO-C ₂ QH ₄₁ was concentrated under reduced pressure.

— On the other hand, dissolve (111-: 1501¾) in 3 ml of methanol and 0.3 ml of water, adjust the pH to 7 with a 20% aqueous cesium carbonate solution, and concentrate under reduced pressure. boiling, and the residue obtained by concentration under reduced pressure was dissolved in DMF1.5Ml, a solution obtained by dissolving crude MsO_C ₂ οΗ ₄₁ previously obtained in DMF4ml added, at room temperature for 7 days at 40 ° C The reaction mixture was stirred for 6 days, water was added, and the mixture was extracted with benzene Z ethyl acetate = 1 / 2.The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. Mouth form: methanol = 60: 1) to give 126.5 mg of the title compound as a colorless syrup.

l Anonymous (500MHz, DMSO-ds) δ

 8.26 (iH, d, J-8.0HZ), 7.93C1H, d, J = 8.0Hz), 6.76-6.29 (3H, br), 4.33-4.29C1H, m), 4.18-4.ll (lH, m ), 4.01-3.89 (2H, m), 3.08-2.99 (2H, m), 2.58C2H.t, J = 7.0Hz), 2.47 (6H, 2s), 2.03 (3H, s), 1.81 (3H, s), 1.77C2H, t, J = 6.0Hz), 1.71-1.14 (49H, m), 0.89-0.84 (9H, m)

MS m / z (FAB); 876 (MH +)

Synthesis of _{- (Arg-0C 2 .H 41} Ac-Leu) (2) Asechiru -L- leucyl -L- arginine eicosyl ester

Ac-Leu-Arg (Pmc) -OC 2. 125 mg of H was dissolved in 1.2 ml of chloroform, 1.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The crude product obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (form: methanol = 10: 1) to give 41.9 mg of the title compound as a white solid. Obtained.

 Kasumi (500MHz, DMSO-ds) d:

8.31 (lH, d, J = 7.5Hz), 7.98 (1H.d, J = 8.0Hz), 7.56C1H, brt), 7.42-6.65 (3H, br), 4.31 (lH, dt, J-8.0, 8.0 Hz), 4.24-4.16 (1H, ra), 4.05-3.96 (2H, m), 3.15-3.03 (2H, m), 1.83C3H, s), 1.79-1.71 (lH, ra), 1.68-1.46 (4H , m), 1.42C2H, t, J = 6.5Hz), 1.32-1.16C36H, m), 0.89—0.84 (9H, m)

MS m / z (FAB); 610 (T)

 [Example 22]

Preparation of acetyl-L-leucyl-shi-arginine docosyl ester (Compound No. 22) (Formula (22))

 AcLSO ^^ (22)

(1) acetyl-shi-rosyl--2,2,5,7,8-pentamethylchroman-6-sulfonyl-L-arginine docosyl ester (Ac-Leu-Arg (Pmc) -OC ₂₂ H ₄₃ ) Synthesis of

300 mg of 1-docosanol was dissolved in 6ffll of chloroform, and triethylamine 256 1 and methanesulfonyl π-1421 were added thereto, followed by stirring at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfate Natoriu厶to give the crude product MsO-C ₂₂ H ₄₃ and concentrated in vacuo.

On the other hand, 200 ng of Ac-Leu-Arg (Pmc) was dissolved in 4 mi of methanol and 0.4 ml of water, adjusted to pH 7 with a 20% cesium carbonate aqueous solution, and concentrated under reduced pressure. Azeotropic Ri by the DMF, the residue obtained by concentration under reduced pressure was dissolved in 2 ml of DMF, the crude product MsO-C ₂₂ H ₄₃ previously obtained in a mixture of 0 ^ 5.6ml and black port Holm 5.6ml The solution was added and stirred at room temperature for 1 day and stirred at 40 ° C for 6 days. Water was added to the reaction solution, and extracted with ethyl benzene acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form on chromatograph: form from chromato: methanol = 5: 1). Then, 130 mg of the title compound was obtained as a colorless syrup.

'Η Marauder R (500i \ fflz, DMS0-d ₅ ) o:

 8.26C1H.d, J = 7.5Hz), 7.93 (1H, d, J = 8.0Hz), 6.75-6.23 (3H, br), 4.33-4.28C1m), 4.18-4.09 (lH, m), 3.99-3.89 (2H, m), 3.03-2.99 (2H, m), 2.58C2H, t, J = 7.0Hz), 2.47 (6H, 2s), 2.03 (3H, s), 1.81 (3H.s), 1.77C2H, t, J = 6.5Hz), 1.72-1.18C53H, m), 0.89-0.84 (9H, m)

MS iii / z (FAB); 904 (MH ⁺ )

(2) Asechiru -L- leucyl -L- arginine docosyl ester (Ac- by _{eu-Arg - 0C 22 H 43} ) Synthesis of

The Ac-Leu-Arg (Pmc) -0C 22 H 43 123. 6mg dissolved in black port Holm 1.2 ml, added preparative Rifuruoro acetate 1.2 ml, and stirred at room temperature overnight. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 53. Omg of the title compound as a white solid.

^! H (500MHz, DMS0- _ds ) <5:

 8.3K1H, J = 7.5Hz), 7.98 (1H, d, J = 8.5Hz), 7.55C1H, brt), 7.42-6.68 (3H, br), 4.32-4.28 (1H, m), 4.24-4 18C1H, m), 4.02-3.92C2H, m), 3.11-3.06 (2H, m), 1.82 (3H, s), 1.80-L 71 (1H, m), 1.68-1.33 (8H, m) , 1.32-1.14 (38H, m), 0.89-0.84 (9H, m)

MS m / z (FAB); 638 (MH +)

 [Example 23]

Preparation of acetyl-shi-leucyl-L-arginine hexacosyl ester (Compound No. 23) (Formula (23))

 AcLRO- ^ '(23)

(1) Asechiru - teeth - leucyl ^{- N G -2, 2,5, 7} , 8- pentamethyl chroman - 6-scan Ruhoniru - to L- arginine hexa cosyl ester (Ac-Leu- Arg (Pmc) -OC 23 H ₅ 4 3

3) Synthesis of

Twenty-four milligrams of trihexacosanol was dissolved in 5: 1 form of chloroform, and triethylamine 180〃1 and methanesulfonyl chloride were added, followed by stirring at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sulfate Natoriumu to give the crude product concentrated in vacuo MsO- C _2S H ₃₃ c

On the other hand, 200 mg of Ac-Leu-Arg (Pmc) was dissolved in 4 ml of methanol and 0.4 ml of water, adjusted to pH 7 with a 20% aqueous cesium carbonate solution, and concentrated under reduced pressure. The residue obtained by azeotropic distillation with DMF and drying under reduced pressure was dissolved in ₂ m of DMF, and the crude product of MsO_C 2SH ₅ s previously obtained dissolved in a mixture of 9 ml of DMF and 9 ml of black hole form was added. Then, the mixture was stirred at 40 C for an entire day. Water was added to the reaction solution, and extracted with ethyl benzenenoacetate = 1/2. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform-form: methanol = 5: 1) to give the title compound 166. Img Was obtained as a colorless syrup.

JH organ (500MHz, DMS0- _ds ) δ:

 8.26 (lH, d, J-7.0Hz), 7.93 (1H, d, J = 8.0Hz), 7.11-6.26 (3H, br), 4.37-4.29 (lH, m), 4.20-4.10 (ΙΗ, πι), 4.03-3.89 (2H, m), 3.09- 2.99 (2H, m), 2.58C2H, t, J = 7.0Hz), 2.47 (6H, 2s), 2.03 (3H, s), L81 (3H , s), 1.77 (2H, t, J = 6.5Hz), 1.72-1.08C61H, m), 0.89-0.84 (9H, m)

MS m / z (FAB); 960 (MH ⁺ )

(2) Asechiru - Synthesis of hexa waist esters to have Aruginin _{(Ac-Leu- Arg- 0C 2S H} 53) - I port Isil

The Ac-Leu-Arg (Pmc) -0C 2S H 53 162.2mg dissolved in black port Holm 1.6 ml, the door Rifuruoro acetate 1.6ral mixture is stirred at room temperature overnight. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel gel column chromatography (chloroform: methanol = 10: 1) to obtain 95.6 mg of the title compound as a white solid. Ή NM (500MHz, DMS0- _ds ) d:

 8.3K1H, d, J = 7.5Hz), 7.98 (1H, J = 8.0Hz), 7.57 (lH, brt), 7.43-6.64 (3H, br), 4.35-4.S0C1H, m), 4.22-4.21 ( 1H, m), 4.08-3.95 (2H, ni), 3.14-3.05 (2H.m), 1.82 (3H, s), 1.81-1.71 (1H, m), 1.63-1.39 (8H, m), 1.36- 1.17 (44H, m), 1.06 (2H, t, J = 7.5Hz), 0.89-0.84 (9H, m)

MS m / z (FAB); 694 (MH +)

 [Example 24]

Preparation of acetyl-L-leucyl-L-arginine tricontyl ester (Compound No. 24) (Formula (24))

 (1) Synthesis of acetyl-L-leucyl--2,2,5,7,8-pentamethylchroman-6-sulfonylarginine triacontyl ester (Ac-Leu-Arg [Pmc) -0 CsoHsi)

400 mg of 1-triacon phenol was dissolved in 8 ml of glo-mouth form, and Trieti.lamine 2541 and methanesulfonyl chloride 141 / zi were added, followed by stirring at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure MsO- C _3. To give the crude product H _S1.

On the other hand, 200 mg of Ac-Leu-Arg (Pmc) was dissolved in 4 ml of methanol and 0.4 ml of water, adjusted to pH 7 with a 20% aqueous cesium carbonate solution, and concentrated under reduced pressure. Azeotropic Ri by the image F, the residue dissolved obtained by drying under reduced pressure was dissolved in 2 ml of DMF, the crude product MsO-C ₃₀ H s 1 previously obtained in a mixture of DMF 12ml and black port Holm 12ml The mixture was added and stirred at 40 ° C. for 8 days. Water was added to the reaction solution, and the mixture was extracted with benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform-chloroform: methanol = 5: 1) to give the title compound 230.5 fflg was obtained as a colorless syrup.

