JPS6315280B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention generally relates to peptides having selective biological activity in inhibiting the secretion of growth hormone (hereinafter simply referred to as "GH"), insulin, and glucagon. More specifically, the present invention relates to a peptide that is effective in selectively suppressing only the secretion of GH from the pituitary gland or only the secretion of glucagon or insulin from the pancreas. Peptides that have the effect of inhibiting the secretion of growth hormone are patented in the US Patent No. 1 by Guillemin et al.
Specification No. 3904594 discloses its characteristics. This peptide has been named "Somatostatin." Somatostatin (this substance is also known as somatotropin release inhibitor) is a tetradecapeptide and has the following structure: Somatostatin, linear somatostatin (dihydrosomatostatin) and various acylated derivatives of somatostatin and dihydrosomatostatin are disclosed in the aforementioned US patent applications. Somatostatin and a number of somatostatin analogs exhibit activity in inhibiting GH secretion from anterior pituitary cells and in vivo inhibition of insulin and glucagon secretion in rats when cultured in vitro and dispersed. The use of somatostatin to selectively suppress only the secretion of GH, insulin, or glucagon has become widely considered desirable. Efforts have been made to develop somatostatin analogs that have selective biological activity and inhibit only the secretion of GH, insulin or glucagon. Although there are reports documenting a difference in the amount of somatostatin required to suppress insulin compared to glucagon in in vitro studies using human and perfused rat pancreas, somatostatin and some somatostatin analogs have In terms of inhibition, the potency is almost the same. It has been discovered that by replacing the amino acid components in the backbone of somatostatin and dihydrosomatostatin with specific amino acids, peptides having selective biological activity in inhibiting the secretion of GH, insulin, or glucagon can be obtained. The present invention was completed based on this knowledge. As a convenient shorthand, the novel peptides of the present invention are referred to as substituted amino acid moieties, substitution positions, and substitutions made to somatostatin (hereinafter simply referred to as "SS") or dihydrosomatostatin (hereinafter simply referred to as "DHSS"). (abbreviated as ")". The scientific names used to describe the peptides of the present invention have been assigned in accordance with common practice and the procedures described above. Unless otherwise indicated, scientific names refer to the L-form of the contemplated amino acids. The novel peptide of the present invention is defined by the formula below. where the individual amino acids of the peptide are
They are numbered from left to right to facilitate identification. [In the formula (a), X ₁ is Des-Asn, and X ₂ is D-
Trp, X ₃ is Ser and X ₄ is Cys, or (b) X ₁ is Asn and X ₂ is Trp,
X ₃ is D-Ser and X ₄ is Cys, or (c) X ₁ is Asn, X ₂ is Trp, and X ₃ is Ser.
and X ₄ is D-Cys, or (d)X ₁
is Asn, X ₂ is D-Trp, X ₃ is Ser, and X ₄ is D-Cys. [des-Asn ⁵ ]-[D-Trp ⁸ ]-SS; [D-Ser ¹³ ]-SS; [D -Cys ¹⁴ ]-SS; [D-Trp ⁸ ]-[D-Cys ¹⁴ ]-SS. Also included within the scope of the invention are pharmaceutically acceptable acid addition salts of the peptides. Examples of such acid addition salts include hydrochloride, hydrobromide, sulfate, phosphate, maleate, acetate, citrate, benzoate, succinate, malate, ascorbic acid. salt, tartrate, etc. However, it is not limited to these. One of the intermediates used in the synthesis of compounds of formula () of the present invention is of the formula R-Ala-Gly-Cys-(R ¹ )-Lys(R ² )-
(X ₁ )—Phe—Phe—(X ₂ )—Lys (R ³ )—Thr
(R ⁴ )—Phe—Thr (R ⁵ )—(X ₃ )—(R ⁶ )—
It is represented by (X ₄ )—(R ⁷ )—(X ₅ ) (wherein R is either hydrogen or an α-amino protecting group). α- denoted by R
Amino protecting groups are those known to those skilled in the art to be useful in the stepwise synthesis of polypeptides.
