JPH0820533A - Bacterial shock treatment - Google Patents

Abstract

(57) [Summary] (Modified) [Purpose] To provide a novel therapeutic agent for bacterial shock. [Structure] A therapeutic agent for bacterial shock containing a spagarin-related compound represented by the general formula [1] and a pharmacologically acceptable salt thereof as an active ingredient. [In the formula, X ₀ represents — (CH ₂ ) _1-5 — or a phenylene group which may have a substituent, a represents an integer of 3 to 7, and X ₁
Is _{- (CH 2) 0-2 -CH (} R 00) - (CH 2) 0-2 - ( wherein R ₀₀ are _{-H, -OH, -OCH 3, -OCH} 2 CH 3
Or an -CH ₂ OH. ), X ₂ is —NH (CH ₂ ).
_{4 NH- (CH 2) 3 -NH} -R 02 ( wherein R ₀₂ represents a residue obtained by removing hydrogen, the hydroxyl group from the carboxyl group of an amino acid or peptide.)]

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a therapeutic agent for bacterial shock containing a compound related to spagarin as an active ingredient.

[0002]

2. Description of the Related Art As a treatment for bacterial shock, administration of antibiotics is carried out for the purpose of eliminating bacteria which are the source of infection. In addition, administration of corticosteroids, anticoagulants, diuretics, glucose, insulin, potassium, digitalis, etc. and infusion therapy are carried out for systemic management during shock. The spagarin-related compound is a derivative of spagarin isolated from a bacterium belonging to the genus Bacillus and is known to have antitumor activity, immunopotentiating activity, and immunosuppressive activity depending on the type of derivative (Japanese Patent Laid-Open No. 62152/1983). No. 1989, No. 129119, and No. 90164, 1988.
issue). Many of the compounds of the following general formula [1] are disclosed in these publications, and most of the compounds represented by [B-1] are the compounds represented by [B-2] in JP-A-59-42356. Many of them are disclosed in Japanese Unexamined Patent Publication No. 131458/1990, [B-
Most of the compounds represented by 3] are disclosed in JP-A No. 4524/1988.
No. 7 is disclosed.

[0003]

The current therapeutic methods for bacterial shock are inadequate, and there is a strong demand for the development of new highly safe drugs.

[0004]

Therefore, the present inventors have discovered that a spagarin-related compound or a salt thereof improves symptoms caused by endotoxin shock, and found that it is promising as an excellent therapeutic agent for bacterial shock. It was

Namely, the present invention has the general formula [1] _{Gu-X 0 - (CH 2} ) a -CONH-X 1 -CO-X 2

[Wherein Gu is a guanidino group and X ₀ is-(C
H ₂ ) _1-5- or a phenylene group which may have a substituent,
a represents an integer of 3 to 7, X _{1 is-} (CH ₂ ) _{0-2-
CH (R 00) - (CH} 2) 0-2 - ( wherein R ₀₀ are -H, -O
_{H, -OCH 3, -OCH 2 CH} 3 or -CH ₂ OH
Indicates. ), X ₂ is —NH (CH ₂ ) ₄ NH— (CH ₂ ) ₃
-NH-R ₀₂ (wherein R ₀₂ represents a residue obtained by removing a hydroxyl group from a carboxyl group of hydrogen, an amino acid or a peptide)] and a pharmacologically acceptable salt thereof. The present invention relates to a therapeutic agent for bacterial shock contained as an active ingredient.

Examples of the compound contained in the above general formula [1] include, for example, the general formula [B-1].