] H new (500MHz, D S0- _ds ) δ:

 8.26C1H, d, J = 7.0 Hz), 7.93 (1H, d, J = L 0 Hz), 4.37-4.29 (1H, m), 4.13-4.09 (lH, m), 3. 99-3.91 (2H, m), 3.08-3.00 (2H, m), 2.61-2.56 (2H, m), 2.47 (6H, 2s), 2.03 (3H , S), 1.81 (3H, s), 1.62-1.18 (69H, m), 0.88-0.84C9H, m)

MS m / z (FAB); 1016 (MH ⁺ )

(2) Asechiru - L-leucyl -L- arginine triacontyl ester (Ac - Leu-Arg-0C 3 .H sl) Synthesis of

Ac - Leu-Arg (Pmc) -0C 3. 223.6 mg of H _sl was dissolved in 2.2 ml of chloroform, 2.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 91.lmg of the title compound as a white solid.

^: H concealed (500MHz. DMS0-d _s ) δ:

8.31 (lH, d, J-7.0HZ), 7.97QH, d, J = 8.0Hz), 7.54 (lH, brt), 7.35-6.61 (3H, br), 4.38-4.28 (lH, m), 4.26-4. 18 (1H, m), 4.02-3. 95 (2H, m), 3.48-3.39 (2H, m), 3.12-3.08 (2H, m), 1.82 (3H .s), 1.79-1. 69 (1H.m), 1.68-1.38C8H, m); 1.32-1.12 (50H, m), 1.06 (2H, t, J = 6.5Hz), 0.89 -0.84 (9H, m) MS m / z (FAB); 750 (MH ⁺ )

 [Example 25]

Preparation of acetyl-L-leucyl-arginine cholesteryl ester (Compound No. 25) (Formula (25))

AcLSO

(1) Synthesis of acetyl-leucyl-arginine cholesteryl ester Dissolve 200 mg of cholesterol in 2 ml of DMF, and add Ac-Leu-Arg (Pmc) 616.3 rag,

A solution prepared by dissolving 82.8 mg of DMAP and 346.6 mg of WSCi hydrochloride in 4 ml of DMF was added, and the mixture was stirred at room temperature for 24 hours and at 40 ° C for 3 days. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 247.7iiig of a crude product of the title compound as a white solid. Dissolve this in 2.5 ml of black-mouthed form and add trifluoroacetic acid

2.5 ml was added, and the mixture was left at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 19.7 mg of the title compound as a white solid.

 (500MHz, DMSO-d 6) δ

8.3K1H, m), 7.97 (lH, m), 7.50 (1H.brt), R.38-6.62 (3H, br), 5.36-5.30 (lH, ra ), 4.49-4.41 C1H, m), 4.38-4.26 (1H, m), 4.18-4.08 (1H, m), 3.15 -3. 02C2H, m), 2.29-2.12 (2H, m), 2.02- 1.88 (3H, m), 1.87-0.74 (51H, m),

0.65 (3H, s)

MS m / z (FAB); 698 (MH ⁺ 〉

 [Example 26]

Preparation of acetyl-shi-leucyl-L-arginine-n-dodecyl ester (Compound No. 26) (Formula (26))

(1) Asechiru - ^{L-leucyl--N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-scan Ruhoniru - L-arginine - n-dodecyl ester (Ac-Leu-Arg (Pmc ) - 0C Synthesis of _{1 2} H _{2 5} )

50 mg of n-dodecyl alcohol was dissolved in 1.5 ml of methylene chloride, and triethylamine 51 and methanesulfonyl chloride 421 were added, followed by stirring at room temperature for 1.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, Extracted with Holm. The organic layer was dried over anhydrous sodium sulfate to give the crude product ¾'isO-C _{1 2} H _{2 5} and concentrated in vacuo. On the other hand, 30 mg of Ac-Leu-Arg (Pmc) was dissolved in 1.6 ml of methanol and 0.16 ml of water, adjusted to pH 8 with a 20% cesium carbonate aqueous solution, and concentrated under reduced pressure. Was azeotroped with DMF, the residue obtained by drying under reduced pressure was dissolved in DMF0 .8ml, the crude product MsO-C _{I 2} H _{2 5} previously obtained was added, and 6 ®閭攪stirred at room temperature. Water was added to the reaction solution, and extracted with benzene / ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (form / methanol = 15/1), and 32.8 mg of the title compound was obtained as a colorless syrup. As obtained.

1 HNMR (500MHz, DMSO-ds) δ:

 8.26C1H, d, J = 8.0Hz), 7.93 (1H, d, J = 8.0Hz), 6, 80-6.30 (3H, br), 4.33 (1

H, dt, J = 9.0 Hz, 9.0 Hz), 4.20-4.12 (1H, m), 4.03-3.94 (2H, m), 3.03-3.00 (2H, m), 2.59C2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.03 (3H, s), 1.82C3H, s),

I.78C2H, t, J = 6.5Hz), 1.74-1. 19 (27H, m), 0.91-0.80 (9H, m)

MS m / z (FAB); 76+)

Synthesis of (2) Asechiru -L- Roshiiru -L- Aruginin -n- dodecyl ester _{(Ac- Leu- A rg-GC 1} 2 H 25)

Ac- dissolved in _{Leu-Arg- (Pmc) -0C 12} H 2 527. 3 rag a black hole Holm 0 · 3 ml, added Torifuruoro acetate 0.5 ml, and stirred at room temperature for 3 hours, the reaction was concentrated under reduced pressure The obtained crude product was purified by silica gel column chromatography (form: methanol = 5: 1) to give 15.Omg of the title compound as a colorless syrup.

¹ Marauder R (500MHz, DMS0- _ds ) δ:

8.31 (lH, d, J = 7.5Hz), 7.98 (1H, d, J = 8.5Hz), 7.71 (lH'brt), 7.60-6.85 (3H, br), 4, SlClH , dt, J = 8.0 Hz '8.0 Hz), 4.25-4.18 (1H, m), 4.05-3.96 (2H, m), 3.13-3.03 (2H, m) , 1.82C3H, s), 1.80-1.71 (1H, m), 1.67-1.33C 8H, m), 1.32-1.19 (18H, m), 0.91-0.83 (9H, m) MS ID / Z (FAB); 498 (MH +)

 [Example 27]

 Preparation of cetyl-shi-leucyl-L-arginine-n-tetradecyl ester (Compound No. 27) (Formula (2))

AcLSO (27)

 , ' 13

(1) Asechiru -L- leucyl -N ^G -2,2, 5,7, 8- pentamethyl chroman - 6- scan Ruhoniru -L- arginine - n-tetradecyl ester (Ac- Leu- ArgCPm -Od 4H29) Synthesis of

50 mg of n-tetradecyl alcohol was dissolved in 1.5 ιη メ チ レ ン of methylene chloride, and triethylamine and methanesulfonyl chloride were added thereto, followed by stirring at room temperature for 1.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, vacuum enrichment to yield the crude product MsO-C ₁₄ H _23. On the other hand, 80 m of Ac-Leu-Arg (Pmc) was dissolved in 1.6 ml of methanol and 0.16 ml of water, adjusted to pH 8 with a 20% cesium carbonate aqueous solution, and concentrated under reduced pressure. The residue obtained by azeotropic distillation with DMF and drying under reduced pressure was dissolved in 0.8 ml of DMF, the crude product of MsO-d Ji ₂₉ obtained above was added, and the mixture was stirred at room temperature for 7 days. Water was added to the reaction solution, and extracted with benzene / ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was subjected to silica gel column chromatography (form: π-mouth form / methanol = 15:

Purification in 1) gave 4.2 mg of the title compound as a colorless syrup.

1 thigh ffi (500MHz, DMS0- _ds ) δ:

 8.27C1H, d, J = 7.5Hz), 7.93 (1H, d), 7.10-6.30 (3H, br), 4.36-4.30C1H, m), 4.20-4.13 (1H, m) '4.04-3.93 (2H, m), 3.09-3.00 (2H, m), 2.59 (2H, t, J = 6.5 Hz), 2.48 (6H, 2s), 2.03 (3H, s), 1.82 (3H, s), 1.81-1.20 ( 37H, m), 0.91-0.81 (9H, m)

MS m / z (FAB); 792CMH +) (2) Synthesis of acetyl-L-leucyl-L-arginine-n-tetradecyl ester (Ac-Eu-Arg-Od Ji ₂₃ )

Ac- dissolved in Leu-Arg- (Pmc) -OCi ₄ the H ₂₃ 39.2 mg black port Holm 0.4 ml, added Torifuruoro acetate 0.8 ml, was concentrated under reduced pressure to give the mixture was stirred for 5 hours at room temperature, the reaction mixture crude The product was purified by silica gel column chromatography (form / methanol = 5/1) to give 21.3 mg of the title compound as a colorless syrup.

^One leg IR (500MHz, DMS0- _ds ) δ

 8.32C1H, J = 7.0Hz), 7.98 (1H, d, J = 8.0Hz), 7.59 (1H, brt), 7.45-6.7 0 (3H, br), 4.30 (1H, dt 'J = 8.0Hz, 8.0 Hz), 4.23-4.18 (1H, m), 4.06-3.97 (2H, m), 3.13-3.06 (2H, m), 1.82 (3H, s), 1.80-1.70 (1H, m), 1.68-1.40 (8H, m), 1.31-1.18C22H, m), 0.90-0.82 (9H, m)

MS m / z (FAB); 526 (MH ^<+> )

 [Example 28]

 Preparation of acetyl-L-leucyl-L-arginine-n-hexadecyl ester (Compound No. 28) (Formula (28))

 AcLRO (28)

 \ ノ u

(1) Asechiru -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6 - sulfonyl -L- arginine - to n- hexadecyl ester (Ac-Leu-Arg (Pmc ) - Synthesis of OC16H33)

50 mg of n-hexadecyl alcohol was dissolved in 1.5 ml of methylene chloride, and 751 of triethylamine and 421 of methanesulfonyl chloride were added, followed by stirring at room temperature for 1.5 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, vacuum enrichment to yield the crude product MsO-C _IS H _33. On the other hand, 80 mg of Ac-Leu-Arg (Pmc) was dissolved in 1.6 ml of methanol and 0.16 ml of water, and the pH was adjusted to 8 And concentrated under reduced pressure. Was azeotroped with DMF, and dried under reduced pressure to give the residue was dissolved in DMF0.8Ml, the crude product MsO-d _S H ₃₃ previously obtained, and the mixture was stirred between ambient temperature at 7 ®. Water was added to the reaction solution, and extracted with benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 15: 1), and 34.lmg of the title compound was converted into a colorless syrup. Obtained.