Among the types of α-amino protecting groups represented by R, there are, for example, the following. (1) Acyl type protection such as formyl, trifluoroacetyl, phthalyl, toluenesulfonyl (tosyl), benzenesulfonyl, nitrophenylsulfenyl, tritylsulfenyl, o-nitrophenoxyacetyl, chloroacetyl, acetyl, etc. Groups; (2) Aromatic urethane type protection such as benzyloxycarbonyl and substituted benzyloxycarbonyls such as p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc. groups; (3) aliphatic urethane-type protecting groups such as α-t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, allyloxycarbonyl; (4) cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxy Alicyclic urethane-type protecting groups such as carbonyl; (5) Thiourethane-type protecting groups such as phenylthiocarbonyl; (6) Alkyl-type protecting groups such as triphenylmethyl (trityl) and benzyl; and (7) ) trialkylsilane groups such as trimethylsilane. Among the α-amino protecting groups represented by X, t-butyloxycarbonyl is preferred. R ¹ and R ⁷ are each a protecting group for Cys or D-Cys, S-p-methoxybenzyl, S-p
-Methylbenzyl, S-acetamidomethyl, S-
selected from the group consisting of trityl, S-benzyl, and the like. A preferred protecting group is Sp-methoxybenzyl. R ¹ and/or R ⁷ may be hydrogen;
This means that there are no protecting groups on the sulfur group. R ² and R ³ can each be a protecting group for a side chain amino substituent of lysine, or R ² and/or R ³ can be hydrogen, indicating that a protecting group is present on the side chain amino substituent. means not. Examples of suitable side chain amino protecting groups include benzyl, chlorobenzyloxycarbonyl, benzyloxycarbonyl, tosyl, t-amyloxycarbonyl, t-butyloxycarbonyl, and the like. The selection of the side chain amino protecting group is not an absolute requirement of the invention, except that the protecting group must be such that it is not removed during deprotection of the α-amino group during the synthesis process. Therefore, the α-amino protecting group and the side chain amino protecting group cannot be the same. R ⁴ , R ⁵ and R ⁶ are protecting groups for the hydroxy groups of Thr and Ser, and include acetyl, benzoyl, t
-butyl, trityl, tetrahydropyranyl, benzyl, 2,6-dichlorobenzyl and benzyloxycarbonyl.
A preferred protecting group is benzyl. R ⁴ and/or
Or R ⁵ and/or R ⁶ can be hydrogen, meaning that there is no protecting group on the hydroxyl group. X ₁ , X ₂ , X ₃ and X ₄ are as defined above. X ₅ is -OH, -OCH ₃ , esters, amides, hydrazides, and solid resin supports represented by the formulas -O-CH ₂ -polystyrene resin support and O-CH ₂ -benzyl-polystyrene resin support selected from the group consisting of a benzyl ester anchor bond or a hydroxymethyl ester anchor bond for use in solid phase synthesis attached to a body. Preferably, the polymer is a copolymer of styrene with about 0.5-2.0% divinylbenzene as a crosslinking agent. The crosslinking agent renders the polystyrene polymer completely insoluble in certain organic solvents.
In the above formula, R, R ¹ , R ² , R ³ , R ⁴ ,
At least one of R ⁵ , R ⁶ and R ⁷ is a protecting group. In selecting the particular side chain protecting group to be used in the synthesis of a peptide of formula, the following rules must be followed. (a) The protecting group must be stable to the reaction reagents and under the reaction conditions chosen for the removal of the α-amino protecting group at each step of the synthesis; (b) The protecting group must characteristics must be maintained. Therefore, it should not be separated under coupling conditions: (c) The side chain protecting group should be removable under reaction conditions that do not alter the peptide chain at the end of the synthesis containing the desired amino acid product. There must be. Peptides of the formula can be synthesized using solid phase synthesis methods. This synthesis uses an α-amino protected resin and starts from the C-terminus of the peptide. The starting material is α
-Amino and S-protected Cys can be produced by coupling to chloromethylated or hydroxymethyl resins. The production of hydroxymethyl resin was carried out by Bodanszky et al.
