WO1992004373A1

WO1992004373A1 - Peptide having antiallergic activity

Info

Publication number: WO1992004373A1
Application number: PCT/JP1991/001146
Authority: WO
Inventors: Hideo Nakamura; Kiyomi Nakanishi; Ikuhisa Yakuo; Yasuo Ariyoshi; Noriki Nio
Original assignee: Dainippon Pharmaceutical Co., Ltd.; Ajinomoto Co., Inc.
Priority date: 1990-08-31
Filing date: 1991-08-29
Publication date: 1992-03-19

Abstract

A peptide having an amino acid sequence useful as the preventive and remedy for allergic diseases, represented by the following general formula (I), and salt thereof: A-B-Asp-C-D-Ile-E-F-G, wherein A represents Ala or Pro, B represents Phe or Cha, C represents Ile, Leu, tert-Leu or Val, D represents Phe, Tyr or Cha, E represents Gly, Lys or Arg, F represents Lys, Arg or Orn, and G represents OH, NH2, NHEt, Lys, Ser, Thr, OMe, (α) or (β), and wherein each amino acid residue may be any of the D, L and racemic forms, provided that at least one among all the amino acid residues must be the D form(s) when A, B, C, D, E, F and G represent Pro, Phe, Leu, Phe, Arg, Lys and OH, respectively.

Description

ぺすアぺぺぺぺぺ

Technical field

The present invention relates to regulatory peptides and salts thereof that are useful as preventive and therapeutic agents for Allergic disease.

Background technology

The leave of absence prevents oneself by taking and excluding non-self from the job. Immediately, it recognizes a part of the foreign substance as an antigen and produces an antibody against the antigen. The produced antibody reacts with the newly invading antigen to form an antigen ♦ antibody complex, and the foreign substance is eliminated. In the case where such an anti-protozoal reaction is an adverse reaction to the living body, which may cause damage to one's own organization, The Allergic reaction, which is generally referred to as Allergies, is based on its mechanism and is based on Ge】 1 and Coo sibs, and has four types (I to V> Class I to type are based on the reaction between antigen and humoral.Antibodies occur in a short time, so they are immediate type. Allergic, type IY is a relatively slow response due to cellular immunity, and is called a delayed allergic. Diseases that succumb to type I allergies include bronchial asthma, allergitis, measles, --Intestinal allergies may occur. In recent years, the number of these allergic diseases has been increasing and the number of patients has become a social problem.

Type I allergic reaction is an immunoglobulin that is immunized against an antigen (allergen) that is κ, the allergic agent. Hereafter, it is described as IgE. ) The IgE receptor (or the Fee receptor) on the surface of the fertilized cells in the antibody and tissue and the basophil membrane in the blood. ) And are combined to form the basis. Immediately, when allergen invades the organism, IgE antibodies against it are produced from B cells, and the membranes of fertile cells and basophils are produced. It binds to hundreds of thousands of IgE receptors present on the surface with extremely high affinity. Polyvalent allergens that re-enter the bound E on the cell membrane surface are bound, and some IgE molecules are cross-linked via this. It is. This acts as a trigger, causing some interaction between the receptor molecules, activating the enzyme system in the cell membrane, and causing fertilization. Occurrence of decondylar granules of abscesses present in cells and basophils occurs. As a result, SRS-A and the chemical transfer substances such as histamine and serotoun present in the granules are released from the cells, and the blood vessels are permeated. It has been thought that it causes transient hypertension, contraction of the smooth muscles, increased secretion function, etc., and that various allergic diseases are caused. Yes. Therapeutic agents for allergy diseases include antagonists to chemical transfer substances such as antihistamines, and sodium cromoglycate. Chemical transfer substances such as proteins, etc. Inhibitors of dissociation, steroids, etc. are commonly used, but these are allergic type I allergies. It does not hinder the binding between the IgE-Fe e receptor, which is the root of the system, and its use is restricted by side-effects and administration methods. There is a limit.

Disclosure of the invention

The present inventors have found that a specific peptide has an antiallergic effect, and have completed the present invention.

The present invention relates to a peptide having an amino acid sequence represented by the following formula [I]:

A-B-Asp-C-D-li e-F-G [I] (where A is Al a or Pro, B is Phe or Cha, C is lie, Leu, ter t-Leu or Val, D for Phe, Tyr or Cha, E for Gly, Lys or Arg, F for Lys, Arg or Orn, G for OH , NH2, NHE t, L s, Ser, Thr, OMe,

Or IVPN- ©. Each amino acid residue can be D-type, L-type, or racemic-type. However, when A is Pro, B is Phe, CJ ^ Leu, D force i Phe, E is Arg, F is Lys, and G is OH, all aminos are --One or more of the acid residues must be D-type.)

And its salts.

A useful compound in the present invention is a peptide in which G is NH2, NHEt, OMe, 〉> or Ν ί> or Ν ί in formula [I]. Or its salt. In addition, in formula [I], a peptide or a salt thereof in which at least one or more of each amino acid residue is necessarily of D-type is also preferable. Particularly useful compounds in the present invention are as follows: In Formula [1], Α is Pro, B is Phe, C is Leu, D force is Phe, E is Arg, F is Lys, G is NH2 peptide or its salt. These compounds have an excellent anti-allergic effect and are also stable against degradation by enzymes, cells, serum and the like. The irritation to the skin is low.

The peptide of the present invention can be produced by a liquid phase method or a solid phase method commonly used for peptide synthesis. That is, the DCC (N, N, -dicyclohexylcarbodiimide) method, the active ester method, the mixed acid anhydride method, the azide method, The constituent amino acids are sequentially condensed from the C-terminal to the N-terminal by using an acid anhydride method, an enzymatic method, or the like. In addition, two or more kinds of peptide fragments consisting of two or more amino acids are preliminarily synthesized, and those fragments are reduced. A method of jointly leading to the target peptide can also be adopted.

Government functions that should not be involved in the reaction in this reaction process ___ is protected by a protecting group. Is the coercive鎪group § Mi amino groupゝexample if, base down di Le O key imposes Le Bo two Le, t - flop Chi le O key imposes Honoré Po two Honoré, p-bi full _χ two Le There are 9-year-old Russian ponyir and 91-fluorenylmethylcarbonyl. Examples of the protecting group for the guar-dino group include, for example, 4-methoxy-2,3,6-trimethylbenzensulfonyl group and methyl group. Len-21 one-hole group is mentioned. Examples of the preserving group for Carbosil S include a group capable of forming, for example, an phenolic ester, a benzyl ester, and the like. .

