RU2454425C2 - Metastin derivatives and use thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to stable metastin derivatives, having excellent biological activity. The disclosed metastin derivatives improve stability, gelation tendency is reduced, pharmacokinetics are also improved, and an excellent cancer metastasis suppressing activity or a cancer growth suppressing activity is exhibited.

EFFECT: metastin derivatives of the present invention also have a gonadotropic hormone secretion suppressing activity and sex hormone secretion suppressing activity.

5 cl, 4 tbl, 18 ex

Description

FIELD OF THE INVENTION

The present invention relates to derivatives of metastin and their use.

State of the art

Known human metastin (also called KiSS-1 peptide) (WO00 / 24890) and mouse or rat metastin (WO01 / 75104). Sustained release formulations containing metastin are also known (WO02 / 85399).

According to reports, metastin has the effect of suppressing cancer metastasis and is thus effective in preventing / treating cancer (e.g. lung cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, colorectal cancer, colon cancer, prostate cancer , ovarian cancer, cervical cancer, breast cancer, kidney cancer, bladder cancer, brain tumor, and so on); metastin also has the effect of controlling pancreatic function and is effective for the prevention / treatment of pancreatic diseases (for example, acute or chronic pancreatitis, pancreatic cancer, and so on); and in addition, metastin has the effect of controlling placental function and is effective for the prevention / treatment of choriocarcinoma, cystic skid, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or abnormal delivery (WO00 / 24890, WO01 / 75104 / 85399).

DESCRIPTION OF THE INVENTION

The present invention relates to stable derivatives of metastin having excellent biological activities (activity suppressing metastasis of cancerous tumors, activity suppressing growth of cancerous tumors, activity stimulating secretion of gonadotropin hormones, activity stimulating secretion of sex hormones, activity suppressing secretion of gonadotropin hormones, activity suppressing secretion of sex hormones and Further).

The authors of the present invention carried out intensive studies to solve the above problems and as a result found that when substituting the metastin-forming amino acids with some other amino acids, blood stability, solubility and so on unexpectedly improve significantly, the tendency to gelation decreases, the pharmacokinetics also improve, and excellent suppression activity is demonstrated cancer metastasis or cancer growth inhibition activity. Also, the inventors of the present invention unexpectedly found that these metastin derivatives have an effect of suppressing the secretion of gonadotropin hormone, an effect of suppressing the secretion of sex hormones and so on, which are completely different from the effects known so far. Based on these findings, the authors of the present invention conducted further studies and carried out the present invention.

Thus, the present invention relates to the following objects and the like.

[1] A metastin derivative represented by the following formula, or a salt thereof:

(Where:

V 'represents a group represented by the formula:

n is 0 or 1;

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

W ² represents N or CH;

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

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

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

R ² represents (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) C _{1- 8} an alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic cyclic group;

R ³ represents (1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having an additional substituent, (2) an aralkyl group having an optionally substituted basic group and optionally having an additional substituent, (3) C _1-4 alkyl a group having a non-aromatic cyclic hydrocarbon group containing not more than 7 carbon atoms, having an optionally substituted basic group, and optionally having an additional substituent, or (4) a C _1-4 alkyl group having a nonarom an atic heterocyclic group containing not more than 7 carbon atoms, having an optionally substituted basic group and optionally having an additional substituent;

R ⁴ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) an optionally substituted 5-14 membered aromatic heterocyclic a group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condenser bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and, (6) optional a substituted non-aromatic heterocyclic group having at most 7 carbon atoms;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of: (1) an optionally substituted C _6-12 aromatic hydrocarbon group, (2) an optionally substituted 5-14 membered aromatic heterocyclic a group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condenser bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and (6) optionally substituted a non-aromatic heterocyclic group having no more than 7 carbon atoms;

A represents:

(1) a nitrogen atom substituted with a hydrogen atom or a C _1-3 alkyl group;

(2) a carbon atom substituted by a hydrogen atom or a C _1-3 alkyl group;

(3) O; or

(4) S;

A 'represents:

(1) a carbon atom, which optionally can be substituted by a hydrogen atom, O, S, a halogen atom, an optionally halogenated C _1-3 alkyl group, a carbamoyl group or a hydroxyl group;

(2) a nitrogen atom, which optionally can be substituted by a hydrogen atom or an optionally halogenated C _1-3 alkyl group;

(3) O; or

(4) S;

Q ² represents:

(1) CH ₂ , CO, CS or CH = CH ₂ , which optionally can be substituted with one or two C _0-4 alkyl groups, optionally substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups, a halogen atom and an amino group;

(2) NH, which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group; or,

(3) O;

Y represents:

(1) a group represented by the formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -COCH ₂ -, -CH ₂ S-, -CSCH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH = CH-, which may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl a group, a hydroxyl group and a halogen atom;

(2) an optionally substituted C _6-7 aromatic hydrocarbon group;

(3) an optionally substituted 4-7 membered aromatic heterocyclic group consisting of 1-5 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(4) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms; or,

(5) an optionally substituted non-aromatic heterocyclic group having no more than 5 carbon atoms, and when Y represents (2), (3), (4) or (5), Q ² may be a chemical bond.

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

(1) a hydrogen atom;

(2) an optional amino acid residue, continuously or non-continuously attached from the C-terminal end of the 1st to 48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the formula:

J ¹ -J ² -C (J ³ ) (Q ³ ) Y ¹ C (J ⁴ ) (Q ⁴ ) Y ² C (J ⁵ ) (Q ⁵ ) Y ³ C (J ⁶ ) (Q ⁶ ) C ( = Z ¹⁰ ) -

(where J ¹ represents (a) a hydrogen atom or (b) (i) a C _1-20 acyl group, (ii) a C _1-20 alkyl group, (iii) a C _6-14 aryl group, (iv) a carbamoyl group , (v) a carboxyl group, (vi) a sulfino group, (vii) an amidino group, (viii) a glyoxyloyl group or (ix) an amino group, said group may optionally be substituted with a substituent containing an optionally substituted cyclic group; J ² represents (1) NH optionally substituted with a C _1-6 alkyl group, (2) CH ₂ optionally substituted with a C _1-6 alkyl group, (3) O or (4) S; each of J ³ - J ⁶ represents represents a hydrogen atom or a C _1-3 alkyl group;

each of Q ³ - Q ⁶ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of:

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 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) an optionally substituted sulfhydryl group;

or a hydrogen atom; J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, 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 can be combined together to form a ring; Y ¹ - Y ³ each represents a group represented by the formula: —CON (J ¹³ ) -, —CSN (J ¹³ ) -, —C (J ¹⁴ ) N (J ¹³ ) -, or —N (J ¹³ ) CO- (where J ¹³ and J ¹⁴ each represent a hydrogen atom or a C _1-3 alkyl group); and Z ¹⁰ represents a hydrogen atom, O or S);

(4) a group represented by the formula:

J ¹ -J ² -C (J ⁷ ) (Q ⁷ ) Y ² C (J ⁸ ) (Q ⁸ ) Y ³ C (J ⁹ ) (Q ⁹ ) C (= Z ¹⁰ ) -

(where each of J ¹ and J ² has the same meanings as above, J ⁷ -J ⁹ have the same meanings as for J ³ , Q ⁷ - Q ⁹ have the same meanings as for Q ³ , Y ² and Y ³ have the same meanings as above, Z ¹⁰ has the same meanings as above, J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined together to form a ring);

(5) a group represented by the formula:

J ¹ -J ² -C (J ¹⁰ ) (Q ¹⁰ ) Y ³ C (J ¹¹ ) (Q ¹¹ ) C (= Z ¹⁰ ) -

(where J ¹ and J ² have the same meanings as above, J ¹⁰ and J ¹¹ have the same meanings as for J ³ , Q ¹⁰ and Q ¹¹ have the same meanings as for Q ³ , Y ³ has the same meanings as above, Z ¹⁰ has the same meanings as above, J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined together to form a ring);

(6) a group represented by the formula: J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ ) -

(where, J ¹ and J ² have the same meanings as above, J ¹² has the same meanings as for J ³ , Q ¹² has the same meanings as for Q ³ , and Z ¹⁰ has the same meanings as indicated above; J ¹² and Q ¹² can be combined together, or J ² and Q ¹² can be combined together to form a ring); or,

(7) a group represented by the formula: J ¹ - (where J ¹ has the same meanings as above); the bonds between YQ ² , Q ² -A 'and A'-A, each independently represent a single or double bond);

provided that excluded

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ (CH ₂ NH) Gly-Leu-Arg (Me) -Trp-NH ₂ ,

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ ,

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ and

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg (Me) -Trp-NH ₂ .

[2] A metastin derivative according to [1] or a salt thereof, wherein:

Z ¹ , Z ⁵ and Z ⁷ each represent a hydrogen atom;

Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent O;

R ¹ represents (2) a C _1-8 alkyl group optionally substituted with an optionally substituted hydroxyl group;

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

R ³ represents (1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having an additional substituent;

R ⁴ represents (4) a C _1-4 alkyl group, which optionally can be substituted by an optionally substituted 5-14 membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom, or (4) S;

A 'represents (1) a carbon atom substituted by a hydrogen atom or O;

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _1-4 alkyl groups, which optionally can be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups; and,

Y represents (1) a group represented by the formula: —CONH—, —CSNH—, —NHCO—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH = CH— or —CH ₂ CH ₂ -C _1-6 , which optionally can be substituted with a substituent selected from the group consisting of an alkyl group, a hydroxyl group and a halogen group.

[3] A metastin derivative represented by the following formula, or a salt thereof:

XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂

Where

XX0 is formyl, C _1-20 alkanoyl, cyclopropanecarbonyl, 6- (acetyl-D-arginylamino) caproyl, 6 - ((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norleucylamino) caproyl, 4- (D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyl tyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3- (pyridin-3-yl) propionyl, adipoyl, glycoloyl or 6-aminocaproyl;

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

XX3 is D-Asp, D-Dap, D-Ser, D-Gln, D-His, D-NMeAla, D-NMePhe, Aze (2), Pic (2), Pic (3), Hyp, Thz, NMeAla, Gly, Aib, Abz (2), Abz (3), Sar, Leu, Lys, Glu, β-Alanine, Pzc (2), Orn, His (3Me), Tyr (PO ₃ H ₂ ), Pro ( 4NH ₂ ), Hyp (Bzl), Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D -3-pyridylalanine, D-4-pyridylalanine, Aad, Pro (4F) or a chemical bond;

XX4 represents Asn, 2-amino-3-ureidopropionovuyu acid, N ^β -formildiaminopropionovuyu acid, N ^β -atsetildiaminopropionovuyu acid, N ^ω -pentilasparagin, N ^ω -tsiklopropilasparagin, N ^ω -benzilasparagin, 2,4-diaminobutanoic acid, His, Gln, Cit or D-Asn;

XX5 is Ser, Thr, Val, NMeSer, Gly, Ala, Hyp, D-Ala, Dap or D-Thr;

T represents a group represented by formula II:

Z ⁴ represents a hydrogen atom, O or S;

R ² represents (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) C _{1- 8} an alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic cyclic group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condensiro bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and (6) optionally substituted a non-aromatic heterocyclic group having no more than 7 carbon atoms;

A represents:

(1) a nitrogen atom substituted by a hydrogen atom or a C _1-3 alkyl group,

(2) a carbon atom substituted by a hydrogen atom or a C _1-3 alkyl group,

(3) O, or

(4) S;

A 'represents:

(1) a carbon atom, which optionally can be substituted by a hydrogen atom, O, S, a halogen atom, an optionally halogenated C _1-3 alkyl group, a carbamoyl group or a hydroxyl group,

(2) a nitrogen atom, which optionally can be substituted by a hydrogen atom or an optionally substituted C _1-3 alkyl group,

(3) O, or,

(4) S;

Q ² represents:

(1) CH ₂ , CO, CS or CH = CH ₂ , which may optionally be substituted with a C _0-4 alkyl group optionally substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, a C _1-3 alkoxy group, an atom halogen and amino groups,

(2) NH, which may optionally be substituted with an optionally substituted C _1-4 alkyl group with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, or

(3) O;

Y represents:

(1) a group represented by the formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -COCH ₂ -, -CH ₂ S-, -CSCH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH = CH-, which may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl group, hydroxyl group and halogen atom,

(2) an optionally substituted C _6-7 aromatic hydrocarbon group,

(3) an optionally substituted 4-7 membered aromatic heterocyclic group consisting of 1-5 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(4) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms, or,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms, and when Y represents (2), (3), (4) or (5), Q ² may be a chemical bond;

the bonds between YQ ² , Q ² -A 'and A'-A, each independently represent a single or double bond;

XX9 represents Arg, Orn, Arg (Me) or Arg (asymMe ₂ ); and,

XX10 is Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine;

provided that excluded

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ (CH ₂ NH) Gly-Leu-Arg (Me) -Trp-NH ₂ ,

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ ,

Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ and

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg (Me) -Trp-NH ₂ .

In the formula "XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂ " described above, each of the "-" bonds between XX0, XX2, XX3, XX4, XX5, T, XX9, XX10 and NH ₂ has a different meaning. For example, the “-” bond between XX0-XX1 means a bond between an alkanoyl group and an amino group in XX2; the "-" bonds between XX2-XX3, XX3-XX4, XX4-XX5, XX5-T, T-XX9 and XX9-XX10 usually mean a bond between C = O and NH in the amide bond to bind adjacent amino acid residues; and the “-” bond between XX10-NH ₂ means a carbonyl group and an amino group in XX10. That is, in the bond between amino acid residues, a bond means a bond between C = O and NH, where said carboxyl and amino group residues are involved in the reaction, respectively. Specific communication examples include those represented by structural formulas in Table 1, described below.

[4] A metastin derivative according to [3] or a salt thereof, wherein:

XX0 is formyl, C _1-6 alkanoyl or glycoloyl;

XX2 represents D-Tyr or a chemical bond;

XX3 is Aze (2), Hyp, Gly, Aib, Leu, Lys, Glu, His (3Me), Tyr (PO ₃ H ₂ ), Pro (4F) or Hyp (Bzl);

XX4 represents Asn or 2-amino-3-ureidopropionic acid;

XX5 represents Ser or Thr;

Z ⁴ represents O;

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom, or (4) S;

A 'represents (1) a carbon atom substituted by a hydrogen atom, or O;

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _0-4 alkyl groups, which optionally can be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups;

Y represents (1) a group represented by the formula: —CONH—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH ₂ CH ₂ -, CSNH—, —NHCO— or —CH = CH -, which may optionally be substituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a hydroxyl group and a halogen atom;

XX9 represents Arg or Arg (Me); and,

XX10 represents Phe or Trp.

[5] A metastin derivative according to [3], or a salt thereof, or a prodrug thereof, wherein:

XX0 represents C _1-12 alkanoyl;

XX2 represents D-Tyr;

XX3 is Hyp, Pro (4F) or Glu;

XX4 represents Asn or 2-amino-3-ureidopropionic acid;

XX5 represents Thr;

Z ⁴ represents O,

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom, or (4) S;

A 'represents (1) a carbon atom substituted by a hydrogen atom or O;

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _1-4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups;

Y represents (1) a group represented by the formula: —CONH—, —CSNH—, —NHCO—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH = CH— or —CH ₂ CH ₂ -, which optionally may be substituted with a C _1-6 alkyl group, a hydroxyl group or a halogen atom;

XX9 represents Arg or Arg (Me); and,

XX10 represents Trp.

[5a] The compound further, or a salt or prodrug thereof:

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 796),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ala-Leu-Arg (Me) -Trp-NH ₂ (compound No. 803),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ser-Leu-Arg (Me) -Trp-NH ₂ (compound No. 804),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Aib-Leu-Arg (Me) -Trp-NH ₂ (compound No. 811),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Abu-Leu-Arg (Me) -Trp-NH ₂ (compound No. 818),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 822),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Ala-Leu-Arg (Me) -Trp-NH ₂ (compound No. 823),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Dap-Leu-Arg (Me) -Trp-NH ₂ (compound No. 827),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ser (Me) -Leu-Arg (Me) -Trp-NH ₂ (compound No. 828),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ O) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 834),

Ac-D-Tyr-Hyp-Asn-Thr-Pya (2) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 839),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Val-Leu-Arg (Me) -Trp-NH ₂ (compound No. 847),

Ac-D-Tyr-Hyp-Asn-Thr-Pya (3) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 848),

Ac-D-Tyr-Hyp-Asn-Thr-Pya (4) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 849),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 850),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (COCH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 851),

Ac-D-Tyr-Glu-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 852),

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 853),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ NH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 854),

Ac-D-Tyr-Hyp-Asn-Thr-Ala (cPr) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 855),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((S) CHOH-CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 857),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((S) CHOH- (E) CH =) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 858),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((E) CH = CH) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 859),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((R) CHOH- (E) CH =) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 866),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((R) CHOH-CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 867),

Ac-D-Tyr-Hyp-Asn-Thr-αMePhe-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 869),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (2Me) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 871),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (3Me) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 873),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (4Me) -Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 875),

Ac-D-Tyr-Hyp-Alb-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 885),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 892),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ CH ₂ ) Leu-Arg (Me) -Trp-NH ₂ (compound No. 893),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 894),

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 895),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 902),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 903),

Ac-D-Tyr-Glu-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 904),

Ac-D-Tyr-Glu-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 905),

Ac-D-Tyr-Hyp-Alb-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 906),

Ac-D-Tyr-Glu-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 907),

Ac-D-Tyr-Glu-Alb-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 908),

Ac-D-Tyr-Asp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 909),

Ac-D-Tyr-Aad-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 910),

Ac-D-Tyr-Lys-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 911),

Ac-D-Tyr-Aib-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 912),

Ac-D-Tyr-Hyp-Gln-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 913),

Ac-D-Tyr-Hyp-Cit-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 914),

Ac-D-Tyr-Hyp-Glu-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 915),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 916),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂ (compound No. 917),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Nva-Arg (Me) -Trp-NH ₂ (compound No. 918),

Ac-D-Tyr-Hyp-Asn-Thr-Nal (2) -Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 919),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂ (compound No. 920),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Nva-Arg (Me) -Trp-NH ₂ (compound No. 921),

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂ (compound No. 923),

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Nva-Arg (Me) -Trp-NH ₂ (compound No. 924),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ (compound No. 925),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ (compound No. 926),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ (compound No. 927),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ S) Leu-Arg (Me) -Trp-NH ₂ (compound No. 929),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ (CH ₂ S) Leu-Arg (Me) -Trp-NH ₂ (compound No. 931),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Nle-Arg (Me) -Trp-NH ₂ (compound No. 932),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Leu (Me) -Arg (Me) -Trp-NH ₂ (compound No. 933),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Cha-Arg (Me) -Trp-NH ₂ (compound No. 934),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg-Trp-NH ₂ (compound No. 940),

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ala (cPr) -Arg-Trp-NH ₂ (compound No. 942),

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ S) Gly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 944),

Ac-D-Tyr-Hyp-Asn-Thr-Ala (cBu) -Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 945),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cBu) -Arg (Me) -Trp-NH ₂ (compound No. 946),

Ac-D-Tyr-Hyp-Alb-Ala-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 947),

Ac-D-Tyr-Hyp-Alb-Ser-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 948),

Ac-D-Tyr-Hyp-Alb-Gly-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 949),

Ac-D-Tyr-Hyp-Alb-Dap-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 951),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg-Trp-NH ₂ (compound No. 952),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 953),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg-Trp-NH ₂ (compound No. 956),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg (Me) -Trp-NH ₂ (compound No. 957),

Ac-D-Tyr-Pro (4F) -Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 959), or,

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ CH ₂ ) AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 968).

