JPS63218698A - Auricular peptide derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to atrial (atriaI) useful for the treatment of hypertension.
) Regarding natriuretic polypeptide derivatives.

PRIOR ART Recently, alpha human atrial natriuretic polypeptide (α-hANP) was isolated from human atrium and identified as a polypeptide consisting of 28 amino acids represented by the following formula %.

The diuretic effect of a-hANP is reported to be about 1000 times that of 70semide, which is used as an antihypertensive diuretic. It has also been reported that α-hANP increases urinary sodium and urinary excretion.

However, σ-hANP or its derivatives are not commercially available, chemically and enzymatically stable, and σ-hAN
Research has been conducted on ANP, which has a more lasting and stronger effect than P.

To date, hypertension has been classified into hypertension with an obvious etiology and hypertension with no obvious etiology.

The former is classified as secondary hypertension and is mainly caused by renal disease,
These include those caused by endocrine disorders, preeclampsia, arterial embolism, and central nervous system diseases. On the other hand, the latter hypertension whose etiology is unknown is classified as essential hypertension, and 80 to 90% of hypertensive patients fall into this category. Secondary hypertension can be improved by treating the disease that causes it, but essential hypertension whose etiology is unknown can be treated by, for example, administering antihypertensive diuretics or vasodilators as symptomatic treatment. be done. Recently, it has been reported that the above a-hA N P is one of the substances involved in the causes of heart disease or essential hypertension, and research on essential hypertension regarding σ-hANP has been attracting attention.

Structure and Effects of the Invention The present invention provides novel peptides having antihypertensive, natriuretic, diuretic, and vasodilatory activities.

The biologically active peptide has the following formula %E, where R8 is absent or hydrogen, acetyl, S
er, S er S er, D-Args Argx
Apa, AhepasAoalArgSerSer
, or ArgArgSerSer.

R8 is CyS, Mpa or Pen, R, is PheC
ha, L-Tic, D-Tic or Na11R4
is GlylPro.

D-Ala or Ala, Rs is Gly, Pros
Aca, rnAMBA, Ala or D-Ala, R
, is Arg, DArg, Lys or Guy, R,
Ile, Leu, PrGly or cty,
R, is Asp or Gly, R, is D-A rgSA
rg, Cys or G 1ys R+ O is I le
.

R11 is Cys or Pens Rl! is OH,N
H2, ChaArg%ArgSProArg, Gly
Arg, PheArgPheLys, AoaArg,
Asn5er% SerPheArg or AsnSe
rPhaArg, m is 0, In is 0 or 11 A compound having the amino acid sequence, and a pharmaceutically acceptable salt, ester or amide thereof.

The amino acid components in the above peptide structure are indicated by conventional abbreviations as follows.

Amino acid abbreviation alanine
Ala6-aminocaproic acid
Aca7-aminohebutanoic acid
A hepa8-aminooctanoic acid A
oa5-aminopentanoic acid Apa lumiarginine Arg asparagine
Asn aspartic acid
Asp Asparagine and/or Aspartate sx Cyclohexylalanine Cha Cystine Cys Glutamine
Gin glycine
Gly Isoleucine Il
e-leucine Leu-lysine
Lysm-aminomethylbenzoic acid mAMBA methionine
Metβ-mercaptogropionic acid
Mpa Luminaphthylalanine Nal Ornithine Orn Penicillamine Pen Phenylalanine
Phe-proline
Pr.

Glopargylglycine PrGly Serine Ser Tetrahydroisoquinoline-3-carboxylic acid ic Threonine Thr Tyrosine
Tyr Optically active amino acids have the L-configuration unless otherwise specified.

The term "allyl" refers to phenyl, benzyl, naphthyl groups.

Examples of pharmaceutically acceptable non-toxic acid addition salts include:
Contains salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, malic acid, tartaric acid, citric acid, succinic acid, and malonic acid. It will be done. Other pharmaceutically acceptable salts include inorganic nitrate, sulfate, acetate, malate, formate, lactate, tartrate, succinate, titrate, p-toluenesulfonate, or metal salts such as sodium, potassium, calcium, ammonium , ammonium or amino salts such as triethylamine salts, etc., and these are produced by conventional methods.

Pharmaceutically acceptable non-toxic esters of compounds of formula (I) include, for example, straight or branched C8-C, alkyl esters. As an ester, C, ~
Includes C7 cycloalkyl esters. C, -C,
Alkyl esters are preferred. Esters of the compound of formula (I) are prepared by conventional methods.

Pharmaceutically acceptable non-toxic amides of the compound of formula (I) include, for example, ammonia, primary C1-C, alkylamines, secondary C, -C, dialkylamines (wherein the alkyl is linear and (including branched chains). In the case of secondary amines, a 5- to 6-membered heterocyclic ring containing one nitrogen atom may be formed. Preferred amides are ammonia, C, -C, alkyl primary amines,
C8~C.

It is an amide obtained from a dialkyl secondary amine. Amides of compounds of formula (I) are also prepared by conventional methods.

The daily dosage of the compound of the present invention is easily determined depending on the patient's condition, but is usually about 0.2 to 250 me/day.
kg range. Unit dose compositions may be prepared to provide the daily doses described above.

The amount of active ingredient that is combined with excipients to produce a unit dosage form may vary depending on the patient, mode of administration, etc.

However, the specific dose for a particular patient depends on the type of compound used, the patient's age, weight, health status, gender, diet, time of administration, route of administration, rate of excretion, concomitant drugs, and the extent of the disease to be treated. It may change depending on.

The compounds of the present invention can be administered orally, parenterally, by inhalation, rectally, or topically, and are formulated into unit dosage forms containing conventional non-toxic pharmaceutically acceptable carriers, excipients, etc. . Parenteral administration includes subcutaneous, intravenous, intramuscular, sternal, and injection administration.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be prepared according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a nontoxic injectable solution or suspension in a nontoxic parenteral diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles or solutions include water, Ringer's solution, isotonic sodium chloride, and the like. In addition, sterile, fixed oils are also employed as a solvent or suspending medium. For this purpose, commercially available fixed oils are employed such as synthetic no- or diglycerides.

Additionally, fatty acids such as oleic acid find use in injectable formulations.

Herbal medicines for rectal administration are prepared by mixing the drug with suitable non-irritating excipients such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at rectal temperature, so that they can be administered in the rectum. melts and releases the drug.

Solid preparations for oral administration include capsules, tablets, emulsions, powders, and granules. In such solid formulations, the active compound is present in at least one inert excipient, such as sucrose,
Mixed with lactose, starch, etc. Such formulations may contain lubricants such as magnesium stearate in addition to inert excipients in a conventional manner. capsules,
In the case of tablets and emulsions, buffering agents may also be included. Tablets and emulsions may be lightly enteric coated.

Vehicles for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, containing conventional inert diluents, such as water.

Such formulations may contain additives such as wetting agents, emulsifying agents, suspending agents, and sweetening agents, flavoring agents, and aromatic agents.

The novel polypeptides of the invention and their salts are useful as vasodilators. Therefore, the present invention provides formula (I)
A vasodilator composition containing the novel polypeptide or a salt thereof as an active ingredient is also provided.

The polypeptide of the present invention can be produced by conventional methods such as condensing amino acids one by one to elongate the peptide chain, coupling seven fragments of two or several amino acids, or a combination of these methods. Produced by peptide synthesis method.

Condensation of two amino acids, one amino acid and one peptide, or one peptide and another peptide can be carried out using conventional condensation methods, such as the amide method, mixed acid anhydride method, DCC (dicyclo hexylcarbodiimide) method, active ester method (p-nitrophenyl ester method, N-hydroxysuccisoimide ester method, cyan methyl ester method, etc.), Woodward reagent K (Woodward
reagent K) method, DCC-HOBT (1
-hydroxybenzotriazole) method. These condensation reactions are carried out either by solution methods or solid phase synthesis methods. When extending a peptide chain using the solid phase method, the C-terminal amino acid is linked to an insoluble carrier. As the insoluble carrier, anything that reacts with the carboxyl group of the C-terminal amino acid to form a bond that can be released can be used, such as halomethyl resins such as chloromethyl resins and bromomethyl resins, hydroxymethyl resins, aminomethyl resins, Examples include benzhydrylamine resin and t-alkyloxycarbonyl hydrazide resin.

As in normal polypeptide synthesis, the amino acid a
The branched amino group and carboxy group at the ω position are protected and deprotected as desired. As a protecting group for an amino group, for example, benzyloxycarbonyl (Z)
, o-chlorobenzyloxycarbonyl [(2-(1)
Z], p-nitrobenzyloxycarbonyl [Z(N○
=)], p-methoxybenzyloxycarbonyl [Z(
OMe)], ]L-7'toxycarponyl Boc), t
-amyloxycarbonyl (Aoc), isobornyloxycarbonyl, adamantyloxycarbonyl)-2-propyloxycarbonyl (B poc
), 9-fluorenylmethoxycarbonyl (Fmoc)
, methylsulfonylethoxycarbonyl (MSC), trifluoroacetyl, phthalyl, formyl, 2-nitrophenylsulfenyl (NPs), diphenylphosphinothionyl (Ppt), and dimethylphosphinothionyl (Mpt).

Examples of protective groups for carboxyl groups include benzyl ester (O B zl), cyclohexyester, and 4-nido-benzyl ester [O B zl (N O *)].
,] L-butyl ester OtBu), 4-pyridyl methyl ester (OPic), and the like.

In the synthesis of the peptide of the present invention, specific amino acids having functional groups other than amino and carboxy groups in their branch chains, such as arginine, cysteine, and serine, are
If desired, it can also be protected with a suitable protecting group. For example, the guanidino group (NG) of arginine is nitro,
p-Toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyloxybenzenesulfonyl, 4-methoxy-2.6-dimethylbenzenesulfonyl (Mds), 1.3.5-trimethylphenylsulfonyl (Mts) It is preferable to protect the The thiol group of cysteine is benzyl, p
-methoxybenzyl, triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl (4
- MeB zl), 2,4,6-drimethylbenzyl (Tmb), etc. are preferred. Further, the hydroxy group of serine is preferably protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl, or the like.