'HNMRCBOOMHz.DMSO-ds) δ

 8.26 (1H, d, J = 7.5Hz), 7.93 (1H, d, J = 8.0Hz), 7.00-6.30 (3H, br), 4.33 (1H, dt, J = 6.0Hz), 4.21-4.12 (1H , M), 4.03-3.94 (2H, m), 3.09-3.00 (2H, m), 2.60 (2H, t, J = 6.5¾), 2.47 (6H, 2s), 2.03 (3H, s), 1.81 (3H, s), 1.78 (2H, t, J = 6.5Hz), 1.74-1.18C41K m), 0.9-0.80 (9H, m)

MS m / zCFAB); 820 (MH +)

Synthesis of n- to hexadecyl ester (Ac-L eu-Arg- 0C 1S H 33) - (2) Asechiru -L- leucyl -L- arginine

332.9 mg of Ac-Leu-Arg- (Pmc) -0CisH ₂ was dissolved in 0.3 ml of chloroform, 0.7 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 5 hours.The reaction mixture was concentrated under reduced pressure to obtain a crude product. Was purified by silica gel column chromatography (form: methanol = 5: 1) to give 12.3 mg of the title compound as a colorless syrup.

¹ thigh ffi (500MHz, DMS0- _ds ) δ

 8.32C1H, d, J = 7.5Hz), 7.98 (1H, d, J = 8.OHz), 7.57 (lf rt), 7.45-6.7 0 (3H, br), 4.31 (IH, dt, J = 8.0Hz , 8. OHz), 4.26-4.20C1H, m), 4.08-3.97 (2H, m), 3.14-3.08 (2H, m), 1.82 (3H, s), 1.80-1.70 (1H.m), 1.67 -1.38 (8H, m), 1.32-1.17C26H, m), 0.90-0.82 (9H, m)

MS m / z (FAB); 554CMH

 [Implementation line 29]

Acetyl-shi-leucyl-L-arginine-η-octyldecyl ester (compound Article number 29) (Formula (29))

(1) Synthesis O Kuta decyl alcohol 5.22g of methanesulfonyl O carboxymethyl Okutadekan (MsO-C ₁₃ H _3T) was dissolved in methylene chloride 157 ml, tri Echiruamin 5.38Ml, methanesulfonyl chloride Li de 2.24 In addition, stirred for 30 minutes at room temperature did. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound 6.3 as a white solid. . 1-screen (60MHz'CDCl ₃₎ (5:

 4.50-4.40 (2H, m), 3.02 (3H, s), 1.60-0, 80 (35H, m),

(2) Asechiru -L- leucyl -N ^G -2,2,5,7,8- pen evening methyl chroman - 6-sulphonyl -L- arginine - n-O Kuta-decyl ester (Ac-Leu-Arg (Pmc ) Synthesis of -OC13H37) 500 mg of Ac-Leu-Arg- (Pmc) was dissolved in 10 ml of methanol and lm 1 of water, adjusted to pH 8 with a 20% cesium carbonate aqueous solution, and concentrated under reduced pressure. The residue obtained by azeotropic distillation with DMF and drying under reduced pressure was dissolved in 5 ml of DMF, 0.88 g of MsO_C ₁₈ H 3τ was added, and the mixture was stirred at room temperature for 7 days. Water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography. (Form: methanol = 15: 1) to give 453 mg of the title compound as a colorless syrup • was.

¹囊 ffi (500MHz, DMS0- _ds ) δ

8.26C1E d, J = 7.0Hz), 7.93 (1H, d, J-8.5Hz), 7.00-6.40 (3H, br), 4.33 (1H, dt, J = 9.0Hz, 9.0Hz), 4.20-4.10 ( 1H, m), 4.05-3.93 (2H, m), 3.06-3.00 (2H, ra), 2.58C2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.03 (3H, s), ^ 3H , s), 1.77C2H, t, J = 6.5Hz), 1.74-1.19 (45H, m), 0.91-0.80 (9H, m) MS m / z (FAB); 848 (MH +)

(3) Asechiru -L- leucyl -L- arginine - n-O click evening Synthesis of decyl ester (A c-Leu-Arg- OC 13 H 37)

The Ac-Leu-Arg- (Pmc) -0Ci 8 H 3 T 453mg was dissolved in black port Holm 4.5ml, bets Rifuruoro acetate 4.5ml was added and stirred at room temperature for 1.5 hours, the reaction was concentrated under reduced pressure to give The crude product was purified by silica gel column chromatography (form: methanol = 5: 1) to obtain 330 mg of the title compound as a white solid.

¹ Marauder R (500MHz, DMS0-d _s ) δ

 8.32C1H, d, J = 7. OHz), 7.98 (1H, d, J = 7.5Hz), 7.45C1H, brt), 7.35 -6.6 0 (3H, br), 4.32 (1H, dt, J = 8. OHz, 7.5), 4.26-4.18 (1H, m), 4.05-3.96 (2 H, m), 3.11-3.05 (2H, m), 1.82 (3H, s), 1, 80-1.40 (9H, m) , 1.32-1.18 (30H, m), 0.92-0.80 (9H, m)

MS m / z (FAB); 582 (MH ⁺ )

 [Example 30]

n-Dodecanoyl-L-leucyl-L-arginine methyl ester (Compound No. 30) (Preparation of formula (30)

(1) 9-O-les methoxy carbonyl ^{- N G -2, 2, 5} , 7, 8- Pentamechiruku Roman - 6-sulfonyl -L- arginine - n-O Kuta-decyl ester (Foioc- Arg (Pmc) - OMe)

 It was dissolved in 500 mg of Fraoc-Arg (Pmc) in 10 ml of THF, 3.8 ml of trimethylsilyldiazomethane was added, and the mixture was stirred at room temperature for 20 minutes. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to obtain 520 mg of the title compound as a white solid.

JH NM C500¾fflz, DMS0-d ₃ ) (5 ： 7.89 (2H, d, J = 7.5 Hz), 7.77 (1H, d, J = 7.5 Hz), 7.70 (2H, dd, J = 3. OHz, 7.5 Hz), 7 41 (2H, t 'J = 7.5Hz), 7.33C2H, t, J = 7.5Hz), 6.90-6.30 (3H, br), 4.33-4.20 (3H, m), 4. 05-

3.96 (1H, m), 3.61 (3H, s), 3.06-2, 98 (2H, m), 2.57 (2H, t, J = 6.5Hz), 2.48 ( 3H, s), 2.47C3H, s) 2.02 (3H, s), 1.76 (2H, t, J = 6.5Hz), 1.76-1.32 (4H, m), 1.25 ( 6H.2s)

MSm / z (FAB): 677 (MH ⁺ )

(2) 9-Furuorenirume butoxycarbonyl -L- leucyl ^{-N G -2, 2, 5,} 7, 8 - pentamethyl chroman - 6-sulphonyl -L- Ryo arginine methyl ester (Fmoc-Leu-Arg (Pmc ) - OMe)

 469 mg of Fmoc-Arg (Pmc) -0Me was dissolved in DMF9. 0.94 ml of getylamine was added, and the mixture was stirred at room temperature for 25 minutes. The reaction mixture was concentrated under reduced pressure to give a crude product, which was dissolved in F6.3 ml, added with WSC I hydrochloride (266 mg, H0Btl87 mg, Finoc-Leu490 mg), and stirred at room temperature for 22 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with a black hole form. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 544 mg of the title compound as a white solid. Was.

XH NMR (500 MHz, DMS0- _ds ) 6:

 8.23C1H, d, J = 7.5Hz), 7.88 (2H, d, J = 7.5Hz), 7.72 (2H, dd, J = 4.5Hz, 7.5Hz), 7.45 (1H, d 'J = 8. OHz), 7.41 (2H, t, J = 7.5Hz), 7.31 (2E t, J = 7.5Hz), 7.10-6.25 (4H , br), 4.35-4. 17 (3H, m), 4.12-4.0.0 (1H, m), 3.59 (3H, s), 3, 08-2. 98 (2H , M), 2.56C2H, t, J = 7. OHz), 2.4 (6H, 2s), 2.02 (3H, s), 1.75 (2H, t, J = 6.5Hz) , 1.75-1.36 (8H, m), 1.24 (6H, 2s), 0.92-0.82 (6H, m)

MS m / z (FAB); 790 (MH +)

(3) n-Dodekanoiru -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine methyl ester (CuH ^ - (00) - Leu- Arg ( Pmc) -OMe) 50 mg of Fmoc-Leu-Arg (Pmc) -0 e was dissolved in 3 ml of DMF, 0.3 ml of dinitylamine was added, and the mixture was stirred at room temperature for 20 minutes. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in methylene chloride (1 ml), and triethylamine 171-1 and dodecanoyl chloride 221 were added, followed by stirring at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 20: 1) to give 32.5 mg of the title compound as a colorless syrup As obtained. ^{J H NMR (500MHz, DMS0-} d 8) <5:

 8.21 (IE d, J = 7.5Hz), 7.86 (1H, d, J = 8. OHz), 6.80-6.30 (3H, br), 4.33 (1H, dt, J = 7.5Hz, 8.0Hz), 4.20- 4.13 (1H, m), 3.58 (3H.s), 3.07-3.00 (2H, m), 2.59 (2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.15-2.00 (2H, m) , 2.03 (3H, s), 1.77 (2H, t, J = 6.5Hz), 1.72-1.36 (9H, m), 1.30-1.17 (22H, m), 0.90-0.80 (9H, m)

MS m / z (FAB); 750 (MH +) ''

(4) n-Dodekanoiru -L- leucyl -L- arginine methyl ester _{(CHH 23 _ (C = 0} ) -Leu-Arg-OMe) Synthesis of

28.3 mg was dissolved in 0.3 mi of black mouth form, 0.3 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain 12.4 mg of the title compound as a colorless syrup.

! H NJffi (500MHz, DMS0-d ₅ ) <5:

 8.24 (1H, d, J = 7.5Hz), 7, 90 (1H, d, J = 7.5Hz), 7.55C1H, brt), 7.50-6.70 (3H, br), 4.37-4.30 (1H, m), 4.27-4.10 (1H, m), 3.61 (3H, s), 3.12-3.06 (2H, m), 2.18-2.02 (2H, m), 1.80-1.39C9H, m), 1.32-1.17 (16H, m), 0.92-0.81 (9H, m) MS m / z (FAB): 484 (MH +)

 [Example 31]

n-tetradecanoyl-L-leucyl-L-arginine methyl ester (compound Article number 31) (Formula (31))

'^ LRCIe ( ³¹ )

(1) II- Tetoradekanoiru -L- [pi Ishiru ^{-N G -2, 2, 5,} 7, 8- Pentamechiruku Roman - 6-sulphonyl -L- arginine methyl ester _{[3 H 2 T - (O0)} -Le u- Arg (Pmc) -OMe).