[6] A compound selected from:

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 894),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 902),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ (compound No. 903),

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ (compound No. 926),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ (compound No. 927),

Ac-D-Tyr-Hyp-Alb-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 953) and

Ac-D-Tyr-Pro (4F) -Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 959).

[7] A metastin derivative according to [1] or a salt thereof or a prodrug thereof.

[8] A metastin derivative according to [3] or a salt thereof or a prodrug thereof.

[9] A drug containing a metastin derivative according to [1] to [6] or a salt thereof or a prodrug thereof.

[10] The medicament according to [9] above, which is an agent for suppressing cancer metastases or an agent for suppressing cancer.

[11] The medicine according to [9] above, which is a cancer prophylaxis / treatment agent.

[12] The drug according to [9] above, which is an agent for controlling placental function.

[13] The medicament according to [9] above, which is a prophylaxis / treatment for choriocarcinoma, cystic skid, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or labor induction.

[14] The drug according to [9] above, which is an agent for improving gonadal function.

[15] The medicament according to [9] above, which is a prophylaxis / treatment for hormone-dependent cancer, infertility, endometriosis, puberty or uterine fibroids.

[16] The drug according to [9] above, which is an agent for inducing or stimulating ovulation.

[17] The drug according to [9] above, which is an agent that enhances the secretion of gonadotropin hormone, or an agent that enhances the secretion of sex hormone.

[18] The medicament according to [9] above, which is a prophylaxis / treatment for Alzheimer's disease, mild cognitive impairment, or autism.

[19] The drug according to [17] above, which is an agent for inhibiting the production of gonadotropin hormone or sex hormone.

[20] The drug according to [17] above, which is an agent for inhibiting the production of the human protein OT7T175 (metastin receptor), consisting of the amino acid sequence represented by SEQ ID NO: 9.

[21] The drug according to [19] or [20] above, which is an agent for the prophylaxis / treatment of hormone dependent cancer.

In addition, the present invention provides the following objects and the like.

[22] A method for suppressing cancer metastasis or suppressing cancer growth, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[23] A method for the prevention / treatment of cancer, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[24] A method for controlling placental function, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[25] A method for the prophylaxis / treatment of choriocarcinoma, cystic drift, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or labor induction, which comprises administering to the mammal an effective dose of a metastin derivative according to any of [1] - [ 6] or its salt, or its prodrug.

[26] A method for improving gonadal function, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[27] A method for the prevention / treatment of hormone-dependent cancer, infertility, endometriosis, early puberty or uterine fibroids, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof .

[28] A method of inducing or stimulating ovulation, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[29] A method of stimulating the secretion of a gonadotropin hormone or stimulating the secretion of sex hormones, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[30] A method for the prophylaxis / treatment of Alzheimer's disease, mild cognitive impairment or autism, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[31] A method for inhibiting the production of a gonadotropin hormone or sex hormone, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[32] A method for inhibiting the production of the human protein OT7T175 (metastin receptor), consisting of the amino acid sequence represented by SEQ ID NO: 9, which comprises administering to the mammal an effective dose of a metastin derivative according to any of [1] to [6] or a salt thereof, or its prodrugs.

[33] A method for the prevention / treatment of hormone-dependent cancer, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof or a prodrug thereof.

[34] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for suppressing cancer metastases or an agent for suppressing the development of cancer.

[34a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in suppressing cancer metastases or inhibiting the development of cancer.

[35] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis / treatment of cancer.

[35a] A metastin derivative according to any one of [1] to [6] or its salt, or its prodrug, for use in the prevention / treatment of cancer.

[36] The use of a metastin derivative in accordance with any one of [1] to [6] or its salt, or its prodrug, to provide an agent for controlling placental function.

[36a] A metastin derivative according to any one of [1] to [6] or a salt thereof, or a prodrug thereof, for use in controlling placental function.

[37] The use of a metastin derivative in accordance with any one of [1] - [6] or its salt, or its prodrug, for the preparation of a prophylaxis / treatment for choriocarcinoma, cystic skid, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal metabolism glucose, abnormal fat metabolism, or labor excitement.

[37a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in the prophylaxis / treatment of choriocarcinoma, cystic skid, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or childbirth.

[38] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, to provide an agent for improving gonadal function.

[38a] A metastin derivative according to any one of [1] to [6] or a salt thereof, or a prodrug thereof, for use in improving gonadal function.

[39] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis / treatment of hormone-dependent cancer, infertility, endometriosis, puberty or uterine fibroids.

[39a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in the prophylaxis / treatment of hormone-dependent cancer, infertility, endometriosis, puberty or uterine fibroids.

[40] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the preparation of an agent for inducing or stimulating ovulation.

[40a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in inducing or stimulating ovulation.

[41] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent that enhances the secretion of gonadotropin hormone, or an agent that enhances the secretion of sex hormone.

[41a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in stimulating the secretion of a gonadotropin hormone or the secretion of sex hormones.

[42] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis / treatment of Alzheimer's disease, mild cognitive impairment, or autism.

[42a] A metastin derivative according to any one of [1] to [6] or a salt thereof or a prodrug thereof for use in the prophylaxis / treatment of Alzheimer's disease, mild cognitive impairment, or autism.

[43] The use of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for inhibiting the production of a gonadotropin hormone or sex hormone.

[43a] A metastin derivative according to any one of [1] to [6] or a salt thereof, or a prodrug thereof, for use in inhibiting the production of a gonadotropin hormone or sex hormone.

[44] The use of a metastin derivative in accordance with any one of [1] to [6] or its salt, or its prodrug, for the preparation of an agent for inhibiting the production of the human protein OT7T175 (metastin receptor), consisting of the amino acid sequence represented by SEQ ID NO: 9.

[44a] A metastin derivative according to any one of [1] to [6], or a salt thereof, or a prodrug thereof, for use in inhibiting the production of the human protein OT7T175 (metastin receptor), consisting of the amino acid sequence represented by SEQ ID NO: 9.

[45] The use of a metastin derivative in accordance with any of [1] to [6] or a salt thereof, or a prodrug thereof, for the manufacture of an agent for the prophylaxis / treatment of hormone-dependent cancer.

[45a] A metastin derivative according to any one of [1] to [6] or a salt thereof, or a prodrug thereof, for use in the prophylaxis / treatment of hormone-dependent cancer.

In addition, the present invention relates to the following features, and the like.

[46] (1) An agent for controlling pancreatic function, (2) an agent for preventing / treating acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent that enhances the secretion of pancreatic glucagon, an agent, or an agent for stimulating urination, ( 4) a tool for the prevention / treatment of obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disorders i, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinomas, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) a means to suppress the secretion of gonadotropin hormone or a means to suppress the secretion of sex hormones, or (6) a means to prevent follicular suppuration of the ovaries, a means of stopping the menstrual cycle or contraceptive, which contains a metastin derivative in accordance with any of [1] - [6] or its salt, or its prodrug.

[47] (1) A method for controlling pancreatic function, (2) a method for preventing / treating acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent, an agent that enhances the secretion of pancreatic glucagon or an agent for stimulating urination, (4) an agent for the prevention / treatment of obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorders, resistance to insulin, unstable diabetes, fatty atrophy, insulin allergy, insulinomas, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) an agent for suppressing the secretion of gonadotropin hormone or an agent for suppressing the secretion of sex hormones, or (6) an agent for preventing follicular exposure , a menstrual cycle inhibitor or contraceptive, which comprises administering to the mammal an effective dose of a metastin derivative in accordance with any one of [1] to [6] or a salt thereof, or a prodrug.

[48] The use of a metastin derivative in accordance with any of [1] to [6] or its salt, or its prodrug, for the manufacture of (1) a means for controlling pancreatic function, (2) an agent for the prophylaxis / treatment of acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent, an agent that enhances the secretion of pancreatic glucagon or an agent to stimulate urination, (4) an agent for the prevention / treatment of obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension , diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) gonotropon suppressants or suppressing the secretion of sex hormones, or (6) a means to prevent follicular suppuration of the ovaries, a means of stopping the menstrual cycle or contraceptive.

The metastin derivative of the present invention, its salts, or their prodrugs have excellent blood stability, in addition, an excellent inhibitory effect of cancer metastasis or an action that inhibits the growth of a cancerous tumor, and can be used as an agent for the prophylaxis / treatment of cancerous tumors (e.g. lung cancer , stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, colon cancer, colon cancer, prostate cancer, ovarian cancer, cervical cancer, milk cancer gland and so on). The metastin derivative of the present invention, its salt or its prodrugs have the effects of pancreatic regulation functions and can be used as medications for the prevention / treatment of pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, and so on). The metastin derivative of the present invention, its salts or their prodrugs have effects of the functions of the regulation of the placenta and can be used as medications for the prevention / treatment of choriocarcinoma, cystic skid, destroying cystic skid, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or labor excitement.

Also, the metastin derivative of the present invention or a salt or prodrug thereof has the effects of increasing sugar levels, stimulating the secretion of glucagon in the pancreas and stimulating urination, and can be used as a means for the prevention / treatment of obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes beta, fatty atrophy, allergies to insulin, insulinomas, arteriosclerosis, thrombotic disorders or lipotoxicity.

In addition, the metastin derivative of the present invention or a salt or prodrug thereof has excellent activity of stimulating the secretion of gonadotropin hormone, stimulating the secretion of sex hormones, inducing ovulation or stimulating ovulation, and can be used as low toxic and stable agents, for example, agents for improving gonadal function, agents for the prevention / treatment of hormone-dependent cancer (for example, prostate cancer, breast cancer, and so on), infertility, endometriosis , Early puberty, myoma of the uterus, etc., agents for inducing or stimulating ovulation, gonadotropic secretion enhancing agents hormone contraceptives, reinforcing agents hormone secretagogue or the like.

Further, the metastin derivative of the present invention or a salt or prodrug thereof can be used as agents for the prophylaxis / treatment of Alzheimer's disease, moderate cognitive impairment, autism, and so on.

The metastin derivative of the present invention or a salt or prodrug thereof can be used as agents for suppressing the secretion of gonadotropin hormone or suppressing the secretion of sex hormones; agents for inhibiting the production of gonadotropin hormone or sex hormone; agents for inhibiting the production of human OT7T175 (metastin receptor) protein, consisting of the amino acid sequence represented by SEQ ID NO: 9; agents for the prophylaxis / treatment of hormone-dependent malignant tumors (e.g., prostate cancer, breast cancer, and so on; in particular, hormone-sensitive prostate cancer, hormone-sensitive breast cancer, and so on); means for the prevention / treatment of endometriosis; means to prevent follicular suppuration of the ovaries; means of stopping the menstrual cycle; funds for the treatment of uterine fibroids; agents for the treatment of early puberty; contraceptives and so on.

In addition, the metastin derivative of the present invention, or a salt or prodrug thereof, can be used as agents for enhancing immunity (for example, agents for preventing infections after bone marrow transplantation, agents for enhancing immunity in cancer, and so on); immunostimulants (for example, regeneration of the thymus, restoration of the thymus, increased growth of T cells and so on); agents for the prevention / treatment of bulbospinal muscle atrophy; means to protect the ovaries; agents for the prevention / treatment of benign prostatic hypertrophy (BPH); agents for the prevention / treatment of a gender identity disorder; or in vitro fertilization (IVF) agents. In addition, they can be used as agents for the prophylaxis / treatment of infertility, hypogonadism, oligospermia, azoospermia, aspermia, asthenospermia, or necrospermia. In addition, they can be used to treat hormone-dependent diseases (for example, sex hormone-dependent cancer, such as prostate cancer, uterine cancer, breast cancer, pituitary tumor, and so on), prostatic hypertrophy, endometriosis, uterine fibroids , early puberty, dysmenorrhea, amenorrhea, menstrual syndrome, multi-chambered ovary syndrome, postoperative relapse of the above cancers, metastasis of the above cancers, hypopituitarism, dwarfism (case minutes, when the secretion of growth hormone is disrupted hyposecretion of pituitary hormone, etc.), menopausal disorder, indefinite complaint, sex hormone dependent disorders such as bone diseases associated with impaired calcium and phosphorus metabolism. It is also used for contraception (or infertility when using the opposite effects after the cessation of the drug) and so on.

In addition, metastin per se or DNA encoding metastin, and so on, can also be used as agents to suppress the secretion of gonadotropin hormone or the secretion of sex hormones; funds to reduce the production of gonadotropin hormone or suppress sex hormone; means for reducing the production of human OT7T175 (metastin receptor) protein, consisting of the amino acid sequence represented by SEQ ID NO: 9; agents for the prophylaxis / treatment of hormone-dependent cancers (for example, prostate cancer, breast cancer, and so on; in particular, hormone-sensitive prostate cancer, hormone-sensitive breast cancer, and so on); means for the prevention / treatment of endometriosis; means to prevent follicular suppuration of the ovaries; funds that stop the menstrual cycle; funds for the treatment of uterine fibroids; agents for the treatment of early puberty; contraceptives and so on.

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

Here, when Z ² , Z ⁴ , Z ⁶ or Z ⁸ represents a hydrogen atom, the group represented by> C = Z ² ,> C = Z ⁴ ,> C = Z ⁶ or> C = Z ⁸ each indicates to structure> CH _2.

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

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

Z ¹ represents preferably a hydrogen atom.

Z ² is preferably O.

Z ⁴ is preferably O.

Z ⁵ is preferably a hydrogen atom.

Z ⁶ is preferably O.

Z ⁷ represents preferably a hydrogen atom.

Z ⁸ is preferably O.

Preferred combinations of Z ¹ , Z ² , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ further include cases where Z ¹ represents a hydrogen atom, each of Z ⁵ and Z ⁷ represents a hydrogen atom or C _1-3 an alkyl group and each of Z ² , Z ⁴ , Z ⁶ and Z ⁸ represents O or S.

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

(a) the case when Z ¹ represents a hydrogen atom, Z ⁵ represents a hydrogen atom, Z ⁷ represents a hydrogen atom, Z ² represents O, Z ⁴ represents O, Z ⁶ represents O and Z ⁸ represents O ;

(b) the case where Z ¹ represents a hydrogen atom, Z ⁵ represents a hydrogen atom, Z ⁷ represents a hydrogen atom, Z ² represents O, Z ⁴ represents O, Z ⁶ represents O and Z ⁸ represents S ;

(c) the case where Z ¹ represents a hydrogen atom, Z ⁵ represents a hydrogen atom, Z ⁷ represents a methyl group, Z ² represents O, Z ⁴ represents O, Z ⁶ represents O and Z ⁸ represents O ; and so on. Among others, (a) and (b) are preferred, more preferred (a).

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

The term “C _1-8 alkyl group” as used includes, 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 so on, a cyclic C _3-8 alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on. Among others, a C _1-3 alkyl group, such as methyl, ethyl and so on, are particularly preferred.

The term "optionally substituted carbamoyl group" as used includes, for example, carbamoyl, mono-C _1-6 alkylcarbamoyl groups (e.g. methylcarbamoyl, ethylcarbamoyl and so on), di-C _1-6 alkylcarbamoyl groups (e.g. dimethylcarbamoyl, diethylcarbamoyl, etc.), a mono- or di-C _6-14 arilkarbamoilnye group (e.g., phenylcarbamoyl, 1-naftilkarbamoilnuyu, 2-naftilkarbamoilnuyu etc.), mono- or di-5- or 7-membered heterocyclic carbamoyl group containing, besides carbon atoms, 1-4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl, etc.) and the like.

The term “optionally substituted hydroxyl group” as used includes, for example, a hydroxy 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, and so on. The "optionally substituted C _1-6 alkoxy group", "optionally substituted C _6-14 aryloxy group" and "optionally substituted C _7-16 aralkyloxy group" used are as indicated for the "optionally substituted C _1-6 alkoxy group", "optionally substituted C _6-14 aryloxy groups "and" optionally substituted C _7-16 aralkyloxy groups "in substituent group A, which will be described later.

As used herein, the term “aromatic cyclic group” in an “optionally substituted aromatic cyclic group” includes, for example, an aromatic hydrocarbon group, an aromatic heterocyclic group, an aromatic fused-ring group, an aromatic fused heterocyclic group, and so on.

The term “aromatic hydrocarbon group” as used includes, for example, a C _6-14 aryl group such as phenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, cyclooctatetraenyl, and so on.

The term "aromatic heterocyclic group" as used includes, for example, a 5-14 membered, preferably 5-10 membered, more preferably a 5 or 6 membered aromatic heterocyclic group containing, in addition to carbon atoms, 1-4 hetero atoms of 1 or 2 atom species selected from nitrogen, sulfur and oxygen atoms. Specific examples are thienyl (e.g. 2-thienyl, 3-thienyl), furyl (e.g. 2-furyl, 3-furyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl), pyrazinyl, pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g. 1-pyrrolyl, 2 -pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (e.g. 3-pyridazinyl, 4-pyridazinyl), isothiazolyl (e.g. 3-isothiazolyl), isoxazolyl (e.g. 3-isoxazolyl) and so on.

The term “aromatic fused-ring group” as used includes a C _8-14 aromatic fused-ring group such as naphthyl (eg, 1-naphthyl, 2-naphthyl), antryl (eg, 2-antryl, 9-antryl) and the like .

