JPS63234000A - Novel polypeptides, production thereof, pharmaceutical composition containing said polypeptides and its use - 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 The present invention relates to novel polypeptides, processes for their preparation, pharmaceutical compositions containing said polypeptides and their use as pharmaceutically active compounds.

Zara (details: 1) The present invention has 1 hexapeptide residue.
position (N-terminus)] a cysteine residue, a phenylalanine residue which may be substituted with 2 positions, a tryptophan residue which may be substituted with a benzene ring at position 3, and an e at position 4.
- has a residue which may be N-alkylated, an amino acid residue at the 5th position, a cysteine or cystinol residue at the 6th position (C-terminus), and the polypeptide is monocyclic. In this case, the sulfur atom of the cysteine residue at the 1st position and the sulfur atom of the cystine or cystinol residue at the 6th position are linked to form a -5-5-bridge; in this case, the 1st position is the 1st position.

3tfL, residues at position s and position 6 are each independently D
- or L-configuration, and the residues at the 3rd, 4th, and 5th positions may each be independently α-N-alkylated. Linear or monocyclic polypeptides (however, l-1-CD)
-Phe -Cys -Phe-(D)Trp -1111111goLys -Thr -Cys -Thr-ol) and provide the salts and complex salts of

The parasitic compounds according to the invention have the general formula IA11
2345 6 [In formula.

Human is water, Cl-12 alkyl, C-phenylalkyl or 2λCo-.

(that time.

1) 艮 is hydrogen "1-11 alkyl, phenyl or C7
-10 phenylalkyl, or 11) RCO- is a) halogen, nitro, amino, hydroxy.

C1-3 alkyl and/or Cl-3 alkoxy1
L- or D-phenylalanine residues which may thus be ring-substituted.

b) natural a-amino acids or corresponding D-amino acid residues other than those defined in ga) above; or C) the individual amino acid residues are the same or different;
A dipeptide residue selected from those defined in a) and/or b) above.

Amino acid residue M; the α-amino group of a) and b) and the N-terminal amino group of dipeptide residue C) may be alkylated with 7- or di-Cl-12) A' is hydrogen or , A is C alkyl or! -12 When it is C7-10 phenyl alkyl.

Similarly, C alkyl or C7-10 phenylalkyl.

B is halogen, nitro, amino, hydroxy, Cl-3
-Phe+ which may be ring-substituted by alkyl and/or C1-3 alkoxy.

C may be α-N-methylated (also halogen, nitro, amino, hydroxy), 1-3 alkyl and/or Cl-3 alkoxyf, and thus benzene ring substituted - (L) -or-(D)-Tr
p+.

D may be α-N-methylated or ε-N-
-LBy+ which may be C1-3 alkylated.

In E, MM may be α-N-methylated.

Natural α-amino acid or corresponding D-amino acid (however.

R is hydrogen or Cl-3 alkyl, R2 is hydrogen or physiological E is acceptable. Ester residues that can be physiologically hydrolyzed.

R3 is hydrogen, 1-3 alkyl, phenyl or C7-1
o Phenylalkyl.

艮 is water""1-3 alkyl, or when R3 is hydrogen or methyl, it is -CH(R5)-X.

R5 is hydrogen, -(CH2)2-OR or -(Cf(
2) 3-OH or an m substituent attached to the α-carbon atom of a natural α-amino acid.

and R1 and R2 have the same meanings as above.

R6 is hydrogen or Cl-3 alkyl, R7 is water'tt, Cl-3 alkyl, phenyl or C
7-'10 phenylalkyl, -CH(R5)-
(The group have an L- or D-configuration.

However, D- and/or L-cysteine residues are present only at positions 1 and 6]. Cys -Phe-(
D) Trp - and its salts and complex salts.

Throughout this specification and claims, halogen refers to fluorine,
means chlorine and bromine.