 Fmoc-Leu-Arg (Pmc) -0Me50nig synthesized by the method of Example 30 was dissolved in 3 ml of DMF, 0.3 ml of getylamine was added, and the mixture was stirred at room temperature for 20 minutes. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 1 ml of methylene chloride, triethylamine and tetradecanoyl chloride 261-1 were added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane: acetone = 2: 1) to give the title compound 23.2 nig as a white solid. As obtained.

l NMR (500MHz. DMS0-ds) (?:

 8. 2K1H, d, J = 7.5Hz), 86, (1H, d, J = 8. OHz), 6.90-6. 30 (3H, br), 4.33 (1H, dt, J = 7.5 Hz, 8.OHz), 4.21-4.14 (1H, m), 3.58 (3H, s), 3.06-2.99 (2H, m), 2.59 (2H, t, J = 6.5 Hz), 2.47 (6H, 2s), 2.16-2.00 (2H, m), 2.03 (3H, s), 1.77 (2H, t, J = 6.5 Hz), 1.73-1.40 (9H, m), 1.32-1.19C26H, m), 0.90-0.80 (9H, m)

MS m / z (FAB); 778 (MH +)

(2) n-Tetoradekanoiru -L- leucyl - L-arginine methyl ester _{(C 1 3 H 27 - (} C = 0) -Leu- Arg-OMe) Synthesis of

C i

19 mg was dissolved in 0.2 ml of chloroform, 0.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol = 5: 1) to obtain 14.8 mg of the title compound as a colorless syrup. ^J H MR (500fflz, DMS0-d ₃ ) d:

 8.27C1 d, J = 8. OHz), 7.90C1H, d, J = 8. OHz), 7.35 (1H, brt), 7.50-6.70 (3H, br), 4.32 ( 1H, dt, J = 8. OHz, 8. OHz) '4.27-4.22 (1H, m)' 3.61 (3H, s), 3.13-3. 07C2H, m), 2.16-2.02 ( 2H, m>, 1.80-1.40 (9H, m), 1.32-1.18 (20H, m), 0.91-0.82 (9H, m)

 MS m / z (FAB); 512 (MH +)

 [Example 3 2]

Preparation of n-hexadecanoyl-L-mouth isyl-L-arginine methyl ester (Compound No. 32) (Formula (32))

(1) to the n- Kisadekanoiru - ^{L-leucyl--N G -2, 2, 5,} 7, 8- Pentamechiruku Roman - 6-sulphonyl -L- arginine methyl ester _{(C 1 5 H 3 I -} (O0) -Le Synthesis of u-Arg (Pmc) -OMe)

 50 mg of Fmoc-Leu-Arg (Pmc) -0Me synthesized by the method of Example 30 was dissolved in 3 ml of DMF, 0.3 ml of getylamine was added, and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure to give a crude product, which was dissolved in 1 ml of methylene chloride, to which were added triethylamine 1 and hexanedecanoyl chloride 291, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane: acetone = 2: 1) to obtain 34.2 mg of the title compound as a white foam. Was.

! H MR (500MHz, DMSO- _ds ) (5:

8.21C1H, d,

OHz), 6.90-6.30 (3H, br), 4.33 (1H, dt, J = 7.5Hz, 8.0Hz), 4.21-4.15 (1H, m), 3.58 (3H, s), 3. 06-2. 99 (2H, m), 2.59 (2H, t, J = 6.5Hz), 2.47C6H, 2s), 2.17-2.00 (2H, m), 2.03 (3H, s), 1.77 C2H, t, J = 6.5Hz), 1.75-1.38 (9H, m), 1.32-1, 15 (30H, m), 0.91-0.81 (9H, m) MS m / z (FAB): 806 (MH ⁺ )

(2) to the n- Kisadekanoiru -L- leucyl -L- arginine methyl ester - Synthesis of _{(C 1 5 H 3 I (} CO) -Leu-Arg-OMe)

_{C 1 5 H 3 1 - (} C = 0) a -Leu-Arg CPmc) -OMel 9mg dissolved in black port Holm 0. 3 ml, added Torifuruoro acetate 0. 3 ml, and 3 o'clock閭攪stirred at room temperature. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol = 5: 1) to obtain 11.3 mg of the title compound as a colorless syrup.

JH MR (500MHz, DMS0- _ds ) (5:

 8.27C1 d, J = 7.5Hz), 7.90 (1H, d, J = 8.5Hz), 7.53 (1H, brt), 7.50-6.70 (3H, br), 4. 32-4. 30 (1H, dt 'J = 8. OHz, 8. OHz), 4.28-4.21 (IH, m)' 3.61 (3H, s), 3.15-3.05 (2 m) , 2.16-2.02 (2H, m), 1.80-1.40 (9H, m), 1.31-1.15C24H, m), 0.90-0.8 K9 m)

 MS m / z (FAB); 540 (MH +)

 [Example 3 3]

Preparation of n-octadecanoyl-L-n-isyl-L-arginine methyl ester (Compound No. 33) (Formula (33))

(1) n - old Kutadekanoiru - L-Roishiru ^{-N G -2, 2, 5,} 7, 8 - Bae Ntamechirukuro Man - 6-sulphonyl -L- arginine methyl ester _{(CH 3 3 - (C =} 0) - Leu -Ar g (Pmc) -O e)

50 mg of Fmoc-Leu-Arg (Pmc) -0Me synthesized by the method of Example 30 was dissolved in 3 ml of DMF, 0.3 ml of getylamine was added, and the mixture was stirred at room temperature for 20 minutes. The product obtained by concentration under reduced pressure of the reaction solution was dissolved in 1 ml of methylene chloride, triethylamine 17 "1 and hexadecanoyl chloride 401 were added, and the mixture was stirred at room temperature for 30 minutes. The organic layer was extracted with anhydrous sodium sulfate. After drying with lime, the crude product obtained by compression under reduced pressure was purified by silica gel column chromatography (hexane: acetone = 2: 1) to obtain 32.3 mg of the title compound as a colorless syrup.

XH (500MHz, MSO- _ds ) 5:

 8.2K1H 'd, J = 8.OHz), 7.86 (1H, d, J = 3.OHz), 6.80-6.30 (3H, br), 4.33 (1H, dt, J = 7.5Hz, 8.OHz), 4.21-4.15C1H, m), 3.58 (3H, s), 3.06-3.00 (2H, m), 2.59 (2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.15-2.00 (2H, m ), 2.03 (3H, s), 1.77 (2H, t, J = 6.5Hz), 1.73-1.36 (9H, m), 1.33-1.17 (34H, m), 0.91-0.82 (9H, m)

MS m / z (FAB); 834 (MH +)

 (2) n-octadecanoyl-L-leucyl-L-arginine methyl ester (C 1

28. lrag was dissolved in 0.3 ml of chloroform, 0.3 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 3 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain the title compound II.Onig as a colorless syrup.

! H N¾n? (500MHz, DS0-ds) <5 ：

 8.27 (IE d, J = 7.0Hz), 7.90 (1H, d. J = 8. OHz), 7.60 (1H, brt), 7.50-6.30 (3H, br), 4.32C1H, dt, J = 7. OHz , 8, OHz), 4.27-4.20 (1H, m), 3.61 (3H, s), 3.13-3.08 (2H.m), 2.15-2.02 (2H, m), 1.80-1.40 (9H, m) , 1.32-1.17 (28H, m), 0.92-0.83 (9H, m)

 MS m / z (FAB); 568 (MH

 [Example 34]

 Preparation of leucyl-L-arginine-n-octadecyl ester (Compound No. 34) (Formula (34))

LR0 (34)

17 (1) N-9-Fluorenylmethoxycarbonyl-L-mouth isyl 2,2,5,7,8-pentamethylchroman-6-sulfonyl-L-arginine-n-octadecylester (Fmoc- Leu-Arg (Pmc) - 0C _{1 3} H _{3 T)} synthesis of

Arg synthesized by the method of Example 30 (Prac) -. A 0C _{1 3} H ₃₇ 83. lmg dissolved in DMF1.7Ml, WSCI hydrochloride 46fflg, H0Bt32mg, the Fmoc-Leu84 8mg added, at room temperature for 1 hour攪捽did. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with a mixed solution of benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 30: 1) to give 154 mg of the title compound as a colorless syrup .

N¾iR (500MHz, DMS0-d ₆ ) ^:

8.22C1H, d, J = 7.5Hz), 7.83 (2H, d, J = 7.5Hz), 7.72 (2H, dd, J = 3.5Hz, 7.5Hz), 7.46 (1H, d, J = 8.0Hz) , 7.41 (2H't, J = 7.5Hz), 7.31 (2H, 2H, t, J = 7.5Hz), 7.05-6.30 (3H, br), 4.33-4.04 (5H, m), 4.02-3.92 (2H, m), 3.08-2.97 (2H, m), 2.56 (2H, t, J = 6.5Hz), 2.46 (6H, 2s), 2.01 (3H, s), I. 75C2H, t, J-6.5Hz), 1.75-1.15C45H, m), 0.90-0.80 (9H, m)

MS m / z (FAB); 1028 (MH +)

(2) L-leucyl ^{-N- G 2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - n-O Kuta-decyl ester (Leu-Arg (Pmc) -0C 1 3 H ₃₇ )

The Fmoc- Leu-Arg (Pmc) -0C ls H 37 123mg was dissolved in DMF2.5Ml, added Jechiru completion Min 0.25 ml, and stirred at room temperature for 2 hours. The product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 74.6 mg of the title compound as a colorless capsule. . ^! H NMR (500MHz, DMS0- _ds ) (5:

8.13C1H, d, J = 7.5Hz), 6.80-6.30 (3H, br), 4.23-4. 17C1H, m), 4.02-3. 96 (2H, m), 3.20-3 15 (1H, m), 3.08-2.99 (2H, m), 2.58 (2H, t, J = 6.5Hz), 2.4 (6H, 2 s), 2.03C3H, s) , 1.73C2H, t, J = 6.5Hz), 1.75-1. 1.6 (45H, nO '0.90-0.81 (9H, m) MS m / z (FAB); 806 (MH

(3) Synthesis of L-leucyl-L-arginine-n-octadecyl ester (Leu-Arg-0C _IS H _3T )

5.5 mg of Leu-Arg (Pmc) -0C ₁₃ H _3T was dissolved in black form 551, and trifluoracetic acid 55/1 was added, followed by stirring at room temperature for 4.5 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: water = 7: 3: 0.5) to obtain 5.lmg of the title compound as a white solid. .