The term "aromatic condensed heterocyclic group" as used includes, for example, a 5-14 membered (preferably 5-10 membered) bicyclic or tricyclic aromatic heterocyclic group containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 types selected from nitrogen, sulfur and oxygen atoms, or a monovalent group formed by the removal of one optional hydrogen atom from a 7-10 membered aromatic bridging hetero ring in a 5-14 membered (preferably 5-10 membered) ring containing, in addition to atom s carbon, 1-4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen. Specific examples of these useful groups are quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (e.g. 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 (for example, 2-benzo [b] furanyl, 3-benzo [b] furanyl) and the like.

The term “substituent” in the “aromatic cyclic group” as used includes a substituent selected from substituent group A, which will be described later.

As 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-indolomethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclohexylmethyl, phenyl, acetoxymethyl, methoxymethyl and so on; among others, hydroxymethyl, 1-hydroxyethyl, benzyl, 4-hydroxybenzyl, 3-indolmethyl, methyl, isobutyl and so on are more preferred, more preferably hydroxymethyl, 1-hydroxyethyl and so on, and most preferably 1-hydroxyethyl.

R ² represents (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) C _{1- 8} an alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic cyclic group. Among others, preferred are (1) a hydrogen atom, (2) a cyclic or linear C _1-10 alkyl group, or (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group. Particularly preferred are a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group.

The term “cyclic C _1-10 alkyl group” as used includes, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

Examples of the linear C _1-10 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl and so on.

The term “C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group” as used includes, for example, a C _3-7 cycloalkyl-C _1-3 alkyl group such as cyclopentylmethyl, cyclohexylmethyl and so on.

Examples of R ² include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, benzyl, hydroxymethyl, 2-carbamoylethyl, tert-pentyl and so on; among others, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl and so on are more preferred, more preferably propyl, isopropyl, isobutyl, cyclopropylmethyl and so on.

R ³ represents:

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

(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 of not more than 7 carbon atoms, having an optionally substituted basic group, and optionally having an additional substituent, or,

(4) a C _1-4 alkyl group having a non-aromatic heterocyclic group of not more than 7 carbon atoms, having an optionally substituted basic group, and optionally having an additional substituent; in particular, preferably, (1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having an additional substituent.

The term “optionally substituted basic group” as used includes, for example, (1) a guanidino group optionally having 1 or 2 substituents of C _1-6 alkyl, C _1-6 acyl (eg methyl, ethyl, propyl, isopropyl, butyl, acetyl , propionyl and so on) and so on, (2) an amino group, optionally having 1-3 substituents from C _1-6 alkyl, C _1-6 acyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl and so on) and so on, (3) a C _1-6 alkylcarbonylamino group (e.g. acetamido) optionally substituted with a guanidino group optionally having 1 or 2 substituents from C _1-6 alkyl, C _1-6 acyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl and so on) and so on, (4) C _1-6 alkylcarbonylamino group (e.g. acetamido), optionally substituted with an amino group, optionally having 1-3 substituents of C _1-6 alkyl, C _1-6 acyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl and so on), and so on. Among others, guanidino, N-methylguanidino, N, N-dimethylguanidino, N, N'-dimethylguanidino, N-ethylguanidino, N-acetylguanidino, amino, N-methylamino, N, N-dimethylamino, aminoacetamido, guanidinoamino, are preferred. things like that.

The term "additional substituent" as used, other than the "optionally substituted basic group", includes a substituent selected from the group of substituents A described below.

Examples of the “C _1-8 alkyl group” are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl and so on.

The term “aralkyl group” as used includes, 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 so on.

The term "non-aromatic cyclic hydrocarbon group of not more than 7 carbon atoms" as used includes, for example, a C _3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term "non-aromatic heterocyclic group of not more than 7 carbon atoms" as used includes, for example, a 5-10 membered non-aromatic heterocyclic group containing, in addition to 1-7 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen and so on. Specific examples used are pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g. 2-oxazolidinyl), imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, for example) , 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and so on.

Examples of the used “C _1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and so on.

As 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-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, aminomethyl, aminoacetamidomethyl, guanidinoacetamidomethyl, 2- (guanidinocarbonyl) ethyl, (2) 4- guanidinobenzyl, 4-aminobenzyl, (3) 4-guanidinocyclohexylmethyl, 4-amine cyclohexylmethyl, (4) 1-amidinopiperidine-4-ylmethyl, 4-pyridylmethyl and the like; among others, preferred are 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, and so on, in particular, preferably 3-guanidinopropyl, 3- (N -methylguanidino) propyl, 3- (N, N- imethylguanidino) propyl, 3- (N, N'-dimethylguanidino) propyl, 3- (N-ethylguanidino) propyl, 3- (N-acetylguanidino) propyl, 4-guanidinobutyl, 4- (N-methylguanidino) butyl, 2-guanidinoethyl , 4-aminobutyl and so on, and most preferably 3-guanidinopropyl and 3- (N-methylguanidino) propyl.

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

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 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 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 carbon atoms; particularly preferred is (4) a C _1-4 alkyl group, which optionally can be substituted with an optionally substituted 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen atoms oxygen and sulfur.

Examples of the used “C _1-4 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and so on.

The term “C _6-12 aromatic hydrocarbon group” as used includes, for example, a monocyclic C _6-12 aromatic hydrocarbon group such as phenyl, cyclooctatetraenyl, and so on.

The term "5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms" as used includes, for example, a 5-14 membered, preferably 5-10- a membered, more preferably 5- or 6-membered monocyclic aromatic heterocyclic group containing, in addition to 1-7 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms. Specific examples used include thienyl (e.g. 2-thienyl, 3-thienyl), furyl (e.g. 2-furyl, 3-furyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), thiazolyl (e.g. , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl), pyrazinyl, pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g. 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (e.g. 3-pyridazinyl , 4-pyridazinyl), from othiazolyl (e.g. 3-isothiazolyl), isoxazolyl (e.g. 3-isoxazolyl) and so on.

The term “C _8-14 aromatic fused-ring group” as used includes, for example, naphthyl (eg 1-naphthyl, 2-naphthyl), antryl (eg 2-antryl, 9-antryl) and so on.

The term "5-14 membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms" as used includes, for example, a 5-14 membered (preferably 5- 10-membered) bicyclic or tricyclic aromatic heterocyclic group containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, or a monovalent group formed by the removal of one optional hydrogen atom from 7 -10- a member aromatic bridging hetero ring in a 5-14 membered (preferably 5-10 membered) ring containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms. Specific examples used are quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl), isoquinolyl (e.g. 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 (for example, 2-benzo [b] furanyl, 3-benzo [b] furanyl) and so on.

The term "non-aromatic cyclic hydrocarbon group of not more than 7 carbon atoms" as used includes, for example, a C _3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term "non-aromatic heterocyclic group of not more than 7 carbon atoms" as used includes, for example, a 5- or 10-membered non-aromatic heterocyclic group containing, in addition to 1-7 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen atoms, sulfur and oxygen, such as pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g. 2-oxazolidinyl), imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), p (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-pipe ridinyl), piperazinyl (e.g. 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and so on.

Substituents used for said “C _6-12 aromatic hydrocarbon group”, “5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms”, “ C _8-14 aromatic fused-ring group "," 5-14-membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms "," non-aromatic cyclic hydrocarbon groups from no more than 7 carbon atoms "and a" non-aromatic heterocyclic group of no more than 7 carbon atoms "include, for example, substituents selected from oxo, a halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (e.g. 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 aryl, 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 alkylamino (e.g. methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino and so on), optionally substituted mono- or di-C _2-6 alkenylamino (e.g. vinylamino, propenylamino, isopropenylamino), not byazatelno substituted C _2-6 alkynylamino (e.g., 2-butyn-1-yl-amino, 4-pentyn-1-yl-amino, 5-hexyne-1-yl-amino), optionally substituted mono- or di-C _{3 -8} cycloalkylamino (e.g. cyclopropylamino, cyclohexylamino), optionally substituted C _6-14 aryl amino (e.g. phenylamino, diphenylamino, naphthylamino), optionally substituted C _1-6 alkoxyamino (e.g. methoxyamino, ethoxyamino, propoxyamino, isopropoxyamino) , formylamino, optionally substituted with C _1-6 alkylcarbonylamino (e.g. acetylamino, propionylamino, pivaloylamino and so gave e) optionally substituted C _3-8 cycloalkylcarbonylamino (e.g. cyclopropylcarbonylamino, tsiklopentilkarbonilamino, cyclohexylcarbonylamino, etc.), an optionally substituted C _6-14 aryl-carbonylamino (e.g., benzoylamino, naphthoylamino, etc.), an optionally substituted C _1-6 alkoxy carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), an optionally substituted C _1-6 alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, etc.), eobyazatelno substituted C _6-14 arylsulfonylamino (e.g., phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.)], formyl, carboxy, optionally substituted C _1-6 alkylcarbonyl (e.g., acetyl, propionyl, pivaloyl, etc.), optionally substituted C _3-8 cycloalkylcarbonyl (e.g. cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methyl-cyclohexyl-carbonyl and so on), optionally substituted C _6-14 aryl-carbonyl (e.g. benzoyl, 1-naphthoyl, 2-naphthoyl and so further) optionally substituted with C _{7-1 6} aralkyl carbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), an optionally substituted 5-7 membered heterocyclic carbonyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (e.g. nicotinoyl, isonicotinoyl, tenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and so on), optionally esterified carboxyl, optionally substituted carbamoyl, optionally substituted methyl _1-6 b, ethylsulfonyl and so on), optionally substituted C _1-6 alkylsulfinyl (e.g. methylsulfinyl, ethylsulfinyl and so on), optionally substituted C _6-14 arylsulfonyl (e.g. phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and so on) optionally substituted C _6-14 arylsulfinyl (e.g. phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl and so on), optionally substituted C _1-6 alkylcarbonyloxy (e.g. acetoxy, propionyloxy and so on), optionally substituted C _6-14 aryl carbonyloxy (e.g. benzoyloxy, on phthylcarbonyloxy and so on), optionally substituted C _1-6 alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, and so on), optionally substituted mono-C _1-6 alkylcarbamoyloxy (e.g. methylcarbamoyloxy, ethylcarbamoyloxy, optionally di-C _1-6 alkylcarbamoyloxy (e.g., dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted mono- or di-C _6-14 arilkarbamoiloksi (e.g., phenylcarbamoyloxy, and that naftilkarbamoiloksi etc.), an optionally substituted heterocyclic group, sulfo, sulfamoyl, sulfinamoil, sulfenamoil or a group of two or more (e.g. 2 or 3) of these substituents combined, and the like (Substituent Group A). The number of substituents is not particularly limited, but these rings may have from 1 to 5, preferably from 1 to 3 substituents at suitable positions, and when there are two or more substituents, each substituent may be the same or different.

The term “optionally esterified carboxyl group” as used in substituent group A includes, for example, optionally substituted C _1-6 alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), optionally substituted C _6-14 aryloxycarbonyl ( e.g., phenoxycarbonyl and so on), optionally substituted C _7-16 aralkyloxycarbonyl (e.g., benzyloxycarbonyl, phenyloxycarbonyl and so on) and the like.

The term “C _1-6 alkyl” as used in “optionally substituted C _1-6 alkyl” in substituent group A includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl , neopentyl, hexyl and so on.

The term "C _2-6 alkenyl" in "optionally substituted C _2-6 alkenyl" in Substituent group A includes, for example, vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5 -hexen-1-yl and so on.

The term “C _2-6 alkynyl” as used in “optionally substituted C _2-6 alkynyl” in the substituent group A includes, for example, 2-butyn-1-yl, 4-pentin-1-yl, 5-hexin-1-yl and so on.

The term “C _3-8 cycloalkyl” as used in “optionally substituted C _3-8 cycloalkyl” in substituent group A includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term “C _6-14 aryl” used in “optionally substituted C _6-14 aryl” in substituent group A includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2 -antryl and so on.

The term “C _7-16 aralkyl” as used in “optionally substituted C _7-16 aralkyl” in substituent group A includes, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl , 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and so on.

The term “C _1-6 alkoxy” as used in “optionally substituted C _1-6 alkoxy” in the substituent group A includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and so on.

The term “C _6-14 aryloxy” as used in “optionally substituted C _6-14 aryloxy” in the substituent group A includes, for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy and so on.

The term “C _7-16 aralkyloxy” as used in “optionally substituted C _7-16 aralkyloxy” in substituent group A includes, for example, benzyloxy, phenethyloxy and so on.

The term “C _1-6 alkylthio” as used in “optionally substituted C _1-6 alkylthio” in substituent group A includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio and so on.

The term “C _6-14 arylthio” as used in “optionally substituted C _6-14 arylthio” in substituent group A includes, for example, phenylthio, 1-naphthylthio, 2-naphthylthio, and so on.

The term “C _7-16 aralkylthio” as used in “optionally substituted C _7-16 aralkylthio” in substituent group A includes, for example, benzylthio, phenethylthio, and so on.

The substituents in the indicated groups are “C _1-6 alkoxy-carbonyl”, “C _1-6 alkyl group”, “C _2-6 alkenyl”, “C _2-6 alkynyl”, “C _1-6 alkoxy”, “C _{1 -6} alkylthio, C _1-6 alkylamino, C _2-6 alkenylamino, 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-carbonylamino "," C _1-6 alkylsulfonylamino "," C _1-6 alkylcarbonyloxy "," C _1-6 alkoxycarbonyloxy "," mono-C _1-6 alkylcarbamoyloxy "and" di-C _1-6 alkylcarbamoyloxy "in the group of substituents A include, for example, from 1 to 5 substituents selected, for example, from an atom halogen (e.g. fluorine atom, chlorine atom, bromine atom, iodine atom), 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 alkoxycarbonyl, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, optionally esterified carboxyl described above, carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl ( e.g. methylcarbamoyl, ethylcarbamoyl and so on), di-C _1-6 alkylcarbamoyl (e.g. dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and so on), mono- or di-C _6-14 arylcarbamoyl (e.g. Imer, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and so on), mono- or di-5-7-membered heterocyclic carbamoyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and so on) and the like.

Substituents for the groups C _6-14 aryloxycarbonyl, C _7-16 aralkyloxycarbonyl, 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 arylcarbonyl", "C _7-16 aralkylcarbonyl", "5-7-membered heterocyclic carbonyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, "" C _6-14 arylsulfonyl, "" C _6-14 arylsulfinyl, "" C _3-8 cycloalkylcarbonylamino, "" C _6-14 arylcarbonylamino, "" C _6-14 arylsulfonyl but, "" C _6-14 arylcarbonyloxy "and" mono- or di-C _6-14 arilkarbamoiloksi "in Substituent Group A include, for example, from 1 to 5 substituents selected from, for example, halogen, hydroxy, carboxy, nitro, , cyano, optionally substituted C _1-6 alkyl described above, optionally substituted C _2-6 alkenyl described above, optionally substituted C _2-6 alkynyl described above, optionally substituted C _3-8 cycloalkyl described above, optionally substituted C _1-6 alkoxy as described above, optionally substituted by C _1-6 alkylthio as described above, optionally substituted C _1-6 alkylsulfinyl described above; optionally substituted C _1-6 alkylsulfonyl described above; optionally esterified carboxyl described above; carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl, di-C _1-6 alkylcarbamoyl, mono - or di-C _6-14 arylcarbamoyl, mono- or di-5-7-membered heterocyclic carbamoyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, and the like .

The term "optionally substituted heterocyclic group" as used in substituent group A includes, for example, a 5-14 membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen atoms sulfur and oxygen, which optionally can be substituted with a halogen atom, hydroxy, carboxy, nitro, cyano, optionally substituted with C _1-6 alkyl described above, optionally substituted with C _2-6 alkenyl described above, optionally substituted with C _2-6 alkynyl as described above, optionally substituted by C _3-8 cycloalkyl as described above, optionally substituted by C _6-14 aryl as described above, optionally substituted by C _1-6 alkoxy as described above, optionally substituted by C _1-6 alkylthio as described above, optionally substituted C _6-14 arylthio described above, optionally substituted C _7-16 aralkylthio described above, optionally substituted C _1-6 alkylsulfinyl described above, optionally substituted C _6-14 arylsulfinyl described above, optionally substituted C _{1 -6} alkylsulfonyl, described th above, optionally substituted C _6-14 arylsulfonyl described above, the optionally esterified carboxyl described above, carbamoyl, tiokarbamoilom, mono-C _1-6 alkylcarbamoyl, di-lower alkylcarbamoyl, mono- or di-C _6-14 arilkarbamoilom mono or a di-5- or 7-membered heterocyclic carbamoyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, or the like; preferably, (i) a 5-14 membered (preferably 5-10 membered) aromatic heterocyclic group is used, (ii) a 5-10 membered non-aromatic heterocyclic group or (iii) a monovalent group formed by the removal of one optional hydrogen atom from 7 A 10-membered aromatic bridging ring, and the like; among others, a 5 membered aromatic heterocyclic group is preferably used. Particularly used are an aromatic heterocyclic group such as thienyl (e.g. 2-thienyl, 3-thienyl), furyl (e.g. 2-furyl, 3-furyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl ), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g. 2-oxazolyl, 4-oxazolyl), quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl, 5- quinolyl, 8-quinolyl), isoquinolyl (e.g. 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl), pyrazinyl, pyrimidinyl (e.g. 2-pyrimidinyl, 4-pyrimidinyl), pyrrolyl (e.g. 1-pyrrolyl , 2-pyrroles , 3-pyrrolyl), imidazolyl (e.g. 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), pyridazinyl (e.g. 3-pyridazinyl, 4- pyridazinyl), isothiazolyl (eg 3-isothiazolyl), isoxazolyl (eg 3-isoxazolyl), 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 (for example, 2-benzo [b] furanyl, 3-benzo [b] furanyl) and so on, a non-aromatic heterocyclic group, such as pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g. 2-oxazolidinyl), imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, , 4-piperidinyl), piperazinyl (e.g. 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and so on.

The term “optionally substituted carbamoyl group” as used in substituent group A includes a carbamoyl group, which optionally can be substituted with optionally substituted C _1-6 alkyl, optionally substituted with C _2-6 alkenyl, optionally substituted with C _2-6 alkynyl, optionally substituted with C _{3- 8} cycloalkyl, optionally substituted C _6-14 aryl, optionally substituted heterocyclic group described above and so description and specific examples are carbamoyl, thiocarbamoyl, mono-C _1-6 alkylcarbamoyl (e.g., IU ylcarbamoyl, ethylcarbamoyl etc.), di-C _1-6 alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C _1-6 alkyl (C _1-6 alkoxy) carbamoyl (e.g., methyl (methoxy) carbamoyl, ethyl (methoxy) carbamoyl), mono- or di-C _6-14 arylcarbamoyl (e.g. phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and so on), mono- or di-5-7-membered heterocyclic carbamoyl containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamo yl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and so on), 5-7 membered cyclic carbamoyl (e.g. 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, hexamethyleneiminocarbonyl) and the like.