Compounds of the invention are described by Stuart et al. (John M.

Stewart & Janis D. Young
g) "Solid Phase Peptide Synthesis", 2nd edition (1984), particularly in Examples 1 and 2 of the experimental section thereof.

The compounds of the invention are also described by Bodansky et al. (M.

Bodanszky, Y. S. Klausner, &
M. A. Ondetti) “Peptide Synthesis” 2nd edition (
It can also be produced by the partial solid phase synthesis method, polycondensation method and classical solution method described in 1976).

The present invention will be described in more detail with reference to Examples below, but the present invention is not limited thereto.

Example 1 Preparation of Seryl-Ceryl Cysteinyl-Phenylalanyl-Glycyl-Glycyl-Arginyl-Isoleucyl-Asbarthyl-Arginyl-Isoleucyl Cysteinyl-Phenylalanyl-Arginyl-Protected Peptide Resin: N-a-t- Boc arginyl (NGTos)-0 Manifield resin 0.5-1. Oy is placed in a solid phase peptide synthesis vessel and amino acids are coupled to the peptide resin in the following order.

Boc-Phe, Boa-Cys(4-Me
Bzl), Boc-I leSBoc-Arg (NGT
os), Boc-Asp (β-cyclohexyl), Bo
a-1 1e, Boc-Arg (NGTos),
Boa-Gly, Boa-Glys Boc-P
hesBoc-Cys(4-MeBzl), Boc
- Ser (Bzl), Boc - Ser (Bzl
) Protected peptide resin = Ser according to specification A below.
(Bzl) - Ser (Bzl) - Cys (4
-MeBzl) -Phe - G ly - G l
y-Arg(NGTos)-Ile-A
sp(β-cyclohexyl)-Arg(NGTo
s) −1 1e −Cys(4 −MeBzl)
- Pha-Arg (NGTos) - Obtain resin.

After the synthesis reaction, the protected peptide resin was dissolved in DMF20.
+*(washed out 3 times with step 1 and transferred from the reaction vessel to a 6QraQ sintered glass funnel, then the resin was washed out with CH*CQz30
Wash 3 times with shoulder a. This resin is dried under reduced pressure for 3 hours and then weighed.

Specification A 1, Deprotection = 50% trifluoroacetic acid (TFA) with 2% anisole and 0.5% ethanedithiol C
H j C Qx in bath solution v/v/v).

2. Neutralization: 10% diisopropylethylamine (DIE
A) CH. In CQ2 solution (v/v).

3. Each coupling: CHIC of 0.2M Boa-amino acid derivative in N,N-dimethylformamide (DMF) and 0.2M diisopropylcarbodiimide
Q. Let the solution react for 45 minutes.

4. Resin cleaning: 10% DI EA (7) CH, Cff
! In solution.

5. Each coupling: 0-2M Boa-amino acid derivative (same as step 3) in DMF solution, 0.2M diisopropylcarbodiimide CH2CQ, and react for 45 minutes.

6. Protection (Cap) = 0.3M acetylimidazole D
In MF solution.

7. Move on to processing of the next amino acid residue. 8. After binding the final amino acid to complete the peptide chain, remove the protecting group (t-Boc) in the same manner as in step 1.

Example 2 Preparation of Seryl-Ceryl Cysteiny-Phenylalanyl-Glycyl-Glycyl-Arginyl-Isoleucyl-Asbarthyl-Arginyl-Isoleucyl Cysteiny-Phenylalanyl-Arginyl Cyclic Disulfide: Protected peptide of Example 1. 5g of Anisole 2 + IQ
and 15 ml of liquid hydrogen fluoride (HF) at 0° C. for 60 minutes. The HF and anisole are removed from the resin in vacuo and the resin is washed with ethyl ether or ethyl acetate 2x25ffa under a nitrogen atmosphere. The crude peptide is extracted from the resin by treatment with 6×50 mα of 20% aqueous acetic acid. The acetic acid solution was diluted with distilled water to 1.5
The pH of the solution was adjusted to 8.3 with 80 mα of concentrated ammonium hydroxide. This solution is O,,0
Oxidize with an excess amount of 1NKsFe(CN)a. The resulting yellow solution is stirred at room temperature for 60 minutes while maintaining the pH at 8.3.

First, the pH was adjusted to 5.5 with glacial acetic acid 50-, and then the ion exchange resin Bio-Rad AG
cycle) Remove excess ferry and 7 erocyanide ions by adding 10 mg. The mixture is stirred at room temperature for 20 minutes. The resin is filtered off and washed with 3×25 mI2 of 20% aqueous acetic acid. Combine the aqueous solutions, XAD
-16 molecules through a column containing 300 g of adsorption resin. Desalt the sample by washing the column with distilled water 3I2. This sample is eluted from the column with 50% ethanol water 1500+af. The combined ethanol fractions are concentrated in vacuo to about 100 m<2, taken up in 100 m<2 of distilled water and lyophilized to obtain a dry amorphous powder. This dry powder was subjected to high performance liquid chromatography (HP) using 10% trifluoroacetic acid and acetonitrile as organic medium.
LC). Dynamax (R)
12 to 15 m using AI N I N) (: Ia millimeter reverse phase column 2.lc depth X25C11 length)
Preactive analysis is performed at a flow rate of 12/min. VYD
HPL using AC218TP I Oμcps reverse phase column (0,46c+*X20c+x length)
Perform C analysis. As a result, 2011 g of the title compound (
6%).

Amino acid analysis: Asp (1,03), 5et (1,60
), Gly (2,00), Cys (0,88), l1e
(1,94), Phe (2,00), Arg (3,26
);FAB"(M+H)"M/Z: l 615゜Example 3 Arginyl-Arginyl-Seryl-Serylcysteiny-Phenylalanyl-Glycyl-Glycyl-Arginyl-Isoleucyl-Asbarthyl-Arginyl-Inleucylcysteine Preparation of Nyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc arginyl(NGTos)-O
Add amino acids to Manifield resin in the following order: Boc-P
he%Boc-Cys(4-MeBzl), Boc-1
1e-SBoc-Arg (NGTos), Boc-As
p(β-cyclohexyl), Boc-I le, B
oc-Arg(NGTos), Boa-Gly, Bo
c-Gly, Boc-Phe.

Boc-Cys (4-MeBzl), Boc-5er
(Bzl), Boc-5er (Bzl), Boc-
Arg(NGTos), BOC-Arg(NG
0.39 g of protected peptide resin obtained by binding with
is separated from the resin and purified in the same manner as in Example 2. The title compound 31M+9 is obtained as a white powder.

FAB”(M+H)”M/Z:1927 Amino acid analysis:
Arg (5-05), Asp (1,00), Cys (2
, 21), Gly (2, 11), tte (1, 77),
Phe(1,82), 5er(1,73) Example 4 Arginyl-Arginyl-Seryl-Selyl-Cysteinyl-Phenylalanyl-Glycyl-Glycyl-Arginyl-Inleucyl-Asbarthyl-Arginyl-Isoleucyl Cysteinyl Cyclic Preparation of disulfide: N-a-t-Boa-Cys(4-MaBzl)-0
Add amino acids to the manifold resin in the following order: Boc −
11es Boc-Arg (NGTos), Boc-A
sp(β-cyclohexyl), Boc-I 1e%B
oc-Arg(NGTos), Boc-Gly, Bo
c-Gly%Boc-Phes Boc-Cys(4-
MeBzl), Boc-5er(Bzl), Boc
-5er (Bzl), Boc-Arg (NGTos),
0.39 g of the protected peptide resin obtained by binding with Boc-Arg (NGTos) is separated from the resin and purified in the same manner as in Example 2. The title compound 16■ is obtained as a white powder.

FAB”(M+H)”M/Z:l 624 amino acid analysis: Arg (3,9), Asp (1,0), Cys (1,
3), Gly(2,2), IJe(1,9), Phe(
1,2), 5er(1,7) Example 5 Preparation of serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucilcysteiny-phenylalanyl-arginyl cyclic disulfide : N-a-t-Boc-Arg(NGTos)-0 manifold resin with amino acids in the following order: Boc-Phe, Boa-Cys(4-MeBz
l), Boc-I le, Boa-Arg(NG
Tos), Boc-Asp (β-cyclohexyl), B
oa-11e%Boc-Arg(NGTos),
Boa-GlylBoc-Gly, Boa-Phe.

Boa-Cys(4-MeBzl), Boa-5e
The protected peptide resin 0.459 obtained by binding with r(Bzl) is separated from the resin and purified in the same manner as in Example 2. The title compound 23+19 is obtained as a white powder.

FAB”(M+H)”M/Z:1529 Amino acid analysis:
Arg(3,0), Asp(1,0), Cys(1,3
), Gly(2,2), 1ie(1,8), Phe(2
. Amino acids were added to N-a-L-Boc-Arg(NGTos)-Qv Nifield resin in the following order: Boc-Phe, Boc-Cys(4-MeBz
l), Boc-11e, Boc-Arg(NG
Tos), Boa-Asp (β-cyclohexyl), B
oa-11es Boc-ArgCN GTos)
, Boa-Gly, Boc-Gly%Boc-Phe
.

0.7 g of the protected peptide resin obtained by bonding with B oc -Cys (4-MeB zl) was acetylated with acetic anhydride in pyridine, and the protected peptide was prepared in Example 2.
It is treated with HF (liquid) and purified in the same manner as above. The title compound is obtained as a white powder.