In the polypeptides represented by formula 1, the following meanings or combinations thereof are desirable: 1.1. Preferable K is C1-11 alkyl or C7-
10 phenylalkyl, especially C7-10 phenylalkyl, more preferably phenethyl, and RCO
has the meaning of 3), b) or C). (1,1,R
When CO has the meaning of 3), b) or C),
The α-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residue C) are preferably unalkylated or monoalkylated,
In particular, it is mono-C1-8 alkylated, more preferably monomethylated. Most preferably the N-terminus is not alkylated.

1.3. When RCO has the meaning a), it is 3') an L- or D-phenylalanine residue optionally mono-N-Cl-12 alkylated or an L-
Alternatively, D-tyrosine is preferable. More preferably, λ') is an L- or D-phenylalanine residue or L- or D-N-(CI-8 alkyl)
It is a phenylalanine residue. Most preferably 3')
is an O-phenylalanine or o-N-(C,8alkyl)phenylalanine residue, in particular an O-phenylalanine or 0-(N-methyl)phenylalanine residue.

1.4, when RCO has the meaning b) or C), the defined residue is preferably lipophilic. Thus, preferred residues b) are b') α-amino acid residues with a hydrocarbon side chain, such as leucine and norleucine residues, which residues are L- or D-
Preferable residues have the same or different individual amino acid residues, and have the above-mentioned 3') and b')
is a dipeptide residue selected from those defined in .

1.5, the most preferred RCO is the meaning of a), especially λ'
) has the meaning of

2, B is -phe-.

3, C is -(D)Trp-.

4.0 is -Lys +, -MeLys- or -Ly
s(j-Me)-1, especially -Lγ.

5, E is a natural α-amino acid, especially the residue of -Thr-.

hydrogen or methyl). In the latter case, the r moiety -C:H(R5)-X preferably has the L-configuration.

6.1, k3 is preferably hydrogen.

6.2, natural α-amino acids (i.e., formula 11 N −
(Jl As a substituent bonded to the α-carbon atom of (R5)-C00i(), R5 is preferably -CI-120H
.

-CH(C1-13)-OH, isobutyl or benzyl, or R5 is (CH2)2-OH or (
CH2)3-Q)i. In particular, it is -Cfi2
0) 1"" Cki 2- OR2 group, especially the formula -
CH2-0R2, and R2 preferably has hydrogen or the meaning shown in the following 7 items. Particularly preferred is hydrogen.

7. As a physiologically acceptable and physiologically hydrolysable ester residue, R2 is preferably HCO, C2
-12 alkoxycarbonyl, C8-12 phenylalkylcarbonyl or benzoyl.

The residues at positions 8.2 and 7 preferably have an L-configuration.

9, Yl and Y2 preferably together represent a direct bond.

The compounds according to the invention are characterized in that A is hydrogen, C1-3 alkyl, C7-10 phenylalkyl or 2RCO-, A' is hydrogen, 艮is hydrogen, C1-3 alkyl, phenylmata is C7- 1
0 phenylalkyl, or RCO is a) halogen, nitro, amino, hydroxy, C1-3
an L- or D-phenylalanine residue optionally substituted monocyclically by alkyl or C1-3 alkoxy; or b) a residue of a natural α-amino acid or a corresponding D-amino acid other than that defined in a) above; the amino groups of amino acid residues a) and b) are the same group, R2 is hydrogen, R3 is hydrogen or C1-3 alkyl, R7 is hydrogen or C1-3 alkyl, and Polypeptides of formula I above, and acid addition salts and complex salts thereof, in which Yl and Y2 together represent a direct bond.

The polypeptides of the invention may exist as their salts or complex salts. Acid addition salts are obtained, for example, with organic acids, polymeric acids and inorganic acids. Examples of such acid addition salts include hydrochloride and acetate. Complex salts are compounds of formula 1 combined with inorganic substances, such as inorganic salts or complex salts. It is understood to be a known type of compound obtained by adding hydroxides and/or polymeric organic substances, such as rhesium salts or zinc salts.

