KR20070031949A - Metastin derivatives and use thereof - Google Patents

Abstract

The present invention provides stable metastine derivatives having excellent biological activity (cancer metastasis inhibiting activity, cancer growth inhibiting activity, etc.). By modifying the constituent amino acids of metastins with specific modifiers, metastin derivatives have been found that have improved blood stability and the like than the original metastins and exhibit excellent cancer metastasis inhibiting activity or cancer growth inhibiting activity. In addition, it has been shown to have an effect of inhibiting gonadotropin secretion, suppressing sex hormone secretion, etc., and having completely different effects from those previously known.

Description

Metastin Derivatives and Uses thereof {METASTIN DERIVATIVES AND USE THEREOF}

The present invention relates to metastin derivatives and their use.

Metastine derived from humans (also called KiSS-1 peptide) (WO 00/24890) and metastines derived from rat or mouse (WO 01/75104) are known. Sustained release formulations containing metastine are also known (WO 02/85399).

Reportedly, metastine has a cancer metastasis inhibitory effect and can be used to treat cancer (eg, lung cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, kidney cancer, Effective for preventing or treating bladder cancer, brain tumors, etc.); Metastine also has a pancreatic function modulatory effect, which is effective in preventing or treating pancreatic diseases (eg, acute or chronic pancreatitis, pancreatic cancer, etc.); Metastine also has a function of placental function, which is effective in preventing or treating chorionic carcinoma, hydatid mole, invasive condition, miscarriage, fetal development, abnormal glucose metabolism, abnormal lipid metabolism or abnormal delivery (WO 00 / 24890; WO 01/75104; WO 02/85399).

An object of the present invention is to provide a stable metastin derivative having excellent biological activity (cancer metastasis inhibiting activity, cancer growth inhibiting activity, etc.).

As a result of intensive studies to solve the above problems, the inventors have unexpectedly modified the amino acid constituting metastine with specific modification groups, thereby unexpectedly showing the metastine derivatives having improved blood stability compared to the original metastine, and the like. It has been found to exhibit excellent cancer metastasis inhibiting activity or cancer growth inhibiting activity. Furthermore, the inventors have unexpectedly found that these metastin derivatives have gonadotropin secretion inhibitory action, sex hormone secretion inhibitory action, and the like, which are completely different from those known to date. Based on these findings, the inventors continued further investigations to complete the present invention.

That is, the present invention provides the following features and the like.

(1) metastin derivatives (II) represented by the following formula or salts thereof:

[In meals:

V is a group represented by the following formula:

Or a group represented by the formula:

n represents 0 or 1;

W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1 and when W ¹ is O, n represents 0);

W ² represents N or CH;

Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group;

Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S;

R ² is (1) a hydrogen atom or (2) a cyclic or linear C _1-10 alkyl group, (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) an optionally substituted carbamoyl group, A C _1-8 alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted hydroxyl group and an optionally substituted aromatic ring group;

R ³ is (1) an C _1-8 alkyl group having an optionally substituted basic group, optionally having additional substituents, (2) an aralkyl group having an optionally substituted basic group, optionally having an additional substituent, (3) optionally substituted A C _1-4 alkyl group having a non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms having a basic group and optionally having additional substituents, or (4) having 7 or less carbon atoms having an optionally substituted basic group and optionally having additional substituents A C _1-4 alkyl group having a non-aromatic heterocyclic group;

R ⁴ represents a C _1-4 alkyl group which may be optionally substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , Optionally substituted 5- to 14-membered aromatic heterocyclic group, (3) optionally substituted C _8-14 aromatic conjugated ring group, consisting of hetero atoms selected from the group consisting of oxygen and sulfur atoms, (4) 3 to 11 An optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, And (6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms;

Q ¹ represents a C _1-4 alkyl group which may be optionally substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , Optionally substituted 5- to 14-membered aromatic heterocyclic group, (3) optionally substituted C _8-14 aromatic conjugated ring group, consisting of hetero atoms selected from the group consisting of oxygen and sulfur atoms, (4) 3 to 11 An optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, And (6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms;

Q ² is CH ₂ , (2) carbamoyl and hydroxyl groups, which may be optionally substituted with an optionally substituted C _1-4 alkyl group having a substituent selected from the group consisting of (1) carbamoyl groups and hydroxyl groups It represents an optionally substituted C ₁ random which may be substituted, NH _-4 alkyl group, or (3) O with substituents selected from the group consisting of;

Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH _2- , or -CH = CH- (which may be optionally substituted by C _1-6 alkyl group);

Z ⁹ represents a hydrogen atom, O or S;

P and P 'may be the same or different and may combine P and P' or P and Q ¹ together to form a ring, respectively:

(1) hydrogen atoms;

(2) an optional amino acid residue that is linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the following formula:

(In the meal:

J ¹ is (a) a hydrogen atom or (b) (i) a C _1-15 acyl group, (ii) a C _1-15 alkyl group, (iii) a C _6-14 aryl group, (iv) a carbamoyl group, (v A) carboxyl group, (vi) sulfino group, (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group, wherein the groups may be optionally substituted with a substituent including an optionally substituted ring group;

J ² represents (1) NH optionally substituted with C _1-6 alkyl group, (2) CH ₂ optionally substituted with C _1-6 alkyl group, (3) O or (4) S;

J ³ to J ⁶ each represent a hydrogen atom or a C _1-3 alkyl group;

Q ³ to Q ⁶ represent a C _1-4 alkyl group which may optionally have a hydrogen atom or a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group,

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(3) an optionally substituted C _8-14 aromatic conjugated ring group,

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms,

(6) an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms,

(7) an optionally substituted amino group,

(8) an optionally substituted guanidino group,

(9) an optionally substituted hydroxyl group,

(10) an optionally substituted carboxyl group,

(11) an optionally substituted carbamoyl group, and

(12) optionally substituted sulfhydryl groups;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ are combined with each other, or J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ , or Y ³ and Q ⁶ may be combined with each other to form a ring;

Y ¹ to Y ³ each represent a group represented by the following formula:

-CON (J ¹³ )-, -CSN (J ¹³ )-, -C (J ¹⁴ ) N (J ¹³ )-or -N (J ¹³ ) CO-, wherein J ¹³ and J ¹⁴ are each hydrogen atoms Or a C _1-3 alkyl group); And,

Z ¹⁰ represents a hydrogen atom, O or S);

(4) a group represented by the following formula:

(In the meal:

J ¹ and J ² each have the same meaning as described above;

J ⁷ to J ⁹ have the same meaning as for J ³ ;

Q ⁷ to Q ⁹ have the same meaning as for Q ³ ;

Y ² and Y ³ each have the same meaning as described above;

Z ¹⁰ has the same meaning as described above;

J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ may be combined with each other, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ may be combined with each other to form a ring. have);

(5) a group represented by the following formula:

(In the meal:

J ¹ and J ² have the same meaning as described above;

J ¹⁰ and J ¹¹ have the same meaning as for J ³ ;

Q ¹⁰ and Q ¹¹ have the same meaning as for Q ³ ;

Y ³ has the same meaning as described above;

Z ¹⁰ has the same meaning as described above;

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ may be combined with each other, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ may be combined with each other to form a ring);

(6) a group represented by the following formula:

(In the meal:

J ¹ and J ² have the same meaning as described above;

J ¹² has the same meaning as for J ³ ;

Q ¹² has the same meaning as for Q ³ ;

Z ¹⁰ has the same meaning as described above; And,

J ¹² and Q ¹² may be combined with each other, or J ² and Q ¹² may be combined with each other to form a ring); or,

(7) a group represented by the following formula:

J ^1-

(In the meal:

J ¹ has the same meaning as described above), provided that 1-54, 2-54, 3-54, 4-54, 5-54, 6-54, 7 of the amino acid sequence represented by SEQ ID NO: 1 -54, 8-54, 9-54, 10-54, 11-54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54 , 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32 -54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54, 41-54, 42-54, 43-54, 44-54 , Except for peptides consisting of the amino acid sequences 45-54, 46-54, 47-54, 48-54 or 49-54).

(2) The metastin derivative (II) or salt thereof according to (1), wherein V is a group represented by the following formula:

(Wherein each symbol has the same meaning as defined in (1)).

(3) The metastin derivative (II) or salt thereof according to (1), wherein V is a group represented by the following formula:

(Wherein each symbol has the same meaning as defined in (1)).

The present invention further provides the following features and the like.

(4) A prodrug of metastine derivative (II) or a salt thereof according to (1).

(5) A drug containing the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(6) The drug of (5), which is a cancer metastasis inhibitor or a cancer growth inhibitor.

(7) The drug according to (5), which is an agent for preventing or treating cancer.

(8) The drug according to (5), which is a pancreatic function modulator.

(9) The drug according to (5), which is an agent for preventing or treating acute or chronic pancreatitis or pancreatic cancer.

(10) The drug according to (5), which is a placental function modulator.

(11) The drug according to (5), which is a prophylactic or therapeutic agent for chorionic carcinoma, larynx, invasive, abortion, fetal dysfunction, abnormal glucose metabolism, abnormal lipid metabolism or induction of labor.

(12) The drug according to (5), which is a gonad function improving agent.

(13) The drug according to (5), which is an agent for preventing or treating hormone-dependent cancer, infertility, endometriosis, early puberty or uterine fibroids.

(14) The drug according to (5), which is an ovulation induction or stimulant.

(15) The drug according to (5), wherein the gonadotropin secretion promoter or sex hormone secretagogue is used.

(16) The drug according to (5), which is an agent for preventing or treating Alzheimer's disease or mild cognitive impairment.

(17) A method for inhibiting cancer metastasis or cancer growth, comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(18) A method for preventing or treating cancer, comprising administering to a mammal an effective amount of a metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(19) A method for controlling pancreatic function, comprising administering to the mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(20) A method for preventing or treating acute or chronic pancreatitis or pancreatic cancer comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(21) A method for controlling placental function comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(22) chorionic carcinoma, award status, invasive status, miscarriage, fetal insufficiency, abnormal glucose, comprising administering to the mammal an effective amount of the metastin derivative (II) according to (1), or a salt thereof, or a prodrug thereof Method of preventing or treating metabolism, abnormal lipid metabolism or induction of labor.

(23) A method for improving gonad function, comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(24) hormone-dependent cancer, infertility, endometriosis, early puberty, comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof Or methods of preventing or treating uterine fibroids.

(25) A method of inducing or stimulating ovulation comprising administering to a mammal an effective amount of a metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(26) A method for promoting gonadotropin secretion or sex hormone secretion comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(27) A method for preventing or treating Alzheimer's disease or mild cognitive disorder comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(28) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof for the production of a cancer metastasis inhibitor or a cancer growth inhibitor.

(29) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the manufacture of a prophylactic or therapeutic agent for cancer.

(30) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof for the preparation of a pancreatic function modulator.

(31) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the manufacture of a prophylactic or therapeutic agent for acute or chronic pancreatitis or pancreatic cancer.

(32) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof for the preparation of a placental function modulator.

(33) The metastin derivative (II) according to (1), or a preparation thereof, for the manufacture of a prophylactic or therapeutic agent for chorionic carcinoma, larynx, invasive, abortion, fetal dysfunction, abnormal glucose metabolism, abnormal lipid metabolism or delivery Salts, or prodrugs thereof.

(34) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the preparation of a gonadal function improving agent.

(35) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the manufacture of a prophylactic or therapeutic agent for hormone-dependent cancer, infertility, endometriosis, early puberty or uterine fibroids.

(36) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for producing an ovulation inducing or stimulating agent.

(37) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the manufacture of a gonadotropin secretion accelerator or a sex hormone secretagogue.

(38) Use of a metastin derivative (II) or a salt thereof, or a prodrug thereof according to (1) for the manufacture of an agent for the prophylaxis or treatment of Alzheimer's disease or mild cognitive impairment.

(39) A pancreatic glucagon secretion accelerator comprising the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(40) A urine formation accelerator containing the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(41) obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retina, containing the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof Prophylactic or therapeutic agents for conditions, edema, urination disorders, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulinoma, atherosclerosis, thrombotic disorders or lipotoxicity.

(42) A method for promoting pancreatic glucagon secretion comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(43) A method for promoting urine formation comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof.

(44) obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, comprising administering to a mammal an effective amount of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof , Methods of preventing or treating diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorder or lipotoxicity.

(45) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof for the preparation of a pancreatic glucagon secretion accelerator.

(46) Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof for the production of a urine formation accelerator.

(47) obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorder, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulin species, artery Use of the metastin derivative (II) according to (1) or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis or treatment of sclerosis, thrombotic disorder or lipotoxicity.

(48) gonadotropin secretion inhibitors or sex hormone secretion inhibitors containing metastin derivative (III) or salts thereof, or prodrugs thereof represented by the following formula:

[In meals:

V 'is a group represented by the following formula:

A group represented by the following formula:

Or a group represented by the following formula:

Represents;

n represents 0 or 1;

W ¹ represents N, CH or O, provided that when W ¹ is N or CH, n represents 1 and when W ¹ is O, n represents 0;

W ² represents N or CH;

Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group;

Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S;

R ¹ is a C _1-8 alkyl group optionally substituted with a substituent selected from the group consisting of (1) a hydrogen atom, (2) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and an optionally substituted aromatic ring group, (3 A cyclic or linear C _1-10 alkyl group or (4) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (5) an optionally substituted aromatic ring group;

R ² is (1) a hydrogen atom or (2) a cyclic or linear C _1-10 alkyl group, (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) an optionally substituted carbamoyl group, A C _1-8 alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted hydroxyl group and an optionally substituted aromatic ring group;

R ³ is (1) an C _1-8 alkyl group having an optionally substituted basic group, optionally having additional substituents, (2) an aralkyl group having an optionally substituted basic group, optionally having an additional substituent, (3) optionally substituted A C _1-4 alkyl group having a non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms having a basic group and optionally having additional substituents, or (4) having 7 or less carbon atoms having an optionally substituted basic group and optionally having additional substituents A C _1-4 alkyl group having a non-aromatic heterocyclic group;

R ⁴ represents a C _1-4 alkyl group which may be optionally substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen Optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of hetero atoms selected from the group consisting of oxygen and sulfur atoms, (3) optionally substituted C _8-14 aromatic conjugated ring groups, (4) 3 to 11 carbon atoms Optionally substituted 5- to 14-membered aromatic conjugated heterocyclic groups consisting of atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms, and ( 6) optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms;

Q ¹ represents a C _1-4 alkyl group which may be optionally substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen Optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of hetero atoms selected from the group consisting of oxygen and sulfur atoms, (3) optionally substituted C _8-14 aromatic conjugated ring groups, (4) 3 to 11 carbon atoms Optionally substituted 5- to 14-membered aromatic conjugated heterocyclic groups consisting of atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms, and ( 6) optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms;

Q ² is (2) CH ₂ , (2) carbamoyl and hydroxyl groups which may be optionally substituted with an optionally substituted C _1-4 alkyl group having a substituent selected from the group consisting of carbamoyl groups and hydroxyl groups NH, which may be optionally substituted with an optionally substituted C _1-4 alkyl group having a substituent selected from the group consisting of (3) O; Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH _2- , or -CH = CH- (which may be optionally substituted with C _1-6 alkyl groups);

Z ⁹ represents a hydrogen atom, O or S;

P and P 'may be the same or different and may combine P and P' or P and Q ¹ with each other to form a ring, which is represented below:

(1) hydrogen atoms;

(2) an optional amino acid residue that is linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the following formula:

(In the meal:

J ¹ is (a) a hydrogen atom or (b) (i) a C _1-15 acyl group, (ii) a C _1-15 alkyl group, (iii) a C _6-14 aryl group, (iv) a carbamoyl group, (v A) carboxyl group, (vi) sulfino group, (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group, wherein the groups may be optionally substituted with a substituent including an optionally substituted ring group;

J ² represents (1) NH optionally substituted with C _1-6 alkyl group, (2) CH ₂ optionally substituted with C _1-6 alkyl group, (3) O or (4) S;

J ³ to J ⁶ each represent a hydrogen atom or a C _1-3 alkyl group;

Q ³ to Q ⁶ each represent a hydrogen atom or a C _1-4 alkyl group which may optionally have a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group,

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(3) an optionally substituted C _8-14 aromatic conjugated ring group,

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms,

(6) an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms,

(7) an optionally substituted amino group,

(8) an optionally substituted guanidino group,

(9) an optionally substituted hydroxyl group,

(10) an optionally substituted carboxyl group,

(11) an optionally substituted carbamoyl group, and

(12) optionally substituted sulfhydryl groups;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ are combined with each other, or Z ¹ and R ¹ , J ² and Q ³ , Y ¹ and Q ⁴ , Y ² And Q ⁵ , or Y ³ and Q ⁶ may be combined with each other to form a ring;

Y ¹ to Y ³ each represent a group represented by the following formula:

-CON (J ¹³ )-, -CSN (J ¹³ )-, -C (J ¹⁴ ) N (J ¹³ )-or -N (J ¹³ ) CO-, wherein J ¹³ and J ¹⁴ are each hydrogen atoms Or a C _1-3 alkyl group;

Z ¹⁰ represents a hydrogen atom, O or S);

(4) a group represented by the following formula:

(In the meal:

J ¹ and J ² each have the same meaning as described above;

J ⁷ to J ⁹ have the same meaning as for J ³ ;

Q ⁷ to Q ⁹ have the same meaning as for Q ³ ;

Y ² and Y ³ each have the same meaning as described above;

Z ¹⁰ has the same meaning as described above;

J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ may be combined with each other, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ may be combined with each other to form a ring. have);

(5) a group represented by the following formula:

(In the meal:

J ¹ and J ² have the same meaning as described above;

J ¹⁰ and J ¹¹ have the same meaning as for J ³ ;

Q ¹⁰ and Q ¹¹ have the same meaning as for Q ³ ;

Y ³ has the same meaning as described above;

Z ¹⁰ has the same meaning as described above;

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ may be combined with each other, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ may be combined with each other to form a ring);

(6) a group represented by the following formula:

(In the meal:

J ¹ and J ² have the same meaning as described above;

J ¹² has the same meaning as for J ³ ;

Q ¹² has the same meaning as for Q ³ ;

Z ¹⁰ has the same meaning as described above;

J ¹² and Q ¹² may be combined with each other, or J ² and Q ¹² may be combined with each other to form a ring); or,

(7) a group represented by the following formula:

J ¹ -wherein J ¹ has the same meaning as described above.

(49) The inhibitor according to (48), wherein the metastin derivative (III) is the metastin derivative (II) according to (1).

(50) The inhibitor according to (48), wherein V 'is a group represented by the following formula:

(In formula, each symbol has the same meaning as described in (48).).

(51) The inhibitor according to (48), wherein V 'is a group represented by the following formula:

(In formula, each symbol has the same meaning as described in (48).).

(52) The inhibitor according to (48), wherein V 'is a group represented by the following formula:

(Wherein each symbol has the same meaning as described in claim 48).

(53) The inhibitor according to (48), wherein the metastin derivative (III) is:

(화합물 번호 141), (One)

(Compound number 141),

(화합물 번호 174), (2)

(Compound number 174),

(3) 3- (3-indolyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 260),

(4) 3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 269),

(5) 2- (indol-3-yl) ethylcarbamoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 279),

(6) D-Tyr-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 286),

(7) D-Tyr-Asn-Trp-Asn-Ser-PheΨ (CSNH) Gly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 296),

(8) TyrΨ (CH ₂ NH) Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 300),

(9) D-Tyr-D-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 303),

(10) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 305),

(11) D-Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂ (Compound No. 318),

(12) D-Tyr-Asn-Trp-Asn-Ser-PheΨ (NHCO) Gly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 319),

(13) 3- (3-pyridyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 322),

(14) 4-imidazolacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 323),

(15) GuAmb-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 332),

(16) GuAmb-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 333),

(17) GuAmb-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 334),

(18) 3- (3-indolyl) propionyl-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 339),

(19) Benzoyl-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 341),

(20) indole-3-acetyl-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 345),

(21) Ac-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 346),

(22) Benzoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 353),

(23) 3- (3-indolyl) propionyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 354),

(24) Ac-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 358),

(25) 2- (indol-3-yl) ethylcarbamoyl-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 364),

(26) 2- (indol-3-yl) ethylcarbamoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 369),

(27) (2S) -2-acetoxy-3-phenylpropionyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 373),

(28) (2S) -2- (3-indolylpropionyloxy) -3-phenylpropionyl-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 379),

(29) (2S) -2-benzoyloxy-3-phenylpropionyl-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 380),

(30) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 385),

(31) 3- (3-pyridyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 386),

(32) dibenzylcarbamoyl-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 393),

(33) benzylphenethylcarbamoyl-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 417),

(34) Benzoyl-PheΨ (NHCO) Gly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 423),

(35) Benzoyl-AzaPhe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 431),

(36) 3-pyridinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 432),

(37) 2-pyridinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 435),

(38) 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 436),

(39) Propionyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 437),

(40) Isobutyryl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 438),

(41) cyclohexanecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 439),

(42) Phenylacetyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 440),

(43) Benzoyl-Pya (2) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 441),

(44) 6-Methylnicotinoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 445),

(45) pyrazinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 446),

(46) cyclopropanecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 447),

(47) trifluoroacetyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound number 448),

(48) Benzoyl-Cha-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 449),

(49) cyclopropanecarbonyl-Cha-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 451),

(50) (R) -3-hydroxy-2-methylpropionyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 452),

(51) 2-hydroxyisobutyryl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 453),

(52) 3-furancarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 454),

(53) pyrrole-2-carbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 455),

(54) 4-imidazolcarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 459),

(55) 6-hydroxynicotinoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 462),

(56) 6-chloronicotinoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 463),

(57) 6- (trifluoromethyl) nicotinoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 464),

(58) Dimethylcarbamoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 467),

(59) 1-azetidinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 468),

(60) 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 471),

(61) 4-aminobenzoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 472),

(62) 4-aminomethylbenzoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 473),

(63) pyrrole-3-carbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 474),

(64) pyrimidine-4-carbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH 2 (Compound No. 475),

(65) pyrimidine-2-carbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 479),

(66) pyridazine-4-carbonyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 480),

(67) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Har-Trp-NH ₂ (Compound No. 481),

(68) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Lys-Phe-NH ₂ (Compound No. 487),

(69) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Har-Phe-NH ₂ (Compound No. 488),

(70) D-Tyr-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 490),

(71) D-Tyr-D-Pya (4) -Asn-Trp-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 491),

(72) D-Tyr-D-Pya (4) -Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 492),

(73) D-Tyr-D-Pya (4) -Thr-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 493),

(74) D-Tyr-D-Pya (4) -Asn-Ser-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 496),

(75) D-Tyr-D-Pya (4) -Asn-Ser-Cha-Ala-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 497),

(76) D-Tyr-D-Pya (4) -Asn-Ile-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 498),

(77) 3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 499),

(78) 3-phenylpropionyl-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 500),

(79) D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 501),

(80) D-Tyr-Pya (4) -Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 502),

(81) D-Tyr-D-Trp-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 503),

(82) 6-aminocaproyl-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 504),

(83) 3-phenylpropionyl-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 505),

(84) 3-phenylpropionyl-Asn-Ile-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 506),

(85) 3-phenylpropionyl-Asn-Ser-Trp-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 507),

(86) 3-phenylpropionyl-Asn-Ser-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 508),

(87) Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 509),

(88) Ac-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 510),

(89) D-Tyr-D-Trp-Ala-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 511),

(90) D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 512),

(91) D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 513),

(92) D-Tyr-D-Phe-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 514),

(93) D-Tyr-D-Pya (4) -Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 515),

(94) des (1) -Ac- [D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9] MS10 (Compound No. 516),

(95) des (1-3) -3-phenylpropionyl- [Hyp5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 517),

(96) des (1-3) -3-phenylpropionyl- [Cha6, Arg (Me) 9, Trp10] MS10 (Compound No. 518),

(97) des (1-3) -phenylacetyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 519),

(98) des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7] MS10 (Compound No. 521),

(99) des (1-3) -benzoyl- [Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 522),

(100) des (1-3) -benzoyl- [Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 523),

(101) des (1-3) -3-phenylpropionyl- [Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 524),

(102) des (1)-[D-Tyr2, D-Pya (4) 3, Hyp5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 527),

(103) des (1)-[D-Tyr2, D-Pya (4) 3, Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 528),

(104) des (1)-[D-Tyr2, D-Pya (4) 3, Tle5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 529),

(105) des (1)-[D-Tyr2, D-Pya (4) 3, Phg5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 530),

(106) des (1-3) -3-phenylpropionyl- [Pic (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 531),

(107) des (1-3) -3-phenylpropionyl- [Aze (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 532),

(108) des (1-3) -3-phenylpropionyl- [D-Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 533),

(109) des (1-3) -cyclopropanecarbonyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 534),

(110) des (1-3) -2-naphthoyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 535),

(111) [Arg 1, D-Tyr 2, D-Pya (4) 3, AzaGly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 536),

(112) Arg- [Arg1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 537),

(113) Arg- [Acp1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 538),

(114) des (1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 539),

(115) des (1)-[D-Tyr2, D-Trp3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 540),

(116) D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 541),

(117) D-Arg-D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 542),

(118) des (1-3) -benzoyl- [Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 545),

(119) des (1-3) -3-phenylpropionyl- [Ser (Ac) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 546),

(120) des (1)-[D-Tyr2, D-Pya (4) 3, Ser (Ac) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 547),

(121) des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9,10Ψ, CSNH] MS10 (Compound No. 548),

(122) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 550),

(123) Ac-D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 551),

(124) D-Dap- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 552),

(125) D-Nle- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 553),

(126) D-Arg- [β-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 554),

(127) D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 555),

(128) D-Arg-D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 556),

(129) D-Arg-D-Arg-D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 557),

(130) des (1) -Ac- [D-Tyr2, D-Trp3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 558),

(131) des (1-2) -3- (4-hydroxyphenyl) propionyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 559),

(132) D-Arg- [Acp1, D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 561),

(133) des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 562),

(134) des (1) -Ac- [D-Tyr2, D-Trp3, Aze (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 563),

(135) des (1) -Ac- [D-Tyr2, D-Trp3, Val5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 564),

(136) des (1) -benzoyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 565),

(137) des (1) -cyclopropanecarbonyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 566),

(138) des (1) -butyryl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 567),

(139) Ac- [D-Arg1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 568),

(140) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5,6Ψ7, CH2NH, Arg (Me) 9, Trp10] MS10 (Compound No. 569),

(141) des (1) -Me- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 570),

(142) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9] MS10 (Compound No. 571),

(143) des (1)-[D-Trp2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 572),

(144) des (1) -Ac- [D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 573),

(145) des (1) -Ac- [D-Tyr2, D-Trp3, Gln4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 576),

(146) des (1) -Ac- [D-Tyr2, D-Trp3, Ser4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 577),

(147) des (1) -Ac- [D-Tyr2, D-Trp3, Thr4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 578),

(148) des (1) -Ac- [D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 579),

(149) des (1) -Ac- [D-Tyr2, D-Trp3, Ser (Me) 5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 580),

(150) des (1) -Ac- [D-Tyr2, D-Trp3, Dap (Ac) 4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 584),

(151) des (1) -Ac- [D-Tyr2, D-Trp3, Dap (For) 4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 585),

(152) des (1) -Ac- [D-Tyr 2, Thr 5, D-Phe 6, AzaGly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 586),

(153) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Nal (2) 10] MS10 (Compound No. 589),

(154) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Thi10] MS10 (Compound No. 590),

(155) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Tyr10] MS10 (Compound No. 591),

(156) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Phe (4F) 10] MS10 (Compound No. 592),

(157) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Hph10] MS10 (Compound No. 594),

(158) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Cha10] MS10 (Compound No. 595),

(159) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Leu10] MS10 (Compound No. 596),

(160) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 597),

(161) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Arg (Me) 9, Trp10] MS10 (Compound No. 598),

(162) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10] MS10 (Compound No. 599),

(163) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10] MS10 (Compound No. 600),

(164) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg (Me) 9, Trp10] MS10 (Compound No. 601),

(165) des (1) -Ac- [D-NMeTyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 Compound No. 602),

(166) des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, D-Phe6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 603),

(167) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Tos) 9, Trp10] MS10 (Compound No. 604),

(168) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (NO2) 9, Trp10] MS10 (Compound No. 605),

(169) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me2) asym9, Trp10] MS10 (Compound No. 607),

(170) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me2) sym9, Trp10] MS10 (Compound No. 608),

(171) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Et) 9, Trp10] MS10 (Compound No. 609),

(172) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys (Me2) 9, Trp10] MS10 (Compound No. 610),

(173) des (1) -Ac- [Tyr 2, D-Pya (4) 3, Thr 5, Aza Gly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 611),

(174) des (1) -For- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 612),

(175) des (1) -propionyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 613),

(176) des (1) -amidino- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 614),

(177) des (1) -Ac- [Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 615),

(178) des (1) -Ac- [D-Ala2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 616),

(179) des (1) -Ac- [D-Leu2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 617),

(180) des (1) -Ac- [D-Phe2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 618),

(181) des (1) -Ac- [D-Nal (1) 2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 619),

(182) des (1) -Ac- [D-Nal (2) 2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 620),

(183) des (1) -Ac- [D-Lys2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 621),

(184) des (1) -Ac- [D-Glu2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 622),

(185) des (1) -Ac- [D-Tyr 2, Thr 5, Aza Gly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 623),

(186) des (1) -Ac- [D-Tyr2, Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 624),

(187) des (1) -Ac- [D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 625),

(188) des (1) -Ac- [D-Tyr2, D-Leu3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 626),

(189) des (1) -Ac- [D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 627),

(190) des (1) -Ac- [D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 628),

(191) des (1) -Ac- [D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 629),

(192) des (1) -Ac- [D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 630),

(193) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Ala6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 631),

(194) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 632),

(195) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 633),

(196) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 634),

(197) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Pya (4) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 635),

(198) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, NMePhe6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 636),

(199) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 637),

(200) des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 638),

(201) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Trp10] MS10 (Compound No. 639),

(202) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg (Me) 9, Trp10] MS10 (Compound No. 641),

(203) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg (Me) 9, Trp10] MS10 (Compound No. 642),

(204) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg (Me) 9, Trp10] MS10 (Compound No. 643),

(205) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg (Me) 9, Trp10] MS10 (Compound No. 644),

(206) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Har9, Trp10] MS10 (Compound No. 645),

(207) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Har (Me) 9, Trp10] MS10 (Compound No. 646),

(208) des (1) -Ac- [D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 647),

(209) [Gly1, D-Tyr2, D-Trp3, Thr5, Aza Gly7, Arg (Me) 9, Trp10] MS10 (Compound No. 648),

(210) Ac- [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 649),

(211) [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 650),

(212) Ac- [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 651),

(213) pGlu-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 652),

(214) des (1) -Ac- [D-Tyr2, D-Trp3, D-Asn4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 653),

(215) des (1) -Ac- [D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 654),

(216) des (1) -Ac- [D-Tyr2, D-Trp3, NMeAsn4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 655),

(217) des (1) -Ac- [D-Tyr2, D-Trp3, NMeSer5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 656),

(218) des (1) -Ac- [D-Tyr 2, Pro 3, Thr 5, Aza Gly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 657),

(219) des (1) -Ac- [D-Tyr2, D-Pya (2) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 658),

(220) des (1) -Ac- [D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 659),

(221) des (1) -Ac- [D-Tyr2, D-Pya (3) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 660),

(222) des (1) -Ac- [D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 661),

(223) des (1) -Ac- [D-Tyr 2, Tic 3, Thr 5, Aza Gly 7, Ar g (Me) 9, Trp 10] MS 10 (Compound No. 662),

(224) des (1) -Ac- [D-Trp2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 663),

(225) des (1) -Ac- [Tyr 2, Thr 5, Aza Gly 7, Arg (Me) 9, Trp 10] MS 10 (Compound No. 664),

(226) des (1-2)-[D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 665),

(227) des (1-2) -Ac- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 666),

(228) des (1-2) -hexanoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 667),

(229) des (1-2) -cyclohexanecarbonyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 668),

(230) des (1-2) -benzoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 669),

(231) des (1-2) -3-pyridinepropionyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 670),

(232) des (1-2) -adifoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 671),

(233) des (1) -Ac- [D-Tyr2, NMeTrp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 672),

(234) des (1-2) -6-aminocaproyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 674),

(235) [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 675)

(236) Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 676)

(237) Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg (Me) 9, Trp10] MS10 (Compound No. 677)

(238) Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ile8, Arg (Me) 9, Trp10] MS10 (Compound No. 678)

(239) des (1-2) -amidino- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 679)

(240) des (1-2) -glyloyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 680)

(241) des (1) -glycloyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 681)

(242) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg (Me) 9, Trp10] MS10 (Compound No. 682)

(243) des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9] MS10 (Compound No. 685)

(244) des (1) -Ac- [D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 686)

(245) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya (4) 9, Trp10] MS10 (Compound No. 688)

(246) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, D-Trp10] MS10 (Compound No. 689)

(247) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 691)

(248) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 692)

(249) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Tyr (Me) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 693)

(250) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Nal (2) 6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 694)

(251) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 695)

(252) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 696)

(253) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg (Me) 9, Trp10] MS10 (Compound No. 698)

(254) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, γMeLeu8, Arg (Me) 9, Trp10] MS10 (Compound No. 699)

(255) des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Aib8,, Arg (Me) 9, Trp10] MS10 (Compound No. 700)

(256) des (1) -Ac- [D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 701)

(257) des (1) -Ac- [D-Tyr2, D-Trp3, Asp (NHMe) 4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 702)

(258) des (1) -Ac- [D-Tyr2, D-Trp3, Asp (NMe2) 4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 703).

(54) The inhibitor according to (48) to (53), which is a downregulator for gonadotropin or sex hormone.

(55) The inhibitor according to (48) to (53), which is a downregulator for human OT7T175 (methastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9.

(56) The inhibitor according to (48) to (55), which is an agent for preventing or treating hormone-dependent cancer.

(57) A method for inhibiting gonadotropin secretion or sex hormone secretion comprising administering to a mammal an effective amount of a metastin derivative (III) or a salt thereof, or a prodrug thereof according to (48).

(58) A method for downregulating gonadal stimulating hormone or sex hormone, comprising administering to a mammal an effective amount of a metastin derivative according to (48) or a salt thereof, or a prodrug thereof.

(59) of a human OT7T175 (methastine receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9 comprising administering to a mammal an effective amount of a metastin derivative according to (48) or a salt thereof, or a prodrug thereof Down regulation method.

(60) A method of preventing or treating hormone-dependent cancer comprising administering to a mammal an effective amount of a metastin derivative according to (48) or a salt thereof, or a prodrug thereof.

(61) Use of a metastin derivative or salt thereof according to (48), or a prodrug thereof, for the preparation of a gonadotropin secretion inhibitor or a sex hormone secretion inhibitor.

(62) Use of a metastin derivative or salt thereof, or a prodrug thereof according to (48) for the preparation of a downregulator for gonadotropin or sex hormone.

(63) Use of the metastin derivative according to (48) or a salt thereof, or a prodrug thereof for the production of a downregulator for human OT7T175 (methastine receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9.

(64) Use of a metastin derivative or salt thereof, or a prodrug thereof according to (48) for the manufacture of an agent for the prophylaxis or treatment of hormone-dependent cancer.

(65) a metastin derivative or a salt thereof represented by the following formula:

(In the meal:

XX0 is formyl, C _1-6 alkanoyl, cyclopropanecarbonyl, 6- (acetyl-D-arginylamino) caproyl, 6-((R) -2,3-diaminopropionylamino) caproyl , 6- (D-norylsilamino) caproyl, 4- (D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyltyro Sil, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3- (pyridin-3-yl) propionyl, adipoyl or 6-aminocaproyl;

XX2 represents Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or bond arm;

XX3 is Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3- Pyridylalanine or D-4-pyridylalanine;

XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyldiaminopropionic acid or N ^β -acetyldiaminopropionic acid;

XX5 represents Ser, Thr or Val;

XX6 represents Phe, Tyr, Trp, Tyr (Me), Thi, Nal (2), Cha, 4-pyridylalanine or 4-fluorophenylalanine;

AzaGlY represents azaglycine;

XX8 represents Leu, Nva or Val;

XX9 represents Arg, Orn, Arg (Me) or Arg (symMe2);

XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine).

(66) D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 305),

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 385),

D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 501),

Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 509),

D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 512),

Ac-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 516),

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 540),

D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 541),

Benzoyl-Asn-Ser-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 545),

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -PheΨ (CSNH) NH ₂ (Compound No. 548),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 550),

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 551),

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 552),

D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 553),

D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 555),

Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 558),

3- (4-hydroxyphenyl) propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 559),

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 562),

Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 564),

Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 566),

Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 567),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 571),

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 579),

Ac-D-Tyr-D-Trp-Asn-Ser (Me) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 580),

Ac-D-Tyr-D-Trp-Dap (Ac) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 584),

Ac-D-Tyr-D-Trp-Dap (For) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 585),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Nal (2) -NH ₂ (Compound No. 589),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Thi-NH ₂ (Compound No. 590),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Tyr-NH ₂ (Compound No. 591),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂ (Compound No. 592),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂ (Compound No. 599),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂ (Compound No. 600),

Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 602),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (symMe2) -Trp-NH ₂ (Compound No. 608),

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 612),

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 613),

Ac-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 615),

Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 616),

Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 617),

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 618),

Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 621),

Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 623),

Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 625),

Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 626),

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 627),

Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 629),

Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 630),

Ac-D-Tyr-D-Trp-Asn-Thr-Pya (4) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 635),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 637),

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 638),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg (Me) -Trp-NH ₂ (Compound No. 642),

Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 648),

Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 649),

D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 650),

Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 651),

pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 652),

Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 657),

Ac-D-Tyr-D-Pya (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 658),

Ac-D-Tyr-D-Pya (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 660),

Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 662),

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 663),

Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 666),

Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 667),

3-pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 670),

Adipoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 671),

Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 672),

6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 674), or salts thereof.

(67) Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 550),

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 551),

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 552),

Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 558),

3- (4-hydroxyphenyl) propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 559),

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 562),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 571),

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 579),

Ac-D-Tyr-D-Trp-Dap (For) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 585),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Nal (2) -NH ₂ (Compound No. 589),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂ (Compound No. 592),

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 612),

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 613),

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 618),

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 627),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 637),

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 638),

Ac-D-Tyr-D-Pya (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 658),

Ac-D-Tyr-D-Pya (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 660),

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 663), or salts thereof.

(68) The inhibitor according to (48), which is an immune enhancer (an infection preventive agent after bone marrow transplantation, an immune enhancer for cancer).

(69) The inhibitor according to (48), which is a prophylactic / treatment agent forbulbospinal muscular dystrophy.

(70) The inhibitor according to (48), which is a prophylactic / treatment agent for ovarian protection.

(71) The inhibitor according to (48), which is a prophylactic / treatment agent for benign prostatic hyperplasia (BPH).

(72) The inhibitor according to (48), which is a prophylactic / treatment agent for sexual identity disorder.

(73) The inhibitor according to (48), which is a prophylactic / treatment agent for in vitro fertilization (IVF).

Brief description of the drawings

1 shows an evaluation of the chemotactic inhibitory activity of Compound Nos. 322, 305, 303, 286, 232 and 141 using hOT7T175-expressing CHO cells. On the abscissa, FBS- means the absence of FBS, FBS + means the presence of FBS, 322 means the addition of compound No. 322, 305 means the addition of compound No. 305 and 303 is the compound Means addition, 286 means addition of compound number 286, 232 means addition of compound number 232, 141 means addition of compound number 141, (1-54) means metastine (1-54 ), And (45-54) means the addition of metastin 45-54. The vertical axis shows relative activity when the chemotactic activity is 100% in the presence of FBS.

FIG. 2 shows an assessment of tumor growth inhibitory activity of Compound No. 322 and Metastin (1-54) using tumor mice with cell line SW620 derived from human colon carcinoma, wherein the value is (mean) + (standard error) Indicates. The symbols o, o, o, o and o are the case where vehicle (distilled water), compound number 322 (0.1 mM), compound number 322 (1 mM), and metastin (methastin 1-54) are added, respectively. The obtained result is shown. The horizontal axis represents the number of days after the injection. Bars on the abscissa indicate the duration of administration. The vertical axis represents the tumor size (i).

FIG. 3 shows an assessment of tumor growth inhibitory activity of Compound No. 305 and Metastin (1-54) using tumor mice with cell line SW620 derived from human colon carcinoma, wherein the value is (mean) + (standard error) Indicates. The symbols o, o, o and o are the results obtained when vehicle (distilled water), compound number 305 (0.1 mM), compound number 305 (1 mM), and metastin (methastin 1-54) were added, respectively. Indicates. The horizontal axis represents the number of days after the injection. Bars on the abscissa indicate the duration of administration. The vertical axis represents the tumor size (i).

Figure 4 shows the results obtained by monitoring the change in blood glucose concentrations when intravenous injection of metastine into rats under anesthesia. In the figure, symbols ○, ▲, ● and ◆ represent the blood glucose concentrations of the saline administration group, the metastin 17 nmol / kg administration group, the metastin 80 nmol / kg administration group, and the metastin 170 nmol / kg administration group, respectively. The value represents (mean + SE) (n = 5). The symbol * indicates that the P-value is 0.05 or less when compared with the saline administration group, and the symbol ** indicates that the P-value is 0.01 or less when compared with the saline administration group.

5 shows the results obtained by monitoring the change in blood glucagon concentration when intravenous injection of metastine into rats under anesthesia. In the figure, the symbols o and o represent the blood glucagon concentration in the saline administration group and the metastin 80 nmol / kg administration group, respectively. Values represent (mean + SE) (n = 6-9). The symbol * indicates that the P-value is 0.05 or less when compared with the saline administration group, and the symbol ** indicates that the P-value is 0.01 or less when compared with the saline administration group.

Figure 6 shows the results obtained by monitoring the change in blood insulin concentrations when intravenous injection of metastine into rats under anesthesia. In the figure, symbols ○ and ● represent the blood insulin concentrations in the saline administration group and the metastin 80 nmol / kg administration group, respectively. Values represent (mean + SE) (n = 6-9).

Fig. 7 shows the results obtained by monitoring changes in blood corticosterone concentrations when methine was injected intravenously into rats under anesthesia. In the figure, symbols ○ and ● represent the blood corticosterone concentrations in the saline administration group and the metastin 80 nmol / kg administration group, respectively. Values represent (mean + SE) (n = 4-5).

FIG. 8 shows the results obtained by monitoring changes in blood thyroid hormone (T3) concentrations when methine was intravenously injected into rats under anesthesia. In the figure, symbols ○ and ● represent the thyroid hormone (T3) concentrations in the blood in the saline administration group and the metastin 80 nmol / kg administration group, respectively. Values represent (mean + SE) (n = 4-5).

Figure 9 shows the results obtained by monitoring the change in blood glucose concentration when intravenous injection of metastine into rats under anesthesia. In the figure, symbols ○ and ● represent blood glucose concentrations in the saline administration group and the metastin 80 nmol / kg administration group, respectively. Values represent (mean + SE) (n = 6-9). The symbol * indicates that the P-value is 0.05 or less when compared with the saline-administered group.

Fig. 10 shows the results obtained by monitoring the change in blood glucose concentration when intravenous injection of metastin derivatives into rats under anesthesia. In the figure, symbols ○, ●, and ▲ denote blood glucose concentrations in the saline administration group, the KiSS1-305 80 nmol / kg administration group, and the metastin 80 nmol / kg administration group, respectively. The value represents (mean + SE) (n = 5). The symbol * indicates that the P-value is 0.05 or less when compared with the saline administration group, and the symbol ** indicates that the P-value is 0.01 or less when compared with the saline administration group.

FIG. 11 shows the results obtained by monitoring changes in blood glucagon concentration when intravenous injection of metastine into rats under anesthesia. In the figure, symbols ○, ●, and ▲ indicate the concentrations of glucagon in the blood in the saline administration group, KiSS1-305 (Compound No. 305) 80 nmol / kg administration group, KiSS1-322 (Compound No. 322) 80 nmol / kg administration group, respectively. . The value represents (mean + SE) (n = 5). The symbol * indicates that the P-value is 0.05 or less when compared with the saline-administered group.

12 shows the concentration of estradiol contained in rat plasma. In the figure, the ordinate and abscissa represent estradiol concentrations and drug receiving groups, respectively.

13 shows the concentration of progesterone contained in rat plasma. In the figure, the ordinate and abscissa represent estradiol concentrations and drug receiving groups, respectively.

14 shows changes in blood FSH concentrations of immature rats by metastin injection.

FIG. 15 shows the change in blood LH concentration of immature rats by metastin injection.

16 shows changes in blood progesterone concentrations of immature rats by metastin injection.

17 shows changes in blood FSH concentrations of rats by metastin injection.

18 shows changes in blood LH concentrations of rats by metastin injection.

19 shows changes in blood testosterone concentrations in rats by metastin injection.

20 shows the number of oocytes per 1 rat in each dose group measured in Test Example 13. FIG. In the figure, symbol ◆ represents data per rat individual, and symbol 나타낸다 represents the mean value in each dose group.

21 shows the blood estradiol concentration in each administration group measured in Test Example 13. FIG. In the figure, the symbol A represents data per rat individual, and the symbol A represents an average value in each administration group.

22 shows the blood progesterone concentration in each administration group measured in Test Example 13. FIG. In the figure, the symbol A represents data per rat individual, and the symbol A represents an average value in each administration group.

Best Mode of Embodiment of the Invention

In the above formulas, n represents 0 or 1; W ¹ represents N, CH or O, provided that when W ¹ is N or CH, n represents 1 and when W ¹ is O, n represents 0; W ² represents N or CH; Z ¹ , Z ³ , Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group; Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S;

In this case, when Z ² , Z ⁴ , Z ⁶ or Z ⁸ represents a hydrogen atom, the structure of the moiety represented by> C = Z ² ,> C = Z ⁴ ,> C = Z ⁶ or> C = Z ⁸ Each represents a structure of> CH ₂ .

The C _1-3 alkyl group used includes methyl group, ethyl group, propyl group and isopropyl group.

W ¹ is preferably N and W ² is preferably CH.

In a preferred combination of Z ¹ to Z ⁸ , Z ¹ and Z ³ each represent a hydrogen atom, Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _1-3 alkyl group, and Z ² , Z ⁴ , Z ⁶ and Z ^{The case where 8} represents O or S is included.

More preferably, combinations of Z ¹ to Z ⁸ include the followings:

(a) Z ¹ is a hydrogen atom, Z ³ is a hydrogen atom, Z ⁵ is a hydrogen atom, Z ⁷ is a hydrogen atom, Z ² is O, Z ⁴ is O, Z ⁶ is O and Z ⁸ Is O;

(b) Z ¹ is a hydrogen atom, Z ³ is a hydrogen atom, Z ⁵ is a hydrogen atom, Z ⁷ is a hydrogen atom, Z ² is O, Z ⁴ is O, Z ⁶ is O and Z ⁸ Is S;

(c) Z ¹ and Z ³ are hydrogen atoms, Z ⁵ is a hydrogen atom, Z ⁷ is a methyl group, Z ² is O, Z ⁴ is O, Z ⁶ is O, and Z ⁸ is O ; Etc. In these cases, (a) and (b) are preferable.

R ¹ is a C _1-8 alkyl group optionally substituted with a substituent selected from the group consisting of (1) a hydrogen atom, (2) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and an optionally substituted aromatic ring group, (3 A cyclic or linear C _1-10 alkyl group or (4) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (5) an optionally substituted aromatic ring group. Particularly preferred R ¹ is C _1-8 optionally substituted with a substituent selected from the group consisting of (1) a hydrogen atom or (2) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and an optionally substituted aromatic ring group. Alkyl groups, and more preferably C ₁ substituted with a substituent selected from the group consisting of (1) a hydrogen atom or (2) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and an optionally substituted aromatic ring group _-8 alkyl groups are mentioned.

As the "C _1-8 alkyl group" used, for example, a linear C _1-8 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, Neopentyl, hexyl, heptyl, octyl and the like, and cyclic C _3-8 alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Particular preference is given to C _1-3 alkyl groups such as methyl, ethyl and the like.

As the "optionally substituted carbamoyl group" used, for example, carbamoyl, mono-C _1-6 alkylcarbamoyl groups (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _{1- 6} alkyl-carbamoyl group (e.g., dimethylcarbamoyl, diethyl-carbamoyl, methyl-carbamoyl, etc.), a mono- or di -C _{6 -14} aryl-carbamoyl group (e.g., phenylcarbamoyl, 1- Naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), mono- or di-5- containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Or 7-membered heterocyclic carbamoyl groups (eg 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcar Barmoile, etc.).

As the "optionally substituted hydroxyl group" used, for example, a hydroxyl group, an optionally substituted C _1-6 alkoxy group, an optionally substituted C _6-14 aryloxy group, an optionally substituted C _7-16 aralkyloxy group Etc. The "optionally substituted C _1-6 alkoxy group,""optionally substituted C _6-14 aryloxy group" and "optionally substituted C _7-16 aralkyloxy group" are used for "optionally substituted" in the substituent group A described below. C _1-6 alkoxy group, "" optionally substituted C _6-14 aryloxy group "and" optionally substituted C _7-16 aralkyloxy group ".

Examples of the "aromatic ring group" in the "optionally substituted aromatic ring group" include an aromatic hydrocarbon group, an aromatic heterocyclic group, an aromatic conjugated ring group, and an aromatic conjugated heterocyclic group.

Examples of the "aromatic hydrocarbon group" used include C _6-14 aryl groups such as phenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, cyclooctatetraenyl, and the like.

As the "aromatic heterocyclic group" used, for example, 5- to 14-membered, including 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, preferably Preferably 5- to 10-membered, more preferably 5- or 6-membered aromatic heterocyclic groups. Embodiments include thienyl (eg 2-thienyl, 3-thienyl), furyl (eg 2-furyl, 3-furyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyri) Dill), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl), pyrazinyl, pyrimidinyl (eg, 2 -Pyrimidinyl, 4-pyrimidinyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg 1-imidazolyl, 2-imidazolyl , 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (eg 3-pyridazinyl, 4-pyridazinyl), isothia Zolyl (eg 3-isothiazolyl), isooxazolyl (eg 3-isooxazolyl) and the like.

As the "aromatic conjugated ring group" used, a C _8-14 aromatic conjugated ring group such as naphthyl (eg 1-naphthyl, 2-naphthyl), anthryl (eg 2-antryl, 9-antryl) ).

As the "aromatic conjugated heterocyclic group" used, for example, 5- to 14 containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms A 1-membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic group, or 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Is a monovalent group formed by removing one optional hydrogen atom from a 7- to 10-membered aromatic crosslinked-heterocycle in a 5- to 14-membered (preferably 5- to 10-membered) ring. Embodiments of these groups used include quinolyl (eg 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (eg 1-isoquinolyl , 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), indolyl (eg 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, benzo [b ] Thienyl, (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl), benzo [b] furanyl (eg 2-benzo [b] furanyl, 3-benzo [b] Furanyl) and the like.

As the "substituent" used for the "aromatic ring group", there is a substituent selected from the substituent group A described below.

With respect to R ¹ , a hydrogen atom, carbamoylmethyl, 2-carbamoylethyl, hydroxymethyl, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolmethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, cyclohexylmethyl, phenyl, acetoxymethyl, methoxymethyl and the like, preferably, hydroxymethyl, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 3-indolemethyl, methyl , Isobutyl and the like are used, and more preferably, hydroxymethyl, 1-hydroxyethyl and the like are used.

R ² is (1) a hydrogen atom, (2) a cyclic or linear C _1-10 alkyl group, (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) an optionally substituted carbamoyl group, C _1-8 alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted hydroxyl group and an optionally substituted aromatic ring group. Of these, preferred are (1) a hydrogen atom, (2) a cyclic or linear C _1-10 alkyl group, or (3) C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group. In particular, (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group is preferable.