FAB”(M+H)”M/Z:l 483 amino acid analysis: Arg (1,85), Asp (0,94), Cys (
0,8), Gly(2,02), l1e(1,48),
Phe ('2.00) Example 7 Preparation of β-mercaptopropionyl-phenylalanyl-glycyl-glycyl-arginyl-in-leucyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a-t-Boc-Arg(NGTos)-Q Ma-Field resin with amino acids in the following order: Boc-Phe%Boc-Cys(4-MeBzl
), Boc-11eSBoc-Arg(NGTos
), Boc-Asp (β-cyclohexyl), Boc
-11e, Boc-Arg(NGTos), Boc
-Glys Boc-Gly, Boc-Phes Protected peptide resin obtained by bonding with mercaptopropionic acid (Mpa) 0.475 g
is separated from the resin and purified in the same manner as in Example 2. The title compound 33u is obtained as a white powder.

FAB"(M+H)"M/Z:l 425 amino acid analysis 2 Arg (2,9), Asp (1,0), Cys (0,
7), Gly(2,2), ll5(1,8), Phe(
2,0) Example 8 Preparation of cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl cyclic disulfide: N -a -t -Boc -Cys(4- MeBzl
)-0 Manifold resin with amino acids in the following order: B
oc-11e, Boa-Arg(NGTos), B
oc-Asp (β-cyclohexyl), Boa-I
le, Boc-Arg(NGTos), Boc-G
ly, Boc-Gly, Boa-Phe, Boc
The protected peptide resin 0.5009 obtained by binding with -Cys(4-MeBzl) is separated from the resin and purified in the same manner as in Example 2. Title compound 17+1
19 is obtained as a white powder.

FAB”(M+H)”M/Z:l 137 amino acid analysis: Arg (1,8), Asp (0,9), Cys (1,
1), Gly (2-2), l1e (1-4), Phe (
0,9) Example 9 Preparation of cysteinyl-phenylalanyl-glycyl-arginyl-isoleucyl-asbarthyl-arginyl-isoleucycysteinyl cyclic disulfide: N -a -t -Boc -Cys (4-MeBz - Amino acids were added to Q Ma-Field resin in the following order: Bo
a-11es Boc-Arg(NGTos),
Boa-Asp (β-cyclohexyl), Boc-I, Boc-Arg (NATos), Boc-Gly,
Boc-Phe, Boc-Cys (4-MeB zl
) 0.400g of protected peptide resin obtained by bonding with
is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 13my is obtained as a white powder.

FAB"(M+H)"M/Z:l 080 amino acid analysis: Arg (1,9), Asp (1,0), Cys (1,
4), Gly(1,0), l1e(1,8), Phe(
1,0) Example 1O Preparation of cysteinyl-phenylalanyl-D-alanyl-glycyl-arginyl-isoleucyl-aspartyl-arginyl-inleucyl-cysteinyl cyclic disulfide: N-a-t-Boc-Cys(4-MeBzl)- 0
Add amino acids to the manifold resin in the following order: Boc −
11e, Boc-Arg (NGTos), Boa-A
sp (β-cyclohexyl), Boc-r Is,
Boc-Arg (NGTos), Boc-Glys B
oc-D-Ala, Boc-Phe, Boc
0.400 g of the protected peptide resin obtained by binding with -Cys(4-MeB zl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. Title compound 61
11 g are obtained as a white powder.

FAB"CM+H)"M/Z:1151 Amino acid analysis:
Ala (0,6), Arg (2-2), Asp (1,0
), Cys(1,6), Gly(1-3), 1ie(1
. -t-Boc-Cys
(4-MeBzl)-0v=Field resin with amino acids in the following order: Boc-11eSBoc-Arg(N
GTos), Boc-Asp (β-cyclohexyl),
Boa-11e, Boa-Arg (NGTos),
Boc-Pro, Boa-GIy, Boc-P
he, Boa-Cys(4-MeBzl), Boc
-5er (Bzl), Boa -5er (Bzl) Protected peptide resin obtained by binding with -5er (Bzl) 0.4009
is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 18 mg of the title compound are obtained as a white powder.

FAB"CM+H)"M/Z:l 351 amino acid analysis = Arg (2, 1), Asp (1, 0), Cys (1,
8), Gly(1,1), rle(1,8), Phe(
1,0), 5er(1,4), Pro(1-0) Example 12 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl Preparation of cyclic disulfide diN-a-t-Boc-Cys (
4-MeBzl) -〇 Amino acids were added to Manifield resin in the following order: Boc-11es Boc-Arg(N
GTos), Boc-Asp (β-cyclohexyl),
Boc-I In, Boc-Arg(NGTos)
, Boc-Gly, Boc-Glys Boc-P
he, Boc-Cys(4-MeBzl), Boc
-5er (Bzl), BOC-5er (Bzl) 0.300g of protected peptide resin obtained by binding
is subjected to liquid HF treatment and purification as in Example 2. The title compound 31u is obtained as a white powder.

FAB”(M+H)”M/Z:1311 Amino acid analysis:
Arg(2,0), Asp(0,8), Cys(1
, 8), GJy (1, 7), l1e (1, 8), Phe
(0,9), 5et(1,4) Example 13 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-inleucyl-asbarthyl-arginyl-isoleucilcysteinyl-phenylalanyl-arginyl cyclic Preparation of disulfide: N-a-L-Boc-Arg(NGTos)
-0 manifold resin in the following order of amino acids: Boc-Phe%Boa-Cys (4-MeBzl),
Boc-Ile, Boa-Arg(NGTos),
Boc-Glys Boc-I leSBoc-Arg
(NGTos), Boc-Gly, Boc-Gly,
Boc-Phe, Boc-Cys (4-MeBzl
), Boc-5er (Bzl), Boc-5er (
Protected peptide resin obtained by binding with Bzl) 0.
759 is subjected to liquid HP treatment and purification as in Example 2. The title compound 55119 is obtained as a white powder.

FAB"CM+H)"M/Z:1556 Amino acid analysis:
Arg (3,06), Cys (2,01), Gly (3
,33), l1e(2,13), Phe(2,13),
5er(1,69) Example 14 Preparation of seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-lidyl-isoleucil-asbarty-arginyl-in leucylcysteinyl-phenylalanyl-arginyl cyclic disulfide: N- a -t-Boa-Arg(NGTos)-0 manifold resin with amino acids in the following order: Boc-Phe, Boa-Cys(4-MeBzl)
, Boc-11e, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boa-I
le, Boa-Lys(2Ca-Z), Boc-
GlylBoc-Gly, Boa-Phe.

Boc-Cys(4-MeBzl), Boc-5e
0.73 g of the protected peptide resin obtained by combining r(Bzl) and Boc-5er(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 74119 is obtained as a white powder.

FAB”(M+H)”M/Z:1586 Amino acid analysis:
Arg (1,94), Asp (1,06), Cys (1
,85), Gly(2,18), l1e(2,00),
Lys (0,92), Phe (1,96), 5er (1
, 76) Example 15 Preparation of cyclic disulfide: Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-in leucyl-asbarthyl-ridyl-in leucylcysteinyi-phenylalanyl-arginyl: N-a-t- Boc-Arg(NGTos)-C)v
Add amino acids to Nifield resin in the following order: Boc-Phe, Boc-Cys (4-MeBzl)
, Boc-I le, Boc-Lys[(2-Cf
f) Zl, Boc-Asp (β-cyclohexyl), B
oa-IIe, Boa-Arg(NGTos),
Boc-Gly, Boc-Gly, Boc-Phe
.

Boc-Cys (4-MeBzl), Boc-5er
(Bzl), Boc-Ser(Bzl) The protected peptide resin 0.969 obtained by bonding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 50+19 is obtained as a white powder.

FAB”(M+H)”M/Z:l 586 amino acid analysis: Arg(2,02), Asp(1,10), Cys(
1,87), Gly (2,16), 11e (2,01)
, Lys(0,98), Phe(2,05), 5er(
1,83) Example 16 Preparation of cyclic disulfide: Seryl-ceryl-cysteinyl-enyl alani-alanyl-glycyl-arginyl-isoleucy-asbarthyl-arginyl-leucyl-cysteinyl-enyl alanyl-arginyl: N-a- t-Boc-Arm (NGTos) -〇 Amino acids were added to Manifield resin in the following order: Boc-Phe, Boc-Cys (4-MeBz
l), Boc-11e% Boc-Arg (NGTos)
, Boc-Asp (β-cyclohexyl), Boa-
11e, Boa-Arg (NGTos), Boc-G
lylBoa-Alaq Boa-PhesB oc
-Cys(4-MeB zl), BoC-5er(Bz
1), 0.81 g of the protected peptide resin obtained by binding with Boc-5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 51 mg of the title compound are obtained as a white powder.

FAB"CM+H)"M/Z:1628 Amino acid analysis:
AIa (1,04), Arg (3,01), Asp (1
,01), Cys(1,78), Gly(1,17),
11e (1,94), Phe (2,01), 5er (1
,76) Example 17 Seryl-seryl-cysteinyl-phenylalanyl-(
D) Preparation of -alanyl-glycyl-arginyl-inleucyl-aspartyl-arginyl-inleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: Add the following amino acids to N-a-t-Boc-Arg(NGTos)-0 manifold resin. Order: Boa-PhelBoC-Cys (4-MeBzl),
Boc-11+3% Boa-Arg(NG To
s), Boc-Asp (β-cyclohexyl), Boc
-11e%Boc-Arg(NGTos), Boa-
GlySBoc-D-Ala, Boa-Phe,
Boc-Cys(4-MaBzl), Boa-5e
r(Bzl) and Boc-5er(Bzl), 1.3g of the protected peptide resin obtained by combining
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 6911Ig is obtained as a white powder.