Embedded image

[Wherein X _is- (CH ₂ ) _1-5 -or -C ₆
H ₄ −, r is an integer of 3 to 7, R ₆ is a residue obtained by removing one hydrogen atom from an α-amino group of an α-amino acid and a hydroxyl group from an α-carboxyl group, or ω −.
A residue obtained by removing one hydrogen atom from an ω-amino group of an amino acid and a hydroxyl group from an α-carboxyl group, which may have a functional group in the residue is shown. ] A spagarin-related compound represented by the general formula [B-2]

[Chemical 6]

[Wherein Y _is- (CH ₂ ) _1-5- or -C ₆
H ₄ −, W is a hydrogen atom or a residue obtained by removing a hydroxyl group from a carboxyl group of an amino acid or a peptide, m is 0, 1 or 2, n is 1 or 2,
s represents an integer of 3 to 7. ] The spagarin-related compound represented by

General formula [B-3]

[Chemical 7]

[Wherein U is-(CH ₂ ) _1-3 -or -C ₆
H ₄ —, R ₂ is —H, —OH, —OCH ₃ , —O.
CH ₂ CH ₃ or —CH ₂ OH is shown, R ₄ is a hydrogen atom or a residue obtained by removing a hydroxyl group from a carboxyl group of an amino acid or peptide, and t is an integer of 3 to 7. ] The spagarin related compound etc. which are represented by these are mentioned.

When X _{0 in the} general formula [1] represents a phenylene group, the phenylene group may have a substituent. Substituents include halogen atoms such as chlorine, fluorine and bromine, and C _1-5 lower alkyl groups such as methyl, ethyl, propyl, t-butyl and pentyl, methoxy, ethoxy, propoxy, t-butoxy and pentoxy. And C _1-5 lower alkoxy groups and the like.

As-(CH ₂ ) _1-5 --of X ₀ ,-(C
H _{2) 3} - or - (CH _{2) 5} - are preferred. The compound represented by the general formula [1] may form a salt with an acid, and may be an inorganic acid or an organic acid as long as it is non-toxic as an acid for forming a salt. The inorganic acid is not particularly limited, but hydrochloric acid, sulfuric acid, nitric acid and the like are preferable. The organic acid is also not particularly limited, but methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid and the like are preferable.

Next, in the spagarin-related compound of the general formula [B-1], R ₆ is a residue obtained by removing one hydrogen atom from the α-amino group of the α-amino acid and a hydroxyl group from the α-carboxyl group or ω. A residue obtained by removing one hydrogen atom from the ω-amino group of an amino acid and a hydroxyl group from the α-carboxyl group, which may have a functional group in the residue, and is a known α- or ω- There is no particular limitation as long as it is a residue derived from an amino acid.

Further, in the residues derived from α- or ω-amino acids, those having an optically active carbon are L
Any of-, D- and DL-types can be used.

Typical examples of R ₆ are glycine, alanine, α-aminobutyric acid, proline, valine, norvaline, isoleucine, alloisoleucine, leucine, norleucine, serine, homoserine, threonine,
Alosreonine, o-methylserine, o-ethylserine, o-methylhomoserine, o-ethylhomoserine, o
-Methylthreonine, o-ethylthreonine, o-methylarrosreonine, o-ethylalrosreonine, ornithine, lysine, aspartic acid, glutamic acid, asparagine, glutamine, arginine, phenylalanine,
Tyrosine, histidine, tryptophan, cysteine,
Homocysteine, S-methyl cysteine, S-ethyl cysteine, methionine, ethionine, and other α-amino acids, a residue obtained by removing one hydrogen atom from the α-amino group and a hydroxyl group from the α-carboxyl group, and β-alanine, γ Hydrogen atom from the ω-amino group of amino acids such as -aminobutyric acid, δ-aminovaleric acid and ε-aminocaproic acid
And a residue obtained by removing a hydroxyl group from an α-carboxyl group and the like.

Typical specific examples of the spagarin-related compound of the general formula [B-1] are listed in Table 1. The general formula [B
When R _{6 in [} -1] has an asymmetric carbon atom, the configuration may be any of S, R and SR.

[0018]

[Table 1]

In the general formula [B-2] of the present invention, examples of W include a hydrogen atom or a residue obtained by removing a hydroxyl group from the carboxyl group of the following amino acid or the following peptide. The configuration of amino acid residues is S, R except glycine, β-alanine and γ-aminobutyric acid.
Or it shows SR type.