Examples of the cyclic C _1-10 alkyl group to be used include C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples of linear C _1-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl Etc.

As a C _1-10 alkyl group which consists of a cyclic alkyl group and a linear alkyl group used, a C _3-7 cycloalkyl-C _1-3 alkyl group, such as cyclopentylmethyl, cyclohexylmethyl, etc. are mentioned, for example.

Examples of R ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexylmethyl, benzyl, hydroxymethyl, 2-carbamoylethyl, tert-pentyl and the like; Among these, preferable are methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferred are propyl, isopropyl, isobutyl and the like.

R ³ represents:

(1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having additional substituents,

(2) an aralkyl group having an optionally substituted basic group and optionally having an additional substituent,

(3) a C _1-4 alkyl group having a non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms having an optionally substituted basic group and optionally having additional substituents, or

(4) a C _1-4 alkyl group having a non-aromatic heterocyclic group having 7 or less carbon atoms, optionally having a basic group, and optionally having additional substituents.

As the "optionally substituted basic group" used, for example, (1) C _1-6 alkyl, C _1-6 acyl (eg, methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.) and the like. Guanidino groups optionally having one or two substituents from (2) C _1-6 alkyl, C _1-6 acyl (eg, methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.), and the like. Amino groups optionally having 1 to 3 substituents from (3) C _1-6 alkyl, C _1-6 acyl (eg, methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.), and the like. Or a C _1-6 alkylcarbonylamino group optionally substituted with a guanidino group optionally having two substituents (eg acetamido), (4) C _1-6 alkyl, C _1-6 acyl (eg methyl, ethyl , Amino groups optionally having 1 to 3 substituents from propyl, isopropyl, butyl, acetyl, propionyl, etc.) Substituted C _1-6 alkylcarbonylamino groups (eg, acetamido). Of these, preferred are guanidino, N-methylguanidino, N, N-dimethylguanidino, N, N'-dimethylguanidino, N-ethylguanidino, N-acetylguanidino, amino , N-methylamino, N, N-dimethylamino, aminoacetamido, guanidinoacetamido, amidino and the like.

"Additional substituents" other than "optionally substituted basic groups" used include substituents selected from the substituent group A described below.

Examples of the "C _1-8 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and the like. .

As the "aralkyl group" used, for example, a C _7-16 aralkyl group such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3 -Phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like.

Examples of the "non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms" used include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As the "non-aromatic heterocyclic group having 7 or less carbon atoms" to be used, for example, containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 7 carbon atoms 5- to 10-membered non-aromatic heterocyclic groups and the like. Specific examples of use include pyrrolidinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (eg 2-oxazolidinyl), imidazolinyl ( For example, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (eg, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- Piperidinyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and the like.

Examples of the "C _1-4 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

For R ³ , for example, (1) 3-guanidinopropyl, 3- (N-methylguanidino) propyl, 3- (N, N-dimethylguanidino) propyl, 3- (N, N'-dimethylguanidino) propyl, 3- (N-ethylguanidino) propyl, 3- (N-propylguanidino) propyl, 3- (N-acetylguanidino) propyl, 4-guani Dinobutyl, 4- (N-methylguanidino) butyl, 2-guanidinoethyl, 2- (N-methylguanidino) ethyl, 4-aminobutyl, 4- (N-methylamino) butyl, 4 -(N, N-dimethylamino) butyl, 3-aminopropyl, 2-aminoethyl, aminomethyl, aminoacetamidomethyl, guanidinoacetamidomethyl, 2- (guanidinocarbonyl) ethyl, ( 2) 4-guanidinobenzyl, 4-aminobenzyl, (3) 4-guanidinocyclohexylmethyl, 4-aminocyclohexylmethyl, (4) 1-amidinopiperidin-4-ylmethyl, 4 -Pyridylmethyl and the like, preferably 3-guanidinopropyl, 3- (N-methylguanidino) propyl, 3- (N, N-dimethylguanidino) Propyl, 3- (N, N'-dimethylguanidino) propyl, 3- (N-ethylguanidino) propyl, 3- (N-propylguanidino) propyl, 3- (N-acetylguanidino ) Propyl, 4-guanidinobutyl, 4- (N-methylguanidino) butyl, 2-guanidinoethyl, 2- (N-methylguanidino) ethyl, 4-aminobutyl, 4- (N -Methylamino) butyl, 4- (N, N-dimethylamino) butyl, 3-aminopropyl, 2-aminoethyl, 4-aminobenzyl, aminoacetamidomethyl, guanidinoacetamidomethyl, etc. are used, More preferably, 3-guanidinopropyl, 3- (N-methylguanidino) propyl, 3- (N, N-dimethylguanidino) propyl, 3- (N, N'-dimethylguanidino ) Propyl, 3- (N-ethylguanidino) propyl, 3- (N-acetylguanidino) propyl, 4-guanidinobutyl, 4- (N-methylguanidino) butyl, 2-guani Dinoethyl, 4-aminobutyl and the like are used.

R ⁴ represents a C _1-4 alkyl group which may be optionally substituted with a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group;

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(3) an optionally substituted C _8-14 aromatic conjugated ring group;

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, and

(6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms; And preferably a C _1-4 alkyl group substituted with a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group;

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(3) an optionally substituted C _8-14 aromatic conjugated ring group;

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms; And,

(6) An optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms.

Examples of the "C _1-4 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

The "C _6-12 aromatic hydrocarbon group" used includes, for example, a monocyclic C _6-12 aromatic hydrocarbon group such as phenyl, cyclooctatetraenyl and the like.

As the "5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", for example, nitrogen in addition to 1 to 7 carbon atoms , 5 to 14-membered, preferably 5- to 10-membered, more preferably 5- or 6-membered groups comprising 1 to 4 heteroatoms selected from sulfur and oxygen atoms Cyclic aromatic heterocyclic groups. Embodiments used include thienyl (eg 2-thienyl, 3-thienyl), furyl (eg 2-furyl, 3-furyl), pyridyl (eg 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl), pyrazinyl, pyrimidinyl ( For example, 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg 1-imidazolyl, 2- Imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (eg 3-pyridazinyl, 4-pyridazinyl) , Isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl) and the like.

As the "C _8-14 aromatic conjugated ring group" to be used, for example, naphthyl (eg 1-naphthyl, 2-naphthyl), anthryl (eg 2-antryl, 9-anthryl) and the like There is this.

"An optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of a hetero atom selected from the group consisting of 3 to 11 carbon atoms and nitrogen, oxygen and sulfur atoms", for example, to 3 to 11 carbon atoms In addition, 5- to 14-membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic groups containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms. Or 7-in a 5- to 14-membered (preferably 5- to 10-membered) ring comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms There is a monovalent group formed by removing one optional hydrogen atom from a 10-membered aromatic crosslinked-hetero ring. Embodiments used include quinolyl (eg 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (eg 1-isoquinolyl, 3 Isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), indolyl (eg 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, benzo [b] thier Nyl, (eg 2-benzo [b] thienyl, 3-benzo [b] thienyl), benzo [b] furanyl (eg 2-benzo [b] furanyl, 3-benzo [b] furanyl ).

Examples of the "non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms" used include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As the "non-aromatic heterocyclic group having 7 or less carbon atoms" to be used, for example, containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 7 carbon atoms 5- or 10-membered non-aromatic heterocyclic groups such as pyrrolidinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (eg 2-oxazolidinyl) , Imidazolinyl (eg 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3- Piperidinyl, 4-piperidinyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and the like.

These "C _6-12 aromatic hydrocarbon groups,""5- to 14-membered aromatic heterocyclic groups consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms,""C _8-14 Aromatic conjugated ring groups, "" 5- to 14-membered aromatic conjugated heterocyclic groups consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, "" non-aromatic cyclic having 7 or less carbon atoms hydrocarbon group "and" substituent group is the number of carbon atoms is used for the "non-aromatic heterocyclic ring 7 or less, for example, oxo, a halogen atom (e.g., fluorine, chlorine, bromine and iodine), C _{1 -3} alkylenedioxy (Eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-14 sub Reel, optionally substituted C _7-16 aralkyl, optionally substituted C _1-6 alkoxy, hydroxy, optionally substituted C _6-14 aryloxy, optionally substituted C _7-16 aralkyloxy, mercapto, optionally substituted C _1-6 alkylthio, optionally substituted C _6-14 arylthio, optionally substituted C _7-16 aralkylthio, optionally substituted amino [amino, optionally substituted mono- or di-C _1-6 alkyl- Amino (eg methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, etc.), optionally substituted mono- or di-C _2-6 alkenyl-amino (eg vinylamino, propenyl Amino, isopropenylamino), optionally substituted C _2-6 alkynylamino (eg, 2-butyn-1-yl-amino, 4-pentyn-1-yl-amino, 5-hexyn-1-yl-amino ), Optionally substituted mono- or di-C _3-8 cycloalkyl-amino (eg cyclopropylamino, cyclohexylamino), optionally substituted C _6-14 arylamino (eg Vs. phenylamino, diphenylamino, naphthylamino), optionally substituted C _1-6 alkoxyamino (eg, methoxyamino, ethoxyamino, propoxyamino, isopropoxyamino), formylamino, optionally substituted C _1-6 alkylcarbonylamino (eg, acetylamino, propionylamino, pivaloylamino, etc.), optionally substituted C _3-8 cycloalkylcarbonylamino (eg, cyclopropylcarbonylamino, cyclopentylcar Carbonylamino, cyclohexylcarbonylamino, etc.), optionally substituted C _6-14 aryl-carbonylamino (eg, benzoylamino, naphthoylamino, etc.), optionally substituted C _1-6 alkoxy-carbonylamino (eg, Methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc., optionally substituted C _1-6 alkylsulfonylamino (e.g. methylsulfonylamino, ethylsulfonylamino, etc.) ), Random Substituted C _6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), formyl, carboxy, optionally substituted C _1-6 alkylcarbonyl (Eg, acetyl, propionyl, pivaloyl, etc.), optionally substituted C _3-8 cycloalkylcarbonyl (eg cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl- Carbonyl, etc.), optionally substituted C _6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), optionally substituted C _{7-16 aralkylcarbonyl} (eg, phenylacetyl, 3-phenylpropionyl and the like), optionally substituted 5- to 7-membered heterocyclic carbonyl (including 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms) For example, nicotinoyl, isonicotinoyl, tennoyl, furoyl, morpholinocarbonyl, tee Morpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), optionally esterified carboxyl, optionally substituted carbamoyl group, optionally substituted C _1-6 alkyl Sulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), optionally substituted C _1-6 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), optionally substituted C _6-14 arylsulfonyl (eg , Phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), optionally substituted C _6-14 arylsulfinyl (eg, phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), Optionally substituted C _1-6 alkylcarbonyloxy (eg, acetoxy, propionyloxy, etc.), optionally substituted C _6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), optionally Substituted C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), Substituted mono-C _1-6 alkylcarbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), optionally substituted di-C _1-6 alkylcarbamoyloxy (eg, dimethylcar Barmoyloxy, diethylcarbamoyloxy, etc.), optionally substituted mono- or di-C _6-14 arylcarbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), optionally substituted A heterocyclic group, sulfo, sulfamoyl, sulfinamoyl, sulfenamoyl, or a group obtained by combining two or more (eg, two or three) substituents thereof, and the like. There is no particular limitation on the number of the substituents, but these rings may have 1 to 5, preferably 1 to 3 substituents at the molar position, and when two or more substituents are present, each substituent is the same or different. can do.

“Any esterified carboxyl” used in substituent group A is, for example, optionally substituted C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert -Butoxycarbonyl, etc.), optionally substituted C _6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), optionally substituted C _7-16 aralkyloxy-carbonyl (eg, benzyloxycarbonyl , Phenethyloxycarbonyl and the like), and the like.

Examples of the substituent (s) "optionally substituted C _1-6 alkyl" as used in the group A "C _1-6 alkyl", for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- Butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

As "C _2-6 alkenyl" in "optionally substituted C _2-6 alkenyl" used in Substituent Group A, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4 -Penten-1-yl, 5-hexen-1-yl and the like.

As "C _2-6 alkynyl" in "optionally substituted C _2-6 alkynyl" used in Substituent Group A, for example, 2-butyn-1-yl, 4-pentyn-1-yl, 5- Hexyn-1-yl and the like.

Examples of the "C _3-8 cycloalkyl" in the "optionally substituted C _3-8 cycloalkyl" used in the substituent group A include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The substituent of the C _6-14 aryl optionally substituted C _6-14 aryl group that are used in the A, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenyl-yl, 3-biphenyl-yl, 4-biphenylyl, 2-antryl and the like.

As "C _7-16 aralkyl" in "optionally substituted C _7-16 aralkyl" used in the substituent group A, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naph Dimethylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl), and the like. .

Examples of the substituent which the group A in the "optionally substituted C _1-6 alkoxy", "C _1-6 alkoxy", for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec Butoxy, pentyloxy, hexyloxy and the like.

Examples of the "C _6-14 aryloxy" in the "optionally substituted C _6-14 aryloxy" used in the substituent group A include phenyloxy, 1-naphthyloxy, 2-naphthyloxy and the like.

As the substituent, "optionally substituted C _7-16 aralkyloxy", "C _7-16 aralkyloxy" as used in the group A, for example, such as benzyloxy, phenethyl-oxy.

As "C _1-6 alkylthio" in "optionally substituted C _1-6 alkylthio" used in substituent group A, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- Butylthio, tert-butylthio, and the like.

Examples of the "C _6-14 arylthio" in the "optionally substituted C _6-14 arylthio" used in the substituent group A include phenylthio, 1-naphthylthio, 2-naphthylthio and the like.

Examples of the "C _7-16 aralkylthio" in the "optionally substituted C _7-16 aralkylthio" used in the substituent group A include benzylthio, phenethylthio, and the like.

These "C _1-6 alkoxy-carbonyl,""C _1-6 alkyl groups,""C _2-6 alkenyl,""C _2-6 alkynyl,""C _1-6 alkoxy,""C _{1- 6} alkylthio, "C _1-6 alkyl-amino," C _2-6 alkenyl-amino, "" C _2-6 alkynylamino, "C _1-6 alkoxyamino,""C _1-6 alkylcarbonyl , "" C _1-6 alkylsulfonyl, "" C _1-6 alkylsulfinyl, "" C _1-6 alkylcarbonylamino, "" C _1-6 alkoxy-carbonyl-amino, "" C _1-6 Alkylsulfonylamino, "" C _1-6 alkylcarbonyloxy, "" C _1-6 alkoxy-carbonyloxy, "" mono-C _1-6 alkylcarbamoyloxy "and" di-C _1-6 Substituents used in the substituent group A for "alkylcarbamoyloxy" include, for example, halogen atoms (e.g., fluorine atoms, chlorine atoms, bromine atoms, iodine atoms), carboxy, hydroxy, amino, mono- or di -C _1-6 alkylamino, mono- or di-C _6-14 arylamino, C _3-8 cycloalkyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkylthio, C _1-6 alkylsulphate Finyl, C _1-6 alkylsulfonyl, any of the esterified carboxyls described above, carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl (eg, methylcarbamoyl, ethylcarba Moyl, etc.), di-C _1-6 alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), mono- or di-C _6-14 arylcarbamoyl ( Phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur and oxygen atoms Mono- or di-5- to 7-membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienyl Carbamoyl, 3-thienylcarbamoyl, etc.), and the like.

"C _6-14 aryloxy-carbonyl,""C _7-16 aralkyloxy-carbonyl,""C _3-8 cycloalkyl,""C _6-14 aryl,""C _7-16 aralkyl, "" C _6-14 aryloxy, "" C _7-16 aralkyloxy, "" C _6-14 arylthio, "" C _7-16 aralkylthio, "C _3-8 cycloalkyl-amino, C _{6 -14} arylamino, "C _3-8 cycloalkylcarbonyl,""C _6-14 aryl-carbonyl,""C _{7-16 aralkylcarbonyl} ,""in addition to carbon atoms from nitrogen, sulfur and oxygen atoms 5- to 7-membered heterocyclic carbonyl containing 1 to 4 heteroatoms selected, "" C _6-14 arylsulfonyl, "" C _6-14 arylsulfinyl, "" C _3-8 cycloalkylcarbonylamino, "" C _6-14 aryl-carbonylamino, "" C _6-14 arylsulfonylamino, "" C _6-14 aryl-carbonyloxy "and" mono- or di -C _6-14 aryl-carbamoyl-oxy "as the substituent used in the substituent group a with respect to, for example, a halogen atom, a hydroxy, carboxy, Trojan, cyano, the above-described optionally substituted C _1-6 alkyl, the above-described optionally substituted C _2-6 alkenyl group, the above-described optionally substituted C _2-6 alkynyl group, the above-described optionally substituted C _3-8 cycloalkyl, optionally substituted C _1-6 alkoxy described above, optionally substituted C _1-6 alkylthio described above, optionally substituted C _1-6 alkylsulfinyl described above, optionally substituted above C _1-6 alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl, di-C _1-6 alkylcarbamoyl, described above, _Mono- or di-C _6-14 arylcarbamoyl, mono- or di-5--7 comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms -1 to 5 substituents selected from -membered heterocyclic carbamoyl and the like.

As the "optionally substituted heterocyclic group" used in the substituent group A, for example, 5- to 1 or 2 hetero atoms including 1 or 2 hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms As a 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group, a halogen atom, hydroxy, carboxy, nitro, cyano, optionally substituted C _1-6 alkyl described above, optionally substituted C described above _2-6 alkenyl, optionally substituted C _2-6 alkynyl as described above, optionally substituted C _3-8 cycloalkyl as described above, optionally substituted C _6-14 aryl as described above, optionally substituted as described above C _1-6 alkoxy, optionally substituted C _1-6 alkylthio as described above, optionally substituted C _6-14 arylthio as described above, optionally substituted C _7-16 aralkylthio as described above, optional as described above Substituted C _1-6 alkylsulfinyl, optionally substituted C _6-14 arylsulfinyl described above, Optionally substituted C _1-6 alkylsulfonyl, optionally substituted C _6-14 arylsulfonyl described above, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono-C _{1-6 described above} Alkylcarbamoyl, di-lower alkylcarbamoyl, mono- or di-C _6-14 arylcarbamoyl, one or two hetero atoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms 1 to 4 Heterocyclic groups which may be optionally substituted with a mono- or di-5- or 7-membered heterocyclic carbamoyl or the like including a dog; Preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group, (ii) a 5- to 10-membered non-aromatic heterocyclic group or (iii) 7- to Monovalent groups formed by one optional hydrogen atom from a 10-membered crosslinked-hetero ring, and more preferably, a 5-membered aromatic heterocyclic group. Specifically aromatic heterocyclic groups such as thienyl (eg 2-thienyl, 3-thienyl), furyl (eg 2-furyl, 3-furyl), pyridyl (eg 2-pyridyl, 3- Pyridyl, 4-pyridyl), thiazolyl (eg 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (eg 2-oxazolyl, 4-oxazolyl), quinolyl (eg , 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (eg 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl , 5-isoquinolyl), pyrazinyl, pyrimidinyl (eg 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (eg 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , Imidazolyl (eg 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (Eg 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxane Reel), indolyl (eg 1-indolyl, 2-indolyl, 3-indolyl), 2-benzothiazolyl, benzo [b] thienyl, (eg 2-benzo [b] thienyl, 3 -Benzo [b] thienyl), benzo [b] furanyl (eg 2-benzo [b] furanyl, 3-benzo [b] furanyl), and the like, non-aromatic heterocyclic groups such as pyrrolidinyl (such as , 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (eg 2-oxazolidinyl), imidazolinyl (eg 1-imidazolinyl, 2-imi Dazolinyl, 4-imidazolinyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1 Piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and the like.

As the "optionally substituted carbamoyl group" used in the substituent group A, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted Carbamoyl group, which may be optionally substituted with substituted C _3-8 cycloalkyl, optionally substituted C _6-14 aryl, optionally substituted heterocyclic group, and the like, and examples thereof include carbamoyl, thiocarbamoyl, mono -C _1-6 alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), di-C _1-6 alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethyl Carbamoyl, etc.), C _1-6 alkyl (C _1-6 alkoxy) carbamoyl (eg, methyl (methoxy) carbamoyl, ethyl (methoxy) carbamoyl), mono- or di-C _{6 -14} arylcarbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, and the like), linear from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Mono- or di-5- to 7-membered heterocyclic carbamoyl (eg, 2-pyridylcarbamoyl, 3-pyridylcarba) comprising 1 to 4 heteroatoms of choice Moyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like), 5- to 7-membered cyclic carbamoyl (eg 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, hexamethyleneiminocarbonyl), and the like.

As used herein, "optionally substituted amino" includes optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl as described above, optionally substituted C _2-6 alkynyl as described above, Optionally substituted C _3-8 cycloalkyl as described above, optionally substituted C _6-14 aryl as described above, optionally substituted C _1-6 alkoxy, formyl as described above, optionally substituted C _1-6 alkyl as described above Carbonyl, optionally substituted C _3-8 cycloalkylcarbonyl as described above, optionally substituted C _6-14 aryl-carbonyl as described above, optionally substituted C _1-6 alkoxy-carbonyl as described above, described above There is amino, which may be optionally substituted with one or two groups selected from one optionally substituted C _1-6 alkylsulfonyl, optionally substituted C _6-14 arylsulfonyl, and the like.

More preferably, "C _6-12 aromatic hydrocarbon group,""5- to 14-membered aromatic heterocyclic group consisting of a hetero atom selected from the group consisting of 1 to 7 carbon atoms and nitrogen, oxygen and sulfur atoms,"" C _8-14 aromatic conjugated ring group, "" a 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, "" with 7 or less carbon atoms Substituents for "non-aromatic cyclic hydrocarbon group" and "non-aromatic heterocyclic group having 7 or less carbon atoms" include halogen atom, hydroxy, C _1-6 alkoxy, optionally halogenated C _1-6 alkyl, optionally halogenated C _{1 -6} alkoxy, amino, nitro, cyano and the like.

Examples of R ⁴ used are:

(1) "C _1-4 alkyl group with an optionally substituted C _6-12 aromatic hydrocarbon group" such as benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 3, 4-difluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 3-trifluoromethylbenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4 Cyanobenzyl, phenethyl and the like;

(2) "C _1-4 alkyl groups having an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 2-pyrid Dilmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl and the like;

(3) "C _1-4 alkyl groups with optionally substituted C _8-14 aromatic conjugated ring groups" such as 1-naphthylmethyl, 2-naphthylmethyl, inden-2-ylmethyl and the like;

(4) "C _1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 3- Indolemethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl and the like;

(5) "C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms", such as cyclohexylmethyl, cyclopentylmethyl, indan-2-ylmethyl, and the like;

(6) "C _1-4 alkyl groups having an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms", such as 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3 -Yl, indolin-3-yl and the like, preferably benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, 4-nitrobenzyl , 4-chlorobenzyl, 4-methoxybenzyl, 4-cyanobenzyl, 3-trifluoromethylbenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, pentafluorobenzyl, 3-pyri Dilmethyl, 4-pyridylmethyl, 3-indolmethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl, 1-naphthylmethyl, 2-naph Dimethylmethyl, cyclohexylmethyl, phenethyl and the like, and more preferably benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, 4- Nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-sia Nobenzyl, 3-trifluoromethylbenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, pentafluorobenzyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-indolemethyl, 3 -Benzo [b] thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohexylmethyl and the like.

Q ¹ represents a C _1-4 alkyl group optionally substituted with a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group;

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(3) an optionally substituted C _8-14 aromatic conjugated ring group;

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms; And

(6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms; And the same substituents as in R ⁴ are used.

Examples of Q ¹ are:

(1) "C _1-4 alkyl group with an optionally substituted C _6-12 aromatic hydrocarbon group" such as benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 3, 4-difluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4 Cyanobenzyl, phenethyl and the like;

(2) "C _1-4 alkyl groups having an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 2-pyrid Dilmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl and the like;

(3) "C _1-4 alkyl group having an optionally substituted C _8-14 aromatic conjugated ring group," such as 1-naphthylmethyl, 2-naphthylmethyl, inden-2-ylmethyl;

(4) "C _1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 3- Indolemethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl and the like;

(5) "C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms", such as cyclohexylmethyl, cyclopentylmethyl, indan-2-ylmethyl, and the like;

(6) "C _1-4 alkyl groups having an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms", such as 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3 -Yl, indolin-3-yl and the like; Preferably, cyclohexylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, pentafluorobenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl , 2-naphthylmethyl, 3-indolemethyl, 2-thienylmethyl and the like and more preferably benzyl, 4-fluorobenzyl, cyclohexylmethyl and the like.

Q ² is CH ₂ , (2) carbamoyl and hydroxyl groups, which may be optionally substituted with an optionally substituted C _1-4 alkyl group having a substituent selected from the group consisting of (1) carbamoyl groups and hydroxyl groups NH, or (3) O, which may be optionally substituted with an optionally substituted C _1-4 alkyl group having a substituent selected from the group consisting of:

Examples of the "C _1-4 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

Preferably, Q ² is CH ₂ , CH (CH ₃ ), CH (CH ₂ OH), NH, or the like.

Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH _2- , or -CH = CH- (which may be optionally substituted with C _1-6 alkyl groups).

Examples of the "C _1-6 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

Preferably, Y is a group represented by the formula: -CONH-, -CSNH-, -NHCO-, -CH ₂ NH-, -CH ₂ O-, -COO- or -CSO- (more preferably , A group represented by the following formula: -CONH-, -CSNH-, -NHCO- or -CH ₂ NH-).

Z ⁹ represents a hydrogen atom, O or S, preferably O or S;

At this time, when Z ⁹ is a hydrogen atom, the structure of the moiety represented by> C = Z ⁹ represents a structure of> CH ₂ .

P and P 'may be the same or different and each may form a ring by combining P and P' or P and Q ¹ together, and represents:

(1) hydrogen atoms;

(2) an optional amino acid residue that is linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the following formula:

(식 중, 각 기호는 상기 기술된 바와 동일한 의미를 가진다);

Wherein each symbol has the same meaning as described above;

(4) a group represented by the following formula:

(식 중, 각 기호는 상기 기술된 바와 동일한 의미를 가진다);

Wherein each symbol has the same meaning as described above;

(5) a group represented by the following formula:

(식 중, 각 기호는 상기 기술된 바와 동일한 의미를 가진다);

Wherein each symbol has the same meaning as described above;

(식 중, 각 기호는 상기 기술된 바와 동일한 의미를 가진다); 또는,(6) a group represented by the following formula:

Wherein each symbol has the same meaning as described above; or,

(7) a group represented by the following formula: J ^1- (wherein J ¹ has the same meaning as described above).

Specific examples of the " optional amino acid residues linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence represented by SEQ ID NO: 1 " are as follows:

J ¹ is (a) a hydrogen atom or (b) (i) a C _1-15 acyl group, (ii) a C _1-15 alkyl group, (iii) a C _6-14 aryl group, (iv) a carbamoyl group, (v A) carboxyl group, (vi) sulfino group, (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group (the groups may be optionally substituted with a substituent including an optionally substituted ring group).

As the "ring group" used, for example, "optionally substituted aromatic hydrocarbon group," "optionally substituted aromatic heterocyclic group," "optionally substituted aromatic conjugated ring group," "optionally substituted aromatic conjugated heterocyclic group," , "" Optionally substituted non-aromatic cyclic hydrocarbon group "," optionally substituted non-aromatic heterocyclic group ", and the like, and" aromatic hydrocarbon group "," aromatic heterocyclic group "," aromatic conjugated ring group "and" aromatic " As the conjugated heterocyclic group, the same groups set forth above are used.

Examples of the "non-aromatic cyclic hydrocarbon group" used include C _3-8 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As the "non-aromatic heterocyclic group" used, for example, 5- or 10 comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 7 carbon atoms -Membered non-aromatic heterocyclic groups such as pyrrolidinyl (eg 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (eg 2-oxazolidinyl), imidazoli Nyl (eg 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (eg 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (eg 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and the like.

Substituents optionally present on the "ring group" include the same substituents set forth for the group of substituents described above.

As the "C _1-15 acyl group" to be used, for example, formyl, C _1-14 alkylcarbonyl (eg, C _1-6 alkylcarbonyl such as acetyl, propionyl, pivaloyl, etc.) have.

Examples of the "C _1-15 alkyl group" used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl , Decanyl and the like.

Examples of the "C _6-14 aryl group" used include phenyl, 1-naphthyl, 2-naphthyl, biphenyl and the like.

(1) C _1-15 acyl groups which may be optionally substituted with substituents including ring groups include (i) formyl, (ii) C _1-14 alkylcarbonyl (eg, C _1-6 alkylcarbonyl, such as Acetyl, propionyl, pivaloyl and the like), (iii) C _3-8 cycloalkylcarbonyl (eg, cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methylcyclohexylcarbonyl, etc.), (iv) C _3-8 cycloalkyl-C _1-6 alkylcarbonyl (eg cyclopropylacetyl, cyclopentylacetyl, cyclohexylacetyl, etc.), (v) C _6-14 aryl-carbonyl (eg benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _6-14 aralkylcarbonyl (eg, phenylacetyl, 3-phenylpropionyl, etc.), (vi) selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms 5- to 7-membered monocyclic heterocyclic carbonyl containing 1 to 2 heteroatoms (eg, nicotinoyl, iso Cotinoyl, tennoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, etc.), (vii) in addition to carbon atoms 5- to 7-membered monocyclic heterocyclic-C _1-6 alkylcarbonyl (eg, 3-pyridylacetyl) containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms , 4-pyridylacetyl, 2-thienylacetyl, 2-furylacetyl, morpholinoacetyl, thiomorpholinoacetyl, piperidine-2-acetyl, pyrrolidin-2-ylacetyl, etc.), (viii ) 5- to 14-membered (preferably 5- to 10-membered) comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms Bicyclic or tricyclic aromatic heterocyclic carbonyl (eg, 2-indolecarbonyl, 3-indolecarbonyl, 2-quinolylcarbonyl, 1-isoquinolylcar Carbonyl, 2-benzo [b] thienylcarbonyl, 2-benzo [b] furanylcarbonyl, etc.), (ix) one or two species selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms 5- to 14-membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic C _1-6 alkylcarbonyl (eg, 2-indole) containing 1 to 4 heteroatoms of Acetyl, 3-indoleacetyl, 2-quinolylacetyl, 1-isoquinolylacetyl, 2-benzo [b] thienylacetyl, 2-benzo [b] furanylacetyl, etc.), and preferably, acetyl , 2-indolecarbonyl, 3-indolecarbonyl, 3-indoleacetyl, 3-indolepropionyl, 2-indolincarbonyl, 3-phenylpropionyl, diphenylacetyl, 2-pyridinecarbonyl, 3-pyridine Carbonyl, 4-pyridinecarbonyl, 1-pyridinioacetyl, 2-pyridineacetyl, 3-pyridineacetyl, 4-pyridineacetyl, 3- (1-pyridinio) propionyl, 3- (pyridine-2- 1) propionyl, 3- ( Pyridin-3-yl) propionyl, 3- (pyridin-4-yl) propionyl, 4-imidazolacetyl, cyclohexanecarbonyl, 1-piperidineacetyl, 1-methyl-1-piperidinioacetyl, 4-piperidinecarbonyl, 2-pyrimidinecarbonyl, 4-pyrimidinecarbonyl, 5-pyrimidinecarbonyl, 2-pyrimidineacetyl, 4-pyrimidineacetyl, 5-pyrimidineacetyl, 3- ( Pyrimidin-2-yl) propionyl, 3- (pyrimidin-4-yl) propionyl, 3- (pyrimidin-5-yl) propionyl, butanoyl, hexanoyl, octanoyl, D-glucuro Yl, amino- (4-hydroxyphenyl) acetyl) and the like.

(2) As the C _1-15 alkyl group which may be optionally substituted with a substituent including a ring group, for example, (i) mono- or di-C _1-15 alkyl (eg, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl), (ii) mono- or di-C _3-8 cyclo Alkyl (eg, cyclopropyl, cyclopentyl, etc.), (iii) mono- or di-C _3-8 cycloalkyl-C _1-7 alkyl (eg, cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl, etc.), ( iv) 1 to 2 heteroatoms selected from mono- or di-C _7-15 aralkyl (e.g. benzyl, phenethyl, etc.), (v) nitrogen, sulfur and oxygen atoms in addition to carbon atoms Mono- or di-5- to 7-membered monocyclic heterocyclic-C _1-6 alkyl group containing (eg 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, furfuryl, etc.) , (vi) Mono- or di-5- to 14-membered (preferably 5- to 1 to 4) containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms 10-membered) bicyclic or tricyclic aromatic heterocyclic-C _1-6 alkyl group (e.g. 2-indolmethyl, 3-indolmethyl, 3- (indol-3-yl) propyl, 2-quinolylmethyl, 1 Isoquinolylmethyl, 2-benzo [b] thienylmethyl, 2-benzo [b] furanylmethyl, etc.), and preferably, methyl, ethyl, benzyl, 3- (indol-3-yl) Profile, etc.

(3) As the C _6-14 aryl group used which may be optionally substituted with a substituent including a ring group, for example, a C _6-14 aryl group (eg, phenyl, naphthyl, biphenyl) can be given. , (I) a C _6-14 carbocyclic group (e.g., cycloalkyl, phenyl, 1-naphthyl, 2-naphthyl, etc.), (ii) one selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms; 5- to 7-membered monocyclic heterocyclic groups containing 1 to 4 heteroatoms (eg, 3-pyridyl, 2-thienyl, etc.), (iii) nitrogen in addition to 3 to 11 carbon atoms , 5- to 14-membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic groups comprising 1 to 4 heteroatoms selected from sulfur and oxygen atoms (preferably For example, 2-indolyl, 3-indolyl, 2-quinolyl, 1-isoquinolyl, 2-benzo [b] thienyl, 2-benzo [b] furanyl, and the like) may be optionally substituted.

(4) An optionally substituted carbamoyl group to be used that may be optionally substituted with a substituent including a ring group, for example, (i) carbamoyl, (ii) mono- or di-C _1-15 alkylcart Barmoyl groups (eg methylcarbamoyl, ethylcarbamoyl), (iii) mono- or di-C _3-8 cycloalkyl-carbamoyl (eg cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclo Hexylcarbamoyl, etc.), (iv) mono- or di-C _3-8 cycloalkyl-C _1-6 alkyl-carbamoyl (eg cyclopropylmethylcarbamoyl, cyclopentylmethylcarbamoyl, 2- Cyclohexylethylcarbamoyl, etc.), (v) mono- or di-C _6-14 aryl-carbamoyl (eg, phenylcarbamoyl, etc.), mono- or di-C _6-14 aralkyl- _carba Moyl (eg benzylcarbamoyl, phenethylcarbamoyl, etc.), (vi) one or two hetero selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Mono- or di-5- to 7-membered monocyclic heterocyclic carbamoyl containing 1 to 4 characters (eg 3-pyridinecarbamoyl, 2-thiophencarbamoyl, piperidine-3 -Ylcarbamoyl, etc.), (vii) mono- or di-5- to 7-membered groups comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms Cyclic heterocyclic-C _1-6 alkylcarbamoyl (eg, 3-pyridylmethylcarbamoyl, 2- (pyridin-2-yl) ethylcarbamoyl, 2- (piperidin-1-yl) Ethylcarbamoyl, etc.), (viii) mono- or di-5- to 14 comprising 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms -Membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic carbamoyl (eg 4-indolecarbamoyl, 5-indolecarbamoyl, 3-quinolylcar Moyl, 5-quinolylcarbamoyl, etc.), (ix) mono- or di-containing one to two heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms -5- to 14-membered (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic-C _1-6 alkylcarbonyl (e.g. benzimidazol-2-ylmethylcarbamoyl , 2- (indol-3-yl) ethylcarbamoyl and the like), (x) 5- to 7-membered cyclic carbamoyl (eg 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, Hexamethyleneiminocarbonyl, etc.), (xi) C _1-15 acylcarbamoyl (herein C _1-15 acyl is used a C _1-15 acyl group which may be optionally substituted with a substituent including a ring group) "it has the same meaning as for), (xii) in the C _1-15 alkylamino, carbamoyl (herein C _1-15 alkyl" C _1-15 acyl group "in" optionally substituted with a substituent comprising a ring Be in, "have the same meaning as for), (xiii) C _6-14 aryl-amino-carbamoyl (herein, C _6-14 aryl group" C _1-15 alkyl group "in the" C _1-15 alkyl chain And the same meaning as for " C _6-14 aryl group ", which may be optionally substituted with a substituent including a group), and preferably 2- (indol-3-yl) ethylcarbamoyl and the like.

(5) As the carboxyl group to be used, which may be optionally substituted with a substituent including a ring group, for example, (i) C _1-15 alkyloxycarbonyl (herein C _1-15 alkyl is a substituent comprising a ring group) _Has the same meaning as for "C _1-15 alkyl group" in "C _1-15 alkyl group", which may be optionally substituted with, eg, tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxy carbonyl), (ii) C _6-14 aryloxy-carbonyl ( "C _6- C _6-14 aryl herein in the" which may optionally be substituted with a substituent comprising a ring, C _6-14 aryl group " ₁₄ aryl group ”, such as phenoxycarbonyl).

(6) As the sulfino group used, which may be optionally substituted with a substituent including a ring group, for example, (i) C _1-15 alkylsulfonyl (herein C _1-15 alkyl includes a ring group; Has the same meaning as for "C _1-15 alkyl group" in a C _1-15 alkyl group, which may be optionally substituted with a substituent, such as benzylsulfonyl), (ii) C _6-14 arylsulfonyl (here from C _6-14 aryl have the same significance as for the "C _6-14 aryl group" in the "which may be substituted with any substituents comprising a chain, C _6-14 aryl group", e.g., tosyl), etc. There is this.

(7) As the amidino group to be used, which may be optionally substituted with a substituent including a ring group, for example, (i) amidino, (ii) C _1-15 alkylamidino (herein C _1-15 alkyl _Has the same meaning as for "C _1-15 alkyl group" in "C _1-15 alkyl group, which may be optionally substituted with a substituent including a ring group, eg, N-methylamidino), (iii) C _1-15 acyl amidino (herein, C _1-15 acyl are as defined as for the "C _1-15 acyl group" in the "which may optionally be substituted with a substituent comprising a ring, C _1-15 acyl group" , Such as N-acetylamidino).

(8) As the glyoxyloyl group, which may be optionally substituted with a substituent including a ring group, for example, (i) C _1-15 alkyloxalyl (herein C _1-15 alkyl includes a ring group) _Has the same meaning as for "C _1-15 alkyl group" in "C _1-15 alkyl group", which may be optionally substituted with a substituent such as ethyloxalyl), (ii) C _6-14 aryloxalyl ( C _6-14 aryl herein has the same meaning as for “C6-14 aryl group” in “C6-14 aryl group, which may be optionally substituted with a substituent including a ring group, such as phenyloxalyl) Etc.

(9) As the amino group to be used, which may be optionally substituted with a substituent including a ring group, for example, (i) C _1-15 alkylamino (herein C _1-15 alkyl is optionally defined as a substituent comprising a ring group). it is optionally substituted C _1-15 alkyl has the same meaning as that for the C _1-15 alkyl group "," at ").

Among those described above, J ¹ is preferably a hydrogen atom, formyl, acetyl, 3-indolecarbonyl, 3- (indol-3-yl) propionyl, 3-phenylpropionyl, diphenylacetyl, 3- (Pyridin-3-yl) propionyl, 4-imidazolacetyl, cyclohexanecarbonyl, 1-piperidineacetyl, 1-methyl-1-piperidinioacetyl, 4-piperidinecarbonyl, hexanoyl, Amino- (4-hydroxyphenyl) acetyl, D-glucuronyl, 2- (indol-3-yl) ethylcarbamoyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, amidino , 4-guanidomethylbenzoyl, benzoyl, 3-indoleacetyl, benzyloxycarbonyl, tosyl, phenyl, benzyl, phenethyl, 3-pyridinecarbonyl, 2-pyridinecarbonyl, 4-pyridinecarbonyl, propionyl Isobutyryl, phenylacetyl, 2-methylnicotinoyl, 5-methylnicotinoyl, 6-methylnicotinoyl, pyrazinecarbonyl, cyclopropanecarbonyl, trifluoroacetyl, (R) -3-hydroxy rock 2-methylpropionyl, 2-hydroxyisobutyryl, 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolecarbonyl, 6-hydroxynicotinoyl, 6-chloronicotinoyl, 6- (trifluoromethyl) nicotinoyl, dimethylcarbamoyl, 1-azetidinecarbonyl, 2-azetidinecarbonyl, 4-aminobenzoyl, 4-aminomethylbenzoyl, pyrrole-3-carbonyl, pyri Midine-4-carbonyl, pyrimidine-2-carbonyl, pyridazine-4-carbonyl, 6-aminocaproyl, glycyl, glycylglycyl, glycylglyciglycyl, alanylalanylalanyl , Alanyl alanyl alanyl alanyl, acetyl glycyl, acetyl glycyl glycyl, acetyl glycyl glycyl glycyl, acetyl alanyl alanyl alanyl, acetyl alan alan alan alan alan alanyl, D-argi Nillglysyl, D-arginylglycylyl glycyl, D-arginylglycylylglycidyl, D-arginylalanylalanylalanyl, D-arginylalanylalanylalanylalanyl, Cetyl-D-arginylglycyl, acetyl-D-arginylglycylylgyl, acetyl-D-arginylglycylylglycidyl, acetyl-D-arginylalanylalanylalanyl, acetyl-D- Arginylalanylalanylalanylalanyl, cyclopropanecarbonyl, cyclopentanecarbonyl, cyclobutanecarbonyl, cyclohexanecarbonyl, 1-naphthoyl, 2-naphthoyl, arginyl, arginyl arginyl, 6 -(Arginylamino) caproyl, 6- (D-arginylamino) caproyl, 6- (D-arginyl-D-arginylamino) caproyl, 6- (acetyl-D-arginylamino) capro 1, 6-((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norrousylamino) caproyl, 3- (D-arginylamino) propionyl, 4- (D -Arginylamino) butyryl, 4- (D-arginyl-D-arginylamino) butyryl, 4- (D-arginyl-D-arginyl-D-arginylamino) butyryl, 3- ( 4-hydroxyphenyl) propionyl, butyryl, methyl, adipo , Pyroglutamyl, glycoloyl and the like, more preferably hydrogen atom, formyl, acetyl, propionyl, 3-indolecarbonyl, 3- (indol-3-yl) propionyl, 3-phenylpropionyl, 3 -(Pyridin-3-yl) propionyl, 4-imidazolacetyl, cyclohexanecarbonyl, hexanoyl, amino- (4-hydroxyphenyl) acetyl, 2- (indol-3-yl) ethylcarbamoyl, 9-fluorenylmethoxycarbonyl, amidino, 4-guanidomethylbenzoyl, benzoyl, 3-indoleacetyl, benzyl, phenethyl, 3-pyridinecarbonyl, 2-pyridinecarbonyl, 4-pyridinecarbonyl, Isobutyryl, phenylacetyl, 6-methylnicotinoyl, pyrazinecarbonyl, cyclopropanecarbonyl, trifluoroacetyl, (R) -3-hydroxy-2-methylpropionyl, 2-hydroxyisobutyryl , 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolcarbonyl, 6-hydroxynicotinoyl, 6-chloronicotinoyl, 6- (trifluoromethyl) nicotinoyl, Dimethylcarbamoyl, 1-azetidinecarbonyl, 4-aminobenzoyl, 4-aminomethylbenzoyl, pyrrole-3-carbonyl, pyrimidine-4-carbonyl, pyrimidine-2-carbonyl, pyridazine-4 -Carbonyl, 6-aminocaproyl, cyclopropanecarbonyl, 2-naphthoyl, arginyl, 6- (arginylamino) caproyl, 6- (D-arginylamino) caproyl, 6- (D- Arginyl-D-arginylamino) caproyl, 6- (acetyl-D-arginylamino) caproyl, 6-((R) -2,3-diaminopropionylamino) caproyl, 6- (D -Norrousylamino) caproyl, 3- (D-arginylamino) propionyl, 4- (D-arginylamino) butyryl, 4- (D-arginyl-D-arginylamino) butyryl, 4 -(D-arginyl-D-arginyl-D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, butyryl, adipoyl, pyroglutamyl and the like are used.

J ² represents NH optionally substituted with (1) C _1-6 alkyl group, (2) CH ₂ optionally substituted with C _1-6 alkyl group, (3) O or (4) S.

_{Examples of} the "C _1-6 alkyl group" used include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like.

Preferably, J ² is NH.

J ³ to J ¹² each represent a hydrogen atom or a C _1-3 alkyl group.

Examples of the "C _1-3 alkyl group" to be used include methyl, ethyl, propyl and isopropyl.

Preferably, J ³ is a hydrogen atom.

Preferably, J ⁴ is a hydrogen atom.

Preferably, J ⁵ is a hydrogen atom.

Preferably, J ⁶ is a hydrogen atom.

Preferably, J ⁷ is a hydrogen atom.

Preferably, J ⁸ is a hydrogen atom.

Preferably, J ⁹ is a hydrogen atom.

Preferably, J ¹⁰ is a hydrogen atom.

Preferably, J ¹¹ is a hydrogen atom.

Preferably, J ¹² is a hydrogen atom.

Q ³ to Q ¹² each represent a hydrogen atom or a C 1-4 alkyl group which may optionally have a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group;

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(3) an optionally substituted C _8-14 aromatic conjugated ring group;

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms;

(6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms;

(7) an optionally substituted amino group;

(8) optionally substituted guanidino groups;

(9) an optionally substituted hydroxyl group;

(10) optionally substituted carboxyl groups;

(11) an optionally substituted carbamoyl group; And,

(12) optionally substituted sulfhydryl groups.

Preferably, Q ³ to Q ⁹ include a hydrogen atom or a C _1-4 alkyl group having a substituent selected from the group consisting of:

(1) an optionally substituted C _6-12 aromatic hydrocarbon group;

(2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(3) an optionally substituted C _8-14 aromatic conjugated ring group;

(4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms;

(6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms;

(7) an optionally substituted amino group;

(8) optionally substituted guanidino groups;

(9) an optionally substituted hydroxyl group;

(10) optionally substituted carboxyl groups;

(11) an optionally substituted carbamoyl group; And,

(12) optionally substituted sulfhydryl groups.

"Optionally substituted C _6-12 aromatic hydrocarbon groups,""optionally substituted 5- to 14-membered aromatic heterocyclic groups, consisting of hetero atoms selected from the group consisting of 1 to 7 carbon atoms and nitrogen, oxygen and sulfur atoms , "" Any substituted C _8-14 aromatic conjugated ring group, "" Optionally substituted 5- to 14-membered aromatic conjugated hetero, consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms. Ring groups, "" optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms "and" optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms "are the same as those set forth above.

(1) As C _1-4 alkyl group having an optionally substituted C _6-12 aromatic hydrocarbon group, for example, benzyl, 4-hydroxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4- Aminobenzyl and the like.

(2) a C _1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, for example, 2 -Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-imidazolemethyl and the like are used.

(3) As a C _1-4 alkyl group having an optionally substituted C _8-14 aromatic conjugated ring group, for example, 1-naphthylmethyl, 2-naphthylmethyl and the like are used.

(4) As a C _1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, for example, 3-indolmethyl, 1-formylindol-3-ylmethyl, 2-quinolylmethyl and the like are used.

(5) As a C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, for example, cyclohexylmethyl and the like are used.

(6) As C _1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms, for example, piperidin-1-ylmethyl and the like are used.

(7) As a C _1-4 alkyl group having an optionally substituted amino group, for example, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 4-acetamidobutyl and the like are used.

(8) As a C _1-4 alkyl group having an optionally substituted guanidino group, for example, 3-guanidinopropyl, 3- (N-tosyl) guanidinopropyl and the like are used.

(9) As the C _1-4 alkyl group having an optionally substituted hydroxyl group, for example, hydroxymethyl, 1-hydroxyethyl, benzyloxymethyl and the like are used.

(10) As a C _1-4 alkyl group having an optionally substituted carboxyl group, for example, carboxymethyl, 2-carboxyethyl, benzyloxycarbonylmethyl and the like are used.

(11) As a C _1-4 alkyl group having an optionally substituted carbamoyl group, for example, carbamoylmethyl, 2-carbamoylethyl, xanthylcarbamoyl, and the like are used.

(12) As a C _1-4 alkyl group having an optionally substituted sulfhydryl group, for example, sulfhydrylmethyl, 2- (methylsulhydryl) ethyl and the like are used.

(13) As the unsubstituted C1-4 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are used.

Preferably, Q ³ is a hydrogen atom, 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl, methyl, isobutyl, hydroxymethyl, carboxymethyl, 4-aminobutyl and the like, more preferably , 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl and the like.

Preferably, as Q ⁴ , carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl, 4-imidazolemethyl, isobutyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 4- Aminobutyl and the like, more preferably carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl and the like.

Preferably, Q ⁵ is benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1- Naphthylmethyl, 2-naphthylmethyl, 3-indolemethyl, 1-formylindol-3-ylmethyl, 2-quinolylmethyl, cyclohexylmethyl, hydroxymethyl, 1-hydroxyethyl, methyl, isopropyl , Isobutyl, sec-butyl, carboxymethyl, 4-aminobutyl, and the like, more preferably benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridyl Methyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolmethyl, 2-quinolylmethyl, cyclohexylmethyl, 1-hydroxyethyl, isopropyl, Isobutyl, sec-butyl and the like.

Preferably, Q ⁶ is methyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl and the like, more preferably carbamoylmethyl and the like.

Preferably, Q ⁷ is 4-hydroxybenzyl, carbamoylmethyl, 3-pyridylmethyl, methyl, isobutyl, benzyl, 4-aminobutyl, 3-indolemethyl, and the like, more preferably 4-hydroxy Oxybenzyl and the like.

Preferably, Q ⁸ is benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-naphthylmethyl, 3-indolemethyl, hydroxymethyl, cyclohexylmethyl, sec-butyl, 1-hydroxyethyl, methyl, methyl, isobutyl, 4-aminobutyl, 3-carboxypropyl, and the like, more preferably 4-pyridylmethyl, 3-indolemethyl, sec-butyl and the like.

Preferably, Q ⁹ is a hydrogen atom, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, ureidomethyl, acetamidomethyl, formamidemethyl, methyl Carbamoylmethyl, dimethylcarbamoylmethyl and the like, and more preferably carbamoylmethyl and ureidomethyl.

Preferably, Q ¹⁰ is 4-hydroxybenzyl, 3-indolemethyl, methyl, 1-hydroxyethyl, 3-guanidinopropyl, and the like, more preferably 3-indolemethyl and the like.

Preferably, Q ¹¹ is carbamoylmethyl or the like.

Preferably, Q <^12> is methyl, carbamoylmethyl, etc., More preferably, it is carbamoylmethyl etc.

Y ¹ to Y ³ each represent a group represented by the following formula: -CON (J ¹³ )-, -CSN (J ¹³ )-, -C (J ¹⁴ ) N (J ¹³ )-or -N (J ¹³ ) CO- (J ¹³ and J ¹⁴ each represent a hydrogen atom or a C _1-3 alkyl group).

As the C _1-3 alkyl group represented by J ¹³ and J ¹⁴ , methyl, ethyl, propyl or isopropyl is used.

J ¹³ is a hydrogen atom.

J ¹⁴ is a hydrogen atom.

Y ¹ is preferably a group represented by the following formula: -CONH- or -CH ₂ NH- and the like.

Y ² is preferably a group represented by the following formula: -CONH- or -CH ₂ NH- and the like.

Y ³ is preferably a group represented by the following formula: -CONH- and the like.