The term “optionally substituted amino” as used in substituent group A includes amino, which optionally may be substituted with 1 or 2 groups selected from optionally substituted C _1-6 alkyl described above, optionally substituted C _2-6 alkenyl described above, optionally substituted C _2-6 alkynyl described above, optionally substituted C _3-8 cycloalkyl described above, optionally substituted C _6-14 aryl described above, optionally substituted C _1-6 alkoxy described above, formyl optionally substituted C _1-6 alkylcarbonyl described above, optionally substituted C _3-8 cycloalkylcarbonyl described above, optionally substituted C _6-14 arylcarbonyl described above, optionally substituted C _1-6 alkoxycarbonyl described above, optionally substituted C _1-6 alkylsulfonyl described above, optionally substituted C _6-14 arylsulfonyl and the like.

More preferably, the substituents used for the indicated groups are “C _6-12 aromatic hydrocarbon group”, “5-14 membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms "," C _8-14 aromatic fused-ring group "," 5-14-membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms "," non-aromatic cycle a personal hydrocarbon group of not more than 7 carbon atoms "and a" non-aromatic heterocyclic group of not more than 7 carbon atoms "are a halogen atom, hydroxy, C _1-6 alkoxy, optionally halogenated C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, amino, nitro, cyano and so on.

Examples of R ^{4 used} include:

(1) “C _1-4 alkyl group having 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 so on;

(2) "C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 2 -pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl and so on;

(3) a “C _1-4 alkyl group having an optionally substituted C _8-14 aromatic fused-ring group” such as 1-naphthylmethyl, 2-naphthylmethyl, inden-2-ylmethyl and so on;

(4) "C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 3-indolmethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl and so on;

(5) "C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group of not more than 7 carbon atoms", such as cyclohexylmethyl, cyclopentylmethyl, indan-2-ylmethyl and so on;

(6) “C _1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group of not more than 7 carbon atoms”, such as 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin-3-yl and so on; among others, benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-cyanobenzyl, 3-trifluoromethylbenzyl, 3,4 are preferred -dichlorobenzyl, 3,4-difluorobenzyl, pentafluorobenzyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-indolmethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl, 1-naphthylmethyl, 2-naphtha , cyclohexylmethyl, phenethyl and so on. Particularly preferred are 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-pyridylmethyl, 4-pyridylmethyl, 3-indolmethyl, 3-benzo [b] thienylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, cyclohexylmethyl and so on, and, in particular, preferably 3 -indolmethyl.

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent (preferably a substituent selected from the group consisting of (1), (2) and (5) described below) selected from the group consisting of :

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 carbon atoms;

these substituents used are the same as those indicated for R ⁴ .

Examples of used Q ¹ include:

(1) “C _1-4 alkyl group having 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 so on,

(2) "C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 2 -pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 4-thiazolylmethyl and so on,

(3) a “C _1-4 alkyl group having an optionally substituted C _8-14 aromatic fused-ring group” such as 1-naphthylmethyl, 2-naphthylmethyl, inden-2-ylmethyl and so on,

(4) "C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", such as 3-indolmethyl, 1-formylindol-3-ylmethyl, 3-benzo [b] thienylmethyl, 2-quinolylmethyl and so on,

(5) "C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms", such as cyclohexylmethyl, cyclopentylmethyl, indan-2-ylmethyl and so on,

(6) "C _1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group having no more than 7 carbon atoms", such as 3-piperidylmethyl, 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin-3-yl and so on; among others, preferably used are cyclohexylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, pentafluorobenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolomethyl, 3-piperid thienylmethyl and so on; more preferably benzyl, 4-fluorobenzyl, 4-pyridylmethyl, cyclohexylmethyl, 3-piperidylmethyl, 2-piperidylmethyl and so on, and most preferably benzyl and cyclohexylmethyl.

Q ² represents: (1) CH ₂ , CO, CS or CH = CH ₂ , which optionally can be substituted with a C _0-4 alkyl group, optionally substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _{1 -3} alkoxy groups, a halogen atom and an amino group, (2) NH, which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, or (3) O; among others, preferred is (1) CH ₂ or CH = CH ₂ , optionally substituted with one or two C _1-4 alkyl groups, which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _{1- 3} alkoxy groups and amino groups.

The term “C _0-4 alkyl group” is used to mean a bond or a C _1-4 alkyl group. In other words, a “C ₀ alkyl group” refers to a bond (for example, a chemical bond “-”). Accordingly, a “CH ₂ substituted C ₀ alkyl group which is substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, a C _1-3 alkoxy group and an amino group” is CH ₂ substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, C _1-3 alkoxy groups and amino groups.

A “C _0-4 alkyl group” is preferably a C _1-4 alkyl group.

The term “C _1-4 alkyl group” as used includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and so on.

The term “C _1-3 alkoxy group” as used includes, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, and so on.

Preferred Q ² are CH ₂ , CH (CH ₃ ), CH (CH ₂ OH), C (CH ₃ ) ₂ , CH ₂ CH ₃ , CH (CH ₂ CH ₃ ), CH (CH ₂ NH ₂ ), CH ( CH ₂ OCH ₃ ), CH (CH (CH ₃ ) ₂ ), NH and the like, more preferably CH ₂ , CH (CH ₃ ), CH (CH ₂ OH), C (CH ₃ ) ₂ , CH ₂ CH ₃ , CH (CH ₂ CH ₃ ), CH (CH ₂ NH ₂ ), CH (CH ₂ OCH ₃ ) and CH (CH (CH ₃ ) ₂ ).

Y represents:

(1) a group represented by the formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -COCH ₂ -, -CH ₂ S-, -CSCH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH = CH-, which may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl group, hydroxyl group and halogen atom;

(2) an optionally substituted C _6-7 aromatic hydrocarbon group;

(3) an optionally substituted 4-7 membered aromatic heterocyclic group consisting of 1-5 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(4) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms; or

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms, and when Y is (2), (3), (4) or (5), Q ² may be a chemical bond.

The term “C _1-6 alkyl group” as used includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and so on.

Y includes (1) a group represented by the formula: -CONH-, -CSNH-, -NHCO-, -CH ₂ NH-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -COCH ₂ -, -CH ₂ CH ₂ - or -CH = CH-, which may optionally be substituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a hydroxyl group and a halogen atom (among others, a group represented by the formula: -CONH-, -CSNH-, -NHCO-, -CH ₂ NH-, -CH ₂ O-, -CH ₂ S-, -COO-, -CSO-, -COCH ₂ -, -CH ₂ CH ₂ -, -CH (OH) CH ₂ - or -CH = CH-, especially the group represented by the formula: -CONH-, -CSNH-, -NHCO-, -CH ₂ NH-, -CH ₂ O-, -COCH ₂ -, -CH ₂ CH ₂ -, -CH (OH) CH ₂ - or -CH = CH-, more preferably, a group represented pho muloy: -CONH-, -CSNH-, -NHCO-, -CH ₂ O-, -CH ₂ S-, -COCH ₂ -, -CH = CH- or -CH ₂ CH ₂ -).

A represents:

(1) a nitrogen atom substituted with a hydrogen atom or a C _1-3 alkyl group;

(2) a carbon atom substituted by a hydrogen atom or a C _1-3 alkyl group;

(3) O; or

(4) S.

A preferably includes (1) a nitrogen atom substituted by a hydrogen atom or a C _1-3 alkyl group (among others, a nitrogen atom substituted by a hydrogen atom); (2) a carbon atom substituted by a hydrogen atom or a C _1-3 alkyl group (among others, a carbon atom substituted by a hydrogen atom); or (4) S.

A 'represents:

(1) a carbon atom, which optionally can be substituted by a hydrogen atom, O, S, a halogen atom, an optionally halogenated C _1-3 alkyl group, a carbamoyl group or a hydroxyl group;

(2) a nitrogen atom, which optionally can be substituted by a hydrogen atom or an optionally halogenated C _1-3 alkyl group;

(3) O; or

(4) S;

Preferably, A ′ includes (1) a carbon atom, which optionally can be substituted by a hydrogen atom, O, S, a halogen atom, an optionally halogenated C _1-3 alkyl group, a carbamoyl group or a hydroxyl group (among others, a carbon atom substituted by a hydrogen atom or O).

Preferably, V ′ is a group represented by the following formula.

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

(1) a hydrogen atom,

(2) an optional amino acid residue, continuously or non-continuously connected from the C-terminal end of the 1st to 48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (54 amino acid residues of human metastin);

(3) a group represented by the formula:

J ¹ -J ² -C (J ³ ) (Q ³ ) Y ¹ C (J ⁴ ) (Q ⁴ ) Y ² C (J ⁵ ) (Q ⁵ ) Y ³ C (J ⁶ ) (Q ⁶ ) C ( = Z ¹⁰ ) -

(where each character has the same meaning as described above),

(4) a group represented by the formula:

-J ¹ -J ² -C (J ⁷ ) (Q ⁷ ) Y ² C (J ⁸ ) (Q ⁸ ) Y ³ C (J ⁹ ) (Q ⁹ ) C (= Z ¹⁰ ) -

(where each character has the same meaning as described above),

(5) a group represented by the formula:

J ¹ -J ² -C (J ¹⁰ ) (Q ¹⁰ ) Y ³ C (J ¹¹ ) (Q ¹¹ ) C (= Z ¹⁰ ) -

(where each character has the same meaning as described above),

(6) a group represented by the formula:

J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ ) -

(where each character has the same meaning as described above), or,

(7) a group represented by the formula: J ¹ -

(where J ¹ l has the same meaning as described above).

Specific examples of the term "optional amino acid residue continuously or non-continuously linked from the C-terminal end of the 1st to 48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 12" include:

(1) Asn-

(2) Trp Asn-,

(3) Asn Trp Asn-,

(4) Tyr Asn Trp Asn-,

(5) Asn Tyr Asn Trp Asn-,

(6) Pro Asn Tyr Asn Trp Asn-,

(7) Leu Pro Asn Tyr Asn Trp Asn-,

(8) Asp Leu Pro Asn Tyr Asn Trp Asn-,

(9) Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(10) Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(11) Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(12) Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(13) Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(14) Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(15) Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(16) Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(17) Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(18) Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(19) Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(20) Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(21) Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(22) Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(23) Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(24) Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(25) Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(26) His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(27) Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(28) Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(29) Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(30) Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(31) Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(32) Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(33) Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(34) Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(35) Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(36) Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(37) Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(38) Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(39) Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(40) Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(41) Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(42) Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(43) Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(44) Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(45) Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn-,

(46) Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn- ,

(47) Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn -,

(48) Gly Thr Ser Leu Ser Pro Pro Pro Glu Ser Ser Gly Ser Arg Gln Gln Pro Gly Leu Ser Ala Pro His Ser Arg Gln Ile Pro Ala Pro Gln Gly Ala Val Leu Val Gln Arg Glu Lys Asp Leu Pro Asn Tyr Asn Trp Asn- and the like.

J ¹ represents (a) a hydrogen atom or (b) (i) a C _1-20 acyl group, (ii) a C _1-20 alkyl group, (iii) a C _6-14 aryl group, (iv) a carbamoyl group, ( v) a carboxyl group, (vi) a sulfino group or (vii) an amidino group, (viii) a glyoxyloyl group or (ix) an amino group, these groups may optionally be substituted with a substituent containing an optionally substituted cyclic group;

The term “cyclic group” as used includes, for example, “an optionally substituted aromatic hydrocarbon group”, “an optionally substituted aromatic heterocyclic group”, an “optionally substituted aromatic condensed-ring group”, an “optionally substituted aromatic condensed heterocyclic group”, and “an optionally substituted non-aromatic cyclic hydrocarbon group "," optionally substituted non-aromatic heterocyclic group "and so on, and using examples The terms “aromatic hydrocarbon group”, “aromatic heterocyclic group”, “aromatic fused-ring group” and “aromatic fused heterocyclic group” are the same as above.

The term “non-aromatic cyclic hydrocarbon group” as used includes a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term "non-aromatic heterocyclic group" as used includes a 5-10 membered non-aromatic heterocyclic group containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, such as pyrrolidinyl (e.g. 1-pyrrolidinyl , 2-pyrrolidinyl, 3-pyrrolidinyl), oxazolidinyl (e.g. 2-oxazolidinyl), imidazolinyl (e.g. 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, piperidinyl, 4-piperidinyl) piperazinyl (e.g. 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino and so on.

A substituent optionally present in the “cyclic group” includes the same substituents as in the group of substituents A described above.

The term “C _1-20 acyl group” as used includes, for example, formyl, C _1-18 alkyl carbonyl (eg C _1-18 alkyl carbonyl such as acetyl, propionyl, pivaloyl, octanoyl, decanoyl, palmitoyl and so on ) etc.

The term “C _1-20 alkyl group” as used includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl, tridecyl, pentadecyl and so on.

The term “C _6-14 aryl group” as used includes, for example, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, and so on.

(1) a C _1-15 acyl group, which may optionally be substituted with a substituent containing a cyclic group, includes (i) formyl, (ii) C _1-14 alkylcarbonyl (e.g. C _1-6 alkylcarbonyl such as acetyl, propionyl, pivaloyl and so on), (iii) C _3-8 cycloalkylcarbonyl (e.g. cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methylcyclohexylcarbonyl and so on), (iv) C _3-8 cycloalkyl-C _1-6 alkylcarbonyl (e.g. cyclopropylacetyl, tsiklopentilatsetil, cyclohexylacetyl, etc.), (v) C _6-14 arylcarbonyl (e.g., benzoyl, 1-naphthoyl, 2-naphth yl and so on), C _6-14 aralkylcarbonyl (e.g., phenylacetyl, 3-phenylpropionyl, etc.), (vi) 5-7-membered monocyclic heterocyclic carbonyl containing, besides carbon atoms, 1-4 heteroatoms 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (e.g. nicotinoyl, isonicotinoyl, tenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl and so on), (vii) 5-7 membered monocyclic , which contains, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from atoms of az one oxygen and sulfur, -C _1-6 alkylcarbonyl (e.g., 3-pyridylacetyl, 4-pyridylacetyl, 2-thienylacetyl, 2-furilatsetil, morpholinoacetyl, tiomorfolinoatsetil, piperidine-2-acetyl, pyrrolidine-2-ylacetyl, etc.) , (viii) a 5-14 membered (preferably 5-10 membered) bicyclic or tricyclic aromatic heterocyclic carbonyl containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen (eg 2-indolecarbonyl, 3-indolecarbonyl, 2-quinolylcarbonyl, 1-isoquinolylcarbonyl, 2-benzo [b] thienylcarbonyl, 2- benzo [b] furanylcarbonyl and so on), (ix) a 5-14 membered (preferably 5-10 membered) bicyclic or tricyclic aromatic heterocycle that contains, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 types selected from nitrogen, sulfur, and oxygen atoms, —C _1-6 alkylcarbonyl (eg, 2-indoleacetyl, 3-indoleacetyl, 2-quinolylacetyl, 1-isoquinolylacetyl, 2-benzo [b] thienylacetyl, 2-benzo [b] furanylacetyl and so on) and so on, among others, acetyl, 2-indolecarbonyl, 3-indolecarbonyl, 3-indoleacetyl, 3-indolepropionyl, 2 are preferably used. -indolinecarbonyl, 3-phenylpropionyl, diphenylacetyl, 2-pyridinecarbonyl, 3-pyridinecarbonyl, 4-pyridinecarbonyl, 1-pyridinioacetyl, 2-pyridinacetyl, 3-pyridinacetyl, 4-pyridinacetyl, 3- (1-p-pyridineacetyl -2-yl) propionyl, 3- (pyridin-3-yl) propionyl, 3- (pyridin-4-yl) propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, 1-piperidinacetyl, 1-methyl-1-piperidinioacetyl, 4-piperidinecarbonyl , 2-pyrimidinecarbonyl, 4-pyrimidinecarbonyl, 5-pyrimidinecarbonyl, 2-pyrimidine acetyl, 4-pyrimidine acetyl, 5-pyrimidine acetyl, 3- (pyrimidin-2-yl) propionyl, 3- (pyrimidin-4-yl) propio yl, 3- (pyrimidin-5-yl) propionyl, butanoyl, hexanoyl, octanoyl, D-glyukuronoil, amino- (4-hydroxyphenyl) acetyl), and so on.

(2) a C _1-20 alkyl group (preferably a C _1-17 alkyl group, more preferably a C _1-15 alkyl group) which may optionally be substituted with a substituent containing a cyclic group, includes, for example, (i) mono- or di-C _1-20 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl, tridecyl, pentadecyl ), (ii) mono- or di-C _3-8 cycloalkyl (e.g. cyclopropyl, cyclopentyl and so on), (iii) mono- or di-C _3-8 cycloalkyl-C _1-12 (preferably C _{1- 9} more preferably C _1-7 ) alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl and so on), (iv) mono- or di-C _7-20 (preferably C _7-17 , more preferably C _7-15 ) aralkyl (e.g. benzyl, phenethyl and so on), (v) a mono- or di-5-7-membered monocyclic heterocycle, which, in addition to carbon atoms, contains 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen, a -C _1-6 alkyl group (e.g. 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, furfuryl and so on), (vi) mono- or di-5-14-membered (preferably 5-10 member o) a bicyclic or tricyclic aromatic heterocycle, which contains, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, -C _1-6 alkyl (for example, 2-indolmethyl, 3 -indolmethyl, 3- (indol-3-yl) propyl, 2-quinolylmethyl, 1-isoquinolylmethyl, 2-benzo [b] thienylmethyl, 2-benzo [b] furanylmethyl and so on) and so on); among others, methyl, ethyl, benzyl, 3- (indol-3-yl) propyl, etc. are preferably used.

(3) a C _6-14 aryl group, which optionally can be substituted with a substituent containing a cyclic group, includes, for example, a C _6-14 aryl group (e.g. phenyl, naphthyl, biphenyl), which optionally can be substituted (i) C _6-14 carbocyclic group (for example, cycloalkyl, phenyl, 1-naphthyl, 2-naphthyl and so on), (ii) a 5-7-membered monocyclic heterocyclic group containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 types selected from nitrogen, sulfur, and oxygen atoms (e.g. 3-pyridyl, 2-thienyl, and so on), (iii) 5-14 membered (pre meaningly a 5-10 membered) bicyclic or tricyclic aromatic heterocyclic group containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (e.g., 2-indolyl, 3- indolyl, 2-quinolyl, 1-isoquinolyl, 2-benzo [b] thienyl, 2-benzo [b] furanyl, and so on) and so on.