FAB"CM+H)"M/Z:1628 Amino acid analysis:
A1a (1,05), Arg (3,01), Asp (1
,06), Cys(1,91), cly(1-10),
11e (2,00), Phe (2-06), 5et (1
, 78) Example 18 Preparation of seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-glycyl-asbarthyl-arginyl-leucylcysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t- BoC-Arg(NGTos)
Amino acids were added to the -0 manifold resin in the following order: Boc-Phe, Boa-Cys (4-MeBzl
), Boc-11e, Boc-Arg(NG T
os), Boa-Asp (β-cyclohexyl), Bo
c-Glyt Boc-Arg (NGTos), Boc
-Glys Boc-GlySBoc-Phe.

Boc-Cys(4-MeBzl), Boc-5e
Protected peptide resin 1.19 obtained by combining r(Bzl) and Boa-5er(Bzl),
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 60119 is obtained as a white powder.

FAB”(M+H)”M/Z:l 559 amino acid analysis: Arg (3,09), Asp (1,07), Cys (
1,80), Gly (3,22), IIe (1,03
), Phe (2,11), 5er (1,94) Example 1
9 Preparation of cysteinyl-phenylalanyl-glycyl-prolyl-arginyl-inleucyl-asbarthyl-arginyl-isoleucycysteinyl cyclic disulfide: N-a-t-Boa-Cys(4-MeBzl
) −02=Field resin with amino acids in the following order: B
oa-Ile, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boc-1
1e, Boc-Arg (NGTos), Boa-Pr
o, Boc-cty, Boa-PheSBoc-Cy
0.5 g of the protected peptide resin obtained by binding with s(4-MeBzl) is separated from the resin and purified in the same manner as in Example 2. The title compound 11m+9 is obtained as a white powder.

F A B”(M+H)”M/Z: 1177 Amino acid analysis: Arg (2,14), Asp (1,05),
Cys (1,95), Gly (1,16), 1ie (1
, 89), Pro (0,88), Phe (0,95) Example 20 Seryl-serylcysteinyl-phenylalanyl-glycyl-prolyl-arginyl-inleucyl-asbarthyl-arginyl-inleucylcysteinyl- Preparation of phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg (NGTos) - Amino acids were added to Manifield resin in the following order: BoC-Phe, Boc-Cys (4-MeBzl)
), Boc-11e1Boc-Arg(NG To
s), Boc-Asp (β-cyclohexyl), Boc
-11e, BoC-Arg (NGTos), Boc
-Pro, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-5e
0.74 g of the protected peptide resin obtained by combining r(Bzl) and Boc-5er(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 6 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:l 655 amino acid analysis: Arg(2,82), Asp(1,01), Cys(
1,54), Gly (1,42), l1e (2,00)
, Pro(1,09), Phe(2,04), 5et(
1,34) Example 21 Preparation of serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl cyclic disulfide: N -a -t -Boa -Cys(4 -MeBzl
)-Q Manifold resin with amino acids in the following order: Bo
c-11e, Boc-Arg (NGTos), Bo
a-Asp (β-cyclohexyl), Boc-I l
e, Boc-Arg (NGTos), Boa-Gly
, Boa-Glys Boa-Phe, Boa-
Cys (4-MaBzl), Boa-Ser (Bzl)
0.5 g of protected peptide resin obtained by combining
HF (liquid) in the same manner as in Example 2! & subjected to processing and refining. 22 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:1224 Amino acid analysis:
Arg (1,97), Asp (1-12), Cys (2
,01), Gly(2,25), l1e(1,82),
Phe (1,06), 5et (0,97) Example 22 Cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-
Preparation of arginyl cyclic disulfide: N-a-t-Boc-Arg(NGTos)
-C)? Amino acids were added to the bifield resin in the following order: Boc -Phes Boc -Cys (4-MeBz
l), Boc-I le, Boc-Arg (NGTo
s), Boc-Asp (β-cyclohexyl), Boa
-I Ies Boc-Arg(NGTos), Bo
c-Gly, Boc-GlySBoc-Phe.

0.49 g of the protected peptide resin obtained by bonding with Boa-Cys (4-MeBzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 59 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:l 441 amino acid analysis: Arg (3,09), Asp (1-00), Cys (
1,7), Gly (2,0), I 1e (1,98),
Phe(1,85) Example 23 Preparation of cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-inleucyl-asbarthyl-arginyl-isoleucycysteinyl-asparaginyl-seryl cyclic disulfide : N-a-t-Boa-Arg(NGTos)-0 manifold resin with amino acids in the following order: Boc-PheSBoc-5er(Bzl), Bo
a-ASns Boc-Cys(4-MeB zl)
, Boc-11elIBoc-Arg(NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
Ile%Boc-Arg(NGTos), Boa-G
lysBoc-G17% Boc-Phe, Boa-
0.5g of protected peptide resin obtained by bonding with Cys(4-MeBzl),
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 24yxy is obtained as a white powder.

FAB"(M+H)"M/Z:l 641 amino acid analysis: Arg (2-95), Asx (2,00), Cys (
1,9), cly(2,00), l1e(1,8), P
he(1,9), 5er(0,8) Example 24 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-inleucylcysteinyl-asparaginyl-seryl Preparation of phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg(NGTos) -〇?
-1-Field resin with amino acids in the following order: Boc-Phe, Boc-5er (Bzl), B
oc-Asn, Boc-Cys(4-MeB zl
), Boa-I le, Boc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boa
-11e, Boa-Arg (NGTos), Boc
-G I X5 Boc-Gly, Boc-Pheb
Boa-Cys (4-MeBzl), Boa-5e
Example 2
It is subjected to HF (liquid) treatment and purification using the same count. 10 m5 of the title compound are obtained as a white powder.

In FAB (M+1()”M/Z: l 8 1 7
Amino acid analysis: Asx (2,00), Arg (3,10
), 5et(2-5), Gly(2,00), Cys(
1-6), 1ie (1,85), Phe (1,75) Example 25 Seryl-Seryl-Penicillamini-Phenylalanyl-Glycyl-Glycyl-Arginyl-Inleucyl-Asbarthyl-Arginyl-Isoleucilyl Steinil
Preparation of phenylalanyl-arginyl cyclic disulfide: N-a-t-Boa-Arg(NGTos)-Q Manifold resin with amino acids in the following order: Boa-Phex Boc-Cys(4-MeBz
l), Boc-11e, Boc-Arg (NGTos
), Boa-Asp (β-cyclohexyl), Boa
-11e, Boc-Arg (NGT os), Boc
-Gly%Boc-Glys Boc-Phe.

Boc-Pen (4-MeBzl), Boc-5er
(Bzl), Boc-5er (Bzl), and 0.5 g of protected begtide resin obtained by combining
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 26 was obtained as a white powder.

FAB”(M+H)”M/Z:l 643 amino acid analysis: Asp (1,00), 5er (1,7), Gly (2
,00), Cys(0,9), Pen(0-5), It
o(1.

95), Phe (0,85), Arg (2,95) Example 26 Seryl-cerylcysteinyl-enylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucil-penicilla miniroof Preparation of enylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg(NGTos)-0 manifold resin with amino acids in the following order: Boc-Phe, Boc-Pen(4-MeBz
l), Boc-11e, Boc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boc-
11e, Boc-Arg(NGTos), Boc-
Gly%Boc-GlySBoc-Phe.

Boa-Cys (4-MeBzl), Boa-5er
(Bzl) and Boc-5et (Bzl).
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2.

Example 27 Preparation of seryl-seryl-cysteinyl-β-naphthylalanyl-glycyl-glycyl-arginyl-isoleucyl-aspartyl-arginyl-isoleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a -t-Boa-Arg (NGTos) -o
Amino acids were added to Mafield resin in the following order: Boc-Phe, Boc-Cys (4-MeBzl)
, Boc-11eSBoc-Arg (NGTos), B
oc-Asp (β-cyclohexyl), Boa-I
le, Boc-Arg(NGT os), Boc-G
ly, Boc-GlySBoc-β-Na1, Bo
c-Cys(4-MeB zl), Boc-5er
(Bzl) and Boa-5er (Bzl).
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 10 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:l 664 amino acid analysis: Asp(0,9), 5et(1-6), Gly(1
,9), Cys(1,3), l1e(1,7), Phe
(1,0), Arg(2,9) Example 28 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-glycyl-isoleucil-asbarthyl-arginyl-inleucylcysteinyl-phenylalanyl-arginyl cyclic Preparation of disulfides: N-a-t-Boc-Arg(NGTos)-0v Nifield resin with amino acids in the following order: Boc-Phe, Boc-Cys(4-MeBz
l), Boc-11e, Boa-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boc
-11e, Boc-GlylBoc-Gly, Bo
c-Gly, Boc-Phe, Boc-Cys (4
-MeBzl), Boc -5er(Bzl), Boc
0.5 g of the protected peptide resin obtained by binding with -5er (Bzl),
Subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 17 is obtained as a white powder.

FAB”(M+H)”M/Z: l 516 amino acid analysis: Asp(1,0), 5er(1,4), Gly(2
,9), Cys(1,4), 1ie(1,9), Phe
(1-9), Arg (1-9) Example 29 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide Preparation: N-a-L-Boc-Arg(NGTos)-
0? Amino acids were added to Nifield resin in the following order: Boc -Phe, Boc -Cys (4-MeBz
l), Boc-I lelBoc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boc
-11e%Boc-Gly%B.

c-Gly, Boc-Phe, Boa-Cys (4
-MeBzl), Boc -5er(Bzl), 13o
The protected peptide resin 0.59 obtained by binding with c-5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 27rrIg is obtained as a white powder.