The present invention also provides methods for producing the compounds of the present invention. These compounds can be prepared by methods known in the art of peptide chemistry or by obvious chemical equivalents thereof, for example a) protected linear or monocyclic polypeptides containing hexapeptide residues as defined above; , in particular removing at least one ff1ffl group from a protected polypeptide having the structure shown in formula 1, b) each peptide unit having at least one protected or unprotected form; A protected or unprotected linear or monocyclic polypeptide containing an amino acid or aminoalcohol residue, the peptide unit of which contains a hexapeptide residue as defined above, in particular a structure as shown in formula 1. The two peptide units are linked by an amide bond, such that an unprotected polypeptide having a protected or conjugate Φ≠ is obtained, and further, if necessary, carrying out the method of step a). , C) a functional group at the N-terminus or C-terminus of a protected or unprotected linear or monocyclic polypeptide containing a hexapeptide residue as defined above, in particular a functional group of formula 1
The A or F rl group of the protected or unprotected polypeptide having the structure shown in is converted into another N-terminal or C-terminal functional group, in particular another A or F group, and if necessary, 2 ) carrying out the method of step: d) oxidizing a linear polypeptide containing a hexapeptide as defined above, in particular a polypeptide of formula 1 in which Yl and Y2 are each hydrogen, to obtain a linear polypeptide as defined above; by a method comprising forming a monocyclic polypeptide, in particular a polypeptide of formula 1 in which Yl and Y2 are taken together in a direct bond, and then, if necessary, converting the polypeptide thus obtained into its salts or complex salts. can get.

The above method is carried out, for example, in a manner similar to that described in the Examples below. Unless a method for making a starting material is specifically stated, the compound is known and can be made and purified according to known methods.

The polypeptides of the invention and their pharmaceutically acceptable salts and complex salts exhibit valuable pharmacological activity as demonstrated in animal studies. In particular, they exhibit a growth hormone secretion inhibitory effect, as shown, for example, by suppression of serum growth hormone concentrations in rats.

This test is performed using male rats anesthetized with Nembut@l (trade name for Bendoparbital Sodium). Test compounds are administered at various logarithmically staggered doses using at least four rats for each dose. Rats are sacrificed 15 minutes after administration, blood is collected, and serum growth hormone concentrations are determined by radioimmunoassay. 0.01 of the compound of the present invention
It is active in this test when administered intravenously or intramuscularly at ~100 μg/2.

Accordingly, the polypeptides, salts and complex salts described above are useful in the treatment of ataxias with pathologies involving or associated with hypersecretion of growth hormone, such as in the treatment of diabetes, vascular disease, and acromegaly.

The above-mentioned polypeptides, salts and complex salts thereof may also be used, for example, for (1) pancreatic juice secretion.
Scandinavian Journal of Gastroenteritis (5cand, J. rek) et al.

Qajeroent, ) 6, 423 (1971) and (II) for the measurement of gastric juice secretion, standard animal tests 1 showed inhibition of gastric and pancreatic juice secretion: Males Wats (220-280 g) were kept in individual cages in the laboratory for several days (14 hours of light per day), and 48 hours immediately before the experiment.
Subjects are fasted for an hour (but water is allowed ad libitum). At the beginning of the experiment, the animals are anesthetized with ether and the pylorus is ligated, and then 100 μg/Ko of pentagas l-IJ is subcutaneously administered to promote gastric secretion. Test compound is administered intramuscularly at the same time. After 30 minutes, the animals are sacrificed, the gastric fluid volume is measured, and the acid concentration is assayed (titrated with thymol blue). Calculate the acid excretion layer and calculate the percent inhibition relative to the untreated control.

The polypeptide ring according to the invention is administered at 2io-9-10
-5g/! It is effective in the above test (1) in which the drug was administered intramuscularly at a dosage of 0.01 to 100 μg/Kg.

Pharmaceutically acceptable salts and complex salts of the polypeptide rings of the present invention exhibit activity comparable to that of the free compound in the above test methods.