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ , J ⁶ and Q ⁶ , J ⁷ and Q ⁷ , J ⁸ and Q ⁸ , J ⁹ and Q ⁹ , J ¹⁰ and Q ¹⁰ , J ¹¹ And Q ¹¹ , and J ¹² and Q ¹² may be combined with each other to form a ring. In this case, for example, C (J ³ ) (Q ³ ), C (J ⁴ ) (Q ⁴ ), C (J ⁵ ) (Q ⁵ ), C (J ⁶ ) (Q ⁶ ), C ( J ⁷ ) (Q ⁷ ), C (J ⁸ ) (Q ⁸ ), C (J ⁹ ) (Q ⁹ ), C (J ¹⁰ ) (Q ¹⁰ ), C (J ¹¹ ) (Q ¹¹ ) or C ( J ¹² ) (Q ¹² ) forms cyclopentane, cyclohexane, piperidine and the like.

Z ¹ and R ¹ , J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ , Y ³ and Q ⁶ , J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ , J ² And Q ¹⁰ or Y ³ and Q ¹¹ , and J ² and Q ¹² (preferably, J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ , Y ³ and Q ⁶ , J ² and Q ⁷ , Y ² and Q ⁸ , Y ³ and Q ⁹ , J ² and Q ¹⁰ , Y ³ and Q ¹¹ , and J ² and Q ¹² ) may be combined with each other to form a ring. Alternatively, the ring formed may be optionally substituted or annealed.

If Z ¹ and R ¹ , J ² and Q ³ , J ² and Q ⁷ , J ² and Q ¹⁰ , or J ² and Q ¹² can be combined with each other to form a ring, for example, Z ¹ -N -CH-R ¹ , J ² -C (J ³ ) (Q ³ ), J ² -C (J ⁷ ) (Q ⁷ ), J ² -C (J ¹⁰ ) (Q ¹⁰ ) or J ² -C ( J ¹² ) (Q ¹² ) forms azetidine, pyrrolidine, piperidine or thiazolidine. Alternatively, the ring formed may be optionally substituted or annealed. Z ¹ -N-CH-R ¹ is preferably azetidine, pyrrolidine, 4-hydroxypyrrolidine, piperidine and the like.

If Y ¹ and Q ⁴ , Y ² and Q ⁵ , Y ³ and Q ⁶ , Y ² and Q ⁸ , Y ³ and Q ⁹ , or Y ³ and Q ¹¹ can be combined with each other to form a ring, for example For example, Y ¹ C (J ⁴ ) (Q ⁴ ), Y ² C (J ⁵ ) (Q ⁵ ), Y ³ C (J ⁶ ) (Q ⁶ ), Y ² C (J ⁸ ) (Q ⁸ ), Pyrrolidine-2-carbonyl, piperidine-2-carbonyl or thiazolidine-4- by Y ³ C (J ⁹ ) (Q ⁹ ), or Y ³ C (J ¹¹ ) (Q ¹¹ ) Carbonyl is formed. Alternatively, the ring formed may be optionally substituted or annealed.

A group represented by the following formula:

Preferred examples of are the following:

A group represented by the following formula:

Preferred examples of the following include:

A group represented by the following formula:

Preferred examples of the following include:

Fmoc Trp Asn-,

Boc Tyr Asn-,

Tyr Asn-,

D-Trp Asn-,

Ac Trp Asn-,

Amidino Trp Asn-,

Ac Ala Asn-,

Ac Arg Asn-,

Ac Thr Asn-

D-Tyr D-Pya (4)-

3- (4-hydroxyphenyl) propionyl D-Trp Asn-

D-Trp Asn-

Ac D-Trp Asn-

Hexanoyl D-Trp Asn-

Cyclohexanecarbonyl D-Trp Asn-

Benzoyl D-Trp Asn-

3-pyridinepropionyl D-Trp Asn-

Adifoil D-Trp Asn-

6-aminocaproyl D-Trp Asn-

Amidino D-Trp Asn-

Glycoloyl D-Trp Asn-, and the like.

Group represented by the following formula: J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ )-

Preferred examples of the following include:

Fmoc Asn-,

3- (indol-3-yl) propionyl Asn-,

3-indolecarbonyl Asn-,

3-indoleacetyl Asn-,

4- (indol-3-yl) butyryl Asn-,

Diphenylacetyl Asn-,

Hexanoyl Asn-,

Cyclohexanecarbonyl Asn-,

2- (indol-3-yl) ethylcarbamoyl Asn-,

3- (3-pyridyl) propionyl Asn-,

4-imidazoleacetyl Asn-,

Piperidinecarbonyl Asn-,

1-piperidineacetyl Asn-,

1-methyl-1-piperidinioacetyl Asn-,

1-pyridinioacetyl Asn-,

D-glucuronyl Asn-,

3-phenylpropionyl Asn-,

3-phenylpropionyl Ala-,

Benzoyl Asn-,

Ac Asn-,

Cyclopropanecarbonyl Asn-,

2-naphthoyl Asn-, etc.

Preferred examples of the group represented by the following formula: J ¹ -include the following:

Hydrogen atom,

GuAmb-,

3- (3-indolyl) propionyl-,

3- (3-pyridyl) propionyl-,

Benzoyl-,

Indole-3-carbonyl-,

Indole-3-acetyl-,

Ac-,

Hexanoyl-,

Z-,

Tos-,

3-phenylpropionyl-,

2- (indol-3-yl) ethylcarbamoyl-,

benzyl-,

Phenethyl-,

2-pyridinecarbonyl-,

4-pyridinecarbonyl-,

Propionyl,

Isobutyryl,

Cyclohexanecarbonyl-,

Phenylacetyl-,

2-methylnicotinoyl-,

5-methylnicotinoyl-,

6-methylnicotinoyl-,

Pyrazinecarbonyl-,

Cyclopropanecarbonyl-,

Trifluoroacetyl-,

(R) -3-hydroxy-2-methylpropionyl-,

2-hydroxyisobutyryl-,

3-furancarbonyl-,

Pyrrole-2-carbonyl-,

4-imidazolcarbonyl-,

6-hydroxynicotinoyl-,

6-chloronicotinoyl-,

6- (trifluoromethyl) nicotinoyl-,

Dimethylcarbamoyl-,

1-azetidinecarbonyl-,

2-azetidinecarbonyl-,

4-aminobenzoyl-,

4-aminomethylbenzoyl-,

Pyrrole-3-carbonyl-,

Pyrimidine-4-carbonyl-,

Pyrimidine-2-carbonyl-,

Pyridazine-4-carbonyl-, and the like.

Metastin derivative (I) in metastin derivative (III) of the present invention, wherein V 'represents a group represented by the following formula:

(Where each symbol has the same meaning as defined above) is a class of compounds disclosed in the specification filed in PCT / JP03 / 16978, while V ′ is a group represented by the formula:

Wherein each symbol has the same meaning as defined above, or a group represented by the following formula:

The metastin derivatives (II) representing (where each symbol has the same meaning as defined above) are novel compounds.

In the metastin derivative (III), all compounds in which the groups represented by each symbol are arbitrarily combined are preferably used. Of these, compounds represented by the following compound numbers (Tables 1 to 11) are preferable.

Compound number 51: [NMePhe10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-NMePhe-NH ₂

Compound number 53: des (1-3) -Fmoc-MS10

Fmoc-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 54: des (1-2) -Fmoc-MS10

Fmoc-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 55: des (1) -Fmoc-MS10

Fmoc-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 56: [Lys2] MS10

Tyr-Lys-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 57: [Asp2] MS10

Tyr-Asp-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 58: [Tyr2] MS10

Tyr-Tyr-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 59: [Leu2] MS10

Tyr-Leu-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 60: [Pya (3) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Pya (3) -NH ₂

Compound number 61: [Phe (4F) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (4F) -NH ₂

Compound number 67: [Ala3] MS10

Tyr-Asn-Ala-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 68: [Leu3] MS10

Tyr-Asn-Leu-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 69: [Ser3] MS10

Tyr-Asn-Ser-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 70: [Asp3] MS10

Tyr-Asn-Asp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 71: [Lys3] MS10

Tyr-Asn-Lys-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 72: [Ala1] MS10

Ala-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 73: [Leu1] MS10

Leu-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 74: [Ser1] MS10

Ser-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 75: [Asp1] MS10

Asp-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 76: [Lys1] MS10

Lys-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 77: [Phe (4CN) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (4CN) -NH ₂

Compound number 78: [Trp (For) 3, Phe (4CN) 10] MS10

Tyr-Asn-Trp (For) -Asn-Ser-Phe-Gly-Leu-Arg-Phe (4CN) -NH ₂

Compound number 79: [Hph10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Hph-NH ₂

Compound number 81: [NMeArg9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-NMeArg-Phe-NH ₂

Compound number 82: [Arg (Me) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 83: [Arg (asy Me ₂ ) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (asyMe ₂ ) -Phe-NH ₂

Compound number 87: des (4-5) -Boc-MS10

Boc-Tyr-Asn-Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 88: des (4-5) -MS10

Tyr-Asn-Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 90: [Lys9,9Ψ10, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-LysΨ (CH ₂ NH) Phe-NH ₂

Compound number 91: [8Ψ9, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-LeuΨ (CH ₂ NH) Arg-Phe-NH ₂

Compound number 97: [Har9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Har-Phe-NH ₂

Compound number 98: [Lys (Me ₂ ) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Lys (Me ₂ ) -Phe-NH ₂

Compound number 101: [Ser7] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Ser-Leu-Arg-Phe-NH ₂

Compound number 105: [Nle8] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Nle-Arg-Phe-NH ₂

Compound number 107: [Val8] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Val-Arg-Phe-NH ₂

Compound number 109: [Tyr10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Tyr-NH ₂

Compound number 110: [Nal (2) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Nal (2) -NH ₂

Compound number 111: [Phe (F5) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (F5) -NH ₂

Compound number 112: [Cha10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Cha-NH ₂

Compound number 114: des (1-3) -3- (3-indolyl) propionyl-MS10

3- (3-Indolyl) propionyl-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 121: des (1-4)-[Trp5] MS10

Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 123: [NMeLeu8] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-NMeLeu-Arg-Phe-NH ₂

Compound number 126: [NMeSer5] MS10

Tyr-Asn-Trp-Asn-NMeSer-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 127: [D-Asn4, NMePhe6] MS10

Tyr-Asn-Trp-D-Asn-Ser-NMePhe-Gly-Leu-Arg-Phe-NH ₂

Compound number 128: [10Ψ, CSNH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-PheΨ (CSNH) NH ₂

Compound number 129: [Arg (symMe ₂ ) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (symMe ₂ ) -Phe-NH ₂

Compound number 130: [Phe (4Cl) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (4Cl) -NH ₂

Compound number 131: [Phe (4NH ₂ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (4NH2) -NH ₂

Compound number 132: [Phe (4NO ₂ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (4NO ₂ ) -NH ₂

Compound number 133: [Nal (1) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Nal (1) -NH ₂

Compound number 134: [Trp10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Trp-NH ₂

Compound number 137: [Nle9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nle-Phe-NH ₂

Compound number 138: [Cit9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Cit-Phe-NH ₂

Compound number 140: [Arg (Me) 9, NMePhe10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -NMePhe-NH ₂

Compound number 141: [D-Tyr1, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 142: [D-Tyr1, D-Trp3, Arg (Me) 9] MS10

D-Tyr-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 143: [D-Trp3, Arg (Me) 9] MS10

Tyr-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 144: des (1-3) -Fmoc- [Arg (Me) 9] MS10

Fmoc-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 145: des (1-2) -Fmoc- [Arg (Me) 9] MS10

Fmoc-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 146: [10Ψ, CSNH, D-Tyr1] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-PheΨ (CSNH) NH ₂

Compound number 150: [Tyr6] MS10

Tyr-Asn-Trp-Asn-Ser-Tyr-Gly-Leu-Arg-Phe-NH ₂

Compound number 151: [Nal (1) 6] MS10

Tyr-Asn-Trp-Asn-Ser-Nal (1) -Gly-Leu-Arg-Phe-NH ₂

Compound number 152: [Nal (2) 6] MS10

Tyr-Asn-Trp-Asn-Ser-Nal (2) -Gly-Leu-Arg-Phe-NH ₂

Compound number 153: [Phe (F5) 6] MS10

Tyr-Asn-Trp-Asn-Ser-Phe (F ₅ ) -Gly-Leu-Arg-Phe-NH ₂

Compound number 154: [Phe (4F) 6] MS10

Tyr-Asn-Trp-Asn-Ser-Phe (4F) -Gly-Leu-Arg-Phe-NH ₂

Compound number 156: [Cha6] MS10

Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg-Phe-NH ₂

Compound number 163: [6Ψ7, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-PheΨ (CH2NH) Gly-Leu-Arg-Phe-NH ₂

Compound number 165: [Dap (Gly) 9] -MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dap (Gly) -Phe-NH ₂

Compound number 166: [6Ψ7, CSNH] MS10

Tyr-Asn-Trp-Asn-Ser-PheΨ (CSNH) Gly-Leu-Arg-Phe-NH ₂

Compound number 169: [D-Tyr1, Ala3, Arg (Me) 9] MS 10

D-Tyr-Asn-Ala-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 170: [D-Tyr1, Ser3, Arg (Me) 9] MS 10

D-Tyr-Asn-Ser-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 171: [D-Tyr1, Cha3, Arg (Me) 9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 172: [D-Tyr1, Cha6, Arg (Me) 9] MS 10

D-Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 173: [D-Tyr1, Ala7, Arg (Me) 9] MS 10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg (Me) -Phe-NH ₂

Compound number 174: [D-Tyr1, Arg (Me) 9, Trp10] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound number 176: [AzaGly7] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg-Phe-NH ₂

Compound number 181: [D-Tyr1, Cha3,6, Arg (Me) 9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Cha-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 182: [D-Tyr1, Cha3, 6, Arg (Me) 9, Trp10] MS10

D-Tyr-Asn-Cha-Asn-Ser-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound number 183: [Phe (4NH ₂ ) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Phe (4NH ₂ ) -Phe-NH ₂

Compound number 184: [Phe (4-guanidino) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Phe (4-Guanidino) -Phe-NH ₂

Compound number 185: [Dap (GnGly) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dap (GnGly) -Phe-NH ₂

Compound number 186: [Trp (For) 10] MS 10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Trp (For) -NH ₂

Compound number 187: [Abu8] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Abu-Arg-Phe-NH ₂

Compound number 189: [Ala (3-Bzt) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Ala (3-Bzt) -NH ₂

Compound No. 190: [D-Tyr1, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 191: [D-Tyr1, Ser3, AzaGly7, Arg (Me) 9] MS 10

D-Tyr-Asn-Ser-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 192: [D-Tyr1, Arg (Et) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Et) -Phe-NH ₂

Compound number 193: [D-Tyr1, Arg (n-Pr) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (n-Pr) -Phe-NH ₂

Compound number 194: [D-Tyr1, Arg (Ac) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Ac) -Phe-NH ₂

Compound number 197: [Phe (3F) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3F) -NH ₂

Compound number 198: [Phe (3,4F ₂ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3,4F ₂ ) -NH ₂

Compound number 199: [Phe (3,4Cl ₂ ) 10] MS 10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3,4Cl ₂ ) -NH ₂

Compound number 200: [Phe (3CF ₃ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3CF ₃ ) -NH ₂

Compound number 201: [Ala (2-Qui) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Ala (2-Qui) -NH ₂

Compound No. 203: [D-Tyr1, Cha6, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Cha-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 204: [D-Tyr1, Ala7, Arg (Me) 9] MS 10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg (Me) -Phe-NH ₂

Compound number 205: [D-Tyr1, Thr3, Arg (Me) 9] MS10

D-Tyr-Asn-Thr-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 206: [D-Tyr1, Ile3, Arg (Me) 9] MS10

D-Tyr-Asn-Ile-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 207: [D-Tyr1, Ser4, Arg (Me) 9] MS 10

D-Tyr-Asn-Trp-Ser-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 208: [D-Tyr1, Thr4, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Thr-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 209: [D-Tyr1, Gln4, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Gln-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 210: [D-Tyr1, Ala4, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Ala-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 211: [D-Tyr1, Thr5, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 212: [D-Tyr1, Ala5, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ala-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 213: [D-Tyr1, Val8, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Val-Arg (Me) -Phe-NH ₂

Compound number 214: [D-Tyr1, Gln2, Arg (Me) 9] MS10

D-Tyr-Gln-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 215: [D-Tyr1, Thr2, Arg (Me) 9] MS10

D-Tyr-Thr-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 216: des (1)-[D-Asn2, Arg (Me) 9] MS10

D-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 217: des (1)-[D-Tyr2, Arg (Me) 9] MS10

D-Tyr-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 218: [N ((CH ₂ ) ₃ Gn)] Gly 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-N ((CH ₂ ) ₃ Gn) Gly-Phe-NH ₂

Compound number 220: [Arg (Et) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Et) -Phe-NH ₂

Compound No. 221: [D-Tyr1, Thr3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 222: des (1)-[D-Tyr2, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 223: des (1-2)-[D-Trp3, Arg (Me) 9] MS10

D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 224: des (1)-[D-Tyr2, D-Trp3, Arg (Me) 9] MS10

D-Tyr-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 225: des (1)-[D-Asn2, D-Trp3, Arg (Me) 9] MS10

D-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 226: des (1)-[D-Tyr2, Ser3, Arg (Me) 9] MS10

D-Tyr-Ser-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 227: des (1)-[D-Tyr2, Thr3, Arg (Me) 9] MS10

D-Tyr-Thr-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 228: des (1)-[D-Tyr2, Ile3, Arg (Me) 9] MS10

D-Tyr-Ile-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 229: [D-Tyr1, Val3, Arg (Me) 9] MS 10

D-Tyr-Asn-Val-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 230: [D-Tyr1, D-Asn2, Arg (Me) 9] MS10

D-Tyr-D-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 231: [D-Tyr1, D-Asn2, D-Trp3, Arg (Me) 9] MS10

D-Tyr-D-Asn-D-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 232: [D-Tyr1, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 233: [D-Tyr1, Il3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Ile-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 234: [D-Tyr1, Val3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Val-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 235: [D-Tyr1, Ala3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 236: [D-Tyr1, D-Trp3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 237: [D-Tyr1, D-Asn2, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 238: [D-Tyr1, D-Asn2, D-Trp3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 239: des (1)-[D-Tyr2, Ser3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Ser-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 240: des (1)-[D-Tyr2, Ile3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Ile-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 241: des (1)-[D-Tyr2, Thr3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 242: des (1)-[D-Tyr2, D-Trp3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 244: [D-Tyr1, Phe3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 245: [D-Tyr1, Nal (1) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Nal (1) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 246: [D-Tyr1, Nal (2) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Nal (2) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 247: [D-Tyr1, Phe (2Cl) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe (2Cl) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 248: [D-Tyr1, Phe (3Cl) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe (3Cl) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 249: [D-Tyr1, Phe (4Cl) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe (4Cl) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 250: [D-Tyr1, Phe (4NH2) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe (4NH ₂ ) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 251: [D-Tyr1, Pya (3) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Pya (3) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 252: [D-Tyr1, D-Ala3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-D-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 253: [D-Tyr1, Pro3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Pro-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 254: des (1)-[D-Tyr2, Phe3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 255: des (1)-[D-Tyr2, Nal (2) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Nal (2) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 256: des (1)-[D-Pya (3) 2, Phe3, AzaGly7, Arg (Me) 9] MS10

D-Pya (3) -Phe-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 257: [D-Tyr1, D-Asn2, Phe3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Phe-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 258: [D-Pya (3) 1, AzaGly7, Arg (Me) 9] MS10

D-Pya (3) -Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 259: [D-Ala1, AzaGly7, Arg (Me) 9] MS10

D-Ala-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 260: des (1-3) -3- (3-indolyl) propionyl- [AzaGly7, Arg (Me) 9] MS10

3- (3-Indolyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 261: [7Ψ8, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-GlyΨ (CH ₂ NH) Leu-Arg-Phe-NH ₂

Compound number 265: des (1-3) -indole-3-carbonyl- [AzaGly7, Arg (Me) 9] MS10

Indole-3-carbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 266: des (1-3) -indole-3-acetyl- [AzaGly7, Arg (Me) 9] MS10

Indole-3-acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 267: des (1-3) -4- (3-indolyl) butyryl- [AzaGly7, Arg (Me) 9] MS10

4- (3-indolyl) butyryl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 268: des (1-3) -diphenylacetyl- [AzaGly7, Arg (Me) 9] MS10

Diphenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 269: des (1-3) -3-phenylpropionyl- [AzaGly7, Arg (Me) 9] MS10

3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 270: [D-Tyr1, Phe3, Ser-Phe5, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe-Asn-Ser-Phe-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 271: des (1-2)-[AzaGly7, Arg (Me) 9] MS10

Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 272: des (1-2) -acetyl- [AzaGly7, Arg (Me) 9] MS10

Acetyl-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 273: des (1-2) -amidino- [AzaGly7, Arg (Me) 9] MS10

Amidino-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 274: des (1-2) -acetyl- [Ala3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 275: des (1-2) -acetyl- [Arg3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Arg-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 276: des (1-2) -acetyl- [Thr3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 277: des (1-3) -n-hexanoyl- [AzaGly7, Arg (Me) 9] MS10

n-hexanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 278: des (1-3) -cyclohexanecarbonyl- [AzaGly7, Arg (Me) 9] MS10

Cyclohexanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 279: des (1-3) -2- (indol-3-yl) ethylcarbamoyl- [AzaGly7, Arg (Me) 9] MS10

2- (indol-3-yl) ethylcarbamoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 281: [D-Tyr1, Pya (2) 6, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Pya (2) -Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 282: [D-Tyr1, Pya (4) 6, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Pya (4) -Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 283: [D-Tyr1, D-Asn2, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 284: [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 285: [D-Tyr1, Pya (2) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Pya (2) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 286: [D-Tyr1, Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 287: [D-Tyr1, D-Ser2, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Ser-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 288: [D-Tyr1, D-His2, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-His-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 289: des (1)-[D-Pya (3) 2, AzaGly7, Arg (Me) 9] MS10

D-Pya (3) -Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 290: [D-Pya (3) 1, D-Asn2, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Pya (3) -D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 291: [D-Pya (3) 1, D-Tyr2, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Pya (3) -D-Tyr-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 293: [4Ψ5, CH ₂ NH] MS10

Tyr-Asn-Trp-AsnΨ (CH ₂ NH) Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 294: [1Ψ2, CH ₂ NH] MS10

TyrΨ (CH ₂ NH) Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound number 295: [2Ψ3, CH ₂ NH] MS10

Tyr-AsnΨ (CH ₂ NH) Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 296: [6Ψ7, CSNH, D-Tyr1, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ (CSNH) Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 297: [D-Tyr1, Thr5, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 298: [D-Tyr1, D-Asn2, Thr5, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 299: [1Ψ2, CH ₂ NH, AzaGly7, Arg (Me) 9] -MS10

TyrΨ (CH ₂ NH) Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 300: [1Ψ2, CH ₂ NH, D-Trp3, AzaGly7, Arg (Me) 9] -MS10

TyrΨ (CH ₂ NH) Asn-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 301: [D-Tyr1, Ala (2-Qui) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Ala (2-Qui) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 302: [D-Tyr1, D-Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 303: [D-Tyr1, D-Asn2, Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 304: [D-Asn2, Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

Tyr-D-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 305: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 306: [D-Pya (4) 1, D-Asn2, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Pya (4) -D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 307: [7Ψ8, CH ₂ NH, D-Tyr1, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-GlyΨ (CH ₂ NH) Leu-Arg (Me) -Phe-NH ₂

Compound number 308: [6Ψ7, CH ₂ NH, D-Tyr1, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ (CH ₂ NH) Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 310: [Nar9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nar-Phe-NH ₂

Compound number 311: [Nar (Me) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Nar (Me) -Phe-NH ₂

Compound number 312: [Har (Me) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Har (Me) -Phe-NH ₂

Compound number 313: [Dab9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dab-Phe-NH ₂

Compound number 314: [Orn9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Orn-Phe-NH ₂

Compound No. 315: des (1)-[D-Asn2, Cha3, AzaGly7, Arg (Me) 9] MS10

D-Asn-Cha-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 316: [D-Tyr1, D-Asn2, Thr3, AzaGly7, Arg (Me) 9, Phe (4F) 10] MS10

D-Tyr-D-Asn-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂

Compound No. 317: [D-Tyr1, D-Asn2, Pya (4) 3, AzaGly7, Arg (Me) 9, Phe (4F) 10] MS10

D-Tyr-D-Asn-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂

Compound No. 318: [D-Tyr1, AzaGly7, Arg (Me) 9, Phe (4F) 10] MS10

D-Tyr-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂

Compound number 319: [6Ψ7, NHCO, D-Tyr1, Arg (Me) 9] MS10

D-Tyr-Asn-Trp-Asn-Ser-PheΨ (NHCO) Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 322: des (1-3) -3- (3-pyridyl) propionyl- [AzaGly7, Arg (Me) 9] MS10

3- (3-Pyridyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 323: des (1-3) -4-imidazoleacetyl- [AzaGly7, Arg (Me) 9] MS10

4-imidazoleacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 324: des (1-3) -4-piperidinecarbonyl- [AzaGly7, Arg (Me) 9] MS10

Piperidinecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 325: des (1-3) -1-piperidineacetyl- [AzaGly7, Arg (Me) 9] MS10

1-piperidineacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 326: des (1-3) -1-methylpiperidinio-1-acetyl- [AzaGly7, Arg (Me) 9] MS10

1-Methylpiperidino-1-acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 327: des (1-3) -1-pyridinioacetyl- [AzaGly7, Arg (Me) 9] MS10

1-Pyridinoacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 328: des (1-3) -D-glucuronyl- [AzaGly7, Arg (Me) 9] MS10

D-glucuronyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 375: 2-aminoethyl-Gly- [D-Tyr1, Arg (Me) 9] MS10

2-Aminoethyl-Gly-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 385: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 386: des (1-3) -3- (3-pyridyl) propionyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

3- (3-Pyridyl) propionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 387: Dap- [D-Tyr1, Arg (Me) 9] MS10

Dap-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 397: Methylthiocarbamoyl-Sar- [D-Tyr1, Arg (Me) 9] MS10

Methylthiocarbamoyl-Sar-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe-NH ₂

Compound number 400: (S) -1- (quinolin-8-yl-carbamoyl) -4-thiapentylcarbamoyl- [D-Tyr1, Arg (Me) 9] MS10

(S) -1- (quinolin-8-yl-carbamoyl) -4-thiapentylcarbamoyl-D-Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg (Me) -Phe -NH ₂

Compound number 481: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Har9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound number 486: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Orn9] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Orn-Phe-NH ₂

Compound No. 487: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Lys9] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Lys-Phe-NH ₂

Compound number 488: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Har9] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Har-Phe-NH ₂

Compound number 489: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Har (Me) 9] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Har (Me) -Phe-NH ₂

Compound number 490: des (1)-[D-Tyr2, Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 491: des (1)-[D-Tyr2, D-Pya (4) 3, Trp5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Trp-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 492: des (1)-[D-Tyr2, D-Pya (4) 3, Ala4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 493: des (1)-[D-Tyr2, D-Pya (4) 3, Thr4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Thr-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 494: des (1,4)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 495: des (1-3)-[D-Tyr4, Pya (4) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-Pya (4) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 496: des (1)-[D-Tyr2, D-Pya (4) 3, Cha6, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound number 497: des (1)-[D-Tyr2, D-Pya (4) 3, Cha6, Ala7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Cha-Ala-Leu-Arg (Me) -Trp-NH ₂

Compound No. 498: des (1)-[D-Tyr2, D-Pya (4) 3, Ile5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ile-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 499: des (1-3) -3-phenylpropionyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 500: des (1-3) -3-phenylpropionyl- [Ala 4, Aza Gly 7, Arg (Me) 9, Trp 10] MS 10

3-phenylpropionyl-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 501: des (1)-[D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 502: des (1)-[D-Tyr2, Pya (4) 3, Ala4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-Pya (4) -Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 503: des (1)-[D-Tyr2, D-Trp3, Ala4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 504: [Acp1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

Acp-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 505: des (1-3) -3-phenylpropionyl- [Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 506: des (1-3) -3-phenylpropionyl- [Ile5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ile-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 507: des (1-3) -3-phenylpropionyl- [Trp6, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ser-Trp-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 508: des (1-3) -3-phenylpropionyl- [Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ser-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 509: des (1-3) -benzoyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 510: des (1-3) -Ac- [AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 511: des (1)-[D-Tyr2, D-Trp3, Ala4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Ala-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 512: des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 513: des (1)-[D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 514: des (1)-[D-Tyr2, D-Phe3, Ala4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Phe-Ala-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 515: des (1)-[D-Tyr2, D-Pya (4) 3, Val5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 516: des (1) -Ac- [D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9] MS10

Ac-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 517: des (1-3) -3-phenylpropionyl- [Hyp5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Hyp-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 518: des (1-3) -3-phenylpropionyl- [Cha6, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ser-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound number 519: des (1-3) -phenylacetyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

Phenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 521: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg-Phe-NH ₂

Compound number 522: des (1-3) -benzoyl- [Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 523: des (1-3) -benzoyl- [Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 524: des (1-3) -3-phenylpropionyl- [Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Pro-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 527: des (1)-[D-Tyr2, D-Pya (4) 3, Hyp5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Hyp-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 528: des (1)-[D-Tyr2, D-Pya (4) 3, Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Pro-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 529: des (1)-[D-Tyr2, D-Pya (4) 3, Tle5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Tle-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 530: des (1)-[D-Tyr2, D-Pya (4) 3, Phg5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Phg-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 531: des (1-3) -3-phenylpropionyl- [Pic (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Pic (2) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 532: des (1-3) -3-phenylpropionyl- [Aze (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Aze (2) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 533: des (1-3) -3-phenylpropionyl- [D-Pro5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-D-Pro-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 534: des (1-3) -cyclopropanecarbonyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

Cyclopropanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 535: des (1-3) -2-naphthoyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

2-naphthoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 536: [Arg1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

Arg-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 537: Arg- [Arg1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

Arg-Arg-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 538: Arg- [Acp1, D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

Arg-Acp-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 539: des (1)-[D-Tyr2, D-Trp3, Val5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 540: des (1)-[D-Tyr2, D-Trp3, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 541: D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 542: D-Arg-D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 545: des (1-3) -benzoyl- [Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-Asn-Ser-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 546: des (1-3) -3-phenylpropionyl- [Ser (Ac) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-phenylpropionyl-Asn-Ser (Ac) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 547: des (1)-[D-Tyr2, D-Pya (4) 3, Ser (Ac) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Pya (4) -Asn-Ser (Ac) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 548: des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9,10Ψ, CSNH] MS10

D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -PheΨ (CSNH) NH ₂

Compound number 550: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH

Compound No. 551: Ac-D-Arg- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 552: D-Dap- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 553: D-Nle- [Acp1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 554: D-Arg- [β-Ala1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-β-Ala-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 555: D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 556: D-Arg-D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 557: D-Arg-D-Arg-D-Arg- [γ-Abu1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-D-Arg-D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 558: des (1) -Ac- [D-Tyr2, D-Trp3, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 559: des (1-2) -3- (4-hydroxyphenyl) propionyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

3- (4-hydroxyphenyl) propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 561: D-Arg- [Acp1, D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Arg-Acp-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 562: des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 563: des (1) -Ac- [D-Tyr2, D-Trp3, Aze (2) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Aze (2) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 564: des (1) -Ac- [D-Tyr2, D-Trp3, Val5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 565: des (1) -benzoyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 566: des (1) -cyclopropanecarbonyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 567: des (1) -butyryl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 568: Ac- [D-Arg1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Arg-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 569: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5,6Ψ7, CH ₂ NH, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ (CH ₂ NH) Gly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 570: des (1) -Me- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Me-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 571: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound number 572: des (1)-[D-Trp2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Trp-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 573: des (1) -Ac- [D-Tyr2, D-Trp3, Abu4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Abu-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 576: des (1) -Ac- [D-Tyr2, D-Trp3, Gln4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Gln-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 577: des (1) -Ac- [D-Tyr2, D-Trp3, Ser4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Ser-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 578: des (1) -Ac- [D-Tyr2, D-Trp3, Thr4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Thr-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 579: des (1) -Ac- [D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 580: des (1) -Ac- [D-Tyr2, D-Trp3, Ser (Me) 5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Ser (Me) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 584: des (1) -Ac- [D-Tyr2, D-Trp3, Dap (Ac) 4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Dap (Ac) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 585: des (1) -Ac- [D-Tyr2, D-Trp3, Dap (For) 4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Dap (For) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 586: des (1) -Ac- [D-Tyr2, Thr5, D-Phe6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 589: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Nal (2) 10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Nal (2) -NH ₂

Compound No. 590: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Thi10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Thi-NH ₂

Compound No. 591: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Tyr10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Tyr-NH ₂

Compound No. 592: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Phe (4F) 10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂

Compound No. 594: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Hph10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Hph-NH ₂

Compound No. 595: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Cha10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Cha-NH ₂

Compound No. 596: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Leu10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Leu-NH ₂

Compound No. 597: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, D-Phe6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 598: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 599: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Orn9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂

Compound No. 600: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂

Compound No. 601: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, D-Phe6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 602: des (1) -Ac- [D-NMeTyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 603: des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, D-Phe6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pya (4) -Asn-Thr-D-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 604: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Tos) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Tos) -Trp-NH ₂

Compound No. 605: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (NO2) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (NO2) -Trp-NH ₂

Compound No. 607: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me2) asym9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me2) asym-Trp-NH ₂

Compound No. 608: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me2) sym9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me2) sym-Trp-NH ₂

Compound No. 609: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Et) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Et) -Trp-NH ₂

Compound No. 610: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys (Me2) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys (Me2) -Trp-NH ₂

Compound No. 611: des (1) -Ac- [Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 612: des (1) -For- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 613: des (1) -propionyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 614: des (1) -amidino- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Amidino-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 615: des (1) -Ac- [Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 616: des (1) -Ac- [D-Ala2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 617: des (1) -Ac- [D-Leu2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 618: des (1) -Ac- [D-Phe2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 619: des (1) -Ac- [D-Nal (1) 2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Nal (1) -D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 620: des (1) -Ac- [D-Nal (2) 2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Nal (2) -D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 621: des (1) -Ac- [D-Lys2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 622: des (1) -Ac- [D-Glu2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Glu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 623: des (1) -Ac- [D-Tyr2, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 624: des (1) -Ac- [D-Tyr2, Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 625: des (1) -Ac- [D-Tyr2, D-Ala3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 626: des (1) -Ac- [D-Tyr2, D-Leu3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 627: des (1) -Ac- [D-Tyr2, D-Phe3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 628: des (1) -Ac- [D-Tyr2, D-Thr3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Thr-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 629: des (1) -Ac- [D-Tyr2, D-Lys3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 630: des (1) -Ac- [D-Tyr2, D-Glu3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 631: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Ala6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Ala-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 632: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Leu6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Leu-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 633: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Lys6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Lys-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 634: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Glu6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Glu-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 635: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Pya (4) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Pya (4) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 636: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, MePhe6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-MePhe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 637: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 638: des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, Phe (4F) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 639: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Lys9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Lys-Trp-NH ₂

Compound No. 641: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Ala8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ala-Arg (Me) -Trp-NH ₂

Compound No. 642: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Val8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg (Me) -Trp-NH ₂

Compound No. 643: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Phe8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Phe-Arg (Me) -Trp-NH ₂

Compound No. 644: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Ser8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ser-Arg (Me) -Trp-NH ₂

Compound No. 645: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Har9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har-Trp-NH ₂

Compound No. 646: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Har (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Har (Me) -Trp-NH ₂

Compound No. 647: des (1) -Ac- [D-Tyr2, D-Trp3, Asp4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asp-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 648: [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 649: Ac- [Gly1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 650: [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 651: Ac- [D-Tyr1, D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 652: des (1) -pGlu- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 653: des (1) -Ac- [D-Tyr2, D-Trp3, D-Asn4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-D-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 654: des (1) -Ac- [D-Tyr2, D-Trp3, D-Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-D-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 655: des (1) -Ac- [D-Tyr2, D-Trp3, MeAsn4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-MeAsn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 656: des (1) -Ac- [D-Tyr2, D-Trp3, MeSer5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-MeSer-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 657: des (1) -Ac- [D-Tyr2, Pro3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 658: des (1) -Ac- [D-Tyr2, D-Pya (2) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pya (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 659: des (1) -Ac- [D-Tyr2, D-Trp3, allo-Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-allo-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 660: des (1) -Ac- [D-Tyr2, D-Pya (3) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pya (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 661: des (1) -Ac- [D-Tyr2, D-Pro3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 662: des (1) -Ac- [D-Tyr2, Tic3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 663: des (1) -Ac- [D-Trp2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 664: des (1) -Ac- [Tyr2, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 665: des (1-2)-[D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 666: des (1-2) -Ac- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 667: des (1-2) -hexanoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 668: des (1-2) -cyclohexanecarbonyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Cyclohexanecarbonyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 669: des (1-2) -benzoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Benzoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 670: des (1-2) -3-pyridinepropionyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

3-Pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 671: des (1-2) -adipoyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Adipionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 672: des (1) -Ac- [D-Tyr2, NMeTrp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 674: des (1-2) -6-aminocaproyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

6-Aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 675: [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 676: Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 677: Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Nva8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Nva-Arg (Me) -Trp-NH ₂

Compound No. 678: Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Ile8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Ile-Arg (Me) -Trp-NH ₂

Compound number 679: des (1-2) -amidino- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Amidi-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound number 680: des (1-2) -glyloyl- [D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Glycloloyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 681: des (1) -glycloyl- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Glycloloyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 682: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Gln8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Gln-Arg (Me) -Trp-NH ₂

Compound No. 685: des (1) -Ac- [D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9] MS10

Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 686: des (1) -Ac- [D-Tyr2, D-Trp3, Gly4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Gly-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 688: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Pya (4) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Pya (4) -Trp-NH ₂

Compound No. 689: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, D-Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -D-Trp-NH ₂

Compound No. 691: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Tyr6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 692: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Trp6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Trp-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 693: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Tyr (Me) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Tyr (Me) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 694: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Nal (2) 6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Nal (2) -AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 695: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Thi6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Thi-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 696: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Cha6, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Cha-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 698: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, Abu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Abu-Arg (Me) -Trp-NH ₂

Compound No. 699: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, AzaGly7, γMeLeu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-γMeLeu-Arg (Me) -Trp-NH ₂

Compound number 700: des (1) -Ac- [D-Tyr2, D-Trp3, Thr5, Aib8,, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg (Me) -Trp-NH ₂

Compound No. 701: des (1) -Ac- [D-Tyr2, D-Trp3, Dap4, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Dap-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 702: des (1) -Ac- [D-Tyr2, D-Trp3, Asp (NHMe) 4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asp (NHMe) -Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 703: des (1) -Ac- [D-Tyr2, D-Trp3, Asp (NMe2) 4, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-D-Trp-Asp (NMe2) -Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

However, the metastine derivative (III) of the present invention has the following amino acid sequence within the amino acid sequence represented by SEQ ID NO: 1-54 (Compound No. 1), 2-54, 3-54, 4-54, 5- 54, 6-54, 7-54, 8-54, 9-54, 10-54, 11-54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54, 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30- 54, 31-54, 32-54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54 (compound number 2), 41-54 Amino acid sequence of 42-54 (Compound No. 32), 43-54, 44-54, 45-54 (Compound No. 3), 46-54 (Compound No. 4), 47-54, 48-54 or 49-54 It does not include a peptide consisting of (original human metastin or a partial peptide thereof).

In the metastin derivative (II), all compounds in which the groups represented by each symbol are in any combination are preferably used. Among these, the compound represented by the following compound number is preferable.

For metastin derivatives (II), preferably metastin derivatives or salts thereof represented by the formula:

(In the meal:

XX0 is formyl, C _1-6 alkanoyl (eg, acetyl, propionyl, butyryl, hexanoyl, etc .; preferably acetyl, propionyl, butyryl; more preferably acetyl), cyclopropanecarbonyl, 6- (acetyl-D-arginylamino) caproyl, 6-((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norrousylamino) caproyl, 4- (D Arginylamino) butyryl, or 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyltyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglu Tamil, 3- (pyridin-3-yl) propionyl, adipoyl or 6-aminocaproyl (preferably acetyl, etc.);

XX2 represents Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or binding arm (preferably D-Tyr or binding arm; more preferably D-Tyr );

XX3 is Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3- Pyridylalanine or D-4-pyridylalanine (preferably D-Trp or D-4-pyridylalanine);

XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyldiaminopropionic acid or N ^β -acetyldiaminopropionic acid (preferably Asn);

XX5 represents Ser, Thr or Val (preferably Ser or Thr);

XX6 represents Phe, Tyr, Trp, Tyr (Me), Thi, Nal (2), Cha, 4-pyridylalanine or 4-fluorophenylalanine (preferably Phe or 4-fluorophenylalanine);

AzaGly represents azaglycine;

XX8 represents Leu, Nva or Val (preferably Leu);

XX9 represents Arg, OrnArg (Me), or Arg (symMe2) (preferably Arg (Me));

XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine (preferably Phe or Trp). Also preferred are compounds represented by the following compound numbers or salts thereof:

The metastin derivatives (II) or salts or prodrugs thereof of the present invention have excellent blood stability in addition to excellent cancer metastasis and cancer growth inhibitory activity, and thus can cause cancer (eg, lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer). , Rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, etc.). The metastin derivatives (II) or salts or prodrugs thereof of the present invention have a pancreatic function-modulating action and are useful as a prophylactic or therapeutic agent for pancreatic diseases (eg, acute or chronic pancreatitis, pancreatic cancer, etc.). The metastine derivative (II) or salts or prodrugs thereof of the present invention have a placental function regulating effect of chorionic carcinoma, aphrodisiac, invasive condition, abortion, fetal dysfunction, abnormal glucose metabolism, abnormal lipid metabolism or induction of labor. Useful as a prophylactic or therapeutic agent.

Furthermore, the metastin derivatives (II) or salts or prodrugs thereof of the present invention have an effect of increasing sugar concentration, promoting pancreatic glucagon secretion and promoting urine formation, and thus obesity, hyperlipidemia, type II diabetes, hypoglycemia, hypertension, diabetic It is useful as a prophylactic or therapeutic agent for neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity.

In addition, the metastin derivatives (II) or salts or prodrugs thereof of the present invention are excellent in gonadotropin secretion promotion, sex hormone secretion promotion, ovulation induction or ovulation stimulating activity, and thus, low toxicity stable agents such as gonads Function improving agents, hormone-dependent cancers (e.g., prostate cancer, breast cancer, etc.), infertility, endometriosis, premature puberty, uterine myomas, etc., prevention or treatment, ovulation induction or stimulation agents, gonadotropin secretion accelerators, contraceptives, sex hormone secretagogues Useful as, etc.

In addition, the metastin derivatives (II) of the present invention or salts or prodrugs thereof are useful as prophylactic or therapeutic agents for Alzheimer's disease, mild cognitive impairment and the like.

Metastine derivatives (III) of the present invention [including methine derivatives (II) and metastin derivatives (I)] or salts or prodrugs thereof are useful as: gonadotropin secretion or sex hormone secretion inhibitors; Gonadotropin or sex hormone downregulators; Human OT7T175 (methastin receptor) protein downregulators consisting of the amino acid sequence represented by SEQ ID NO: 9; Agents for the prevention or treatment of hormone-dependent cancers (eg, prostate cancer, breast cancer, etc .; in particular, hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.); Prophylactic or therapeutic agents for endometriosis; Ovarian follicle maturation inhibitors; Menstrual cycle-suspending agents; Uterine fibroids; Early puberty treatments; Contraceptives, etc.

In addition, the metastine derivatives (III) of the present invention [including the methastine derivatives (II) and the metastine derivatives (I)] or salts or prodrugs thereof are useful as: immune enhancing agents (infection prevention agents after bone marrow transplantation) , Immune enhancers for cancer); CPM prophylaxis / treatment; Ovarian protectants; Benign prostatic hyperplasia (BPH) prophylaxis / treatment; Prevention / treatment of gender identity disorders; Or agents for in vitro fertilization (IVF). In addition, it is useful as a prophylactic / treatment agent for infertility, hypogonadism, sperm deficiency, spermatosis, inability to ejaculate, sperm disability, or sperm death. It also includes hormone-dependent diseases such as prostate cancer, uterine cancer, breast cancer, sex hormone dependent cancers such as pituitary tumors, prostatic hyperplasia, endometriosis, uterine fibroids, premature puberty, dysmenorrhea, amenorrhea, menstrual syndrome, polycystic ovary syndrome, said Postoperative recurrences of the above mentioned cancers, metastases of the above mentioned cancers, hypothalamic hypoplasia, dwarfism (when the secretion of growth hormone is reduced in connection with the low secretion of pituitary hormones), menopausal disorders, indefinite complaints, sex hormones It is useful for dependency disorders such as calcium phosphorus bone metabolism disorders. This is applicable for contraception (or infertility if a recoil action after drug withdrawal is used).

In addition, metastine itself, DNA encoding metastine and the like are also useful as: gonadotropin secretion or sex hormone secretion inhibitors; Gonadotropin or sex hormone downregulators; Human OT7T175 (methastin receptor) protein downregulators consisting of the amino acid sequence represented by SEQ ID NO: 9; Agents for the prevention or treatment of hormone-dependent cancers (eg, prostate cancer, breast cancer, etc .; in particular, hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.); Prophylactic or therapeutic agents for endometriosis; Ovarian follicle maturation inhibitors; Menstrual cycle-stopping agent; Uterine fibroids; Early puberty treatments; Contraceptives, etc.

Best mode for carrying out the invention

The metastin derivatives (I) and (II) of the present invention can be prepared by known peptide synthesis methods. As the peptide synthesis method, for example, either solid phase synthesis or liquid phase synthesis can be used. That is, the partial peptide or amino acid which can constitute the peptide of the present invention can be condensed repeatedly in the remaining part to obtain a product having the desired sequence. If the product has a protecting group, these protecting groups are removed to give the desired peptide. Known condensation and protecting group removal methods are described in (i) to (v) below.

After completion of the reaction, conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography and recrystallization can be combined to purify and isolate the product to obtain partial peptides of the present invention. If the peptide obtained by the above methods is in free form, the peptide can be converted into a suitable salt by known methods; If the protein is obtained in the form of a salt, it can be converted to the free form by known methods.

For the condensation of protected amino acids or peptides, various activating reagents for protein synthesis can be used, but trisphosphonium salts, tetramethyluronium salts, carbodiimides and the like are particularly preferred. Examples of trisphosphonium salts include benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), bromotris (pyrrolidino) phosphonium hexafluorophosphate (PyBroP) and 7 -Azabenzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyAOP), and an example of a tetramethyluronium salt is 2- (1H-benzotriazol-1-yl) -1 , 1,3,3-hexafluorophosphate (HBTU), 2- (7-azabenzotriazol-1-yl) -1,1,3,3-hexafluorophosphate (HATU), 2- (1H -Benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2- (5-norbornene-2,3-dicarboxyimido) -1 , 1,3,3-tetramethyluronium tetrafluoroborate (TNTU) and O- (N-succimidyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU) ; Examples of carbodiimides include DCC, N, N'-diisopropylcarbodiimide (DIPCDI) and N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl); Etc. For condensation using these reagents, addition of racemization inhibitors (eg HONB, HOBt, HOAt, HOOBt, etc.) is preferred. The solvent used for condensation may be appropriately selected from solvents known to be available for condensation. For example, acid amides such as anhydrous or hydrous N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like, halogenated hydrocarbons such as methylene chloride, chloroform and the like, alcohols such as Sulfoxides such as trifluoroethanol, phenol and the like, tertiary amines such as dimethyl sulfoxide and the like, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile and propionitrile and the like, Esters such as methyl acetate, ethyl acetate and the like, or suitable mixtures thereof, and the like are used. The reaction temperature is appropriately selected in the range known to be applicable to the peptide binding reaction, and is usually appropriately selected in the range of about -20 ° C to 50 ° C. Activated amino acid derivatives are generally used in 1.5 to 6 fold excess. In the case of solid phase synthesis, condensation is checked by the ninhydrin reaction; If condensation is insufficient, the condensation reaction can be repeated to complete condensation without removing the protecting group. If condensation is still insufficient after repetition of the reaction, the unreacted amino acid is acylated with acetic anhydride or acetylimidazole, offsetting any adverse effects on subsequent reactions.

Examples of protecting groups used to protect the amino group of the starting amino acid include Z, Boc, tert-pentyloxycarbonyl, isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, ac Danyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulphenyl, diphenylphosphinothioyl, Fmoc, trityl and the like. Examples of protecting groups for carboxyl groups include allyl, 2-adamantyl, 4-nitrobenzyl, 4- in addition to the C _1-6 alkyl groups, C _3-8 cycloalkyl groups and C _7-14 aralkyl groups for R described above. Methoxybenzyl, 4-chlorobenzyl, phenacyl group, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and the like.

The hydroxyl groups of serine and threonine can be protected, for example, by esterification or etherification. Suitable groups for the esterification include lower (C _2-4 ) alkanoyl groups such as acetyl groups, aroyl groups such as benzoyl groups and the like derived from organic acids. Examples of suitable groups for etherification include benzyl groups, tetrahydropyranyl groups, tert-butyl groups, trityl groups (Trt) and the like.

Examples of the group for protecting the phenolic hydroxyl group of tyrosine include Bzl, Cl ₂ -Bzl, 2-nitrobenzyl, Br-Z, tert-butyl and the like.

Examples of groups used to protect the imidazole moiety of histidine include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt, Fmoc and the like.

Examples of protecting groups for guanidino groups of arginine include Tos, Z, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), p-methoxybenzenesulfonyl (MBS), 2,2,5 , 7,8-pentamethylchroman-6-sulfonyl (Pmc), mesitylene-2-sulfonyl (Mts), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), Boc, Z, NO ₂ and the like.

Examples of protecting groups for the side chain amino groups of lysine include Z, CI-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde) and the like. have.

Examples of protecting groups for indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr and the like.

Protective groups for asparagine and glutamine include Trt, xanyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and the like.

Examples of activated carboxyl groups in the starting material include the corresponding acid anhydrides, azides, activated esters [esters with alcohols (eg pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, Cyanomethyl alcohol, p-nitrophenol, HONB, N-hydroxysuccimid, 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt)]. As an amino acid in which the amino group in a substance is activated, the corresponding phosphorus containing amides are used.

To remove (separate) the protecting group, the following is used: catalytic reduction under hydrogen gas flow in the presence of a catalyst such as Pd-black or Pd-carbon; Anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trimethylsilane bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris (trifluoro) boron, boron tribromide Or acid treatment with a mixed solution thereof, base treatment with diisopropylethylamine, triethylamine, piperidine, piperazine and the like, and reduction with sodium in liquid ammonia. Removal of the protecting group by the acid treatment described above is generally carried out at temperatures of approximately -20 ° C to 40 ° C. In acid treatment, cationic scavengers such as anisole, phenol, thioanisole, m-cresol, p-cresol and the like, dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol and the like It is efficient to add. Furthermore, 2,4-dinitrophenyl groups known as protecting groups for the imidazole of histidine are removed by treatment with thiophenol. The formyl group used as a protecting group for indole of tryptophan is used for the above-mentioned acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol and the like with alkalis such as dilute sodium hydroxide solution, dilute ammonia and the like. By removing.

The protection of the functional groups that should not be involved in the reaction in the starting material, the protecting groups, the removal of protecting groups and the activation of the functional groups involved in the reaction can be appropriately selected from known groups and known methods.