(4) An optionally substituted carbamoyl group, which may optionally be substituted with a substituent containing a cyclic group, includes (i) carbamoyl, (ii) mono- or di-C _1-15 alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl), (iii) mono - or di-C _3-8 cycloalkylcarbamoyl (e.g. cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl and so on), (iv) mono- or di-C _3-8 cycloalkyl-C _1-6 alkyl-carbamoyl (e.g. cyclopropylmethylcarbamoyl, cyclopentyl 2-tsiklogeksiletilkarbamoil etc.) (v) mono- or di-C _6-14 and ylcarbamoyl (e.g., phenylcarbamoyl, etc.), mono- or di-C _6-14 aralkyl-carbamoyl (e.g., benzylcarbamoyl, phenethylcarbamoyl, etc.), (vi) a mono- or di-5-7 membered monocyclic heterocyclic carbamoyl, containing, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (for example, 3-pyridinecarbamoyl, 2-thiophenecarbamoyl, piperidin-3-ylcarbamoyl and so on), (vii) mono- or di-5-7-membered monocyclic heterocycle, which contains, in addition to carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, -C _1-6 alkylcarbamoyl (e.g. 3-pyridylmethylcarbamoyl, 2- (pyridin-2-yl) ethylcarbamoyl, 2- (piperidin-1-yl) ethylcarbamoyl and so on), (viii) mono or a di-5-14 membered (preferably 5-10 membered) bicyclic or tricyclic aromatic heterocyclic carbamoyl containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen (e.g. 4-indolecarbamoyl, 5-indolocarbamoyl, 3-quinolylcarbamoyl, 5-quinolylcarbamoyl and so on), (ix) mono- or di-5-14 membered (preferably 5-10 - membered) bicyclic or tricyclic aromatic heterocyclic-C _1-6 alkylcarbonyl containing, in addition to 3-11 carbon atoms, 1-4 heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms (e.g. benzimidazole-2-ylmethylcarbamoyl, 2- (indol-3-yl) ethylcarbamoyl and so on), (x) 5-7-membered cyclic carbamoyl (e.g. 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, hexamethyleneiminocarbonyl and so on), (xi) C _1-15 acylcarbamoyl (C _1-15 acyl, who used herein have the same meanings as the "C _1-15 acyl group" in the "C _1-15 acyl z uppe, which may be optionally substituted with a substituent containing a cyclic group "), (xii) C _1-15 alkilaminokarbamoil (C _1-15 alkyl as used herein has the same meaning as the" C _1-15 alkyl group "in "C _1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group"), (xiii) C _6-14 arylaminocarbamoyl (C _6-14 aryl, which is used here, has the same meanings as "C _{6 -14 an} aryl group which may optionally be substituted with a substituent containing a cyclic group "), and so on; among others, 2- (indol-3-yl) ethylcarbamoyl and so on are preferably used.

(5) A carboxyl group, which optionally may be substituted with a substituent containing a cyclic group, includes (i) C _1-15 alkyloxycarbonyl (C _1-15 alkyl here has the same meanings as "C _1-15 alkyl group" in " A C _1-15 alkyl group optionally substituted with a cyclic group substituent, for example tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), (ii) C _6-14 aryloxycarbonyl (C _6-14 aryl has the same meanings here as "C _6-14 aryl group" in the "C _6-14 aryl group which optionally m Jet be substituted with a substituent containing a cyclic group ", for example phenoxycarbonyl), and so on.

(6) A sulfino group, which may optionally be substituted with a substituent containing a cyclic group, includes (i) C _1-15 alkylsulfonyl (C _1-15 alkyl, which is used here, has the same meaning as the "C _1-15 alkyl group "in a" C _1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group, for example benzylsulfonyl), (ii) C _6-14 arylsulfonyl (C _6-14 aryl, which is used here, has the same meanings, as the “C _6-14 aryl group” in the “C _6-14 aryl group, which may optionally be substituted with with a cyclic group, for example, tosyl), and so on.

(7) An amidino group which may optionally be substituted with a substituent containing a cyclic group includes (i) amidino, (ii) C _1-15 alkylamidino (C _1-15 alkyl, which is used here, has the same meanings as "C _1-15 alkyl group "in" a C _1-15 alkyl group which may optionally be substituted with a substituent containing a cyclic group, for example N-methylamidino), (iii) C _1-15 acylamidino (C _1-15 acyl, which is here used, has the same meanings as the “C _1-15 acyl group” in the “C _1-15 acyl group, which may optionally be substituted a substituent containing a cyclic group, for example N-acetylamidino) and so on.

(8) A glyoxyloyl group, which may optionally be substituted with a substituent containing a cyclic group, includes (i) C _1-15 alkyloxalyl (C _1-15 alkyl, which is used here, has the same meanings as "C _1-15 alkyl the group “in” a C _1-15 alkyl group which may optionally be substituted with a substituent containing a cyclic group, for example ethyloxalyl), (ii) C _6-14 aryloxalyl (C _6-14 aryl, which is used here, has the same meanings as "C _6-14 aryl group" in the "C _6-14 aryl group which may be optionally substituted replaced Titel containing cyclic group ", e.g. feniloksalil) and so on.

(9) An amino group which may optionally be substituted with a substituent containing a cyclic group includes (i) C _1-15 alkylamino (C _1-15 alkyl, which is used here, has the same meanings as "C _1-15 alkyl group "in a" C _1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group ").

Among the above, preferred examples of J ^{1 used} include a hydrogen atom, formyl, acetyl, 3-indolecarbonyl, 3- (indol-3-yl) propionyl, 3-phenylpropionyl, diphenylacetyl, 3- (pyridin-3-yl) propionyl, 4- imidazoleacetyl, cyclohexanecarbonyl, 1-piperidinacetyl, 1-methyl-1-piperidinioacetyl, 4-piperidinecarbonyl, hexanoyl, amino (4-hydroxyphenyl) acetyl, D-glucuronoyl, 2- (indol-3-yl) ethylcarbamoyl, 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) -3-2-hydroxy-hydroxy hydroxyisobutyryl, 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolecarbonyl, 6-hydroxynicotinoyl, 6-chloronicotinoyl, 6- (trifluoromethyl) nicotinoyl, dimethylcarbamoyl, 1-azetidinecarbonyl, 2-azetidinecarbonyl, 4-aminobenyl, 4-aminobenyl -3-carbonyl, pyrimidine-4-carbonyl, pyrimidine-2-carbonyl, pyridazine-4-carbo nile, 6-aminocaproyl, glycyl, glitsilglitsil, glitsilglitsilglitsil, alanilalanilalanil, alanilalanilalanilalanil, atsetilglitsil, atsetilglitsilglitsil, atsetilglitsilglitsilglitsil, atsetilalanilalanilalanil, atsetilalanilalanilalanilalanil, D-arginilglitsil, D-arginilglitsilglitsil, D-arginilglitsilglitsilglitsil, D-arginilalanilalanilalanil, D-arginilalanilalanilalanilalanil acetyl-D- arginylglycyl, acetyl-D-arginylglycylglycyl, acetyl-D-arginylglycylglycylglycyl, acetyl-D-arginylalanilanylalanyl, acetyl-D-argynylalanylalilanylalanyl, cyclopr pancarbonyl, cyclopentanecarbonyl, cyclobutanecarbonyl, cyclohexanecarbonyl, 1-naphthoyl, 2-naphthoyl, arginyl, arginyl arginyl, 6- (arginylamino) caproyl, 6- (D-arginylamino) caproyl, 6- (D-arginyl-D-arginyl, - (acetyl-D-arginylamino) caproyl, 6 - ((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norleicylamino) 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, adipoyl, pyroglutamyl, glycololoyl and so on; among others, preferred are a hydrogen atom, formyl, acetyl, propionyl, 3-indolecarbonyl, 3- (indol-3-yl) propionyl, 3-phenylpropionyl, 3- (pyridin-3-yl) propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, hexanoyl, amino (4-hydroxyphenyl) acetyl, 2- (indol-3-yl) ethylcarbamoyl, 9-fluorenylmethoxycarbonyl, amidino, 4-guanidomethylbenzoyl, benzoyl, 3-indolacetyl, benzyl, phenethyl, 3-pyridinecarbonyl, 2-p 4-pyridinecarbonyl, isobutyryl, phenylacetyl, 6-methylnicotinoyl, pyrazinecarbonyl, cyclopropanecarbonyl, trifluoroacetyl, (R) -3-hydroxy-2-methylpr pionyl, 2-hydroxyisobutyryl, 3-furancarbonyl, pyrrole-2-carbonyl, 4-imidazolecarbonyl, 6-hydroxynicotinoyl, 6-chloronicotinoyl, 6- (trifluoromethyl) nicotinoyl, dimethylcarbamoyl, 1-azetidinecarbonyl, 4-aminobenzenethyl, 4-aminobenzenethyl -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-norleucylamino) 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 so on, and acetyl is particularly preferred.

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

The term “C _1-6 alkyl group” as used includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and so on.

Preferably, J ² represents NH.

Each of J ³ - J ¹² represents a hydrogen atom or a C _1-3 alkyl group.

The term “C _1-3 alkyl group” as used includes methyl, ethyl, propyl, isopropyl and so on.

Preferably, J ³ represents a hydrogen atom.

Preferably, J ⁴ represents a hydrogen atom.

Preferably, J ⁵ represents a hydrogen atom.

Preferably, J ⁶ represents a hydrogen atom.

Preferably, J ⁷ represents a hydrogen atom.

Preferably, J ⁸ represents a hydrogen atom.

Preferably, J ⁹ represents a hydrogen atom.

Preferably, J ¹⁰ represents a hydrogen atom.

Preferably, J ¹¹ represents a hydrogen atom.

Preferably, J ¹² represents a hydrogen atom.

Each of Q ³ - Q ¹² represents a C _1-4 alkyl group, which optionally can be substituted with a substituent selected from the group consisting of:

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 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) an optionally substituted sulfhydryl group;

or a hydrogen atom.

In particular, preferred Q ³ - Q ⁹ is 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 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 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) an optionally substituted sulfhydryl group,

or a hydrogen atom.

Used the terms "optionally substituted C _6-12 aromatic hydrocarbon group", "optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms", "optionally substituted C _8-14 aromatic condensed-ring group", "optionally substituted 5-14-membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and hetero atoms selected from the group consisting of and ohm nitrogen, oxygen and sulfur "," optionally substituted non-aromatic cyclic hydrocarbon group having not more than 7 carbon atoms "and" optionally substituted non-aromatic heterocyclic group having not more than 7 carbon atoms "have the same meanings as defined above.

(1) As the 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 so on are used Further.

(2) As the C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, use, for example , 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-imidazolmethyl and so on.

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

(4) As the C _1-4 alkyl group having an optionally substituted 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, use for example, 3-indolmethyl, 1-formylindol-3-ylmethyl, 2-quinolylmethyl and so on.

(5) As the C _1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having at most 7 carbon atoms, for example, cyclohexylmethyl and so on are used.

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

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

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

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

(10) As the C _1-4 alkyl group having an optionally substituted carboxy group, for example, carboxylmethyl, 2-carboxyethyl, benzyloxycarbonylmethyl and so on are used.

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

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

(13) As an unsubstituted C _1-4 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and so on are used.

Preferred examples of the used Q ³ include: a hydrogen atom, 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl, methyl, isobutyl, hydroxymethyl, carboxymethyl, 4-aminobutyl and so on, in particular, preferably 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl and so on.

Preferred examples of the used Q ⁴ include: carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl, 4-imidazolemethyl, isobutyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 4-aminobutyl and so on, in particular, preferably carbamoylmethyl, 2-carbamoylethyl, 4 -hydroxybenzyl and so on.

Preferred examples of the used Q ⁵ include: benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolomethyl, 1 -formylindol-3-ylmethyl, 2-quinolylmethyl, cyclohexylmethyl, hydroxymethyl, 1-hydroxyethyl, methyl, isopropyl, isobutyl, sec-butyl, carboxymethyl, 4-aminobutyl and so on, in particular, preferably benzyl, 2-chlorobenzyl, 3 -chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolmethyl, 2-quinolylmethyl, cyclohexylmethyl, 1-hydroxyethyl, isopropyl, isobutyl, sec-butyl and so on.

Preferred examples of the used Q ⁶ are: methyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl and so on, in particular, preferably carbamoylmethyl and so on.

Preferred examples of the used Q ⁷ are: 4-hydroxybenzyl, carbamoylmethyl, 3-pyridylmethyl, methyl, isobutyl, benzyl, 4-aminobutyl, 3-indolmethyl and so on, in particular, preferably 4-hydroxybenzyl and so on.

Preferred examples of the used Q ⁸ include: benzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-naphthylmethyl, 3-indolomethyl, hydroxymethyl, cyclohexylmethyl, sec-butyl, 1-hydroxyethyl, methyl, methyl, isobutyl, 4-aminobutyl , 2-carboxyethyl, 3-carboxylpropyl and so on, more preferably 4-pyridylmethyl, 3-indolmethyl, 2-carboxyethyl, sec-butyl, and in particular, preferably 2-carboxyethyl.

Preferred examples of the used Q ⁹ include: a hydrogen atom, methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoyl ethyl, ureidomethyl, acetamidomethyl, diethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl and so on, in particular, preferably carbamoylmethyl, etc. .

Preferred examples of the used Q ¹⁰ include: 4-hydroxybenzyl, 3-indolomethyl, methyl, 1-hydroxyethyl, 3-guanidinopropyl and so on, in particular, preferably 3-indolmethyl and so on.

Preferred examples of the used Q ¹¹ include: carbamoylmethyl and so on.

Preferred examples of the used Q ¹² include: methyl, carbamoylmethyl and so on, in particular, preferably carbamoylmethyl and so on.

Each of Y ¹ - Y ³ represents a group represented by the formula: —CON (J ¹³ ) -, —CSN (J ¹³ ) -, —C (J ¹⁴ ) N (J ¹³ ) -, or —N (J ¹³ ) CO - (where each of J ¹³ and J ¹⁴ represents 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 are used.

J ¹³ is preferably a hydrogen atom.

J ¹⁴ is preferably a hydrogen atom.

Y ¹ is preferably a group represented by the formula: —CONH— or —CH ₂ NH— and so on.

Y ² is preferably a group represented by the formula: —CONH— or —CH ₂ NH— and so on, in particular, preferably a group represented by the formula: —COCN—.

Y ³ represents, preferably, a group represented by the formula: —CONH— and so on.

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 can be combined together to form a ring. In this case, 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 ) can form, for example, cyclopentane, cyclohexane, piperidine and so on.

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 , Y ³ and Q ⁹ , J ² and Q ¹⁰ , 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 ) can be combined together to form a ring. Also, the formed ring may be substituted or form a fused ring.

When 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 form a ring, the ring is represented by the group 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 ), including for example, azetidine, pyrrolidine, piperidine or thiazolidine. Also, the formed ring may be substituted or may form a fused ring. As Z ¹ —N — CH — R ¹ , azetidine, pyrrolidine, 4-hydroxypyrrolidine, piperidine and so on are preferably used.

When 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 form a ring, the ring is represented by the group 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 ), Y ³ C (J ⁹ ) (Q ⁹ ) or Y ³ C (J ¹¹ ) (Q ¹¹ ) including, for example, pyrrolidine-2-carbonyl, piperidine-2-carbonyl or thiazolidine-4-carbonyl. Also, the formed ring may be substituted or may form a fused ring.

When Y ² and Q are combined together to form a ring, the formation of pyrrolidine-2-carbonyl by Y ² C (J ⁸ ) (Q ⁸ ) is preferred.

Z ¹⁰ represents a hydrogen atom, O or S; O and S are preferred, among others, and O is particularly preferred.

Preferred examples of the group represented by the formula:

J ¹ -J ² -C (J ³ ) (Q ³ ) Y ¹ C (J ⁴ ) (Q ⁴ ) Y ² C (J ⁵ ) (Q ⁵ ) Y ³ C (J ⁶ ) (Q ⁶ ) C ( = Z ¹⁰ ) -

include:

Tyr Asn Trp Asn-,

Tyr Asn Trp D-Asn-,

Tyr Asn D-Trp Asn-,

Tyr D-Asn Trp Asn-,

D-Tyr Asn Trp Asn-,

Tyr Lys Trp Asn-,

Tyr Asp Trp Asn-,

Tyr Tyr Trp Asn-,

Tyr Leu Trp Asn-,

Tyr Asn Ala Asn-,

Tyr Asn Leu Asn-,

Tyr Asn Ser Asn-,

Tyr Asn Asp Asn-,

Tyr Asn Lys Asn-,

Ala Asn Trp Asn-,

Leu Asn Trp Asn-,

Ser Asn Trp Asn-,

Asp Asn Trp Asn-,

Lys Asn Trp Asn-,

Tyr Asn Trp (For) Asn-,

D-Tyr Asn D-Trp Asn-,

D-Tyr Asn Ala Asn-,

D-Tyr Asn Ser Asn-,

D-Tyr Asn Cha Asn-,

D-Tyr Asn Thr Asn-,

D-Tyr Asn Ile Asn-,

D-Tyr Gln Trp Asn-,

D-Tyr Thr Trp Asn-,

D-Tyr Asn Val Asn-,

D-Tyr D-Asn Trp Asn-,

D-Tyr D-Asn D-Trp Asn-,

D-Tyr Asn Phe Asn-,

D-Tyr Asn Nal (1) Asn-,

D-Tyr Asn Nal (2) Asn-,

D-Tyr Asn Phe (2Cl) Asn-,

D-Tyr Asn Phe (3Cl) Asn-,

D-Tyr Asn Phe (4Cl) Asn-,

D-Tyr Asn Phe (4NH ₂ ) Asn-,

D-Tyr Asn Pya (3) Asn-,

D-Tyr D-Asn Phe Asn-,

D-Tyr D-Asn Cha Asn-,

D-Tyr D-Asn Thr Asn-,

D-Tyr Asn Pya (2) Asn-,

D-Tyr Asn Pya (4) Asn-,

D-Tyr D-Ser Trp Asn-,

D-Tyr D-His Trp Asn-,

D-Pya (3) D-Asn Cha Asn-,

D-Pya (3) D-Tyr Cha Asn-,

TyrΨ (CH ₂ NH) Asn Trp Asn-,

D-Tyr AsnΨ (CH ₂ NH) Trp Asn-,

TyrΨ (CH ₂ NH) Asn D-Trp Asn-,

D-Tyr Asn Ala (2-Qui) Asn-,

D-Tyr Asn D-Pya (4) Asn-,

D-Tyr D-Asn Pya (4) Asn-,

Tyr D-Asn Cha Asn-,

Dap D-Tyr Asn Trp Asn-

Arg D-Tyr D-Pya (4) Asn-

Arg Arg D-Tyr D-Pya (4) Asn-

Arg Acp D-Tyr D-Pya (4) Asn-

D-Arg Acp D-Tyr D-Trp Asn-

D-Arg D-Arg Acp D-Tyr D-Trp Asn-

Ac D-Arg Acp D-Tyr D-Trp Asn-

D-Dap Acp D-Tyr D-Trp Asn-

D-Nle Acp D-Tyr D-Trp Asn-

D-Arg β-Ala D-Tyr D-Trp Asn-

D-Arg γ-Abu D-Tyr D-Trp Asn-

D-Arg D-Arg γ-Abu D-Tyr D-Trp Asn-

D-Arg D-Arg D-Arg γ-Abu D-Tyr D-Trp Asn-

Gly D-Tyr D-Trp Asn-

Ac Gly D-Tyr D-Trp Asn-

D-Tyr D-Tyr D-Trp Asn-

Ac D-Tyr D-Tyr D-Trp Asn-

pGlu D-Tyr D-Trp Asn-

Tyr D-Tyr D-Trp Asn-

Ac Tyr D-Tyr D-Trp Asn-

etc.