Chem. Ind. (London) 38, 1597-98 (1966). Chloromethylated resins are commercially available from Bio Rad Laboratories, Richmond, California. The production of the resin is also described by SteWart et al. in "Solid Phase Peptide Synthesis" (published by Freeman, San Francisco), Chapter 1, pp. 1-6. Disclosed. α-Amino and S-protected Cys were converted to chloromethylated resins by the method disclosed by Monahan and Gilon in Biopolymer 12, 2513-19 (1973). Following attachment of the α-amino and S-protected Cys to the resin support, the α-amino protecting group is removed using, for example, trifluoroacetic acid in methylene chloride, trifluoroacetic acid alone or HCl in dioxane. The deprotection is carried out at temperatures ranging from about 0° C. to room temperature. “The Peptides” by Schroder and Lubke
Other standard cleavage agents and conditions can be used to remove certain alpha-amino protecting groups, as disclosed in 1, pp. 72-75 (Academic Press, 1965). After removing the α-amino protecting group of Cys, stepwise coupling of the remaining α-amino and side chain protected amino acids in the desired order yields compounds of formula;
Alternatively, instead of adding each amino acid individually to the compound, several amino acids can be precoupled before being added to the solid phase reactor. The selection of suitable coupling agents is known to those skilled in the art. Particularly suitable as a coupling agent is N,N ¹ -dicyclohexylcarbodiimide. Activating agents used in solid phase synthesis of peptides are well known to those skilled in the art of peptide synthesis. Examples of suitable activators are (i) N,N-diisopropylcarbodiimide, N
-Ethyl-N ¹ -(y-dimethylaminopropylcarbodiimide); (ii) Cyanamides such as N,N-dibenzyl cyanamide; (iii) Keteimines; (iv) N-Ethyl-5 - Phenyl isoxazolium - 3 ¹ - Isoxazolium salts such as sulfonates; (v) imidazolides, pyrazolides, 1,
Aromatic monocyclic nitrogen-containing heterocyclic amides containing 1 to 4 nitrogen atoms in the ring, such as 2,4-triazolides. Heterocyclic amides that can be suitably used include N,N ¹ -carbonyldiimidazole, N,N ¹ -carbonyldi-1,2,4
(vi) alkoxylated acetylenes such as ethoxyacetylene; (vii) compounds that form miscible anhydrides with the carboxyl moiety of amino acids, such as ethyl chloroformate and isobutyl chloroformate; and (viii) These include nitrogen-containing heterocyclic compounds having a hydroxyl group on one nitrogen ring, such as N-hydroxyphthalimide, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. Other activators and their use in coupling peptides are disclosed in Schloder and Lubke, supra, Chapter 2, and in Kappoor, J. Pham. Sci., 59, pp. 1-27 (1970). ing. Each protected amino acid or amino acid series conjugate was introduced into a solid-phase reactor in an approximately 4-fold excess amount, and the coupling reaction was carried out in a 1:1 mixed solvent of dimethylformamide and methylene chloride, or in dimethylformamide or methylene chloride alone. Perform in a solvent. If incomplete coupling occurs, the coupling procedure is repeated again before removing the α-amino protecting group and then coupling the next amino acid. The success of the coupling reaction in each synthetic step is monitored by ninhydrin reaction. Regarding this ninhydrin reaction, E. Keyser (E.
Kaiser et al. in Analyt.Biochem., 34595 (1970). After synthesizing the desired amino acid sequence of formula, the peptide is removed from the resin support by treatment with a reagent such as liquid hydrogen fluoride. This hydrogen fluoride not only cleaves the peptide from the resin, but also cleaves all remaining side chain protecting groups R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ and R ⁷ and the α-amino protecting group R are also removed to directly generate a linear peptide of formula. [In the formula (a), X ₁ is Des-Asn, and X ₂ is D-
Trp, X ₃ is Ser and X ₄ is Cys, or (b) X ₁ is Asn and X ₂ is Trp,
X ₃ is D-Ser and X ₄ is Cys, or (c) X ₁ is Asn, X ₂ is Trp, and X ₃ is Ser.
and X ₄ is D-Cys, or (d)X ₁
is Asn, X ₂ is D-Trp, X ₃ is Ser, and X ₄ is D-Cys. The cyclic peptide of the formula can be obtained by oxidizing the peptide of the formula according to a conventional method. That is, according to the method described by Rivier et al. in Biopolymers, 17, 1927-1938, 1978, a peptide of the formula (chain peptide) was dissolved in 1% acetic acid, and dissolved in potassium ferricyanide solution. When added dropwise to , a disulfide bond (SS bond) is generated between Cys residues, producing a peptide (cyclic peptide) of the formula. Also, the peptide of the formula is easily oxidized in the air to the peptide of the formula. Alternatively, the peptide bound to the resin support can be separated from the resin by alcoholysis and subsequent hydrolysis of the recovered C-terminal methyl ester to convert it to an acid. Any side chain protecting groups can then be removed as described above or by catalytic reduction using conditions that keep the Trp moiety intact (e.g.
It can be removed by other methods such as Pd on _BaSO4 . If hydrogen fluoride is used for removal, anisole is incorporated into the reaction vessel as a scavenger. The aforementioned solid phase synthesis methods are well known to those skilled in the art and have been described by Merrifield in J.