When the condensation reaction is carried out using the solid phase method, usually, the carboxy group at the C-terminal end of the starting amino acid or polybutadiene fragment is used. The sil group is changed to chloromethyl resin, oxymethyl resin, ρ-alkoxy benzyl alcohol tree JI ) F--Fluorescent methine resin H-, 4-Methylbenz hydrinole resin, 4-1 (2,, 4 *) — Hydroxy resin (funoki resin), 4- (2 ', 4'-dimethyl-fu-el-Pnoc-aminomethyl) It should be bound to a carrier such as phenoxy resin.

After the completion of the condensed reaction, the protecting group is removed by the method described in each protecting group to obtain the desired peptide. In the case of the solid phase method, the process of cutting the bond between the C-terminal of the protective peptide and the resin is also required. ,

-6 — need

In addition, the peptides of the invention are refined according to the usual methods. Examples include ion exchange chromatography, reversed-phase liquid chromatography, and chromatographs. It is.

The peptide of the present invention can be converted to salts by treating it with various inorganic or organic acids according to a conventional method. The salts thereof include inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulphate, and phosphate, and acetates and salts thereof. Reflux mouth acetic acid, citrate, maleic acid, maleic acid, fumaric acid, tartaric acid, lactate, methansulfonate clay, Organic acids such as fensulfonate are listed, and the hydroxides and / or hydrates of Al-Kali metal alloys and Al-Kali earth metal shoes are also available. It can also be converted into salt by treating with salt. For example, potassium salt, sodium salt, calcium salt, lysine salt and the like can be mentioned.

The peptide or its salt according to the present invention is useful as a therapeutic agent for Allergic disease.

The following is a description of the peptides of the present invention! g The following describes test examples of receptor antagonistic action.

Test Example 1 g E receptor antagonism

Passive sensitization of human leukocytes to the patient's blood is blousance. Kru et al., CJ. J. Pruzansky et al., The Journal of Immunolog 131, 1949-1953, 1983].

(1) EDTA 4 al was added to 50 aI of peripheral blood collected from healthy donors immediately after blood collection. This blood was mixed with 12.5 nl of 8% dextran-3% glucose aqueous solution of physiological saline, mixed, and allowed to stand at room temperature for 60 minutes. The upper eyebrows

The sediment (leukocyte) obtained by centrifugation at 1200 ° C for 10 minutes was mixed with Tris-EDTA buffer (a buffer obtained by adding EDTA 4 mM to Tris-A buffer described later; PH7.6). ), And washed once with lactate buffer (PH3.9). Incubate at 0 for 5 minutes. After that, the cells were washed, and the EDTA and heparin were added to the Tis-A solution (Tris (hydroxymethyl) amide). 25 uM, NaC I 120iM _r KC 15 nM, buffer containing 0.03% of human serum albumin; PH7.6) was used to screen the cell suspension of 1-2 x 10 ⁷ eel Is / ml It was made.

(2) Add 0.7 轼 I of the test compound to the cell suspension, incubate at 37 ° C for 30 minutes, add 0.2nl of serum from a patient with bronchial asthma. It was powerful.

(3) After further incubating this for 120 minutes, it was centrifuged away.

(4) The sediment obtained by centrifugation was washed twice with Tris-A buffer. After washing, wash with Tris-ACM buffer (Tris-A buffer). Adjust the cell suspension to 2 to 8 × 10 ⁶ ceHsZ Bl with a buffer containing MgC I 2 BM and CaC ₁₂ 0.8 F M: pH 7.6), and add the cell suspension 0.7 al. Dani extract or vehicle (all solvents) as allergen. 0. (Add 37ia1 and incubate for 45 minutes at 37. After stopping the reaction by cooling on ice, centrifugation was performed, and the amount of histamine contained in the supernatant and the sediment (in the cells) was measured by Techicon. It was measured using a photoanalyzer with the Shiraganaian photometric method [RPSiraganian, Analytical Biochemistry 57, 383-394, 1974]. The min-inhibition inhibition rate was calculated from a comparison with a vehicle control group (a group in which no test compound was added and to which allergen was added).

The results are shown in Table 1 as the inhibition rate of histamine release of the test compound. In the tables below, the test compound numbers 1 to 24 mean the peptides of Examples 1 to 24, respectively.

S

In

The test compound is an anti-nuclear antibody from human basophils.

Strongly suppressed emigration

Test example 2: Intradermal topical administration to suppress salvousus tsutsu-tunnel reaction The reaction of the Brow スヅキトト Ρ (Ρ-κ) reaction is described in Bisgard et al. [H. Bisgaard et al., Allergy 40, 417-423, 1985]. GM Murphy et al. [GM Murphy et a 1., Deraatologica 177, 338-340, 1888].

Female quizzals weighing 2.5 to 4.0 kg were used. Under ketamine anesthesia, the shaved back skin] is marked with a magic link on the T at a distance of 2 to 3 cm, and each point is sensitive to dust. Intradermal injections were performed on 20 ノ sites of diluent or saline (branch group) in the sera of patients with bronchial asthma. Forty-eight hours later, under ketamine anesthesia, 20 ίί ^ / part of Tilida-oil spill was intradermally injected into the same part and formed 20 minutes later. The major and minor axes of the wheal were measured with calipers. The test compound was dissolved in a physiological saline solution, and 4 hours per sanole one hour before the passive sensitization by the serum of the bronchial breath patient. Intradermal injections of 20 mm each were performed. The control group was treated with saline and administered saline without treatment. The PK reaction inhibition rate of the test compound was calculated by subtracting the value of the blank group from the size of the wheal (long axis X short axis) of the test compound-administered group. Later, it was found by comparison with the control group. The significance test for the PK response suppression rate is based on the Student's t-test using the value of wheal size as an indicator. It went.

The results are shown in Table 2 as P-1 (reaction inhibition rate) of the test compound. You

Table 2

There was a significant difference (PO.01) from the test compound untreated control group,

In contrast to the Ρ-Κ reaction, Test Compound 1 showed a strong application-dependent suppression effect at doses of 0.002 to 20 gZ.