Preferred examples of the group represented by the formula:

J ¹ -J ² -C (J ⁷ ) (Q ⁷ ) Y ² C (J ⁸ ) (Q ⁸ ) Y ³ C (J ⁹ ) (Q ⁹ ) C (= Z ¹⁰ ) -

include:

Fmoc Asn Trp Asn-,

D-Asn Trp Asn-,

D-Tyr Trp Asn-,

D-Tyr D-Trp Asn-,

D-Tyr Ser Asn-,

D-Tyr Thr Asn-,

D-Tyr Ile Asn-,

D-Tyr Phe Asn-,

D-Tyr Nal (2) Asn-,

D-Pya (3) Phe Asn-,

D-Pya (3) Trp Asn-,

D-Tyr D-Pya (4) Asn-,

D-Asn Cha Asn-

D-Tyr D-Pya (4) Ala-

D-Tyr D-Pya (4) Thr-

D-Tyr Pya (4) Ala-

D-Tyr D-Trp Ala-

D-Tyr D-Trp Abu-

D-Tyr D-Phe Ala-6-Aminocaproyl-

D-Tyr D-Pya (4) Asn-

Ac D-Tyr D-Pya (4) Asn-

Benzoyl D-Tyr D-Trp Asn-

Cyclopropanecarbonyl D-Tyr D-Trp Asn-

Butyryl D-Tyr D-Trp Asn-

Me D-Tyr D-Trp Asn-

Ac D-Tyr D-Trp Gln-

Ac D-Tyr D-Trp Ser-

Ac D-Tyr D-Trp Thr-

Ac D-Tyr D-Trp Alb-

Ac D-Tyr D-Trp Dap (Ac) -

Ac D-Tyr D-Trp Dap (For) -

Ac D-Tyr Trp Asn-

Ac D-NMeTyr D-Trp Asn-

For D-Tyr D-Trp Asn-

Propionyl D-Tyr D-Trp Asn-

Amidino D-Tyr D-Trp Asn-

Ac D-Ala D-Trp Asn-

Ac D-Leu D-Trp Asn-

Ac D-Phe D-Trp Asn-

Ac D-Nal (1) D-Trp Asn-

Ac D-Nal (2) D-Trp Asn-

Ac D-Lys D-Trp Asn-

Ac D-Glu D-Trp Asn-

Ac D-Tyr D-Ala Asn-

Ac D-Tyr D-Leu Asn-

Ac D-Tyr D-Phe Asn-

Ac D-Tyr D-Thr Asn-

Ac D-Tyr D-Lys Asn-

Ac D-Tyr D-Glu Asn-

Ac D-Tyr D-Trp Asp-

Ac D-Tyr D-Trp D-Asn-

Ac D-Tyr D-Trp NMeAsn-

Ac D-Tyr Pro Asn-

Ac D-Tyr D-Pya (2) Asn-

Ac D-Tyr D-Pya (3) Asn-

Ac D-Tyr D-Pro Asn-

Ac D-Tyr Tic Asn-

Ac Tyr Trp Asn-

Ac D-Tyr NMMeTrp Asn-

Glycoloyl D-Tyr D-Trp Asn-

Ac D-Tyr D-Trp Gly-

Ac D-Tyr D-Trp Dap-

Ac D-Tyr D-Trp Asp (NHMe) -

Ac D-Tyr D-Trp Asp (NMe ₂ ) -

Ac-D-Tyr-D-Trp-Asp (NHPen) -

Ac-D-Tyr-D-Trp-Asp (NHcPr) -

Ac-D-Tyr-D-Trp-Asp (NHBzl) -

Ac-D-Tyr-D-Trp-Alb-

Ac-D-Tyr-D-Pya (4) -Alb-

Ac-D-Tyr-Aze (2) -Asn-

Ac-D-Tyr-Pic (2) -Asn-

Ac-D-Tyr-Hyp-Asn-

Ac-D-Tyr-Thz-Asn-

Ac-D-Tyr-Gly-Asn-

Ac-D-Tyr-Aib-Asn-

Ac-D-Tyr-D-NMeAla-Asn-

Ac-D-Tyr-D-Gln-Asn-

Ac-D-Tyr-D-His-Asn-

Ac-D-Tyr-D-Trp-Dab-

Ac-D-Tyr-Ala-Asn-

Ac-D-Tyr-Leu-Asn-

Ac-D-Tyr-Ser-Asn-

Ac-D-Tyr-Lys-Asn-

Ac-D-Tyr-Glu-Asn-

Ac-D-Tyr-Pzc (2) -Asn-

Ac-D-Tyr-Orn-Asn-

Ac-D-Tyr-Thr-Asn-

Ac-D-Tyr-His (3Me) -Asn-

Ac-D-Tyr-Tyr (PO ₃ H ₂ ) -Asn-

Glycoloyl-D-Tyr-Hyp-Asn-

Ac-D-Tyr-Pro (4NH ₂ ) -Asn-

Ac-D-Tyr-Hyp (Bzl) -Asn-

Ac-D-Tyr-D-NMePhe-Asn-

Ac-D-Tyr-Hyp-Alb-

Ac-D-Tyr-Hyp-His-

Ac-D-Tyr-Hyp-Gln-

Ac-D-Tyr-Hyp-D-Asn-

Ac-D-Tyr-Hyp-Cit-

Ac-D-Tyr-Glu-Alb-

Ac-D-Tyr-Aad-Asn-

Ac-D-Tyr-Pro (4F) -Asn-

etc; in particular, the following groups are preferred.

Ac D-Tyr Hyp Asn-

Ac D-Tyr Glu Asn-

Ac-D-Tyr-Hyp-Alb-

Ac-D-Tyr-Glu-Alb-

Ac-D-Tyr-Pro (4F) -Asn-

Preferred examples of the group represented by the formula:

J ¹ -J ² -C (J ¹⁰ ) (Q ¹⁰ ) Y ³ C (J ¹¹ ) (Q ¹¹ ) C (= Z ¹⁰ ) -

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-Pyridinopropionyl D-Trp Asn-

Adipoyl D-Trp Asn-

6-Aminocaproyl D-Trp Asn-

Amidino D-Trp Asn-

Glycoloyl D-Trp Asn-

etc.

Preferred examples of the group represented by the formula:

J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ ) -

include:

Fmoc Asn-,

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

3-Indolecarbonyl Asn-,

3-Indolecetyl 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-piperidine acetyl Asn-,

1-Methyl-1-piperidinioacetyl Asn-,

1-Pyridinioacetyl Asn-,

D-Gluconyl 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 formula:

J ^1-

include:

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-imidazolecarbonyl-

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-

4- [bis- (2-pyridylmethyl) aminomethyl] benzoyl-

etc.

In the present invention, preferred P is Ac-D-Tyr-Hyp-Asn, Ac-D-Tyr-Glu-Asn, or Ac-D-Tyr-Hyp-Alb-.

The metastin derivatives of the present invention or their salts are preferably compounds represented by the formula I described above, or their salts, where:

Z ¹ , Z ⁵ and Z ⁷ each represent a hydrogen atom;

Z ² , Z ⁴ , Z ⁶ and Z ⁸ each represent O;

R ¹ represents (2) a C _1-8 alkyl group optionally substituted by an optionally substituted hydroxyl group;

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

R ³ represents (1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having an additional substituent;

R ⁴ represents (4) a C _1-4 alkyl group, which optionally can be substituted by an optionally substituted 5-14 membered aromatic condensed heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms,

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom;

A 'represents (1) a carbon atom substituted by a hydrogen atom or O;

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _1-4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups;

Y represents (1) a group represented by the formula: —CONH—, —CSNH—, —NHCO—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH = CH— or —CH ₂ CH ₂ -, which may optionally be substituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a hydroxyl group or a halogen atom.

More preferably, the metastin derivatives of the present invention or its salts are compounds represented by the following formula, or salts thereof:

XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂

Where:

XX0 is formyl, C _1-20 alkanoyl, cyclopropanecarbonyl, 6- (acetyl-D-arginylamino) caproyl, 6 - ((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norleucylamino) caproyl, 4- (D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyl tyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3- (pyridin-3-yl) propionyl, adipoyl, glycoloyl or 6-aminocaproyl;

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

XX3 is D-Asp, D-Dap, D-Ser, D-Gln, D-His, D-NMeAla, D-NMePhe, Aze (2), Pic (2), Pic (3), Hyp, Thz, NMeAla, Gly, Aib, Abz (2), Abz (3), Sar, Leu, Lys, Glu, β-Alanine, Pzc (2), Orn, His (3Me), Tyr (PO ₃ H ₂ ), Pro ( 4NH ₂ ), Hyp (Bzl), Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-Ala, D-Leu, D-Phe, D-Lys, D-Glu, D-2-pyridylalanine, D -3-pyridylalanine, D-4-pyridylalanine, Aad, Pro (4F) or a chemical bond;

XX4 represents Asn, 2-amino-3-ureidopropionovuyu acid, N ^β -formildiaminopropionovuyu acid, N ^β -atsetildiaminopropionovuyu acid, N ^ω -pentilasparagin, N ^ω -tsiklopropilasparagin, N ^ω -benzilasparagin, 2,4-diaminobutanoic acid, His, Gln, Cit or D-Asn;

XX5 is Ser, Thr, Val, NMeSer, Gly, Ala, Hyp, D-Ala, Dap or D-Thr (more preferably, Ser, Thr, Val, NMeSer, Gly, Ala, Hyp, D-Ala or D- Thr);

T is a group represented by formula II:

Where

Z ⁴ represents a hydrogen atom, O or S;

R ² represents (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) C _{1- 8} an alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic cyclic group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condensiro bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and (6) optionally substituted a non-aromatic heterocyclic group having no more than 7 carbon atoms;

A represents:

(1) a nitrogen atom substituted with a hydrogen atom or a C _1-3 alkyl group;

(2) a carbon atom substituted by a hydrogen atom or a C _1-3 alkyl group;

(3) O; or

(4) S;

A 'represents:

(1) a carbon atom, which optionally can be substituted by a hydrogen atom, O, S, a halogen atom, an optionally halogenated C _1-3 alkyl group, a carbamoyl group or a hydroxyl group;

(2) a nitrogen atom, which optionally can be substituted by a hydrogen atom or an optionally halogenated C _1-3 alkyl group;

(3) O; or

(4) S;

Q ² represents:

(1) CH ₂ or CH = CH ₂ , which optionally can be substituted with a C _0-4 alkyl group, optionally substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, a C _1-3 alkoxy group and an amino group;

(2) NH, which optionally can be substituted by an optionally substituted C _1-4 alkyl group with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group; or,

(3) O;

Y represents:

(1) a group represented by the formula: -CONH-, -CSNH-, -CH ₂ NH-, -NHCO-, -CH ₂ O-, -COCH ₂ -, -CH ₂ S-, -CSCH ₂ -, -CH ₂ SO-, -CH ₂ SO ₂ -, -COO-, -CSO-, -CH ₂ CH ₂ - or -CH = CH-, which may optionally be substituted with a substituent selected from the group consisting of C _1-6 alkyl group, hydroxyl group and halogen atom;

(2) an optionally substituted C _6-7 aromatic hydrocarbon group;

(3) an optionally substituted 4-7 membered aromatic heterocyclic group consisting of 1-5 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;

(4) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms; or

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 5 carbon atoms, and when Y represents (2), (3), (4) or (5), Q ² may be a chemical bond;

the bonds between YQ ² , Q ² -A 'and A'-A, each independently represent a single or double bond;

XX9 represents Arg, Orn, Arg (Me) or Arg (asymMe ₂ ); and,

XX10 is Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine; provided that these compounds are excluded

Ac-D-Tyr-D-Trp-Asn-Thr-PheΨ (CH ₂ NH) Gly-Leu-Arg (Me) -Trp-NH ₂ , Ac-D-Tyr-D-Trp-Asn-Thr-Phe- Gly-Leu-Arg (Me) -Trp-NH ₂ , Ac-D-Tyr-D-Trp-Asn-Thr-D-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ and Ac-D- Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg (Me) -Trp-NH ₂ .

More preferably, the metastin derivatives of the present invention or their salts are compounds represented by the following formula, or their salts:

XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂

Where:

XX0 is formyl, C _1-6 alkanoyl or glycoloyl;

XX2 represents D-Tyr or a chemical bond;

XX3 is Aze (2), Hyp, Gly, Aib, Leu, Lys, Glu, His (3Me), Tyr (PO ₃ H ₂ ), Pro (4F) or Hyp (Bzl);

XX4 represents Asn or 2-amino-3-ureidopropionic acid;

XX5 represents Ser or Thr;

T represents a group represented by formula II described above;

Z ⁴ represents O;

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom;

A 'represents (1) a carbon atom substituted by a hydrogen atom or O,

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _0-4 alkyl groups, which optionally can be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups;

Y represents (1) a group represented by the formula: —CONH—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH ₂ CH ₂ -, CSNH—, —NHCO— or —CH = CH -, which may optionally be substituted with a substituent selected from the group consisting of a C _1-6 alkyl group, a hydroxyl group and a halogen atom;

XX9 represents Arg or Arg (Me); and,

XX10 represents Phe or Trp.

Derivatives of metastin of the present invention or their salts, which are preferred, are, in particular, compounds represented by the following formula, or their salts:

XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂

Where:

XX0 represents C _1-12 alkanoyl;

XX2 represents D-Tyr;

XX3 is Hyp, Pro (4F) or Glu;

XX4 is Asn, 2-amino-3-ureidopropionic acid;

XX5 represents Thr;

T represents a group represented by formula II described above;

Z ⁴ represents O;

R ² represents a linear C _1-10 alkyl group or a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms;

A represents (1) a nitrogen atom substituted by a hydrogen atom, (2) a carbon atom substituted by a hydrogen atom;

A 'represents (1) a carbon atom substituted by a hydrogen atom or O;

Q ² represents (1) CH ₂ or CH = CH ₂ optionally substituted with one or two C _1-4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of a carbamoyl group, a hydroxyl group, C _1-3 alkoxy groups and amino groups;

Y represents (1) a group represented by the formula: —CONH—, —CSNH—, —NHCO—, —CH ₂ O—, —CH ₂ S—, —COCH ₂ -, —CH = CH— or —CH ₂ CH ₂ -, which optionally may be substituted with a C _1-6 alkyl group, a hydroxyl group or a halogen atom;

XX9 represents Arg or Arg (Me); and,

XX10 represents Trp.

In the present invention, Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂ (SEQ ID NO: 16) refers to metastin 10 (Metastin 10), i.e., MS10.

In the examples described below, the N-terminal Tyr and C-terminal Phe in MS10 are considered 1- and 10-positions, respectively.

Tyr- Asn- Trp- Asn- Ser- Phe- Gly- Leu- Arg- Phe- NH ₂ one 2 3 four 5 6 7 8 9 10

For example, compound No. 796 (EXAMPLE 1): des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Arg (Me) 9, Trp10] MS10 denotes a peptide where the N-terminal Tyr (1-position) is deleted, Asn at position 2 is replaced by D-Tyr, Trp at position 3 is replaced by Hyp, Ser at position 5 is replaced by Thr, Arg at position 9 is replaced by Arg (Me), the C-terminal (position 10) is replaced by Trp and the amino group is replaced by D-Tyr at position 2 is converted to Ac.

The chemical bonds “-” between XX0, XX2, XX3, XX4, XX5, T, XX9, XX10 and NH ₂ in the formula “XX0-XX2-XX3-XX4-XX5-T-XX9-XX10-NH ₂ " have the following meanings, respectively .

The chemical bond "-" in the formula "XX0-XX1" refers to the bond between the group represented by XX0 and the amino group (α-amino group) contained in XX2. More specifically, “XX0-XX1” indicates that the hydrogen atom in the amino group (NH ₂ ) contained in XX2 is substituted by the group represented by XX0.

The chemical bond “-” in the formula “XX2-XX3” means that the carboxyl group (α-carboxyl group) contained in XX2 is attached to the amino group (α-amino group) in XX3 via an amide bond. Also, the chemical bonds "-" in the formula "XX3-XX4," "XX4-XX5" and "XX9-XX10" have the same meanings as described above.

The chemical bond “-” in the formula “XX5-T” is a bond between the carboxyl group (α-carboxyl group) in XX5 and the group represented by the group represented by T. More specifically, -OH in the carboxyl group (-COOH) contained in XX5 is substituted by the group represented by T.

The chemical bond “-” in the formula “T-XX9” is a bond between the group represented by T and the amino group (α-amino group) in XX9. More specifically, the hydrogen atom in the amino group (NH ₂ ) contained in XX9 is substituted by the group represented by T.

The chemical bond “-” in the formula “XX10-NH ₂ ” is a bond between the carboxyl group (α-carboxyl group) contained in XX10 and —NH ₂ . More specifically, the —OH in the carboxyl group (—COOH) contained in XX10 is substituted with —NH ₂ .

When XX2 or / and XX3 are chemical bonds "-," said chemical bonds "-" have the same meanings as described above.