Specifically, the polypeptides, their salts and complex salts are useful in the treatment of gastrointestinal disorders, such as gastric ulcers, gastrointestinal bleeding and acute pancreatitis. For the above uses, depending on the compound to be used, the method of administration, and the intended treatment,
Dosage can vary.

However, from about 20 x 10-9g per day to about 0
．． Satisfactory results are generally obtained when 3η/Ky is administered in 2 to 4 divided doses or in a controlled release form. For larger mammals, the total daily dose is about 0.002'9 (e.g. about 0.07
Cape) ~ about 2011! Ii and, for example, in the case of parenteral administration, suitable unit dosage forms include solid or liquid preparations, with the addition of fillers or carriers therefor.
A polypeptide according to the invention contains from about 0.0005119 (eg, about 0.02 ■) to about 10 ■ or an equivalent amount thereof or a pharmaceutically acceptable salt or complex salt thereof.

According to the foregoing, the present invention further provides 1) ataxias due to pathologies consisting of or associated with hypersecretion of growth hormone (e.g., diabetes, vascular disease, acromegaly, and gastrointestinal incontinence (e.g., gastric ulcers, gastrointestinal bleeding); and acute pancreatitis) in a patient in need of said treatment comprising administering to said patient an effective amount of a polypeptide according to the invention, or a pharmaceutically acceptable salt or complex salt thereof. Methods and 1) together with a pharmaceutically acceptable filler or carrier,
A pharmaceutical composition containing a polypeptide according to the present invention or a pharmaceutically acceptable salt or complex salt thereof is provided.

In the following examples, all temperatures are expressed in degrees Celsius (C''C) and [α] values are uncorrected. The following abbreviations are used: Ac0Hjl11 Acetic acid Asp-diol m Asparagine-diol residue B
oc I: +lt-butoxycarbonyl BTF
A x boron-tris-trifluoroacetate DCCI = dicyclohexylcarbodiimide D
MF N, N-dimethylformamide) 10
BT +Ji-hydroxybenzotriacylHy--N HNH2Leu-ol-leucinol residue MB,l
-p-methoxybenzylMe -methylMeOH-methanolMePhe --(N-ylthyl)-Phe-NE
t3 W triethylamine ONP 4-nitrophenoxyPhe (p
F) Corp-F-Phe-Phe-o1 -phenylalaninol residue 5er-oI xerinol residue-N)i-C)1 (CH20H)2 TFA Thr-ol trifluoroacetic acid
Benzyloxycarbonyl Example IA (Reference Example) H-(D)P he -Cys-P he-(D)Tr
p-Lys-Thr-Cys-Thr-oI
Boc-(D)Phe-Cys (MBzl)-Ph
e-(D)Trp-Lys (Boc)-Thr-Cy
s-(MBzl)-Thr-oI Q, 7 Q f
O and thioanisole 6.0- at 0° TFA9m/
dissolve in

After cooling the solution to -10°, 2M BTFA
A solution 12- consisting of and TFA is added under stirring.

After stirring for 1.5 hours at -5° to -10°,
Add 50 rnl of cold anhydrous methanol (-70°).

After another 5 minutes, anhydrous ether IL and about 5N hydrochloric acid 5
-/ether mixture is added under stirring. The precipitated product was collected, washed briefly with ether, and the residue was dissolved in dioxane/
Dissolve immediately in 2.5 L of water (7:3). Adjust to p) 17-7.5 by adding dilute ammonia water. one-fifth of the mixture
Until no H groups are detected (e.g. Elman
lmann) Test) Stir in an open container at room temperature.

Hydrochloric acid is added to adjust the pH to 3-4, the resulting solution is concentrated under reduced pressure, and the product is lyophilized. A small amount of lyophilized product
Gel-chromatography (Bio-Rad) in 0% acetic acid and using 10% acetic acid.
Purify in step 4). The combined compartments containing the desired product were also lyophilized to yield the title compound: [α]20--4
2° (c=0.5.95% acetic acid).