This P- 1 (reaction was caused by the sensitization of the bronchial asthma patient's serum to the Tyridani antibody in the blood. The specific 1 gE binds to the receptor on the surface of the fertilized cell membrane present in the skin of the skin, and the combined IgE is associated with the chiridani antigen. This resulted in the formation of a type I allergy reaction, thus suppressing the PK reaction by the treatment S before receiving sensitization. Indicates that the test compound antagonizes the binding of the test compound to the IgE receptor, indicating that the test compound is susceptible to the Tilidanii antigen. It is also evident from the fact that treatment with a pre-sensitized miromoma IgE prior to 3 sensitization suppresses the P-K reaction. This type I It is generally known that the Lugi reaction is more similar to the human I-type reaction than the other experimental royalties. Such a sal (In response to the reaction, the fact that Test Compound 1 showed a strong inhibitory effect by the treatment before passive sensitization means that Test Compound 1 did not. It suggests its usefulness as an anti-allergy agent.

Test Example 3: Stability against degradation by cells and serum The peptide of Example 1 was used as the test compound, and the same as (1) and (2) of Test Example 1 After performing the same procedure, the incubation time after the addition of serum was 0-minute. On the other hand, the same operation as (1), (2) and (3) in Test Example 1 was performed, and the incubation time after blood serum addition was 120 minutes. The material was taken. After centrifugation of each sample, the supernatant obtained was adsorbed on SEP-PAK C18 and washed with deionized water and Tris-A buffer. After the conflict, it was eluted with 2.5 nl of 50% methanol and 2.5 nl of 100% methanol. The test compound in the eluate was quantified by high performance liquid chromatography.

The test compound was not present in the sample at 120 minutes of incubation time compared to 100% of the test compound S in the sample at 0 minutes after serum addition. 63.2% of that remained.

Therefore, it was found that the compound of the present invention has high stability to cells and serum.

Test example 4: Irritation to sal hide fflf

Female quizzes weighing 2.5-4.0 kg were used. ^ Hair Marks were placed at 2-3 cm intervals on the arm skin with a magic sink, and each point was treated with the physiological saline solution or saline solution of the peptide of Example 1. Physiological saline water (Blank group)

Each part was injected intradermally. The dose of the peptide of Example 1 was about 20 g. Twenty minutes later, the length and minor axis of the wheals formed were measured with calipers.

The results are shown in Table 3 as wheal size.

Table 3

Test Compound 1 showed high skin intensity and mild skin irritation in the 20 # g Z region, but the effect was transient.

Test Example 5: Acute poison

Std: ddY female mouse (body weight 22-27 g)> 3 animals were dissolved with the -peptide of Example 1 dissolved in physiological saline and lOOng / _kg body weight Intravenous administration was performed at a rate of no more than 2 weeks after the administration of the drug.

As is evident from the above test results, the peptides or salts thereof of the present invention are based on IgE receptor antagonism. It shows possible anti-allergic effects and can be used for bronchial asthma, --Prevention and treatment of Algeri's disease such as rhinitis rhinitis, Strawberry measles, atopic dermatitis, eczema, and Algergic ophthalmitis. It can be used for medical treatment. However, the peptide or salt thereof of the present invention has stability against degradation by enzymes, cells, serum, etc., and punctures the skin. Intensity is low.

The route of administration of the peptide or salt thereof of the present invention may be either oral administration or non-administrative administration. Parenteral administration includes subcutaneous injections, intravenous injections, intramuscular injections, rectal or topical injections, and veterinary injections. Local administration to the eyes, skin, trachea, etc. is preferred. The dosage of the peptide or its salt according to the present invention may vary depending on the type of the compound, the method of administration, the condition of the patient, the age, and the like. It is usually from _0.01 to 100 _ns once, preferably from _0.1 to 10 times a day, from 1 to 3 times a day. The peptide or the batter of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the carrier for the drug, a substance K which is commonly used in the field of the drug and does not react with the peptide or its salt of the present invention is used. It is. Specifically, for example, lactose, glucose, manutat, dextrin, cyclodextrin, starch, sucrose, Magnesium aluminum silicate, synthetic aluminum silicate, crystal cellulose, canolepox methylcellulose Trim, Hydroxy mouth Vimelane dump, Card box _____________________________________________________________________________________________________________________________________0_0_________________________________________ No_4_4_3 Loose, low-replacement hydroxyl mouth Virulence, Hydroxy-open Virulence Senorose, Polyvinylinole , Volume alcohol, light J? Anhydrous calcium acid, magnesium stearate, talc, tragacanth, pennite , Bee gum, carboxyl vinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium rauryl sulfate, grease Lin, fatty acid glycerin ester, refined lanolin, glycerin gelatin, polysorbate, macrogol, Vegetable oil, low, fluid paraffin, white petrolatum, fluorocarbon, non-ionic surfactant, propylene glycol , Water, etc. are listed. Dosage forms include tablets, capsules, condyles, powders, syrups, rubs, suppositories, softeners, creams, gels, patches, Inhalants, injections, eye drops, drops, and the like can be mentioned. These preparations are manufactured according to a conventional method. In addition, liquid preparations may be dissolved in water or other suitable medium or used in a liquid form. Tablets and condyle granules may be coated in a known manner. In the case of a propellant, it is prepared by dissolving the peptide of the present invention or a salt thereof in water, but if necessary, a physiological saline solution is used. Alternatively, it may be dissolved in a glucose solution, or a buffer or preservative. May be added.