: H MR (500MHz, DMS0- _ds ) <5:

 8.70 (1H, brd), 7.66 (1H, fart), 7.50-6.70 (3H, br), 4.32-4.27C1H.m), 4.08-4.00 (2H, m), 3.67-3.59 (1H, m), 3.13 -3.08 (2H, m), 1.82-1.18 (39H, m), 0.93 -0.82C9H, m)

MS m / z (FAB); 540 (MH ⁺ )

 [Example 35]

 Preparation of leucyl-L-arginine-n-hexadecylamide (Compound No. 35) [Formula (35)]

LRNH (35)

(1) -9 Suruorenirume butoxycarbonyl -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulphonyl -L- arginine - n-to Kisade Shiruami de (Fmoc-to eu -Arg (Prac) -NHC _ls H ₃₃ )

Construed dissolved the synthesized _{Arg (Pnic) -NHC ls H 33} 233mg by the method of Example 30 to DMF4.7Ml, WSCI hydrochloride 135 mg, the H0Bt95rag. Fmoc-Leu 248mg was added, and stirred for 1.5 h at room temperature. Hydrochloric acid was added to the reaction solution, and extracted with a mixed solution of benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title compound 356nig as a white solid. I got it.

^! H (500MHz, DMS0- _ds ) o:

 7.90-7.75 (4H, m), 7.70 (2H, t, J = 7.5Hz), 7.50C1H, d, J = 8.5Hz), 7.44-7.27 (4H, m), 6.80-6.30 (3H, br ), 4.36-4.16 (3H, m), 4.10-4.00 (1H.m), 3.08-2.97C4H, m), 2.56 (2H, m), 2.56 (2H, t, J = 6.5Hz), 2.46 (6H, 2s), 2.02 (3H, s), 1.75C2H, t, J = 6.5Hz), 1.67-1.17C41H, m), 0.90-0.80 (9H, in) MS m / z (FAB); 999 ( MH one

(2) L-leucyl ^{- N G -2, 2, 5} , 7, 8- pentamethyl chroman - 6-sulfonyl - L-arginine - _n - to Kisadeshiruami de (Leu- Arg (Pmc) - HC ls H 33) Synthesis of

Fmoc-Leu-Arg (Pmc) - was dissolved HCi _S H _{3 3} 225tng to F4.5ML, added Jechirua Min 0.45 ml, and stirred at room temperature for 1 hour. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 171 mg of the title compound as a colorless syrup.

^! HM (500MHz, DS0-ds) δ:

 7.98 (lH, brd), 7.87 (1H, brt), 6.80-6.28 (3H, br), 4.33 (1H, t, J = 5.5Hz), 4.23-4.18 (lH, br), 4.08 (2H, dt, J-5.5Hz), 3.05- 2.98 (4H, m), 2.59 (2

(H, t, J = 6.5Hz), 2.47C6H, 2s), 2.03 (3H, s), 1.78C2H, t, J = 6.5Hz), 1.75-

I.18 (41H, m), 0.90—0.81 (9H, m)

MS m / z (FAB); 777 (MH

(3) - leucyl - L-synthesis arginine -n- to Kisadeshiru Ryomi de _{(Leu-Arg- HC 1S H 33} )

Was dissolved _{Leu-Arg (Prac) -NHC ls} H 33 8.9mg to black port Holm 89 1, triflumizole Ruoro acetate 89 1, and the mixture was stirred at room temperature for 4.5 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol: water = 7: 3: 0.5) to give 2.6 mg of the title compound as a white solid. Obtained as body.

^! H MR (500MHz, DMS0- _ds ) o:

 8.26-3. 15 (lH, br), R. 96 (1H, t, J = 5.5Hz), R. 52 [lH, brt), 7.40-6.65 (3H, br), 4.25C1H, br), 3.13-3.00 (4H, m), 1.75-1.19 (35H, m), 0.90-0.8K 9H, m)

 MS m / z (FAB); 511 (MH

 [Example 36]

Acetyl-L-glutamyl-L-leucyl-s-arginine-n-octyldecylester (Compound No. 36) (Preparation of formula (36)

Ac (36)

 I T

(1) -9 Furuorenirume butoxycarbonyl - § - tert-butyl -L- glutaminyl mill -L- leucyl ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sulfonyl Le -L- Synthesis of arginine-n-octyl decyl ester (Fmoc-Glu (OtBu) -Leu-Arg (Pmc) -0C _{I 3} H ₃₇ )

50 mg of Leu-Arg (Pmc) -OC ₁₃ H ₃₇ was dissolved in ₁ ml of DMF, 24 nig of WSCI hydrochloride, 17 mg of HOBt, and 53 mg of Fmoc-Glu (0tBu) were added, followed by stirring at room temperature for 14 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with a mixed solution of benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give the title compound 64nig as a colorless syrup .

] H MR (500MHz, DMS0- _ds ) δ:

8.25C1H, d, J = 6.5Hz), 7.90-7.82 (3H, m), 7.71C2H, t, J = 7.5Hz), 7.49C1H, d, J = 8.5Hz), 7.4K2H, t. J = 7.5Hz), 7.32 (2H, t, J = 7.5Hz), 7.10-6.30 (3H, br), 4.36-3.91 (8H, m), 3.08-2.99 (2H, m), 2.57 (2H, t, J = 6.5Hz), 2.4 (6H, 2s), 2.20 (2H 丄 J = 8.0Hz), 2.02 (3H, s), 1.90-1.17 (56H, m), 0.90 -0.79C9H, m)

 MS m / z (FAB); 1213 (MH +)

(2) Asechiru-7-tert-heptyl -L- glutamyl -L- leucyl -N ^G -2,2,5, 7,8 - pentamethyl chroman - 6-sulphonyl -L- arginine - II- Okutadeshirue ester (Ac -Glu (OtBu) -Leu-Arg (Pmc) -OC _I3 H ₃₇ )

25.5 mg of Fmoc-Glu (0tBu) -Leu-Arg (Pmc) -0Ci ₃ H37 was dissolved in 0.5 mi of DMF, 0.05 ml of getylamine was added, and the mixture was stirred at room temperature for 20 minutes. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in pyridine (0.6 ml), acetic anhydride (41) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product was purified by silica gel column chromatography (form: methanol = 20: 1), and 21.4 mg of the title compound was obtained as a colorless syrup. Obtained.

JH NM (500MHz, D SO-ds) δ:

 8.16 (1Η, d, J = 7.0Hz), 7.9 (1H, d, J = 8. OHz), 7.87 (1H, d, J = 8.5Hz), 6.70 -6.30C3 br), 4.32-4.13 (3H , m), 4.02-3.93 (2H, m), 3.08-3.00 (2 m),

2.58C2H, t, J = 6.5Hz), 2.47 (6H, m), 2.20 (2H, t, J = 8. OHz), 2.03 (3H, s),

1.83 (3H, s), 1.88-L19C56H.m), 0.90-0.81 (9H, m)

MS m / z (FAB); 1033 (MH +)

(3) Asechiru -L- Darutamiru - L-leucyl -L- arginine - n-Okutade Synthesis sill ester (Ac-Gl U- Leu- Arg- 0C 8 H 3 τ!)

20.4 mg of Ac-Glu (0tBu) -Leu-Arg (Pmc) -0Ci ₃ H ₃ 7 was dissolved in 0.2 ml of chloroform, 0.4 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography.

The residue was purified with (form: methanol: water = 7: 3: 0.5) to give the title compound (15.7 nig) as a colorless gel.

 NMR (500MHz, DMSO-ds) δ

12.09C1H, brs), 8.24 (1H, d, J = 7.5Hz), 7.99 (1H, d, J = 3. OHz), 7.8 (IH, d, J = 8.5Hz), 7.59C1H, brt), 7.50-6.70 (3H, br), 4.31 (1H, dt, J = 7.5Hz), 4.25-4. 18C1H, m), 4.04-3.97 (2H, π '3.12-3.08 (2H.m), 2.23 (2H, t, J = 8.0Hz), 1.85 (3H, s), 1, 79-1.40C9H, m), 1. 31-1. 19 (32H, m), 0.90-0.80 (9H, m)

MS in / z (FAB); 711 (MH

 [Example 3 7]

Preparation of acetyl-L-glutamyl-L-leucyl-L-arginine-n-hexadecylamide (Compound No. 37) (Formula (37))

AcE Ran ^ (37)

(1) Asechiru - § -tert- butyl - L-glutamyl - L-leucyl ^{- N G -2, 2, 5} , 7, 8- pentamethyl chroman - hexa Deshiruami de to 6- sulfonyl -L- arginine -II- Synthesis of (Ac-Glu (OtBu) -Leu-Arg (Pmc) -NHC _ls H ₃₃ )

113 mg of Leu-Arg (Pmc) -HC ₁₅ H _{3 3} was dissolved in 2.2 ml of DMF, and 54 mg of WSC I hydrochloride, 7 mg of H0Btl, 119 mg of Fmoc-GluCOtBu) were added, and the mixture was stirred at room temperature for 14 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted with black hole form. After the organic layer was dried over anhydrous sodium sulfate, the crude product obtained by concentration under reduced pressure was dissolved in 3.6 ml of DMF, 0.36 ml of diethylamine was added, and the mixture was stirred at room temperature for 30 minutes. The crude product obtained by concentrating the reaction solution under reduced pressure was dissolved in 3.6 ml of pyridine, 30 I of acetic anhydride was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 78.3 mg of the title compound as a white solid. Was.

XH reader (500MHz, DMS0- _ds ) o:

8.02C1H, d, J = 7.5Hz), 7.94 (1H, d, J = 8.0Hz), 7.78 (1H, d, J = 8.0Hz), 7.67 (IH't) '6. 80-6.30 (3H, br), 4.28-4.09 (3H, m), 3.09-2.96 (4H, m), 2.53 (2H 丄 J = 6.5Hz), 2.47C6H, 2s), 2.21 (2H, t, J = 8.0 Hz), 2.03 (3H, s), 1.8 3 (3H, s), 1.77C2H, t, J = 6.5Hz), 1.73-1.13C52H, in), 0.90-0.80 (9H, ra) MS m / z (FAB); 1004 (MH

(2) Asechiru -L- Guru evening mill -L- leucyl - teeth - arginine - Synthesis of the n- Kisadeshiru Ami de (Ac-Glu-Leu-Arg -NHC IS H 33)

The Ac-Glu (0tBu) -Leu- Arg (Pfflc) -NHC ls H 33 18.9fflg dissolved in black port Holm 0.2 ml, added Torifuruoro acetate 0.4Mi, and stirred at room temperature for 2 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel gel chromatography π-matography (form: methanol: water = 7: 3: 0.5) to give 21.8 mg of the title compound in white Obtained as a solid.