The raw material is obtained as follows: a) Z-Lys (Boc) -Thr -OMe
Z-Lys (Boc) as dicyclohexylamine salt
) Chloroformic acid isobutyl ester 13.5- is added to a solution consisting of -OH569 and THF1200- while stirring, while cooling to -20° in advance. After further stirring at -15 °C for 20 min, kl-Thr-OM
Add a cold solution [-21°] consisting of e hydrochloride 219- and T)IF 600d. Triethylamine 17- is added dropwise at -15°C and the reaction mixture is stirred at 0° for 18 hours, after which time the product is concentrated under reduced pressure. After dilution with ether/ethyl acetate (1:1), the precipitated dicyclohexylamine salt is removed. The P solution is sequentially washed with water, 2N citric acid, 10% potassium hydrogen carbonate, and water. The organic layer is dried over Glauber's salt and concentrated under reduced pressure to give the title compound as a residue. [α]. -14° ((wl
, DMF) b) Z -Phe-(D)Trp-OHZ-
Phe -OHg, 0g and acetonitrile 150-
After cooling the mixture to -18°, 3.4 In! of N-methylmorpholine was added. and chloroformic acid isobutyl ester 4.14 are added sequentially. The solution was heated at -15° for 15 minutes.
Stir for a minute, then add H-(Di Trp-OH6,2F, IN
Sodium hydroxide 30- and acetonitrile 100-
Add a cold solution consisting of and continue stirring at -56 to 0° for a further 18 hours. The reaction mixture is concentrated under reduced pressure, diluted with water and extracted three times with a small amount of ether. The pH of the aqueous layer was adjusted to about 2 by adding 4N sulfuric acid, and the precipitate was extracted with ether/acetic acid.

The organic layer is washed with water and dried with Glauber's salt. After concentrating under reduced pressure,
Crystallization of the residue from ether/petroleum ether gives the title compound. Melting point 113°C9 [α] and 0=-5' (C=
0.9, DMF).

c) Z-Phe-(D)Trp-Lys (B
oc ) -Thr -OhZ -Lys (Boc)
-Thr -0 value 5.09 and methanol 150-
A mixture consisting of: is hydrogenated in the presence of palladium-carbon. The product was collected and washed with methanol, and the tear fluid was concentrated under reduced pressure.
OH4,8f! , HOBT2.0Ptcl.

and DMF50+d and dissolve.

The solution was cooled to -15° and DCCI2. IP and DM
A mixture consisting of F15yR1 is added under stirring.

The solution is further stirred at 0° for 2 days, concentrated under reduced pressure and diluted with acetic acid/ether (1:1) to remove the precipitated dicyclohexylurea. P solution was mixed with 2N citric acid [10%
Wash sequentially with potassium bicarbonate and water. The organic layer is dried with mirabilite and concentrated.

The residue was chromatographed on silica gel using methylene chloride/methanol as the eluent. The fractions containing the desired product are collected and concentrated under reduced pressure to yield the title compound. [α]20=-7° (C=0.9°DMF).

d) H-Phe-(D)Trp-Lys (Boc
) -Tbr'-OMeZ -Phe'-(qTrp
After hydrogenation of a mixture of -Lys (Boc) -Thr-OMel, 21 and methanol 50- in the presence of 10% palladium-carbon, the solution was filtered and concentrated under reduced pressure to produce the title compound as a foam. get. [α] = -18° (c = l, methanol).

e) Boc-(D) Phe-Cys (MB
z1) -0HBoc-(II)Phe-OHI
After a solution consisting of 6 P and THF 300++7 is previously cooled to -20 c', NEt38,4- and chloroformic acid isobutyl ester 8,3- are sequentially added thereto. After stirring the resulting mixture at -15° for 10 minutes, H-Cys-(MBzl)-αζNEt311
．． 5-Chiyo and a mixture of 400% THF/water (5:1) is added dropwise. The reaction mixture was stirred at 00 for about 2 days, concentrated under reduced pressure, diluted with 1.3 L of water, and extracted with ether. After adjusting the volume to 2.0 by adding 4N sulfuric acid to the aqueous layer, the precipitate was extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with ether/1% acetic acid. The compartments containing the desired product are combined and concentrated under reduced pressure to yield the title compound.