In another method of obtaining the amide of the peptide, for example, the α-carboxyl group of the carboxy terminal amino acid is first protected by amidation; Thereafter, the peptide chain is stretched from the amino group side to the desired length. Thereafter, peptides (or amino acids) in which only the protecting group of the N-terminal α-amino group in the peptide chain is removed and only the protecting group of the C-terminal carboxyl group are removed from the peptide. The two peptides are condensed in the solvent mixture described above. The details of the condensation reaction are the same as described above. After purification of the protected peptide obtained by the condensation, all protecting groups are removed by the method described above to give the desired crude peptide. This crude peptide is purified by various known purification methods. Lyophilization of the main fractions yields the amide of the desired peptide.

When the metastine derivatives (I) and (II) of the present invention are present as coordination isomers, diastereomers, morph isomers and the like, each can be isolated by the separation and purification methods described above, if desired. Additionally, if the compound of the invention is a racemate, it can be separated into S isomers and R isomers by conventional optical cleavage methods.

When the metastine derivatives (I) and (II) of the present invention have stereoisomers, the present invention includes all of these isomers alone and isomers present as mixtures thereof.

In addition, the metastin derivatives (I) and (II) of the present invention may be hydrated or unhydrated.

Metastine derivatives (I) and (II) of the present invention may be labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S) and the like.

Throughout this specification, peptides are presented according to conventional methods of describing peptides, ie, with N-terminus (amino terminus) on the left and C-terminus (carboxyl terminus) on the right. In peptides, the C-terminus is usually in the form of an amide (-CONH ₂ ), a carboxyl group (-COOH), a carboxylate (-COO-), an alkylamide (-CONHR) or an ester (-COOR), the amide (-CONH ₂ ) is particularly preferred. Examples of esters or alkylamides as R include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; C _3-8 cycloalkyl groups such as cyclopentyl, cyclohexyl and the like; C _6-12 aryl groups such as phenyl, α-naphthyl and the like; C _7-14 aralkyl groups such as phenyl-C _1-2 -alkyl groups such as benzyl, phenethyl and the like, or α-naphthyl-C _1-2 -alkyl groups such as α-naphthylmethyl and the like; There are pivaloyloxymethyl groups, which are widely used as oral esters and the like.

Examples of the salt of the metastin derivative (I) of the present invention include metal salts, salts with ammonium, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Preferred examples of the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; Alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, and the like; Aluminum salts; Etc. Preferred examples of salts with organic bases include trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'- Salts with dibenzylethylenediamine and the like. Preferred examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and salts with aspartic acid, glutamic acid and the like are preferred as salts with acidic amino acids.

Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.), ammonium salts, etc. This is preferred. When the compound has a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methane Salts with sulfonic acid, p-toluenesulfonic acid and the like are preferred.

Prodrugs of metastine derivatives (III) or salts thereof (hereinafter sometimes referred to simply as metastine derivatives (III) of the present invention) are those of the present invention under physiological conditions in vivo or by reactions due to enzymes, gastric acids, etc. It means a metastin derivative which is converted into metastin derivative (III). That is, the prodrug of the present invention is a metastin derivative which is converted into metastin derivative (III) of the present invention through enzymatic oxidation, reduction, hydrolysis, or the like, or a metastin derivative of the present invention through hydrolysis by gastric acid or the like. Metastin derivatives that are converted to (III).

Prodrugs of the metastine derivatives (I) of the present invention or salts thereof (hereinafter sometimes referred to briefly as the metastine derivatives (I) of the present invention) and the metastine derivatives of the present invention (II) or salts thereof The prodrugs of the invention (hereinafter briefly referred to as metastine derivatives (II) of the present invention) are the same as those described for the prodrugs of the metastine derivatives (III) of the present invention.

Examples of prodrugs of the metastine derivative (III) of the present invention are the following: metastine derivatives in which the amino group of the metastine derivative (III) of the present invention is substituted with acyl, alkyl, phosphoric acid or the like (e.g., the metastine of the present invention) The amino group of the derivative (III) is eicosanoyl, alanyl, pentylaminocarbonyl (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl, tetrahydrofuranyl, pyrroli Metastin derivatives substituted with dilmethyl, pivaloyloxymethyl, tert-butyl, and the like); Metastin derivatives in which the hydroxy group of the metastin derivative (I) of the present invention is substituted with acyl, alkyl, phosphoric acid, boric acid and the like (e.g., the hydroxy group of the metastin derivative (III) of the present invention is acetyl, palmitoyl, propanoyl, Metastin derivatives substituted with pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl and the like); And metastin derivatives in which the carboxyl group of the metastin derivative (III) of the present invention is substituted with an ester, an amide or the like (for example, the carboxyl group of the metastin derivative (III) of the present invention is ethyl ester, phenyl ester, carboxymethyl ester, dimethylamino Methyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester, cyclohexyloxyca Metastin derivatives substituted with ribonylethyl ester, methylamide, and the like); Etc. These metastin derivatives can be prepared from the metastin derivatives (I) of the present invention by methods known per se.

Prodrugs of the metastine derivative (III) of the present invention are described in "Pharmaceutical Research and Development", Vol. 7 (Drug Design), pp. 163-198, 1990, Hirokawa Publishing Co. By physiological conditions as described in the present invention.

The metastin derivatives (I), (II) or (III) or salts or prodrugs thereof of the present invention (hereinafter sometimes referred to simply as compounds of the present invention) have cancer metastasis inhibiting activity or cancer growth inhibiting activity. Thus, the metastin derivatives are useful for the prevention or treatment of drugs, such as all cancers (eg, lung cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, etc.).

The compound of the present invention also has a pancreatic function modulating action, and thus is useful as a pancreatic function modulator as an agent for preventing or treating various pancreatic diseases (eg, acute or chronic pancreatitis, pancreatic cancer, etc.).

The compound of the present invention also has a placental function regulating agent, which is a drug for the prevention or treatment of chorionic carcinoma, aphrodisiac, invasive state, miscarriage, fetal dysfunction, abnormal glucose metabolism, abnormal lipid metabolism or induction of labor Useful as

Furthermore, the compounds of the present invention have an effect of increasing the concentration of sugar, promoting the release of pancreatic glucagon and promoting the formation of urine, and thus are useful as drugs such as hyperglycemic agents, pancreatic glucagon secretion accelerators or urine formation accelerators, which include obesity, hyperlipidemia, Type II diabetes, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes, fat atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipids Useful for the prevention or treatment of toxicity.

In addition, the compounds of the present invention may also promote gonadotropin (eg, FSH, LH, etc.) secretion, sex hormones (eg, androgens (eg, testosterone, androstenedione, etc.), estrogens (eg, estradiol, estrone, etc.) , Progesterone, etc.] Promotes secretion, improves gonad function, induces or promotes ovulation, and sexual maturation, which can lead to gonadotropin, ovulation induction or stimulation, gonadotropin secretion or sex hormone secretion, or hormone-dependent cancer. [E.g., prostate cancer, breast cancer, etc.], infertility [e.g. irregular menstruation, dysmenorrhea, amenorrhea, amenorrhea induced by weight loss, secondary amenorrhea, aovulation, hypoovarianism, hypogonadism, spermatogenesis failure, Hypogonadism (e.g., erectile dysfunction), genital atrophy, testicular atrophy, testicular dysfunction, atherosclerosis, hypoandrogen Nemia (hypoandrogenemia, etc.), endometriosis, early puberty, uterine myoma, etc. can be used as a prophylactic or therapeutic agent.

In addition, prodrugs of the metastin derivatives (I) or (II) or salts thereof of the present invention are useful as prophylactic or therapeutic agents for Alzheimer's disease, mild cognitive disorders and the like.

Furthermore, the compounds of the present invention have good blood stability compared to native metastine such as metastine 54 (1-54) or metastine 10 (45-54).

Metastine derivatives (III) of the present invention [including methine derivatives (II) and metastine derivatives (I)] or salts or prodrugs thereof may include gonadotropin secretion or sex hormone secretion inhibitors; Gonadotropin (eg FSH, LH) or sex hormones [eg, androgens (eg testosterone, androstenedione), estrogens (eg estradiol, estrone), progesterone] downregulators; In particular, downregulation of gonadotropin or sex hormone (wherein downregulation of gonadotropin or sex hormone may be a regular decrease in LHRH or depletion of LHRH) or the amino acid sequence represented by SEQ ID NO. Useful for suppressing gonadotropin secretion or sex hormone secretion through downregulation of human OT7T175 (methastin receptor) protein; Agents for the prevention or treatment of hormone-dependent cancers (eg, prostate cancer, breast cancer, etc .; in particular, hormone-sensitive prostate cancer, hormone-sensitive prostate cancer, etc.); Prophylactic or therapeutic agents for endometriosis; Ovarian follicle maturation inhibitors; Menstrual cycle-stopping agent; Uterine fibroids; Early puberty treatments; Or as a contraceptive.

Metastine derivatives (III) of the present invention [including methastine derivatives (II) and metastine derivatives (I)] or salts or prodrugs thereof, metastine itself, or DNAs encoding metastine, have a normal effector activity. If present, an effective amount of metastine derivative sufficient to inhibit gonadotropin or sex hormone secretion is administered to the site or tissue at which the therapeutic effect is to be exerted so that the metastin derivative exhibits an effect of inhibiting gonadal stimulating hormone secretion or sex hormone secretion. It is present in an amount greater than necessary (ie, metastine derivatives in excess of the normal effective amount that exerts the effects of inhibiting cancer metastasis, inhibiting cancer growth, etc., or gonadotropin secretion, sex hormone secretion, etc.). Administration). Specific examples include sustained or continuous administration of a normal effective amount (including dosing techniques that slowly release the pharmaceutical ingredients by bolus administration); Etc. In addition, more sufficient agonist activity (super-) than the metastine derivative (III) of the present invention (including the methastine derivative (II) and the metastin derivative (I)) or salts thereof or prodrugs thereof, etc. is required. Agonist activity), it is possible to sustain greater activity than would be exerted at the required dosage at the site or tissue where the therapeutic effect would be expected. Therefore, administration of a normal effective amount for suppressing gonadotropin or sex hormone secretion is sufficient, thereby exhibiting gonadotropin secretion or sex hormone secretion inhibitory action.

That is, the secretion of gonadotropin or sex hormone to metastine derivative (III) [including methine derivative (II) and metastin derivative (I)] or salts or prodrugs thereof, or metastine itself, metastine-encoding DNA, etc. Is administered in an effective amount sufficient to inhibit. As a result, gonadotropin may be maintained at the site or tissue where the pharmacological action is to be exerted, such that the metastin derivative or the like is present in a larger amount than the required dose or sustains greater activity than is indicated by the required dose. It becomes possible to exert a hormone secretion or sex hormone secretion inhibitory effect.

Pharmaceutical compositions containing a compound of the present invention are low in toxicity and therefore, as such are directly or in the form of pharmaceutical preparations such as tablets (including dragees and film coated tablets), powdered dosage forms, granules, capsules (including soft capsules), In liquid dosage forms, injections, suppositories, sustained release dosage forms, and the like, and may be safely administered orally or parenterally (eg, topically, rectally, intravascularly, etc.).

The compound of the present invention is contained in the pharmaceutical formulation of the present invention at about 0.01 to about 100% by weight based on the total weight of the formulation.

The dosage of the compound of the present invention may vary depending on the subject, organ, condition, route of administration, and the like, and when administered orally, the compound is generally about 0.1 to about 100 mg per day in a cancer patient (60 kg body weight). , Preferably from about 1.0 to about 50 mg and more preferably from about 1.0 to about 20 mg. In parenteral administration, the single dose of the compound may vary depending on the subject, organ, condition, route of administration, etc., and in the case of injectable dosage forms, the compound is usually given to cancer patients (60 kg body weight) about 1 day. It is advantageous to administer at a dosage of 0.01 to about 30 mg, preferably about 0.1 to about 20 mg, and more preferably about 0.1 to about 10 mg. For other animal species, the corresponding dosages converted in weight per 60 kg may be administered.

Pharmaceutically acceptable carriers that can be used to prepare the pharmaceutical formulations of the invention include various organic or inorganic carrier materials commonly used as materials for pharmaceutical formulations. These materials include, for example, excipients, lubricants, binders and disintegrants in solid dosage forms, and solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid dosage forms. In addition, if desired, additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like may be suitably used in appropriate amounts.

Examples of excipients include, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, hard silicic acid, and the like.

Examples of useful glidants are, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like. have.

Examples of disintegrating agents include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium laurylsulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; Hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Examples of isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

Examples of buffers include, for example, buffered solutions such as phosphates, acetates, carbonates, citrates and the like.

Examples of sedatives include, for example, benzyl alcohol and the like.

Examples of preservatives include, for example, p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include, for example, sulfite, ascorbic acid, α-tocopherol and the like.

Furthermore, the compounds of the present invention may be used in combination with other drugs than the compounds of the present invention.

Examples of drugs that can be used in combination with a compound of the present invention (hereinafter referred to as concomitant drugs) include chemotherapeutic agents, hormone therapy agents, immunotherapy agents, and the like for the treatment of cancer.

Examples of "chemotherapeutic agents" include, for example, alkylating agents, antimetabolic agents, anticancer antibiotics, and anticancer agents derived from plants.

Examples of "alkylating agents" include, for example, nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, Impulsulfane Tosylate, Busulfan, Nimustine Hydrochloride, Mitobronitol, Rnelphalan, Dacarbazine, Lanimustine, Estramusstin Sodium Phosphate, Triethylenemelamine, Carmustine, Romustine, Streptozosin Fifobroman, etogluside, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, avamustine, dibropidium hydrochloride, fortemustine, prednisostin, fumitepa, Ribomustine, temozolomide, threoxulfan, trophosphamide, ginostatin stymalamer, carbocuone, adozelesin, cystemustine, bizelesin and the like.

Examples of “antimetabolic” include, for example, mercaptopurine, 6-mercaptopurine riboside, thiinosine, methotrexate, enositabine, cytarabine, cytarabine oxphosphate, ancitabine hydrochloride, 5-FU drug (such as , Fluorouracil, tegapur, UFT, doxyfluidine, carmofur, gallocitabine, emitfur, etc.), aminopterin, leukoborin calcium, tabloid, butosin, polycarbonate calcium, lebopolynate Calcium, cladribine, emitepur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxuridine, mitoguazone, thiazoprine, ambamustine and the like.

Examples of “anticancer antibiotics” include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, Doxorubicin hydrochloride, aclarubicin hydrochloride, pyrarubicin hydrochloride, epirubicin hydrochloride, neocarcinostatin, mishramycin, sarcommycin, carcinophylline, mitotans, zorubicin hydrochloride, mitoxanthrone Hydrochloride, idarubicin hydrochloride, and the like.

Examples of “plant anticancer agents” include, for example, etoposide, etoposide phosphate, vinblastine sulphate, vincristine sulphate, vindesine sulphate, teniposide, paclitaxel, docetaxel, vinorelbine and the like.

Examples of “hormone therapeutics” include, for example, phosphestrol, diethylstilbestrol, chlorotriacene, methoxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazole, allylestrenol, Gestrione, mepartricin, raloxifene, ormeloxyphene, levormeloxyphene, anti-estrogens (eg tamoxifen citrate, toremifene citrate, etc.), pill dosage forms, mepitiostane, testolactone, Aminoglutetimides, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprolinin, etc.), droroxifene, epithiostanol, ethynylestradiol sulfonate, aromatase inhibitors ( For example, pardrosol hydrochloride, anastrozole, letrozole, exemestane, borosol, formestan, etc., anti-androgens (eg, flutamide, vicars) Tamide, nilutamide, etc.), 5α-reductase inhibitors (e.g., finasteride, epristeride, etc.), adrenocorticohormonal drugs (e.g. dexamethasone, prednisolone, betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (e.g., Abiraterone, etc.), retinoids and drugs that delay retinoid metabolism (eg, liarosol, etc.), among which LH-RH agonists (eg, goserelin acetate, buserelin, leuproleline, etc.) are preferred. Do.

Examples of "immunotherapeutic agents (BRM)" include, for example, fishvanyl, crestine, schizophyran, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisol, polysaccharide K, procodazole and the like.

When the compound of the present invention and the concomitant drug are used in combination, the following excellent effects are obtained, for example.

(1) The dose of the compound of the present invention can be reduced compared to the dose when administered alone.

(2) According to the condition (mild, severe, etc.) of a patient, the drug used together with the compound of this invention can be selected.

(3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer.

(4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be continued.

(5) A synergistic effect can be obtained by using the compound of the present invention and a concomitant drug in combination.

In addition, the compounds of the present invention may reduce the levels of testosterone, thereby weakening the concentration immediately after dosing. That is, when a combination drug, such as an LH-RH agonist (such as goserelin acetate, buserelin, leuprorelin, etc .; preferably leuprorelin) is used in combination with a compound of the present invention, the level of testosterone is reduced to The concentration may be weakened immediately after administration of the compound of the invention. In addition, the combination of concomitant drugs such as LH-RH agonists (such as goserelin acetate, buserelin, leuprolinin, etc .; preferably leuprorelin) and the compounds of the present invention further prolong the maintenance of hormone-dependent periods As such, it can be used advantageously.

Hereinafter, using together and using the compound (I) of this invention and a combined drug is called "the combined agent of this invention."

In the use of the combination preparation of the present invention, the timing of administration of the compound of the present invention and the combination drug is not limited; The compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof may be simultaneously administered to a subject to be administered or may be administered with a certain time difference. The dosage of the concomitant drug may be modified according to the dosage used clinically, and may be appropriately selected depending on the administration target, administration route, disease, combination, and the like.

Although the dosage form of the combined preparation of this invention is not specifically limited, It is sufficient to use the compound of this invention in combination with a combined drug at the time of administration. Such dosage forms include, for example, (1) administration of a single dosage form obtained by simultaneously mixing together a compound of the invention and a combination drug, and (2) two administrations separately prepared from a compound of the invention and a combination drug. Simultaneous administration via the same route of administration of the form, (3) staggered administration through the same route of administration of two dosage forms separately prepared from the compound of the invention and the concomitant drug, (4) the compound and combination of the invention Simultaneous administration via different routes of administration of the two dosage forms separately prepared from the drug, (5) timed administration through different routes of administration of the two dosage forms separately prepared from the compounds of the invention and the combination drug) For example, the administration of the compound of the present invention and the concomitant drug in this order, or the reverse order.

The combination formulations of the present invention are of low toxicity, so that pharmaceutical formulations such as tablets (including dragases and film coated tablets) obtained by mixing the compounds of the present invention or (and) the combination drugs described above with a pharmaceutically acceptable carrier Orally or parenterally (eg, topically, rectally, intravascularly, etc.) as powdered dosage forms, granules, capsules (including soft capsules), liquid dosage forms, injections, suppositories, sustained release dosage forms, and the like. May be administered. Injection dosage forms can be administered intravenously, intramuscularly or subcutaneously, intravenously, intramuscularly or subcutaneously.

As the pharmaceutically acceptable carrier which can be used in the preparation of the combination preparation of the present invention, various organic or inorganic carrier materials usually used as pharmaceutical preparation materials can be mentioned. These materials include, for example, excipients, lubricants, binders and disintegrants in solid dosage forms, and solvents, dissolution aids, suspending agents, isotonic agents, buffers, sedatives, and the like, in liquid dosage forms. In addition, if necessary, conventional additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like may be appropriately used in appropriate amounts.

Examples of excipients include, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, hard silicic acid, and the like.

Examples of useful glidants are, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose, saccharose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like. have.

Examples of disintegrating agents include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.

Examples of suspending agents include, for example, surfactants such as stearyltriethanolamine, sodium laurylsulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like; Hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Examples of isotonic agents include, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.

Examples of buffers include, for example, buffered solutions such as phosphates, acetates, carbonates, citric acid salts and the like.

Examples of sedatives include, for example, benzyl alcohol and the like.

Examples of preservatives include, for example, p-hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.

Examples of the antioxidant include, for example, sulfite, ascorbic acid, α-tocopherol and the like.

In the combination preparation of the present invention, the ratio of the compound of the present invention to the concomitant drug can be appropriately selected depending on the administration target, administration route, disease, combination, and the like.

For example, the amount of the compound of the present invention contained in the combination preparation of the present invention varies depending on the dosage form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50, based on the total weight of the preparation Wt%, more preferably about 0.5-20 wt%.

The amount of concomitant drug contained in the combination preparation of the present invention varies depending on the dosage form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably based on the total weight of the preparation About 0.5 to 20 weight percent.

The amount of an additive such as a carrier contained in the combination preparation of the present invention varies depending on the dosage form of the preparation, but is usually about 1 to 99.99 wt%, preferably about 10 to 90 wt%, based on the total weight of the preparation.

These amounts may be the same even when the compound of the present invention and the concomitant drug are separately prepared.

These formulations can be prepared by a method known per se, which is generally used.

For example, injection dosage forms can be prepared by dispersing a compound of the invention or a combination drug (e.g., Tween 80 (manufactured by Atlas Powder Company, USA), HCO 60 (manufactured by Nikko Chemicals Co., Ltd.), polyethylene glycol, carboxymethyl). Cellulose, sodium alginate, etc.), stabilizers (such as ascorbic acid, sodium pyrosulfite), surfactants (such as polysorbate 80, macrogol, etc.), solubilizers (such as glycerin, ethanol, etc.), buffers (such as , Phosphoric acid or alkali metal salts thereof, citric acid or alkali metal salts thereof), isotonic agents (e.g. sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH adjusting agents (e.g. hydrochloric acid, sodium hydroxide, etc.), preservatives (e.g. ethyl p -Oxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (e.g., concentrated glycerin, meglumine, etc.), dissolution aids (e.g., propylene glycol , Saccharose, etc.), sedatives (e.g., glucose, benzyl alcohol, etc.), vegetable oils, such as olive oil, sesame oil, cottonseed oil, corn oil, etc., dissolved, suspended or emulsified in dissolution aids, such as propylene glycol, to prepare oily injections, It can be manufactured.

Oral dosage forms include, for example, excipients (e.g., lactose, saccharose, starch, etc.), disintegrants (e.g., starch, calcium carbonate, etc.), binders (e.g., starch, gum ara) for the compounds or combination drugs of the present invention. Vic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, etc.), glidants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) and other additives are added and the resulting mixture is compressed and In this case, the compressed product can be prepared in a conventional manner by coating by a method known per se for taste masking, enteric decomposition or sustained release. As the coating agent for this purpose, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Prulonic F68, cellulose acetate phthalate, hydroxypropylmethyl cellulose Phthalates, hydroxymethyl cellulose acetate succinate, Eudragit (manufactured by Rohm Company, Germany, methacrylic acid / acrylic acid copolymer) and dyes (eg iron oxide, titanium dioxide). Oral dosage forms may be immediate release dosage forms or sustained release dosage forms.

For example, in suppositories, the compounds or combination drugs of the present invention can be prepared into oily or aqueous solid, semi-solid or liquid compositions by methods known per se. Oily bases used in the compositions described above include, but are not limited to, glycerides of higher fatty acids (eg, cacao butter, uitepsol (manufactured by Dynamite Nobel Company, Germany), etc.), intermediate fatty acids (eg, dynamite Nobel Company). , Manufactured by Germany, etc.], vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.), and the like. Aqueous bases are, for example, polyethylene glycol and propylene glycol. Examples of the base for the aqueous gel include natural rubber, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.

Examples of such sustained release dosage forms include sustained release microcapsules and the like.

Sustained release microcapsules are obtainable by methods known per se, and are preferably prepared and administered in a sustained release dosage form by the method [2] shown below.

Preferably, the compounds of the present invention are prepared in dosage forms for oral administration, such as solid dosage forms (eg, powder dosage forms, granules, tablets, capsules), or dosage forms for rectal administration such as suppositories. Particularly preferred is a dosage form for oral administration.

Combination drugs are formulated into the dosage forms described above, depending on the type of drug.

[1] sustained release or immediate release preparation of a compound of the present invention or a combination drug and a preparation thereof, [2] sustained or immediate release preparation of the compound of the present invention or a combination drug and a preparation thereof and [3] a compound of the present invention or a combination drug Sublingual, oral or rapid oral disintegration formulations and their preparation are specifically described.

[1] injections and preparation thereof

Injectables obtained by dissolving a compound of the present invention or a combination drug in water are preferred. Injectables may contain benzoate and / or salicylate.

Such injections are obtained by dissolving the compound or combination drug of the invention and optionally benzoate and / or salicylate in water.

Examples of the benzoate and / or salicylate described above include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts, meglumine salts, salts of organic acids such as tromethamol, and the like. There is this.

The concentration of the compound or combination drug of the present invention in the injection is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of benzoate and / or salicylate is 0.5 to 50 w / v%, preferably 3 to 20 w / v%.

Furthermore, in the preparations, additives generally used in injections such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solubilizers (glycerine, ethanol, etc.), Buffers (phosphate and alkali metal salts thereof, citric acid and alkali metal salts thereof), isotonic agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropylmethyl cellulose, dextrin), pH adjusters (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl p -Oxybenzoate, benzoic acid, etc.), a solubilizer (concentrated glycerin, meglumine, etc.), a dissolution aid (propylene glycol, saccharose, etc.), and a sedative (glucose, benzyl alcohol, etc.) are appropriately added. Any of these additives are added in amounts commonly used in injections.

The pH of the injection is adjusted to 2 to 12, preferably 2.5 to 8.0 by the addition of a pH adjuster.

The injectables are obtained by dissolving the compound or combination drug of the invention and optionally benzoate and / or salicylate, and, if necessary, all of the above additives in water. These components may be dissolved in any order following the same method as for conventional injections.

The aqueous solution for injection is preferably warmed and may be used as an injection after filtration sterilization by filtration or may be provided as an injection by autoclave as in conventional injections.

The aqueous injection solution is preferably autoclaved under high pressure for 5 to 30 minutes, for example at 100 to 121 ° C.

Furthermore, the preparation may be in the form of a solution endowed with antimicrobial activity, so that it can be used as a multi-dose form in divided administration.

[2] sustained release or immediate release preparations and preparations thereof

Preferred sustained release formulations comprise a core containing a compound of the invention or a combination drug, which is optionally coated with a water insoluble substance or swellable polymer. For example, sustained release formulations for oral administration in a once-daily dosage form are preferred.

Examples of the water-insoluble substance used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, and polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate. Acrylic acid polymers such as acrylic acid / methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacryl Acids, methacrylic acid alkylamide copolymers, poly (methyl methacrylate), polymethacrylates, aminoalkyl methacrylate copolymers, poly (methacrylate anhydrides), glycidyl methacrylate copolymers, in particular, Eudragit series (Rohm & Pharma) such as Eudragit RS-100, RL-1 00, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / chlorotrimethyl methacrylate / ethyl ammonium copolymer) and Eudragit NE-30D (methyl methacrylate / ethyl Hardened oils such as acrylate copolymers), such as hardened castor oil (e.g., LUBRI wax (Freund Industrial Co., Ltd.), etc., waxes such as carnauba wax, fatty acid glycerin esters, paraffin and the like, glycerin fatty acid esters Ryu.

The swellable polymer preferably has a polymer having an acidic removable group and exhibits pH-dependent swelling, and an acidic dissociation group that swells in acidic pH, such as a gastric swelling with less swelling in a neutral pH, such as the small intestine and large intestine. Polymer.

Examples of such polymers having an acidic dissociation group and exhibiting pH-dependent swelling are crosslinked polyacrylic acid polymers such as carbomers 934P, 940, 941, 974P, 980, 1342, etc., polycarbophil and calcium polycarbophil (all BF Goodrich Chemicals), Hivis Wakos 103, 104, 105 and 304 (all manufactured by Wako Pure Chemical Industries, Ltd.).

Coatings used in sustained release formulations may further contain hydrophilic materials.

Examples of hydrophilic materials include polysaccharides that may have sulfate groups, such as pullulan, dextrin, alkali metal alginate, and the like, polysaccharides having hydroxyalkyl or carboxyalkyl groups such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl Cellulose, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, polyethylene glycol, and the like.

The amount of the water insoluble substance contained in the coating of the sustained release formulation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to about 75 % (w / w), and the swellable polymer content is about 3 to about 30% (w / w), preferably about 3 to about 15% (w / w). The coating may also contain a hydrophilic material, wherein the amount of hydrophilic material contained in the coating is about 50% (w / w) or less, preferably about 5 to about 40% (w / w), more preferably About 5 to about 35% (w / w). As used herein,% (w / w) above means weight percent based on the coating composition which is the remainder of the coating solution after removal of any solvent (eg, water, lower alcohols such as methanol, ethanol, etc.).

The sustained release formulation is prepared by preparing a nucleus containing the drug as described below, and then heating the resulting nucleus to a water-insoluble substance or a swellable polymer or dissolving or dispersing such a substance in a solvent. It is prepared by coating with one coating solution.

I. Preparation of Drug-Containing Nuclei

The form of the drug-containing nucleus (hereinafter sometimes referred to simply as nucleus) coated with the coating agent is not particularly limited, but is preferably prepared in particulate form such as granules, granules, and the like.

If the nuclei are granules or particulates, their average particle size is preferably about 150 to about 2,000 μm, more preferably about 500 to about 1,400 μm.

The nucleus can be prepared by conventional methods. For example, the drug is mixed with suitable excipients, binders, disintegrants, lubricants, stabilizers and the like and then subjected to wet extrusion granulation, fluid bed granulation, and the like.

The drug content in the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w).

Examples of excipients contained in the nucleus include sugars such as saccharose, lactose, mannitol, glucose and the like, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Among these, crystalline cellulose and corn starch are preferable.

Examples of binders used are polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like. Examples of disintegrating agents include calcium carboxymethyl cellulose (ECG505), sodium croscarmellose (Ac-Di-Sol), crosslinked polyvinyl pyrrolidone (crospovidone), and low-substituted hydroxypropyl cellulose (L-HPC). Etc. Of these, hydroxypropyl cellulose, polyvinyl pyrrolidone and low-substituted hydroxypropyl cellulose are preferred. Examples of the lubricant and the anti-agglomerating agent include talc, magnesium stearate and inorganic salts thereof, and examples of the lubricant include polyethylene glycol and the like. Examples of stabilizers include acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid and the like.

In addition to the methods described above, the nuclei can be prepared by other methods, such as tumbling granulation methods, pan coating methods, fluidized bed coating methods and melt granulation methods, in which the inert carrier particles as a nucleus seed are used. To the solvent is added a small amount of the drug or mixture of excipients, lubricants and the like while spraying a binder dissolved in a suitable solvent such as water, lower alcohols (such as methanol, ethanol and the like). Examples of inert carrier particles include those made from saccharose, lactose, starch, crystalline cellulose and waxes. Preferably, the average particle size of these carriers is from about 100 μm to about 1,500 μm.

In order to separate the drug and the coating agent contained in the nucleus, the surface of the nucleus may be coated with a protective material. Examples of protective materials include the hydrophilic and water insoluble materials described above. Preferred protective materials are polyethylene glycols or polysaccharides having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropylmethyl cellulose and hydroxypropyl cellulose. The protective material may include acids such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, and the like, and stabilizers such as talc. When using a protective material, the amount thereof coated is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w).

The protective material may be coated by conventional coating methods, in particular, the nucleus is spray-coated with the protective material by a fluidized bed coating method, a fan coating method or the like.

II. Coating of nuclei with coating

The nucleus obtained in I is coated with a coating solution prepared by melting or heating the above-described water-insoluble substance and pH-dependent swellable polymer and hydrophilic substance or dissolving or dispersing them in a solvent to obtain a sustained release formulation.

As a coating method of the nucleus to a coating solution, spray-coating etc. are mentioned, for example.

The composition ratio of the water insoluble substance, the swellable polymer and the hydrophilic substance in the coating solution may be appropriately selected to be within the amount of each component contained in the coating agent.

The amount of coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably about 5 to about, based on the nucleus (excluding the protective material coating). 35% (w / w).

As the solvent for the coating solution, water and an organic solvent can be used alone or as a mixture thereof. When using a mixture, the ratio of water and organic solvent (water / organic solvent: weight ratio) may vary in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it can dissolve a water insoluble substance, and examples of the solvent include lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, and lower alkanones such as Acetone, acetonitrile, chloroform, methylene chloride and the like. Among these, lower alcohols are preferable, and ethyl alcohol and isopropyl alcohol are more preferable. Water and a mixture of water and an organic solvent are preferably used as the solvent for the coating solution. In this case, in order to stabilize the coating solution, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, or the like may be added to the coating solution, if necessary.

In order to carry out the coating by spray coating, it may be coated using conventional coating methods. Specifically, the coating solution is sprayed on the nucleus by a fluidized bed coating method, a pan coating method, or the like. At this time, lubricants such as talc, titanium oxide, magnesium stearate, calcium stearate, hard silicic anhydride, and the like, and plasticizers such as glycerin fatty ester, hardened castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. It can also be added.

After coating with the coating, an antistatic agent such as talc may also be admixed if necessary.

Immediate release preparations may be liquid (solutions, suspensions, emulsions, etc.) or solids (particles, pills, tablets, etc.). Parenteral preparations such as oral preparations and injections may be used, with oral preparations being preferred.

Immediate release preparations may contain carriers, additives and excipients (hereinafter sometimes abbreviated as excipients) commonly used in the pharmaceutical art, in addition to drugs which are active ingredients. Pharmaceutical excipients are not particularly limited as long as they are excipients commonly used in the pharmaceutical field. Examples of excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (manufactured by Avicel PH101, Asahi Kasei Corporation, etc.), powdered sugar, granulated sugar, mannitol, light silicate anhydride, magnesium carbonate, calcium carbonate, L -Cysteine and the like, corn starch and mannitol are preferred. Any of these excipients may be used alone or in combination with each other. The amount of excipient is, for example, from about 4.5 to about 99.4 w / w%, preferably from about 20 to about 98.5 w / w%, more preferably from about 30 to about 97 w, based on the total weight of the immediate release formulation. / w%

The content of the drug in the immediate release preparation may suitably be selected from about 0.5% to about 95%, preferably about 1% to about 60%, based on the total amount of the immediate release preparation.

If the immediate release preparation is an oral solid preparation, the preparation contains, in addition to the components described above, a disintegrant. Examples of disintegrating agents include calcium carboxymethyl cellulose (ECG505 manufactured by GOTOKU CHEMICAL Co., Ltd.), sodium croscarmellose (eg, Ac-Di-Sol manufactured by Asahi Kasei Corporation), crospovidone (eg , COLIDON CL manufactured by BASF, low-substituted hydroxypropyl cellulose (Shin-Etsu chemical Co., Ltd.), carboxymethyl starch (MATSUTANI CHEMICAL INDUSTRY Co., Ltd.), sodium carboxymethyl starch (manufactured by KIMURA SANGYO EXORITAB) and partial α starch (PCS manufactured by Asahi Kasei Corporation). For example, a disintegrant that disrupts the granules may be used by water absorption or swelling upon contact with water or by forming channels between the active ingredient, including the nucleus, and the excipient. Any of these disintegrants may be used alone or in combination with each other. The amount of disintegrant used may be appropriately selected by the type and amount of drug used and the design of the specific formulation having the desired release performance. For example, the amount is about 0.05 to about 30 w / w%, preferably about 0.5 to about 15 w / w%, based on the total weight of the immediate release formulation.

When the immediate release preparation is an oral solid preparation, the preparation may optionally contain, in addition to the components described above, additives commonly used in solid preparations. Examples of additives include binders (eg sucrose, gelatin, powdered gum arabic, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, polyvinyl pyrrolidone, pullulan, dextrin, etc.) Lubricants (polyethylene glycol, magnesium stearate, talc, light silicic anhydrides (e.g. NIPPON AEROSIL)), surfactants (e.g. anionic surfactants such as sodium alkylsulfate, nonionic surfactants) Active agents such as polyoxyethylene fatty esters, polyoxyethylene sorbitan fatty esters, polyoxyethylene castor oil derivatives, etc.), colorants (e.g. tar-based colorants, caramels, colcothar, titanium oxide, riboflavin), If necessary, corrigents (e.g. sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. (C) Further, there may be also added as a stabilizer an organic acid, such as tartaric acid, citric acid, succinic acid, fumaric acid or the like.

As the binder, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone and the like are preferably used.

Immediate release formulations may be prepared by mixing the above described components, kneading the mixture if necessary, and then molding according to the conventional pharmaceutical preparation techniques. The mixing may be carried out by a commonly used method, for example, mixing, kneading and the like. Specifically, when the immediate release preparation is in the form of particles, a vertical granulator and a multipurpose kneader (HATA IRON WORKS CO., LTD.) Are manufactured by the same method as the method for producing the nucleus of the sustained release preparation described above. The formulations may be prepared by mixing the components using a fluid bed granulator FD-5S (POWREX CORPORATION) and the like, and then granulating the resultant by wet extrusion granulation or fluid bed granulation.

Each of the immediate release formulations and the sustained release formulations thus obtained can be combined as is or by conventional methods with appropriate pharmaceutical excipients into separate pharmaceutical formulations, and then administered in combination with one another at the same time or at regular intervals. Can be prepared. Alternatively, the two formulations may be combined as such or together with suitable pharmaceutical excipients in a single oral dosage form (eg, granules, granules, tablets, capsules). The two preparations in granule or fine granule form may also be filled in a single capsule for oral administration.

[3] sublingual, oral or intraoral rapid disintegrating preparations and preparations thereof

Sublingual, oral or intraoral rapid disintegration formulations may be in the form of solid formulations, such as tablets, or in the form of oral mucosal patches (films).

The sublingual, buccal or intraoral rapid disintegration formulation is preferably a formulation containing a compound of the present invention or a combination drug and excipient. The formulation may also contain adjuvants such as glidants, isotonic agents, hydrophilic carriers, water-dispersible polymers, stabilizers and the like. In addition, in order to promote absorption and enhance bioavailability, the preparation may also contain β-cyclodextrin or β-cyclodextrin derivatives (eg, hydroxypropyl-β-cyclodextrin, etc.).

Examples of the excipient include lactose, saccharose, D-mannitol, starch, crystalline cellulose, hard silicic anhydride and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are preferred. Examples of tonicity agents include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin and urea, with mannitol being particularly preferred. Hydrophilic carriers include, for example, swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinked polyvinyl pyrrolidone, hard silicic anhydride, silicic acid, dicalcium phosphate, calcium carbonate and the like, and crystalline cellulose (e.g., Microcrystalline cellulose). As the water-dispersible polymer, for example, gum (e.g. tragacanth gum, acacia gum, guar gum), alginate (e.g. sodium alginate), cellulose derivatives (e.g. methyl cellulose, carboxymethylcellulose, hydroxy) Methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose), gelatin, water soluble starch, polyacrylic acid (e.g. carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polycarbophil , Ascorbic acid palmitic acid salt, and the like, and hydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin, carboxymethyl cellulose, polyvinyl pyrrolidone and polyethylene glycol are preferable. Hydroxypropylmethyl cellulose is particularly preferred. As the stabilizer, for example, cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, citric acid and ascorbic acid are particularly preferred.

The sublingual, buccal or intraoral rapid disintegration preparation can be prepared by mixing the compound of the present invention or a combination drug and excipient by a method known per se. Furthermore, if desired, the above-mentioned auxiliaries such as glidants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like can also be admixed. After mixing the above-described components simultaneously or at regular time intervals, the mixture is compressed into tablets to obtain sublingual, oral or intraoral rapid disintegrating tablets. In order to obtain a suitable hardness, the components can be humidified or wetted and dried using a solvent such as water, alcohol or the like before or after tableting.

In preparing oral mucosal patches (films), the compounds or combination drugs of the present invention and the above-described water-dispersible polymers (preferably hydroxypropyl cellulose, hydroxypropylmethyl cellulose), excipients and the like are used as solvents, such as After dissolving in water or the like, the resulting solution is cast into a film. In addition, additives such as plasticizers, stabilizers, antioxidants, preservatives, colorants, buffers, sweeteners and the like can be added to the formulation. Glycols such as polyethylene glycol, propylene glycol, and the like may be added to impart proper elasticity to the film, and bioadhesive polymers (eg, polycarbophil, carbopol) to enhance the adhesion of the film to the mucosal lining of the oral cavity. ) May also be added. The cast pours the solution onto a non-adhesive surface, spreads the solution to a uniform thickness (preferably approximately 10 to 1000 microns) using a coater such as a doctor blade and then dries the solution. To form a film. The thus formed film is dried at room temperature or with warming, and then cut into pieces each having a desired surface area.

Preferred orally rapid disintegrating preparations are, for example, rapid diffusion formulations of solid reticular bodies comprising a compound or combination drug of the invention and a water-soluble or water-diffusing carrier inert to the compound or combination drug of the invention. The network can be formed by subliming the solvent from a solid composition containing a solution of the compound of the present invention or a combination drug in a suitable solvent.

In addition to the compounds of the present invention or combination drugs, the composition of the oral rapid disintegrating preparation preferably contains a matrix former and a secondary component.

Examples of matrix formers include, but are not limited to, animal or vegetable proteins from gelatin, dextrins and soybeans, wheat, tea seed, and the like; Rubber substances such as gum arabic, guar gum, agar, xanthan gum and the like; Polysaccharides; Alginate; Carboxymethyl cellulose; Carrageenan; Dextran; Pectins; Synthetic polymers such as polyvinyl pyrrolidone; Materials derived from gelatin-gum arabic complexes and the like. Matrix formers also include sugars such as mannitol, dextrose, lactose, galactose, trehalose and the like; Cyclic sugars such as cyclodextrin and the like; Inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate and the like; Amino acids having 2 to 12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine and the like.

One or more matrix formers may be incorporated into a solution or suspension prior to solidification. The matrix former may be present in addition to the surfactant, or in the absence of the surfactant. The matrix former not only contributes to forming the matrix itself, but also helps to maintain the diffusion of the compound or combination drug of the present invention in solution or suspension.

The composition may contain secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavors, sweeteners, taste masking agents and the like. Suitable colorants include, for example, red, black and yellow iron oxides, FD & C dyes available from ERIS & EVERALD, such as FD & C Blue 2 and FD & C Red 40 and the like. Examples of suitable fragrances are mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape flavor and combinations thereof. Examples of suitable pH adjusting agents are citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Examples of suitable sweeteners are aspartame, acesulfame K and thaumatine. Examples of suitable taste masking agents are sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents and microencapsulated apomorphine.

The formulations generally contain a compound of the present invention or a combination drug in an amount of about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, and preferably, the preparation (sublingual tablet, oral cavity described above) And at least 90% of the compounds or concomitant drugs of the present invention (in water) within a period of about 1 to about 60 minutes, preferably about 1 to about 15 minutes, more preferably about 2 to about 5 minutes. Oral rapid disintegrating agents which disintegrate or disintegrate within about 1 to about 60 seconds, preferably about 1 to about 30 seconds, more preferably about 1 to about 10 seconds after administration to the oral cavity.

The amount of such excipients described above is from about 10 to about 99 weight percent, preferably from about 30 to about 90 weight percent, based on the total weight of the formulation. The amount of β-cyclodextrin or β-cyclodextrin derivative is from about 0 to about 30 weight percent based on the total weight of the formulation. The amount of lubricant is about 0.01 to about 10 weight percent, preferably about 1 to about 5 weight percent, based on the total weight of the formulation. The amount of tonicity agent is from about 0.1 to about 90 weight percent, preferably from about 10 to about 70 weight percent, based on the total weight of the formulation. The amount of hydrophilic carrier is from about 0.1 to about 50 weight percent, preferably from about 10 to about 30 weight percent based on the total weight of the formulation. The amount of water-dispersible polymer is from about 0.1 to about 30% by weight, preferably from about 10 to about 25% by weight, based on the total weight of the formulation. The amount of stabilizer is from about 0.1 to about 10 weight percent, preferably from about 1 to about 5 weight percent, based on the total weight of the formulation. If desired, the formulations described above may also contain additives such as colorants, sweeteners, preservatives and the like.

The dosage of the combination preparation of the present invention varies depending on the kind, age, weight, condition, dosage form, route of administration, administration period, and the like of the compound of the present invention.

The dosage of the compound of the present invention may vary depending on the subject to be administered, the target organ, the condition, the route of administration, and the like. For oral administration, the compound is generally used in cancer patients (body weight 60 kg) about 0.1 to about 1 day 100 mg, preferably from about 1.0 to about 50 mg and more preferably from about 1.0 to about 20 mg. In parenteral administration, the single dose of the compound may vary depending on the subject, organ, condition, route of administration, etc., and in the case of injectable dosage forms, the compound is generally administered about 1 day to cancer patients (60 kg body weight). It is preferred to administer in amounts of 0.01 to about 30 mg, preferably about 0.1 to about 20 mg, and more preferably about 0.1 to about 10 mg. For other animal species, the corresponding dose in terms of weight per 60 kg may be administered. Of course, the amount may vary depending on the individual conditions described above; In such a case, an amount less than the amount given above may be sufficient, or may be larger than the above range.

The concomitant drug can be set in any range of amounts so long as no side effects are caused. The daily dosage of the concomitant drug may vary depending on the severity of the disease, the age, sex, weight and sensitivity of the subject, the duration and interval of administration, the nature of the pharmaceutical formulation, the dosage form, the type and type of active ingredient, etc., and are not particularly limited. Do not. For example, for oral administration, the dosage is about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg in terms of drug; Usually, the amount is divided into 1 to 4 times a day.

When administering a pharmaceutical formulation of the invention, the compound of the invention and the concomitant drug may be administered simultaneously. Alternatively, the concomitant drug is administered first, followed by the compound of the present invention, or the compound of the present invention is administered first, followed by the concomitant drug. If they are administered at regular intervals, the interval depends on the active ingredient administered, the dosage form and the route of administration; When the concomitant drug is administered first, the compound of the present invention may be administered within 1 minute to 3 days, preferably 10 minutes to 1 day, more preferably 15 minutes to 1 hour after administration of the concomitant drug. . When the compound of the present invention is administered first, the concomitant drug may be administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, more preferably 15 minutes to 1 hour after administration of the compound of the present invention. .

As a preferred method of administration, for example, about 0.001 to 200 mg / kg of the combined drug in the form of an oral dosage form, and about 15 minutes later, about 0.005 to 0.5 mg / kg of the compound of the present invention in the form of a parenteral preparation Parenteral administration as a daily dose.

As metastine, for example, human metastine disclosed in WO 00/24890, mouse or rat metastine disclosed in WO 01/75104, and the like are used.

As a specific example of human metastin, the peptide etc. which consist of 8-54 amino acid residues containing the N-terminal 47-54 amino acid sequence in the amino acid sequence shown by SEQ ID NO: 1 are mentioned.

The "peptide comprising an N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 and consisting of 8 to 54 amino acid residues", the N-terminal 47-54 amino acid in the amino acid sequence represented by SEQ ID NO: 1 It can be any peptide as long as it is a peptide comprising a sequence and consisting of 8 to 54 amino acid residues, but the physiological activity of these peptides (eg, receptor binding activity, signal transduction, blood sugar synergism, pancreatic glucagon secretion, urine formation). Promoting action, etc.) means substantially the same. Specifically, (i) a peptide having an amino acid sequence represented by SEQ ID NO: 1, (ii) a C-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 and having 8 to 54 amino acid residues. A peptide or the like is used.

More specifically, human metastine to be used includes (i) a peptide consisting of the amino acid sequence represented by SEQ ID NO: 1 (human metastin 54 (1-54)), (ii) within the amino acid sequence represented by SEQ ID NO: 1 Peptide consisting of the N-terminal 40-54 amino acid sequence (human metastin 15 (40-54); SEQ ID NO: 15), (iii) peptide consisting of the N-terminal 45-54 amino acid sequence within the amino acid sequence represented by SEQ ID NO: 1 (Human metastin 10 (45-54); SEQ ID NO: 16), (iv) a peptide consisting of the N-terminal 46-54 amino acid sequence within the amino acid sequence represented by SEQ ID NO: 1 (human metastin 9 (46-54); SEQ ID NO: 17), (v) a peptide consisting of the N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 8 (47-54); SEQ ID NO: 18), and the like.

As mouse metastin (A), for example, (i) a peptide comprising an N-terminal 134-141 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 3 and consisting of 8 to 52 amino acid residues is used. Specific examples of the mouse metastin (A) to be used include (i) a peptide consisting of the N-terminal 90-141 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 3, (ii) the N- in the amino acid sequence represented by SEQ ID NO: 3 A peptide consisting of the terminal 132-141 amino acid sequence, (iii) a peptide consisting of the N-terminal 127-141 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 3, and the like.

As mouse metastin (B), for example, (i) a peptide comprising an N-terminal 138-145 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 5 and consisting of 8 to 52 amino acid residues is used. Specific examples of the mouse metastin (B) to be used include (i) a peptide composed of the N-terminal 94-145 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 5.

As the rat metastin, for example, (i) a peptide comprising an N-terminal 112-119 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 7 and consisting of 8 to 52 amino acid residues is used. Specific examples of the rat metastins to be used include (i) a peptide consisting of the N-terminal 68-119 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 7, and (ii) the N-terminal 110- in the amino acid sequence represented by SEQ ID NO: 7. Peptides consisting of the 119 amino acid sequence, (iii) peptides consisting of the N-terminal 105-119 amino acid sequence within the amino acid sequence represented by SEQ ID NO: 7, and the like.

Throughout this specification, metastine is marked according to conventional peptide notation, ie the N-terminus (amino terminus) is on the left and the C-terminus (carboxyl terminus) is on the right. In the peptide represented by SEQ ID NO: 1, the C-terminus may be any form of carboxyl group (-COOH), carboxylate (-COO-), amide (-CONH ₂ ) and ester (-COOR). At this time, examples of the ester group represented by R include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; C _3-8 cycloalkyl groups such as cyclopentyl, cyclohexyl and the like; C _6-12 aryl groups such as phenyl, α-naphthyl and the like; C _7-14 aralkyl such as phenyl-C _1-2 alkyl group such as benzyl, phenethyl and the like; α-naphthyl-C _1-2 alkyl groups such as α-naphthylmethyl and the like; And pivaloyloxymethyl groups widely used as oral esters.

Further, as metastine, a peptide in which an amino group of an N-terminal methionine residue is protected with a protecting group (eg, a C _1-6 acyl group, such as a C _2-6 alkanoyl group, such as formyl group, an acetyl group, etc.); Those where the N-terminal region is cleaved in vivo and the glutamyl group thus formed is pyroglutamine; Substituents (eg, -OH, -SH, amino groups, imidazole groups, indole groups, guanidino groups, etc.) on the side chains of the amino acids of the molecule are suitable protecting groups (eg, C _1-6 acyl groups, such as C _2-6 eggs). Canoyl groups such as formyl group, acetyl group, etc.), or complex peptides such as glycopeptides bound to sugar chains.

For the salts of metastine of the invention, preference is given to salts with physiologically acceptable acids (eg inorganic acids or organic acids) or bases (eg alkali metal salts) and the like, in particular physiologically acceptable acid addition salts. Examples of such salts include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid); And salts with organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

As the DNA encoding metastine, for example, DNA encoding human metastins described in WO 00/24890, DNA encoding mouse or rat metastins described in WO 01/75104, and the like are used.

The DNA encoding the metastine can be any of genomic DNA, genomic DNA library, cDNA derived from the cells and tissues described above, cDNA library derived from the cells and tissues described above and synthetic DNA. The vector used in the library may be any of bacteriophage, plasmid, cosmid and phagemid. The DNA can also be amplified directly by reverse transcriptase polymerase chain reaction (hereinafter abbreviated as RT-PCR) using whole RNA or mRNA fragments prepared from the cells and tissues described above.

DNA encoding human metastin, mouse metastin precursor (A), mouse metastin precursor (B) or rat metastin precursor is a base represented by SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8, respectively. Having a base sequence capable of hybridizing to a DNA comprising a sequence or to a nucleotide sequence represented by any nucleotide sequence represented by SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8 under highly stringent conditions. It can be any DNA so long as it is DNA encoding human metastin, mouse metastin (A), mouse metastin (B) or rat metastin.