These preparations can contain the peptides or salts thereof according to the invention in a proportion of at least 0.005%, preferably from 0.05 to 10%. . These preparations may also contain other components of therapeutic value.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Examples.The abbreviations used in the present specification have the following meanings,

Ala Alanin

Arg Arginine

Asp Aspartic acid

Gly glycine

I le isoleucine

L eu leucine

Lys lysine

Phe Penalalanin

Pro Brolin

Ser Serine

Tyr tyrosine

Thr threonine

Val Valin Cha ^ -cyclohexylalanine

Orn ornithine

tert-Leu tert-leucine C (CH _s ) ₃ CHNH ₂ C 00 H

Bzl benzyl group

Boc t-butyloxycarbonyl group

Bu .t ¹ : -butyl group

Cl-Z 2-chlorobenzyloxycarbonyl group

Etethyl group

F moc 9 Monofluorenylmethyloxycarbonyl group Me Methyl group

Mtr 4-Methoxy 2,3,6-trimethylbenzenesulfonyl group

Mts methylene mono 2-sulfonyl group

DCC dicyclohexylcarbodiimide

DMF dimethylformamide

HOBt-hydroxybenzotriazole H00 Bt 3—Hydroxyl 4-oxo-3,4-Dihydro

-1, 2, 3-benzotriazine

TFA trifluoroacetic acid

TMSOTf Trimethylsilyl trifluoromethanesulfonate In the following examples, all amino acids mean L-form unless otherwise specified.

Example 1

Pro-Phe—Asp-Leu-Phe—Ile-Arg ~ Lys-NH ₂ · Hydrochloride

p-Methylbenzhydrylamine resin · HC1 (0.64 mimol resin) 781 w (0.5 mimol) was transferred to a semi-automated peptide synthesizer (Labortec SP 640, 50 «reaction vessel>) and messed up with dimethylformamide (20»). The resin was swollen for 30 minutes to swell the resin, which was subjected to the following operation to release amino groups.

a) In DMF 20i ^, after 1 minute of shaking, the mixture was shaken (twice). b) After 20 minutes of stirring in a 2% pyridin-DMF solution 2 On for 3 minutes, the solution was filtered.

c) 20% piperidine-DMF solution After shaking for 10 minutes in 20 wells, 0

d) Wash 4 times with DMF 20 «£ (30 seconds each).

e) Wash twice with 20 propane of isopropanol (1 minute each).

Kaiser test (E. Kaiser et al., Analytical Biochemistry,

34, 595-598, 1970), Fmoc-Lys (Boc) corresponding to the C-terminal was condensed to this resin as follows.

f) The resin was swollen by shaking twice with DMF 20% (for 1 minute each).

g) A DMF solution (20) of Fmoc-Lys (Boc) (703 w, 1.50 mmol) and HO Bt (223 * 9, 1.65 mmol) was added and shaken for 1 minute.

h) 1 M dicyclohexylcarposimid methylene chloride solution 1 8 * was added and shaken for 70 minutes.

i) Wash twice with DMF20W (1 minute each).

j) Wash twice with isobrovanol 2.

After confirming that the Kaiser test was negative, it was cycled to condense the second and subsequent amino acid residues. In other words, the same operation as shown in a) to e) was performed to remove the Fraoc group (if the Kaiser test did not show any customizability, this cycle was repeated until the sample showed the customizability). g) Step is carried out with Fraoc-Arg (Mtr). 縮合) -j). (If the Kaiser test does not show a negative result, it was repeatedly condensed until it became negative.) Thereafter, similarly, the Fmoc group removal cycle and the Fmoc amino acid condensation cycle are repeated to repeat Fraoc-Ile, Fraoc-Phe, Fmoc-Leu, Fmoc-Asp (0 Bu ヽ Fmoc-one Phe, Boc-Pro). Condensed.

The Boc-Pro-Phe-Asp (0Bu) -Leu-Phe-Ile-Arg (Mtr) -Lys (Boc) resin thus obtained was desorbed from the resin as follows. That is, after washing twice with methylene chloride 20 »and drying under reduced pressure, 1.31 159 protected peptide resin was obtained. To this were added thioanisole (1 ») and ethanedithiol (0.5« ί), and the mixture was stirred at room temperature for 10 minutes. To this was added trifluoroacetic acid (1), and the mixture was further stirred at room temperature for 10 minutes. After cooling with ice, TMSOTf (2.34 ») was added, and the mixture was stirred for 30 minutes, returned to room temperature, and further stirred for 2 hours. To this, about 10 ether was added, and the resulting precipitate and the resin were collected by filtration, and about 10 l ^ of trifluoroacetic acid was added thereto, to extract the desired peptide. The solution was poured with about 150 ether, filtered, washed twice with ether to obtain a white powder (607 «?), Which was sufficiently dried over NaOH, and suspended in water. Neutralized with 5% NH ₄ OH, concentrated under reduced pressure, and lyophilized The resulting white powder was subjected to reverse phase liquid chromatography to obtain the desired Pro-Phe-Asp-Leu-Phe-Ile- arg- Lys- were collected _two fractions NH min, elution fractions obtained were concentrated to dryness. then, distilled water was added After repeated drying and drying several times, a small amount of distilled water was added and freeze-dried. Purified Te Pro- P he- Asp- Leu- P he- I le- Arg- Lys- give the NH ₂ · TF A salt 179 w (34.6% yield).

Of these, 100 to 9 were taken, dissolved in 6.5 * of ultrapure water, and subjected to a weakly basic ion-exchange resin Dowex WGR-2 (59) in Cl_ form with 10% hydrochloric acid. The flow-through fraction and the water-washed fraction were combined for a total of 40 · ^, concentrated under reduced pressure, dissolved in a small amount of ultrapure water, and freeze-dried. In this way, Pro-Phe-Asp-Leu-Phe-Ile-Arg-Lys-NH2 · hydrochloride 80 «9 was obtained.

An aliquot of the purified product was analyzed for its amino acid sequence using a gas-phase protein sequencer. Pro, Phe, Asp, Leu, Phe, Ile, Arg, and Lys corresponded to the desired peptide sequence. In addition, the molecular weight was measured by FAB mass spectrometer to be mz 1034.90 (M + H) ⁺ , which was in agreement with the theoretical value (1034.62). Furthermore, when hydrolyzed with 6N-HCl aqueous solution and subjected to amino acid analysis, the ratio of Asp 1.01, Pro 0.95, Ile 0.98, Leu 0.99, Phe 1.95, Lys0.99, Arg 0.99 was obtained, which agreed with the theoretical value. . In addition, it was confirmed that thin-layer chromatography and reverse-phase liquid chromatography were single.