(1) Amino acids Alanine, Arginine, Ornithine, Aspartic acid,
Asparagine, cysteine, cystine, glutamic acid,
Glutamine, pyroglutamic acid, histidine, lysine,
Glycine, proline, hydroxyproline, isoleucine, leucine, methionine, phenylalanine, phenyl-substituted phenylalanine, serine, homoserine, threonine, tyrosine, tryptophan, valine, phenylglycine, parahydroxyphenylglycine, 4-hydroxymethyl-3-hydroxyphenylglycine, β-alanine, γ-aminobutyric acid, α-aminobutyric acid, 3-amino-2-hydroxy-4-phenylbutyric acid, etc.

(2) Peptide 2-3 in which the amino acids of the above (1) are used alone or in combination.
A di- or tripeptide in which individual amino acids are condensed is desirable.

For example, alanylalanine, leucylleucine, valilvaline, phenylalanylphenylalanine, tyrosyltyrosine, phenylglycylphenylglycine, glycylglycine, isoleucylisoleucine,
Examples include leucylphenylalanine, phenylalanylleucine, leucylphenylglycine, phenylglycylleucine, glycylglycylglycine, phenylglycylphenylglycylphenylglycine, phenylalanylphenylalanylphenylalanine and leucylleucylleucine. .

Preferred amino acids or peptides include phenylglycine, phenylalanine, leucine,
Examples include aspartic acid, tryptophan, alanine, and peptides in which two or three of these amino acids are condensed.
More preferred are phenylglycine and leucyl leucine.

Representative compounds of the general formula [B-2] of the present invention include, for example, the compounds shown in Tables 2 to 4 below. In the general formula [B-2], the configuration of the carbon atom marked with * may be S, R or SR.

[0025]

[Table 2]

[0026]

[Table 3]

[0027]

[Table 4]

However, phG in the table is C ₆ H ₅ --CH (N
The H ₂₎ CO-, Leu-Leu is (CH _{3) 2} CHCH ₂
CH (NH ₂ ) CONHCH (CH ₂ CH (CH ₃ ) ₂ ) CO
Indicates-.

R ₄ in the general formula [B-3] of the present invention includes a hydrogen atom or a residue obtained by removing the hydroxyl group from the carboxyl group of the amino acid or peptide mentioned in the above general formula [B-2].

The representative groups of R ₄ are shown below. Wherein _{X 1, X 2 -C 6 H} 4 - (CH 2) r -CH (N
H ₂ ) CO- [wherein r is 0 or 1, X ₁ and X ₂ represent a substituent on the phenyl group, X ₁ is —H or —OH, and X ₂ is —H.
It represents H or -CH ₂ OH. ] The group shown by

Formula X _3- (CH ₂ ) _b --CH (X ₄ ) CO
- [integer of b in formula 0 to 4, X ₃ is -H, -COOH,
-OH, -NH ₂ or -CONH _2, X ₄ represents -H or -NH _2, at least one of a X ₃ and X ₄ represents a -NH _2. ] The group shown by

Formula H- (A) _y- [wherein y is 1 or 2 and A is -NHCH (CH ₂ CH
(CH _{3) 2)} -CO- or -NC ₄ H ₇ -CO- indicates, when y = 2, both assumed to be a peptide bond. However, -NC ₄ H ₇ - represents a 1,2-pyrrolidinylene group. ] Or a group represented by

The formula C ₆ H ₅ --CH ₂ CH (NH ₂ )-C
And a group represented by H (OH) CO-.

Among the compounds represented by the general formula [B-3], U in the general formula [B-3] is preferably -C ₆
H ₄ —, R ₂ is —CH ₂ OH, R ₄ is (L or D) C
_{6 H 5 -CH (NH 2)} CO -, (L) C 6 H 5 -CH 2
_{CH (NH 2) CO -,} (L) p-HO-C 6 H 4 -CH
_{2 CH (NH 2) CO -} , (L) CH 3 CH (NH 2) CO
_{-, (L) (CH 3} ) 2 CHCH 2 CH (NH 2) CO- or _{(L, L) (CH 3} ) 2 CHCH 2 CH (NH 2) CO
_{NHCH (CH 2 CH (CH 3} ) 2) , etc. CO-, compound or a pharmacologically acceptable salt thereof.