Am.Chem.Soc., 85, p. 2149 (1964). The peptides of the invention having selective effects on inhibiting the secretion of GH, insulin and glucagon are believed to be of particular importance in the treatment of diabetes.
The traditional view of diabetes has been that the disease is caused solely by a defect in insulin production. However, as clinical and research experience has become more extensive, it has become clear that, in addition to disorders of insulin secretion, several factors act on diabetes. It is known that in diabetes, insulin is usually deficient, but glucagon is usually present in excess. Today, the presence of glucagon is at least as important a factor in diabetes as the absence of insulin. The fact that insulin deficiency is usually accompanied by an excess of glucagon complicates the study of glucagon's role in diabetes. While it is easy to add extra amounts of hormones (eg insulin), reducing the concentration of glucagon has proven extremely difficult. The discovery of somatostatin prompted research into the role of glucagon in diabetes. Somatostatin inhibits both insulin and glucagon secretion. The role of somatostatin in diabetes research is “Science”, vol. 188, 920-
It is detailed in a 923-page paper published on May 30, 1975. However, there are several problems with using somatostatin as a diabetes treatment. Along with glucagon, somatostatin also suppresses insulin secretion. Therefore,
A need has been recognized for peptides that have selective effects in inhibiting insulin and glucagon secretion in connection with diabetes treatment. The novel peptides of the invention provide such selective effects.
More specifically, certain peptides of the invention are effective in inhibiting glucagon secretion, but have less effect on inhibiting insulin secretion. The following examples illustrate various features of the invention. However, the scope of the present invention is not limited by these Examples. Example 1 Peptides of the invention are generally disclosed in U.S. Patent No. 3,904,595.
It was synthesized by a solid phase method according to the method described in the specification. The synthesis was carried out stepwise on a chloromethylated resin. The resin was composed of fine beads (20-70 microns in diameter) of synthetic resin made by copolymerization of styrene and 1-2% divinylbenzene. The benzene nucleus of this resin was chloromethylated using chloromethyl ether and stannic chloride in a Friedel-Crafts reaction. The chlorine introduced in this way is
It is a reactive benzyl chloride type bond. In the Friedel-Crafts reaction, the resin is 0.5 to 2
This is done until it contains millimoles of chlorine. In the following, the synthesis of peptides will be further explained, with the chemical names of the reaction components used first listed, followed by their common abbreviations in brackets. From then on, the reaction components are designated by common abbreviations. The structural formula below, The peptide represented by was synthesized by a solid phase method as described below. The other peptides mentioned above were also synthesized by the same method. Tert-butyloxycarbonyl of Cys
S-paramethoxybenzyl (Boc-SpOMe-
Bzl) derivatives were coupled to the resin by one of three methods: (i) refluxing in ethanol in the presence of triethylamine; (ii) cesium salts of Boc-protected amino acids were dissolved in dimethylamide (DMF) overnight. (iii) potassium salt of Boc-protected amino acid in dimethyl sulfoxide (DMSO) for 2 hours;
Keep at 80℃. Only 1 mEq of protected Cys was used per 1 milliequivalent (mEq) of Cl on the resin. Method (iii) is described in more detail below: 0.9 mEq of potassium tertiary butoxide (KOtBut) was added per mEq of amino acid to a slurry of protected Cys dissolved in resin and DMSO. The reaction mixture was exposed to air for as short a time as possible so that no amber color was observed. Reaction at a temperature of 80°C for 2 hours produced a substituted resin suitable for peptide synthesis (resin
(approximately 0.2 mEq of amino acid derivative per 1 g). After deprotection and neutralization, the peptide chain was assembled on the resin. Deprotection, neutralization, and addition of each amino acid were performed according to Table 1 below. N-t-butyloxycarbonyl (Boc) derivatives of each amino acid were used, but
As the α-amino protecting group for the alanine residue at position 1, any protecting group (benzyloxycarbonyl, Z, Boc, etc.) can be used as long as it can be removed with HF. After deprotecting the first residue (i.e. SpOMe Bzl Cys) according to Table 1 (steps 3-8), Ser The NBoc derivative is then added.
The side chain of Ser is protected with benzyl ether (OBzl). The 0-benzyl (OBzl) protecting group is also used to protect threonine. p-Nitrophenyl ester (ONp) was used to activate the carboxyl end group of Asn. O-nitrophenyl esters can likewise be used for this purpose. The formyl group is reliable for the protection of indole N--H. Benzyloxycarbonyl (Z) or benzyloxycarbonyl-2Cl [Z(2-Cl)] was used as a protecting group for the Lys side chain.