Example 2

Synthesis of Pro-Phe-Asp-Leu-Tyr-Ile-Arg-Lys-TFA salt

Fraoc-Lys (Boc) resin (p-alkoxybenzyl alcohol resin with Fmoc-Lys (Boc) introduced in the ratio of 0.52 millimol Zg resin) The suspension was suspended in dimethylformamide (20 * ί) in a solid-phase reactor of Merrifield and shaken for 30 minutes to swell the Fnoc-Lys (Boc) resin. This was subjected to the following Fmoc group removal cycle.

a) After passing for 1 minute in DMF20 *, 過 t was passed (twice).

b) Shaking in 20% piperidine-DMF solution 20 * for 3 minutes, followed by filtration.

c) A 20% piperidine-DMF solution was shaken for 10 minutes in 20 l ^, and then filtered to remove the Frooc group. d) Wash 4 times with DMF 2 (30 seconds each).

e) Wash twice with Isobranol 20 * (1 minute each).

Here, it was confirmed by the Kaiser method that the Fmoc group had been completely removed, and if it was incomplete, the above removal cycle was repeated. If they were completely removed, they were subjected to the following synthesis cycle.

f) The H—Lys (Boc) resin obtained in the Fmoc group removal cycle was swollen by passing twice with DMF 20 *.

g) A DMF solution (20 *) of Fmoc-Arg (Mtr) (548 «?, 0.9 mmol) and HO Bt (146«, 1.08 mmol) was added and shaken for 1 minute.

h) 1 M dicyclohexylcarposimid methylene chloride solution 0.

99 * was added and shaken for 70 minutes.

i) Wash twice with DMF20 »(1 minute each).

j) Wash twice with 20 shoulders of isopropanol (1 minute each).

Here, it was confirmed whether or not the condensation was completed by the Kaiser method. If the condensation was incomplete, the above-described condensation cycle was repeated. Also complete If the condensation had been completed, the reaction mixture was subjected to the FBOC group removal cycle again, and then subjected to the condensation cycle of step g) using Fmoc-Ile. Thereafter, the FBOC group removal cycle and the Fmoc amino acid condensation cycle were similarly repeated to repeatedly condense Frooc-Tyr (But), Fmoc-Leu, Fmoc-Asp (0But), Fmoc-Phe, and Boc-Pro. Thus obtained Boc- Pro- Phe- Asp (0 But) -Leu-Tyr (Bu 1) - a l ie -Arg (Mtr) -Lys ( Boc) Resin was subjected to desorption step from the following resins.

Wash twice with 20 shoulders of methylene chloride, suspend in methylene chloride (12.3 ")-anisole (2.00 *)-thiophenol (0.Ί mixed solution) and add trifluoroacetic acid (20). The resin was removed by shaking, and ether was added to the obtained liquid No. 1 to give a white precipitate (325 * 9), followed by trifluoroacetic acid (13.5 ««)-thioa. After adding a mixed solution of disole (1.5 «t) and monothiophenol (0.60«), the mixture was stirred for 5 hours, and ether was added to the reaction solution. 80 »9). The obtained white powder was subjected to reverse phase liquid chromatography, the required Pro-Phe-Asp-Leu-Tyr-Ile-Arg-Lys fraction was collected, and the eluted fraction obtained was concentrated to dryness. . Then, distilled water was added and the mixture was repeatedly concentrated and dried several times, then dissolved in a small amount of distilled water and freeze-dried. Pro-Phe-Asp-Leu-Tyr-Ile-Arg-Lys-TFA salt 101w thus purified was obtained (yield 32.5%).

An aliquot of the purified product was analyzed for its amino acid sequence using a gas-phase protein sequencer. Pro, Phe, .Asp, Leu, Tyr, Ile.Arg, and Lys corresponded to the desired peptide sequence. In addition, the molecular weight was measured by FAB mass spectrometer and found to be mZz 1051.81 (M + H) ⁺ , which was in agreement with the theoretical value (1051.59). Furthermore, when hydrolyzed with 6N-HC1 aqueous solution and subjected to amino acid analysis, the ratio of Asp 1.00, Pro 0.95, Ile 0.93, Leu 1.00, Tyr 0.94, Phe 0.99, Lys 0.97, Arg 0.94 was obtained, which is in agreement with the theoretical value.

In addition, thin-layer liquid chromatography and reversed-phase liquid liquid chromatography It was confirmed to be single.

Example 3

P ro-P he-A sp-Leu-P he-I le- Gly- Lys

The same reaction and treatment as in Example 2 were performed to synthesize the above peptide. Yield: 34.9%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Gly, Lys

m / z 936 (M + H) ⁺ (theoretical 936)

Amino acid analysis: Asp 1.01, Pro 0.98, Gly 1.00, lie 0.92, Leu 0.99, Phe 1.89, Lys 0.98 Example 4

Pro—Phe—Asp—Val—Phe—Ile-Arg-Lys-Ser · TFA Salt synthesis

The same reaction and treatment as in Example 2 were performed to synthesize the above peptide, yield: 52.5% Amino acid sequence: Pro, Phe, Asp, Val, Phe, Ile, Arg, LysSer

m / z 1108.80 (M + H) ⁺ (theoretical 1108.62) Amino acid analysis: Asp 1.03, Ser 0.93, Pro 1.00, lie 0.95, Val 0.97, Phe 1.90, Lys 1.00, Arg 0.95

Example 5

Pro— Synthesis of Phe-Asp-Leu-Phe-Ile-Arg-Orn-Ser and TFA salt

The same reaction and treatment as in Example 2 were performed to synthesize the above peptide, yield: 14.2%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, unknown (the presence of an unidentified peak considered to be Orn), Ser

m / z 1108.80 (M + H) ⁺ (theoretical value 1108.62) Amino acid analysis value: Asp 1.01, Ser 0.93, Pro 0.98, lie 0.93, Leu 0.99, Phe 1.88, Arg 0.94 (Orn Unidentified peak corresponding to one residue of the amino acid considered to be

Ala- P he- Asp- Leu- P he- I le- Arg-Lys

The same reaction and treatment as in Example 2 were performed to synthesize the above dibutide. Yield: 32.9%

Amino acid sequence: Ala, Phe, Asp, Leu, Phe, Ile, Arg, Lys

ni / z 1009.67 (M + H) ⁺ (theoretical: I 009.58) Amino acid analysis: Asp 1.00, Ala 1.00, I le 0.95,

Leu 1.00, Phe 1.95, Ls 0.98, Arg 0.97 Example 7

Pro- Phe- Asp- I le- Phe- I le- Arg- synthesis of L s- NH ₂ · TFA salt

4- (2 ', 4'dimethoxyphenyl-Fmoc-aminomethyl) -phenoxy resin (0.40 millimol Zg resin) 750 «9 (0.3 millimol) "

-31- was placed in a semi-automated peptide synthesizer (Labortec SP 640, 50 »^ reaction vessel), suspended in dimethylformamide (20«), and shaken for 30 minutes to swell the resin. Thereafter, the same reaction and treatment as in Example 2 were performed to synthesize the above dibutide.