Examples of Compounds of General Formula [B-3] Examples of the compound of general formula [B-3] of the present invention include compounds shown in Tables 5-10.

[0036]

[Table 5]

[0037]

[Table 6]

[0038]

[Table 7]

[0039]

[Table 8]

[0040]

[Table 9]

[0041]

[Table 10]

The compounds [B-1] to [B-3] form a salt with an acid, and the acid for forming the salt is an inorganic acid or an organic acid as long as it is pharmacologically acceptable. Either can be used. As the inorganic acid, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like are preferable. Examples of the organic acid include acetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, glutaric acid, citric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid. , Aspartic acid, glutamic acid and the like are preferable.

Any of the spagarin-related compounds used in the present invention can be produced by a known method or a method analogous thereto using a known compound or a related compound thereof.

Among the compounds of the above [B-1] to [B-3], a preferable compound is X in the general formula [1].
₀ - (CH _{2) 3-5} - or a phenylene group, a is 3 to 7 integers, X ₁ is -CH (OH) -, - CH (OCH
_{3) -, - CH 2 CH} (OH) CH 2 - or -CH (C
H ₂ OH) -, X ₂ is _{-NH (CH 2) 4 NH (} CH 2) 3
NH ₂ or _{-NH (CH 2) 4 NH (} CH 2) 3 NH-L
An example is a spagarin-related compound that is eu.

Among these compounds, those having higher activity include the following compounds and their pharmacologically acceptable salts. _{Gu- (CH 2) 6 -CONHCH (} OH) CONH (C
_{H 2) 4 NH (CH 2} ) 3 -NH 2 ( Compound No.B-3-
_{37) Gu-C 6 H 4} - (CH 2) 3 -CONHCH (CH 2 O
_{H) CONH (CH 2) 4} -NH (CH 2) 3 NH 2 ( Compound _{No.B-1-5) Gu-C 6} H 4 - (CH 2) 3 -CONHCH (CH 2 O
_{H) CONH (CH 2) 4} -NH (CH 2) 3 NH-Leu
(Compound No. B-3-2) [In the formula, Gu is a guanidino residue (H ₂ NC (NH) NH).
-), Leu is leucyl residues _{((CH 3) 2 CHCH 2} C
H represents a (NH ₂₎ CO-). )

When this compound is used as a therapeutic agent for bacterial shock, it is administered alone or in admixture with an excipient or carrier as an injection, oral preparation, suppository or the like. As the excipient and carrier, those which are pharmaceutically acceptable are selected, and the type and composition thereof are determined by the administration route and administration method. For example, water, alcohols or soybean oil, animal and vegetable oils such as peanut oil, sesame oil, mineral oil or synthetic oils are used as the liquid carrier. As the solid carrier, sugars such as lactose, maltose and sucrose, amino acids, cellulose derivatives such as hydroxycellulose, organic acid salts such as magnesium stearate and the like are used.

Excipients used in the injection include mannitol, maltose, dextran, lactose, cyclodextrin, chondroitin sulfate, gelatin, human serum albumin, among which maltose, lactose, chondroitin sulfate, gelatin, human Serum albumin is preferred. A lyophilized formulation is prepared with these excipients, which is administered at the time of administration by dissolving it in a suitable solvent for injection, for example, sterile water, physiological saline, glucose solution, electrolyte solution, amino acid solution or the like for intravenous administration. You can also

In addition, during the composition of the preparation of the present invention, the pH
An acid, an alkali or an appropriate amount of a buffer may be added for the purpose of preparation and the like.

The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injection solution, it is usually
It should contain 1 to 30% by weight, preferably 1 to 10% by weight of the active ingredient. In the case of oral administration, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid carrier or liquid carrier. Generally, tablets, capsules, powders and granules are 5 to 1
It contains 00% by weight, preferably 25 to 98% by weight of the active ingredient.