: H-Oki (500MHz, DMSO-ds) δ

 12.09C1H.brs), 8.03C1H, d, J = 7.5Hz), 7.9K2H.2d, J = 7.5Hz), 7.74 (1H, t), 7.49 (lH, brt), 7.40-6.70 (3H, br) , 4.29-4.12 (3H, m), 3.12-3.00 (4 Η, πι), 2.24C2H, t, J = 8.0Hz), 1.85 (3H, s), .1.74-1.18C37H, m), 0.90-0.8 0 (9H, m)

 MSm / z (FAB); 682 Gffl +)

 [Example 3 8]

Preparation of n-hexadecanoyl-L-leucyl-L-arginine-n-octadecyl ester (Compound No. 38) (Formula (38))

(1) n-to Kisade force Noiru -L- leucyl ^{-N G - 2, 2, 5} , 7, 8- Bae Ntamechirukuro Man - 6-sulphonyl -L- arginine - n-O Kuta decyl ester (C ₁₅ H ₃₁ Synthesis of-(C = 0) -Leu-Arg (Pmc) -OCi ₈ H ₃ T)

Was dissolved in _{Leu-Arg (Pmc) -0Ci8H 3} 7l6.6rag methylene chloride 0.33 ml, triethyl Chiruamin 6 I, the hexa decanoyl chloride Li de 13 1 to the mixture was stirred for 3 hours at room temperature. Water was added to the reaction solution, and extracted with chloroform. The orange layer After drying over anhydrous sodium sulfate and concentrating under reduced pressure, the crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 9 mg of the title compound as a white solid. Obtained.

! H (500MHz, DMS0- _ds ) δ:

 8.19C1H, d, J = 7.5Hz), 7.86 (1H, d J = 8.0Hz), 6.80-6, 30 (3H, br), 4.33 (1H, d, J = 7.0Hz), 2.47 (6H, 2s) '4.19-4.10 (1H, m), 4.01-3.94 (2H, m)' 3.0 • 6-3.00 (2H, m), 2.58 (2H, t, J = 6.5Hz), 2.17 (2H, t, J = 7.5Hz), 2.15-2.03C 2H, m), 2.03C3H, s), 1.77 (2H, t, J = 6, 5Hz), 1.73-1.10C71H, m), 0.90-0.80 (12H, m)

 MS m / z (FAB); 1044 (MH +)

(2) to the n- Kisadekanoiru - L-leucyl -L- arginine - n- Okutadeshiru ester _{(C 15 H 31 - (00} ) - Leu- Arg-0C 13 H 37) Synthesis of

15.6 mg of C ₁₅ H ₃₁ CC = 0) -Leu-Arg (Pmc) -OC ₁₈ H ₃₇ was dissolved in 0.2 ml of chloroform, 0.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 5: 1) to obtain 8.9 mg of the title compound as a white solid. '

! H anonymous _{(500MHz, DMS0-d 8)} δ:

 8.26ClH, d, J = 7.5Hz), 7.89 (1H, d, J = 8.0Hz), 7.44 (lH, brt), 7.40-6.60 (3H, br), 4.36-4.30 (1H, m), 4.24- 4.18 (1 H, m), 4.00 (2H, t, J = 6.0Hz), 3.13-3.07C2H.in), 2.20- 2.01 (2H, m), 1.80-1.4 11H, m), 1.31-1.18 C55H, m), 0.91-0.82 (12H, m)

MS m / z (FAB); 778 CMH ⁺ )

 [Example 3 9]

Preparation of n-hexadecanoyl-L-leucyl-shi-arginine-n-hexadecylamide (Compound No. 39) (Formula (39)) 0

 (39)

· ", ₁₃

(1)-L-Kisadekanoiru to n- leucyl ^{-N c -2, 2, 5,} 1, 8- Pentamechiruku Roman - 6-sulfonyl - L-arginine - to n- Kisadeshiruami de _{(C 15 H 31 - (C} = 0) -Leu-Arg (Pmc) -NHC _ls H ₃₃ )

Was dissolved in _{Leu-Arg (Pmc) -NHCisH 33} 11.7mg of methylene chloride 0.23 ml, birds Echiruamin, the hexa decanoyl chloride Li de 9 U added to, and 3 Toki閭stirred at room temperature. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 20: 1) to give 6.3 mg of the title compound as a white solid. Obtained.

JH NMR (500MHz, DMS0-d 5) δ:

 7.94 (1Η, d, J = 7.5Hz), 7.75-7.70 (2H, m), 6.80-6.30 (3H, far), 4.25-4.10 (2H, m), 3.06-2.8 (4H, m), 2.58C2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.15-2.04C2H, m), 2.03 (3H, s), 1.77C2H, t, J = 6.5Hz), 1.67-1.18C61H, m), 0.9 0-0.80C12H, m)

MS m / z (FAB); 1015GlH +)

(2) n- to Kisadekanoiru -L- leucyl - L-Ryo arginine - Synthesis of the n- Kisadeshiru Ami _{F (C 15 H 3 i- (} C = 0) -Leu-Arg-NHCi 8 H 3 3)

334.9 mg of Ci ₅ H3i- (C = 0) -Leu-Arg (Pmc) -NHCi0H was dissolved in 0.05 ml of chloroform, 0.05 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form: methanol = 7: 1) to obtain 1.9 mg of the title compound as a white solid.

XH anonymous _{(500MHz, DMS0-d 5)} d:

7.97 (lH, d, J-8.0Hz), 7.85 (1H, d, J = 8.0Hz). 7.75 (1H, t, J = 6.0Hz), 7.51 (lH, brt), 7.40- 6.70 (3H, br), 4.24-4.04 (2H, m), 4.00 (2H, t, J = 6.0Hz), 3.12-2.99C4H, m), 2.16-2.05C2H, m ), 1.72-1.13C61H, m), 0.90-0.82 (12H, m)

MS m / z (FAB); 749 (MH ⁺ )

 [Example 40]

Preparation of acetyl-L-aralanyl-L-arginine-n-octadecyl ester (Compound No. 40) (Formula (40))

AcAO ^, γ (40)

(DN-9-Furuorenirume butoxycarbonyl -L- Araniru ^{-N G -2, 2, 5,} 7, 8 - pentamethyl chroman - 6-sulphonyl -L- Ryo arginine - n-Okutadeshi glycol ester (Fmoc-Ala-Arg ( Pmc) -OC ₁₃ H ₃₇ )

 ^ ^^-! ^^^! ! ^! ^, And 7.7 mg of WSCI hydrochloride, 15.5 mg of HOBt, and 13 mg of Fmoc-Ala-hydrate were added, followed by stirring at room temperature for 3 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with a mixture of benzene: ethyl acetate = 1: 2. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol = 15: 1) to give 20 mg of the title compound in white Obtained as a top.

: H NMR (500MHz, DMS0-ds) δ:

 8.22C1H, d, J = 7.5Hz), 7.88 (2H, d, J = 7.5Hz), 7.72 (2H, dd, J = 3.5Hz, 7.5Hz), 7.46C1H, d, J = 8.0Hz), 7.41 (2H, t, J = 7.5Hz), 7.31 (2H, 2H, t, J = 7.5Hz), 7.00-6.30 (3H, br), 4.33-4.03C5H, m), 4.01-3.93 (2H'm) , 3.08-2.97 (2H, m), 2.56 (2H, t, J = 6.5Hz), 2.46 (6H, 2s), 2.01 (3H, s), 1.75C2H, t, J = 6.5Hz) '1.75-1.15 (C39H, m), 0.85C3H, t, J = 7.0Hz)

MS m / z (FAB); 986 (MH

(2) Asechiru -L- Araniru -N ^G -2, 2, 5, Ryo, 8-pentamethyl chroman - 6- Sulfonyl - L-arginine - _n - O Kuta dissolve synthesis Fmoc- the _{Ala-Arg (Pmc) -0C 13} H 3 7l9.7mg to DiiF0.4ml decyl ester (Ac-Ala-Arg (Pnic ) -OCI SHST) Then, 0.04 ml of getylamine was added, and the mixture was stirred at room temperature for 10 minutes. The crude product obtained by depressurizing and concentrating the reaction solution was dissolved in pyridine (0.45 ml), acetic anhydride 41 was added, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give 6.4 mg of the title compound as a white solid. Obtained.

! H N R (500MHz, DMSO-ds) δ:

 8.21 (lH, d, J = 7..0Hz), 7.98 (1H, d. J = 8.5Hz), 7.00-6.30 (3H, br), 4.33-4 • 26 (lH, m), 4.20-4.12 ( 1H, m), 4.03-3.93 (2H, m), 3.08-3.00 (2H, m), 2.58 (2H, t, J = 6.5Hz), 2.47 (6H, 2s), 2.03 (3H, s) , L, 81 (3H, s), 1.77C2H, t, J = 6.5Hz), 1.72-1.15 (39H, m), 0.85C3H, t, J = 7.0Hz)

MS m / z (FAB): 806 (MH ⁺ )

(3) Synthesis of acetyl-L-aralanyl-L-arginine-n-octadecyl ester (Ac-Aia-Arg-0C ₁₃ H ₃₇ )

The Ac-Ala- Arg (Pmc) -0C i3 H 37 5.4mg dissolved in black port Holm 0.05 ml, was added tri Furuoro acid 0.05Flil, and stirred at room temperature for 1 hour. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 8: 1) to obtain 1.8 mg of the title compound as a colorless syrup.

(500MHz, DMS0-d _s ) δ:

8.26C1H, d, J = 8.0Hz), 8.03 (1H, d, J = 7.5Hz), 7.46C1H, brt), 7.40-6.60 (3H, br), 4.31-4.20 (2H, m), 4.08-3.98 (2H, m), 3.12-3.07 (2H, m), 1.82 (3H, s), 1.80-1.46 (6H, m), 1.31-1.16C33H, m), 0.85C3L J = 7.0Hz) MS m / z (FAB); 540 (T)

[Example 4 1] Acetylleucylarginine- (16-acetoxy-n-hexadecyl) ester (Compound No. 41) (Formula (41))

Ac. GAc (41)

(1) Synthesis of 16-acetoxy-n-hexadenicol

 1,16-Hexadecanediol lOOmg was dissolved in pyridine l.Omi, acetic anhydride 37 ^ 1 was added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 53.lmg of the title compound in white. Obtained as a solid.