Yield: 20.0%

Amino acid sequence: Pro, Phe, Asp, Ile, Phe, Ile, Arg, Lys

m / z 1034.90 (M + H) ⁺ (theoretical 1034.62)

Amino acid analysis: Asp 1.00, Pro 0.94, Ile 1.84,

Phe 1.91, Lys 0.99, Arg 0.94

Example 8

Pro—Phe-Asp—Leu—Cha—Ile-Arg-Lys-NH ₂ · Synthesis of TFA salt

The same reaction and treatment as in Example 7 were performed to synthesize the above peptide. Yield: 58.4%

Amino acid sequence: Pro, Phe, Asp, Leu, unknown (Cha part), Ile, Arg, Lys

m / z 1040.94 (M + H) ⁺ (theoretical 1040.66)

Analysis value of amino acid: Asp 1.01, Pro 0.98, I le 0.90, Leu 0.99, Phe 0.95, Lys 0.98, Arg 0.92 (the presence of a red identification peak corresponding to one amino acid residue considered to be Cha) Example 9

Pro-Phe-Asp-Leu-Phe-Ile-Lys-Arg

The same reaction and treatment as in Example 2 were performed to synthesize the above peptide. Yield: 26.7%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Lys, Arg

m / z 1035.89 (M + H) + (theoretical 1035.62)

Amino acid analysis: Asp 1.00, Pro 0.94, Ile 0.93,

Leu 1.00, Phe 1.92, Ls 0.96, Arg 0.97 Example 10 Pro—Phe-Asp-tert-Leu-Phe—] le—Arg—Lys—NH 2 ♦ Synthesis of TFA salt

The same reaction and treatment as in Example 7 were performed to synthesize the above-mentioned peptide. Yield: 23.2%

Amino acid sequence: Pro, Phe, Asp, unknown (there is an unidentified beak considered to be tert-Leu), Phe, Ile, Arg, Ls

m / z 1034.51 (M + H) ⁺ (theoretical 1034.62) Amino acid analysis: Asp 1.01, Pro 0.95, Ile 1.00,

Phe 1.95, Lys 1.00, Arg 0.99 (there is an unidentified peak corresponding to one amino acid residue considered to be tert-Leu) Example 11

Pro-Phe—Asp-Leu-Phe—Ile-Arg-D—Synthesis of Lys * TFA salt

Boc—D—Lys (CI-Z) Merrif iekl resin 600–9 to which 0.5 mmol was bound was placed in a reaction vessel of an automatic peptide synthesizer (Applied Biosystems, 43 OA) and subjected to the synthesis program. Then, the following processing was performed.

a) Treatment with methylene chloride solution containing 33% trifluoroacetic acid (80 seconds)

b) Treatment with methylene hydride solution containing 50% trifluoroacetic acid (18.

5 minutes)

c) Methylene chloride washing (3 times)

d) Treatment with methylene chloride solution containing 10% diisoprovirethylamine (1 minute, 2 times)

e) Wash with dimethylformamide (5 times)

g) 4 ml of a dimethylformamide solution containing 1.0 mmol of a symmetrical anhydride of Boc-Arg (Mts) was added, and the reaction vessel was stirred for 18 minutes.

f) Methylene chloride washing (5 times)

Then, after subjecting to the Boc group elimination cycle of a :) to e), the g) step was subjected to a condensation cycle performed with Boc-Ile. Thereafter, the Boc group removal cycle and the Boc amino acid condensation cycle are repeated in the same manner. Phe, Boc-Leu, Boc-Asp (O Bzl), Boc-Phe and Boc-Pro were sequentially condensed. The Boc-Pro-Phe-Asp (0Bzl) -Leu-Phe-Ile-Arg (Mts) -D-Lys (CI-Z) resin thus obtained was desorbed from the same resin as in Example 1. After the steps and purification, the desired peptide was synthesized. .

Yield: 20.8%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Ls

m / z 1035.53 (M + H) ⁺ (theoretical 1035.59) Amino acid analysis: Asp 1.00, Pro 0.93, Ile 0.98, Leu 1.00, Phe 1.95, Lys 0.99, Arg 0.99 Example 12

Synthesis of Pro-Phe-Asp-Leu-Phe-Ile-D-Arg—Lys-TFA salt

The same reaction and treatment as in Example 2 were performed to synthesize the above dibutide. Yield: 46.3% --

Damino acid sequence: Pro, Phe, Asp. Leu, Phe, Ile, Arg, Lys

m / z 1035.75 (M + H) ⁺ (theoretical 1035.59) Amino acid analysis: Asp 1.02, Pro 0.86, lie 0.98,

Leu 0.98, Phe 1.94, Lys 0.98, Arg 1.02 Example 13

D-Pro-D-Phe-D-Asp-D-Leu-D-Phe-D-I le-Arg-D-Lys * Synthesis of TFA salt

The same reaction and treatment as in Example 11 were performed to synthesize the above peptide. Yield: 18.7%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile ヽ Arg, Lys

tn / z 1035.84 (M + H) ⁺ (theoretical 1035.59) Amino acid analysis: Asp 1.00, Pro 0.86, Ile 0.95, Leu 1.00, Phe 1.95, Ls 1.00, Arg 1.00 Example 14

Pro— P he- Asp- Leu- Phe— I le— Arg— Lys- N HE t «Synthesis of TFA salt

4- (2 ', 4'-Dimethoxyphenyl-2-hydroxymethyl) 1-hydroxy resin 19 (0.6 mimol) was placed in a peptide synthesis vessel for the manual solid-phase method, and dimethylformamide (30 After shaking, the resin was swollen with a shaker for minutes.After filtration, Fmoc-Lys- (Bo c) 842w (1.8 mimol), dimethylaminopyridine 11 (0.09 mimol), methylmorpholine 471 (0.43 mmol) and 1.8 M 1M DCCZ in methylene chloride were added, and the mixture was shaken at room temperature for 6 hours, and washed twice with dimethylformamide, isopropanol, and then with methylene chloride. Thus, 1.50? Of Fmoc-Lys (Boc) was introduced at a ratio of 0.25 mirimorno-g-fat, which was suspended in dimethylformamide (2 and shaken for 30 minutes to obtain Fmoc-Lys (Boc). (Boc) The resin was swollen.