The dose is determined according to the age, body weight, symptom of the patient, the purpose of treatment and the like. Generally, the dose is 1 to 100 mg / kg · day for parenteral administration and 5 to 50 for oral administration.
It is 0 mg / kg-day. The compound has relatively low toxicity,
Moreover, it is characterized by no serious organ damage due to continuous administration.

[0051]

OPERATIONS General formulas [B-1], [B-2] and [B-
3] shows the effect of the spagarin-related compound represented by [3] in improving bacterial shock in experimental examples.

Experimental Example Action of Spagarin-related Compound on Hypoglycemia during Endotoxin Shock in Mice Experimental Method Lipopolysaccharide (LPS) in female BALB / c mice, 12.
5 μg was injected intraperitoneally, and 6 hours later, blood was collected. The amount of glucose (mg / dl) in plasma was measured by Fuji Dry Chem Analyzer. Compounds related to spagarin 10 mg /
It was administered intraperitoneally at a dose of kg / day for 7 consecutive days until the day before LPS injection. The experimental results were shown as a ratio of blood glucose level before and after LPS injection (7 to 8 animals per group, mean value ± standard deviation).

[0053]

[Table 11] Effects of spagarin-related compounds on hypoglycemia during endotoxin shock in mice ───────────────────────────────── ─── Compound number Ratio of decreased blood glucose level to normoglycemic level (%) (ratio to control group) ──────────────────────────── ───────── Experiment 1 Control group 49.6 ± 10.1 (100) B-3-37 66.9 ± 5.4 ** (135) Experiment 2 Control group 48.4 ± 11.2 (100) B-2-40 54.8 ± 12.3 (113) B-1-5 58.9 ± 7.1 * (122) B-3-2 61.6 ± 11.5 * (127) Experiment 3 Control group 44.2 ± 8.8 (100) B-3-38 51.1 ± 9.7 (116) B-1-1 46.6 ± 6.1 (1 05) B-1-2 49.4 ± 9.8 (112) ────────────────────────────────── ── * p <0.05, ** p <0.01 (t-test)

[0054]

EXAMPLES Examples of the present invention will be specifically shown below, but the present invention is not limited thereto. Example 1 Injectable compound Compound No. B-3-37 10 parts by weight, lactose 20 parts by weight, pH with 1N-hydrochloric acid and distilled water for injection (appropriate amount)
500 parts by weight of the drug solution adjusted to 4.0 is obtained. The prepared drug solution is sterilized and filtered with a membrane filter, then dispensed into a glass container for injection and freeze-dried. After the completion of freeze-drying, a freeze-dried preparation for injection containing 100 mg of Compound No. B-3-37 in one vial is obtained.

Example 2 Granules Compound No. B-3-37 (50 parts by weight), lactose (600 parts by weight), crystalline cellulose (330 parts by weight) and hydroxypropylcellulose (20 parts by weight) were mixed well and a roll type compressor (roller compactor registered trademark) was used. ),
It was crushed and sieved so as to be between 16 mesh and 60 mesh to give granules.

Example 3 Tablets Compound No. B-3-37 30 parts by weight, crystalline lactose 120
By weight, 147 parts by weight of crystalline cellulose and 3 parts by weight of magnesium stearate were mixed in a V-type mixer, and then tableted to give 300 mg tablets.

Reference Example 1 10- {N- (11-guanidinoundecanoyl) -γ
-Amino-β- (S) -hydroxybutanoyl} -1,
5,10-Triazadecane trihydrochloride (Compound No. B-
2-40) Synthesis

(A) 10- {N- (11-guanidinoundecanoyl) -γ-amino-β- (S) -hydroxybutanoyl} -1,5-di-benzyloxycarbonyl-1,5,10 -Triazadecane / hydrochloride 11-guanidinoundecanoic acid / hydrochloride 3.3 g (1
1.71 mmol) was dissolved in 40 ml of dimethylformamide, and N-hydroxysuccinimide 1.63 was added under ice cooling.
g (14.05 mmol) and N, N'-dicyclohexylcarbodiimide (2.92 g, 14.05 mmol) were added, and the mixture was reacted overnight at room temperature. The precipitate is filtered off and the filtrate is used as it is in the next reaction.