XH NMR (500MHz, DMS0- _ds ) 6:

 4.05 (2H, t, J = 7.0Hz), 3.63C2H, dd, J = 5.5Hz, 6.5Hz), 2.04 (3H, s), 1.67-1.52 (4H , Ra), 1.39-1.22 (24H, m)

MS m / z (FAB); 301 (MH ⁺ )

(2) Asechiruroishiru ^{-N G -2, 2, 5,} 7, 8- pentamethyl chroman - 6-sul Ho sulfonyl arginine - (16 Asetokishi to -n- Kisadeshiru) Synthesis of ester

Dissolve 30 mg of Ac-Leu-Arg (Pmc) in 0.15 ml of DMF, add 19 mg of WSC I hydrochloride and 6 mg of DMAP, and add a solution of AcCKCH ₂ ) _ls -0H15fflg in 0.15 ml of DMF, and add at room temperature. Stir for 18 hours. IN hydrochloric acid was added to the reaction solution, and the mixture was extracted with a mixed solution of benzene / ethyl acetate = 1/2. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain the title compound 38fflg as a colorless syrup.

^! H Oki (500 t, CDCl ₃ ) 0:

4.55-4.31 (2H, m), 4.15-4.01 (4H, m), 3.22-3.16 (2H, in), 2.63 (2H, t, J = 6 . 5H z), 2.58 (3H.s), 2.57 (3H, s), 2.17 (3H, s), 2.04 (6H.2s), 1.80 (2H, t, J = 7 OH z), 1. 93-1. 21 (41H, m), 0.97-0.88 (6H, m)

MS m / z (FAB); 878 (MH—)

 C3) Synthesis of acetylleucylarginine- (16-acetoxy-n-hexadecyl) ester

Ac-Leu-Arg (Pmc) 0- (CH ₂ ) i0Ac35rag was dissolved in 0.3 ml of chloroform, 0.3 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product obtained was dissolved in acetonitrile and washed with hexane. The acetonitrile layer was concentrated under reduced pressure to obtain 41 mg of a crude product of the title compound as a pale yellow syrup.

XH awake (500MHz, DMS0- _ds ) δ:

8.31 (lH, d, J = 7.5Hz), 7.99-.91 (1H, m), 7.46 (lH, .brt), 7.40-6.50 (3H, br) , 4.40-4.28 (1H, m), 4.25-4.16 (1H, m), 4, 07-3.93 (4H, m), 3.12-3.05 (2H , m), 1.99C3H, s), 1.82C3H, s), 1.80-1.18 (41), 0.92-0.84C6H, m) MS m / z (FAB); 612 (MH ⁺ )

 [Example 4 2]

 Preparation of acetyl-leucylarginine- (15-acetoxypentadecyl) ester (Compound No. 42) (Formula [42])

AcLSO- • OAc (42) Synthesis of acetyl-leucyl-N ^c -2,2,5,7,8-pentamethylchroman-6-sulfonylarginine- (15-tert-butyldimethylsiloxy-n-pentadecyl) ester 3.0 g of 1,15-pentanedecanediol was dissolved in 15 ml of MF, 1.0 g of imidazole and 2.22 g of tert-butyldimethylchlorosilane were added, and the mixture was stirred at room temperature overnight. The reaction solution was added to water, extracted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thus, 1.38 g of a crude product of 15-tert-butyldimethylsiloxypentadecanol was obtained.

—On the other hand, 421.1 mg of Ac-Leu-Arg (Pmc), 172.7 mg of DMAP and 271.0 mg of WSCI hydrochloride were dissolved in 4 ml of DMF, and the crude 15-tert-butyldimethylsiloxy-n-pentanodecanol obtained earlier was dissolved there. A solution prepared by dissolving 170 mg of the compound in 1 ml of DMF was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (form: methanol / methanol = 40/1 → 25/1) to obtain 315.6 mg of the title compound. Was obtained as a colorless syrup. ^: H organ (500MHz, DMSO-ds) δ:

8.30- 8.25C1H, m), 7.94-7.89 (1H, m), 6.78-6.41 (3H, br), 4.39-4.32 (1H, ra), 4.19-4.09 (lH, m), 4.03-3.92 (2H, m), 3.06-2.98 (2H, m), 2.57 (2H, t, J = 7.0Hz) ₍ 2.49C6H, 2s), 2.01 (3H, s), 1.81 (3H, s), 1.76C2H, t, J = 7.0Hz), 1.72-1.18C41H, m), 0.87-0.81 (15H, m), 0.00 (6H, s)

MS m / z (FAB); 936 (MH ^<+> )

(2) Asechiruroishiru ^{-N G - 2, 2, 5} , 7, 8- Bae pointer methyl chroman - 6-sulfonyl arginine - (15 arsenide Dorokishi -n- pentadecyl) Synthesis of ester Asechiruroishiru -N ^G - 2, 2 , 5,7,8-Penyu methyl chroman-6-sulfonylarginine- (15-tert-butyldimethylsiloxy-n-vinyl decyl) ester 311.6 mg was dissolved in THF 4.5 ml, and 1M TBAF (THF solution ) Was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (chloroform / methanol = 20/1) to obtain 239.2 mg of the title compound as a colorless syrup . ^J H NMR (500MHz, DMSO-ds) o:

8.31- 8.26C1H, m), 7.95- 7.90 (1H, m), 6.79-6.28 (3H, br), 4.40- 4.32 (1H, m), 4.30 (lH, t, J = 5.5Hz), 4.21-4.08 (1 H, m), 4.03-3.89C2H, m), 3.21- 3.15 (2H, m), 3.11-2.93 (4H, m), 2.53 (2H, t, J = 6.5Hz) '2.49 (6H, 2s), 2.03 (3H, s), 1.82-1.80 (3H, m) , 1.79-1.76 (2H, m), 1.72-1.18 (37H, m), 0.95- 0.83C6H, m)

MS ra / z (FAB); 822 (MH ⁺ )

(3) Asechiruroishiru ^{- N G - 2, 2,} 5, 1, 8- Bae pointer methyl chroman - 6-sulfonyl arginine - (15 Asetokishipen evening decyl) Synthesis of ester

Asechiruroishiru ^{-N G -2, 2, 5,} 7,8- pentamethyl chroman - 6-sulfonyl arginine - was dissolved (15 hydroxocobalamin di pentadecyl) ester 80. Omg the pyridinium Jin 1.0 ml, acetic anhydride 18.8 ^ 1 was added and stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and washed with 0.5N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The crude product obtained was purified by silica gel column chromatography (chloroform / methanol = 15/1) to give 78.3 rag of the title compound as a colorless syrup .

8.31-8.26C1H, m), 7.94- 7.90 (1H, m), 6.78- 6.29 (3H, br), 4.39-4.32 (1H, m), 4.21-4.08 (lH, m), 4.02- 3.89 (4H, m), 3.06- 2.96 (2H, m), 2.58 (2H, t, 7.0Hz), 2.49 (6H, 2s), 2,03 (3H, s), 1.98C3H, s), 1.81-1.79 (3H, m), 1.79-1.76C2H, m), 1.73-1.18 (39H, m), 0.95-0.83 (6H, in)

MS m / z (FAB); 864 (MH ^<+> )

 (4) Synthesis of acetylleucylarginine- (15-acetoxypentadecyl) ester

Dissolve 74.5 mg of acetylleucyl-2,2,5,7,8-pentamethylchroman-6-sulfonylanginine- (15-chloroethoxypentyl decyl) ester in 0.8 of chloroform, add 0.8rol of trifluoroacetic acid, and add room temperature. And stirred overnight. The crude product obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography (form / methanol = 8/1) to obtain 55.3 mg of the title compound as a colorless capsule. 'ΗOki (500MHz, DMS0-d _g ) δ

 8.33-8.31 (1Η, m), 7.98- 7.93 (1H, m), 7.46 (1H, brt), 7.34- 6.64 (3H, s), 4.36-4.30C1H, m), 4.22- 4.18 (1H, ra) , 4.05- 3.96 (4H, m), 3.09C2H, t, J = 6.5Hz), 1.99C3H, s), 1.83-1.82 (3H, m), 1.79-1.24 (33H, in), 0.90-0.84 (6H , in)

 MS m / z (FAB); 598 (MH +)

 Next, test examples are shown for the results of measuring the IL-8, SDF-1 and RANTES antagonistic activities of the amino acids of the present invention.

 (Test Example 1)

(1) Measurement of IL-8 antagonist activity

Human THP-1 (monocyte-derived cell line) cells were tested for the affinity of the IL-8 amino acid derivative of the present invention for the receptor by the following method by a binding test using ( ¹²⁵ I) iL-8. .

THP-1 cells were passaged at RPM Bok 1640 medium containing 10% FCS (FBS), suspended the cells in logarithmic growth phase 5xiO ^s cell / 400 ul in R ΡΜί-1640 medium containing 0.1% © shea serum albumin It became cloudy.

⁽¹²⁵ ί) Ι Mr to the suspension - mixture 8 with (final concentration 0.06 mM specific activity 2200 Ci / mmol), and the amino acid derivative D'- PBS or DMS0 solution 4 1 of the present invention (final concentration 100 M) did. After incubating for 2 hours in ice and centrifuging, the wells were washed 5 times with Inil D-PBS. Finally, the cells were suspended in D'-PBS lmi, and the total radioactivity of the cells was measured.

THP-1 specific binding of cells to ^(I25 DlL-8 (THP- 1 bound to other than IL-1 receptor on the cell ⁽¹²⁵ I) IL- 8) is die Amino acid derivatives of the present invention of the operation In addition, 0.12 M IL-82 ill was added to the THP-1 cell suspension and determined.

THP-1 to cells ⁽¹²⁵ ί) Ι Mr - specific binding of 8 was determined by subtracting the non-semi-specific binding amount from the total binding.

That is, the inhibition rate (%) of the amino acid derivative of the present invention at a 100 M dose for the specific binding of ΤΗΡ-1 cells to IL-8 was determined by the following formula. Inhibition rate (%) 2 [(total binding amount-non-specific binding amount) 1 (binding amount when the amino acid derivative of the present invention is added-non-specific binding amount)] _÷ (total binding amount-non-specific binding amount) ) X100

 (2) Measurement of SDF-1 and RANTES antagonist activity

Wherein (1) the ⁽¹²⁵ I) in place of ^{IL-8 (125 I) SDF-} 1 and ⁽¹²⁵ i) a RANTES used in the same concentration was measured antagonistic activity against these. Table 1 shows the results.