Specific examples of these chemical bonds include bonds represented by the structural formulas shown in TABLE 1, described below and so on.

In the metastin derivatives of the present invention, all compounds where the groups described above are optionally combined are preferably used. Among others, the following compounds are preferred.

MS10: Tyr- Asn- Trp- Asn- Ser- Phe- Gly- Leu- Arg- Phe- NH ₂ one 2 3 four 5 6 7 8 9 10

(Compound No. 796)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂ ,

(Compound No. 803)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ala7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ala-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 804)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ser7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ser-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 811)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Aib7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Aib-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 818)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Abu7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Abu-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 822)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 823)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ala7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Ala-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 827)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Dap7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Dap-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 828)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ser (Me) 7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Ser (Me) -Leu-Arg (Me) -Trp-NH ₂

(Compound No. 834)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ O) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ O) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 839)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Pya (2) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Pya (2) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 847)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Val7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Val-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 848)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Pya (3) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Pya (3) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 849)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Pya (4) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Pya (4) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 850)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ CH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 851)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (COCH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (COCH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 852)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 853)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 854)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ NH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ NH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 855)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ala (cPr) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Ala (cPr) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 857)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ ((S) CHOH-CH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((S) CHOH-CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 858)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ ((S) CHOH- (E) CH =) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((S) CHOH- (E) CH =) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 859)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ ((E) CH = CH) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((E) CH = CH) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 866)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ ((R) CHOH- (E) CH =) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((R) CHOH- (E) CH =) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 867)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ ((R) CHOH-CH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ ((R) CHOH-CH ₂ ) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 869)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, αMePhe6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-αMePhe-Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 871)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe (2Me) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe (2Me) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 873)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe (3Me) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe (3Me) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 875)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe (4Me) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe (4Me) -Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 885)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Phe-Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 892)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 893)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ CH ₂ ) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 894)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 895)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 902)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 903)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 904)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 905)

des (1) -Ac- [D-Tyr2, Glu3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 906)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 907)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 908)

des (1) -Ac- [D-Tyr2, Glu3, Alb4, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Alb-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 909)

des (1) -Ac- [D-Tyr2, Asp3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Asp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 910)

des (1) -Ac- [D-Tyr2, Aad3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Aad-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 911)

des (1) -Ac- [D-Tyr2, Lys3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Lys-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 912)

des (1) -Ac- [D-Tyr2, Aib3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Aib-Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 913)

des (1) -Ac- [D-Tyr2, Hyp3, Gln4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Gln-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 914)

des (1) -Ac- [D-Tyr2, Hyp3, Cit4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Cit-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 915)

des (1) -Ac- [D-Tyr2, Hyp3, Glu4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Glu-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 916)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 917)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ser (Me) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂

(Compound No. 918)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Nva8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-Gly-Nva-Arg (Me) -Trp-NH ₂

(Compound No. 919)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Nal (2) 6, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Nal (2) -Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 920)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ser (Me) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂

(Compound No. 921)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Nva8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Nva-Arg (Me) -Trp-NH ₂

(Compound No. 923)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Ser (Me) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ser (Me) -Arg (Me) -Trp-NH ₂

(Compound No. 924)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Nva8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Nva-Arg (Me) -Trp-NH ₂

(Compound No. 925)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂

(Compound No. 926)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂

(Compound No. 927)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂

(Compound No. 929)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ S) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ S) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 931)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Gly7Ψ (CH ₂ S) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ (CH ₂ S) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 932)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Nle8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Nle-Arg (Me) -Trp-NH ₂

(Compound No. 933)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Leu (Me) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Leu (Me) -Arg (Me) -Trp-NH ₂

(Compound No. 934)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6.8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Cha-Arg (Me) -Trp-NH ₂

(Compound No. 940)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ala (cPr) 8, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cPr) -Arg-Trp-NH ₂

(Compound No. 942)

des (1) -Ac- [D-Tyr2, Glu3, Thr5, Cha6, Ala (cPr) 8, Trp10] MS10

Ac-D-Tyr-Glu-Asn-Thr-Cha-Gly-Ala (cPr) -Arg-Trp-NH ₂

(Compound No. 944)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ S) Gly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ S) Gly-Leu-Arg (Me) -Trp-NH ₂

(Compound No. 945)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Ala (cBu) 6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Ala (cBu) -Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 946)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ala (cBu) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-Gly-Ala (cBu) -Arg (Me) -Trp-NH ₂

(Compound No. 947)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Ala5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Ala-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 948)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Ser5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Ser-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 949)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Gly5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Gly-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 951)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Dap5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Dap-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 952)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg-Trp-NH ₂

(Compound No. 953)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 956)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg-Trp-NH ₂

(Compound No. 957)

des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ (CH ₂ CH ₂ ) Leu-Arg (Me) -Trp-NH ₂

(Compound No. 959)

des (1) -Ac- [D-Tyr2, Pro (4F) 3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Pro (4F) -Asn-Thr-Cha-Gly-Ala (cPr) -Arg (Me) -Trp-NH ₂

(Compound No. 968)

des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ CH ₂ ) AzaGly7, Arg (Me) 9, Trp10] MS10

Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ CH ₂ ) AzaGly-Leu-Arg (Me) -Trp-NH ₂

The structural formulas of these compounds are shown in TABLE 1.

[TABLE 1]

The metastin derivatives of the present invention can be prepared by well-known peptide synthesis methods. As peptide synthesis methods, for example, either solid-phase synthesis or liquid-phase synthesis can be used. That is, an incomplete peptide or amino acids that can form the peptide of the present invention are repeatedly condensed with the rest, to obtain a product having the desired sequence. In the case where the product has protective groups, these protective groups are removed to obtain the desired peptide. Well-known methods of condensation and deprotection include methods, for example, described in (1) to (5) below.

(1) M. Bodanszky & M.A. Ondetti: Peptide Synthesis, Interscience Publishers, New York (1966)

(2) Schroeder & Luebke: The Peptide, Academic Press, New York (1965)

(3) Nobuo Izumiya, et al .: Peptide Gosei-no-Kiso to Jikken (Basics and experiments of peptide synthesis), published by Maruzen Co. (1975)

(4) Haruaki Yajima & Shunpei Sakakibara: Seikagaku Jikken Koza (Biochemical Experiment) 1, Tanpakushitsu no Kagaku (Chemistry of Proteins) IV, 205 (1977)

(5) Haruaki Yajima, ed .: Zoku Iyakuhin no Kaihatsu (A sequel to Development of Pharmaceuticals), Vol. 14, Peptide Synthesis, published by Hirokawa Shoten

After completion of the reaction, the product can be purified and isolated by a combination of conventional purification methods, such as solvent extraction, distillation, column chromatography, liquid chromatography and recrystallization, to obtain the peptide of the present invention. When the peptide obtained by the above methods is in free form, the peptide can be converted to the corresponding salt by well-known methods; and conversely, when the peptide is obtained in the form of a salt, it can be converted into its free form by known methods.

For the condensation of protected amino acids or peptides, a number of activating reagents for peptide synthesis can be used, however, trisphosphonium salts, tetramethyluronium salts, carbodiimides and so on are particularly preferred. Examples trisfosfoniya salts include phosphonium hexafluorophosphate (PyBOP), bromtris (pyrrolidino) phosphonium hexafluorophosphate (PyBroP) and 7-azabenzotriazole-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyAOP), examples of tetramethyluronium salts benzotriazol-1-yloxytris (pyrrolidino) include 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-nonborne-2,3-dicarboxyimido) -1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU ) and O- (N-succinimidyl) -1,1,3,3-tetramethy luronium tetrafluoroborate (TSTU); examples of carbodiimides include DCC, N, N'-diisopropylcarbodiimide (DIPCDI) and N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI.HCl); and so on. For condensation using these reagents, the addition of racemization inhibitors (e.g., HONB, HOBt, HOAt, HOOBt and so on) is preferred. The solvents used in the condensation can be suitably selected from the solvents that are commonly used for condensation. For example, acid amides such as anhydrous or aqueous N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and so on, halogenated hydrocarbons such as methylene chloride, chloroform and so on, alcohols such as trifluoroethanol, phenol and so on, sulfoxides such as dimethyl sulfoxide and so on, tertiary amines such as pyridine and so on, ethers such as dioxane, tetrahydrofuran and so on, nitriles such as acetonitrile, propionitrile and so on, esters such as methyl acetate ethyl acetate and so on, or their suitable mixtures and so on. The reaction temperature, respectively, is selected within the range that is suitable for peptide binding reactions, and usually it, respectively, is in the range from about -20 ° C to 50 ° C. Activated amino acid derivatives are usually used in a 1.5-6 fold excess. When using solid-phase synthesis, condensation is determined using the ninhydrin reaction; when the condensation is incomplete, the condensation can be completed by re-condensation without removing the protective groups. When the condensation is incomplete even after a second reaction, the amino acids that have not come into interaction are subjected to acetylation with acetic anhydride or acetylimidazole to eliminate any undesirable effect during the subsequent reaction.

Examples of protecting groups used to protect amino groups in the starting amino acids include Z, Boc, t-pentyloxycarbonyl, izoborniloksikarbonil, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, difenilfosfinotioil, Fmoc , trityl and so on. Examples of protecting groups for the carboxyl group include, in addition to the C _1-6 alkyl group, the C _3-8 cycloalkyl group and the C _7-14 aralkyl group for R described above, allyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4 -chlorobenzyl, phenacyl group, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide and so on.

The hydroxyl group of serine and threonine can be protected, for example, by the formation of a complex or simple ether. Examples of groups suitable for such an ester formation include a group derived from an organic acid, such as a lower (C _2-4 ) alkanoyl group, such as an acetyl group, an aroyl group, such as a benzoyl group, and so on. Examples of a group suitable for ether formation include a benzyl group, a tetrahydropyranyl group, a tert-butyl group, a trityl group (Trt), and so on.

Examples of groups for protecting the phenolic hydroxyl group of tyrosine include Bzl, 2,6-dichlorobenzyl (Cl ₂ -Bzl), 2-nitrobenzyl, Br-Z, tert-butyl and so on.

Examples of groups used to protect the imidazole histidine moiety include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt, Fmoc and so on. Examples of protecting groups for the guanidino group in 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 so on. Examples of protecting groups for the amino group of the lysine side chain include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylidenyl (Dde) and so on.

Examples of protecting groups for indolyl in tryptophan include formyl (For), Z, Boc, Mts, Mtr and so on.

Examples of protecting groups for asparagine and glutamine include Trt, xanthyl (Xan), 4,4'-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob) and so on.

Examples of activated carboxyl groups in the starting product include the corresponding acid anhydrides, azides, activated esters [esters with alcohols (e.g. pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitrophenol, cyanomethyl alcohol, p-nitrophenol, HONB, N-hydroxysuccimide, 1-hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt)], etc. Examples of activated forms of amino groups in the starting material include the corresponding phosphorus amides.

To remove (remove) the protective groups, use is made of catalytic reduction in a stream of hydrogen gas in the presence of a catalyst such as Pd-black or Pd on coal; acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, trimethylsilane bromide (TMSBr), trimethylsilyl trifluoromethanesulfonate, tetrafluoroboric acid, tris (trifluoro) boron, trisomidobisomethiomethyl bromide-di-isomeridomide, or trisomidobisomethiomeri , piperazine, and so on, and reduction with sodium in liquid ammonia. Removal of the protecting groups by the acid treatment described above is usually carried out at a temperature of about −20 ° C. to 40 ° C. When treated with an acid, it is effective to add a cationic cleanser such as anisole, phenol, thioanisole, m-cresol, p-cresol and so on, dimethyl sulfide, 1,4-butanedithiol, 1,2-ethanedithiol and so on. Next, the 2,4-dinitrophenyl group used as the protecting group for imidazole in histidine is removed by treatment with thiophenol. The formyl group used as the indole protecting group in tryptophan is removed by the above treatment with acid in the presence of 1,2-ethanedithiol, 1,4-butanedithiol and so on, as well as by treatment with an alkali metal such as a dilute sodium hydroxide solution, diluted ammonia and so on. Further.

Protection of functional groups that should not be involved in the reaction of the starting products, protecting groups, deprotection and activation of the functional groups included in the reaction can, respectively, be selected from well-known groups and well-known methods.

Methods for producing an amide in a peptide include, for example, solid phase synthesis using resins to form peptamides. In another method for producing amides in a peptide, for example, the α-carboxyl group in the carboxy terminal amino acid is first protected by amidation; then the peptide chain is increased from the amino group to the desired length. Then a peptide is obtained in which only the protective group in the N-terminal α-amino group in the peptide chain has been removed from the peptide, and a peptide (or amino acid) in which only the protective group in the C-terminal carboxyl group has been removed. Two peptides are condensed in a mixture of solvents described above. The characteristics of the condensation reaction are similar to those described above. After purification of the protected peptide obtained by condensation, all protective groups are removed by the method described above to obtain the desired crude peptide. This crude peptide is purified by various known purification methods. Lyophilization of the main fraction gives the amide of the desired peptide.

When the metastin derivative of the present invention is in the form of a configurational isomer, diastereomer, conformer or the like, each can be isolated by separation and purification as described above, if desired. Furthermore, when the compound of the present invention is racemic, it can be resolved into the S isomer and the R isomer by conventional optical resolution.

When the metastin derivative of the present invention contains steric isomers, the present invention includes both these isomers separately and isomers present as a mixture thereof.

In addition, the metastin derivative of the present invention may also be hydrated or unhydrated. The metastin derivative of the present invention may also be labeled with an isotope (e.g., ³ H, ¹⁴ C, ³⁵ S), and so on.

Throughout the description of the present invention, the peptides are presented in accordance with the usual methods for describing peptides, that is, the N-terminus (amino terminus) on the left side, and the C-terminus (carboxyl end) on the right side. In peptides, C-end is typically present in the form of an amide (-CONH _2), carboxyl group (-COOH), carboxylate (-COO ^-), alkylamide (-CONHR) or an ester (-COOR), and it is preferred, in particular amide (-CONH ₂ ). Examples of R in the ester or alkyl amide include a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and so on; A C _3-8 cycloalkyl group such as cyclopentyl, cyclohexyl and so on; A C _6-12 aryl group such as phenyl, α-naphthyl and so on; A C _7-14 aralkyl group such as a phenyl-C _1-2 alkyl group, for example benzyl, phenethyl and so on, or an α-naphthyl-C _1-2 alkyl group such as α-naphthylmethyl and so on; pivaloyloxymethyl group, which is widely used as an ester for oral administration, and the like.

Examples of salts of the metastin derivative of the present invention include a metal salt, an ammonium salt, an organic base salt, an inorganic acid salt, an organic acid salt, a salt with a basic or acidic amino acid, and the like. Preferred examples of metal salts include alkali metal salts such as sodium salts, potassium salts and so on; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts and so on; aluminum salts; etc. Preferred examples of salts with organic bases include salts of trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and so on. Preferred examples of salts of inorganic acids include salts of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and so on. Preferred examples of organic acid salts include salts of 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 so on. Preferred examples of salts with basic amino acids include salts of arginine, lysine, ornithine and so on, and preferred examples of salts with acid amino acids include salts of aspartic acid, glutamic acid, and so on.

Among these salts, pharmaceutically acceptable salts are preferred. For example, when the compound contains an acidic functional group, inorganic salts such as alkali metal salts (e.g. sodium salts, potassium salts and so on), alkaline earth metal salts (e.g. calcium salts, magnesium salts, barium salts and so on) are preferred. ammonium salts and the like. When the compound contains a basic functional group, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and so on, and salts of organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid are preferred. acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid and so on.

A prodrug of a metastin derivative or its salt (hereinafter sometimes simply referred to as a metastin derivative of the present invention) is used to denote a metastin derivative that is converted to a metastin derivative of the present invention under physiological conditions or by interaction with an enzyme, stomach acid, and so on, in vivo . In other words, a prodrug of the present invention relates to a metastin derivative that undergoes enzymatic oxidation, reduction, hydrolysis, and so on, to convert to a metastin derivative of the present invention, or a metastin derivative that undergoes hydrolysis and so on, under the influence of stomach acid and so on. further for conversion to a metastin derivative of the present invention.

Examples of a prodrug of a metastin derivative of the present invention include metastin derivatives, where the amino group in the metastin derivative of the present invention is substituted by acyl, alkyl, phosphoric acid, and so on (e.g., metastin derivatives, where the amino group in the metastin derivative of the present invention is substituted by eicosanoyl, alanyl, pentylaminocarbonyl ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl and so on); derivatives of metastin, where the hydroxy group in the metastin derivative of the present invention is substituted by acyl, alkyl, phosphoric acid, boric acid, and so on (for example, metastin derivatives, where the hydroxy group in the metastin derivative of the present invention is substituted by acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, , alanyl, dimethylaminomethylcarbonyl and so on); and metastin derivatives, where the carboxy group in the metastin derivative of the present invention is substituted with an ester, amide, and so on (for example, metastin derivatives, where the carboxy group of the metastin derivative of the present invention is converted to ethyl ether, phenyl ether, carboxymethyl ether, dimethylaminomethyl ether, pivaloyloxymethyl ether, pivaloyloxymethyl ether, ethoxycarbonyloxyethyl ether, phthalidyl ether, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ether, cyclohexyloxycarbonylethyl ether, methylamide and so on); etc. These metastin derivatives can be obtained from the metastin derivatives of the present invention by themselves by known methods.

The prodrugs of the metastin derivative of the present invention can be prodrugs that are converted to the metastin derivatives of the present invention under physiological conditions, as described in Pharmaceutical Research and Development, Vol. 7, Drug Design, pages 163-198, published 1990 by Hirokawa Publishing Co.

The metastin derivative of the present invention or a salt thereof and their prodrugs (hereinafter sometimes abbreviated as “the compound of the present invention”) have cancer metastasis suppressing activity or cancer tumor suppression activity and can be used as medicaments, including prophylactic / therapeutic agents for cancer all types (e.g. lung cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer, colorectal cancer, colon cancer, prostate cancer cancer, ovarian cancer, cervical cancer, breast cancer, etc.), as inhibitors of cancer metastasis or cancer growth inhibitors.

The compound of the present invention has the effects of pancreatic regulatory functions and is useful as a therapeutic / prophylactic agent for various pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, and so on).

The compound of the present invention has the effects of the functions of regulating the placenta and is applicable as medicines, for example, prophylactic or therapeutic agents for the treatment of choriocarcinoma, cystic skidding, destroying cystic skidding, spontaneous abortion, fetal hypoplasia, abnormal glucose metabolism, abnormal fat metabolism or labor induction.