FAB”(M+H)”M/Z:1458 Amino acid analysis:
Asp(1,0), 5et(1,5), Gly(2,
1), Cys(1,5), l1e(2,0), Phe(
2,1), Arg(2,0) Example 30 Seryl-seryl-cysteinyl-(D) Phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-inleucylcysteinyl-phenylalanyl- Preparation of arginyl cyclic disulfide: Add amino acids to Na-Ni-Boa-Arg (NGTos)-0v Nifield resin in the following order: Boc-Phes Boc-Cys (4-MaBzl)
, Boc-I Ie, Boa-Arg (NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
r Ie, Boc-Arg(NGTos), Boc-
Gly, Boa-Glys Boc-(D)Phe,
Boa-Cys (4-MeBzl), Boc-5e
1.00 g of the protected peptide resin obtained by combining r(Bzl) and Boc-5er(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 36.0+ g of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:1615 Amino acid analysis:
Arg (3,0), Asp (0,9), Cys (1,8
), 1ie (2-0), Phe (2,0), 5er (1
, 4), Gly(2,1) whose 300 MHz NMR is consistent with the structure.

Example 31 Preparation of threonyl-threonyl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-leucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a -t-Boc- Arg(NGTos)-0 manifold resin was loaded with amino acids in the following order: Boa -Phe, Boc -Cys (4-MsBz
l), Boc-11eSBoa-Arg (NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
I 1eSBoc-Arg(NGTos), Boc
-Gly, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-Thr
(Bzl), Boc-Thr (Bzl) The protected peptide resin 0.809 obtained by bonding with Boc-Thr (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 7.01119 is obtained as a white powder.

FAB"(M+H)"M/Z:l 643 amino acid analysis: Arg (3,0), Asp (1,0), Cys (1,
8), l1e(2,O), Phe(2,1), Gly(
2,1), Thr(1,7) Its 300MHz NMR is consistent with the structure.

Example 32 Seryl-seryl-cysteinyl-phenylalanyl-glycyl-(D)alanyl-arginyl-isoleucyl-
Preparation of aspartyl-arginyl-isoleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg(NGTos)-0 manifold resin with amino acids in the following order: Boc-Pha, Boc-Cys( 4-MeBzl)
, Boc-Ile, Boc-Arg(NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
Ile, Boa-Arg(NGTos), Boc-
(D)Ala, Boc-Gly, Boc-Ph
e, Boa-Cys (4-MeBzl), Boc
-5er (Bzl) and Boc -5er (Bzl) 0.80 g of the protected peptide resin obtained by binding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 0 mg of the title compound 9 is obtained as a white powder.

FAB”(M+H)”M/Z:1629 Amino acid analysis:
Arg(2,8), Asp(1,2), Cys(0,0
), ll5(1,9), Phe(2,0), 5et(2
, 2), Gly(1,1), Ala(1,0) Its 300MHz NMR is consistent with the structure.

Example 33 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-ornithine-isoleucilyl-asbarthyl-arginyl-isoleucycysteinyl-
Preparation of phenylalanyl-arginyl cyclic disulfide: N-a-t-Boa-Arg(NGTos)-Q manifold resin with amino acids in the following order: Boc-Phe, Boc-Cys (4-MeBzl)
, Boc-Ile, Boc-Arg(NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
11e1Boc-ornithinel (p-Tos), Boc
-GlylBoc-Gly, Boa-Phe, Bo
c-Cys(4-MeBzl), Boc-Ser(B
zl), Boa-5er (Bzl), and subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 24.211 g of the title compound are obtained as a white powder.

Amino acid analysis: Arg (1,8), Asp (1,0),
Cys(1,7), ll5(1,9), Phe(2,0
), 5et(1,6), Gly(2,1) Its 300MHz NMR is consistent with the structure.

Example 34 Preparation of seryl-cerylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-inleucyl-asbarthyl-arginyl-isoleucycysteinyl-glycyl-arginyl cyclic disulfide: N-a-t-Boc-Arg (NGTos)
-0 manifold resin in the following order of amino acids: Boc-Gly, Boc-Cys (4-MeBzl)
, Boc-11e, Boa-Arg (NGTos),
Boa-Asp (β-cyclohexyl), Boc-I
la, Boc-Arg (NGTos), Boc-G
ly, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-
The protected peptide resin 0.809 obtained by binding Boc-5er (Bzl) and Boc-5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 9+719 is obtained as a white powder.

FAB"CM+H)"M/Z:1523 Amino acid analysis:
Arg(3,1), Asp(1,1), Cys(1,7
), l1e(2,0), Phe(1,1), 5et(1
, 8), cty(3,3) Example 35 Seryl-serylcysteiny-phenylalanyl-glycyl-glycyl-arginyl-in-leucyl-asbarty-arginyl-isoleucycysteiny-phenylalanyl-ridinyl cyclic disulfide Preparation: Boc-Lys(Cff-Z) v Nifield resin with amino acids in the following order: Boc-Pha, Boc-Cys(4-MeBzl)
, Boc-11e, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boc-1
1e, Boc-Arg (NGT os), Boc-G
ly% Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzri, Boc-5er
(Bzl), Boa-5ar(Bzl) 0.75 g of the protected peptide resin obtained by bonding with Boa-5ar(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 21.0 mg of the title compound is obtained as a white powder.

FAB”(M+H)”M/Z:1587 Amino acid analysis:
Arg (2,0), Asp (1,0), Cys (1,8
), 1ie(1,9), Phe(2,0), 5et(1
, 7), Gly(2,0), Lys(1,0) whose 300MHz NMR is consistent with the structure.

Example 36 Seryl-seryl-cysteinyl-phenylalanyl-β
-Alanyl-Arginyl-Isoleucyl-Aspartyl-Arginyl-Isoleucyl-Cysteinyl-Phenylalanyl-Arginyl Cyclic Disulfide Preparation: N-a-t-Boc-Arg(NGTos)-Qv=
Amino acids were added to the field resin in the following order: Boc-Phe, Boc-Cys (4-MeBz
l), Boc-I 1aSBoc-Arg(N GT
os), Boa-Asp (β-cyclohexyl), Bo
a-Ile, Boc-Arg(NGTos)
, Boc-β-Ala1Boc-PhaIIBoc
-Cys(4-MeB zl), Boc-5er(B
zl), Boc-5er (Bzl), was subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 18.0 mg of the title compound is obtained as a white powder.

FAB"CM+H)"M/Z:l 572 amino acid analysis: Arg (3,0), Asp (1,0), Cys (1,
9), l1e(2,0), Phe(2,1), 5er(
1,8) Its 300 MHz NMR is consistent with the structure.

Example 37 Preparation of cyclic disulfide: Seryl-ceryl-cysteinyl-enylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-leucyl-cysteinyl-enylalanyl-arginyl-tyrodinyl cyclic disulfide: Boa7 Tyr(B r -Z)' Amino acids were added to the two-field resin in the following order: Boc-Arg(NGTos), Boc-Phe,
Boc-Cys (4-MeB zl), Boc-1
les Boa-Arg(NGTas), Boc-As
p(β-cyclohexyl), Boc-11e, Boc
-Arg(NGTos), Boc-Gly, Boc-
Glys Boc-Phe, Boc-Cys(4-M
eBzl), Boc-5er(Bzl), Boc-
5er (Bzl) was combined with HF (liquid) in the same manner as in Example 2.
Subject to processing and purification. 32.3 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:1778 Amino acid analysis:
Arg(3,1), Asp(1,1), Cys(1,9
), Gly(2-1), l1e(2,0), Phe(2
,0), 5et(1,8), Thr(0-9) Its 300MHz NMR is consistent with the structure.

Example 38 Seryl-seryl-cysteinyl-cyclohexylalanyl-glycyl-glycyl-arginyl-inleucyl-
Preparation of aspartyl-arginyl-ynleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-at-Boc-Arg(NGTos)-Manifield resin with amino acids in the following order: Boc-Phe, Boc-Cys(4 -MeBz
l), Boc-11e, Boc-Arg(N GT
os), Boc-Asp (β-cyclohexyl), Bo
c-Ile, Boc-Arg(NGTos), B
oc-GlylBoc-Gly, Boa-Cha.

Boc-Cys(4-MeBzl), Boa-
5er (Bzl) and Boa-5et (Bzl), and subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 15.8 mg of the title compound are obtained as a white powder.

FAB"(M+H)"M/Z:l 620 amino acid analysis: Arg (2,8), Asp (1-0), Cys (1,
8), Gly(1,9), l1e(2,0), Phe
(1,0), 5er(1,6) Its 300MHz NMR is consistent with the structure.

Example 39 Preparation of Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-phenylalanylcysteinyl-7enylalanyl-arginyl cyclic disulfide: N -a -t-Boc -Arg(NGTos)-Manifield resin with amino acids in the following order: Boc-Pha, Boc-Cys(4-MeBz
l), Boc-Phe, Boc-Arg(N GT
os), Boc-Asp (β-cyclohexyl), Bo
c-11e, Boc-Arg (NGTos), Bo
c-Gly, Boc-Gly, Boa-Phe
.

Boc-Cys(4-MeBzl), Boa-
5er (Bzl) and Boc -5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 30.5119 is obtained as a white powder.

FAB"(M+H)"M/Z:l 649 amino acid analysis: Arg (3,0), Asp (1-0), Cys (1,
7), Gly(2,1), l1e(1,0), Phe(
2,9), 5et(1,8) whose 300MHz NMR is consistent with the structure.

Example 40 Preparation of seryl-seryl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucyl-asbarthyl-CD)-arginyl-isoleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc -Arg(NGTos)
- Amino acids were added to the manifold resin in the following order: Boc-P, he, Boc-Cys(4-
MeB zl), Boc-11eSBoc-Arg(N
GTos), Boc-Asp (β-cyclohexyl)
, Boc-11eSBoc-(D)-Arg(N
GTos), Boc-Gly% Boc-Cyly% B
oc-Ph6. BOC-CYS (4-MeBzl),
Boc-5er (Bzl), Boa-5er (Bz
1) 0.45 g of the protected peptide resin obtained by bonding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 28+19 is obtained as a white powder.

FAB”(M+H)”M/Z:l 615 amino acid analysis: Arg (3-1), Asp (1,0), Cys (1,
6), Gly(2,2), 1ie(1,9), Phe(
1,8), 5er(1,5) Its 300MHz NMR is consistent with the structure.