This was repeated using the same Fmoc group removal cycle and Fmoc-amino as in Example 1. The acid condensation cycle returns Senri Fmoc- Arg (Mtr), Fmoc- Ile , Fmoc -. Phe, Fmoc- Leu N Fooc- Asp (0 Bu t), Fmoc- Phe, sequentially condensing Boc-Pro.

Thus obtained ^{Boc- Pro- P he- Asp (Bu 1} ) -Leu- to Phe one I le-Ar-g (Mtr ) -Lys (Boc) Resin 2.98? To the following resin. Et al desorption step Attached.

That is, it was suspended in 30% of a 10% acetic acid methylene monochloride solution and stirred at room temperature for 2 hours. The resultant filtrate was concentrated under reduced pressure. About 100 * of ether was added, and the resulting precipitate was collected by filtration.

Pro- Phe- Asp (0 Bu *) -Leu- Phe- Ile- Arg (Mtr)

Lys (Boc) 153 w was obtained. Nigoshi Con hydrochloride Echiruamin 10 * »in methylene chloride and 2» I, after adding Toriechiruamin 12.4 w thereto, the ^{Boc- Pro- Phe- Asp (0 Βυ 1} ) one Leu- Phe- I le- Arg Add (Mtr) -Lys (Boc) 153 w, H 0 B 116.5 w, 0.5 M diisopropylcarbodiimide Z dimethylformamide 0.23, stir under ice-cooling for 2 hours, and leave at room temperature overnight did. This One ter was added, and the resulting white precipitate was collected by filtration, washed twice with ether, and dried under reduced pressure. To the obtained white powder, a mixed solution of trifluoroacetic acid (13.5 ")-thioanisole (1.5")-thiophenol (0.60 ") was added, and the mixture was stirred for 5 hours. Ether was added to the reaction solution, and the mixture was filtered to obtain a white precipitate (12). The white precipitate was subjected to reverse phase liquid chromatography to obtain a white precipitate.

The Pro-Phe-Asp-Leu-Phe-Ile-Arg-Lys-NHEt fraction was collected and the eluted fraction obtained was concentrated to dryness. Subsequently, distilled water was added thereto, and the mixture was concentrated and dried several times, then dissolved in a small amount of Jt of distilled water, and freeze-dried. Thus A portion of the purified Pro- Phe- Asp- Leu- P he- I le- Arg- Lys- NHEt * to give the TFA salt 47 «9 (11.8% yield) ₀ purified product gas phase protein Examination of the amino acid sequence using the sequencer revealed that the sequence of Pro, Phe, Asp, Leu, Phe, Ile, Arg, and Lys corresponded to the desired peptide sequence. The molecular weight was measured by FAB mass spectrometer and found to be mZz 1063.04 (M + H) +, which was in agreement with the theoretical value (1062.65). In addition, 6 N— H When hydrolyzed with CI aqueous solution and subjected to amino acid analysis, the ratio was Asp 1.01, Pro 0.99, lie 0.92, Leu 0.99, Phe 1.90, Lysl.00 Arg 1.10, which agreed with the theoretical value. In addition, it was confirmed to be single in thin-phase chromatography and reverse-phase liquid chromatography.

Example 15

Pro—Phe—Asp—Leu—Phe—Ile—D—Arg—Lys—Synthesis of NH ₂ · TFA salt

The same reaction and treatment as in Example 7 were performed to synthesize the above dibutide, yield: 52.2%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys

m / z 1034.76 (M + H) ⁺ (theoretical 1034.62)

Amino acid analysis: Asp 1.01, Pro 0.92, Ile 0.95,

Leu 0.99, Phe 1.93, Lys 0.98, Arg 0.96

Example 16 Pro— P he— Asp— Leu— Phe— I le— Arg— D— Lys— Synthesis of NH ₂ · TFA salt

The same reaction and treatment as in Example 1 were performed to synthesize the above peptide. Yield: 23.7%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys

m / z 1034.77 (M + H) ⁺ (theoretical 1034.62) Amino acid analysis: Asp 1.00, Pro 0.90, I le 0.96,

Leu 1.00, Phe 1.92, Lys 1.00, Arg 0.98 Example 17

D— Pro— Phe— Asp— Leu— Phe— I le-Arg- Lys-NH ₂ · Synthesis of TFA salt

The same reaction and treatment as in Example 1 were performed to synthesize the above peptide. Yield: 29.3%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys m / z 10 34.74 (M + H) ⁺ (theory 1034.62) Amino acid analysis: Asp 1.01, Pro 0.91, lie 0.93,

Leu 0.99, Phe 1.88, Lys 0.98, Arg 0.94 Example 18

Ala- Phe- Asp- Leu- Phe- I le- Arg- L ys- Synthesis of NH ₂ · TFA salt

The above dibutide was synthesized by carrying out a reaction and treatment in the same manner as in Example 1 _c yield: 20.2%

Amino acid SB sequence: Ala, Phe, Asp, Leu. Phe, Ile, Arg, Lys

in / z 1008.79 (M + H) ⁺ (theoretical 1 008.60) Amino acid analysis: Asp 1.01, Ala 0.98, Ile 0.98, Leu 0.92, Phe1.97, Lys 0.99, Arg 0.99 Example 19

Pro-Phe-Asp-Leu-Phe-Ile-Arg-Ls-IS ^) ♦ Synthesis of TFA salt It was obtained in the same manner as in Example 14 Boc- Pro- Phe- Asp (0 Bu l) - Leu- Phe- I le- Arg (Mtr) - Lys and (Boc) 150 (0.11 mi Rimoru) DMF (0.5 « This was added to a mixture of piperidine (10.5 «methylene monochloride (5" solution) under ice-cooling. H00Bt20 «9 (0.12 mimol), 0.5 M diisopropyl carbodiimide dimethylformamide After stirring for 2 hours, the mixture was allowed to stand at room temperature for 24 hours, and the same reaction and treatment as in Example 14 were performed to synthesize the above peptide.