Specific examples of the DNA hybridizable to the nucleotide sequence represented by any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8 under highly stringent conditions include SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8 Having at least about 70% homology, preferably at least about 80% homology, more preferably at least about 90% homology and most preferably at least about 95% homology to base sequences represented by any of DNA containing a base sequence is mentioned.

Homology of the sequence is determined using the homology calculation algorithm NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) with the following conditions (expected value = 10; gap allowed; filtering = ON; match score = 1; mismatch Score = -3).

Hybridization can be carried out according to a method known per se or a variant of the method, for example described in Molecular Cloning, 2nd edition (J. Sambrook et al., Cold Spring Harbor Lab. Press, 1989). . In addition, commercial libraries can be used according to the instructions of the manufacturer's protocols attached. Preferably, the hybridization can be performed under highly stringent conditions.

The highly stringent conditions used herein are, for example, at a sodium concentration of about 19 to 40 mM, preferably about 19 to 20 mM, at a temperature of about 50 to 70 ° C, preferably about 60 to 65 ° C. . In particular, hybridization conditions at a sodium concentration of about 19 mM at a temperature of about 65 ° C. are most preferred.

Specifically, as the DNA encoding human metastin consisting of the amino acid sequence represented by SEQ ID NO: 1, a DNA consisting of the nucleotide sequence represented by SEQ ID NO: 2 is used. Therefore, for the base sequence encoding human metastin consisting of the various amino acid sequences described above, the base sequence corresponding to each of the partial amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 in the base sequence represented by SEQ ID NO: 2 You can choose.

As the DNA encoding the mouse metastin precursor (A) containing the amino acid sequence represented by SEQ ID NO: 3, a DNA composed of the nucleotide sequence represented by SEQ ID NO: 4 or the like is used. Therefore, for the base sequence encoding the mouse metastin precursor (A) consisting of the various amino acid sequences described above, the base sequence corresponding to each of the partial amino acid sequences in the amino acid sequence represented by SEQ ID NO: 3 is represented by SEQ ID NO: 4 The base sequence can be selected from.

As DNA which encodes the mouse metastin precursor (B) containing the amino acid sequence shown by sequence number 5, the DNA etc. which consist of the base sequence shown by sequence number 6 are used. Therefore, for the base sequence encoding the mouse metastin precursor (B) consisting of the various amino acid sequences described above, the base sequence corresponding to each of the partial amino acid sequences in the amino acid sequence represented by SEQ ID NO: 5 is represented by SEQ ID NO: 6 The base sequence can be selected from.

As DNA which encodes the rat metastin containing the amino acid sequence shown by sequence number 7, the DNA etc. which consist of the base sequence shown by sequence number 8 are used. Therefore, for the base sequence encoding the rat metastin consisting of the various amino acid sequences described above, the base sequence corresponding to each of the partial amino acid sequence in the amino acid sequence represented by SEQ ID NO: 7 in the base sequence represented by SEQ ID NO: 8 You can choose.

More specifically, as the peptide (human metastin 54 (1-54)) consisting of the amino acid sequence represented by SEQ ID NO: 1, a DNA or the like containing the base sequence represented by SEQ ID NO: 2 is used.

As a peptide (human metastin 15 (40-54); SEQ ID NO: 15) consisting of the N-terminal 40-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1, a DNA including the nucleotide sequence represented by SEQ ID NO: 19, or the like This is used.

The peptide consisting of the N-terminal 45-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 10 (45-54); represented by SEQ ID NO: 16) includes a nucleotide sequence represented by SEQ ID NO: 20. DNA and the like are used.

The peptide consisting of the N-terminal 46-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 9 (46-54); represented by SEQ ID NO: 17) includes a nucleotide sequence represented by SEQ ID NO: 21. DNA and the like are used.

The peptide consisting of the N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 8 (47-54); represented by SEQ ID NO: 18) includes a nucleotide sequence represented by SEQ ID NO: 22. DNA and the like are used.

As metastin receptors, partial peptides thereof or salts thereof, for example, human metastin receptors, partial peptides or salts thereof described in WO 00/24890, mouse or rat human metastin receptors described in WO 01/75104, Partial peptides thereof, salts thereof, and the like are used.

Specifically, the metastine receptor includes a protein containing an amino acid sequence identical or substantially identical to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13.

As an amino acid sequence which has an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13, for example, with respect to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13 There is an amino acid sequence having at least about 70% homology, preferably at least about 80% homology, more preferably at least about 90% homology, and most preferably at least about 95% homology.

Homology of amino acid sequences can be measured using the homology calculation algorithm NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) under the following conditions (expected value = 10; gap allowed; matrix = BLOSUM62; filtering = OFF). .

As a protein having an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, an amino acid sequence substantially identical to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13 Proteins having the same activity as those of the protein consisting of the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 are preferred.

Activities of substantially the same properties include, for example, ligand binding activity, signal transduction activity, and the like. By "substantially the same property" is meant that the properties of these activities are qualitatively equivalent. That is, it is preferable that the above-mentioned activity, such as ligand binding activity, signal transduction activity, etc. is equivalent (e.g., about 0.01 to 100 times, preferably about 0.1 to 10 times, more preferably 0.5 to 2 times). Differences such as the level of these activities, the molecular weight of the protein may be present and are acceptable.

Activity such as ligand binding activity, signal transduction activity and the like can be assayed by a method known per se with modifications and measured according to the ligand determination method or screening method described, for example, in WO 00/24890 or WO 01/75104. .

Examples of metastin receptors to be used include (1) (i) one or two or more (preferably about 1 to about 30, more preferably, amino acid sequences represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13); Is an amino acid sequence in which from about 1 to about 10 and most preferably several (1 or 2) amino acids are deleted; (ii) one or two or more (preferably about 1 to about 30, more preferably about 1 to about 10 and most preferably amino acid sequences represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13; Preferably an amino acid sequence with several (1 or 2) amino acids added; (iii) one or two or more (preferably about 1 to about 30, more preferably about 1 to about 10 and most preferably amino acid sequences represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13; Preferably an amino acid sequence in which several (1 or 2) amino acids are inserted; (iv) in the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, 1 or 2 or more (preferably about 1 to about 30, more preferably about 1 to about 10 and most preferred Preferably an amino acid sequence in which several (1 or 2) amino acids are substituted with another amino acid; Or (v) a combination of these amino acid sequences; And proteins including the like.

Throughout this specification, metastine receptors are indicated according to conventional peptide notation, ie the left side is the N-terminus (amino terminus) and the right side is the C-terminus (carboxyl terminus). In a metastine receptor comprising a metastine receptor represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, the C-terminus is a carboxyl group (-COOH), carboxylate (-COO-), amide (-CONH ₂ ) And esters (-COOR). At this time, examples of the ester group represented by R include C _1-6 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and the like; C _3-8 cycloalkyl groups such as cyclopentyl, cyclohexyl and the like; C _6-12 aryl groups such as phenyl, α-naphthyl and the like; C _7-14 aralkyl such as phenyl-C _1-2 alkyl group such as benzyl, phenethyl and the like; α-naphthyl-C _1-2 alkyl groups such as α-naphthylmethyl and the like; And pivaloyloxymethyl groups widely used as oral esters.

When the metastin receptor contains a carboxyl group (or carboxylate) at a position other than the C-terminus, the carboxyl group can be amidated or esterified, and such amides or esters are also included in the receptor proteins of the invention. In this case, the ester group used may be the same group as the C-terminal ester described above.

In addition, the metastin receptor includes those wherein the amino group of the N-terminal methionine residue is protected with a protecting group (eg, a C _1-6 acyl group, such as a C _2-6 alkanoyl group, such as formyl group, an acetyl group, etc.); N-terminal regions are cleaved in vivo such that the glutamyl group thus formed is pyroglutamine; Substituents on the side chains of amino acids in the molecule (eg -OH, -SH, amino groups, imidazole groups, indole groups, guanidino groups, etc.) are suitable protecting groups (eg C _1-6 acyl groups such as C _2-6 eggs) Carboyl groups such as formyl group, acetyl group, etc.), or complex proteins such as glycoproteins bound to sugar chains.

As a specific example of the metastin receptor, human metastin receptor consisting of the amino acid sequence shown by SEQ ID NO: 9, rat metastin receptor consisting of the amino acid sequence shown by SEQ ID NO: 11, mouse metastin consisting of the amino acid sequence represented by SEQ ID NO: 13 Receptors and the like.

The partial peptide of the metastin receptor (hereinafter sometimes referred to simply as the partial peptide) can be any peptide as long as it is a partial peptide of the metastin receptor described above; Those such as protein molecules of the metastin receptor, which are exposed to the outside of the cell membrane and have ligand binding activity, are used.

Specifically, the partial peptide of the metastin receptor consisting of the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 includes a part analyzed to be an extracellular domain (hydrophilic domain) in hydrophobic plotting analysis. Peptides. Peptides containing some hydrophobic domains can likewise be used. In addition, the peptide may be one comprising each domain individually or together with a plurality of domains.

In the metastin receptor, preferred partial peptides are those having at least 20, preferably at least 50 and more preferably at least 100 amino acids of the above-described amino acid sequences constituting the metastin receptor.

The partial peptide may comprise an amino acid sequence in which one or two or more (preferably between about 1 and about 10 and more preferably several (1 or 2)) amino acids of the amino acid sequence described above are deleted; An amino acid sequence with one or two or more (preferably between about 1 and about 10 and more preferably several (1 or 2)) amino acids added to the above-described amino acid sequence; Or a peptide having an amino acid sequence in which one or two or more (preferably between about 1 and about 10 and more preferably several (1 or 2)) amino acids in the above-described amino acid sequence are substituted with other amino acids. Can be.

In partial peptides, the C terminus may be in any form of carboxyl group (-COOH), carboxylate (-COO-), amide (-CONH ₂ ) and ester (-COOR) as in the metastine receptor described above.

Further, as the partial peptide, as in the aforementioned metastin receptor, a peptide in which the amino group of the N-terminal methionine residue is protected with a protecting group; N-terminal regions are cleaved in vivo such that the glutamyl group thus formed is pyroglutamine; And those in which the substituent on the side chain of the amino acid in the molecule is protected with a suitable protecting group, or complex peptides such as glycopeptides bound to sugar chains.

As salts of said metastin receptors or partial peptides, preference is given to salts with physiologically acceptable acids, in particular physiologically acceptable acid addition salts. Examples of such salts include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid); Salts with organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid).

Examples of DNA encoding a metastin receptor or a partial peptide thereof include, for example, DNA encoding a human metastin receptor or a partial peptide thereof described in WO 00/24890, a mouse or rat human metastin receptor described in DWO 01/75104 or DNA encoding the partial peptide thereof and the like are used.

The DNA encoding the metastin receptor or partial peptide thereof may be any of genomic DNA, genomic DNA library, cDNA derived from the cells and tissues described above, cDNA library derived from the cells and tissues described above and synthetic DNA. . The vector used in the library may be any of bacteriophage, plasmid, cosmid and phagemid. The DNA can also be amplified directly by reverse transcriptase polymerase chain reaction (hereinafter abbreviated as RT-PCR) using whole RNA or mRNA segments prepared from the cells and tissues described above.

Specifically, DNA encoding human metastin receptor, mouse metastin receptor or rat metastin receptor is DNA containing each base sequence represented by SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14, or under highly stringent conditions. Human metastin receptor, mouse metastin comprising a nucleotide sequence hybridizable to the nucleotide sequence represented by SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14, and consisting of an amino acid sequence represented by SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14 It can be any DNA so long as it encodes a receptor having an activity of substantially the same properties as the activity of the receptor or rat metastin receptor (eg ligand binding activity, signal transduction activity, etc.).

As an example of DNA that can hybridize to the nucleotide sequence represented by any of SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14, about 70% of the base sequence represented by any of SEQ ID NO: 10, SEQ ID NO: 12, or SEQ ID NO: 14 There is DNA comprising a base sequence having at least homology, preferably at least about 80% homology, more preferably at least about 90% homology and most preferably at least about 95% homology.

Homology of the nucleotide sequence was determined using the homology calculation algorithm NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) the following conditions (expected value = 10; gap allowed; filtering = ON; match score = 1; mismatch score =- 3) can be measured under.

Hybridization can be performed according to methods known per se or variations of these methods, for example, as described in Molecular Cloning, 2nd Edition (J. Sambrook et al., Cold Spring Harbor Lab. Press, 1989). . Commercially available libraries can also be used in accordance with the manufacturer's protocol instructions. Preferably, the hybridization can be performed under highly stringent conditions.

The highly stringent conditions used herein are, for example, at a sodium concentration of about 19 to 40 mM, preferably about 19 to 20 mM, at a temperature of about 50 to 70 ° C, preferably about 60 to 65 ° C. . In particular, hybridization conditions at a sodium concentration of about 19 mM at a temperature of about 65 ° C. are most preferred.

More specifically, as the DNA encoding the human metastin receptor composed of the amino acid sequence represented by SEQ ID NO: 9, a DNA composed of the nucleotide sequence represented by SEQ ID NO: 10 is used.

As the DNA encoding the rat metastin receptor composed of the amino acid sequence represented by SEQ ID NO: 11, a DNA composed of the nucleotide sequence represented by SEQ ID NO: 12 is used.

As the DNA encoding the mouse metastin receptor composed of the amino acid sequence represented by SEQ ID NO: 13, a DNA composed of the nucleotide sequence represented by SEQ ID NO: 14 is used.

Metastine receptors, partial peptides thereof or salts thereof, and DNAs encoding said metastin receptors or partial peptides thereof are obtainable or preparable by the method described in WO 00/24890 or WO 01/75104.

Although this invention is demonstrated in detail with reference to the following Example, a formulation example, and a test example, this invention is not limited to these, Any deformation | transformation may be added in the range which does not deviate from the range of this invention.

In the examples below, the term “room temperature” usually means a temperature of about 10 ° C. to 35 ° C. In percentages, the yield is expressed in moles / mole percent, the solvent used in the chromatography in volume percent and the remainder in weight percent. In proton NMR spectra, no data was found for broad unidentified OH, NH protons, and the like.

The meanings of other abbreviations used in the present specification are as follows.

Acronym Description

10Ψ, CSNH: The C- terminal -CONH ₂ of the 10-position substituted with -CSNH _2.

1Ψ2, CH ₂ NH: -CONH- bond between 1- and 2-positions is replaced with -CH ₂ NH- bond.

2Ψ3, CH ₂ NH: -CONH- bond between the 2- and 3-positions is replaced by a -CH ₂ NH- bond.

3Ψ4, CH ₂ NH: -CONH- bond between 3- and 4-positions is substituted with -CH ₂ NH- bond.

4Ψ5, CH ₂ NH: -CONH- bond between the 4- and 5-positions is replaced with a -CH ₂ NH- bond.

6Ψ7, CSNH: -CONH- bond between 6- and 7-positions is substituted with -CSNH- bond.

6Ψ7, NHCO: The -CONH- bond between the 6- and 7-positions is replaced with a -NHCO- bond.

6Ψ7, CH ₂ NH: -CONH- bond between 6- and 7-positions is substituted with -CH ₂ NH- bond.

6Ψ7, CH ₂ O: The -CONH- bond between the 6- and 7-positions is replaced with a -CH ₂ O- bond.

7Ψ8, CH ₂ NH: -CONH- linkage between 7- and 8-positions is substituted with -CH ₂ NH- bond.

8Ψ9, CH ₂ NH: -CONH- linkage between 8- and 9-positions is substituted with -CH ₂ NH- bond.

9Ψ10, CH ₂ NH: a -CONH- bond between the 9- and 10-positions is replaced with a -CH ₂ NH- bond.

Abu: 2-aminobutanoic acid

Ac: Acetyl

Acp: 6-aminocaproic acid

AcOEt: ethyl acetate

AcOH: acetic acid

Aib: α-aminoisobutanoic acid

Ala (2-Qui): 2-quinolylalanine

Ala (3-Bzt): 3-benzothienylalanine

Alb: Albizziin 2-amino-3-ureidopropionic acid

Arg (Ac): N ^ω -acetylarginine

Arg (Boc ₂ , Me): N ^{ω, ω'} -bis-tert-butoxycarbonyl-N ^ω -methylarginine

Arg (Et): N ^ω -ethyl arginine

Arg (Me): N ^ω -methyl arginine

Arg (asyMe ₂ ) or Arg (Me ₂ ) asym: asymmetric-N ^{ω, ω} -dimethylarginine

Arg (symMe ₂ ) or Arg (Me ₂ ) sym: symmetric-N ^ω, ω'-dimethylarginine

Arg (NO ₂ ): N ^ω -methylarginine

Arg (n-Pr): N ^ω -propyl arginine

Arg (Tos): N ^ω -Tosyl arginine

Asp (NHMe): N ^ω -methyl asparagine

Asp (Nme2): N ^ω -dimethylasparagine

AzaGly: Azaglycine

AzaPhe: Azaphenylalanine

Aze (2): azetidine-2-carboxylic acid

β-Ala: β-alanine

Boc: tert-butoxycarbonyl

Boc ₂ O: di-tert-butyl dicarbonate

Br-Z: 2-bromobenzyloxycarbonyl

Bu ^t : tert-butyl

Bzl: Benzyl

CDI: 1,1'-carbonyldiimidazole

Cha: cyclohexylalanine

CIP: 2-chloro-1,3-dimethylimidazolium tetrafluoroborate

Cit: Citrulline

Clt resin: 2-chlorotrityl resin

Cl-Z: 2-chlorobenzyloxycarbonyl

Dab: 2,4-diaminobutanoic acid

Dap: 2,3-diaminopropionic acid

Dap (Ac): N ^β -acetyldiaminopropionic acid

Dap (For): N ^β -formyldiaminopropionic acid

Dap (Gly): N ^β -glycidyldiaminopropionic acid

Dap (GnGly): N ^β- (N-guanidinoglycyl) diaminopropionic acid

DCM: dichloromethane

DEA: Diethylamine

DIEA: N, N-diisopropylethylamine

DIPCDI: 1,3-diisopropylcarbodiimide

DMAP: 4-dimethylaminopyridine

DMF: N, N-dimethylformamide

EDT: 1,2-ethanedithiol

Fmoc: 9-fluorenylmethoxycarbonyl

For: Formyl

γ-Abu: 4-aminobutanoic acid

γ-MeLeu: γ-methylleucine

Gn: Guanidino

GuAmb: 4-guanidinomethylbenzoyl

Har: Homoarginine

Har (Me): N ^ω -Methyl Homoarginine

HOAt: 1-hydroxy-7-azabenzotriazole

HOBt: 1-hydroxybenzotriazole

HONB: N-hydroxy-5-norbornene-2,3-dicarboxamide

Hph: Homophenylalanine

Hyp: trans-4-hydroxyproline

IndPr: 3- (indol-3-yl) propionyl

Lys (Me ₂ ): N ^{ε, ε} -dimethyllysine

MBHA: p-methylbenzhydrylamine

MeOH: Methanol

Mtt: 4-methyltrityl

N ((CH ₂ ) ₃ Gn) Gly: N- (3-guanidinopropyl) glycine

Nal (1): 1-naphthylalanine

Nal (2): 2-naphthylalanine

Nar: no-arginine

Nar (Me): N ^ω -Methylnorginine

Nle: Norleucine

NMeArg: N ^α -methylarginine

NMeAsn: N ^α -methylasparagine

NMeLeu: N ^α -methylleucine

NMePhe: N ^α -methylphenylalanine

NMeSer: N ^α -methylserine

NMeTrp: N ^α -methyltryptophan

NMeTyr: N ^α -methyltyrosine

Nva: Norvalin

Orn: Ornithine

^{Orn (Mtt): N δ -} (4- methyl-trityl) ornithine

PAL: 5- (4- (9-fluorenylmethoxycarbonyl) aminomethyl3,5-dimethoxyphenoxy) valeric acid

Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl

pGlu: pyroglutamic acid

Phe (2Cl): 2-chlorophenylalanine

Phe (2F): 2-fluorophenylalanine

Phe (3,4Cl ₂ ): 3,4-dichlorophenylalanine

Phe (3,4F ₂ ): 3,4-difluorophenylalanine

Phe (3CF ₃ ): 3-trifluoromethylphenylalanine

Phe (3Cl): 3-chlorophenylalanine

Phe (3F): 3-fluorophenylalanine

Phe (4Cl): 4-chlorophenylalanine

Phe (4CN): 4-cyanophenylalanine

Phe (4F): 4-fluorophenylalanine

Phe (4Gn): 4-guanidinophenylalanine

Phe (4NH ₂ ): 4-aminophenylalanine

Phe (4NO ₂ ): 4-nitrophenylalanine

Phe (4CN): 4-cyanophenylalanine

Phe (F ₅ ): pentafluorophenylalanine

PheΨ (CH ₂ O) Gly: -CONH- bond between Phe and Gly is substituted with -CH ₂ O- bond.

PheΨ (CSNH) -NH ₂ : C-terminal phenylalanylamide is substituted with phenylalanylthioamide.

Phg: Phenylglycine

PhOH: Phenolic

PhSMe: Tioanisole

Pip (2): 2-aminopipecholic acid

Pro: Proline

Pya (2): 2-pyridylalanine

Pya (3): 3-pyridylalanine

Pya (4): 4-pyridylalanine

PyAOP: (7-Azabenzotriazol-1-yloxy) -tris (pyrrolidino) phosphonium hexafluorophosphate

PyBOP: (benzotriazol-1-yloxy) -tris (pyrrolidino) phosphonium hexafluorophosphate

PyBrop: Bromo-tris (pyrrolidino) phosphonium hexafluorophosphate

Sar: N-methylglycine

Ser (Ac): O-acetylserine

Ser (Me): O-methylserine

Thi: 2-thienylalanine

Tic: 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid

TIS: Triisopropylsilane

Tle: tert-leucine

Tos: Tossil

Trp (For): N ⁱⁿ -formyl tryptophan

Trt: Trityl

Tyr (Me): O-methyltyrosine

TyrΨ (CH ₂ NH) Asn: -CONH- bond between Tyr and Asn is substituted with -CH ₂ NH- bond.

TFA: trifluoroacetic acid

TFE: trifluoroethanol

Z: benzyloxycarbonyl

In the present specification and drawings, the codes of bases and amino acids are indicated according to the IUPAC-IUB Commission on Biochemical Nomenclature or by conventional codes in the art, examples of which are shown below. Unless stated otherwise, optical isomers, amino acids that may have the L form are provided.

DNA: deoxyribonucleic acid

cDNA: complementary deoxyribonucleic acid

A: Adenine

T: Thymine

G: guanine

C: cytosine

Y: thymine or cytosine

N: thymine, cytosine, adenine or guanine

R: adenine or guanine

M: cytosine or adenine

W: Thymine or Adenine

S: cytosine or guanine

RNA: ribonucleic acid

mRNA: messenger ribonucleic acid

dATP: deoxyadenosine triphosphate

dTTP: deoxythymidine triphosphate

dGTP: deoxyguanosine triphosphate

dCTP: deoxycytidine triphosphate

ATP: Adenosine Triphosphate

EDTA: Ethylenediaminetetraacetic acid

SDS: Sodium Dodecyl Sulfate

TFA: trifluoroacetic acid

EIA: Enzyme Immunoassay

Gly or G: glycine

Ala or A: Alanine

Val or V: valine

Leu or L: Leucine

Ile or I: Isoleucine

Ser or S: Serine

Thr or T: threonine

Cys or C: Cysteine

Met or M: Methionine

Glu or E: glutamic acid

Asp or D: Aspartic Acid

Lys or K: Lysine

Arg or R: Arginine

His or H: histidine

Phe or F: Phenylalanine

Tyr or Y: tyrosine

Trp or W: Tryptophan

Pro or P: Proline

Asn or N: Asparagine

Gln or Q: Glutamine

pGlu: pyroglutamic acid

Sequence identification numbers in the sequence listing herein refer to the following sequences, respectively.

SEQ ID NO: 1

It represents the amino acid sequence of Metastin derived from humans.

SEQ ID NO: 2

This represents the nucleotide sequence of the DNA encoding human metastine.

SEQ ID NO: 3

This represents the amino acid sequence of mouse metastin precursor (A).

SEQ ID NO: 4

This represents the nucleotide sequence of the DNA encoding mouse metastin precursor (A), which is contained in the plasmid pCMV-mKiSS-1 contained in the transformant Escherichia coli DH10B / pCMV-mKiSS-1. Base sequence.

SEQ ID NO: 5

This represents the amino acid sequence of mouse metastin precursor (B).

SEQ ID NO: 6

This shows the nucleotide sequence of the DNA encoding mouse metastin precursor (B), which is assigned to the plasmid pCR2.1-mKiSS-1.4A contained in the transformant Escherichia coli DH5a / pCR2.1-mKiSS-1.4A. Included nucleotide sequences.

SEQ ID NO: 7

This represents the amino acid sequence of the metastin precursor from rat.

SEQ ID NO: 8

This represents the nucleotide sequence of the DNA encoding the rat metastin precursor.

SEQ ID NO: 9

This shows the amino acid sequence of human OT7T175 (methastin receptor).

SEQ ID NO: 10

This represents the nucleotide sequence of the DNA encoding human OT7T175 (methastin receptor).

SEQ ID NO: 11

This shows the amino acid sequence of rat OT7T175 (methastin receptor).

SEQ ID NO: 12

This represents the nucleotide sequence of the DNA encoding rat OT7T175 (methastin receptor).

SEQ ID NO: 13

This shows the amino acid sequence of mouse OT7T175 (methastin receptor).

SEQ ID NO: 14

This shows the nucleotide sequence of the DNA encoding mouse OT7T175 (methastin receptor).

SEQ ID NO: 15

This represents the amino acid sequence of human metastin 15 (40-54).

SEQ ID NO: 16

This shows the amino acid sequence of human metastin 10 (45-54) (MS10).

SEQ ID NO: 17

This represents the amino acid sequence of human metastin 9 (46-54).

SEQ ID NO: 18

This represents the amino acid sequence of human metastin 8 (47-54).

SEQ ID NO: 19

This represents the nucleotide sequence of the DNA encoding human metastin 15 (40-54).

SEQ ID NO: 20

This represents the nucleotide sequence of the DNA encoding human metastin 10 (45-54).

SEQ ID NO: 21

This represents the nucleotide sequence of the DNA encoding human metastin 9 (46-54).

SEQ ID NO: 22

This shows the nucleotide sequence of the DNA encoding human metastin 8 (47-54).

The transformant Escherichia coli DH10B / pCMV-mKiSS-1 is an international patent organism depositing institution located in Ibaraki, Japan (Postal Code 305-8566), Tsukuba Higashi 1-1-1 Central 6, National Institute of Advanced Industrial Science and Technology ( Former Ministry of International Trade and Industry, Agency of Industrial Science and Technology, National Institute of Bioscience and Human Technology (NIBH) on January 24, 2000, with access number FERM BP-7003, and Osaka City, Osaka, Japan Since December 16, 1999, the Institute for Fermentation (IFO), 2-17-85, Yodogawa-ku, has been deposited with access number IFO 16348.

The transformant Escherichia coli DH5a / pCR2.1-mKiSS-1.4A is a National Institute of Advanced Industrial Science which is an international patent organism depositing institution located at 1-1-1 Central 6, Tsukuba Higashi, Ibaraki, Japan (Postal Code 305-8566). and Technology (formerly Ministry of International Trade and Industry, Agency of Industrial Science and Technology, National Institute of Bioscience and Human Technology (NIBH)) on March 6, 2000 with access number FERM BP-7073, and It has been deposited with the access number IFO 16360 since February 16, 2000 at the Institute for Fermentation (IFO) located at 2-17-85, Yodogawa-ku, Osaka City, Osaka, Japan.

In the present invention, Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂ (SEQ ID NO: 16) is referred to as metastin 10 (methastin 10), ie MS10.

In the examples described below, the N-terminal Tyr and C-terminal Phe of MS10 are counted in the 1- and 10-positions, respectively.

For example, [Hph10] MS10 (Example 1) of Compound No. 79 refers to a peptide in which the C-terminal Phe (10-position) of MS10 is substituted with Hph.

For example, des (1) -MS10 of compound number 4 refers to a peptide from which the N-terminal Tyr (1-position) is deleted.

For example, des (1-3) -Fmoc-MS10 of Compound No. 53 is deleted from the N-terminal Tyr-Asn-Trp (1 to 3-position) and the amino group of Asn at 4-position is modified to Fmoc. Means protected peptide.

Example 1

Synthesis Method A: Preparation of [Hph10] MS10 (Compound No. 79)

수지를 수득하였다. 상기 수지 18.2 mg 에, TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 200 ㎕ 를 첨가하고, 혼합물을 2 시간동안 진탕하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 73/27-63/37 을 이용하여 선형 밀도 구배 용출을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 2.6 mg 의 백색 분말을 수득하였다.Using a 51 mg (about 0.39 mmol / g) Fmoc-Hph-PAL resin prepared by introducing Fmoc-Hph into a commercial PAL resin, peptide chains were extended by a multi-peptide synthesizer ACT-396.

A resin was obtained. To 18.2 mg of the resin, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and the mixture was shaken for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution was performed using 73 / 27-63 / 37. Fractions containing the product were collected and lyophilized to yield 2.6 mg of white powder.

Mass spectrum (M + H) ⁺ 1316.5 (calculated 1316.7)

Elution time on HPLC: 20.6 min

Elution conditions

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A Linear density gradient elution using eluent A / B = 100 / 0-30 / 70 using acetonitrile containing 0.1% TFA and 0.1% TFA in water (35 minutes)

Flow rate: 1.0 ml / min.

Example 2

(Synthesis method B): Preparation of [Trp (For) 10] MS10 (Compound No. 186)

수지 540 mg 을 수득하였다. 상기 펩티드 270 mg 에, 10 mL 의 AcOH/TFE/DCM (1/1/8) 을 첨가하고 혼합물을 30 분간 진탕하였다. 수지를 여과로 제거한 후, 용매를 농축하고, 잔류물을 AcOEt 에 용해시켰다. 그 후, 용액을 포화 NaCl 수용액으로 세정하였다. Na₂SO₄ 로 건조시킨 후, 용매를 농축하고, 잔류물에 디에틸 에테르-석유 에테르를 첨가하여 침전물로서의 68 mg 의

를 수득하였다. 상기 펩티드 22 mg 에, 4 mg 의 HCl H-Trp(For)-NH₂ (Boc-Trp(For)-NH₂ 를 0 ℃에서 30 분간 9.7 N HCl/디옥산으로 처리하여 수득함), 10 mg 의 PyAOP, 5 mg 의 HOAt 및 11 ㎕ 의 DIEA 를 첨가하였다. 혼합물을 15 시간동안 교반하였다. 용매를 농축시킨 후, 잔류물에 클로로포름-디에틸 에테르를 첨가하여,

를 침전물로서 수득하였다. 상기 펩티드에, TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 1 mL 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용 액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 용출액 A: 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 73/27-63/37 을 이용하여 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 2.0 mg 의 백색 분말을 수득하였다.379 mg of Fmoc-Arg (Pbf) -O-Clt resin prepared by introducing Fmoc-Arg (Pbf) -OH into a commercial 2-chlorotrityl chloride resin (Clt resin, 1.33 mmol / g) (about 0.33 mmol / g) using to extend the peptide chain with ABI 433A,

540 mg of a resin were obtained. To 270 mg of the peptide, 10 mL of AcOH / TFE / DCM (1/1/8) was added and the mixture was shaken for 30 minutes. After the resin was removed by filtration, the solvent was concentrated and the residue was dissolved in AcOEt. The solution was then washed with saturated aqueous NaCl solution. After drying over Na ₂ SO ₄ , the solvent was concentrated and diethyl ether-petroleum ether was added to the residue to give 68 mg of precipitate as a precipitate.

Obtained. To 22 mg of the peptide, 4 mg of HCl H-Trp (For) -NH ₂ (obtained by treatment of Boc-Trp (For) -NH ₂ with 9.7 N HCl / dioxane for 30 minutes at 0 ° C.), 10 mg PyAOP, 5 mg HOAt and 11 μl DIEA were added. The mixture was stirred for 15 hours. After concentration of the solvent, to the residue was added chloroform-diethyl ether,

Was obtained as a precipitate. To the peptide, 1 mL of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with acetic acid aqueous solution and the extract was filtered to remove the resin. Subsequently, eluent A on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) A: 0.1% TFA in water and eluent B: Eluent A using 0.1% TFA-containing acetonitrile Linear density gradient elution (30 min) was performed using / B: 73 / 27-63 / 37. Fractions containing product were collected and lyophilized to yield 2.0 mg of white powder.

Mass spectrum (M + H) ⁺ 1369.3 (calculated 1369.6)

Elution time on HPLC: 19.6 min

Elution conditions

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 3

Synthesis Method C: Preparation of [10Ψ, CSNH] MS10 (Compound No. 128)

에, H-LeuArg(Pbf)PheΨ(CSNH)-NH₂ (14 mg 의 Fmoc-LeuArg(Pbf)PheΨ(CSNH)-NH₂ 를 10% DEA/DMF 로 처리하여 수득함), 9 mg 의 PyBrop, 3 mg 의 HOAt 및 7 mL 의 DIEA 를 첨가하고, 혼합물을 15 시간동안 교반하였다. 용매를 농축시킨 후, 거기에 침전을 위해 클로로포름-디에틸 에테르를 첨가하였다. 생성물 10 mg 에, 100 ㎕ 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 72/28-62/38 을 이용하여 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 1.0 mg 의 백색 분말을 수득하였다.After dissolving 264 mg of Boc-Phe-NH ₂ in 20 mL of THF, 1.62 g of Lawesson reagent was added to the solution and stirred for 24 hours. Insoluble matter was removed by filtration, the solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was washed with saturated aqueous NaHCO ₃ solution and then saturated aqueous NaCl solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to give 275 mg (yield 98%) of (S) -2-tert-butoxycarbonylamino-3-phenylpropanthioamide (Boc-PheΨ (CSNH) -NH ₂ ). Obtained as a precipitate. 42 mg of the peptide was treated with 9.7 N HCl at 0 ° C. to remove Boc, and then Fmoc removal by 10% DEA / DMF treatment and condensation by PyBOP / HOBt method were repeated to obtain 66 mg of Fmoc-LeuArg ( Pbf) PheΨ (CSNH) -NH ₂ (yield 93%) was obtained. Of 17 mg prepared as in Example 2

H-LeuArg (Pbf) PheΨ (CSNH) -NH ₂ (obtained by treating 14 mg of Fmoc-LeuArg (Pbf) PheΨ (CSNH) -NH ₂ with 10% DEA / DMF), 9 mg of PyBrop, 3 mg HOAt and 7 mL DIEA were added and the mixture was stirred for 15 h. After the solvent was concentrated, chloroform-diethyl ether was added thereto for precipitation. To 10 mg of product, 100 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (30 minutes) was performed using 72 / 28-62 / 38. Fractions containing the product were collected and lyophilized to yield 1.0 mg of white powder.

Mass spectrum (M + H) ⁺ 1318.4 (calculated 1318.6)

Elution time on HPLC: 21.8 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 4

(Synthesis method D): Preparation of [6Ψ7, CH ₂ NH] MS10 (Compound No. 163)

수지를 수득하였다. 빙냉하에서, 상기 펩티드 15 mg 에 46 ㎕ 의 TMS-Br, 42 ㎕ 의 PhSMe, 38 ㎕ 의 m-크레졸, 18 ㎕ 의 EDT 및 227 ㎕ 의 TFA 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 용매를 증류로 제거한 후, 잔류물에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 72/28-62/38 을 이용하여 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 2.0 mg 의 백색 분말을 수득하였다.The peptide chain was stretched to ABI 433A using 321 mg of a Fmoc-Phe-PAL resin prepared by introducing Fmoc-Phe into a commercial PAL resin to obtain a Fmoc-LeuArg (Pbf) Phe-PAL resin. Fmoc-Gly was condensed to 1/2 volume of the peptide to give 190 mg of Fmoc-GlyLeuArg (Pbf) Phe-PAL resin. After 76 mg of product was Fmoc deprotected, 2 mL of DMF, 50 μl of AcOH, 46 mg of Fmoc-Phe-H and 8 mg of NaBH ₃ CN were added thereto and shaken for 1 hour. After washing the resin, 2 mL of DMF, 22 μl DIEA and 18 μl Z-Cl were added thereto, and the mixture was shaken for 3 hours. After washing the resin, the peptide chain was stretched to ABI 433A,

A resin was obtained. Under ice-cooling, 46 μl of TMS-Br, 42 μl of PhSMe, 38 μl of m-cresol, 18 μl of EDT and 227 μl of TFA were added to 15 mg of the peptide and the mixture was stirred for 2 hours. After the solvent was removed by distillation, diethyl ether was added to the residue, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (30 minutes) was performed using 72 / 28-62 / 38. Fractions containing product were collected and lyophilized to yield 2.0 mg of white powder.

Mass spectrum (M + H) ⁺ 1288.7 (calculated 1288.7)

Elution time on HPLC: 18.2 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A with eluent A / B = 100 / 0-0 / 70 using 0.1% TFA and 0.1% TFA-containing acetonitrile in water (35 min)

Flow rate: 1.0 ml / min.

(Reference Example 1)

Preparation of N-methyl-N, N'-bis-Boc-1-guanylpyrazole

Under nitrogen flow, 720 mg of 60% NaH in oil is dissolved in 20 mL of dry DMF, and 20 mL of 5.59 g of N, N'-bis-Boc-1-guanypyrazole commercially available in the solution is dried. DMF solution was added at 0 ° C. and stirred for 10 minutes. After adding 1.68 mL of methyl iodide thereto, the mixture was stirred at room temperature for 24 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying over Na ₂ SO ₄ , the solvent is concentrated and the concentrate is purified by flush column chromatography (ethyl acetate / n-hexane = 1/4) using silica gel 60 (200 mL) to give 5.35 g (yield). 91.6%) of N-methyl-N, N'-bis-Boc-1-guanylpyrazole.

Elemental Analysis as C ₁₅ H ₂₄ N ₄ O ₄

Calc .: C, 55.54; H, 7. 46; N, 17.27

Found: C, 55.36; H, 7. 48; N, 17.06

Rf1: 0.64, Rf2: 0.79

Developing solvent for TLC: Rf1 (ethyl acetate / n-hexane = 1/2), Rf2 (methanol / chloroform = 2/98)

Elution time on HPLC: 26.7 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-20 / 80 as eluent A in water with 0.1% TFA and 0.1% TFA in water (40 min)

Flow rate: 1.0 ml / min.

(Reference Example 2)

Preparation of N-methyl-N, N'-bis-Z-1-guanylpyrazole

In an argon atmosphere, 40 mg of 60% NaH in oil is dissolved in 5 mL of dry DMF and in this solution 5 mL of dry DMF solution of 380 mg of commercially available N, N'-bis-Z-1-guanylpyrazole. Was added at 0 ° C. and stirred for 10 minutes. After 125 μl of methyl iodide was added thereto, the mixture was stirred at room temperature for 15 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated to give 393 mg of crude product. From the crude product 170 mg were purified by flush column chromatography using silica gel 60 (75 mL) (ethyl acetate / n-hexane = 1/4) to give 152 mg (yield 89.5%) of N-methyl-N, N '-Bis-Z-1-guanylpyrazole was obtained.

Elemental Analysis as C ₂₁ H ₂₀ N ₄ O ₄

Calc .: C, 64.28; H, 5. 14; N, 14.28

Found: C, 64.09; H, 5. 24; N, 14.43

Rf1: 0.50, Rf2: 0.86

Developing solvent for TLC: Rf1 (ethyl acetate / n-hexane = 1/2), Rf2 (methanol / chloroform = 2/98)

Elution time on HPLC: 28.9 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-20 / 80 as eluent A in water with 0.1% TFA and 0.1% TFA in water (40 min)

Flow rate: 1.0 ml / min.

Example 5

(Synthesis method E): Preparation of [Arg (Me) 9] MS10 (Compound No. 82)

Amide MBHA 수지 1080 mg 을 수득하였다. 상기 펩티드 540 mg 에, 10 mL 의 TFA/TIS/DCM (1/5/94) 를 첨가하고, 혼합물을 50 분간 진탕하였다. 상기 수지를 세정한 후, 건조하였다. 2/5 부피의 상기 수지에, 2 mL 의 DMF, 49 mg 의 참조예 1 에서 제조한 N-메틸-N,N'-비스-Boc-1-구아닐피라졸 및 87 ㎕ 의 DIEA 를 첨가한 후, 혼합물을 15 시간동안 진탕하여, 220 mg 의

Amide MBHA 수지를 수득하였다. 상기 펩티드 50 mg 에, 1 mL 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용하여 용출액 A/B: 74/26-64/36 로 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 10.5 mg 의 백색 분말을 수득하였다.Peptide chains were stretched to ABI 433A using 480 mg of Fmoc-Phe-Rink Amide MBHA resin prepared by introducing Fmoc-Phe into commercially available Rink Amide MBHA resin.

1080 mg of Amide MBHA resin was obtained. To 540 mg of the peptide, 10 mL of TFA / TIS / DCM (1/5/94) was added and the mixture was shaken for 50 minutes. The resin was washed and then dried. To 2/5 volumes of the above resin was added 2 mL of DMF, 49 mg of N-methyl-N, N'-bis-Boc-1-guanylpyrazole and 87 μl of DIEA. The mixture is then shaken for 15 hours to give 220 mg of

Amide MBHA resin was obtained. To 50 mg of the peptide, 1 mL of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Subsequently, 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm): Eluent A / B using 0.1% TFA-containing acetonitrile : Linear density gradient elution (30 min) was performed at 74 / 26-64 / 36. Fractions containing product were collected and lyophilized to yield 10.5 mg of white powder.

Mass spectrum (M + H) ⁺ 1316.5 (calculated 1316.7)

Elution time on HPLC: 20.1 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

In this example, N-methyl-N, N'-bis-Boc-1-guanylpyrazole used to convert the 9-position amino acid to N ^ω -methylated Arg is a group of peptides comprising N ^ω -methylated Arg. N ^omega -methylated Arg, which is a reagent useful for the preparation and also for general peptides, wherein N-methyl-N, N'-bis-Boc-1-guanylpyrazole is deprotected after reacting with Orn in the peptide. It is advantageously used for the preparation of peptides comprising.

Furthermore, blood stability is improved by converting Arg into N ^ω -methylated Arg not only in the N ^ω -methylated Arg-containing peptide obtained in this Example, but also in a general peptide. Thus, N ^ω - substituent on the side chain of Arg is methylated, the Arg in the peptide N ^ω - is useful for improving blood stability method which comprises conversion to the methylated Arg.

Furthermore, there is provided a method for improving blood stability, comprising introducing one or two (preferably one) alkyl groups, preferably C _1-4 alkyl groups, more preferably methyl groups, to the side chains of Arg in the Arg-containing peptide. Can be. At this time, the Arg-containing peptide is characterized by, for example, the structure -Arg-XXX- (where XXX represents an amino acid having an aromatic ring group optionally substituted into the side chain, preferably Phe, Trp, Tyr, etc.). Peptides with partial peptides are included.

The N ^ω -methylated Arg-containing peptide also contains N-methyl-N, N'-bis-Boc-1-guanylpyrazole as well as N-methyl-N, N'-bis-Z- prepared in Reference Example 2. It can also be prepared using 1-guanylpyrazole.

Example 6

(Synthesis method F): Preparation of [6Ψ7, CSNH] MS10 (Compound No. 166)

In 10 mL of DMF, 503 mg of HCl H-Gly-OBut is dissolved, 1162 mg of Fmoc-Phe, 608 mg of HOBt, 1874 mg of PyBOP and 784 μl of DIEA are added at 0 ° C. and stirred for 4 hours. It was. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and diethyl ether-petroleum ether was added to give 1.48 g (99% yield) of Fmoc-PheGly-OBut as a precipitate. After dissolving 250 mg of the product in 10 mL of toluene, 404 mg of Lawesson reagent was added to the solution and stirred at 80 ° C. for 2 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to the eluate to give 207 mg (80% yield) of Fmoc-PheΨ (CSNH) Gly-OBut as precipitate. To 103 mg of product, TFA / H ₂ O (95/5) was added and the mixture was stirred for 1 hour. After concentration of the solvent, diethyl ether was added to give 82.4 mg (90% yield) of Fmoc-PheΨ (CSNH) Gly-OH as a precipitate. Using a Fmoc-Phe-PAL resin prepared by introducing Fmoc-Phe into a commercially available PAL resin, the peptide chain was stretched to ABI 433A, and the 80 mg of the extended Fmoc-LeuArg (Pbf) Phe-PAL resin was stretched to Fmoc. Deprotection. Thereafter, 35 mg of Fmoc-PheΨ (CSNH) Gly-OH, 47 mg of PyBrop, 14 mg of HOAt, and 35 μl of DIEA were added to the resin and shaken for 15 hours. After washing the resin, the peptide chain was stretched to ABI 433A A resin was obtained. To 15 mg of product, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and stirred for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (60 minutes) was performed using 77 / 23-57 / 43. Fractions containing the product were collected and lyophilized to yield 1.0 mg of white powder.

Mass spectrum (M + H) ⁺ 1318.7 (calculated 1318.6)

Elution time on HPLC: 20.8 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 7

(Synthesis method G): Preparation of [AzaGly7] MS10 (Compound No. 176)

수지를 수득하였다. 생성물 25 mg 에, 1 mL 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 을 첨가하고, 2 시간동안 진탕하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 74/26-64/36 을 이용하여 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 5.5 mg 의 백색 분말을 수득하였다.The peptide chain was stretched to ABI 433A using 321 mg of Fmoc-Phe-PAL resin prepared by introducing Fmoc-Phe into commercially available PAL resin, and 80 mg of Fmoc-LeuArg (Pbf) Phe-PAL thus stretched. The resin was Fmoc deprotected. After addition of 2 mL of THF and 16 mg of CDI, the mixture was shaken for 2 hours. Thereafter, 6 μl of hydrazine monohydrate was added to the mixture. The mixture was shaken for 1 hour and then the resin was washed. 39 mg of Fmoc-Phe, 93 mg of PyBrop, 27 mg of HOAt and 105 μl of DIEA were added to the system, followed by shaking for 2 hours. After washing the resin, the peptide chain was stretched to ABI 433A

A resin was obtained. To 25 mg of product, 1 mL of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and shaken for 2 hours. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (30 min) was performed using 74 / 26-64 / 36. Fractions containing the product were collected and lyophilized to yield 5.5 mg of white powder.

Mass spectrum (M + H) ⁺ 1303.3 (calculated 1303.6)

Elution time on HPLC: 18.9 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 8

(Synthesis method H): Preparation of [D-Tyr1, AzaGly7, Arg (Me) 9] MS10 (Compound No. 232)

수지 80.3 mg 을 사용하여, 펩티드 사슬을 신장시켜, 97.2 mg 의

-Rink Amide MBHA 수지를 수득하였다.Fmoc-Phe, Fmoc-Orn (Mtt) was introduced into 4 g (0.55 mmol / g) of a commercially available Rink Amide MBHA resin to prepare a Fmoc-Orn (Mtt) -Phe-Rink Amide MBHA resin, and 50 mL of the resin was used. TFA / TIS / DCM (1/5/94) was added, followed by shaking for 50 minutes. After washing the resin, 40 mL of DCM and 2.27 g of N-methyl-N, N'-bis-Boc-1-guanylpyrazole prepared in Reference Example 1 were added thereto. DIEA was added to the mixture to adjust the pH of the solution to 9. The mixture was shaken for 15 hours to yield 4.74 g of Fmoc-Arg (Boc2, Me) Phe-Rink Amide MBHA resin. Separately, 145 mg of Fmoc-NHNH2 HCl was suspended in 10 mL of THF. Under ice-cooling, 89 mg of CDI and 87 mL of DIEA were added to the suspension and stirred at room temperature for 1 hour. Under ice-cooling, 224 mg of H-Leu-OBut HCl solution in 5 mL of DMF was added to the mixture. Returning to room temperature, the mixture was stirred for 18 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to give 230 mg (99% yield) of Fmoc-AzaGly-Leu-OBu ^t . To 187 mg of product, 10 mL of TFA / H ₂ O (9/1) was added and stirred for 1 hour. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with saturated aqueous NaCl solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and diethyl ether was added to give 143 mg of Fmoc-AzaGly-Leu-OH as a precipitate (yield 87%). The resulting Fmoc-AzaGly-Leu-OH, Trt-Phe was introduced into Fmoc-Arg (Boc ₂ , Me) Phe-Rink Amide MBHA resin. To this Trt-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) Phe-Rink Amide MBHA resin, 50 mL of TFA / TIS / DCM (1/5/94) was added and the mixture was shaken for 50 minutes. It was. After the resin was washed and neutralized, Fmoc-Ser (Bu ^t ) and then Fmoc-Asn (Trt) were introduced therein. Generated

Using 80.3 mg of resin, peptide chains were stretched to give 97.2 mg of

-Rink Amide MBHA resin was obtained.

To the obtained resin, 1 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Subsequently, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B: 0.1% TFA-containing acetonitrile: 76 Linear density gradient elution (60 minutes) was performed using / 24-66 / 34. Fractions containing the product were collected and lyophilized to yield 11.7 mg of white powder.

Mass spectrum (M + H) ⁺ 1317.0 (calculated 1317.6)

Elution time on HPLC: 21.0 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 9

Synthesis Method I) Preparation of des (1-3) -3- (3-pyridyl) propionyl- [AzaGly7, Arg (Me) 9] MS10 (Compound No. 322)

수지를 Fmoc 탈보호화한 후, 상기 수지를 실온에서 90 분간 시판중인 3-(3-피리딜)프로피온산 15.2 mg, 15.9 ㎕ 의 DIPCDI 및 200 ㎕ 의 0.5M HOAt/DMF 로 처리하였다. 수득한 수지를 세정 및 건조한 후, 상기 수지에 1 mL 의 TFA/PhSMe/m-크레졸/H₂O/TIS/EDT (80/5/5/5/2.5/2.5) 을 첨가하고, 90 분간 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC SH-343-5 S-5, 120A 컬럼 (20 x 250 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 80/20-60/40 을 이용하여 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 6.0 mg 의 백색 분말을 수득하였다.Of 48.2 mg prepared in Example 8

After the resin was Fmoc deprotected, the resin was treated with 15.2 mg of commercial 3- (3-pyridyl) propionic acid, 15.9 μl DIPCDI and 200 μl 0.5M HOAt / DMF at room temperature for 90 minutes. After washing and drying the obtained resin, 1 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added to the resin and stirred for 90 minutes. It was. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Subsequently, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B: 0.1% TFA-containing acetonitrile: 80 Linear density gradient elution (60 minutes) was performed using / 20-60 / 40. Fractions containing product were collected and lyophilized to yield 6.0 mg of white powder.

Mass spectrum (M + H) ⁺ 987.4 (calculated 987.5)

Elution time on HPLC: 8.1 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 10

Synthesis Method J) Preparation of des (1-2) -amidino- [AzaGly7, Arg (Me) 9] MS10 (Compound No. 273)

수지에 Fmoc-Trp(Boc) 를 도입한 후, 상기 수지를 Fmoc 탈보호화하여,

수지를 수득하였다. 수득한 수지를 DMF 중에서 29.3 mg 의 N,N'-비스-Boc-1-구아닐피라졸 및 34.8 ㎕ 의 DIEA 로 14 시간동안 처리하여, 아미디노-Trp(Boc)Asn(Trt)Ser(Bu^t)Phe-AzaGly-LeuArg(Boc₂,Me)Phe-Rink Amide MBHA 수지를 수득하였다. 수득한 수지를 세정 및 건조한 후, 1 mL 의 TFA/PhSMe/m-크레졸/H2O/TIS/EDT (80/5/5/5/2.5/2.5) 을 첨가하고, 90 분간 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액 으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC SH-343-5 S-5, 120A 컬럼 (20 x 250 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 78/22-58/42 를 이용하여 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 0.6 mg 의 백색 분말을 수득하였다.Of 48.2 mg prepared in Example 8

After introducing Fmoc-Trp (Boc) into the resin, the resin was Fmoc deprotected,

A resin was obtained. The resulting resin was treated with 29.3 mg of N, N'-bis-Boc-1-guanylpyrazole and 34.8 μl of DIEA in DMF for 14 hours to give amidino-Trp (Boc) Asn (Trt) Ser (Bu). ^t ) Phe-AzaGly-LeuArg (Boc ₂ , Me) Phe-Rink Amide MBHA resin was obtained. After the obtained resin was washed and dried, 1 mL of TFA / PhSMe / m-cresol / H 2 O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an acetic acid aqueous solution, and the extract was filtered to remove the resin. Subsequently, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: 78 Linear density gradient elution (60 minutes) was performed using / 22-58 / 42. Fractions containing product were collected and lyophilized to yield 0.6 mg of white powder.