Example 41 Preparation of seryl-seryl-cysteinyl-phenylalanyl-glycyl-glycyl-(D)-arginyl-inleucyl-aspartyl-arginyl-inleucyl-cysteinyl-7enylalanyl-arginyl cyclic disulfide: N-a-t- Boc-Arg(NG Tos
)-manifold resin in the following order: Boc-Phe, Boc-Cys(4-MeBz
l), Boc-I le, Boc-(D)-Arg(
NGTos), Boc-Asp (β-cyclohexyl)
, Boc-Ile, Boc-Arg(NGTos
), Boc-Gly, Boc-Gly, Boc-P
he, Boa-Cys(4-MeBzl), Boc
-5er (Bzl) and Boc -5er (Bzl) 0.45 g of the protected peptide resin obtained by binding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 2519 is obtained as a white powder.

FAB”(M+H)”M/Z:l 615 amino acid analysis: Arg (2-8), Asp (1,0), Cys (1,
5), Gly(2,1), l1e(1,9), Phe(
1,9), 5er(1,5) Its 300MHz NMR is consistent with the structure.

Example 42 Preparation of cyclic disulfide: Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-in-leucyl-asbarthyl-arginyl-isoleucycysteiny-cyclohexylalanyl-arginyl cyclic disulfide: N -a -t-Boc- Arg(NGTos)-Manifield resin with amino acids in the following order: Boc-Cha, Boc-Cys (4-MeBzl)
, Boc-11e, Boa-Arg (NGTos),
Boc-Asp (β-cyclohexyl), Boc-I
le, Boc-Arg(NGTos), Boa-G
ly, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-
5er (Bzl) and Boc -5er (Bzl) was subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 401119 is obtained as a white powder.

FAB"(M+H)"M/Z:l 621 amino acid analysis: Arg (2,9), Asp (1,0), Cys (1,
6), Gly(1,9), l1e(1,9), Phe(
1,0), 5er(1-5) Its 300MHz NMR is consistent with the structure.

Example 43 Preparation of D-arginylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-inleucyl-asbarthyl-arginyl-inleucylcysteinyl-phenylalanyl-arginyl cyclic disulfide: N -at- BoC-Arg(NGTos)-Ma=Field resin with amino acids in the following order: Boa-Phe, Boa-Cys (4-MeBzl)
, Boc-11e, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boc-1
1e, Boc-Arg (NGTos), Boc-Gl
ys 130cmGly, Boc-PhelBoc
-Cys(4-MeBzl), Boc-(D) -Ar
0.45 g of the protected peptide resin obtained by bonding with g(NGT os) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 8I+Ig is obtained as a white powder.

FAB”(M+H)”M/Z:1597 Amino acid analysis:
Arg (3,9), Asp (1-0), Cys (2,0
), Gly(2,4), l1e(2-0), Phe(
2-0) Its 300MHz NMR is consistent with the structure.

Example 44 Arginylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-inleucyl-asbarthyl-arginyl-arginylcysteinyl-phenylalanyl-arginyl Preparation of cyclic disulfide: N-a-t-Boc-Arg (NGTos)-? :
Add amino acids to field resin in the following order: Boa-Phe, Boa-Cys (4-MeBzl)
, Boc-118% BOC-Arg(NGTos)
, Boa-Asp (β-cyclohexyl), Boc-
Ile, Boc-Arg(NGTos), Boc-
Gly, Boa-Gly, Boc-Phe.

Boc-Cys(4-MaBzl), Boa-Arg
0.45 g of the protected peptide resin obtained by bonding with (NGTos) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 391119 is obtained as a white powder.

FAB"CM+H)"M/Z:l 597 amino acid analysis: Arg (3-9), Asp (1,0), Cys (1,
8), Gly(2,0), l1e(1,9), Phe(
1,9) Its 300 MHz NMR is consistent with the structure.

Example 45 Preparation of seryl-seryl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-cyclohexylalanyl-aspartyl-arginyl-isoleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg (NGTos
)−? ,:Field resin with amino acids in the following order: Boc-Phe, Boc-Cys (4-MeBzl)
, Boc-11e, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boc-Ch
a, Boc-Arg (NGTos), Boc-Gly
lBoa-Gly, Boa-Phe.

Boc-Cys(4-Me13zl), Boc
-5er (Bzl) and Boc -5er (Bzl) 0.45 g of the protected peptide resin obtained by binding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 25rRg is obtained as a white powder.

FAB”(M+H)”M/Z:1655 Amino acid analysis:
Arg (3,0), Asp (1-0), Cys (1,6
), Gly(2,0), 1ie(0,9), Phe(1
, 8), 5er(1,5) whose 300 MHz NMR is consistent with the structure.

Example 46 Arginyl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucyl-glycyl-
Preparation of glycyl-inleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boa-Arg (NGTos) - Amino acids were added to Manifield resin in the following order: Boc-Phe, Boc-Cys (4-MeBzl) )
, Boc-I le, Boc-Gly, Boc-G
ly, Boc-11e, Boc-Arg(NGT
os), Boc-Gly, Boc-Gly.

Boc-Ph5SBoa-Cys(4-MeBzl
), Boc-Arg (NGTos) 0.45 g of the protected peptide resin obtained by bonding with Boc-Arg (NGTos) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 5211 g of the title compound are obtained as a white powder.

FAB”(M+H)1M/Z:1439 Amino acid analysis:
Arg(3,0), Cys(1,8), Gly(4,
1), l1e(2,0), Phe(2,0) Part 30
0MHz NMR is consistent with the structure.

Example 47 Preparation of arginylcysteinyl-enylalanyl-glycyl-glycyl-arginyl-leucyl-asbarthyl-arginyl-isoleucycysteinyl-cyclohexylalanyl-arginyl cyclic disulfide: N -a -t -Boc -Arg (NGTos)
- Add amino acids to manifold resin in the following order: Boc-Cha, Boc-Cys (4-MeBzl)
, Boc-11eSBoa-Arg(NGTos)
, Boc-Asp (β-cyclohexyl), Boc-
Ile, Boc-Arg(NGTos), Bo
c-Gly, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-
0.69 g of the protected peptide resin obtained by bonding with Arg(NGTos) was mixed with HF(NGTos) in the same manner as in Example 2.
(liquid) processing and purification. 15 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:l 602 amino acid analysis: Arg(4,0), Asp(1,1), Cys(1,
9), Gly(2,2), ll5(1,8), Phe(
1,1) Its 300 MHz'H NMR is consistent with the structure.

Example 48 Preparation of arginyl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-inleucylcysteinyl-arginyl cyclic disulfide: N-a-t-Boc-Arg (N GTos)
−? ,: Amino acids were added to the field resin in the following order: B oc -Cys (4-MeB zl), Boa -
Ile%Boc-Arg(NGTos), Bo
c-Asp (β-cyclohexyl), Boa-I l
e, Boc-Arg (NGTos), Boc-Gly
s Boc-Glys f30cmPhe%Boc
-Cys(4-MeBzl), Boc-Arg(N
0.40 g of the protected peptide resin obtained by bonding with G Tos) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 1619 is obtained as a white powder.

FAB”(M+H)”M/Z:l 449 amino acid analysis: Arg (4,0), Asp (0,9), Cys (1,
7), Gly(2,0), 1ie(2,Q), Phe(
1,0) Its 300 MHz'H NMR is consistent with the structure.

Example 49 Preparation of seryl-seryl-cysteinyl-D-alanyl-glycyl-glycyl-arginyl-inleucyl-aspartyl-arginyl-isoleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a, -t-Boc-Arg( NGTos)-? :
Amino acids were added to the field resin in the following order: Boc-Phe, Boc-Cys (4-MeBzl
), Boc-11e, Boc-Arg (NGTos)
, Boc-Asp (β-cyclohexyl), Boa-
Ile, Boc-Arg(NGTos), Bo
c-Gly, Boa-Gly, Boa-D-A
la, Boc-Cys(4-MeBzl), Bo
0.40 g of the protected peptide resin obtained by combining a-5er (Bzl) and Boc-5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 24m9 is obtained as a white powder.

FAB”(M+H)”M/Z:1538 Amino acid analysis:
Ala(1,0), Arg(3,0), Asp(1,1
), Cys(1,7), Gly(1,9), Its(2
,0), Phe(10), 5et(1,6) Its 300MHz'HNMR is consistent with the structure.

Example 50 Preparation of arginyl-cysteinyl-phenylalanyl-glycy, ruglycyl-arginyl-isoleucyl-aspartyl-arginyl-inleucyl-cysteinyl-cyclic disulfide: N-a-t-Boa-Cys (4
-MeBzl)-Manifield resin in the following order: Boa-11e, Boc-Arg (NGTos),
Boc-Asp (β-cyclohexyl), Boc-I
le%Boc-Arg(NGTos), Boc-Gl
y, Boc-Glys Boc-Phe, B'oc
-Cys(4-MeBzl), Boc-Asp(N
0.39 g of the protected peptide resin obtained by bonding with GTos) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 31IIIg is obtained as a white powder.

FAB”(M+H)”M/Z:1293 Amino acid analysis:
Arg (3,0), Asp (1,1), Cys (1,7
), Gly(2,1), l1e(2,0), Phe(1
-0) Its 300MHz'HNMR is consistent with the structure.

Example 51 Preparation of 7-amizheptanoyl-cysteinyl-enylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl-enylalanyl-arginyl cyclic disulfide: N-a-4 -Boc-Arg(NGTosl) - Amino acids on manifold resin in the following order: Boc-Phe, Boa-Cys (4-MeBzl)
, Boc-Ile, Boa-Arg(NGTo
s), Boa-Asp (β-cyclohexyl), Boc
-11e, Boa-Arg (NGTos), Boc
-Gly, Boc-Glys Boa-Phe.