 [Table 1] Inhibition rate 100 M) Compound number Chemical formula

 【SH-8 SDF-1 RANTES

1 CH ₃ -CH (-CH ₃ )-(CH ₂ ) ₂ -C (= 0)--0- (CH ₂ ) i T -CH ₃

 80 80 80

2 AC-RO- (CH ₂ ) IT-CH ₃ 40 50 50

6 Ac-KO- (CH ₂ ) ir-CH ₃ 60 70 70

90 80 80

80 80 80

₁ 5-CH;

 80 90 90

1 8 Ac-LRNH- (CH ₂ ) i 5-CH 3 40 50 50

2 0 Ac-ELR0- (CH ₂ ) i 7-CH 3 70 80 80

2 1 Ac-LRO- (CH ₂ ) ₁₈ -CH ₃ 40 50 50

2 2 Ac- and RO- (CH ₂ ) ₁₃ -CH ₃ 40 50 50 ? 3 Ac-LRO- (CH ₂ ) ₂₅ -CH ₃ 40 JΓU)

Ac-LR0- (CH ₂ ) 25-CH ₃ 40 en ODU

9 7 Ac-LRO- (CH ₂ ) ₁₃ -CH ₃ 40 uu

Q Ac-LR0- (CH ₂ ) i 7-CH ₃ 80 / U / U

40 50 50

 40 50 50

3 5 AC-RO- (CH ₂ ) IT-CH ₃ 40 50 50

36 LRNH- (CH ₂ ) i 5-CH ₃ 60 70 70 As shown in this table, the amino acid derivative of the present invention exhibits an antagonistic activity against IL-8, SDF-1 or RAiYTES, and It has been found that diseases caused by chemokines can be prevented.

 [Test Example 2]

 The acute toxicity of the amino acid derivative was examined. That is, 5-week-old ICR mice (male) were divided into 5 mice in each group. After acclimation and rearing for 1 week, the amino acid derivative of the example was dissolved or dispersed in a 0.5% methylcellulose aqueous solution, and a single oral administration ( The dose was 500 rag / kg), and the number of deaths after 6 days was examined. Table 3 shows the results.

As shown in Table 2, administration of any of the amino acid derivatives did not result in death and no acute toxicity was confirmed. [Table 2]

Compound number Deaths Z surviving

1 0/5 2 0/5 3 0/5 4 0/5

 0/5

6 0/5 9 0/5

1 0 0/5 1 2 0/5 1 6 0/5 1 8 0/5 2 0 0/5 2 1 0/5 2 2 0/5 2 3 0/5 2 5 0/5 2 7 0/5

2 9 0/5

3 0 0/5 3 2 0/5 3 5 0/5 3 6 0/5 [Formulation example]

 Compound No. 2 (10 nig), lactose (36 mg), corn starch (150 mg), microcrystalline cellulose (29 mg), and magnesium stearate (5 mg) were mixed, and the mixture was compressed into tablets (230 mgZ). Tablets). Industrial applicability

 According to the present invention, a novel amino acid derivative or a salt thereof can be provided. The novel amino acid derivative of the present invention or a salt thereof has CXC and CC chemokine receptor antagonism, and exhibits excellent effects as a therapeutic or preventive agent for AIDS, allergic diseases, inflammatory diseases and the like.

Claims

Scope of the request. An amino acid derivative represented by the following formula (I) or a salt thereof.

R '-X Lph- -AYR ²

 In the formula, A contains at least one amino acid residue selected from D or L arginine, lysine and orditin, or at least one amino acid residue selected from the group consisting of arginine, lysine and orditin. Indicates a peptide consisting of two or three amino acid residues selected from the group consisting of arginine, lysine, ordinine, leucine, alanine, quinoline, isofucine, glycine, glutamic acid and aspartic acid. .

X ¹ does not exist, or-(C = 0)-,-(C = 0) -NH-,-(C = 0)-0-,-(C = 0) -S-,-NH- ( C = 0)-, -NH- (C = S)-, -NH- (C = 0) -NH-,-NH- (C = S)-NH-,-(S = 0)--S02- Represents a group selected from the group consisting of -NH-, -0- and -S-.

X ² is absent or - (C = 0) -, - (S = 0) -, - S0 2 -, - NH- (00) - or is - NH- (C = S) - and Show.

Y is absent, or - 0 -, - S-, -NH- or - NR ³ - shows the.

RR ² independently represents a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds, or a branched alkenyl group; Alternatively, any one of!? ¹² represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.

3 represents a hydrogen atom, a straight-chain alkyl group having 1-8 carbon atoms, a branched alkyl group, a straight-chain alkenyl group, a branched alkenyl group or a cyclic alkyl group. Further, ph is not present, or when ph is present, the substitution position of the ph group may be any of ortho, meta and para.

An amino acid derivative represented by the following formula (I) or a salt thereof.

The R to X ph- X ² - AYR in ² (I) formula, A is shows the amino acid residue selected Arg of D or L, from Lys and Orn.

X ¹ is not present, or-(C = 0)-,-(C = 0) -NH-,-(C = 0) -0-,-(C = 0)-S-, -NH- ( C = 0) -, -NH- ( C = S) -, - NH- (00) - NH -, - NH- (C = S) station '- (S = 0) - , - S0 2 -, - NH represents a group selected from the group consisting of-, -0- and -S-.

X ² is absent or - (C = 0) -, - (S = 0) -, - S0 2 -, - NH- (C = 0) - or is - NH- (OS) - a Show.

Y is absent, or - 0 -, - S -, - NH- or - NR ³ - shows the.

R ^{2 and} R ² each independently represent a linear alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group containing 1 to 5 double bonds or a branched alkenyl group. Or one of RjR ² represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group.

R ³ represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a linear alkenyl group, a branched alkenyl group or a cyclic alkyl group. Further, the substitution position for the ph group may be any of ortho, meta and para.

An amino acid derivative represented by the following formula (I) or a salt thereof.

Ι ^ -ΧPh-X ² -A- Y- R ² (I)

In the formula, X ¹ , X ² , A and Y are used in the same meaning as in claim 1, and R ¹ is a linear alkyl group having 4 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or Shows a branched alkenyl group.

R ² represents a linear alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group having 1 to 5 double bonds or a branched alkenyl group.

4. The amino acid derivative or a salt thereof according to claim 3, which is represented by the following formula (I).

R ¹ -X is ph-X ² -AY-R ² (I) In the formula, R ¹ , R ² , A and Y are used in the same meaning as in claim 2, and-0 -'- ΝΗ- ( C = 0)-and. X ² represents-(C = 0)-. Y represents -0- or -NH-.

 5. An amino acid derivative represented by the following general formula (I) or a salt thereof.

R ¹ -X to A- Y- R ² (I)

 In the formula, A represents an amino acid residue selected from the group consisting of arginine, lysine, and ordinine;

X ¹ does not exist or represents-(C = 0)-,-(S = 0)-, -SO2-,-NH- (C = 0)-. -NH-(C = S)-,

Y is absent or represents -0-, -S- or -NR ^3- .

R ¹ and R ² are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group. Or ^one of!? ¹ and R ^{2 represents} a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group. R ² may have an acyloxy group at the terminal.

 Represents a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group.

6. In the above formula (H), R ¹ represents a straight-chain alkyl group, branched alkyl group, cyclic alkyl group, straight-chain alkenyl group or branched alkenyl group having 4 to 8 carbon atoms, and R ² represents 12 carbon atoms. The amino acid derivative according to claim 5, which represents a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group containing 1 to 5 double bonds, or a branched alkenyl group having 1 to 5 double bonds. Or its salt.

. In the above formula (H), or not X ¹ is present, - (C = 0) - are shown, Y is - 0- or -. Amino acid derivatives or according NH- to claim 6 showing the R ¹ Represents a linear alkyl group having 4 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group.

R ⁵ is a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds or a branched alkenyl group. The amino acid derivative according to the above. . X ¹ is, - 0 -, -NH- (C = 0) -, shows the. X ² represents-(00)-. The amino acid derivative according to claim 6, wherein Y represents -0- or -NH-.

0. It is represented by the following general formula (IT),

X ¹ to ^{R - A- Y- R 2 (I} )

A contains at least one amino acid residue selected from the group consisting of arginine, lysine, and ordinine; arginine, lysine, ornithine, leucine, alanine, norin, isoleucine, glycine, glutamic acid, and asparagine An amino acid derivative containing a peptide consisting of two or three amino acid residues selected from the group consisting of acids, or a salt thereof. In the formula, X ¹ is absent,-(C = 0)-,-(S = 0)-, -S0 _2- , -NH- (C = 0)-, or -NH- (C = S )-

Y is absent or represents-0-, -S-or -NR ^3- ,

R ¹ and R ² are each independently a straight-chain alkyl group having 12 to 30 carbon atoms, a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a straight-chain alkenyl group having 1 to 5 double bonds, and a branched alkenyl group Or ^one of R ¹ and R ^{2 represents} a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group, or a branched alkenyl group. R ² may have an acyloxy group at the terminal.

R ³ is a hydrogen atom, a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, It represents a cyclic alkyl group, straight-chain alkenyl group or branched alkenyl group. 1 represents a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group, a cyclic alkyl group, a linear alkenyl group or a branched alkenyl group, and R ² represents a linear alkyl group having 12 to 30 carbon atoms. The peptide-containing amino acid derivative according to claim 10, which represents a branched alkyl group, a cyclic alkyl group, a cholesteryl group, a linear alkenyl group containing 1 to 5 double bonds or a branched alkenyl group, or a salt thereof.

2. A power and a A ¹ and A ^2, leucine A ¹ is D or L, Arani emissions, Bruno "phosphorus, isoleucine, the amino acid residue selected from glutamic acid and a group ing from Asuparagin acid, A ² is An amino acid derivative containing the peptide according to claim 10 or 11, which represents an amino acid residue selected from the group consisting of D or L arginine, lysine and orditin, or a salt thereof.

3. X is absent or represents-(C = 0) _, and 'Y represents -0- or -NH-. Amino acid derivative containing a peptide according to any of claims 10 to 12 The body or its salts.

4. A chemokine receptor antagonist comprising the amino acid derivative or a salt thereof according to any one of claims 1 to 13 as an active ingredient.