Mass spectrum (M + H) ⁺ 1082.3 (calculated 1082.6)

Elution time on HPLC: 11.4 min

Elution condition:

Column: YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 11

(Synthesis method K): Preparation of [6Ψ7, NHCO, D-Tyr1, Arg (Me) 9] MS10 (Compound No. 319)

-Rink Amide MBHA 수지를 수득하였다. 생성물 34 mg 에, 200 ㎕ 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 을 첨가하고, 2 시간동안 교반하였다. 에테르를 상기 반응 용액에 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 76/24-66/34 를 이용하여 선형 밀도 구배 용출 (30 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 0.7 mg 의 백색 분말을 수득하였다.5.99 g of Z-Phe was dissolved in 30 mL of MeCN, and 3.94 g of HONB and 4.59 g of WSCD HCl were added to the solution at 0 ° C., followed by stirring at room temperature for 4 hours. While keeping at 0 ° C., 3.4 mL of 25% NH 3 aqueous solution and 10 mL of DMF were added and stirred to the mixture for 4 h. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and diethyl ether was added to give 1.48 g (99% yield) of Z-Phe-NH ₂ as a precipitate. After dissolving 1.94 g of [bis (trifluoroacetoxy) iodo] benzene in 20 mL of MeCN and 5 mL of H ₂ O, 890 mg of the prepared Z-Phe-NH ₂ and 972 were precipitated in the precipitate. Μl of pyridine was added at 0 ° C. and stirred at room temperature for 15 hours. After concentrating the solvent, the concentrate was liquid-liquid separated with diethyl ether-1N HCl aqueous solution, the 1N HCl aqueous solution layer was concentrated and then dried. Half of this volume was dissolved in 5 mL of DMF and 486 μl of mono-tert-butyl malonate and 540 mg of HOBt were added to the solution. Thereafter, 2.08 g of PyBOP and 1394 μl of DIEA were added to the mixture at 0 ° C., and stirred at room temperature for 15 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to give 304 mg (yield 33%) of Z-PheΨ (NHCO) Gly-OBu ^t as a precipitate. After dissolving 154 mg of the product in 20 mL of MeOH, 10% Pd-C was added to the solution and catalytic hydrogenation under hydrogen flow for 2 hours. After removal of the catalyst by filtration, the solvent was concentrated and dried. The residue was dissolved in 10 mL of MeCN and 152 mg of Fmoc-OSu and 78 μl of DIEA were added to the solution and stirred for 15 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and diethyl ether-petroleum ether was added to give 127 mg (yield 68%) of Fmoc-PheΨ (NHCO) Gly-OBu ^t as a precipitate. Fmoc-Leu was introduced into 63 mg of the Fmoc-Arg (Boc ₂ , Me) Phe-Rink Amide MBHA resin prepared in Example 10. After Fmoc deprotection, the resin was Fmoc-PheΨ (NHCO) Gly-OH (prepared by treatment with 25 mg of Fmoc-PheΨ (NHCO) Gly-OBu ^t for 3 minutes with TFA), 300 μl 0.5M HOAt, 78 mg of PyAOP and 52 μl of DIEA were added and shaken for 6 hours. After the resin was washed, 2 mL of DMF, 9 μl of DIEA, and 12 μl of Ac ₂ O were added to the resin, followed by shaking for 30 minutes. After washing the resin, the peptide chain was stretched to ABI 433A,

-Rink Amide MBHA resin was obtained. To 34 mg of product, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and stirred for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (30 min) was performed using 76 / 24-66 / 34. Fractions containing product were collected and lyophilized to yield 0.7 mg of white powder.

Mass spectrum (M + H) ⁺ 1316.3 (calculated 1316.7)

Elution time on HPLC: 18.7 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A with eluent A / B = 100 / 0-0 / 70 using 0.1% TFA and 0.1% TFA-containing acetonitrile in water (35 min)

Flow rate: 1.0 ml / min.

Example 12

(Synthesis method L): Preparation of [N ((CH ₂ ) ₃ Gn) Gly 9] -MS10 (Compound No. 218)

-Rink Amide MBHA 수지를 수득하였다. 상기 생성물에, 1 mL 의 TFA/PhOH/H₂O/TIS/EDT (87.5/5/2.5/2.5/2.5) 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 수지를 여과로 제거하고 농축한 후, 상기 농축물에 에테르를 첨가하였다. 절반 부피의 생성된 침전물을 500 ㎕ 의 DMF 에 용해시키고, 상기 용액에 9 mg 의 1H-피라졸-1-카르복스아미딘 히드로클로라이드 및 22 mL 의 DIEA 를 첨가하고, 15 시간동안 교반하였다. 용매를 증류제거하고, 침전물에 에테르를 첨가하였다. 빙냉하에서, 상기 혼합물에 60 ㎕ 의 PhSMe, 56 ㎕ 의 m-크레졸, 26 ㎕ 의 EDT, 337 ㎕ 의 TFA 및 65 ㎕ 의 TMSBr 를 첨가하고, 2 시간동안 교반하였다. 용매를 증류제거한 후, 잔류물에 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 74/26-64/36 을 이용하여 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 1.8 mg 의 백색 분말을 수득하였다.Peptide chains were stretched to ABI 433A using 192 mg of Fmoc-Phe-Rink Amide MBHA resin to obtain Fmoc-GlyPhe-Rink Amide MBHA resin. After 1/4 volume of product was Fmoc deprotected, 2 mL of DMF, 50 μl of AcOH, 5 mg of Boc-β-Ala-H and 16 mg of NaBH ₃ CN were added thereto and the mixture was allowed to mix for 30 minutes. Shaken. After washing the resin, 71 mg Fmoc-Leu, 56 mg CIP, 27 mg HOAt and 105 mL DIEA were added and shaken for 15 hours. After washing the resin, the peptide chain was stretched to ABI 433A

-Rink Amide MBHA resin was obtained. To the product, 1 mL of TFA / PhOH / H ₂ O / TIS / EDT (87.5 / 5 / 2.5 / 2.5 / 2.5) was added and the mixture was stirred for 2 hours. The resin was removed by filtration and concentrated, then ether was added to the concentrate. Half volume of the resulting precipitate was dissolved in 500 μl of DMF, and 9 mg of 1H-pyrazole-1-carboxamidine hydrochloride and 22 mL of DIEA were added to the solution and stirred for 15 hours. The solvent was distilled off and ether was added to the precipitate. Under ice-cooling, 60 μl of PhSMe, 56 μl of m-cresol, 26 μl of EDT, 337 μl of TFA and 65 μl of TMSBr were added to the mixture and stirred for 2 hours. After distilling off the solvent, ether was added to the residue, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (60 minutes) was performed using 74 / 26-64 / 36. Fractions containing the product were collected and lyophilized to give 1.8 mg of white powder.

Mass spectrum (M + H) ⁺ 1302.5 (calculated 1302.7)

Elution time on HPLC: 18.6 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (35 min)

Flow rate: 1.0 ml / min.

Example 13

(Synthesis method M): Preparation of MS10 (Compound No. 3)

Commercially available p-methyl BHA resin (0.77 mmole / g resin) was charged to the reactor of peptide synthesizer ABI 430A. Boc-Phe.Boc-Arg (Tos), Boc-Leu.Boc-Gly, Boc-Phe.Boc-Ser (Bzl), Boc-Asn.Boc-Trp (For) and Boc-Asn into the resin. .Boc-Tyr (Br-Z) was introduced in this order following Boc-strategy (DCC-HOBt) peptide synthesis to obtain the desired protected peptide resin. 0.11 g of the resin was stirred in 0 mL of anhydrous hydrogen fluoride containing 1 mL of p-cresol and 1.2 mL of 1,4-butanediol for 60 minutes at 0 ° C. The hydrogen fluoride was then distilled off under vacuum. Diethyl ether was added to the residue and the precipitate was filtered off. The precipitate was extracted by addition of 50% acetic acid aqueous solution and the insoluble material was removed. After the extract was fully concentrated, the concentrate was applied to a Sephadex ™ G-25 column (2.0 × 80 cm) filled with 50% acetic acid aqueous solution and then developed with the same solvent. The main fractions were collected and lyophilized to yield 40 mg of white powder. Half volume of this powder was subjected to column chromatography (2.6 x 60 cm) filled with LiChroprep ™ RP-18 and then washed with 200 mL of water containing 0.1% TFA. Then linear density gradient elution was performed with 300 mL of 0.1% TFA and 300 mL of 0.1% TFA-containing 33% acetonitrile. The main fractions were collected and lyophilized to yield 2.2 mg of the desired peptide.

Mass spectrum (M + H) 1302.5 (calculated 1302.6)

Elution time on HPLC: 18.7 min

Elution condition:

Column: Wakosil-II 5C18T 4.6 x 100 mm

Eluent: Eluent A using eluent A / B = 95 / 5-45 / 55 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 14

(Synthesis method N): Preparation of des (1-3) -2- (indol-3-yl) ethylcarbamoyl- [AzaGly7, Arg (Me) 9] MS10 (Compound No. 279)

수지 를 Fmoc 탈보호화하였다.

수지 64 mg (20 ㎛ol) 에, 1.5 mL 의 THF 및 13 mg 의 CDI 를 첨가하고, 2 시간동안 진탕하였다. 상기 혼합물에 32 mg 의 트립타민 히드로클로라이드, 28 ㎕ 의 DIEA 및 500 ㎕ 의 DMF 를 첨가한 후, 24 시간동안 진탕하였다. 그 후 상기 수지를 세정하여, 2-(인돌-3-일)에틸카르바모일-Asn(Trt)Ser(Bu^t)PheAzaGlyLeuArg(Me,Boc₂)Phe-Rink Amide MBHA 수지를 수득하였다. 생성물 15 mg 에, 200 ㎕ 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 을 첨가하고, 2 시간동안 교반하였다. 에테르를 상기 반응 용액에 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 69/31-59/41 을 이용하여 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 1.1 mg 의 백색 분말을 수득하였다.Prepared in Example 8

The resin was Fmoc deprotected.

To 64 mg (20 μmol) of resin, 1.5 mL of THF and 13 mg of CDI were added and shaken for 2 hours. To the mixture was added 32 mg of tryptamine hydrochloride, 28 μl of DIEA and 500 μl of DMF, followed by shaking for 24 hours. The resin was then washed to give 2- (indol-3-yl) ethylcarbamoyl-Asn (Trt) Ser (Bu ^t ) PheAzaGlyLeuArg (Me, Boc ₂ ) Phe-Rink Amide MBHA resin. To 15 mg of product, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and stirred for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (60 minutes) was performed using 69 / 31-59 / 41. Fractions containing the product were collected and lyophilized to yield 1.1 mg of white powder.

Mass spectrum (M + H) ⁺ 1040.2 (calculated 1040.5)

Elution time on HPLC: 20.1 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-0 / 50 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 15

수지의 제조

Preparation of Resin

5 g (0.4 mmol / g) of commercially available Rink Amide MBHA resin was swollen in DMF and treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. After washing the obtained resin with DMF, the resin was washed with 4.213 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt. Trp (Boc) was introduced by treatment with a / DMF solution for 90 minutes to obtain a Fmoc-Trp (Boc) -Rink Amide MBHA resin. In the same manner, Orn (Mtt) was introduced to give 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The obtained resin was washed, swollen with DCM, 50 mL of TFA / TIS / DCM (1/5/94) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt group in the TFA / TIS / DCM (1/5/94) solution and the Mtt group was removed.

The resulting Fmoc-Orn-Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 25 mL of DCM-TFE (4: 1) and 1.946 g (6 mmol) of N-methyl-N, N'-bis-Boc-1-sphere obtained in Reference Example 1 were obtained. Anipyrazole was added. DIEA was added to the mixture to adjust the pH of the solution to 10 and the mixture was shaken for 15 hours to yield 6.195 g of Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. The resin was divided in half and the Fmoc group was removed from the Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin (1 mmol) thus obtained, and H-Leu-Arg (Boc ₂ , Me ) -Trp (Boc) -Rink Amide MBHA resin (1 mmol) was obtained.

Separately, 1.745 g (6 mmol) of Fmoc-NHNH ₂ HCl were suspended in 20 mL of DMF-THF (4: 1). Under ice-cooling, 973 mg (6 mmol) of CDI and 2.09 mL (12 mmol) of DIEA were added to the suspension and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to yield 3.314 g of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin.

Example 16

(Synthesis method O): Preparation of des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 385)

Amide MBHA 수지를 수득하였다. 수득된 수지를 Fmoc 탈보호화하고, 77.6 mg (0.2 mmol) 의 Fmoc_-D-Pya(4)-OH, 104.2 mg (0.2 mmol) 의 PyAOP, 400 ㎕ (0.2 mmol) 의 0.5M HOAt/DMF 및 174.2 ㎕ (0.2 mmol) 의 DIEA 로 실온에서 90 분간 처리하여, _D-Pya(4) 및 그 후 _D-Tyr(^tBu) 을 도입한 후, Fmoc 탈보호화하였다. 이렇게 하여, 135 mg 의

-Rink Amide MBHA 수지를 수득하였다.After swelling 100 mg (0.03 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin in DMF, the resin was poured into 2 mL of 20% piperidine / DMF. The solution was treated for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 77.5 g (0.2 mmol) of Fmoc-Phe-OH, 31.8 μl (0.2 mmol) of DIPCDI and 0.4 mL (0.2 mmol) of 0.5M HOAt / DMF for 90 minutes at room temperature. Treated with solution to introduce Phe. In the same way, Ser ( ^t Bu) and Asn (Trt) are introduced,

Amide MBHA resin was obtained. The obtained resin was Fmoc deprotected and 77.6 mg (0.2 mmol) of Fmoc- _D- Pya (4) -OH, 104.2 mg (0.2 mmol) of PyAOP, 400 μl (0.2 mmol) of 0.5M HOAt / DMF and 174.2 Treatment with μl (0.2 mmol) of DIEA for 90 minutes at room temperature introduced _D- Pya (4) followed by _D- Tyr ( ^t Bu) followed by Fmoc deprotection. In this way, 135 mg

-Rink Amide MBHA resin was obtained.

To the obtained resin, 1 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Subsequently, 0.1% TFA in water and eluent B on preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm) B: Eluent A with 0.1% TFA-containing acetonitrile A linear density gradient elution (60 minutes) was performed at 15 ml / min flow rate using / B: 79 / 21-69 / 31. Fractions containing product were collected and lyophilized. The obtained white powder was dissolved in 10 mL of water, and 100 μl of an ion exchange resin BioRAD AG1 × 8 AcO ⁻ type was added to the solution. While stirring the solution manually, the reaction solution was left for 1 hour. The solution was filtered through a membrane filter to remove the resin, and 6.6 mg of white powder was obtained as acetate.

Mass spectrum (M + H) ⁺ 1204.5 (calculated 1204.6)

Elution time on HPLC: 8.2 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 17

(Synthesis method P): Preparation of des (1-6) -dibenzylcarbamoyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 393)

After swelling 35.2 mg (0.015 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin in DMF, the resin was added to 2 mL of 20% piperidine / DMF. The solution was treated for 20 minutes to remove Fmoc groups. Separately, 19.2 μl (0.1 mmol) of dibenzylamine was dissolved in THF. Under ice-cooling, 16.2 mg (0.1 mmol) of CDI and 2.6 μl (0.015 mmol) of DIEA were added to the solution and stirred at room temperature for 1 hour. After Fmoc deprotection, the resulting solution was added to H-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin and stirred at room temperature for 15 hours.

MBHA 수지에, 1 mL 의 TFA/PhSMe/m-크레졸/H₂O/TIS/EDT (80/5/5/5/2.5/2.5) 을 첨가하고, 혼합물을 90 분간 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 이 절차를 반복하여 2 회 세정하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC SH-343-5 S-5, 120A 컬럼 (20 x 250 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 63/37-53/47 을 이용하여 유속 8 ml/분으로 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하였다. 수득한 백색 분말을 10 mL 의 물에 용해시키고, 상기 용액에 이온교환수지 BioRAD AG1 x 8 AcO^- 형 100 ㎕ 을 첨가하였다. 용액을 간혹 수동으로 교반하면서, 반응 용액을 1 시간동안 방치하였다. 상기 용액을 막필터로 여과하여 수지를 제거하고, 2.2 mg 의 백색 분말을 아세트산염으로서 수득하였다.Obtained

1 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added to the MBHA resin, and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B: 0.1% TFA-containing acetonitrile: 63 A linear density gradient elution (60 minutes) was performed at a flow rate of 8 ml / min using / 37-53 / 47. Fractions containing product were collected and lyophilized. The obtained white powder was dissolved in 10 mL of water, and 100 μl of an ion exchange resin BioRAD AG1 × 8 AcO ⁻ type was added to the solution. While stirring the solution manually, the reaction solution was left for 1 hour. The solution was filtered through a membrane filter to remove the resin and 2.2 mg of white powder was obtained as acetate.

Mass spectrum (M + H) ⁺ 768.7 (calculated 768.4)

Elution time on HPLC: 16.9 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 18

(Synthesis method Q): Preparation of des (1-5) -benzoyl- [6Ψ7, CH2O, Arg (Me) 9, Trp10] MS10 (Compound No. 421)

After dissolving 1.80 g of Z-Phe in 20 mL of MeOH, 73 mg of DMAP and 1.38 g of WSCD HCl were added to the solution at 0 ° C. and stirred at 4 ° C. for 12 hours. The solvent was concentrated and the concentrate was dissolved in AcOEt. The solution was then washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated to give Z-Phe-OMe as an oil. After dissolving in 20 mL of dry THF, 196 mg of LiBH ₄ was added to the solution and stirred at room temperature for 15 hours. The solvent was concentrated and the residue was dissolved in AcOEt and the solution was washed with 1N aqueous HCl solution, saturated aqueous NaHCO ₃ solution and then saturated aqueous NaCl solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and ether-petroleum ether was added to the concentrate to give 1.45 g (85% yield) of Z-Phe-ol as a precipitate. After 60 mg of 60% NaH is suspended in 10 mL of dry THF, 285 mg of Z-Phe-ol, 264 mg of 18-crown-6 and 1.48 mL of tert-butyl bromoacetate are added to the solution at 0 ° C. Was added. Returning to room temperature, the mixture was stirred for 15 hours. After distilling off the solvent in vacuo, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to give 217 mg (yield 54%) of Z-PheΨ (CH ₂ O) Gly-OBu ^t as an oil. . After dissolving 160 mg of Z-PheΨ (CH ₂ O) Gly-OBu ^t in 20 mL of MeOH, 10% Pd-C was added to the solution and catalytic hydrogenation under nitrogen flow for 3 hours. The catalyst was removed by filtration, the solvent was concentrated and then dried. The concentrate was dissolved in 15 mL of DCM and 114 mg of Fmoc-Cl and 139 μl of DIEA were added to the solution and stirred for 12 hours. After distilling off the solvent, the residue was dissolved in AcOEt and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography. Diethyl ether-petroleum ether was added to give 150 mg (yield 77%) of Fmoc-PheΨ (CH ₂ O) Gly-OBu ^t as precipitate. To the precipitate, 31 mg (15 μmol) of H-LeuArg (Me, Boc ₂ ) Trp (Boc) -Rink Amide MBHA resin obtained in the same manner as in Example 15, 19 mg of Fmoc-PheΨ (CH ₂ O) Gly-OH (prepared by treatment of Fmoc-PheΨ (CH ₂ O) Gly-OBu ^t with 50% TFA / DCM for 1 hour), 180 μl 0.5M HOAt, 42 mg PyBrop and 47 μl DIEA was added. The mixture was shaken for 18 hours. After washing the resin, 5 mL of 20% piperidine / DMF was added to the resin and stirred for 30 minutes at room temperature. After washing the resin, 9 μl of benzoyl chloride, 13 μl of DIEA and 1 mL of DMF 1 were added to the resin and stirred at room temperature for 2 hours. After washing and drying the resin, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added to the resin and stirred for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (60 minutes) was performed using 75 / 25-65 / 35. Fractions containing product were collected and lyophilized to yield 2.5 mg of white powder.

Mass spectrum (M + H) ⁺ 782.2 (calculated 782.4)

Elution time on HPLC: 22.1 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-0 / 50 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 19

(Synthesis method R): Preparation of des (1-7) -dibenzylaminocarbamoylacetyl- [Arg (Me) 9, Trp10] MS10 (Compound No. 434)

After dissolving 1.54 mL of mono-tert-butyl malonate, 1.08 g of fluorenylmethanol and 61 mg of DMAP in 20 mL of DCM 20, 1.15 g of WSCD HCl was added to the solution, and at room temperature for 24 hours. Was stirred. The solvent was distilled off under vacuum and the residue was dissolved in AcOEt. The solution was then washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and the concentrate was purified by flush column chromatography to give 1.62 g (96% yield) of tert-butyl fluorenylmethyl malonate. In 20 mL of TFA, 61 mg of tert-butyl fluorenylmethyl malonate were dissolved and the solution was stirred at room temperature for 2 hours. After distilling off the solvent under vacuum, the residue was dissolved in AcOEt and washed with saturated aqueous NaCl solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and purified by flush column chromatography to give 850 mg (yield 67%) of mono-fluorenylmethyl malonate. 5 mL of 20% piperidine / DMF was added to 46 mg (15 μmol) of Fmoc-LeuArg (Me, Boc ₂ ) Trp (Boc) -Rink Amide MBHA resin prepared in the same manner as in Example 15. The solution was shaken for 30 minutes at room temperature. After washing the resin, 42 mg of mono-fluorenylmethyl malonate, 70 mg of PyBrop, 300 μl of 0.5M HOAt / DMF, 52 μl of DIEA and 1 mL of DMF were added to the resin and the mixture was added. Shake for 15 hours. After repeating this procedure twice, 8 μl of Ac 2 O, 5 μl of DIEA and 2 mL of DCM were added and stirred at room temperature for 30 minutes. After the resin was washed and then dried, 5 mL of 20% piperidine / DMF was added to half of the resin and stirred at room temperature for 30 minutes. After washing the resin, 13 mg of dibenzylhydrazine, 28 mg of PyBrop, 120 μl of 0.5M HOAt / DMF, 21 μl of DIEA, and 1 mL of DMF were added and shaken for 15 hours. After the resin was washed and then dried, 200 μl of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added to the resin and stirred for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (120 min) was performed at 83 / 17-63 / 37. Fractions containing the product were collected and lyophilized to yield 21.6 mg of white powder.

Mass spectrum (M + H) ⁺ 767.6 (calculated 767.4)

Elution time on HPLC: 14.5 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 20

(Synthesis method S): Preparation of des (1-5) -4-pyridinecarbonyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 436)

After swelling 340.1 mg (0.1 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin in DMF, the resin was added to 20 mL of 20% piperidine / DMF. The solution was treated for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF and treated with 155.0 mg (0.4 mmol) of Fmoc-Phe-OH, 63.6 μl (0.4 mmol) of DIPCDI and 0.8 mL (0.4 mmol) of 0.5M HOAt / DMF solution at room temperature for 90 minutes. Phe was introduced. After Fmoc deprotection of the obtained Fmoc-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin, 49.2 mg (0.4 mmol) of 4-pyridinecarboxylic acid, 63.6 μl (0.4 mmol) of DIPCDI and 0.8 mL (0.4 mmol) of 0.5 M HOAt / DMF solution were treated for 90 minutes at room temperature. The resin was then washed and dried to yield 353.5 mg of 4-pyridinecarbonyl-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. To the resulting resin, 3.5 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA and Eluent B in water on preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm): Eluent A / with 0.1% TFA-containing acetonitrile B: Linear density gradient elution (60 minutes) was performed at a flow rate of 15 ml / min using 79 / 21-69 / 31. Fractions containing product were collected and lyophilized. The obtained white powder was dissolved in 6 mL of water, and 200 μl of ion-exchange resin BioRAD AG1 × 8 AcO ⁻ type was added to the solution. While stirring the solution manually, the reaction solution was left for 1 hour. The solution was filtered through a membrane filter to remove the resin, yielding 21.6 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 797.8 (calculated 797.4)

Elution time on HPLC: 8.8 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 21

(Synthesis method T): Preparation of des (1-3) -3-phenylpropionyl- [AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 499)

Amide MBHA 수지를 수득하였다. 수득된 수지를 Fmoc 탈보호화한 후, 30.0 mg (0.2 mmol) 의 페닐프로피온산, 31.8 ㎕ (0.2 mmol) 의 DIPCDI 및 0.4 mL (0.2 mmol) 의 0.5M HOAt/DMF 용액으로 실온에서 90 분간 처리하였다. 그 후, 상기 수지를 세정하고, 건조시켜, 209.6 mg 의 3-페닐프로피오닐-Phe-AzaGly-Leu-Arg(Boc₂,Me)-Trp(Boc)-Rink Amide MBHA 수지를 수득하였다. 상기 수득한 수지에, 1.5 mL 의 TFA/PhSMe/m-크레졸/H₂O/TIS/EDT (80/5/5/5/2.5/2.5) 를 첨가하고, 혼합물을 90 분간 교반하였다. 상기 반응 용액에 디에틸 에테르를 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 이 절차를 반복하여 2 회 세정하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC SH-343-5 S-5, 120A 컬럼 (20 x 250 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 71/29-61/39 를 이용하여 유속 8 ml/분으로 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하였다. 수득한 백색 분말을 10 mL 의 물에 용해시키고, 이온교환수지 BioRAD AG1 x 8 AcO^- 형 125 ㎕ 을 상기 용액에 첨가하였다. 용액을 간혹 수동으로 교반하면서, 반응 용액을 1 시간동안 방치하였다. 상기 용액을 막필터로 여과하여 수지를 제거하고, 5.2 mg 의 백색 분말을 아세트산염으로서 수득하였다.After swelling 170.1 mg (0.05 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin in DMF, the resin was added to 5 mL of 20% piperidine / DMF. The solution was treated for 20 minutes to remove Fmoc groups. The resulting resin was washed with DMF and treated with 77.5 mg (0.2 mmol) of Fmoc-Phe-OH, 31.8 μl (0.2 mmol) of DIPCDI, and 0.4 mL (0.2 mmol) of 0.5M HOAt / DMF solution at room temperature for 90 minutes. Phe was introduced. In the same way, Ser ( ^t Bu) and Asn (Trt) are introduced,

Amide MBHA resin was obtained. The obtained resin was Fmoc deprotected and then treated with 30.0 mg (0.2 mmol) of phenylpropionic acid, 31.8 μl (0.2 mmol) of DIPCDI and 0.4 mL (0.2 mmol) of 0.5M HOAt / DMF solution for 90 minutes at room temperature. The resin was then washed and dried to give 209.6 mg of 3-phenylpropionyl-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. To the obtained resin, 1.5 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Subsequently, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: 71 Linear density gradient elution (60 minutes) was carried out at / 29-61 / 39 with a flow rate of 8 ml / min. Fractions containing product were collected and lyophilized. The obtained white powder was dissolved in 10 mL of water, and 125 [mu] l of ion exchange resin BioRAD AG1 x 8 AcO ^- type was added to the solution. While stirring the solution manually, the reaction solution was left for 1 hour. The solution was filtered through a membrane filter to remove the resin and 5.2 mg of white powder was obtained as acetate.

Mass spectrum (M + H) ⁺ 1025.3 (calculated 1025.5)

Elution time on HPLC: 13.6 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 22

(Synthesis method U): Preparation of des (1-5) -benzoyl- [AzaPhe6, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 431)

After 500 mg (2.56 mmol) of benzylhydrazine. 2HCl was dissolved in DCM, the solution was cooled to -78 ° C on dry ice. 727.1 mg (3.33 mmol) of Boc ₂ O and 0.982 ml (5.64 mmol) of DIEA were then added to the solution. Dry ice was removed and the mixture was stirred for 30 minutes. After confirming that the reaction proceeded by TLC, 327 µl (2.82 mmol) of benzoyl chloride and 580.4 µl (3.33 mmol) of DIEA were added to the mixture, followed by stirring at room temperature overnight. Citric acid crystals were added to the reaction solution, and the mixture was concentrated. To the mixture was added 10% citric acid aqueous solution. The precipitated residue was extracted with AcOEt and the extract was washed with 10% aqueous citric acid solution, 5% aqueous NaHCO ₃ solution and then saturated aqueous NaCl solution, and then dried over anhydrous Na ₂ SO ₄ . The obtained residue was crystallized from ether-hexane (1: 1) to give 435.5 mg of white crystals.

After swelling 46.3 mg (0.015 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -NH-Rink Amide MBHA resin in DMF, the resin was added to 5 mL of 20% piperidine. Fmoc groups were removed by treatment with / DMF solution for 20 minutes. The obtained resin was washed with DMF and treated with 3.65 mg (0.023 mmol) of CDI in THF for 1 hour at room temperature. Separately, 32.6 mg (0.1 mmol) of the white powder were treated with 0.3 mL of 4N HCl / dioxane for 1 hour. The solvent is then distilled off and the residue is washed with ether. The obtained residue was dissolved in THF and 17.4 μl (0.1 mmol) of DIEA was added to the solution. The resulting solution was added to the resin and stirred overnight. The resin was washed and dried to give 29.5 mg of Benzoyl-AzaPhe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -NH-Rink Amide MBHA resin. To the obtained resin, 0.5 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then, 0.1% TFA and eluent B in water on preparative HPLC using YMC SH-343-5 S-5, 120A column (20 × 250 mm) Eluent A / B: 0.1% TFA-containing acetonitrile: 66 Linear density gradient elution (60 minutes) was carried out at / 34-56 / 44 with a flow rate of 8 ml / min. Fractions containing the product were collected and lyophilized to yield 3.2 mg of white powder.

Mass spectrum (M + H) ⁺ 797.7 (calculated 797.4)

Elution time on HPLC: 15.3 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A with eluent A / B = 80 / 20-30 / 70 with eluent A / B with 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 23

(Synthesis method V): Preparation of des (1)-[D-Tyr2, D-Pya (4) 3, AzaGly7, Arg (Me) 9,10Ψ, CSNH] MS10 (Compound No. 548)

수지를 수득하였다. 상기 수지에, 10 mL 의 AcOH/TFE/DCM (1/1/8) 을 첨가하고, 30 분간 진탕하였다. 상기 수지를 여과로 제거하고, 용매를 농축하였다. 잔류물을 클로로포름에 용해시키고, 생성된 용액을 포화 NaCl 수용액으로 세정하였다. Na₂SO₄ 로 건조시킨 후, 용매를 농축하고, 상기 농축물에 AcOEt-디에틸 에테르를 첨가하여 320 mg (수율 98%) 의

를 침전물로서 수 득하였다. 한편, 264 mg (1 mmol) 의 Boc-Phe-NH₂ 에 빙냉하에서 5 mL 의 4N HCl/AcOEt 을 첨가하고, 30 분간 교반하였다. 용매를 증류제거하고, 그 후 에테르를 첨가하여 침전시켰다. 침전물을 20 mL 의 DMF 에 용해시키고, 상기 용액에 455 mg 의 Fmoc-Orn(Boc), 540 mg 의 HOBt, 382 mg 의 WSCD.HCl 및 348 ㎕ 의 DIEA 를 첨가하고, 6 시간동안 교반하였다. 용매를 진공하에서 증류제거한 후, 잔류물을 에틸 아세테이트에 용해시키고, 상기 용액을 1N HCl 수용액, 포화 NaHCO₃ 수용액 및 그 후 포화 NaCl 수용액으로 세정하였다. Na₂SO₄ 로 건조시킨 후, 용매를 농축하였다. 에테르-석유 에테르를 상기 농축물에 첨가하여 594.4 mg (수율 99%) 의 Fmoc-Orn(Boc)-Phe-NH₂ 를 침전물로서 수득하였다. 빙냉하에서, 생성물 132 mg 에 5 mL 의 4N HCl/AcOEt 을 첨가하고, 30 분간 교반하였다. 용매를 증류제거한 후, 에테르를 첨가하여, 111.1 mg (수율 94%) 의 Fmoc-Orn-Phe-NH₂.HCl 을 침전물로서 수득하였다. 상기 침전물을 3 mL 의 클로로포름/TFE (3/1) 에 용해시키고, 상기 용액에 참조예 1 에서 수득한 N-메틸-N,N'-비스-Boc-1-구아닐피라졸 194 mg 및 105 ㎕ 의 DIEA 를 첨가하고, 24 시간동안 교반하였다. 용매를 증류제거한 후, 에테르-석유 에테르를 첨가하여, 108.5 mg (수율 72%) 의 Fmoc-Arg(Boc₂,Me)-Phe-NH₂ 를 침전물로서 수득하였다. 5 mL 의 THF 에, 38 mg 의 생성물을 용해시키고, 상기 용액에 142 mg 의 Lawesson 시약을 첨가하고, 15 시간동안 교반하였다. 용매를 진공하에서 증류제거한 후, 잔류물을 에틸 아세테 이트에 용해시키고, 상기 용액을 NaHCO₃ 수용액 및 그 후 포화 NaCl 수용액으로 세정하였다. Na₂SO₄ 로 건조시킨 후, 용매를 농축하였다. 플러시 컬럼 크로마토그래피로 정제 후, 에테르-석유 에테르를 첨가하여, 18.7 mg (수율 48%) 의 Fmoc-Arg(Me,Boc₂)-PheΨ(CSNH)-NH₂ 를 침전물로서 수득하였다. 11 mg 의 생성물에, 1 mL 의 10% DEA/DMF 를 첨가하고, 혼합물을 2 시간동안 교반하였다. 용매를 증류제거한 후, 잔류물을 1 mL 의 DMF 에 용해시키고, 상기 용액에 앞서 수득한

18 mg, 7.6 mg 의 HOBt, 5.4 mg 의 WSCD.HCl 및 4.9 ㎕ 의 DIEA 를 첨가하고, 15 시간동안 교반하였다. 용매를 증류제거하고, 잔류물에 에테르를 첨가하여 침전시켰다. 상기 침전물에, 1 mL 의 TFA/PhSMe/m-크레졸/TIS/EDT (85/5/5/2.5/2.5) 을 첨가하고, 혼합물을 2 시간동안 교반하였다. 에테르를 상기 반응 용액에 첨가하고, 생성된 침전물을 원심분리하고, 상청액을 제거하였다. 세정을 위해 이 절차를 반복하였다. 잔류물을 아세트산 수용액으로 추출하고, 추출물을 여과하여 수지를 제거하였다. 그 후, YMC D-ODS-5-ST S-5 120A 컬럼 (20 x 150 mm) 을 사용한 분취용 HPLC 상에서 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 82/18-72/28 을 이용하여 선형 밀도 구배 용출 (60 분) 을 수행하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 0.9 mg 의 백색 분말을 수득하였다.Fmoc-Leu-OH was introduced into the commercial 2-chlorotritylchloride resin. After Fmoc deprotection, 5 mL of THF and 162 mg of CDI were added to the 403 mg of Fmoc-Leu-O-Clt resin obtained (about 0.62 mmol / g). The mixture was shaken for 1 hour. 97 μl of hydrazine monohydrate was added to the system, the mixture was shaken for 2 hours, and then the resin was washed. To the resin, 581 mg of Fmoc-Phe, 699 mg of PyBrop, 3 mL of 0.5M HOAt / DMF solution and 784 μl of DIEA were added and shaken for 12 hours. After washing the resin, the peptide chain was stretched to ABI 433A to obtain 0.47 g of

A resin was obtained. 10 mL of AcOH / TFE / DCM (1/1/8) was added to the resin, followed by shaking for 30 minutes. The resin was removed by filtration and the solvent was concentrated. The residue was dissolved in chloroform and the resulting solution was washed with saturated aqueous NaCl solution. After drying with Na ₂ SO ₄ , the solvent was concentrated and AcOEt-diethyl ether was added to the concentrate to give 320 mg (yield 98%) of the concentrate.

Was obtained as a precipitate. On the other hand, 5 mL of 4N HCl / AcOEt was added to 264 mg (1 mmol) of Boc-Phe-NH ₂ under ice cooling, followed by stirring for 30 minutes. The solvent was distilled off and then precipitated by addition of ether. The precipitate was dissolved in 20 mL of DMF and 455 mg of Fmoc-Orn (Boc), 540 mg of HOBt, 382 mg of WSCD.HCl and 348 μl of DIEA were added and stirred for 6 hours. After distilling off the solvent in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with 1N HCl aqueous solution, saturated NaHCO ₃ aqueous solution and then saturated NaCl aqueous solution. After drying over Na ₂ SO ₄ , the solvent was concentrated. Ether-petroleum ether was added to the concentrate to give 594.4 mg (99% yield) of Fmoc-Orn (Boc) -Phe-NH ₂ as a precipitate. Under ice-cooling, 5 mL of 4N HCl / AcOEt was added to 132 mg of the product, and stirred for 30 minutes. After distilling off the solvent, ether was added to give 111.1 mg (yield 94%) of Fmoc-Orn-Phe-NH ₂ .HCl as a precipitate. The precipitate was dissolved in 3 mL of chloroform / TFE (3/1) and 194 mg and 105 of N-methyl-N, N'-bis-Boc-1-guanypyrazole obtained in Reference Example 1 in the solution. Μl of DIEA was added and stirred for 24 h. After distilling off the solvent, ether-petroleum ether was added to give 108.5 mg (72% yield) of Fmoc-Arg (Boc ₂ , Me) -Phe-NH ₂ as a precipitate. In 5 mL of THF, 38 mg of the product was dissolved and 142 mg of Lawesson reagent was added to the solution and stirred for 15 hours. After distilling off the solvent under vacuum, the residue was dissolved in ethyl acetate and the solution was washed with aqueous NaHCO ₃ solution and then saturated aqueous NaCl solution. After drying over Na ₂ SO ₄ , the solvent was concentrated. After purification by flush column chromatography, ether-petroleum ether was added to give 18.7 mg (yield 48%) of Fmoc-Arg (Me, Boc ₂ ) -PheΨ (CSNH) -NH ₂ as a precipitate. To 11 mg of product, 1 mL of 10% DEA / DMF was added and the mixture was stirred for 2 hours. After distilling off the solvent, the residue was dissolved in 1 mL of DMF and obtained prior to the solution.

18 mg, 7.6 mg HOBt, 5.4 mg WSCD.HCl and 4.9 μl DIEA were added and stirred for 15 hours. The solvent was distilled off and precipitated by addition of ether to the residue. To the precipitate, 1 mL of TFA / PhSMe / m-cresol / TIS / EDT (85/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 2 hours. Ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated for cleaning. The residue was extracted with an aqueous acetic acid solution and the extract was filtered to remove the resin. Then 0.1% TFA in water and eluent B on preparative HPLC using a YMC D-ODS-5-ST S-5 120A column (20 × 150 mm) Eluent A / B using 0.1% TFA-containing acetonitrile: Linear density gradient elution (60 minutes) was performed using 82 / 18-72 / 28. Fractions containing the product were collected and lyophilized to yield 0.9 mg of white powder.

Mass spectrum (M + H) ⁺ 1181.5 (calculated 1181.6)

Elution time on HPLC: 14.9 min

Elution condition:

Column: Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 100 / 0-0 / 50 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 24

(Synthesis method W): Preparation of Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 550)

After swelling 5 g (0.4 mmol / g) of commercially available Rink Amide MBHA resin in DMF, the resin was treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 4.213 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt / DMF solution. Trp (Boc) was introduced by treatment at room temperature for 90 minutes. In the same manner, Orn (Mtt) was introduced to give 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The obtained resin was washed with DCM and swollen, then 50 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, to remove the Mtt groups.

The resulting Fmoc-Orn-Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 25 mL of DCM-TFE (4: 1) and 1.946 g (6 mmol) of N-methyl-N, N'-bis-Boc-1-sphere obtained in Reference Example 1 were obtained. Anipyrazole was added. DIEA was added to the mixture to adjust the pH of the solution to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. Thus obtained Fmoc group was removed from Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin (2 mmol) and H-Leu-Arg (Boc ₂ , Me) -Trp (Boc)- Rink Amide MBHA resin (2 mmol) was obtained.

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl were suspended in 20 mL of DMF. Under ice-cooling, a suspension of 297 mg (8 mmol) of CDI in 20 mL of THF and then 2.787 mL (16 mmol) of DIEA in 20 mL of THF was added and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to give 6.394 g of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin.

수지를 5%-DIEA/DMF 용액으로 중화시키고, DMF 로 세정하였다. 그 후, 상기 수지를 1.590 g (4 mmol) 의 Fmoc-Thr(^tBu)-OH, 0.636 mL (4 mmol) 의 DIPCDI 및 8 mL (4 mmol) 의 0.5M HOAt/DMF 로 실온에서 90 분간 처리하여 Thr(^tBu) 를 도입하였다. 이어서, 30 mL 의 20% 피페리딘/DMF 용액으로의 20 분간 처리에 의한 Fmoc 탈보호화 및 Thr(^tBu) 의 도입과 유사한 DIPCDI/HOAt 방법에 의한 축합을 반복하여, Asn(Trt), _D-Trp(Boc), 및 _D-Tyr(^tBu) 을 도입하여,

R ink Amide MBHA 수지를 수득하였다. 수득된 수지를 30 mL 의 20% 피페리딘/DMF 용액으로 20 분간 처리하여 Fmoc 기를 제거하였다. 수득된 수지를 세정하여,

-Rink Amide MBHA 수지를 수득하였다. 수득된 수지를 20 mL 의 DMF 중의 188.7 ㎕ (2 mmol) 의 Ac₂O 및 348.4 ㎕ (2 mmol) 의 DIEA 로 실온에서 30 분간 처리하여 N 말단을 아세틸화하였다. 상기 수지를 그 후 세정 및 건조하여, 4.168 g 의

-Rink Amide MBHA 수지를 수득하였다.3.197 g (1 mmol) of the obtained resin was swollen in DMF, and then the resin was treated with 30 mL of 20% piperidine / DMF solution for 20 minutes to remove the Fmoc group. The obtained resin was washed with DMF, and the resin was washed with 1.806 g (4 mmol) of Trt-Phe-OH.0.5AcOEt, 2.086 g (4 mmol) of PyAOP, 8 mL (4 mmol) of 0.5M HOAt / DMF and Treatment with 2.787 mL (16 mmol) of DIEA at room temperature for 90 minutes yielded Trt-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin Phe. After washing with the obtained resin DCM and swelling, 30 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Trt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, removing the Trt groups. Obtained

The resin was neutralized with 5% -DIEA / DMF solution and washed with DMF. The resin was then treated with 1.590 g (4 mmol) of Fmoc-Thr ( ^t Bu) -OH, 0.636 mL (4 mmol) of DIPCDI and 8 mL (4 mmol) of 0.5 M HOAt / DMF at room temperature for 90 minutes. Thr ( ^t Bu) was introduced. Condensation was then repeated by DIPCDI / HOAt method similar to Fmoc deprotection by treatment with 30 mL of 20% piperidine / DMF solution and introduction of Thr ( ^t Bu), followed by Asn (Trt), _D By introducing -Trp (Boc), and _D -Tyr ( ^t Bu),

R ink Amide MBHA resin was obtained. The resulting resin was treated with 30 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed,

-Rink Amide MBHA resin was obtained. The resulting resin was treated with 188.7 μl (2 mmol) of Ac ₂ O and 348.4 μl (2 mmol) of DIEA in 20 mL of DMF at room temperature for 30 minutes to acetylate the N terminus. The resin was then washed and dried to form 4.168 g

-Rink Amide MBHA resin was obtained.

To half of the resin obtained, ie 2.111 g, 15 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the mixture was 90 Stirred for a minute. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. The residue was extracted with an aqueous acetic acid solution, the extract was filtered to remove the resin, and then lyophilized to give crude peptide powder. For half of the remaining resin, deprotection was performed under the same conditions to give a total of about 650 mg of crude peptide powder. About 50 mg of each of the crude peptides obtained was subjected to 0.1% TFA and eluent B in water on preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm): 0.1% TFA- Eluent A / B using acetonitrile containing: 71 / 29-61 / 39, and purified by continuous application of linear density gradient elution (60 minutes) at a flow rate of 15 ml / min. Fractions containing product were collected and lyophilized to yield 255.5 mg of white powder as a purified sample.

All of the white powder was dissolved in 200 mL of an aqueous acetonitrile solution, and 492 μl of the ion exchange resin AG1 x 8 AcO ^- type obtained by converting the commercially available BioRAD AG1 x 8 Cl ^- type to the acetate type by a conventional method. Was added. The reaction solution was left for 1 hour while stirring the reaction solution occasionally. The solution was concentrated to remove as much acetonitrile as possible. The concentrate was then filtered through a membrane filter and lyophilized to yield 225.3 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 1298.7 (calculated 1298.6)

Elution time on HPLC: 15.6 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Eluent A using eluent A / B = 80 / 20-30 / 70 with eluent A in 0.1% TFA and 0.1% TFA in water (25 min)

Flow rate: 1.0 ml / min.

Example 25

Preparation of Ac-des (1)-[D-Tyr2, D-Pya (4) 3, Thr5, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 562)

After swelling 5.455 g (0.455 mmol / g) of a commercial Rink Amide MBHA resin in DMF, the resin was treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 6.319 g (12 mmol) of Fmoc-Trp (Boc) -OH, 1.908 mL (12 mmol) of DIPCDI and 24 mL (12 mmol) of 0.5M HOAt / DMF solution. The mixture was treated at room temperature for 90 minutes to introduce Trp (Boc) to obtain Fmoc-Trp (Boc) -Rink Amide MBHA resin. In the same manner, Orn (Mtt) was introduced to give 3 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The obtained resin was washed with DCM and swollen, then 75 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, to remove the Mtt groups.

The resulting Fmoc-Orn-Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 40 mL of DCM-TFE (4: 1) and 2.919 g (9 mmol) of N-methyl-N, N'-bis-Boc-1-sphere obtained in Reference Example 1 were obtained. Anipyrazole was added. DIEA was added to the mixture to adjust the pH of the solution to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. Fmoc group was removed from Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin (2 mmol) thus obtained, and H-Leu-Arg (Boc 2, Me) -Trp (Boc)- Rink Amide MBHA resin (2 mmol) was obtained.

Separately, 3.489 g (12 mmol) of Fmoc-NHNH2.HCl were suspended in 30 mL of DMF. Under ice cooling, to this suspension was added a suspension of 1.849 mg (11.4 mmol) of CDI in 20 mL of THF and then 4.181 mL (24 mmol) of DIEA and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to yield 8.2496 g of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin.

수지를 수득하였다. 수득된 수지를 Fmoc-탈보호화하였다. 그 후, 상기 수지를 1.476 g (3.8 mmol) 의 Fmoc-_D-Pya(4)-OH, 2.086 mg (4 mmol) 의 PyAOP, 8 mL 의 0.5 M HOAt/DMF (4 mmol) 및 2.439 mL 의 DIEA (14 mmol) 로 실온에서 90 분간 처리하여 _D-Pya(4) 를 도입하였다. 이어서, Thr(^tBu) 의 도입과 유사한 DIPCDI/HOAt 방법에 의해, 상기 수지에 _D-Tyr(^tBu) 를 도입하여,

-Rink Amide MBHA 수지를 수득하였다. 수득된 수지를 30 mL 의 20% 피페리딘/DMF 용액으로 20 분간 처리하여 Fmoc 기를 제거하였다. 수득된 수지를 세정하여

Rink Amide MBHA 수지를 수득하였다. 수득된 수지를 188.7 ㎕ (2 mmol) 의 Ac₂O 및 20 mL 의 DMF 중의 348.4 ㎕ (2 mmol) 의 DIEA 로 실온에서 30 분간 처리하여 N 말단을 아세틸화하였다. 상기 수지를 그 후 세정 및 건조하여, 1 mmol 의

Rink Amide MBHA 수지를 수득하였다.After swelling 2.646 g (1 mmol) of the obtained resin in DMF, the resin was treated with 30 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 1.630 g (4 mmol) of Trt-Phe-OH, 2.086 g (4 mmol) of PyAOP, 8 mL (4 mmol) of 0.5M HOAt / DMF and 2.787 mL ( 16 mmol) of DIEA at room temperature for 90 minutes to obtain Trt-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin Phe. The obtained resin was washed with DCM and swollen, then 30 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Trt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, removing the Trt groups. The obtained H-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DMF solution and washed with DMF. The resin was then treated with 1.590 g (4 mmol) of Fmoc-Thr ( ^t Bu) -OH, 0.636 mL (4 mmol) of DIPCDI and 8 mL (4 mmol) of 0.5 M HOAt / DMF at room temperature for 90 minutes. Thus, Thr ( ^t Bu) was introduced. Subsequently, condensation by a DIPCDI / HOAt method similar to the introduction of Thr ( ^t Bu) and Fmoc deprotection by 20 minutes of treatment with 30 mL of 20% piperidine / DMF solution was carried out,

A resin was obtained. The obtained resin was Fmoc-deprotected. The resin was then added to 1.476 g (3.8 mmol) of Fmoc- _D- Pya (4) -OH, 2.086 mg (4 mmol) of PyAOP, 8 mL of 0.5 M HOAt / DMF (4 mmol) and 2.439 mL of DIEA. Treatment with (14 mmol) at room temperature for 90 minutes introduced _D- Pya (4). Subsequently, _D- Tyr ( ^t Bu) was introduced into the resin by a DIPCDI / HOAt method similar to the introduction of Thr ( ^t Bu),

-Rink Amide MBHA resin was obtained. The resulting resin was treated with 30 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed

Rink Amide MBHA resin was obtained. The obtained resin was treated with 188.7 μl (2 mmol) of Ac ₂ O and 348.4 μl (2 mmol) of DIEA in 20 mL of DMF at room temperature for 30 minutes to acetylate the N terminus. The resin was then washed and dried to give 1 mmol of

Rink Amide MBHA resin was obtained.

To the obtained resin, 30 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged and the supernatant was removed. This procedure was repeated and washed twice. After the residue was extracted with an aqueous acetic acid solution, the extract was filtered to remove the resin and lyophilized to give 949.0 mg of crude peptide powder. About 50 mg of each of the crude peptides obtained was subjected to preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm), Eluent A: 0.05% TFA in water and Eluent B: Initial eluent A / B: 90/10 with 0.05% TFA-containing acetonitrile, A / B: 75/25 which took 7 minutes to increase concentration, and Eluent A / B: 75 / 25- Purification with linear density gradient elution with 65/35 (60 min) followed by continuous application at a flow rate of 15 ml / min. Fractions containing product were collected and lyophilized to give 361.1 mg of white powder as a purified sample.

All of the obtained white powder was dissolved in 200 mL of aqueous acetonitrile solution, and 1.434 mL of the ion exchange resin AG1 x 8 AcO ^- type obtained by converting the commercial BioRAD AG1 x 8 Cl ^- type to the acetate type in a conventional manner. To the solution. The reaction solution was left for 1 hour while stirring the reaction solution occasionally. The solution was concentrated to remove as much acetonitrile as possible. The concentrate was then filtered through a membrane filter and lyophilized to yield 309.3 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 1260.4 (calculated 1260.4)

Elution time on HPLC: 15.5 min

Elution condition:

Column Wakosil-II 5C18 HG (4.6 x 100 mm)

Eluent: linear density gradient elution using eluent A / B = 100 / 0-50 / 50 with 0.1% TFA in water as eluent A and 0.1% TFA as eluent B (25 min)

Flow rate: 1.0 ml / min.