Yield: 18.7%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys

m / z 1102.71 (M + H) ⁺ (theoretical 1102.68) Analytical value of amino acid: Asp 1.01, Pro 1.01, Ile 0.94, Leu 0.99, Phe 1.90, Lys 0.99, Arg 0.94

Example 20

Pro- Phe- Asp- Leu- Phe-I le- Arg- Lys- N, ^-^ ^ Synthesis of TFA salt

Boc—Pro—Phe—Asp (0 But) _ Leu-Phe-Ile-Arg (Mtr) -Lys (Boc) 150 obtained in the same manner as in Example 14.

(0.11 mimol) was dissolved in DMF (0.5 ligature. Under ice-cooling, this was mixed with 1-phenylbiperazine (20 »s—methylene chloride).

Added to the solution. In addition, HOOBt2 Qn ₉ (0.12 mimol), 0.

5M diisopropyl carpoimide / dimethylformamide 0.2

After adding 5 ^, the mixture was stirred under ice-cooling for 2 hours and left at room temperature for 24 hours. Thereafter, the same reaction and treatment as in Example 14 were performed to synthesize the above peptide.

Yield: 16.1%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys

ni / z 1179.73 (M + H) ⁺ (theoretical 1179.70) Amino acid analysis: Asp 1.01, Pro 0.95, I le 0.95

Leu 0.99, Phe 1.95, Lys 1.00, Arg 0.96 Example 2 1

Synthesis of Pro-Phe-Asp-Leu-Phe—Ile-Arg-Lys-OMe and TFA salt

It was obtained in the same manner as in Example 1 4 Boc- Pro- Phe- Asp (0 But) - Leu - Phe - j le _ Arg (Mtr) - Lys (Boc) 1 50 «9 (0. 1 1 Mi Rimoru ) Was dissolved in DMF (0.5n) and added to a solution of methanol (6 jtzl, 0.13) in methylene monochloride under ice-cooling, dimethylaminopyridine 2 »9, N-methylmorpholine 71, To the mixture was added 0.25% of 0.5 M diisopropylcarbodiimidonodimethylformamide, stirred for 2 hours under ice-cooling, and allowed to stand at room temperature for 24 hours.The same reaction and treatment as in Example 14 were carried out, and the above peptide was added. Synthesized.

Yield: 1 0.4%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys

m / z 1 049.72 (M + H) ⁺ (theoretical 1 049.62) Amino acid analysis: Asp 1.03, Pro 0.97, Ile 0.92, Leu 0.97, Phe 1.96, Lys 1.01, Arg 0.96 Example 22

Pro- Cha- Asp- Leu- Cha- I le- Arg- Lys- synthesis and the H ₂ · TFA salt

The same reaction and treatment as in Example 1 were performed to synthesize the above peptide. Yield: 1 2.9%

Amino acid sequence: Pro, unknown (Cha part), Asp, Leu, unknown (Cha part), Ile, Arg, Lys

m / z 1 046.80 (M + H) ⁺ (theoretical 1047.6 1)

Amino acid analysis: Asp 1.03, Pro 0.97, Ile 0.92,

Leu 0.97, Ls 0.99, Arg 0.94 (Unidentified beak equivalent to two amino acid residues considered to be Cha)

Example 23

Pro— Phe— Asp— Leu— Phe-Synthesis of Ile-Arg-Lys-Thr- TFA salt The same reaction and treatment as in Example 2 were performed to synthesize the above peptide. Yield: 25.5%

7 amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, A and g ヽ Lys, Thr

m / z 1 1 36.74 (M + H) ⁺ (excess 1 1 36.6.5) Amino acid analysis: Asp 1.01, Thr 0.98, Pro 0.99, lie 0.92, Leu 0.99, Phe 1.96, Lys 1.02, Arg

0.96

Example 24

Synthesis of Pro-Phe-Asp-Leu-Phe-Ile-Arg-Lys-Lys-TFA salt

The same reaction and treatment as in Example 2 were performed to synthesize the above dibutide. Yield: 49.5%

Amino acid sequence: Pro, Phe, Asp, Leu, Phe, Ile, Arg, Lys ヽ Lys

m / z 1163.79 (M + H) + (theoretical 1163.69) Amino acid analysis: Asp 1.00, Pro 0.92, lie 0.97, Leu 1.00, Phe 1.97, Lys 1.98, Arg 0.98

Industrial applicability

As described above, dibutide and a salt thereof of the present invention are useful as an antiallergic agent for preventing and treating allergic symptoms.

Claims

The scope of the claims

1. a peptide having the amino acid sequence E represented by the following formula [I] and a salt thereof:

A B— Asp— C-D-I le-E— F-G [I]

(Where A is Ala or Pro, B is Phe or Cha, C is

Ile, Leu, tert-Leu or Val, D is Phe, Tyr or Cha, E is Gly, Lys or Arg, F is Lys, Arg or Orn, G is OH, NH ₂ , NHEt, Lys, Ser , Thr, OMe, N> or NJ ^ "^. Each amino acid residue may be any of D-type, L-type and racemic-type, provided that A is Pro, B is Phe, When C is Leu, D is Phe, E is Arg, F is Lys, and G is OH, at least one of the amino acid residues is always D-type.)

2. A peptide having an amino acid sequence represented by the formula [I] according to claim 1, wherein G is NH ₂ , NHEt, 0Me, N> or N ′ N- ^)) The salt <

3. Claims [1] The amino acid sequence represented by the formula [1] A peptide and a salt thereof, in which at least one of the amino acid residues is always D-type.

4. In the peptide having an amino acid sequence represented by the formula [I] according to claim 1, A is Pro, B is Phe, C is Leu, D is Phe, E is Arg, F is Lys, G is a peptide having an amino acid sequence of NH ₂ and salts thereof.

5. A prophylactic or therapeutic agent for an allergic disease, comprising the peptide according to claim 1 or a salt thereof as an active ingredient.