Table: After step 13, an aliquot is taken for the ninhydrin test. If this test is negative, return to step 1 to couple the next amino acid; if this test is positive or somewhat positive,
Return to steps 9-13. When Asn was present in the peptide, Table 1 above was used to couple each amino acid other than Asn to Cys. For peptides of the invention with Asn, steps 1 to 8
were the same, but Table 1(2) was used in the latter half of the coupling reaction.

Table: After step 14, an aliquot was taken and subjected to the ninhydrin test. If the ninhydrin test is negative, return to step 1 to couple the next amino acid.
If the test is positive or slightly positive, proceed to steps 9 to 14.
Repeat. Cleavage of the peptide from the resin (5 g) and deprotection of the side chain protecting groups of the peptide was carried out in hydrofluoric acid (75 ml) in the presence of 8 ml of anisole.
After removing the hydrofluoric acid under high vacuum, the resin-peptide was washed with ether. The dried resin was quickly extracted with 150 ml of 25% acetic acid and diluted to 3000 ml with degassed water _H2O ( _N2 ). The pH of the solution was adjusted to 6.6-7.0 with _NH4OH . The solution was titrated dropwise with stirring with potassium ferricyanide solution (1 g/500 ml H ₂ O) until a permanent yellow color was observed. The solution was allowed to stand for 10 minutes and the PH was adjusted to 5.0 with glacial acetic acid. BiO-Rad
AG ₃ -X ₄ A resin (100-200 mesh, chloride form,
10-15 g) was added to the cloudy solution and stirred for 15 minutes. The solution was passed through celite and passed sequentially through two columns: (a) Bio
Rad AG ₃ -X ₄ A resin (chloride form, 10ml); (b)Bio
ReX-70 resin (cationic form, 100ml). The Celite and resin cake was thoroughly washed with water (500 ml) as applied to columns (a) and (b) above as a wash. The peptide materials were eluted from the Bio ReX-70 resin column with pyridine:acetic acid:water (30:4:66) or 50% acetic acid. Fractions were collected. Only the fraction containing the peptide (positive for ninhydrin reaction) was diluted with water and immediately lyophilized.
1.2 g of cream colored crude material was obtained. A Sephadex G-25F gel column (3
x 200 cm) and eluted with 2N acetic acid. The elution pattern observed at 280 nm (nanometer) showed one large symmetrical peak concentrated at 2Vo (400 mg). This was subsequently subjected to countercurrent distribution (solvent system: n-butanol to acetic acid to water = 4:1:5) using 10 ml per tube as the bottom layer. Distributed 237 times. As a result, the main peaks were found at positions 48 to 64. The compound (250ml) was found to be homogeneous by TLC. The specific optical rotation of the cyclic peptide thus obtained was [α] ²³ _D =-38.2°±1 (c=1, in 1% acetic acid). Amino acid analysis of this material showed the expected proportions of the various amino acids. Active esters can be used for solid phase synthesis, and classical synthetic methods can also be used to produce the peptides of the invention. In vitro efficacy assay The effects of various peptides of the present invention were evaluated by Vale.
by the initial culture of rat anterior pituitary cells enzymatically dissociated by the method disclosed by Endocrinology, 91, pp. 562-571 (1972).
The secretion of GH was tested in vitro. This efficacy assay is performed by processing excised pituitary glands from rats and isolating cells therefrom. These cells were grown in Dulbecco's modified Eagle's medium (Dulbecco's
Modified Eagle Medium) (Dulbeco et al.,
Virology, vol. 8, p. 396, 1949). The cell culture medium is supplied with carbon dioxide and oxygen and kept at 37°C for 4-5 days before use for potency assay.
After changing the medium, the cell culture is incubated for 4 hours, to which specific somatostatin peptides are added. radioimmunoassay analysis
The rate of growth hormone secretion in nanograms (ng)/hour is determined using a method of analysis. The effects of somatostatin (control), dihydrosomatostatin (control) and the peptides of the present invention on inhibiting glucagon and insulin secretion were tested as follows: In Vivo Efficacy Assay Sprague-Dawley
A male rat (weighing 180-220 g) was exposed to light for 14 hours (light was applied from 7 a.m. to 9 p.m.) and then exposed to light for 10 hours.
The rats were housed in a dark, temperature- and humidity-controlled area, and this rack was used for all tests.