B oc -Cys (4-MeB zl), B oc
-A Protected peptide resin 0.459 obtained by binding with hepa was treated in the same manner as in Example 2 to HF (liquid)!
Subjected to processing and purification. The title compound 1619 is obtained as a white powder.

FAB+(M1H)+M/Z:1567 Amino acid analysis:
Arg(3,0), Asp(1,1), Cys(1,2
), Gly(2,4), l1e(1,5), Phe(2
, 0) whose 300 MHz'H NMR is consistent with the structure.

Example 52 Preparation of 8-aminooctanoyl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-ynleucyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a -t- Boc-Arg(NGTosl)-0
- Add amino acids to the resin in the following order: Boc -Phe, Boa -Cys (4-MeBz
l), Boc-11e, Boc-Arg (NGTos
), Boa-Asp (β-cyclohexyl), Boc
-Ile, Boc-Arg(NGTos), B
oa-Gly, Boc-Gly, Boc-Pha.

Boc-Cys(4-MeBzl), Boc-Aoa
0.50 g of the protected peptide resin obtained by bonding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 20+19 is obtained as a white powder.

F A B”(M+H)”M/Z: l 583 amino acid analysis: Arg (3-2), Asp (1,0), C
ys(1,8), Gly(2,1), l1e(1,9)
, Phe(1,9) whose 300 MHz'H NMR is consistent with the structure.

Example 53 Preparation of 5-aminopentanoyl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-ynleucyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t- Boc-Arg (NGTosl) -○- Amino acids on resin in the following order: Boc-Phe, Boa-Cys (4-MeBzl)
, Boc-11e, Boc-Arg(NG To
s), Boc-Asp (β-cyclohexyl), Boc
-11eSBoa-Arg(NGTos), Boa-
Gly, Boc-Gly, Boc-Phe.

Boa-Cys(4-MaBzl), Boc-Apa
0.50 g of the protected peptide resin obtained by bonding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 10 mg of the title compound are obtained as a white powder.

FAB”(M+H)”M/Z:l 539 amino acid analysis: Arg(3,2), Asp(1-0), Cys(1,
8), Gly(2,1), ll5(1-9), Phe(
1,9) Its 300 MHz'H NMR is consistent with the structure.

Example 54 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl-prolyl-arginyl Preparation of cyclic disulfide: N -tr -t -Boa -Arg (NGTos
l) -0-Resin with amino acids in the following order: Boa -Pros Boc -Cys (4-MaBz
l), Boc-I Is%Boa-Arg (NGTos
), Boa-Asp (β-cyclohexyl), BoC-
Ile, Boc-Arg(NGTos), BoC-
Gly, Boc-Gly, Boa-Phe.

Boa-Cys(4-MeBzl), Boc-5e
t(Bzl), Boc-5er(Bzl) 0.50 g of the protected peptide resin obtained by bonding is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 1019 is obtained as a white powder.

FAB”(M+H)”M/Z:l 565 amino acid analysis: Arg(2,2), Asp(1,0), Cys(1,
8), Gly(2,1), l1e(1,9), Phe(
0-9), S er (1, 4), Pro (0, 9) whose 300 MHz"H NMR is consistent with the structure.

Example 55 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-isoleucycysteinyl-seryl-phenylalanyl-arginyl Preparation of cyclic disulfide: N -a -t- Boc-Arg(NGTos)-0-
Add amino acids to the resin in the following order: Boc-Phe, Boc-5er (Bzl), B
oc-Cys(4-MeBzl), Boc-11e,
Boa-Arg (NGTos), Boc-Asp (β
-cyclohexyl), Boc-11e.

Boc-Arg(NGTos), Boc-GlySBo
c-Gly.

Boc-Phe, Boc-Cys(4-MeBzl)
, Boc-Set (Bzl), Boc-5er (Bz
Protected peptide resin obtained by binding in l) 0.50
g is subjected to HF (liquid) treatment and purification as in Example 2. The title compound IOIIIg is obtained as a white powder.

FAB”(M+H)”M/Z:1703 Amino acid analysis:
Arg(3,2), Asp(1,0), Cys(1,8
), Gly(2,2), l1e(2,0), Phe(
0,9), 5er(2,4) Its 300MHz'HNMR is consistent with the structure.

Example 56 Seryl-seryl-cysteinyl-7 enylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-inleucylcysteinyl-8
-Preparation of aminooctanoyl-arginyl cyclic disulfide: N-a-t-Boc-Arg (NGTos) -○- Amino acids were added to the resin in the following order: Boa-Aoa, Boc-Cys (4-MeBzl)
, Boc-I le, Boc-A rg(NG
Tos), Boc-Asp (β-cyclohexyl),
Boc-I 1e, Boa-Arg (NGTos)
, Boc-GlylBoc-Glys Boc-Phe
.

Boc-Cys(4-MeBzl), Boc=5e
The protected peptide resin 0.509 obtained by coupling with r(Bzl), Boa-5er(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in run f12. 10+*g of the title compound are obtained as a white powder.

FAB"(M1H)"M/Z:l 609 amino acid analysis: Arg (3,2), Asp (1,0), Cys (1,
8), G Iy (2-2), l1e (2,0), Phe
(0,9), 5er(1,4) Its 300 MHz"H NMR is consistent with the structure.

Example 57 Preparation of seryl-serylcysteinyl-enylalanyl-glycyl-glycyl-arginyl-leucyl-asbarthyl-arginyl-leucylcysteinyl-tetrahydroisoquinol-3-yl-arginyl cyclic disulfide: N-a-t -Boc-Arg(NGT
os)-0-resin in the following order: Boc-Tic%Boc-Cys(4-MeBzl),
Boc-11e, Boc-Arg (NGTos), B
oc-Asp (β-cyclohexyl), Boc-I
le, Boc-Arg(NGTos), Boa-Gl
y, Boc-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boa-5e
0.50 g of the protected peptide resin obtained by combining r(Bzl) and Boc-5er(Bzf) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 1101A is obtained as a white powder.

Amino acid analysis: Arg (2,2), Asp (1-0),
Cys(1,8), Gly(2,2), l1e(1,9
), Phe(0,9), S, ar(1,4) Its 300MHz'HNMR is consistent with the structure.

Example 58 Preparation of seryl-seryl-cysteinyl-tetrahydroisoquino-3-yl-glycyl-glycyl-arginyl-isoleucyl-aspartyl-arginyl-inleucyl-cysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc -Arg(NGTo
s) -0-@fat and amino acids in the following order: Boc -Phes Boc -Cys (4-MeBz
l), Boc-I 1eSBoc-Arg(N GT
os), Boc-Asp (β-cyclohexyl), Bo
c-11e, BoC-Arg(NGTos), Bo
c-Glys Boc-Gtys Boc-Tic.

Boc-Cys (4-MeBzl), Boc-5er
(Bzl), Boc-5er (Bzl), and subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 10119 is obtained as a white powder.

FAB”(M+H)1M/Z:1626 Amino acid analysis:
Arg(3,2), Asp(1,0), Cys(1,8
), Gly(2,2), 1ie(1-9), Phe(0
, 9), 5ar(1,4) Its 300MHz'HNMR is consistent with the structure.

Example 59 Seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucilyl-asvarthyl-ornithine-ylisoleucilcysteinyl-
Preparation of phenylalanyl-arginyl ring east disulfide: N-a-t-Boc-Arg(NGTos)-○-Resin with amino acids in the following order: Boa-Phe, Boc-Cys(4-MeBz
l), Boc-I le, Boc-Orn(N-To
s), BOC-ASI) (β-cyclohexyl), Bo
c-11e, Boc-Arg (NGTos), Bo
c-Gly, Boa-GlySBoc-Phe.

Boc-Cys (4-MeBzl), Boc-5er
(Bzl), Boc-5er (Bzl), and subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 1011 g of the title compound are obtained as a white powder.

FAB”(M+H)1M/Z:1572 Amino acid analysis:
Arg (2-2), Asp (1,0), Cys (1,8
), Gly(2,2), l1e(1,9), Phe(1
, 9), 5er(1-4) Its 300 MHz'H NMR is consistent with the structure.

Example 60 Preparation of seryl-seryl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-leucyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc- Amino acids were added to Arg(NGTos)-0-resin in the following order: Boc-Phe, Boc-Cys(4-MeBz
l), Boc-11e, Boc-Arg(N GT
os), Boc-Asp (β-cyclohexyl), Bo
c-Lau, Boc-Arg (NGTos), Boc
-Gly, Boc-Gly, Boa-Phe.

Boc-Cys(4-M51BZI), Boa-5
er(Bzl) and Boc-5et(Bzl) are subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 1011 g of the title compound are obtained as a white powder.

FAB"CM+H)"M/Z:1615 Amino acid analysis:
Arg(3,2), Asp(1,0), Cys(1,8
), Gly(2,2), ll5(1,1), Leu(1
, 0), Phe(1,8), 5et(1,4) Its 300MHz"H NMR is consistent with the structure.

Example 61 Preparation of seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-propargylglycyl-asbarthyl-arginyl-isoleucycysteinyl-phenylalanyl-arginyl cyclic disulfide: N -a -t-Boc- Arg(NGTos) -〇 -Amino acids were added to the resin in the following order: Boc -Phex Boa -Cys(4-MeBz
l), Boc-11e, Boc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boc-
PrGlylBoc-Arg (NGTos), Boc-
Gly, Boa-Gly, Boc-Phe.

Boc-Cys(4-MeBzl), Boc-5e
0.50 g of the protected peptide resin obtained by bonding with r(Bzl) and Boa-5er(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 110TR is obtained as a white powder.

FAB”(M+H)”M/Z:1596 Amino acid analysis:
Arg(3,2), Asp(1,0), Cys(1,8
), Gly(2,2), 1ie(1,1), Phe(0
, 9), 5er(1,4) Its 300MHz'HNMR is consistent with the structure.