Example 26

Preparation of Ac-des (1)-[D-Tyr2, D-Trp3, Thr5, AzaGly7, Arg (Me) 9] MS10 (Compound No. 571)

After swelling 2.5 g (0.4 mmol / g) of commercially available Rink Amide MBHA resin in DMF, the resin was treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 1.550 g (4 mmol) of Fmoc-Phe-OH, 0.636 mL (4 mmol) of DIPCDI and 8 mL (4 mmol) of 0.5M HOAt / DMF solution at room temperature. Phe was introduced by treatment for 90 minutes to obtain a Fmoc-Phe-Rink Amide MBHA resin. In the same manner, Orn (Mtt) was introduced to obtain 1 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The resulting resin was washed with DCM and swollen, then 25 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, to remove the Mtt groups.

The resulting Fmoc-Orn-Phe-Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 25 mL of DCM-TFE (4: 1) and 0.973 g (3 mmol) of N-methyl-N, N'-bis-Boc-1-guanylpyrazole obtained in Reference Example 1 Was added to the resin. DIEA was added to the mixture to adjust the pH of the solution to 10, and the mixture was shaken for 15 hours to obtain Fmoc-Arg (Boc ₂ , Me) -Phe-Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. Thus obtained _{Fmoc-Leu-Arg (Boc 2} , Me) -Phe-Rink Amide MBHA resin (1 mmol) Fmoc H-Leu -Arg (Boc 2, Me) to remove a group from the Rink Amide MBHA resin--Phe (1 mmol) was obtained.

Separately, 1.163 g (4 mmol) of Fmoc-NHNH ₂ .HCl were suspended in 10 mL of DMF. Under ice-cooling, 0.568 mg (3.5 mmol) of CDI suspension in 10 mL of THF and then 1.307 mL (7.5 mmol) of DIEA were added to the suspension and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Phe-Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to give 3.134 g of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Phe-Rink Amide MBHA resin.

Rink Amide MBHA 수지를 수득하였다. 이 생성물에, 5 mL 의 DMF, 111 mg 의 AcONB 및 44 mL 의 DIEA 를 첨가하고, 상기 수지를 2 시간동안 진탕하였다. 상기 수지를 세정 후 건조하여, 0.78 g 의

Rink Amide MBHA 수지를 수득하였다. 상기 수지에, 6 mL 의 TFA/티오아니솔/m-크레졸/H₂O/TIS/EDT (80/5/5/5/2.5/2.5) 를 첨가하고, 상기 수지를 2 시간동안 진탕하였다. 상기 수지를 여과로 제거한 후, 용매를 증류제거하였다. 디에틸에테르를 첨가하여, 침전시켰다. 원심분리 후, 상청액 제거에 의한 세정을 2 회 반복하고, 잔류물을 아세테이트 용액으로 추출하였다. 수지를 여과로 제거한 후, 상기 분획을, 용출액 A: 수중 0.1% TFA 및 용출액 B: 0.1% TFA-함유 아세토니트릴을 사용한 용출액 A/B: 71/29-61/39 를 이용한 선형 밀도 구배 용출 (60 분) 로 유속 15 ml/분으로 연속적으로 YMC Pack R&D-ODS-5-B S-5, 120A 컬럼 (30 x 250 mm) 을 사용한 분취용 HPLC 에 적용하여 정제하였다. 생성물을 함유한 분획을 수집하고, 동결건조하여 백색 분말을 정제된 시료로서 수득하였다. 정제된 시료를 동결건조하였다. 553 mg 의 H-Phe-AzaGly-Leu-Arg(Boc₂,Me)-Phe-Rink Amide MBHA 수지를 사용하여 동일한 방식으로 수득한 조 펩티드를 분취용 HPLC 상에서 정제하여 총 237.6 mg 의 정제된 시료를 백색 분말로서 수득하였다.Using this resin, 1.94 g of Trt-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink obtained by condensation of Trt-Phe-OH 0.5AcOEt in the same manner as in Example 24 Amide MBHA resin was washed with DCM. After swelling, 12 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the brownish yellow coloration caused by the free Trt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, removing the Trt groups. The resin was washed to obtain 1.66 g of H-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Phe-Rink Amide MBHA resin. Using 553 mg of the obtained resin, the peptide chain was extended with the peptide synthesizer ABI-433A (Fmoc / DCC / HOBt),

Rink Amide MBHA resin was obtained. To this product, 5 mL of DMF, 111 mg of AcONB and 44 mL of DIEA were added and the resin was shaken for 2 hours. The resin was washed after drying and 0.78 g of

Rink Amide MBHA resin was obtained. To the resin was added 6 mL of TFA / thioanisole / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) and the resin was shaken for 2 hours. After the resin was removed by filtration, the solvent was distilled off. Diethyl ether was added to precipitate. After centrifugation, washing with supernatant removal was repeated twice and the residue was extracted with acetate solution. After the resin was removed by filtration, the fractions were subjected to linear density gradient elution using eluent A: 0.1% TFA in water and eluent B: eluent A / B: 71 / 29-61 / 39 using 0.1% TFA-containing acetonitrile ( 60 min) and purified by preparative HPLC using YMC Pack R & D-ODS-5-B S-5, 120A column (30 x 250 mm) continuously at a flow rate of 15 ml / min. Fractions containing product were collected and lyophilized to give white powder as a purified sample. Purified samples were lyophilized. The crude peptide obtained in the same manner using 553 mg of H-Phe-AzaGly-Leu-Arg (Boc ₂ , Me) -Phe-Rink Amide MBHA resin was purified on preparative HPLC to give a total of 237.6 mg of purified sample. Obtained as a white powder.

The obtained white powder, 236.1 mg, was dissolved in 200 mL of an aqueous acetonitrile solution and the ion exchange resin AG1 x 8 AcO ^- type 935 obtained by converting the commercial BioRAD AG1 x 8 Cl ^- form to the acetate form in a conventional manner. Μl was added to the solution. The reaction solution was left for 1 hour while stirring the reaction solution occasionally. The solution was concentrated to remove as much acetonitrile as possible. The concentrate was then filtered through a membrane filter and lyophilized to give 204.6 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 1259.5 (calculated 1259.6)

Elution time on HPLC: 13.2 min

Elution condition:

Column YMC-AM301 (4.6 x 100 mm)

Eluent: Linear density gradient elution using eluent A / B = 80 / 20-30 / 70 with 0.1% TFA in water as eluent A and 0.1% TFA as eluent B (25 min)

Flow rate: 1.0 ml / min.

Example 27

Preparation of Ac-des (1)-[D-Tyr2, D-Trp3, Alb4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 579)

After swelling 5 g (0.4 mmol / g) of commercially available Rink Amide MBHA resin in DMF, the resin was treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 4.213 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt / DMF solution. The mixture was treated at room temperature for 90 minutes to introduce Trp (Boc) to obtain Fmoc-Trp (Boc) -Rink Amide MBHA resin. In the same manner, Orn (Mtt) was introduced to give 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The obtained resin was washed with DCM and swollen, then 50 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, to remove the Mtt groups.

The resulting Fmoc-Orn-Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 25 mL of DCM-TFE (4: 1) and 1.946 g (6 mmol) of N-methyl-N, N'-bis-Boc-1-guanylpyrazole obtained in Reference Example 1 Was added to the resin. DIEA was added to the mixture to adjust the pH of the solution to 10 and the mixture was shaken for 15 hours to give Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. Fmoc group was removed from Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin (2 mmol) thus obtained, and H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) was removed. -Rink Amide MBHA resin (2 mmol) was obtained.

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl were suspended in 20 mL of DMF. Under ice-cooling, 1.297 mg (8 mmol) of CDI suspension in 20 mL of THF and then 2.787 mL (16 mmol) of DIEA in 20 mL of THF were added and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to give 2 mmol of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin.

Rink Amide MBHA 수지를 수득하였다.Thr condensation was repeated using 868 mg (0.257 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin and DCC / HOBt method using ABI 433A ( ^t Bu), Alb, _D -Trp (Boc), and _D -Tyr ( ^t Bu) Amide MBHA resin was obtained. The N-terminus of the obtained resin was acetylated by treatment with 111 mg (0.5 mmol) of AcONB and 87 μl (0.5 mmol) of DIEA in 5 mL of DMF for 10 hours at room temperature. Subsequently, the resin is washed and dried,

Rink Amide MBHA resin was obtained.

To the obtained resin, 6 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the suspension was shaken for 2 hours. After the resin was removed by filtration, the solvent was distilled off. Diethyl ether was added to precipitate. After centrifugation, washing with supernatant removal was repeated twice and the residue was extracted with acetate solution. After the resin was removed by filtration, the fraction was eluted with linear density gradient using eluent A: 0.1% TFA in water and eluent B: eluent A / B: 69 / 31-59 / 41 with 0.1% TFA-containing acetonitrile. (60 min) Purification by application to preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm), continuously at this flow rate 15 ml / min. Fractions containing the product were collected and lyophilized to give 106.5 mg of white powder as a purified sample.

All of the obtained white powder was dissolved in 100 mL of aqueous acetonitrile solution and 400 μl of the ion exchange resin AG1 x 8 AcO ^- type obtained by converting the commercial BioRAD AG1 x 8 Cl ^- type to the acetate type in a conventional manner. To the solution. The reaction solution was left for 1 hour while stirring the reaction solution occasionally. The solution was concentrated to remove as much acetonitrile as possible. The concentrate was then filtered through a membrane filter and lyophilized to yield 97.5 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 1299.5 (calculated 1299.6)

Elution time on HPLC: 19.0 min

Elution condition:

Column Wakosil-II (4.6 x 100 mm)

Eluent: linear density gradient elution using eluent A / B = 100 / 0-50 / 50 with 0.1% TFA in water as eluent A and 0.1% TFA as eluent B (25 min)

Flow rate: 1.0 ml / min.

Example 28

(Synthesis method X): Preparation of Ac-des (1)-[D-Tyr2, D-Trp3, Dap (For) 4, AzaGly7, Arg (Me) 9, Trp10] MS10 (Compound No. 585)

After swelling 5 g (0.4 mmol / g) of commercially available Rink Amide MBHA resin in DMF, the resin was treated with 50 mL of 20% piperidine / DMF solution for 20 minutes to remove Fmoc groups. The obtained resin was washed with DMF, and the resin was washed with 4.213 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.272 mL (8 mmol) of DIPCDI and 16 mL (8 mmol) of 0.5M HOAt / DMF solution. The mixture was treated at room temperature for 90 minutes to introduce Trp (Boc) to obtain Fmoc-Trp (Boc) -Rink Amide MBHA resin. In the same manner, Orn (Mtt) was introduced to give 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink Amide MBHA resin. The obtained resin was washed with DCM and swollen, then 50 mL of TFA / TIS / TFE / DCM (1/5/19/75) was added, the mixture was shaken for 10 minutes, and the solution was distilled off. This procedure was repeated until the addition of the solution disappeared the yellow coloration caused by the free Mtt groups in the TFA / TIS / TFE / DCM (1/5/19/75) solution, to remove the Mtt groups.

The resulting Fmoc-Orn-Trp (Boc) -Rink Amide MBHA resin was neutralized with 5% -DIEA / DCM solution. After washing with DCM, 25 mL of DCM-TFE (4: 1) and 1.946 g (6 mmol) of N-methyl-N, N'-bis-Boc-1-guanylpyrazole obtained in Reference Example 1 Was added to the resin. DIEA was added to the mixture to adjust the pH of the solution to 10 and the mixture was shaken for 15 hours to give Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin. Fmoc-Leu was introduced into the obtained resin in the same manner as described above. Thus obtained Fmoc group was removed from Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin (2 mmol) and H-Leu-Arg (Boc ₂ , Me) -Trp (Boc)- Rink Amide MBHA resin (2 mmol) was obtained.

Separately, 2.326 g (8 mmol) of Fmoc-NHNH ₂ .HCl were suspended in 20 mL of DMF. Under ice-cooling, 1.297 mg (8 mmol) of CDI suspension in 20 mL of THF and then 2.787 mL (16 mmol) of DIEA in 20 mL of THF were added and stirred at room temperature for 1 hour. The resulting reaction solution was added to the H-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin described above and stirred at room temperature for 15 hours. After completion of the reaction, the resin was washed and dried to give 2 mmol of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin.

-Rink Amide MBHA 수지를 수득하였다. 수득된 수지의 N-말단을, 5 mL 의 DMF 중의 111 mg (0.5 mmol) 의 AcONB 및 87 ㎕ (0.5 mmol) 의 DIEA 로 실온에서 4 시간동안 처리하여 아세틸화하였다. 이어서, 상기 수지를 세정 및 건조하여,

-Rink Amide MBHA 수지를 수득하였다.Condensation was repeated using 868 mg (0.257 mmol) of Fmoc-AzaGly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink Amide MBHA resin and using the DCC / HOBt method using ABI 433A, the introduction of ^{Thr (tB u), Dap (} Mtt), D -Trp (Boc) and _D -Tyr ^(t Bu)

-Rink Amide MBHA resin was obtained. The N-terminus of the obtained resin was acetylated by treatment with 111 mg (0.5 mmol) of AcONB and 87 μl (0.5 mmol) of DIEA in 5 mL of DMF for 4 hours at room temperature. Subsequently, the resin is washed and dried,

-Rink Amide MBHA resin was obtained.

To the obtained resin, 6 mL of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added and the suspension was shaken for 2 hours. After the resin was removed by filtration, the solvent was distilled off. Diethyl ether was added to precipitate. After centrifugation, washing with supernatant removal was repeated twice and the residue was extracted with acetate solution. After the resin was removed by filtration, the fractions were subjected to linear density gradient elution using eluent A: 0.1% TFA in water and eluent B: eluent A / B: 71 / 29-61 / 39 using 0.1% TFA-containing acetonitrile ( 60 min) Purification by application to preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 x 250 mm), continuous at this flow rate 15 ml / min. Fractions containing the product were collected and lyophilized to give 106.5 mg of white powder as a purified sample.

All of the obtained white powder was dissolved in 100 mL of aqueous acetonitrile solution and 400 μl of the ion exchange resin AG1 x 8 AcO ^- type obtained by converting the commercial BioRAD AG1 x 8 Cl ^- type to the acetate type in a conventional manner. To the solution. The reaction solution was left for 1 hour while stirring the reaction solution occasionally. The solution was concentrated to remove as much acetonitrile as possible. The concentrate was then filtered through a membrane filter and lyophilized to give 58.3 mg of white powder as acetate.

Mass spectrum (M + H) ⁺ 1284.7 (calculated 1284.6)

Elution time on HPLC: 17.9 min

Elution condition:

Column Wakosil-II (4.6 x 100 mm)

Eluent: linear density gradient elution using eluent A / B = 100 / 0-50 / 50 with 0.1% TFA in water as eluent A and 0.1% TFA as eluent B (25 min)

Flow rate: 1.0 ml / min.

The structures of the compounds synthesized in Examples 1 to 24 and the physical and chemical properties of these compounds are shown in Tables 1 to 11 below.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

 TABLE 8

TABLE 9

TABLE 10

TABLE 11

The structures of the compounds synthesized as in Examples 1 to 24 and the physicochemical properties of these compounds are shown in Table 12 below.

p [Table 12]

Formulation Example 1:

(1) compound number 305 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 305, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) into a 1 mm mesh sieve and 40 ° C. Dry in and sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 2

(1) compound number 305 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 305 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 3

(1) compound number 305 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

5.0 mg of compound number 305 and 20.0 mg of salt are dissolved in distilled water, and then water is added to the solution so that the total volume is 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Formulation Example 4:

(1) Compound No. 550 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 550, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) in a 1 mm mesh sieve, dried at 40 ° C. Sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 5

(1) Compound No. 550 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 550 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 6

(1) compound number 550 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

5.0 mg of Compound No. 550 and 20.0 mg of salt are dissolved in distilled water and then water is added to the solution to bring the total volume to 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Formulation Example 7:

(1) Compound No. 562 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 562, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) in a 1 mm mesh sieve, dried at 40 ° C. Sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 8

(1) Compound No. 562 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 562 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 9

(1) compound number 562 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

5.0 mg of Compound No. 562 and 20.0 mg of salt are dissolved in distilled water, and then water is added to the solution so that the total volume is 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Formulation Example 10:

(1) compound number 571 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 571, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) in a 1 mm mesh sieve, dried at 40 ° C. Sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 11

(1) compound number 571 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 571 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 12

(1) compound number 571 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

5.0 mg of compound number 571 and 20.0 mg of salt are dissolved in distilled water, and then water is added to the solution so that the total volume is 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Formulation Example 13:

(1) compound number 579 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 579, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) in a 1 mm mesh sieve, dried at 40 ° C. Sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 14

(1) compound number 579 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 579 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 15

(1) compound number 579 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

5.0 mg of compound number 579 and 20.0 mg of salt are dissolved in distilled water, and then water is added to the solution so that the total volume is 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Formulation Example 16:

(1) compound number 585 10.0 mg

(2) 60.0 mg of lactose

(3) corn starch 35.0 mg

(4) gelatin 3.0 mg

(5) magnesium stearate 2.0 mg

A mixture of 10.0 mg of compound number 585, 60.0 mg of lactose and 35.0 mg of corn starch is granulated with 0.03 mL of 10% aqueous gelatin solution (3.0 mg as gelatin) into a 1 mm mesh sieve, dried at 40 ° C. Sift again. The granules thus obtained are mixed with 2.0 mg of magnesium stearate and pressed. The resulting nuclear tablets are coated with sugar in an aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets are polished with yellow beeswax to obtain coated tablets.

Formulation Example 17

(1) compound number 585 10.0 mg

(2) lactose 70.0 mg

(3) corn starch 50.0 mg

(4) 7.0 mg of soluble starch

(5) magnesium stearate 3.0 mg

A mixture of 10 mg of compound 585 and 3.0 mg of magnesium stearate is granulated with 0.07 mL of an aqueous solution of soluble starch (7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. Let's do it. The mixture is compressed to give tablets.

Formulation Example 18

(1) compound number 585 5.0 mg

(2) 20.0 mg of salt

(3) distilled water to make the total volume 2 ml

After dissolving 5.0 mg of compound number 585 and 20.0 mg of salt in distilled water, water is added to the solution so that the total volume is 2.0 ml. The solution is filtered and filled into 2 ml ampoules under sterile conditions. The ampoule is sterilized and sealed to obtain an injectable solution.

Test Example 1

Assay for hOT7T175 Receptor Binding Activity

(1) Preparation of Cy-5-labeled Metastin (40-54)

Amersham Bioscience, Inc. According to the synthetic method of, a synthetic peptide was prepared having a 40-54 amino acid sequence in the amino acid sequence of metastin, in which Cy-5 was introduced through the ε-amino group of lysine located at the amino terminus and amidated at the carboxyl terminus. Using this synthetic peptide, binding inhibition test was done.

SEQ ID NO: (Cy-5)-

(2) Binding inhibition test using test compound, Cy-5-labeled metastin (40-54) and h0T7T175-expressing CHO cells

h0T7T175-expressing CHO cells were cultured in medium (nucleic acid free) containing MEM-10% dialysed serum. The medium was removed and adhered cells were washed with PBS. Then, PBS containing 5 mM EDTA was added and the cells were scraped from flask with cell scraper to scrape the cells from the flask.

After centrifugation, the cells are suspended at 1.11 × 10 ⁵ cells / ml in assay buffer (10 mM HEPES pH 7.4, 140 mM NaCl, 2.5 mM CaCl ₂ , 3 mM MgCl ₂ , 0.5% BSA, 0.01% NaN ₃ ), To the suspension was added Cy-5-labeled metastin (40-54) at a final concentration of 1 nM. To each well of a 96-well Black Clear Bottom Microplate (Applied Biosystems, Inc.), 10 μl of assay buffer containing 1% dimethylsulfoxide was added to examine the total binding, and assayed with assay buffer to investigate nonspecific binding. Add 10 μl of a diluted 10 μm non-labeled peptide (amino acid sequence identical to that of the labeled one) and add 10 μl of the test compound diluted with assay buffer to investigate the binding inhibitory activity of the test compound, and further Into each well, 90 μl of each cell suspension was injected. After 1 hour, the level of Cy-5-labeled metastin (40-54) bound to the cells was measured with the FMAT 8100 HTS system (Applied Biosystems, Inc.). Specific binding is calculated by subtracting nonspecific binding from total binding. The binding inhibitory activity of the test compound is expressed as the ratio (value obtained by subtracting the measured value in the presence of the test compound at total binding) / (specific binding). Receptor binding activities of test compounds are shown in Tables 13-18.

TABLE 13

TABLE 14

TABLE 15

TABLE 16

TABLE 17

TABLE 18

Test Example 2

Intracellular Ca Ion Concentration-Increasing Activity Assay Using FLIPR

According to the method described in JPA 2000-312590, intracellular Ca ion concentration-increasing activity was measured using FLIPR.

Using the CellPhect Transfection Kit (Amersham Pharmacia Biotech, Inc.), the expression plasmid pAK-rOT175 for animal cells was transduced into CHO / dhfr ^- cells to obtain a stable expressing cell line rOT7T175. First, 240 µl of buffer (attached to CellPhect Transfection Kit) was added to 9.6 µg of plasmid DNA dissolved in 240 µl of distilled water and stirred. After the mixture was left for 10 minutes, 480 μl of Buffer B (attached to the CellPhect Transfection Kit) was added to the mixture, which was vigorously stirred to form liposomes containing the DNA. Thereafter, 4 × 10 ⁵ CHO / dhfr ⁻ cells (obtained from ATCC) were inoculated on a 60 mm Petri dish. The cells were incubated in Ham's F-12 medium (Nissui Seiyaku Co., Ltd.) supplemented with 10% fetal bovine serum (BIO WHITTAKER, Inc.) at 37 ° C. in 5% carbon dioxide gas for 2 days, and then the liposome 480 Μl was added dropwise to the cells in the Petri dish. After incubating the cells for 6 hours at 37 ° C. under 5% carbon dioxide gas, the cells were washed twice with serum-free Ham's F-12 medium, 3 μl of 15% glycerol was added to the cells in the petri dish, and the mixture was kept for 2 minutes. Treated. The cells were washed again with serum free Ham's F-12 medium and then incubated for 15 hours in Ham's F-12 medium supplemented with 10% fetal bovine serum at 37 ° C. under 5% carbon dioxide gas. The cells were trypsinized to disperse and recovered from Petri dishes. Recovered cells were seeded in 6-well plates at 1.25 × 10 ⁴ cells / well and Dulbecco's modified Eagle's medium (DMEM) containing fetal bovine serum (JRH BIOSCIENCES, Inc.) 10% dialyzed at 37 ° C. under 5% carbon dioxide gas. Incubation was started in (Nissui Seiyaku Co., Ltd.). The plasmid-transfected transformed CHO cells grew in the medium, but the untransfected cells slowly died. The medium was exchanged on days 1 and 2 to remove dead cells. Approximately 20 colonies of transformed CHO cells that continued to grow on days 8-10 after inoculation were isolated. From the cells in these colonies, cells showing high reactivity to the ligand peptide metastin (hereinafter simply referred to as hOT7T175 / CHO) were selected for the following experiment.

Intracellular Ca ion concentration-increasing activity of the synthetic peptides in hOT7T175 / CHO was measured using FLIPR (Molecular Devices, Inc.).

hOT7T175 / CHO was incubated in DMEM supplemented with 10% dialysed fetal bovine serum (hereinafter abbreviated as dFBS) and hereinafter abbreviated as 10% dFBS / DMEM and provided for the experiment. The hOT7T175 / CHO was suspended at 15 × 10 ⁴ cells / ml in 10% dFBS-DMEM. The suspension was inoculated in a 96-well plate for FLIPR (Black Plate Clear Bottom, Coster, Inc.) at 200 ml each (3.0 × 10 ⁴ cells / 200 ml) and incubated overnight at 37 ° C. in a 5% CO ₂ incubator. . The cells so incubated were used (hereinafter referred to simply as cell plates). 21 mL of HANKS / HBSS (9.8 g of HANKS ', 0.35 g of sodium bicarbonate, 20 mL of 1M HEPES; pH adjusted to 7.4 with 1N sodium hydroxide, and then the mixture was filtered and sterilized), 210 Μl of 250 mM Probenecid and 210 μl fetal bovine serum (FBS) were mixed (HANKS / HBSS-Probenecid-FBS).

Furthermore, two vials of Fluo3-AM (50 μg / vial) were dissolved in 21 μl of dimethylsulfoxide and 21 μl of 20% Pluronic acid. The resulting solution was added to 10 mL of HANKS / HBSS-Probenecid-FBS described above and mixed. After removal of the culture medium, the mixtures were injected at 100 μl per well on cell plates and incubated for 1 hour at 37 ° C. in a 5% CO ₂ incubator (pigment loading). The peptide was dissolved in 1 x 10 ^-3 M in dimethyl sulfoxide. The peptide solution was diluted with HANKS '/ HBSS containing 2.5 mM Probenecid and 0.2% BSA. Dilutions were transferred to 96-well plates for FLIPR (V-Bottom plate, Coster, Inc.) (hereinafter referred to as sample plates). After completing the pigment loading onto the cell plate, the cell plate was washed four times with a plate washer with a wash buffer obtained by adding 2.5 mM Probenecid to HANKS '/ HBSS to leave 100 μl of wash buffer after washing. . The cell plate and the sample plate were placed in FLIPR, and 0.05 mL of sample from the sample plate was automatically transferred to the cell plate using a FLIPR apparatus to promote cell reaction. Changes in intracellular calcium ion concentration over 180 seconds were measured over time.

Intracellular Ca ion concentration-increasing activity [specific activity for methine (1-54)] is shown in Tables 19 to 23.

TABLE 19

TABLE 20

TABLE 21

Table 22

TABLE 23

Test Example 3

Intracellular Ca Ion Concentration-Increasing Activity Assay Using FLIPR

As in Example 2, intracellular Ca ion concentration-increasing activity was measured using FLIPR. However, (1) The evaluation in Test Example 2, which measures the change in intracellular Ca ion concentration over time for 180 seconds, was changed to the evaluation for 40 seconds after the start of the reaction. In addition, (2) the indication about the said activity is changed into EC ₅₀ / MS10 EC ₅₀ from the specific activity with respect to metastin (1-54).

Some of the evaluation results are shown in Table 24.

TABLE 24

Test Example 4

Assay of Cellular Inhibitory Activity in hOT7T175-expressing CHO Cells

hOT7T175-expressing CHO cells (hereinafter hOT7T175) were incubated in DMEM supplemented with 10% dialysis FBS (hereafter 10% dFBS / DMEM) and used in the following assay. hOT7T175 was suspended at 10,000 cells / ml in 10% dFBS / DMEM. The cells were plated at 100 μl per well (1,000 cells / well) on 96 well plates and then incubated overnight at 37 ° C. in a 5% CO ₂ incubator. On the following day, the medium was removed and 90 μl of 10% dFBS / DMEM (hereafter 0.5% BSA / 10% dFBS / DMEM) supplemented with 0.5% BSA was added. Then 10 μl of a solution of metastin or metastin derivatives in 0.5% BSA / 10% dFBS / DMEM was added to each well and incubated at 37 ° C. for 3 days in a 5% CO ₂ incubator. 10 μl of Cell Counting Kit-8 solution (Dojin Chemical Laboratory) was added to each well, incubated for 4 hours at 37 ° C. in a 5% CO ₂ incubator, and the absorbance at 450 nm was measured.

The cell inhibitory activity of metastin (1-54), metastin (45-54) and synthetic compounds is shown in Table 25.

TABLE 25

Test Example 5

Chemotaxis inhibitory activity assay in hOT7T175-expressing CHO cells

hOT7T175-expressing CHO cells (hereinafter hOT7T175) were cultured in DMEM supplemented with 10% dialyzed FBS (hereafter 10% dFBS / DMEM) and used for the assay. In addition, 24-well 6.5 mm Transwell (8.0 μm in diameter) (COSTAR) was treated with fibronectin by the following method. Specifically, 0.5 mL of 1 μg / ml fibronectin (Yagai Co., Ltd.) was added to the upper and lower chambers of the transwell. The mixture was left at room temperature for 10 minutes, then the fibronectin solution was removed and further air-dried. After washing hOT7T175 three times with DMEM, the cells were suspended in DMEM containing 0.5% BSA (hereinafter 0.5% BSA / DMEM) at a density of 2.5 × 10 ⁶ cells / ml. Metastine or metastine derivatives were diluted with 0.5% BSA / DMEM. Add 0.5 μl BSA / DMEM (or 0.5% BSA / DMEM for negative control) supplemented with 600 μl of 20% FBS to the lower chamber of the Transwell, and dilute 50 μl of the cell suspension and metastine or metastin derivatives in the upper chamber. 50 μl of water (or 0.5% BSA / DMEM for positive control) was added. After 7 hours of incubation at 37 ° C. in a 5% CO ₂ incubator, the culture medium was removed and the top of the filter was wiped with a cotton swap moistened with phosphate-buffered saline to remove all cells on top of the filter. . The filter was fixed and stained with DifQuick (International Reagents Corporation) and the number of cells migrated to the bottom of the filter was counted. Chemotaxis inhibitory activity is shown in FIG. 1.

Test Example 6

Assessment of Tumor Growth Inhibitory Activity

In vivo tumor growth inhibitory action of metastin (1-54) (hereinafter referred to as metastin) and compounds (compounds 305 and 322) using tumor mice with cell line SW620 from human colon carcinoma.

An Alza osmotic pump (0.25 μl / hour, 14 day release, Model 1002) filled with 1 mM metastin, 0.1 mM and 1 mM compound (Otsuka Joryusui KK) dissolved in distilled water and 100 μl each of distilled water as a vehicle was subjected to BALB under ether anesthesia. / cAnN-nu mice (6 weeks old, female, Charles River Japan, Inc.) were buried subcutaneously and started intermittent administration for 14 days. The number of experiments was n = 10 in the metastin group and the vehicle group and n = 11 in the two compound groups. On the following days, 20 μL phosphate buffered saline (pH 7.2) (PBS) containing 200 μl of 0.15 M NaCl cell line SW620 (ATCC) from human colon carcinoma was lysed at a density of 2 × 10 ⁶ cells. The resulting solution was injected subcutaneously into the left flank of the mouse. The day when the cells were injected was set to 0 days. Tumors were measured with electronic calipers at 1 or 2 day intervals from days 4 to 13 of cell administration, and tumor sizes were calculated by the following equation: (shorter diameter) diameters longer than ² × / 2. As shown in FIG. 2, the metastin group (24 nmol / day / mouse x 14 days) showed a significant tumor growth inhibitory effect compared to the vehicle group on day 6. On the other hand, Compound No. 322 showed significant tumor growth inhibitory activity on Days 6-8 at 1/10 dose (Metanmol / day / mouse x 14 days) of metastin. In addition, the compound No. 322 group (24 nmol / day / mouse x 14 days) that received the same dose of metastin showed significant tumor growth inhibitory activity as compared to the vehicle group from day 6 to day 11, On day 11, there was a significant tumor growth inhibitory activity compared to the metastin group. The results above show that metastine also shows tumor growth inhibitory activity in vivo, and compound number 322 shows 10 times greater tumor growth inhibitory action than metastin.

The result of compound number 305 is also shown in FIG. 3. The metastin group (24 nmol / day / mouse x 14 days) showed a significant tumor growth inhibitory effect as compared to the vehicle group from day 5 to day 7. On the other hand, the compound No. 305 group (2.4 nmol / day / mouse x 14 days) receiving 1/10 of the metastin dose showed significant tumor growth inhibitory effect compared to the vehicle group on the 5 th to 11 th day. In addition, the group No. 305 (24 nmol / day / mouse x 14 days) that received the same dose as metastin showed significant tumor growth inhibitory activity compared to the vehicle group on days 5-9 and 11, This reveals that compound number 305 also exhibits 10 times higher in vivo tumor growth inhibition than metastin.

Test Example 7

Increasing Sugar Concentration by Metastine

To study the effect on glucose concentration by peripheral administration of metastine, blood was collected by surgery on free-moving animals. Mature Wistar male rats (weight 210-230 g at the time of surgery) were anesthetized by intraperitoneal injection of 50 mg / kg pentobarbital. The left jugular vein was exposed to the dorsal side by fixing to the dorsal pad. Polyethylene tube SP35 (inner diameter 0.5 mm, outer diameter 0.9 mm, Natsume Seisakusho Co., Ltd.) was cut to about 30 cm in length and filled with 200 units / ml of heparin-containing saline. The tube was then inserted into the jugular vein at a depth of about 4.5 cm to fix it. The other end of the tube exposed the jugular vein (dorsal) through the dorsal subcutaneous.

After surgery, the animals were kept overnight. Prior to metastine administration, 300 μl of blood was drawn using a 1 ml syringe for tuberculin and a 25-gauge needle (both Terumo Co., Ltd.). To prevent coagulation, 3 μl of a 300 KIU / ml aprotinin solution containing 3 mg / ml EDTA was placed in the syringe beforehand. 1 mL saline solution (17, 80 or 170 nmol) of Otsuka saline or metastin was injected intravenously in an amount of 1 mL / kg through the tube. Blood was collected from 300 μL from the jugular vein at 0, 5, 15, 30 and 60 minutes after the start of the intravenous injection. The collected blood was centrifuged (13,000 rpm, 5 minutes) using a high speed cooling centrifuge (MR-150, Tomy Seiko Co., Ltd.) to recover the supernatant (plasma). Blood glucose concentration was measured using Fuji Drychem 3500 (FUJI FILM). As shown in FIG. 4, the metastin group showed a significant dose-dependent (p <0.005, n = 5) blood glucose concentration synergistic effect from 5 minutes after intravenous injection compared to the control group. In the blood glucose concentration, there was an extension of the glucose concentration rise time (up to 30 minutes) with an increase in the maximum value as the metastin dose was increased.

Test Example 8

Metastine Promotes Pancreatic Glucagon Secretion

To study the mechanism of synergistic effects of metastine on blood glucose levels, the effects of metastine on blood glucagon, insulin, corticosterone, and thyroid hormone (T3) concentrations, known as hormones affecting blood glucose levels, were examined. . Blood was collected by surgery on free-moving mature Wistar male rats (weight 260-300 g at the time of surgery). After surgery, the animals were kept overnight. Prior to metastin administration, 300 μl of blood was drawn out using a 1 ml syringe for tuberculin and a 25-gauge needle (both Terumo Co., Ltd.). In order to prevent coagulation, 3 μl of a 300 KIU / ml aprotinin solution containing 3 mg / ml EDTA was previously placed in a syringe. 1 mL saline solution of Otsuka saline or metastin (80 nmol / mL) was injected intravenously in an amount of 1 mL / kg through the tube. Blood was collected 300 μl from the jugular vein 1, 3, 5 and 15 minutes after the start of the intravenous injection. The collected blood was centrifuged (13,000 rpm, 5 minutes) using a high speed cooling centrifuge (MR-150, Tomy Seiko Co., Ltd.) to recover the supernatant (plasma). The blood glucagon concentration was determined by the glucagon kit "Daiichi" (Daiichi Radioisotope Laboratories Ltd.), the blood insulin concentration was measured by the rat insulin [ ¹²⁵ I] assay system (Amersham Biosciences), and the blood corticosteroid concentration was determined by the rat corticosterone [ ¹²⁵ I] assay system. (Amersham Biosciences), blood thyroid hormone (T3) concentration was measured using T-3.RIA beads (Dinabott Co. Ltd.), and blood glucose concentration using Fuji Drychem 3500 (FUJI FILM). As shown in FIG. 5, the metastin-administered group showed a significant synergistic effect of blood glucagon concentration 1 minute after injection compared to the control group. Significant synergism of glucagon concentration continued until 5 minutes after injection. On the other hand, in the blood insulin concentration (FIG. 6), the blood corticosterone concentration (FIG. 7) and the blood thyroid hormone (T3) concentration (FIG. 8) did not show the fluctuation by metastin injection. Based on these results and the increase in blood glucose concentration after the increase in the blood glucagon concentration (FIG. 9), the action on the blood glucose concentration by intravenous injection of metastine was induced by the stimulation of glucagon secretion by metastine. Was considered.

Test Example 9

Synergistic Effects of Metastine Derivatives

The effects of the metastin derivatives KiSS305 (Compound 305) and KiSS322 (Compound 322) on blood glucose concentration and blood glucagon concentration were examined. Blood was collected by surgery in the same manner as in Test Example 1 on free-moving mature Wistar male rats (weight 260-3000 g at the time of surgery). After surgery, the animals were kept overnight. Prior to metastin administration, 300 μl of blood was drawn out using a 1 ml syringe for tuberculin and a 25-gauge needle (both Terumo Co., Ltd.). In order to prevent coagulation, 3 μl of a 300 KIU / ml aprotinin solution containing 3 mg / ml EDTA was previously placed in a syringe. A saline solution of Otsuka saline or metastin (80 nmol / mL) was injected intravenously in an amount of 1 mL / kg through the tube. Blood was collected from 300 μL from the jugular vein 2, 5, 15, 30, 45 and 60 minutes after the start of the intravenous injection. The collected blood was centrifuged (13,000 rpm, 5 minutes) using a high speed cooling centrifuge (MR-150, Tomy Seiko Co., Ltd.) to recover the supernatant (plasma). As in Test Example 1 or 2, blood glucose concentration was measured using Fuji Drychem 3500 (FUJI FILM), and blood glucagon concentration was measured using a glucagon kit "Daiichi" (Daiichi Radioisotope Laboratories Ltd.). As shown in Figure 10, both compounds showed an elevated blood glucose concentration. In addition, as shown in Figure 11, both compounds showed an increase in blood glucagon concentration.

Test Example 10

Induction of Ovulation in Immature Rats Using Human Metastine

Equine chorionic gonadotropin (eCG, serotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in saline (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 100 IU / mL. 9: 30-10 am in the dorsal region of female Wistar rats (Charles River Japan, Inc.), 23 days of age, using a 1 mL syringe for tuberculin and a 26-gauge needle (both Terumo Co., Ltd.). ECG was injected subcutaneously in an amount of 10 IU per subject between: 00. After eCG injection, animals were grouped as shown below 47-48 hours later and each drug was injected into each group.

Group A (5 rats):

Human chorionic gonadotropin (hCG, gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in saline at 100 IU / mL and the solution was injected subcutaneously in the back of the individual in an amount of 20 IU per individual.

Group B (5 rats):

Human metastin was dissolved in saline at 100 nmol / mL and the solution was injected subcutaneously subcutaneously in an amount of 20 nmol per individual.

Group C (5 rats):

Human metastin was dissolved in saline at 33.3 nmm1 / mL and the solution was injected subcutaneously subcutaneously in an amount of 6.67 nmol per individual.

Group D (6 rats):

Saline was injected subcutaneously in an amount of 200 μl per subject.

After administration of the above-described drug, the animal was headed 24 to 25 hours later to recover blood, bilateral fallopian tubes and uterus. At the time of blood collection, in order to prevent blood coagulation, 90 μl of a 10 KIU / mL aprotinin solution (Trasylol, Bayer) containing 3 mg / ml EDTA was put in a recovery tube. After blood recovery, the blood was thoroughly blended and the mixture was centrifuged at 2,000G for 25 minutes. After recovering the supernatant, the product was used as a plasma sample.

The count of the number of oocytes was as follows.

When oocyte retention in the tubal bulge was confirmed by observation of the oviduct under a stereoscopic microscope, the bulge was cut out by a syringe having a 27-gauge needle (Terumo), and the oocytes were taken out. After removing the granulosa cells surrounding the oocytes by trypsin treatment, the oocytes were counted. If oocytes in the tubal bulge could not be identified by observing the oviduct under a stereoscopic microscope, a 27-gauge needle with a sharpened tip was inserted into the tubal ostium, and at least 400 µl of the oviduct and the uterus were inserted. The saline solution was run off and washed. The presence of oocytes in the effluent was observed.

The number of oocytes obtained is shown in Table 26.

TABLE 26

In group A, a generalized superovulation treatment group, ovulation of an average of 37.6 oocytes per rat was confirmed. In group B and group C to which metastine was administered, ovulation of an average of 31.8 and 27.6 oocytes was confirmed, respectively. In group D administered saline, the number of oocytes on average was 0.6, indicating that little spontaneous ovulation was observed in the absence of ovulation stimulation.

Estradiol concentrations contained in the plasma collected from the rats shown in Table 22 were measured by a radioimmunoassay (DPC-Estradiol Kit; Diagnostic Products Corporation). The result is shown in FIG.

The results show that in group A, group B and group C, there is no difference in the concentration of estradiol contained in the plasma, but only in the group D to which saline was administered, the concentration of estradiol is extremely high.

Progesterone concentrations contained in plasma were measured by radioimmunoassay (DPC. Progesterone; Diagnostic Products Corporation). The result is shown in FIG.

The results indicate that the progesterone concentration is highest in group A, in group B and group C, the blood concentration is about half of group A, and the progesterone concentration in group D is very low.

In general, the major steroid hormones produced in the ovaries of rats, mice and humans are estrogens in the maturation of the follicles, whereas progesterone is induced after ovulation is induced. Indeed, even in the results of Figs. 12 and 13, in the saline-administered group D, estrogen was maintained in a high state because no ovulation was induced; In group A administered hCG, estrogen production increased. In soldier groups B and C who received metastine, plasma estrogen concentrations were very low, but the concentration of progesterone increased, indicating that metastine induces ovulation through the normal ovulation process in rat ovaries. In addition, since the concentration of progesterone in groups B and C is lower than in group A, metastine is considered to have milder ovarian stimulation.

Test Example 11

Gonadotropin-releasing Activity of Human Metastine in Immature Rats

In a 25-day-old female Wistar rat (Charles River Japan, Inc.), 200 μl of human metastine dissolved in saline at a concentration of 33.3 nmol / mL between 9:00 AM and 10:00 AM As sheep, ie, human metastine, 6.67 nmol was injected subcutaneously in the dorsal region. Blood was collected by migrating the animals before, and 1, 2, and 4 hours after injection of metastin. At the time of blood recovery, in order to prevent blood coagulation, 90 µl of a 10 KIU / mL aprotinin solution (Trasylol, Bayer) containing 3 mg / mL of EDTA was placed in a recovery centrifuge tube. After blood recovery, the blood was thoroughly blended and then centrifuged for 25 minutes at 2,000G. After the supernatant was recovered, the product was used as a plasma sample. The concentrations of FSH (follicle stimulating hormone), LH (luteal stimulating hormone) and progesterone contained in plasma were measured. The rat follicle stimulating hormone (rFSH) with Magnetic Separation [ ¹²⁵ I] Biotrack Assay System, Magnetic Separation Rat progesterone hormone (rLH) [ ¹²⁵ I] Biotrack Assay System, all were measured using Amersham Bioscience, and DPC. Progesterone, Diagnostic Products Corporation).

The results of monitoring changes in blood FSH concentrations from immature rats by metastin injection are shown in FIG. 14. One hour after metastin injection, blood FSH concentrations started to rise significantly, reaching a maximum after two hours. After 4 hours there was a decrease in blood FSH concentration, but it was still higher than the concentration before injection.

The results of monitoring changes in blood LH concentrations from immature rats by metastin injection are shown in FIG. 15. Similar to the case of FSH, 1 hour after metastin injection, blood LH concentrations started to rise significantly and reached maximum after 2 hours. After 4 hours, the blood LH concentration was lowered but was still higher than the concentration before injection.

The results of monitoring changes in blood progesterone concentrations from immature rats by metastin injection are shown in FIG. 16. Reflecting the rise in LH concentration in the blood, the progesterone concentration started to rise slowly 1 hour after the metastin injection, and was significantly higher than the concentration before the injection.

The results in FIGS. 14 and 15 revealed that peripheral administration of metastin induced the release of gonadotropins such as FSH and LH. Ovulation induction by metastine demonstrated in Test Example 9 is considered to be mediated by this gonadotropin release, in particular the release of LH.

The ovulation induction effect demonstrated in Test Example 9 is in the rat to which eCG was administered, but the action in this Test Example shows the result obtained using the untreated rat. Gonadotropin release by metastine does not require pretreatment of eCG.

The results shown in FIG. 16 mean that the release of gonadotropins by injection of metastins results in physiological stimulation to the ovary, resulting in increased production of progesterone.

Test Example 12

Gonadotropin Release Activity in Mature Male Rats by Human Metastine

For 11-week-old male Wistar rats (Charles River Japan, Inc.), between 10:30 and 11:30 am, human metastine dissolved in saline at a concentration of 175 nmol / mL was 200 per individual. 35 nmol was injected subcutaneously in the dorsal area in an amount of μL, ie as human metastin. The animals were guillotine prior to injection of metastin and 1, 2 and 4 hours after injection to recover blood. During blood recovery, in order to prevent coagulation, 300 μl of a 10 KIU / mL aprotinine solution (Trasylol, Bayer) containing 3 mg / ml of EDTA was placed in a recovery centrifuge tube. After blood recovery, the blood was thoroughly blended and then centrifuged for 25 minutes at 2,000G. After the supernatant was recovered, it was used as a plasma sample. The concentrations of FSH (follicle stimulating hormone), LH (luteal stimulating hormone) and testosterone contained in plasma were measured. The rat follicle stimulating hormone (rFSH) with Magnetic Separation [ ¹²⁵ I] Biotrack Assay System, Magnetic Separation Rat progesterone hormone (rLH) [ ¹²⁵ I] Biotrack Assay System, both Amersham Bioscience, and DPC. Total Testosterone, Diagnostic Products Corporation).

The results obtained by monitoring the change in blood FSH concentration of rats by metastin injection are shown in FIG. 17. One hour after metastin injection, blood FSH concentrations started to rise significantly, reaching a maximum after two hours, and still higher after four hours.

The results obtained by monitoring the change in blood LH concentration of rats by metastin injection are shown in FIG. 18. As in the case of FSH, after 1 hour, blood LH concentrations started to rise significantly and reached a maximum after 2 hours. After 4 hours, the blood LH concentration was lowered but was still higher than the concentration before injection.

The results obtained by monitoring changes in blood testosterone concentrations of rats by metastin injection are shown in FIG. 19. Testosterone concentrations showed a sharp rise 1 hour after metastin injection. After 2 and 4 hours, there was a drop in blood testosterone concentration, but at both time points it was still higher than the concentration before injection.

The results in FIGS. 17 and 18 show that peripheral administration of metastine induces release of gonadotropin such as FSH and LH in male rats. Considering the results of Test Example 10, it is considered that metastine is a very important factor in both female and male rats in stimulating the release of gonadotropin.

The results shown in FIG. 19 mean that the release of gonadotropins by injection of metastins stimulates the testis physiologically, thereby increasing the production of testosterone.

From these results, it is considered that the administration of metastin is mediated by the release of gonadotropin, which stimulates testes. This suggests that metastine may also affect male reproductive function, including sperm maturation, hormone secretion, and the like.

Test Example 13

Blood stability test of compound

Blood was drawn from 8-week old Balb / c mice (females), then left at 37 ° C for 30 minutes, and centrifuged at 13000 rpm for 10 minutes to obtain mouse serum. The serum thus obtained was cryopreserved at -80 ° C.

The stability test was performed by adding 5 nmol of a compound (5 µl aqueous solution) to 45 µl of serum and leaving the mixture at 37 ° C. Neglect was performed at three time points including 2, 10 and 30 minutes. The sample after standing to boil for 3 minutes, and then cooled on an ice bath. 200 µl of acetonitrile / water (3/1) was added to the sample, followed by ultrasonic treatment for 5 minutes, and then centrifuged at 5000 rpm for 1 minute. After diluting 150 µl of the supernatant with 250 µl of distilled water, the insolubles were removed by filtration with a filter having a pore size of 0.45 µm, and 200 µl of the filtrate was analyzed by HPLC (220 nm) to determine the peak area of the compound. Under the same conditions, the ratio of the peak area to the area when the compound was treated for 0 minutes was calculated as an average value four times each, and the residual ratio was measured. Next, a graph was created with the calculated residual ratio as the vertical axis and the time as the horizontal axis, an approximation value was calculated by the exponential function, and the time when the residual ratio was 50% was calculated as a half-life.

Analytical HPLC used LC-VP series manufactured by Shimadzu Corporation, and the column was prepared by Wako Pure Chemical Industries, Ltd. Wakosil-II 5C18 HG (4.6 mm x 100 mm) manufactured by Corporation was used. Eluent A (0.1% TFA-containing water) and Eluent B (0.1% TFA-containing acetonitrile) were used as the eluent. Using eluent A / B: 100/0-0/50 (25 min), linear concentration gradient elution was carried out at a flow rate of 1.0 ml / min.

The values of the tested compounds and t _1/2 (min) thereof are shown in Table 27.

TABLE 27

Test Example 14

Induction of Ovulation in Immature Rats Using Metastin Derivatives

Equine chorionic gonadotropin (eCG, serototropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in saline (Otsuka Pharmaceutical Co., Ltd.) at a concentration of 100 IU / mL. Subcutaneously in the dorsal region of a 23-day-old female Wistar rat (Charles River Japan, Inc.), 10 IU of eCG per subject, between 9:00 AM and 10:00 AM, with a 1 mL tuberculin syringe and 26 It was injected using a gauge needle (all Terumo Co., Ltd.). 47-48 hours after eCG injection, grouping was performed as shown below, and each group was injected with each drug.

Group A (5 rats):

Human chorionic gonadotropin (hCG, gonadotropin, Dainippon Pharmaceutical Co., Ltd.) was dissolved in saline at 100 IU / mL and the solution was injected subcutaneously in the back of the body in an amount of 20 IU per individual.

Group B (5 rats):

Compound No. 305 was dissolved in saline at 33.3 nmol / mL and the solution was injected subcutaneously subcutaneously in an amount of 6.7 nmol per individual.

Group C (5 rats):

Compound No. 305 was dissolved in saline at 10.0 nmol / mL and the solution was injected subcutaneously subcutaneously in an amount of 2.0 nmol per individual.

Group D (5 rats):

Compound No. 322 was dissolved in saline at 33.3 nmol / mL and the solution was injected subcutaneously subcutaneously in an amount of 6.7 nmol per individual.

Group E (5 rats):

Compound No. 322 was dissolved in saline at 10.0 nmol / mL and the solution was injected subcutaneously subcutaneously in an amount of 2.0 nmol per individual.

Group F (6 rats):

200 μl of saline per dose was administered subcutaneously.

24 to 25 hours after administration of these drugs, the animals were guillotine to recover blood, bilateral fallopian tubes and uterus. During blood recovery, in order to prevent coagulation, 90 μl of a 10 KIU / mL aprotinine solution (Trasylol, Bayer) containing 3 mg / mL of EDTA was placed in the centrifuge tube for recovery. After blood recovery, the blood was thoroughly blended and then centrifuged for 25 minutes at 2,000G. After the supernatant was recovered, the product was used as a serum sample.

The count of oocytes is described in Eur. J. Endocrinol., 138, 594-600 (1998).

When oocyte retention in the fallopian tube bulge was confirmed by observation of the fallopian tube under a stereoscopic microscope, the bulge was cut out by a 27-gauge Terumo to remove the oocytes. After removing the granulosa cells surrounding the oocytes by trypsin treatment, the oocytes were counted. If the oviduct was observed under a stereoscopic microscope, and there was no retention of oocytes in the tubal bulge, a 27-gauge needle with a sharpened tip was inserted into the oviduct, and 400 µl or more saline in the fallopian tube and the uterus was washed. . Thereafter, the presence or absence of oocytes in the effluent was observed.