[α]20=-18° (C=1.1°DMF).

f) Boc-(D)Phe-Cys (MBzl
) -Phe-(D)Trp-Lys (Boc
) -Thr -OMeBoc-(D)Phe-Cy
s(MBzl)-OH0,67P,H-Phe-(D
ITrp -Lys (BoC) -Thr -OMe
l, Ql, HOBTO, 5ri and DMF 30-
The solution consisting of is previously cooled to -20° and DCCI 0.30 P is added thereto while stirring. The reaction mixture is stirred at -5° to 0° for about 12 hours and then at room temperature for about 4 hours. The precipitated dicyclohexyl urea was removed, and the p solution was washed successively with 2N citric acid, 10% potassium bicarbonate and water. The organic layer is dried with mirabilite, purified, and concentrated.

The product is precipitated by adding ether, dried, and the title compound is obtained. Melting point 160°, [α Kinuta = -30'
(c=1, MeOH).

g) Boc-([j)Phe-Cys (MBzl)
-Phe -(D)Trp -Lys (Boc) -
Thr-NHNH2Boc-([1Phe-Cys
(MBzl)-Phe-(D)Trp-Lys
(Boc)-Thr-OMe 0.9y and DM
Add 1.5 hydrazine hittride to a solution consisting of F15-
Add -. After the solution is left at room temperature for 5 hours, aqueous methanol is added. Quantify the precipitate and add methanol/water (
After washing with 1:9) and drying, the title compound is obtained. Melting point 160°, [α] back = -19° (C = l, DMF
).

10H-Cys(MBzl)-Thr-ol
) Boc-Cys(MBxl)-T to refluoroacetate TFA5Q-
A solution consisting of hr -ol 7.1y, thioanisole 5- and methylene chloride 25- is added and left at room temperature for 20 minutes. After diluting the solution with about 1.5 L of ether,
The precipitate is separated, washed with ether and dried to give the title compound. [α] Wisdom = 8.3° (c = 1.1.95%
Ac0H).

1) Boc-Cys(MBzl)-Thr-o
A mixed solution consisting of fBoc-Cys(hlBzl) -OR6,39 and THF5Q- was cooled in advance to -20', and N-methylmorpholine 2.1- was added thereto with stirring, and then inbutyl chloroformate 2. .4- to -1
Drop at 5°. After stirring for 5 minutes at −15″,
A cold solution (-1
0°). The mixture is stirred at Oo for 2 hours and then at room temperature for 2 hours. 10f3 potassium hydrogen carbonate 50-
was added, diluted with ethyl acetate, and diluted with 2N citric acid.
Wash twice with 10% potassium bicarbonate and then with 30% saline. The organic layer is dried over Glauber's salt and concentrated in vacuo to give the title compound as an oil. [α−+ 20
== −31° (c = 1.3 + DMF).

j) Boc-(D)Phe-Cys(MBzl)
-Phe-(DJ-Trp-Lys (Boc)-
Thr-Cys(MBz1)-Thr-ol
lloc -(,1JPhe-Cys(NiBzl
) -Phe-(D)Trp-Lys(Boc
) -Thr -Ni-X-NH2O, 82F and D
After the mixture consisting of MF30- was previously cooled to -20°, a mixture of about 5N hydrochloric acid and 0.7-ether was added thereto with stirring, and then 0.8M of 101-butyl nitrite was added.
Add the 1-dimethylformamide mixture dropwise.

Stir the mixture for 15 minutes at -20° to -15″.