Rats were fed a standard diet and allowed to drink water ad libitum. Testing was performed at least 5 days after the rats arrived from the supplier between 1400 and 1600 hours. After anesthesia with ether, 0.2 ml of peptide or saline was administered via the external jugular vein. The rats were maintained under anesthesia until the time when blood was collected from the portal vein. Blood sample per ml of blood
Placed in a chilled tube containing 10 mg EDTA and 50 μl 2M benzamidine. Plasma was stored at −20°C for insulin and glucagon measurements. Reduce insulin levels to J.
It was determined by the method of Herbert et al., disclosed in Chem. Endoocr. Metab., 25, 1375 (1965). This method uses porcine insulin antiserum and
I ¹²⁵ - Use an iodinated insulin tracer. Human insulin standards are from Schwarzman (Orange Burke, New York) (Schwary
Mann, Orangeburg, New York).
Glucagon is described in “Methods of Hormone Radioimmunoassay” edited by Jaffe et al.
Radioimmunoassay)” (Academic Press,
New York), p. 317 (1974), according to the method of Faloana and Unger. This method uses glucagon antiserum 30K
use. Glucose was measured using a Beckman Glucose Analyzer.
It was measured by the glucose oxidase method using a Glucose Analyzer. GH measurements were performed on tissue culture medium using the following reagents: NIAMDD rat GH standard (GH-RP-1); NIAMDD monkey anti-rat GH (GH-serum-
3); and high purity rat GH for iodination. All measurements were performed with irregular blocking sequences.
Analysis of variance for differences between treatments was determined by Dunnett and Duncan's multiple range test. Titers were calculated from 4 or 6 point potency assays. Various peptides of the present invention were produced by the solid phase synthesis method described above. The composition of each peptide is shown in Table 2 below. All of these peptides are cyclic peptides. Furthermore, Table 2 shows the inhibitory effects of the peptide of the present invention on the secretion of GH, insulin, and glucagon in comparison with that of somatostatin. That is, the relative strength is shown when the inhibitory effects of somatostatin on GH, insulin, and glucagon secretion are each set as 100. Table 2 also shows the optical rotation of each peptide. The measurement conditions for optical rotation [α] ²³ _D are the same as in Example 1. Because somatostatin suppresses the secretion of both insulin and glucagon, hormones with contradictory physiological activities, it has the disadvantage that it is not recommended for administration to patients with specific diseases. However, as is clear from Table 2, the peptide of the present invention exhibits a selective inhibitory effect on the secretion of insulin and glucagon compared to somatostatin. That is, [des-Asn ⁵ ] [D-Trp ⁸ ]-SS
The peptides represented by [D-Ser ¹³ ]-SS can specifically inhibit only insulin (the insulin/glucagon secretion inhibition ratio of each peptide is 60/1 and >5/1); It is particularly useful in treating patients with insulinomas. On the other hand, [D-Cys ¹⁴ ]
-SS and [D-Trp ⁸ ] [D-Cys ¹⁴ ]-SS can selectively inhibit only glucagon (the insulin/glucagon secretion inhibition ratio of each peptide is 1/15.5 and approximately 1/8 ), these peptides are particularly useful in the treatment of diabetic patients. As described above, the peptide of the present invention is a peptide that can exhibit only a specific activity among the many biological activities that somatostatin has, and can therefore reduce the side effects of somatostatin administration, and is useful for the treatment of specific diseases.

【table】

Claims (1)

[Claims] 1 The following formula: [In the formula (a), X ₁ is Des-Asn, and X ₂ is D-
Trp, X ₃ is Ser and X ₄ is Cys, or (b) X ₁ is Asn and X ₂ is Trp,
X ₃ is D-Ser and X ₄ is Cys, or (c) X ₁ is Asn, X ₂ is Trp, and X ₃ is Ser.
and X ₄ is D-Cys, or (d)X ₁
is Asn, X ₂ is D-Trp, X ₃ is Ser, and X ₄ is D-Cys]. 2. The peptide according to claim 1, wherein X ₁ is des-Asn, X ₂ is D-Trp, X ₃ is Ser and X ₄ is Cys. 3 X ₁ is Asn, X ₂ is Trp, and X ₃ is D
-Ser and X ₄ is Cys. 4 X ₁ is Asn, X ₂ is Trp, and X ₃ is Ser
and X ₄ is D-Cys. 5 X ₁ is Asn, X ₂ is D-Trp, X ₃
The peptide according to claim 1, wherein is Ser and X ₄ is D-Cys.