Oily 10- (γ-amino-β- (S)-
Hydroxybutanoyl) -1,5-di-benzyloxycarbonyl-1,5,10-triazadecane hydrochloride 5.5 g (corresponding to 9.76 mmol) was dissolved in dimethylformamide 40 ml, and triethylamine 1.1 was added under ice cooling.
9 g (11.71 mmol) was added, followed by the above 11
A solution of guanidinoundecanoic acid hydrochloride N-hydroxysuccinimide ester in dimethylformamide,
React overnight at room temperature. The reaction solution is concentrated under reduced pressure, the oily residue is washed twice with 100 ml of n-hexane, and then concentrated under reduced pressure.

The obtained oily substance was subjected to column chromatography on silica gel 60 (manufactured by Merck), and chloroform-methanol 17% aqueous ammonia (6: 2.5:
When developed with a mixed solution of 0.5 v / v), 4.9 g of an oily substance (yield 64.72%) is obtained.

NMR (CD ₃ OD + D ₂ O, exter
na (TMS) delta = 1.2-2.2 (m, 22H), 2.2-2.8.
(M, 4H), 3.1 to 3.8 (m, 12H), 4.0
~ 4.6 (m, H), 5.25 (S, 2H), 5.28
(S, 2H), 7.56 (S: 10H). TLC (chloroform: methanol: 17% aqueous ammonia = 6: 2.5: 0.5%) Rf = 0.42

(B) 10- {N- (11-guanidinoundecanoyl) -γ-amino-β- (S) -hydroxybutanoyl} -1,5-di-benzyloxycarbonyl-1,5,10 -Triazadecane / hydrochloride 4.7 g
(6.05 mmol) was dissolved in 60 ml of methanol,
1.3 g of acetic acid and 0.7 g of palladium black are added, and catalytic reduction is performed at room temperature and atmospheric pressure for 4 hours.

After the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to obtain 4.0 g of an oily substance (quantitative yield). This oily substance was dissolved in 60 ml of distilled water and applied to a column packed with 350 ml of CM-Sephadex (registered trademark) C-25 (Na ⁺ ), and a column between 1800 ml of distilled water and 1800 ml of 0.8 M aqueous sodium chloride solution was added. Elute by the gentle elution method, collect the fractions containing the desired product, concentrate to dryness under reduced pressure, add methanol to the dried product, and filter off the insoluble sodium chloride. The desired product is purified from the obtained oily substance as follows.

The oil obtained in order to remove the small amount of residual sodium chloride is dissolved in 20 ml of methanol,
Apply to a column packed with 200 ml of Sephadex (registered trademark) LH-20, elute with methanol, collect fractions containing the target substance, and concentrate under reduced pressure. The obtained oily substance is dissolved in 35 ml of distilled water, and the insoluble matter is filtered off and freeze-dried to obtain 2.63 g of the desired product (yield 74.93%).

NMR (D ₂ O, 200 MHz) δ = 1.18 to 1.46 (m, 12H), 1.47 to
1.83 (m, 8H), 1.98 to 2.19 (m, 2
H), 2.21 to 2.54 (m, 4H), 3.03 to
3.4 (m, 12H), 4.03 to 4.20 (m,
H). ^{IR (KBr) υ (cm -} ) = 3310,3160,2930,285
0, 1640, 1545, 1455, 1410. [Α] ²⁰ _D + 1.4 ° (C = 1.00, H ₂ O)

Reference Example 2 10- {N- (11-guanidinoundecanoyl) -γ
-Amino-β- (S) -hydroxybutanoyl} -1-
Synthesis of L-leucyl-L-leucyl-1,5,10-triazadecane trihydrochloride (Compound No. B-2-39)