The number of oocytes thus obtained is shown in FIG. 20. In group A, a general-purpose superovulation treatment group, the number of oocytes was an average of 38.0 rats. In groups B, C and D, the number of oocytes on average was 32.6, 29.4 and 29.6, respectively, indicating that ovulation was substantially equivalent to group A. In group E administered 2.0 nmol of compound No. 322, three of five rats ovulated, and the average number of oocytes was 11.6, which was less than that of group A. In addition, in group F as a negative control, ovulation was not observed at all.

The results in FIG. 20 indicate that in order to induce ovulation equivalent to hCG, Compound No. 305 should be administered at least 2.0 nmol per individual and Compound No. 322 at least 6.7 nmol per individual.

The result of measuring the estradiol concentration contained in plasma is shown in FIG. Blood estradiol concentrations were measured by radioimmunoassay (DPC. Estradiol kit, Iatron, Inc.). As shown in FIG. 21, for estradiol, no difference was found between groups A, B, C and D, and high values were shown only in group F. In group E, rats that did not induce ovulation tended to show high levels.

The result of measuring the concentration of progesterone contained in plasma is shown in FIG. Blood progesterone concentrations were measured by radioimmunoassay (DPC. Progesterone, Iatron, Inc.). As shown in FIG. 22, the blood progesterone concentration was the highest in Group A, and in Groups B, C and D, the progesterone concentration showed a value less than half of the value in Group A. Groups E and F had very low numbers.

From the results in FIGS. 21 and 22, normal differentiation from estrogen-producing granulosa cells to progesterone-producing corpus luteum cells is achieved by administering at least 2.0 nmol per compound and at least 6.7 nmol per compound, respectively. Was found to be induced. In addition, when administering Compound No. 305 or KiSS-322, the progesterone concentration was lower than when administered hCG, suggesting that the stimulatory effect of these derivatives on the ovary is more mild than hCG.

Test Example 15

Evaluation of Blood Testosterone Level Reduction of Metastine Peptide Derivatives Using Mature Male Rats

The metastine peptide derivative (hereinafter, peptide) was dissolved in distilled water (Otsuka Joryusui K.K.) to prepare a 2 mM peptide solution. This peptide solution was charged to five ALZET osmotic pumps (Model 2001, volume 0.2 ml, release rate: 0.001 ml / hour, DURECT Corporation). ALZET pumps filled with the peptide solution were implanted in dorsal subcutaneous into five male CD (SD) IGS rats (Charles River Japan, Inc.), 9 weeks old, under ether anesthesia. As a negative control, distilled water (Otsuka Pharmaceutical Co., Ltd.) was charged into five ALZET osmotic pumps and likewise transplanted into five male CD (SD) IGS rats (Charles River Japan, Inc.) respectively. Rats implanted with these pumps were reared for 6 days under normal breeding conditions. After measuring the body weight, the animal was guillotine and blood was drawn out. Per 1 ml of blood, 0.03 ml of aprotinine solution (Trasylol, Bayer) containing 0.1 mg / ml EDTA.2Na was added and the mixture was centrifuged at 1,800 G for 25 minutes to separate / recover plasma. From the obtained plasma, 0.05 ml was applied to a radioimmunoassay (DPC Total Teststeron Kit, Diagnostic Products Corporation) to measure plasma testosterone concentrations in each rat. Values below the limit of measurement (plasma concentration of 0.04 ng / ml) in the radioimmunoassay were treated as zero. The average value of the testosterone concentrations of five rats administered with the peptide was calculated, and the relative value (percent) relative to the average value from five rats administered with distilled water was calculated.

Using this evaluation method, various peptides were evaluated and some of the results are shown in Tables 28 and 29.

TABLE 28

TABLE 29

Test Example 16

In the same manner as in Test Example 14, the evaluation was performed using a 0.1 mM peptide solution, and some of the results obtained are shown in Table 30.

TABLE 30

Test Example 17

Evaluation of Blood Testosterone Level Reduction of Metastine Peptide Derivatives Using Mature Male Rats

The metastine peptide derivative (hereinafter referred to as peptide) was dissolved in 50% DMSO aqueous solution to prepare a peptide solution at 1 mM concentration. The peptide was charged into five ALZET osmotic pumps (Model 2001, volume of 0.2 mL, release rate 0.001 ml / hour, DURECT Corporation). ALZET pumps filled with the peptide solution were implanted into the dorsal subcutaneous, 5 pumps per 1, 9 male CD (SD) IGS rats (Charles River Japan, Inc.) under ether anesthesia. Separately, as a negative control, an ALZET osmotic pump filled with distilled water was implanted into five male CD (SD) IGS rats (Charles River Japan, Inc.). The rats were reared for 6 days under normal breeding conditions. After the body weight was measured, blood was collected by guillotine. To 1 ml of blood, 0.03 ml of aprotinin solution (Trasylol, Bayer) containing 0.1 g / ml EDTA 2Na was added. Plasma was isolated and collected by centrifugation at 1,800 × g for 25 minutes. From the plasma thus obtained, 0.05 ml was applied to a radioimmunoassay (DPC Total Teststerone Kit, Diagnostic Products Corporation) to measure blood testosterone concentrations in each rat. Values below the measurement limit (plasma concentration of 0.04 ng / ml) in the radioimmunoassay were treated as zero. The average value of the testosterone concentrations of five rats administered with the peptide was calculated, and the relative value (percent) to the average value of testosterone concentrations from the five rats administered with distilled water was evaluated. Table 31 shows an example of the results evaluated for various peptides using this evaluation method.

Table 31

[Sequence list free text]

SEQ ID NO: 15 C amidated.

SEQ ID NO: 16 C terminal is amidated.

SEQ ID NO: 17 C terminal is amidated.

SEQ ID NO: 18 C terminal is amidated.

SEQUENCE LISTING <110> Takeda Pharmaceutical Company Limited <120> Metastin Derivatives And Use Thereof <130> G06-0070 <140> PCT / JP2005 / 012021 <141> 2005-06-23 <150> JP 2004-187671 <151> 2004-06-25 <160> 22 <210> 1 <211> 54 <212> PRT <213> Homo sapiens <400> 1 Gly Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln  1 5 10 15 Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly              20 25 30 Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn          35 40 45 Ser Phe Gly Leu Arg Phe      50 <210> 2 <211> 162 <212> DNA <213> Homo sapiens <400> 2 ggtacttctc tgtctccgcc gccggaatct tctggttctc gtcagcagcc gggtctgtct 60 gctccgcact ctcgtcagat cccggctccg cagggtgctg ttctggttca gcgtgaaaaa 120 gacctgccga actacaactg gaactctttc ggtctgcgtt tc 162 <210> 3 <211> 152 <212> PRT <213> Mus musculus <400> 3 Met Tyr Leu Arg Phe Gly Val Asp Val Cys Ser Leu Ser Pro Trp Lys                  5 10 15 Glu Thr Val Asp Leu Pro Leu Pro Pro Arg Met Ile Ser Met Ala Ser              20 25 30 Trp Gln Leu Leu Leu Leu Leu Cys Val Ala Thr Tyr Gly Glu Pro Leu          35 40 45 Ala Lys Val Ala Pro Gly Ser Thr Gly Gln Gln Ser Gly Pro Gln Glu      50 55 60 Leu Val Asn Ala Trp Glu Lys Glu Ser Arg Tyr Ala Glu Ser Lys Pro  65 70 75 80 Gly Ser Ala Gly Leu Arg Ala Arg Arg Ser Ser Pro Cys Pro Pro Val                  85 90 95 Glu Gly Pro Ala Gly Arg Gln Arg Pro Leu Cys Ala Ser Arg Ser Arg             100 105 110 Leu Ile Pro Ala Pro Arg Gly Ala Val Leu Val Gln Arg Glu Lys Asp         115 120 125 Leu Ser Thr Tyr Asn Trp Asn Ser Phe Gly Leu Arg Tyr Gly Arg Arg     130 135 140 Gln Ala Ala Arg Ala Ala Arg Gly 145 150 <210> 4 <211> 456 <212> DNA <213> Mus musculus <400> 4 atgtatctga gatttggcgt tgatgtctgc agcctgagtc cctggaagga gactgtagac 60 ctgccccttc ctcccagaat gatctcaatg gcttcttggc agctgctgct tctcctctgt 120 gtcgccacct atggggagcc gctggcaaaa gtgaagcctg gatccacagg ccagcagtcc 180 ggaccccagg aactcgttaa tgcctgggaa aaggaatcgc ggtatgcaga gagcaagcct 240 gggtctgcag ggctgcgcgc tcgtaggtcg tcgccatgcc cgccggttga gggccccgcg 300 gggcgccagc ggcccctgtg tgcctcccgc agtcgcctga tccctgcgcc ccgcggagcg 360 gtgctggtgc agcgggagaa ggacctgtcc acctacaact ggaactcctt cggcctgcgc 420 tacggcagga ggcaggcggc gcgggcagca cggggc 456 <210> 5 <211> 156 <212> PRT <213> Mus musculus <400> 5 Met Tyr Leu Arg Phe Gly Val Asp Val Cys Ser Leu Ser Pro Trp Lys                  5 10 15 Glu Thr Val Asp Leu Pro Leu Pro Pro Arg Met Ile Ser Met Ala Ser              20 25 30 Trp Gln Leu Leu Leu Leu Leu Cys Val Ala Thr Tyr Gly Glu Pro Leu          35 40 45 Ala Lys Val Ala Pro Leu Val Lys Pro Gly Ser Thr Gly Gln Gln Ser      50 55 60 Gly Pro Gln Glu Leu Val Asn Ala Trp Glu Lys Glu Ser Arg Tyr Ala  65 70 75 80 Glu Ser Lys Pro Gly Ser Ala Gly Leu Arg Ala Arg Arg Ser Ser Pro                  85 90 95 Cys Pro Pro Val Glu Gly Pro Ala Gly Arg Gln Arg Pro Leu Cys Ala             100 105 110 Ser Arg Ser Arg Leu Ile Pro Ala Pro Arg Gly Ala Val Leu Val Gln         115 120 125 Arg Glu Lys Asp Leu Ser Thr Tyr Asn Trp Asn Ser Phe Gly Leu Arg     130 135 140 Tyr Gly Arg Arg Gln Ala Ala Arg Ala Ala Arg Gly 145 150 155 <210> 6 <211> 468 <212> DNA <213> Mus musculus <400> 6 atgtatctga gatttggcgt tgatgtctgc agcctgagtc cctggaagga gactgtagac 60 ctgccccttc ctcccagaat gatctcaatg gcttcttggc agctgctgct tctcctctgt 120 gtcgccacct atggggagcc gctggcaaaa gtggcacctt tggtgaagcc tggatccaca 180 ggccagcagt ccggacccca ggaactcgtt aatgcctggg aaaaggaatc gcggtatgca 240 gagagcaagc ctgggtctgc agggctgcgc gctcgtaggt cgtcgccatg cccgccggtt 300 gagggccccg cggggcgcca gcggcccctg tgtgcctccc gcagtcgcct gatccctgcg 360 ccccgcggag cggtgctggt gcagcgggag aaggacctgt ccacctacaa ctggaactcc 420 ttcggcctgc gctacggcag gaggcaggcg gcgcgggcag cacggggc 468 <210> 7 <211> 130 <212> PRT <213> Rattus sp. <400> 7 Met Thr Ser Leu Ala Ser Trp Gln Leu Leu Leu Leu Leu Cys Val Ala                  5 10 15 Ser Phe Gly Glu Pro Leu Ala Lys Met Ala Pro Val Val Asn Pro Glu              20 25 30 Pro Thr Gly Gln Gln Ser Gly Pro Gln Glu Leu Val Asn Ala Trp Gln          35 40 45 Lys Gly Pro Arg Tyr Ala Glu Ser Lys Pro Gly Ala Ala Gly Leu Arg      50 55 60 Ala Arg Arg Thr Ser Pro Cys Pro Pro Val Glu Asn Pro Thr Gly His  65 70 75 80 Gln Arg Pro Pro Cys Ala Thr Arg Ser Arg Leu Ile Pro Ala Pro Arg                  85 90 95 Gly Ser Val Leu Val Gln Arg Glu Lys Asp Met Ser Ala Tyr Asn Trp             100 105 110 Asn Ser Phe Gly Leu Arg Tyr Gly Arg Arg Gln Val Ala Arg Ala Ala         115 120 125 Arg gly     130 <210> 8 <211> 390 <212> DNA <213> Rattus sp. <400> 8 atgacctcgc tggcttcttg gcagctgctg cttctcctct gtgtggcctc ttttggggag 60 ccactggcaa aaatggcacc tgtggtgaac cctgaaccca caggccaaca gtccggaccc 120 caggaactcg ttaatgcctg gcaaaagggc ccgcggtatg cagagagcaa gcctggggct 180 gcaggactgc gcgctcgccg aacatcgcca tgcccgccgg tggagaaccc cacggggcac 240 cagcggcccc cgtgtgccac ccgcagtcgc ctgatccctg cgccccgcgg atcggtgctg 300 gtgcagcgcg agaaggacat gtcagcctac aactggaact cctttggcct gcgctacggc 360 aggaggcagg tggcgcgggc ggcacggggc 390 <210> 9 <211> 398 <212> PRT <213> Homo sapiens <400> 9 Met His Thr Val Ala Thr Ser Gly Pro Asn Ala Ser Trp Gly Ala Pro                  5 10 15 Ala Asn Ala Ser Gly Cys Pro Gly Cys Gly Ala Asn Ala Ser Asp Gly              20 25 30 Pro Val Pro Ser Pro Arg Ala Val Asp Ala Trp Leu Val Pro Leu Phe          35 40 45 Phe Ala Ala Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile      50 55 60 Tyr Val Ile Cys Arg His Lys Pro Met Arg Thr Val Thr Asn Phe Tyr  65 70 75 80 Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val                  85 90 95 Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Gly Trp Val Leu Gly Asp             100 105 110 Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala         115 120 125 Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr     130 135 140 Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu 145 150 155 160 Ala Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro                 165 170 175 Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro Arg Ala Tyr Cys Ser             180 185 190 Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn         195 200 205 Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr     210 215 220 Ala Ala Met Leu Arg His Leu Gly Arg Val Ala Val Arg Pro Ala Pro 225 230 235 240 Ala Asp Ser Ala Leu Gln Gly Gln Val Leu Ala Glu Arg Ala Gly Ala                 245 250 255 Val Arg Ala Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe             260 265 270 Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu         275 280 285 Gly Pro Ala Gly Ser Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Leu     290 295 300 Lys Thr Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro 305 310 315 320 Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Arg Arg                 325 330 335 Val Cys Pro Cys Ala Pro Arg Arg Pro Arg Arg Pro Arg Arg Pro Gly             340 345 350 Pro Ser Asp Pro Ala Ala Pro His Ala Glu Leu His Arg Leu Gly Ser         355 360 365 His Pro Ala Pro Ala Arg Ala Gln Lys Pro Gly Ser Ser Gly Leu Ala     370 375 380 Ala Arg Gly Leu Cys Val Leu Gly Glu Asp Asn Ala Pro Leu 385 390 395 <210> 10 <211> 1194 <212> DNA <213> Homo sapiens <400> 10 atgcacaccg tggctacgtc cggacccaac gcgtcctggg gggcaccggc caacgcctcc 60 ggctgcccgg gctgtggcgc caacgcctcg gacggcccag tcccttcgcc gcgggccgtg 120 gacgcctggc tcgtgccgct cttcttcgcg gcgctgatgc tgctgggcct ggtggggaac 180 tcgctggtca tctacgtcat ctgccgccac aagccgatgc ggaccgtgac caacttctac 240 atcgccaacc tggcggccac ggacgtgacc ttcctcctgt gctgcgtccc cttcacggcc 300 ctgctgtacc cgctgcccgg ctgggtgctg ggcgacttca tgtgcaagtt cgtcaactac 360 atccagcagg tctcggtgca ggccacgtgt gccactctga ccgccatgag tgtggaccgc 420 tggtacgtga cggtgttccc gttgcgcgcc ctgcaccgcc gcacgccccg cctggcgctg 480 gctgtcagcc tcagcatctg ggtaggctct gcggcggtgt ctgcgccggt gctcgccctg 540 caccgcctgt cacccgggcc gcgcgcctac tgcagtgagg ccttccccag ccgcgccctg 600 gagcgcgcct tcgcactgta caacctgctg gcgctgtacc tgctgccgct gctcgccacc 660 tgcgcctgct atgcggccat gctgcgccac ctgggccggg tcgccgtgcg ccccgcgccc 720 gccgatagcg ccctgcaggg gcaggtgctg gcagagcgcg caggcgccgt gcgggccaag 780 gtctcgcggc tggtggcggc cgtggtcctg ctcttcgccg cctgctgggg ccccatccag 840 ctgttcctgg tgctgcaggc gctgggcccc gcgggctcct ggcacccacg cagctacgcc 900 gcctacgcgc ttaagacctg ggctcactgc atgtcctaca gcaactccgc gctgaacccg 960 ctgctctacg ccttcctggg ctcgcacttc cgacaggcct tccgccgcgt ctgcccctgc 1020 gcgccgcgcc gcccccgccg cccccgccgg cccggaccct cggaccccgc agccccacac 1080 gcggagctgc accgcctggg gtcccacccg gcccccgcca gggcgcagaa gccagggagc 1140 agtgggctgg ccgcgcgcgg gctgtgcgtc ctgggggagg acaacgcccc tctc 1194 <210> 11 <211> 396 <212> PRT <213> Rattus sp. <400> 11 Met Ala Ala Glu Ala Thr Leu Gly Pro Asn Val Ser Trp Trp Ala Pro                  5 10 15 Ser Asn Ala Ser Gly Cys Pro Gly Cys Gly Val Asn Ala Ser Asp Gly             20 25 30 Pro Gly Ser Ala Pro Arg Pro Leu Asp Ala Trp Leu Val Pro Leu Phe         35 40 45 Phe Ala Ala Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile     50 55 60 Phe Val Ile Cys Arg His Lys His Met Gln Thr Val Thr Asn Phe Tyr 65 70 75 80 Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val                 85 90 95 Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Thr Trp Val Leu Gly Asp             100 105 110 Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala         115 120 125 Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr     130 135 140 Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu 145 150 155 160 Thr Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro                 165 170 175 Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro His Thr Tyr Cys Ser             180 185 190 Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn         195 200 205 Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr     210 215 220 Gly Ala Met Leu Arg His Leu Gly Arg Ala Ala Val Arg Pro Ala Pro 225 230 235 240 Thr Asp Gly Ala Leu Gln Gly Gln Leu Leu Ala Gln Arg Ala Gly Ala                 245 250 255 Val Arg Thr Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe             260 265 270 Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu         275 280 285 Gly Pro Ser Gly Ala Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Leu     290 295 300 Lys Ile Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro 305 310 315 320 Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Cys Arg                 325 330 335 Val Cys Pro Cys Gly Pro Gln Arg Gln Arg Arg Pro His Ala Ser Ala             340 345 350 His Ser Asp Arg Ala Ala Pro His Ser Val Pro His Ser Arg Ala Ala         355 360 365 His Pro Val Arg Val Arg Thr Pro Glu Pro Gly Asn Pro Val Val Arg     370 375 380 Ser Pro Ser Val Gln Asp Glu His Thr Ala Pro Leu 385 390 395 <210> 12 <211> 1188 <212> DNA <213> Rattus sp. <400> 12 atggccgcag aggcgacgtt gggtccgaac gtgagctggt gggctccgtc caacgcttcg 60 ggatgcccgg gctgcggtgt caatgcctcg gatggcccag gctccgcgcc aaggcccctg 120 gatgcctggc tggtgcccct gtttttcgct gccctaatgt tgctggggct agtcgggaac 180 tcactggtca tcttcgttat ctgccgccac aagcacatgc agaccgtcac caatttctac 240 atcgctaacc tggcggccac agatgtcact ttccttctgt gctgcgtacc cttcaccgcg 300 ctcctctatc cgctgcccac ctgggtgctg ggagacttca tgtgcaaatt cgtcaactac 360 atccagcagg tctcggtgca agccacatgt gccactttga cagccatgag tgtggaccgc 420 tggtacgtga ctgtgttccc gctgcgtgca cttcaccgcc gcactccgcg cctggccctg 480 actgtcagcc ttagcatctg ggtgggttcc gcagctgttt ccgccccggt gctggctctg 540 caccgcctgt cgcccgggcc tcacacctac tgcagtgagg cgtttcccag ccgtgccctg 600 gagcgcgctt tcgcgctcta caacctgctg gccctatacc tgctgccgct gctcgccacc 660 tgcgcctgct acggtgccat gctgcgccac ctgggccgcg ccgctgtacg ccccgcaccc 720 actgatggcg ccctgcaggg gcagctgcta gcacagcgcg ctggagcagt gcgcaccaag 780 gtctcccggc tggtggccgc tgtcgtcctg ctcttcgccg cctgctgggg cccgatccag 840 ctgttcctgg tgcttcaagc cctgggcccc tcgggggcct ggcaccctcg aagctatgcc 900 gcctacgcgc tcaagatctg ggctcactgc atgtcctaca gcaattctgc gctcaacccg 960 ctgctctatg ccttcctggg ttcccacttc agacaggcct tctgccgcgt gtgcccctgc 1020 ggcccgcaac gccagcgtcg gccccacgcg tcagcgcact cggaccgagc cgcaccccat 1080 agtgtgccgc acagccgggc tgcgcaccct gtccgggtca ggacccccga gcctgggaac 1140 cctgtggtgc gctcgccctc tgttcaggat gaacacactg ccccactc 1188 <210> 13 <211> 396 <212> PRT <213> Mus musculus <400> 13 Met Ala Thr Glu Ala Thr Leu Ala Pro Asn Val Thr Trp Trp Ala Pro  1 5 10 15 Ser Asn Ala Ser Gly Cys Pro Gly Cys Gly Val Asn Ala Ser Asp Asp             20 25 30 Pro Gly Ser Ala Pro Arg Pro Leu Asp Ala Trp Leu Val Pro Leu Phe         35 40 45 Phe Ala Thr Leu Met Leu Leu Gly Leu Val Gly Asn Ser Leu Val Ile     50 55 60 Tyr Val Ile Cys Arg His Lys His Met Gln Thr Val Thr Asn Phe Tyr 65 70 75 80 Ile Ala Asn Leu Ala Ala Thr Asp Val Thr Phe Leu Leu Cys Cys Val                 85 90 95 Pro Phe Thr Ala Leu Leu Tyr Pro Leu Pro Ala Trp Val Leu Gly Asp             100 105 110 Phe Met Cys Lys Phe Val Asn Tyr Ile Gln Gln Val Ser Val Gln Ala         115 120 125 Thr Cys Ala Thr Leu Thr Ala Met Ser Val Asp Arg Trp Tyr Val Thr     130 135 140 Val Phe Pro Leu Arg Ala Leu His Arg Arg Thr Pro Arg Leu Ala Leu 145 150 155 160 Ala Val Ser Leu Ser Ile Trp Val Gly Ser Ala Ala Val Ser Ala Pro                 165 170 175 Val Leu Ala Leu His Arg Leu Ser Pro Gly Pro Arg Thr Tyr Cys Ser             180 185 190 Glu Ala Phe Pro Ser Arg Ala Leu Glu Arg Ala Phe Ala Leu Tyr Asn         195 200 205 Leu Leu Ala Leu Tyr Leu Leu Pro Leu Leu Ala Thr Cys Ala Cys Tyr     210 215 220 Gly Ala Met Leu Arg His Leu Gly Arg Ala Ala Val Arg Pro Ala Pro 225 230 235 240 Thr Asp Gly Ala Leu Gln Gly Gln Leu Leu Ala Gln Arg Ala Gly Ala                 245 250 255 Val Arg Thr Lys Val Ser Arg Leu Val Ala Ala Val Val Leu Leu Phe             260 265 270 Ala Ala Cys Trp Gly Pro Ile Gln Leu Phe Leu Val Leu Gln Ala Leu         275 280 285 Gly Pro Ser Gly Ala Trp His Pro Arg Ser Tyr Ala Ala Tyr Ala Val     290 295 300 Lys Ile Trp Ala His Cys Met Ser Tyr Ser Asn Ser Ala Leu Asn Pro 305 310 315 320 Leu Leu Tyr Ala Phe Leu Gly Ser His Phe Arg Gln Ala Phe Cys Arg                 325 330 335 Val Cys Pro Cys Cys Arg Gln Arg Gln Arg Arg Pro His Thr Ser Ala             340 345 350 His Ser Asp Arg Ala Ala Thr His Thr Val Pro His Ser Arg Ala Ala         355 360 365 His Pro Val Arg Ile Arg Ser Pro Glu Pro Gly Asn Pro Val Val Arg     370 375 380 Ser Pro Cys Ala Gln Ser Glu Arg Thr Ala Ser Leu 385 390 395 <210> 14 <211> 1188 <212> DNA <213> Mus musculus <400> 14 atggccaccg aggcgacatt ggctcccaat gtgacctggt gggctccgtc caacgcttca 60 ggatgcccag gctgcggtgt caacgcctcg gatgacccag gctctgcgcc aaggcccctg 120 gatgcctggc tggttcccct gtttttcgct acactcatgt tgcttgggct ggtcggaaac 180 tcattggtca tctacgttat ctgccgccac aagcacatgc agacagttac caacttctac 240 atcgctaacc tggctgccac agacgtcact ttcctactgt gctgcgtgcc cttcaccgca 300 ctcctctacc cgctgcccgc ctgggtgctg ggagacttca tgtgcaaatt cgtcaactac 360 atccagcagg tctcggtgca agccacatgt gccactctga cggccatgag tgtggaccgc 420 tggtatgtga ctgtgttccc gctgcgtgca cttcaccgcc gcactccgcg cctggccctg 480 gctgtcagcc tcagcatctg ggtggggtca gcagctgtgt ccgccccggt gctggccctg 540 caccgcctgt cgccagggcc tcgcacctac tgcagcgagg cgtttcccag ccgcgccctg 600 gagcgcgcct tcgcgctcta caacctgctg gctctatatc tgctgccgct gctcgccacc 660 tgcgcctgct acggcgccat gctgcgccac ctgggccgtg cggctgtacg ccccgcaccc 720 actgacggcg ccctgcaggg acagctgcta gcacagcgcg ccggagcagt gcgcaccaag 780 gtctcccggc tggtggccgc tgtcgtcctg ctcttcgccg cctgctgggg cccgatccag 840 ctgttcctgg tgcttcaagc cctgggcccc tcgggggcct ggcaccctcg aagctatgcc 900 gcctacgcgg tcaagatctg ggctcactgc atgtcctaca gcaactcggc gctcaatccg 960 ctgctctatg ccttcctggg ttcacacttc agacaggcct tctgccgcgt gtgcccctgc 1020 tgccggcaac gccagcgccg gccccacacg tcagcgcact cggaccgagc tgcaactcac 1080 actgtgccgc acagccgtgc tgcgcaccct gtgcggatca ggagcccgga gcctgggaac 1140 cctgtggtgc gctcgccctg cgctcagagt gaacgcactg cctcactc 1188 <210> 15 <211> 15 <212> PRT <213> Artificial <220> <223> the C-terminus of the polypeptide is amide (-CONH2) form <400> 15 Lys Asp Leu Pro Asn Tyr Asn Trp Asn Ser Phe Gly Leu Arg Phe 1 5 10 15 <210> 16 <211> 10 <212> PRT <213> Artificial <220> <223> the C-terminus of the polypeptide is amide (-CONH2) form <400> 16 Tyr Asn Trp Asn Ser Phe Gly Leu Arg Phe 1 5 10 <210> 17 <211> 9 <212> PRT <213> Artificial <220> <223> the C-terminus of the polypeptide is amide (-CONH2) form <400> 17 Asn Trp Asn Ser Phe Gly Leu Arg Phe 1 5 9 <210> 18 <211> 8 <212> PRT <213> Artificial <220> <223> the C-terminus of the polypeptide is amide (-CONH2) form <400> 18 Trp Asn Ser Phe Gly Leu Arg Phe 1 5 8 <210> 19 <211> 45 <212> DNA <213> Homo sapiens <400> 19 aaggacctgc cgaactacaa ctggaactcc ttcggcctgc gcttc 45 <210> 20 <211> 30 <212> DNA <213> Homo sapiens <400> 20 tacaactgga actccttcgg cctgcgcttc 30 <210> 21 <211> 27 <212> DNA <213> Homo sapiens <400> 21 aactggaact ccttcggcct gcgcttc 27 <210> 22 <211> 24 <212> DNA <213> Homo sapiens <400> 22 tggaactcct tcggcctgcg cttc 24  

Claims (58)

Metastine derivative (II) or salts thereof represented by the formula:

[In meals: V is a group represented by the following formula:

Or a group represented by the formula:

n represents 0 or 1; W ¹ represents N, CH or O (provided that when W ¹ is N or CH, n represents 1 and when W ¹ is O, n represents 0); W ² represents N or CH; Z ^1, Z ^3, Z5 and Z ⁷ each represent a hydrogen atom or a C _{1 -3} alkyl group; Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S; R ² is (1) hydrogen atom or (2) a cyclic or linear C _{1 -10} alkyl, (3) C _{1 -10} alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and represents an optionally substituted C _{1 -8} alkyl group with substituents selected from the group consisting an optionally substituted aromatic ring; R ³ is (1) an C _1-8 alkyl group having an optionally substituted basic group, optionally having additional substituents, (2) an aralkyl group having an optionally substituted basic group, optionally having an additional substituent, (3) optionally substituted having a basic group and optionally having an additional substituent, the carbon number is C _{1 -4} alkyl group having a non-aromatic cyclic hydrocarbon less than 7, or (4) any group having a basic substituted, optionally, is not more than 7 carbon atoms having an additional substituent C _{1 -4} with an non-aromatic heterocyclic group represents an alkyl group; R ⁴ represents an optionally C _{1 -4} alkyl group which may be substituted with substituents selected from the group consisting of (1) an optionally substituted C _{6 -12} aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , oxygen and sulfur atoms comprising hetero atom selected from the group consisting of, optionally substituted 5- to 14-membered aromatic heterocyclic group, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) a 3 to 11 An optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, And (6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms; Q ¹ represents an optionally C _{1 -4} alkyl group which may be substituted with substituents selected from the group consisting of (1) an optionally substituted C _{6 -12} aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , oxygen and sulfur atoms comprising hetero atom selected from the group consisting of, optionally substituted 5- to 14-membered aromatic heterocyclic group, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) a 3 to 11 An optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, And (6) optionally substituted non-aromatic heterocyclic groups having 7 or less carbon atoms; Q ² is (1) carbamoyl group and a hydroxyl group optionally having a substituent selected from the group consisting of which may optionally be substituted with substituted C _{1 -4} alkyl group, CH _{2, (2)} carbamoyl group and a hydroxyl group It represents an optionally substituted C ₁ random which may be substituted, NH _-4 alkyl group, or (3) O with substituents selected from the group consisting of; Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ -, or -CH = CH- (which may optionally be substituted with C _{1 -6} alkyl group); Z ⁹ represents a hydrogen atom, O or S; And, P and P 'may be the same or different and may combine P and P' or P and Q ¹ together to form a ring, respectively: (1) hydrogen atoms; (2) an optional amino acid residue that is linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1; (3) a group represented by the following formula:

(In the meal: J ¹ is (a) hydrogen atom or _{(b) (i) C 1} -15 acyl group, (ii) C _{1 -15} alkyl, (iii) C _{6 -14} aryl group, (iv) carbamoyl group, (v A) carboxyl group, (vi) sulfino group, (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group, wherein the groups may be optionally substituted with a substituent including an optionally substituted ring group; J ² is (1) an optionally substituted C ₁ NH, (2) C ₁ optionally substituted CH _2, (3) O or (4) represents the S _{-6 -6} alkyl group; J ³ to J ⁶ are each a hydrogen atom or a C _{1 -3} alkyl group; Q ³ to Q ⁶ represents a C _{1 -4} alkyl group which may have a substituent selected from the group consisting of a hydrogen atom or optionally to: (1) an optionally substituted C _{6 -12} hydrocarbon group, an aromatic, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, (6) an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms, (7) an optionally substituted amino group, (8) an optionally substituted guanidino group, (9) an optionally substituted hydroxyl group, (10) an optionally substituted carboxyl group, (11) an optionally substituted carbamoyl group, and (12) optionally substituted sulfhydryl groups; J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ are combined with each other, or J ² and Q ³ , Y ¹ and Q ⁴ , Y ² and Q ⁵ , or Y ³ and Q ⁶ may be combined with each other to form a ring; Y ¹ to Y ³ each represent a group represented by the following formula: -CON (J ¹³ )-, -CSN (J ¹³ )-, -C (J ¹⁴ ) N (J ¹³ )-or -N (J ¹³ ) CO-, wherein J ¹³ and J ¹⁴ are each hydrogen atoms or represents a C _{1 -3} alkyl); And, Z ¹⁰ represents a hydrogen atom, O or S); (4) a group represented by the following formula:

(In the meal: J ¹ and J ² each have the same meaning as described above; J ⁷ to J ⁹ have the same meaning as for J ³ ; Q ⁷ to Q ⁹ have the same meaning as for Q ³ ; Y ² And Y ³ each have the same meaning as described above; Z ¹⁰ has the same meaning as described above; J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ may be combined with each other, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ may be combined with each other to form a ring. have); (5) a group represented by the following formula:

(In the meal: J ¹ and J ² have the same meaning as described above; J ¹⁰ and J ¹¹ have the same meaning as for J ³ ; Q ¹⁰ and Q ¹¹ have the same meaning as for Q ³ ; Y ³ has the same meaning as described above; Z ¹⁰ has the same meaning as described above; J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ may be combined with each other, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ may be combined with each other to form a ring); (6) a group represented by the following formula:

(In the meal: J ¹ and J ² have the same meaning as described above; J ¹² has the same meaning as for J ³ ; Q ¹² has the same meaning as for Q ³ ; Z ¹⁰ has the same meaning as described above; And, J ¹² and Q ¹² may be combined with each other, or J ² and Q ¹² may be combined with each other to form a ring); or, (7) a group represented by the following formula: J ^1- (In the meal: J ¹ has the same meaning as described above), provided that 1-54, 2-54, 3-54, 4-54, 5-54, 6-54, 7 of the amino acid sequence represented by SEQ ID NO: 1 -54, 8-54, 9-54, 10-54, 11-54, 12-54, 13-54, 14-54, 15-54, 16-54, 17-54, 18-54, 19-54 , 20-54, 21-54, 22-54, 23-54, 24-54, 25-54, 26-54, 27-54, 28-54, 29-54, 30-54, 31-54, 32 -54, 33-54, 34-54, 35-54, 36-54, 37-54, 38-54, 39-54, 40-54, 41-54, 42-54, 43-54, 44-54 , Except for peptides consisting of the amino acid sequences 45-54, 46-54, 47-54, 48-54 or 49-54). The metastin derivative (II) or a salt thereof according to claim 1, wherein V is a group represented by the formula:

Wherein each symbol has the same meaning as defined in claim 1. The metastin derivative (II) or a salt thereof according to claim 1, wherein V is a group represented by the formula:

Wherein each symbol has the same meaning as defined in claim 1. Prodrug of metastine derivative (II) of claim 1 or a salt thereof. A drug containing the metastin derivative (II) of claim 1 or a salt thereof, or a prodrug thereof. The drug of claim 5, which is a cancer metastasis inhibitor or a cancer growth inhibitor. The drug according to claim 5, which is an agent for preventing or treating cancer. 6. The drug according to claim 5, which is a pancreatic function modulator. The drug according to claim 5, which is an agent for preventing or treating acute or chronic pancreatitis or pancreatic cancer. 6. The drug according to claim 5, which is a placental function modulator. 6. The drug according to claim 5, which is a prophylactic or therapeutic agent for chorionic carcinoma, molar status, invasive status, miscarriage, fetal developmental failure, abnormal glucose metabolism, abnormal lipid metabolism or induction of labor. 6. The drug according to claim 5, which is an agent for improving gonad function. 6. The drug of claim 5, which is a gonadotropin secretion promoter or a sex hormone secretagogue. 6. The drug of claim 5, which is an ovulation induction or stimulant. A method for inhibiting cancer metastasis or cancer growth comprising administering to a mammal an effective amount of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. A method of preventing or treating cancer comprising administering to a mammal an effective amount of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. A method for controlling pancreatic function comprising administering to a mammal an effective amount of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. Chorionic carcinoma, award status, invasive status, miscarriage, fetal developmental insufficiency, abnormal glucose metabolism, abnormality Method of preventing or treating lipid metabolism or induction of labor. A method for improving gonad function, comprising administering to a mammal an effective amount of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. Hormone-dependent cancer, infertility, endometriosis, early puberty or uterine fibroids, comprising administering to a mammal an effective amount of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof Methods of prevention or treatment. A method of inducing or stimulating ovulation comprising administering to a mammal an effective amount of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. A method for promoting gonadotropin secretion or sex hormone secretion comprising administering to a mammal an effective amount of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. A method of preventing or treating Alzheimer's disease or mild cognitive impairment comprising administering to a mammal an effective amount of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof. Use of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the production of a cancer metastasis inhibitor or a cancer growth inhibitor. Use of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the preparation of a prophylactic or therapeutic agent for cancer. Use of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the preparation of a pancreatic function modulator. Metastin derivative (II) according to claim 1 or a salt thereof, for the manufacture of a prophylactic or therapeutic agent for chorionic carcinoma, award status, invasive status, abortion, fetal dysfunction, abnormal glucose metabolism, abnormal lipid metabolism or induction of labor, or Uses thereof prodrugs. Use of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the preparation of a gonadal function improving agent. Use of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the manufacture of a prophylactic or therapeutic agent for hormone-dependent cancer, infertility, endometriosis, early puberty or uterine fibroids. Use of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the preparation of an ovulation inducing or stimulating agent. Use of a metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the preparation of a gonadotropin secretion promoter or a sex hormone secretagogue. Use of the metastin derivative (II) according to claim 1 or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis or treatment of Alzheimer's disease or mild cognitive impairment. Gonadotropin secretion inhibitors or sex hormone secretion inhibitors containing metastin derivative (III) or salts thereof, or prodrugs thereof, represented by the formula:

[In meals: V 'is a group represented by the following formula:

A group represented by the following formula:

Or a group represented by the following formula:

Represents; n represents 0 or 1; W ¹ represents N, CH or O, provided that when W ¹ is N or CH, n represents 1 and when W ¹ is O, n represents 0; W ² represents N or CH; Z ^1, Z ^3, Z ⁵ and Z ⁷ each represent a hydrogen atom or a C _{1 -3} alkyl group; Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent a hydrogen atom, O or S; R ¹ is (1) hydrogen atom, (2) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and an optionally substituted C _{1 -8} alkyl group with substituents selected from the group consisting an optionally substituted aromatic ring, (3 ) cyclic or linear C _{1 -10} alkyl, or (4) cyclic alkyl group and an alkyl group consisting of a straight chain C _{1 -10} alkyl, or (5) represents an optionally substituted aromatic ring; R ² is (1) hydrogen atom or (2) a cyclic or linear C _{1 -10} alkyl, (3) C _{1 -10} alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) an optionally substituted carbamoyl group, an optionally substituted hydroxyl group and represents an optionally substituted C _{1 -8} alkyl group with substituents selected from the group consisting an optionally substituted aromatic ring; R ³ is (1) an C _1-8 alkyl group having an optionally substituted basic group, optionally having additional substituents, (2) an aralkyl group having an optionally substituted basic group, optionally having an additional substituent, (3) optionally substituted having a basic group and optionally having an additional substituent, the carbon number is C _{1 -4} alkyl group having a non-aromatic cyclic hydrocarbon less than 7, or (4) any group having a basic substituted, optionally, is not more than 7 carbon atoms having an additional substituent C _{1 -4} with an non-aromatic heterocyclic group represents an alkyl group; R ⁴ represents an optionally C _{1 -4} alkyl group which may be substituted with substituents selected from the group consisting of (1) an optionally substituted C _{6 -12} aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , oxygen and sulfur atoms optionally comprising a hetero atom selected from the group consisting of substituted 5- to 14-membered aromatic heterocyclic group, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) a 3 to 11 carbons Optionally substituted 5- to 14-membered aromatic conjugated heterocyclic groups consisting of atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms, and ( 6) optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms; Q ¹ represents an optionally C _{1 -4} alkyl group which may be substituted with substituents selected from the group consisting of (1) an optionally substituted C _{6 -12} aromatic hydrocarbon group, (2) 1 to 7 carbon atoms and nitrogen , oxygen and sulfur atoms optionally comprising a hetero atom selected from the group consisting of substituted 5- to 14-membered aromatic heterocyclic group, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) a 3 to 11 carbons Optionally substituted 5- to 14-membered aromatic conjugated heterocyclic groups consisting of atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) optionally substituted non-aromatic cyclic hydrocarbon groups having 7 or less carbon atoms, and ( 6) optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms; Q ² is (1) a carbamoyl group and a hydroxyl group CH _{2, (2)} which may optionally be substituted with an optionally substituted C _{1 -4} alkyl group having a substituent selected from the consisting of a carbamoyl group and a hydroxyl group It represents an optionally NH, or (3) O which may be substituted with an optionally substituted C _{1 -4} alkyl group having a substituent selected from the group consisting of; Y represents a group represented by the following formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -CH ₂ CH ₂ -, or -CH = CH- (which may optionally be substituted with C _{1 -6} alkyl group) represents; Z ⁹ represents a hydrogen atom, O or S; P and P 'may be the same or different and may combine P and P' or P and Q ¹ with each other to form a ring, which is represented below: (1) hydrogen atoms; (2) an optional amino acid residue that is linked continuously or discontinuously from the C terminus of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1; (3) a group represented by the following formula:

(In the meal: J ¹ is (a) hydrogen atom or _{(b) (i) C 1} -15 acyl group, (ii) C _{1 -15} alkyl, (iii) C _{6 -14} aryl group, (iv) carbamoyl group, (v A) carboxyl group, (vi) sulfino group, (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group, wherein the groups may be optionally substituted with a substituent including an optionally substituted ring group; J ² is (1) an optionally substituted C ₁ NH, (2) C ₁ optionally substituted CH _2, (3) O or (4) represents the S _{-6 -6} alkyl group; J ³ to J ⁶ are each a hydrogen atom or a C _{1 -3} alkyl group; Q ³ to Q ⁶ are each a hydrogen atom, or represents a C _{1 -4} alkyl group which may have a substituent optionally selected from the group consisting of: (1) an optionally substituted C _{6 -12} hydrocarbon group, an aromatic, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C _{8 -14} aromatic fused ring group, (4) an optionally substituted 5- to 14-membered aromatic conjugated heterocyclic group consisting of 3 to 11 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having 7 or less carbon atoms, (6) an optionally substituted non-aromatic heterocyclic group having 7 or less carbon atoms, (7) an optionally substituted amino group, (8) an optionally substituted guanidino group, (9) an optionally substituted hydroxyl group, (10) an optionally substituted carboxyl group, (11) an optionally substituted carbamoyl group, and (12) optionally substituted sulfhydryl groups; J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ are combined with each other, or Z ¹ and R ¹ , J ² and Q ³ , Y ¹ and Q ⁴ , Y ² And Q ⁵ , or Y ³ and Q ⁶ may be combined with each other to form a ring; Y ¹ to Y ³ each represent a group represented by the following formula: -CON (J ¹³ )-, -CSN (J ¹³ )-, -C (J ¹⁴ ) N (J ¹³ )-or -N (J ¹³ ) CO-, wherein J ¹³ and J ¹⁴ are each hydrogen atoms or C _{1 -3} alkyl group); Z ¹⁰ represents a hydrogen atom, O or S); (4) a group represented by the following formula:

(In the meal: J ¹ and J ² each have the same meaning as described above; J ⁷ to J ⁹ have the same meaning as for J ³ ; Q ⁷ to Q ⁹ have the same meaning as for Q ³ ; Y ² and Y ³ each have the same meaning as described above; Z ¹⁰ has the same meaning as described above; J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ may be combined with each other, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ may be combined with each other to form a ring. have); (5) a group represented by the following formula:

(In the meal: J ¹ and J ² have the same meaning as described above; J ¹⁰ and J ¹¹ have the same meaning as for J ³ ; Q ¹⁰ and Q ¹¹ have the same meaning as for Q ³ ; Y ³ has the same meaning as described above; Z ¹⁰ has the same meaning as described above; J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ may be combined with each other, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ may be combined with each other to form a ring); (6) a group represented by the following formula:

(In the meal: J ¹ and J ² have the same meaning as described above; J ¹² has the same meaning as for J ³ ; Q ¹² has the same meaning as for Q ³ ; Z ¹⁰ has the same meaning as described above; J ¹² and Q ¹² may be combined with each other, or J ² and Q ¹² may be combined with each other to form a ring); or, (7) a group represented by the following formula: J ¹ -wherein J ¹ has the same meaning as described above. The inhibitor according to claim 33, wherein the metastin derivative (III) is a metastin derivative (II) according to (1). 34. The inhibitor of claim 33, wherein V 'is a group represented by the formula:

(Wherein each symbol has the same meaning as described in claim 33). 34. The inhibitor of claim 33, wherein V 'is a group represented by the formula:

(Wherein each symbol has the same meaning as described in claim 33). 34. The inhibitor of claim 33, wherein V 'is a group represented by the formula:

(Wherein each symbol has the same meaning as described in claim 33). 38. The inhibitor of any one of claims 33-37, which is a downregulator for gonadotropin or sex hormone. The inhibitor according to any one of claims 33 to 37, which is a downregulator for human OT7T175 (methastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9. 40. The inhibitor of any one of claims 33-39, which is an agent for the prophylaxis or treatment of hormone-dependent cancers. A method of inhibiting gonadal stimulating hormone secretion or sex hormone secretion comprising administering to a mammal an effective amount of the metastin derivative (III) or salt thereof, or prodrug thereof. A method for downregulating a gonadotropin or sex hormone comprising administering to a mammal an effective amount of a metastin derivative according to claim 33 or a salt thereof, or a prodrug thereof. A method for downregulating a human OT7T175 (methastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9 comprising administering to a mammal an effective amount of a metastin derivative according to claim 33 or a salt thereof, or a prodrug thereof . A method of preventing or treating a hormone-dependent cancer comprising administering to a mammal an effective amount of a metastin derivative according to claim 33 or a salt thereof, or a prodrug thereof. Use of a metastin derivative according to claim 33 or a salt thereof, or a prodrug thereof, for the preparation of a gonadotropin secretion inhibitor or a sex hormone secretion inhibitor. Use of a metastine derivative according to claim 33 or a salt thereof, or a prodrug thereof, for the manufacture of a downregulator for gonadotropin or sex hormone. Use of a metastin derivative according to claim 33 or a salt thereof, or a prodrug thereof, for the preparation of a downregulator for human OT7T175 (methastine receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9. Use of a metastine derivative according to claim 33 or a salt thereof, or a prodrug thereof, for the manufacture of a prophylactic or therapeutic agent for hormone-dependent cancer. Metastin derivatives or salts thereof represented by the formula:

(In the meal: XX0 are formyl, C _{1 -6} alkanoyl, cyclopropanecarbonyl, 6- (acetyl -D- are ginil amino) caproyl, 6 - ((R) -2,3- diamino propionyl amino) caproyl , 6- (D-norylsilamino) caproyl, 4- (D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyltyro Sil, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3- (pyridin-3-yl) propionyl, adipoyl or 6-aminocaproyl; XX2 represents Tyr, D-Tyr, D-Ala, D-Leu, D-Phe, D-Lys, D-Trp or bond arm; XX3 is Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D-3- Pyridylalanine or D-4-pyridylalanine; XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ^β -formyldiaminopropionic acid or N ^β -acetyldiaminopropionic acid; XX5 represents Ser, Thr or Val; XX6 represents Phe, Tyr, Trp, Tyr (Me), Thi, Nal (2), Cha, 4-pyridylalanine or 4-fluorophenylalanine; AzaGlY represents azaglycine; XX8 represents Leu, Nva or Val; XX9 represents Arg, Orn, Arg (Me) or Arg (symMe2); XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine). D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 305), D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 385), D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 501), Benzoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 509), D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 512), Ac-D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 516), D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 540), D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 541), Benzoyl-Asn-Ser-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 545), D-Tyr-D-Pya (4) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -PheΨ (CSNH) NH ₂ (Compound No. 548), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 550), Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 551), D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 552), D-Nle-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 553), D-Arg-γ-Abu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 555), Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 558), 3- (4-hydroxyphenyl) propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 559), Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 562), Ac-D-Tyr-D-Trp-Asn-Val-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 564), Cyclopropanecarbonyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 566), Butyryl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 567), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 571), Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 579), Ac-D-Tyr-D-Trp-Asn-Ser (Me) -Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 580), Ac-D-Tyr-D-Trp-Dap (Ac) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 584), Ac-D-Tyr-D-Trp-Dap (For) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 585), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Nal (2) -NH ₂ (Compound No. 589), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Thi-NH ₂ (Compound No. 590), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Tyr-NH ₂ (Compound No. 591), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂ (Compound No. 592), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Orn-Trp-NH ₂ (Compound No. 599), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂ (Compound No. 600), Ac-D-NMeTyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 602), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (symMe2) -Trp-NH ₂ (Compound No. 608), For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 612), Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 613), Ac-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 615), Ac-D-Ala-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 616), Ac-D-Leu-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 617), Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 618), Ac-D-Lys-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 621), Ac-D-Tyr-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 623), Ac-D-Tyr-D-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 625), Ac-D-Tyr-D-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 626), Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 627), Ac-D-Tyr-D-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 629), Ac-D-Tyr-D-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 630), Ac-D-Tyr-D-Trp-Asn-Thr-Pya (4) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 635), Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 637), Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 638), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Val-Arg (Me) -Trp-NH ₂ (Compound No. 642), Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 648), Ac-Gly-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 649), D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 650), Ac-D-Tyr-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 651), pGlu-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 652), Ac-D-Tyr-Pro-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 657), Ac-D-Tyr-D-Pya (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 658), Ac-D-Tyr-D-Pya (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 660), Ac-D-Tyr-Tic-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 662), Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 663), Ac-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 666), Hexanoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 667), 3-pyridinepropionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 670), Adipoyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 671), Ac-D-Tyr-NMeTrp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 672), 6-aminocaproyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 674), or salts thereof. Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 550), Ac-D-Arg-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 551), D-Dap-Acp-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 552), Ac-D-Tyr-D-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 558), 3- (4-hydroxyphenyl) propionyl-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 559), Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 562), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂ (Compound No. 571), Ac-D-Tyr-D-Trp-Alb-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 579), Ac-D-Tyr-D-Trp-Dap (For) -Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 585), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Nal (2) -NH ₂ (Compound No. 589), Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Phe (4F) -NH ₂ (Compound No. 592), For-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 612), Propionyl-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 613), Ac-D-Phe-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 618), Ac-D-Tyr-D-Phe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 627), Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 637), Ac-D-Tyr-D-Pya (4) -Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 638), Ac-D-Tyr-D-Pya (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 658), Ac-D-Tyr-D-Pya (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 660), Ac-D-Trp-D-Trp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 663), or salts thereof. A method of enhancing blood stability comprising introducing one or two alkyl groups into the side chain of Arg of an Arg-comprising peptide. A method of enhancing blood stability comprising introducing one alkyl group into the side chain of Arg of an Arg-comprising peptide. A method of enhancing blood stability, comprising converting an Arg side chain of an Arg-comprising peptide into an N ^omega -alkylated Arg. Of claim 52 to A method according to any one of claim 54, wherein the alkyl group is a C _{1 -4} alkyl group; 55. The method of any one of claims 52-54, wherein the alkyl group is a methyl group. 55. The peptide of any one of claims 52 to 54, wherein the Arg-containing peptide is a peptide having a partial peptide characterized by the structure -Arg-XXX-, wherein XXX represents an amino acid having an aromatic ring group optionally substituted in the side chain. Way. 58. The method of claim 57, wherein XXX is Phe, Trp or Tyr.

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