NEt30-564 was added at -256C, then pre-cooled to -15°, H-Cys(MBzl)-τhr
A solution consisting of 0.51F of -o1 Shiohunshio and DMF3- is added, and the mixture is stirred at 15° to 0'' for 20 hours and then at room temperature for 3 hours.
After diluting with J, add Honsuri 404 to precipitate the product. The precipitate is collected in F, washed with aqueous methanol and dried to give the title compound.

Decomposition point 170°, [α] = -20° (c = 1.D
MF).

Example IB (Reference Example) The product of Example 1A above can also be obtained by the following synthetic procedure: The above method and solidification give the following compounds (unless otherwise indicated, all compounds are acetate): Rug, No, No, Φ Practical example 19 Practical example 20 [α]20= -xof (C=1.0, 95% Ac
0)1).

Example 21 [α force=-3(/' (c=1.o, 95% Ac
0H).

Example 22 (cg:l D=-+f (c=1.0, 95
%Aco)x).

Example #i Example 23 The reaction procedure was carried out in the same manner as in Examples vAJ1-22 except for the final oxidation step, and the I-chain polypeptides (i.e., the 1st and 6th positions) corresponding to the individual monocyclic polypeptides were The -Cγ residue of is not specified). That is, excluding the final oxidation step from the process of Example IA, the formula: %Formula%

Claims (6)