(A) 10- {N- (11-guanidinoundecanoyl) -γ-amino-β- (S) -hydroxybutanoyl} -1- (N-tert-butyloxycarbonyl-L-leucyl- L-leucyl) -1,5-10
-Synthesis of triazadecane dihydrochloride 10- {N- (11-guanidinoundecanoyl) -γ
-Amino-β- (S) -hydroxybutanoyl} -1,
5-10-triazadecane trihydrochloride 1.28 g
(2.22 mmol) was dissolved in 40 ml of methanol,
0.25 g (2.47 mmo) of triethylamine under ice cooling
l) is added. Then, an ester of N-tert-butyloxycarbonyl-L-leucyl-L-leucyl and N-hydroxysuccinimide 0.99 g (2.24 m
(mol) and added, and reacted for 2 hours under ice cooling. The reaction solution was concentrated under reduced pressure, the residue was decanted twice with acetone, and then concentrated under reduced pressure to give 2.1 g of white crystals (quantitative yield).
Is obtained.

IR (KBr) υ (cm ⁻ ) = 3270, 2930, 1645, 154
0, 1450, 1360, 1240, 1165.

(B) 10- {N- (11-guanidinoundecanoyl) -γ-amino-β- (S) hydroxybutanoyl} -1- (N-tert-butyloxycarbonyl-L-leucyl-L -Leucyl) -1,5,10-
2.1 g (corresponding to 2.22 mmol) of triazadecane was dissolved in a mixed solvent of 10 ml of methanol and 10 ml of water,
Under ice-cooling, 10 ml of 4N hydrochloric acid-dioxane solution is added, and the mixture is reacted at room temperature for 3 to 5 hours. The reaction solution was concentrated under reduced pressure, the obtained oily substance was dissolved in 30 ml of distilled water, and CM-Sep was used.
hadex (registered trademark) C-25 (Na ⁺ ) 200 ml
Column was filled with 1000 ml of distilled water and 1.0
Elute by a gradient elution method with 1000 ml of an aqueous solution of sodium chloride M, collect the fractions containing the desired product and concentrate to dryness under reduced pressure. Add methanol to the dried product to separate insoluble sodium chloride by filtration. The target product is purified from the obtained oily substance as follows.

The small amount of residual sodium chloride and the oily substance obtained to remove impurities were dissolved in 30 ml of distilled water, and the solution was applied to a column packed with 120 ml of Mitsubishi Kasei HP-20 (registered trademark) to obtain 120 ml of distilled water. Was eluted by a gradient elution method between 20 ml of a 20% aqueous methanol solution and the fractions containing the target compound were collected and concentrated under reduced pressure. The obtained oily substance was dissolved in 10 ml of distilled water, and the insoluble substance was filtered off and lyophilized to give 0.622 g of the desired product (yield 34.5%).
4%) is obtained.

NMR (D ₂ O, 200 NHa) δ = 0.85 to 1.04 (m, 12H), 1.18 to
1.45 (m, 12H), 1.46 to 1.82 (m, 1
4H), 1.82 to 2.02 (m, 2H), 2.21 to
2.53 (m, 4H), 2.96 to 3.41 (m, 12
H), 3.91 to 4.20 (m, 2H), 4.27 to
4.39 (m, H). ^{IR (KBr) υ (cm -} ) = 3270,3070,2930,286
0, 1645, 1540, 1455, 1365.

[0072]

INDUSTRIAL APPLICABILITY The therapeutic agent for bacterial shock containing the spagarin-related compound of the present invention as an active ingredient exhibits an excellent improving effect on hypoglycemia during endotoxin shock.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display area C07K 5/062 8318-4H

Claims (8)