Example 62 Preparation of seryl-cerylcysteinyl-phenylalanyl-methaminomethylbenzoyl-arginyl-isoleucyl-asbarthyl-arginyl-leucylcysteinyl-phenylalanyl-arginyl cyclic disulfide: N-a-t- Boa-Arg(NGTos
)-0-resin in the following order: Boc-PheIIBoc-Cys(4-MeBz
l), Boc-11e, Boc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boa
-I Is, Boc-Arg(NGT as), Bo
c-mAMBA, Boc-Phe, Boc-Cys
(4-MeBzl), Boa-5ar(Bzl), B
The protected peptide resin 0.509 obtained by binding with oc-3er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. 10 u of the title compound is obtained as a white powder.

FAB”(M+H)”M/Z:l 634 amino acid analysis: Arg (2-2), Asp (1,0), Cys (1,
8), l1e(1,9), Phe(1-9), 5er(
1,4) Its 300 MHz'H NMR is consistent with the structure.

Example 63 Preparation of seryl-serylcysteinyl-phenylalanyl-glycyl-glycyl-arginyl-isoleucil-asbarthyl-arginyl-inleucylcysteiny-asparaginyl-ceryl-phenylalanyl cyclic disulfide: N-a-t -Boc-Phs-
0-Resin with amino acids in the following order: Boc-5er (Bzl), Boc-Asn, Boc
-Cys(4-MeBzl), Boa-11a, B
oc-Arg (NGTos), Boc-Asp (β-cyclohexyl), Boc-IIs.

Boc-A rg(NG Tos), Boa-G
ly, Boc-GlysBoc-Phe, Boc
-Cys(4-MeBzl), Boc-5er(Bz
1), 0.50 g of the protected peptide resin obtained by binding with Boc-5er (Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. Title compound 1
0m+9 is obtained as a white powder.

FAB”(M+H)”M/Z:l 660 amino acid analysis: Arg(2,1), Asp(1,8), Cys(1,
8), Gly(2,2), l1e(2,0), Phe(
1,9), 5et(2,4) Its 300MHz'HNMR is consistent with the structure.

Example 64 Preparation of seryl-seryl-cysteinyl-phenylalanyl-glycyl-glycyl-arginyl-in-leucyl-asbarthyl-arginyl-isoleucyl-cysteiny-asparaginyl-seryl cyclic disulfide: N-a-t-Boc-3er Amino acids were added to (Bzl)-0-resin in the following order: Boc-Asn%Boc-Cys(4-MeBzl),
Boc-Ile, Boc-Arg(NGTos),
Boc-Asp (β-cyclohexyl), Boc-1
1e, Boc-Arg (NGTos), Boc-Gl
y, Boc-GlyXBoc-Phe.

Boc-Cys(4-MeBzl), Boc-5e
0.50 g of the protected peptide resin obtained by bonding with r(Bzl) and Boa-5et(Bzl) is subjected to HF (liquid) treatment and purification in the same manner as in Example 2. The title compound 27 is obtained as a white powder.

FAB”(M+H)”M/Z:1513 Amino acid analysis:
Arg(2,1), Asp(1,8), Cys(1,8
), Gly(2-2), l1e(2,0), Phe(0
, 9), 5er(2,4) Its 300MHz'HNMR is consistent with the structure.

Example 65 Seryl-seryl-cysteinyl-phenylalanyl-6
-Amitsukabroyl-Arginyl-Isoleucyl-Aspartyl-Arginyl-Isoleucyl-Cysteinyl-
Preparation of phenylalanyl-arginyl cyclic disulfide: N-a-t-Boc-Arg(NGTos)-0-
Add amino acids to the resin in the following order: Boa-Phe, Boa-Cys (4-MeBzl
), Boc-I le, Boc-Arg (NGTos
), Boc-Asp (β-cyclohexyl), Boc
-11e, Boc-Arg (NGTos), Boc-
AcaSBoa-Phe, Boc-Cys(4-Me
Bzl), Boc-5er (Bzl), Boa-3e
r (protected peptide resin obtained by binding at Bz0.
50 g are subjected to HF (liquid) treatment and purification as in Example 2. 10 mg of the title compound are obtained as a white powder.

FAB"(M+H)"M/Z:l 614 amino acid analysis: Arg (3-1), ASI) (1-0), Cys (1
,8), l1e(2,0), Phe(1,9), 5er
(1,4) Its 300 MHz'H NMR is consistent with the structure.

Example 66 Vasodilation Effect New Zealand female white rabbits (2 to 3 to 9) were anesthetized with bentoparbital sodium (30 mg/kg), and the descending thoracic aorta was removed. The aorta was immediately placed in physiological saline (PSS) with the following composition (millimol): NaCl2
119, KC (24,7, CaCfft2.5, Mg5
0.1.5, NaHCOs 25, KH! PO41,2
, dextrose l 1. Tissue around NazEDTAo, 03° was taken and a 3 mm long ring was placed vertically in a 2 mm tissue bath and attached to a Harvard 9529 transducer at 285,937° C. with a static tension of 1.5 g. Equilibrate the ring for 15 minutes and add lX 10-
'M(-)norepinephrine for 2 minutes and washed with PSS. After equilibration with PSS at 1 hour intervals and washing for 15 minutes each, the tissue was contracted with 6XlO-6M histamine. Thirty minutes after histamine treatment, test compounds were added to each bath in increasing concentrations of 6.55-10. Dilution of the test compound was performed using a 50mM sodium phosphate solution (pH 7,
4). In each test, vehicle and a-h
Vasodilatory responses to ANP were observed in control tissues. Negative 10 g of concentrations resulting in semi-maximal vasodilator effect (ppg) and maximal vasodilator effect (E wax) for α-hANP were recorded. The results are shown in Table 1.

The above is merely for illustrating the invention and the invention is not limited to these compounds. Those skilled in the art will readily understand that the scope of the present invention as defined in the claims includes various other features.

Table 1 (Vasodilator effect) Example number Antagonism test (average pDz) 2
6.4 3 5.7 4 5.0 5 5.0 6 5.0 7 5.0 8 5.4 9 5.0 10 5.5 11 5.1 12 5.3 13 5.0 14 5. 0 15 5.0 16 5.0 17 5.0 18 5.0 19 5.5 20 5.0 21 5.0 22 5.3 2-3 5.4 24 5.5 25 5.8 27 6. 3 28 5.6 29 5.5 Table 1 (continued) Example number Competitive test (average 1) D Ri30
5.0 31 5.0 32 5.6 33 5.0 34 ' 5.2 35 5.0 36 5.0 37 5.0 38 5.5 39 5.0 40 6.5 41 6.6 42 5 .0 43 5.0 44 5.0 45 5.0 46 5.0 47 5゜5 48 5.0 49 5.0 50 5.0 51 5.0 52 6.6 53 5.0 54 6.2 55 5.9 56 6.2 Table 1 (continued) Example number Competitive test (average 1) D2) 577.
1 586.1 59 5.0 60 6.2 61 6.1 62 6.0 63 5.0 64 5.0 65 5.0

Claims (6)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R_1 is absent or hydrogen, acetyl, S
er, SerSer, D-Arg, Arg, Apa, A
hepa, Aoa, ArgSerSer, or Arg
ArgSerSer, R_2 is Cys, Mpa or P
en, R_3 is PheCha, L-Tic, D-Tic
or Nal, R_4 is Gly, Pro, D-Ala or Ala, R_5 is Gly, Pro, Aca, mAM
BA, Ala or D-Ala, R_6 is Arg, D-
Arg, Lys or Gly, R_7 is Ile, Leu
, PrGly or Gly, R_8 is Asp or Gl
y, R_9 is D-Arg, Arg, Cys or Gly
, R_1_0 is Ile, R_1_1 is Cys or Pe
n, R_1_2 are OH, NH_2, ChaArg, Ar
g, ProArg, GlyArg, PheArgPhe
Lys, AoaArg, AsnSer, SerPheA
rg or AsnSerPheArg, m is 0 or 1
, n is 0 or 1] and pharmaceutically acceptable salts, esters, or amides thereof. (2) R_1 is ArgArgSerSer, R_2 is C
ys, R_3 is Phe, R_4 and R_5 are each Gl
y, R_6 is Arg, R_7 is Ile, R_8 is Asp
, R_9 is Arg, R_1_0 is He, R_1_1 is Cys, R_1_2 is PheArg, and m and n are each 1. (3) R_1 is SerSer, R_2 is CyS, R_3
is Phe, R_4 and R_5 are each Gly, R_6 is Arg, R_7 is Ile, R_8 is Asp, and R_9 is A.
rg, R_1_0 is Ile, R_1_1 is CyS, R_
The compound of claim 1, wherein 1_2 is PheArg, and m and n are each 1. (4) R_1 is SerSer, R_2 is Pen, R_3
is Phe, R_4 and R_5 are each Gly, R_6 is Arg, R_7 is Ile, R_8 is Asp, and R_9 is A.
rg, R_1_0 is Ile, R_1_1 is CyS, R_
The compound of claim 1, wherein 1_2 is PheArg, and m and n are each 1. (5) Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 is hydrogen, Aoa, Aha, Apa, Ar
g, D-Arg, SerSer or ArgArgSe
rSer, R_2 is Cys or Pen, R_3 is Ph
e, Cha, L-Tic, D-Tic or L-bet
a-Nal, R_4 is Gly, R_5 is Gly or m
AMBA, R_6 is Arg, Lys or D-Arg,
R_7 is Ile, Leu or PrGly, R_8 is A
sp, R_9 is Arg or D-Arg, R_1_0 is Ile, R_1_1 is Cys, R_1_2 is OH, NH
_2, AsnSer, AsnSerPhe, AsnSe
rPheArg, PheArg, Arg, AoaArg
, L-TicArg, D-TicArg or ChaA
rg] and pharmaceutically acceptable salts, esters or amides thereof. (6) A therapeutic agent for hypertension, comprising the compound according to claim 1 as an active ingredient.