[Claims] (1) Hexapeptide residues include a cysteine residue at the 1st position (N-terminus), a phenylalanine residue that may be substituted with a ring at the 2nd position, a tryptophan residue that may be substituted with a benzene ring at the 3rd position, and a tryptophan residue that may be substituted with a benzene ring at the 4th position. a lysine residue that may be ε-N-alkylated, an amino acid residue at the 5th position, and a lysine residue at the 6th position (G
has a cysteine or cysteinol residue at the end),
When the polypeptide is monocyclic, the sulfur atom of the cysteine residue at position 1 and the sulfur atom of the cysteine or cysteinol residue at position 6 are linked to form an -S-S- bridge; The residues at positions 3, 5, and 6 independently have a D- or L-configuration, and the residues at positions 3, 4, and 5 are each independently α-N-alkylated. Linear or monocyclic polypeptides containing such hexapeptide residues (but not mathematical formulas, chemical formulas, tables, etc.) and their salts and complex salts. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, A is hydrogen, C_1_-_1_2 alkyl, C_7_-_
1_0 phenylalkyl or a group of the formula RCO-, where i) R is hydrogen, C_1_-_1_1 alkyl, phenyl or C_7_-_1_0 phenylalkyl, or ii) RCO- is a) halogen, nitro, amino, hydroxy, C_1_ -_3 alkyl and/or C_1_-
_3 L- or D-phenylalanine residues optionally substituted in the ring by alkoxy, b) residues of natural α-amino acids or corresponding D-amino acids other than those defined in a) above, or c) Dipeptide residues in which the individual amino acid residues are the same or different and are selected from those defined in a) and/or b) above, wherein the α-amino group of the amino acid residues a) and b) and the N-terminal amino group of the dipeptide residue c) may be mono- or di-C_1_-_1_2 alkylated), A' is hydrogen or when A is C_1_-_1_2 alkyl or C_7_-_1_0 phenylalkyl , also C_1_-_1_2 alkyl or C_7_
-_1_0 phenylalkyl, B is halogen, nitro, amino, hydroxy, C_1_
-Phe-, which may be ring-substituted by -_3 alkyl and/or C_1_-_3 alkoxy, C is α
-(L)- or (D )-T
rp-, D may be α-N-methylated, or ε-N-
C_1_-_3 -Lys- which may be alkylated
, E is a natural α, which residue may be α-N-methylated.
- amino acid or corresponding D-amino acid residue, F is the formula -COOR_1, -CH_2OR_2, ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. group, R_3 is hydrogen, C_1_-_3 alkyl, phenyl or C_7_-_1_0 phenylalkyl, R_4 is hydrogen, C_1_-_3 alkyl or R_3
When is hydrogen or methyl, the formula -CH(R_5)-
X, R_5 are hydrogen, -(CH_2)_2-OH or -(CH_2)_3-OH or α of natural α-amino acid
- a substituent bonded to a carbon atom, and X is a group with the formula -COOR_1, -CH_2OR_2, or ▲numerical formula, chemical formula, table, etc. (R_1 and R_2 have the same meanings as above) , R_6 is hydrogen or C_1_-_3 alkyl, R_7 is hydrogen, C_
1_-_3 alkyl, phenyl or C_7_-_1_
0 phenylalkyl and the group -CH(R_5)-X has a D- or L-configuration)) Y_1 and Y_2 are each hydrogen or together represent a direct bond, in which case 1 The residues at positions 1 and 6 each independently have an L- or D-configuration, provided that D- and/or L-cysteine residues are present only at positions 1 and 6 (provided that ▲Math,
The polypeptide according to claim 1, and its salts and complex salts, represented by the chemical formula, table, etc. (3) A is hydrogen, C_1_-_3 alkyl, C_7_-
_1_0 phenyl or a group of formula RCO-, A' is hydrogen, R is hydrogen, C_1_-_3 alkyl, phenyl or C
_7_-_1_0 phenylalkyl or RCO is a) halogen, nitro, amino, hydroxy,
L- or D-phenylalanine residues optionally mono-ring substituted by C_1_-_3 alkyl or C_1_-_3 alkoxy, or b) natural α-amino acids other than those defined in (a) above, or The corresponding D-amino acid residues, but the amino groups of amino acid residues a) and b) may be mono-C_1_-_3 alkylated, F
is a group with the formula -COOR_1, -CH_2OR_2 or ▲a mathematical formula, chemical formula, table, etc., R_2 is hydrogen, R_3 is hydrogen or C_1_-_3 alkyl, R_7 is hydrogen or C_1_-_3 alkyl, and Y_1 and Y_2 are taken together indicates a direct bond, B, C, D,
E, R_1, R_4, R_5, R_6, and X have the same meanings as in claim 2 (provided that ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ ) The polypeptide according to claim 2 and acid addition salts and complex salts thereof. (4) The polypeptide according to claim 2 having the formula ▲ including mathematical formulas, chemical formulas, tables, etc., and acid addition salts and complex salts thereof. (5)a) Protected linear or monocyclic polypeptides containing a hexapeptide as defined in claim 1, in particular having the structure of formula I as defined in claim 2 b) each peptide unit contains at least one amino acid residue or amino alcohol residue in protected or unprotected form; protected or unprotected linear or monocyclic polypeptides, the peptide units of which contain a hexapeptide residue as defined in claim 1, in particular the formula of claim 2
linking two peptide units by an amide bond, such that a protected or unprotected polypeptide having the structure I is obtained, and, if necessary, carrying out the method of step a); c ) a functional group at the N-terminus or C-terminus of a protected or unprotected linear or monocyclic polypeptide containing a hexapeptide residue as defined in claim 1, in particular the formula I of claim 2; The A or F group of a protected or unprotected polypeptide having the structure of
or converted into a group F, and if necessary, a)
d) a linear polypeptide containing a hexapeptide as defined in claim 1, in particular a polypeptide of formula I according to claim 2, wherein Y_1 and Y_2 are each hydrogen; oxidation to produce a monocyclic polypeptide as defined in claim 1, in particular a polypeptide of formula I of claim 2, in which Y_1 and Y_2 are taken together in a direct bond, and then optionally A method for producing a compound according to claim 1 or 2, characterized in that the polypeptide thus obtained is converted into its salts or complex salts. (6) A pharmaceutical composition obtained by adding a pharmaceutically acceptable filler or carrier to the polypeptide claimed in any one of claims 1 to 5 or a pharmaceutically acceptable salt or complex salt thereof.