[Claims] 1. A general formula [1]: [In the formula, X ₀ represents — (CH ₂ ) _1-5 — or a phenylene group which may have a substituent, a represents an integer of 3 to 7, and X ₁
Is _{- (CH 2) 0-2 -CH (} R 00) - (CH 2) 0-2 - ( wherein R ₀₀ are _{-H, -OH, -OCH 3, -OCH} 2 CH 3
Or an -CH ₂ OH. ), X ₂ is —NH (CH ₂ ).
₄ NH- (CH ₂ ) _3- NH-R ₀₂ (wherein R ₀₂ represents hydrogen, a residue obtained by removing a hydroxyl group from a carboxyl group of an amino acid or a peptide), and a drug thereof. Bacterial shock therapeutic agent containing a physically acceptable salt as an active ingredient 2. A general formula [B-1]: [Wherein X has the formula - (CH _{2) 1-5} - or -C ₆ H ₄ - indicates, r is an integer of 3 to 7, R ₆ is the α- amino acid α
A residue obtained by removing one hydrogen atom from an amino group and a hydroxyl group from an α-carboxyl group or a residue obtained by removing one hydrogen atom from an ω-amino group of an ω-amino acid and a hydroxyl group from an α-carboxyl group, A residue which may have a functional group is shown. ) The therapeutic agent for bacterial shock according to claim 1, which comprises a spagarin-related compound represented by the formula (4) and a pharmacologically acceptable salt thereof as an active ingredient. 3. A general formula [B-2]: [Wherein Y is the formula - (CH _{2) 1-5} - or -C ₆ H ₄ - are shown, W is represents a residue obtained by removing the hydroxyl group from the carboxyl group of a hydrogen atom or an amino acid or peptide, also m is 0, 1 or 2, n is 1 or 2, and s is an integer of 3 to 7. ] The therapeutic agent for bacterial shock according to claim 1, which comprises a spagarin-related compound represented by the following formula and a pharmacologically acceptable salt thereof as an active ingredient. 4. A general formula [B-3]: [In the U formula - (CH _{2) 1-5} - or -C ₆ H ₄ - indicates, R ₂ is _{-H, -OH, -OCH 3, -OCH} 2 CH
₃ or —CH ₂ OH, R ₄ is a hydrogen atom or a residue obtained by removing a hydroxyl group from a carboxyl group of an amino acid or peptide, and t is an integer of 3 to 7. ] The therapeutic agent for bacterial shock according to claim 1, which comprises a spagarin-related compound represented by the following formula and a pharmacologically acceptable salt thereof as an active ingredient. 5. In the general formula [1], X ₀ is-(CH ₂ ).
_3-5- or phenylene group, a is an integer of 3 to 7, X
₁ is -CH (OH) -, - CH (OCH 3) -, - CH 2
CH (OH) CH ₂ — or —CH (CH ₂ OH) —,
X ₂ is _{-NH (CH 2) 4 NH (} CH 2) 3 NH 2 or,
_{-NH (CH 2) 4 NH (} CH 2) 3 Supagarin related compounds is NH-Leu or bacterial shock therapy agent according to claim 1 containing their pharmacologically acceptable salt thereof as an active ingredient. 6. formula _{Gu- (CH 2) 6 -CONHCH (} OH) CONH (C
_{H 2) 4 NH (CH 2} ) 3 -NH 2 wherein Gu represents a guanidino group. ] A therapeutic agent for bacterial shock containing as an active ingredient a spagarin-related compound represented by the above or a pharmacologically acceptable salt thereof. 7. A formula _{Gu-C 6 H 4 - (} CH 2) 3 -CONHCH (CH 2 O
_{H) CONH (CH 2) 4} -NH (CH 2) 3 NH 2 [wherein Gu represents a guanidino group. ] A therapeutic agent for bacterial shock containing as an active ingredient a spagarin-related compound represented by the above or a pharmacologically acceptable salt thereof. 8. formula _{Gu-C 6 H 4 - (} CH 2) 3 -CONHCH (CH 2 O
_{H) CONH (CH 2) 4} -NH (CH 2) 3 -NH-Le
u [In the formula, Gu represents a guanidino residue and Leu represents a leucyl residue. ] A therapeutic agent for bacterial shock containing as an active ingredient a spagarin-related compound represented by the above or a pharmacologically acceptable salt thereof.