Also, the compound of the present invention has the effects of increasing sugar levels, stimulating the secretion of pancreatic glucagon and stimulating urination, and is applicable as a hyperglycemic agent, pancreatic glucagon secretion enhancing agent, or urinary stimulating agent, for example, as medicines, including for the prevention or treatment of obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy , Diabetic nephropathy, diabetic retinopathy, edema, urination disorders, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity.

In addition, the compound of the present invention has the effects of stimulating the secretion of gonadotropin hormone (e.g., FSH, LH, etc.), stimulating the secretion of sex hormone [e.g., androgens (such as testosterone, androstedione and so on), estrogens (e.g. estradiol, estrone and so on), progesterone and so on], improving gonadal function, and inducing or stimulating ovulation, as well as the effect of puberty and so on, and thus can be used as a means to improve gonadal fu functions, agents to induce or stimulate ovulation, agents that enhance the secretion of gonadotropin hormone or agents that enhance the secretion of sex hormone, or agents for the prophylaxis / treatment of hormone-dependent cancers [for example, prostate cancer, breast cancer, etc.], infertility [for example , irregular menstrual cycle, dysmenorrhea, amenorrhea causing mass loss amenorrhea, secondary amenorrhea, anovulation, ovarian hypofunction, hypogonadism, impaired spermatogenesis, hypogonadism (e.g. impotence and so on), genital atrophy, testicular atrophy, testicular functional disorder, azoospermia, hypoandrogenemia and so on], endometriosis, puberty, uterine fibroids and so on.

A prodrug of a metastin derivative of the present invention or a salt thereof is also useful as a prophylaxis / treatment for Alzheimer's disease, mild cognitive impairment, autism, and so on.

In addition, the compound of the present invention is useful as an agent for the prophylaxis / treatment of rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, gout, etc.) or the like.

To determine that the compound is used to treat rheumatic diseases, research can be performed by well-known methods. A specific example of research methods is given below.

Used female rats LEW at the age of 6 weeks (weight from 150 to 200 g), 8 rats per group. Bovine type II collagen was dissolved in a 0.05 mol / L acetic acid solution, which was adjusted to a concentration of 3 mg / ml. An equivalent volume of FIA (Freund's incomplete adjuvant) was added to obtain an emulsion. For sensitization (primary immunization), an emulsion was inoculated intracutaneously into the rat flank. Seven days after the initial immunization, in order to enhance immunization, 0.2 ml of a similar emulsion was inoculated into the coccyx subcutaneously. Starting from the day the immunization is increased, inclusive (day 0), an excipient solution and a solution of the compound, respectively, were administered subcutaneously. On day 0, 4, 7, 11, and 14, the volume of the hind legs was measured using a plethysmometer (UGO BASILE), and the average volumes of both hind legs were derived to obtain the base volume of the legs. To evaluate the effect on the volume of paws, obtained by subtracting the previously determined volume value (day 0) of each animal from the values obtained on days 4, 7, 11 and 14, the value was determined for each animal and provided for statistical calculation.

The compound of the present invention is also applicable as:

agents for the prevention / treatment of autism, immunomodulation (thymus regeneration, thymus repopulation, enhanced T-cell growth), hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, thrombotic disorders or lipotoxicity;

agents for the prophylaxis / treatment of hyperlipemia, type II diabetes mellitus, hypertension, diabetic neuropathy, diabetic nephropathy or diabetic retinopathy; sedative; anti-stress agents; remedies for insomnia; agents for treating manic-depressive disease; agents for the prevention / treatment of hypertension (e.g., essential hypertension, renal hypertension, salt-sensitive hypertension, etc.), angina pectoris (e.g. stable angina pectoris, unstable angina pectoris, etc.), myocardial infarction, cerebrovascular disease (e.g. asymptomatic cerebrovascular disease) disorder, transient ischemic attack, apoplexy, cerebro-vascular dementia, hypertensive encephalopathy, cerebral infarction and so on), venous insufficiency, obliterative peripheral circulatory disorders, Raynaud's disease, arteriosclerosis, including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis and so on), thickening of the walls of the vessels or occlusion and organ damage after the intervention (e.g., percutaneous coronary intervention, stent placement, coronary thrombolytic therapy and so on), portal hypertension, respiratory disorders (for example, asthma, pulmonary hypertension and so on); agents for prophylaxis / treatment of impaired glucose tolerance (IGT); an agent that enhances the secretion of insulin, an inhibitor of the transition of IGT to diabetes;

agents for the prevention / treatment of diabetic complications [eg, neuropathy, nephropathy, retinopathy, lens clouding, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (eg, respiratory tract infection, urinary tract infection, gastrointestinal infection, skin and soft infections tissue infection, lower leg infection), diabetic gangrene, xerostomia, hypoacusia, cerebrovascular disorder, peripheral circulatory disorders], osteoporosis, cachexia (eg , cancer cachexia, tuberculous cachexia, diabetic cachexia associated with blood disease cachexia associated with endocrine disease cachexia associated with infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome), fatty liver, polycystic ovary syndrome, renal disease (e.g. , glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis - the last stage of kidney disease), muscular dystrophy, heart attack myocardium, angina pectoris, cerebrovascular disease (e.g. cerebral infarction, apoplexy), Alzheimer's disease, Parkinson's disease, dementia, insulin resistance syndrome, X syndrome, metabolic syndrome, hyperinsulinemia, loss of sensitivity caused by hyperinsulinemia, leukemia, tumors ( skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., deforming spondylitis, deforming arthritis, lumbago, gout, postoperative or post-operative inflammation of the stomach, swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, enteritis, inflammatory bowel disorder (including inflammatory bowel disease), ulcerative colitis, damage to the gastric mucosa (including damage to the gastric mucosa caused by aspirin) ), damage to the mucous membrane of the small intestine, malabsorption, testicular functional disorder, visceral obesity, and so on; and,

to reduce visceral obesity, inhibit visceral fat accumulation, improve glucose metabolism, improve lipid metabolism, suppress production of oxidized LDL, improve lipoprotein metabolism, improve coronary artery metabolism, prevent or treat cardiovascular complications, prevent or treat heart failure complications, reduce residual blood prophylaxis or treatment of anovulation, prophylaxis or treatment of hirsutism, or prophylaxis or treatment of hyperandrogenemia; as a means to improve the function of the pancreas (β cells), a regenerative agent for the pancreas (β cells), means to stimulate regeneration in the pancreas (β cell), appetite regulator, and so on.

The compounds described in WO2004 / 063221, the compounds described in WO2006 / 001499, and the compounds described in WO2007 / 072997, or their salts, can also be used as agents for the prophylaxis / treatment of rheumatic diseases (e.g. rheumatoid arthritis, osteoarthritis, gout and so on) or the like.

More specifically, the compounds described in WO 2004/063221, (metastin derivatives (i) represented, for example, by the following formula, or salts thereof:

[Where

each of Z ¹ , Z ³ , Z ⁵ and Z ⁷ represents a hydrogen atom or a C _1-3 alkyl group; each of Z ² , Z ⁴ , Z ⁶ and Z ⁸ represents a hydrogen atom, O or S;

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

R ² represents (1) a hydrogen atom or (2) a cyclic or linear C _1-10 alkyl group, or (3) a C _1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group;

R ³ represents:

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

(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 of not more than 7 carbon atoms, having an optionally substituted basic group, and optionally having an additional substituent, or,

(4) a C _1-4 alkyl group having a non-aromatic heterocyclic group of not more than 7 carbon atoms, having an optionally substituted basic group, and optionally having an additional substituent;

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

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 carbon atoms;

X represents a group represented by the formula:

-NHCH (Q ¹ ) YQ ² C (= Z ⁹ ) -

(Where:

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

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 carbon atoms;

Q ² represents (1) CH ₂ which optionally can be substituted with a C _1-4 alkyl group optionally substituted with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, (2) NH, which optionally can be substituted with C _{1 -4} an alkyl group optionally substituted with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, or (3) O;

Y represents a group represented by the formula: —CONH—, —CSNH—, —CH ₂ NH—, —NHCO—, —CH ₂ O—, —CH ₂ S— or —CH ₂ CH ₂ -, which may optionally be substituted A C _1-6 alkyl group; and,

Z ⁹ represents a hydrogen atom, O or S); and,

P represents:

(1) a hydrogen atom;

(2) an optional amino acid residue, continuously or non-continuously attached from the C-terminal end of the 1st to 48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the formula:

J ¹ -J ² -C (J ³ ) (Q ³ ) Y ¹ C (J ⁴ ) (Q ⁴ ) Y ² C (J ⁵ ) (Q ⁵ ) Y ³ C (J ⁶ ) (Q ⁶ ) C ( = Z ¹⁰ ) -

(Where,

J ¹ represents (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) a sulfino group, (vii) an amidino group or (viii) a glyoxyloyl group, which optionally can be substituted with a substituent containing an optionally substituted cyclic group;

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

each of J ³ - J ⁶ represents a hydrogen atom or a C _1-3 alkyl group;

each of Q ³ - Q ⁶ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of:

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

(2) an optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms,

(6) an optionally substituted non-aromatic heterocyclic group having at most 7 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,

(12) an optionally substituted sulfhydryl group,

or a hydrogen atom;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, 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 together to form a ring;

each of Y ¹ - Y ³ represents a group represented by the formula:

-CON (J ¹³ ) -, -CSN (J ¹³ ) -, -C (J ¹⁴ ) N (J ¹³ ) - or -N (J ¹³ ) CO- (where each of J ¹³ and J ¹⁴ represents a hydrogen atom or a C _1-3 alkyl group); and,

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

(4) a group represented by the formula:

J ¹ -J ² -C (J ⁷ ) (Q ⁷ ) Y ² C (J ⁸ ) (Q ⁸ ) Y ³ C (J ⁹ ) (Q ⁹ ) C (= Z ¹⁰ ) -

(Where,

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

J ⁷ - J ⁹ have the same meaning as J ³ ;

Q ⁷ - Q ⁹ have the same meaning as Q ³ ;

Y ² and Y ³ have the same meanings 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 can be combined together, or, J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined together to form a ring) ;

(5) a group represented by the formula:

J ¹ -J ² -C (J ¹⁰ ) (Q ¹⁰ ) Y ³ C (J ¹¹ ) (Q ¹¹ ) C (= Z ¹⁰ ) -

(Where,

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

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

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

Y ³ has the same meaning as described above;

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

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined together to form a ring);

(6) a group represented by the formula: J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ ) -

(Where

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

J ¹² has the same meanings as J ³ ;

Q ¹² has the same meanings as Q ³ ;

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

J ¹² and Q ¹² can be combined together, or J ² and Q ¹² can be combined together to form a ring); or,

(7) a group represented by the formula: J ¹ - (where J ¹ has the same meaning as described above)], the following compounds or their salts are preferred:

MS10: Tyr- Asn- Trp- Asn- Ser- Phe- Gly- Leu- Arg- Phe- NH ₂ one 2 3 four 5 6 7 8 9 10

Compound No. 17: [Pya (4) 10] MS10

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

Compound No. 18: [Tyr (Me) 10] MS10

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

Compound No. 19: [Phe (2F) 10] MS10

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

Compound No. 23: [Tyr5] MS10

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

Compound No. 24: [Leu5] MS10

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

Compound No. 30: Acetyl-MS10

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

Compound No. 31: Fmoc-MS10

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

Compound No. 38: [D-Ser5] MS10

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

Compound No. 39: [D-Asn4] MS10

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

Compound No. 40: [D-Trp3] MS10

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

Compound No. 41: [D-Asn2] MS10

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

Compound No. 42: [D-Tyr1] MS10

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

Compound No. 44: [Lys9] MS10

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

Compound No. 45: [Ala8] MS10

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

Compound No. 50: [Ala7] MS10

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

Compound No. 51: [NMePhe10] MS10

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

Compound No. 53: des (1-3) -Fmoc-MS10

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

Compound No. 54: des (1-2) -Fmoc-MS10

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

Compound No. 55: des (1) -Fmoc-MS10

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

Compound No. 56: [Lys2] MS10

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

Compound No. 57: [Asp2] MS10

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

Compound No. 58: [Tyr2] MS10

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

Compound No. 59: [Leu2] MS10

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

Compound No. 60: [Pya (3) 10] MS10

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

Compound No. 61: [Phe (4F) 10] MS10

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

Compound No. 67: [Ala3] MS10

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

Compound No. 68: [Leu3] MS10

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

Compound No. 69: [Ser3] MS10

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

Compound No. 70: [Asp3] MS10

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

Compound No. 71: [Lys3] MS10

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

Compound No. 72: [Ala1] MS10

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

Compound No. 73: [Leu1] MS10

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

Compound No. 74: [Ser1] MS10

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

Compound No. 75: [Asp1] MS10

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

Compound No. 76: [Lys1] MS10

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

Compound No. 77: [Phe (4CN) 10] MS10

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

Compound No. 78: [Trp (For) 3, Phe (4CN) 10] MS10

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

Compound No. 79: [Hph10] MS10

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

Compound No. 81: [NMeArg9] MS10

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

Compound No. 82: [Arg (Me) 9] MS10

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

Compound No. 83: [Arg (asy Me ₂ ) 9] MS10

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

Compound No. 87: des (4-5) -Boc-MS10

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

Compound No. 88: des (4-5) -MS10

Tyr-Asn-Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 90: [9Ψ10, CH ₂ NH] MS10

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

Compound No. 91: [8Ψ9, CH ₂ NH] MS10

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

Compound No. 97: [Har9] MS10

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

Compound No. 98: [Lys (Me ₂ ) 9] MS10

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

Compound No. 101: [Ser7] MS10

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

Compound No. 105: [Nle8] MS10

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

Compound No. 107: [Val8] MS10

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

Compound No. 109: [Tyr10] MS10

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

Compound No. 110: [Nal (2) 10] MS10

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

Compound No. 111: [Phe (F ₅ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (F ₅ ) -NH ₂

Compound No. 112: [Cha10] MS10

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

Compound No. 114: des (1-3) -3- (3-Indolyl) propionyl-MS10

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

Compound No. 121: des (1-4) - [Trp5] MS10

Trp-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 123: [NMeLeu8] MS10

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

Compound No. 126: [NMeSer5] MS10

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

Compound No. 127: [D-Asn4, NMePhe6] MS10

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

Compound No. 128: [10Ψ, CSNH] MS10

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

Compound No. 129: [Arg (symMe ₂ ) 9] MS10

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

Compound No. 130: [Phe (4Cl) 10] MS10

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

Compound No. 131: [Phe (4NH ₂ ) 10] MS10

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

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

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

Compound No. 133: [Nal (1) 10] MS10

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

Compound No. 134: [Trp10] MS10

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

Compound No. 137: [Nle9] MS10

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

Compound No. 138: [Cit9] MS10

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

Compound No. 140: [Arg (Me) 9, NMePhe10] MS10

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

Compound No. 141: [D-Tyr1, Arg (Me) 9] MS10

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

Compound No. 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 No. 143: [D-Trp3, Arg (Me) 9] MS10

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

Compound No. 144: des (1-3) -Fmoc- [Arg (Me) 9] MS10

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

Compound No. 145: des (1-2) -Fmoc- [Arg (Me) 9] MS10

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

Compound No. 146: [10Ψ, CSNH, D-Tyr1] MS10

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

Compound No. 150: [Tyr6] MS10

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

Compound No. 151: [Nal (1) 6] MS10

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

Compound No. 152: [Nal (2) 6] MS10

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

Compound No. 153: [Phe (F ₅ ) 6] MS10

Tyr-Asn-Trp-Asn-Ser-Phe (F ₅ ) -Gly-Leu-Arg-Phe-NH ₂

Compound No. 154: [Phe (4F) 6] MS10

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

Compound No. 156: [Cha6] MS10

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

Compound No. 163: [6Ψ7, CH ₂ NH] MS10

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

Compound No. 165: [Dap (Gly) 9] -MS10

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

Compound No. 166: [6Ψ7, CSNH] MS10

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

Compound No. 169: [D-Tyr1, Ala3, Arg (Me) 9] MS10

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

Compound No. 170: [D-Tyr1, Ser3, Arg (Me) 9] MS10

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 No. 172: [D-Tyr1, Cha6, Arg (Me) 9] MS10

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

Compound No. 173: [D-Tyr1, Ala7, Arg (Me) 9] MS10

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

Compound No. 174: [D-Tyr1, Arg (Me) 9, Trp10] MS10

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

Compound No. 176: [AzaGly7] MS10

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

Compound No. 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 No. 183: [Phe (4NH ₂ ) 9] MS10

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

Compound No. 184: [Phe (4-Guanidino) 9] MS10

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

Compound No. 185: [Dap (GnGly) 9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Dap (GnGly) -Phe-NH ₂

Compound No. 186: [Trp (For) 10] MS10

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

Compound No. 187: [Abu8] MS10

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

Compound No. 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 No. 191: [D-Tyr1, Ser3, AzaGly7, Arg (Me) 9] MS10

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

Compound No. 192: [D-Tyr1, Arg (Et) 9] MS10

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

Compound No. 193: [D-Tyr1, Arg (n-Pr) 9] MS10

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

Compound No. 194: [D-Tyr1, Arg (Ac) 9] MS10

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

Compound No. 197: [Phe (3F) 10] MS10

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

Compound No. 198: [Phe (3.4F2) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3,4F2) -NH ₂

Compound No. 199: [Phe (3.4Cl ₂ ) 10] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe (3.4Cl ₂ ) -NH ₂

Compound No. 200: [Phe (3CF ₃ ) 10] MS10

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

Compound No. 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] MS10

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

Compound No. 205: [D-Tyr1, Thr3, Arg (Me) 9] MS10

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

Compound No. 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] MS10

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

Compound No. 208: [D-Tyr1, Thr4, Arg (Me) 9] MS10

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

Compound No. 209: [D-Tyr1, Gln4, Arg (Me) 9] MS10

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

Compound No. 210: [D-Tyr1, Ala4, Arg (Me) 9] MS10

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

Compound No. 211: [D-Tyr1, Thr5, Arg (Me) 9] MS10

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

Compound No. 212: [D-Tyr1, Ala5, Arg (Me) 9] MS10

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

Compound No. 213: [D-Tyr1, Val8, Arg (Me) 9] MS10

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

Compound No. 214: [D-Tyr1, Gln2, Arg (Me) 9] MS10

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

Compound No. 215: [D-Tyr1, Thr2, Arg (Me) 9] MS10

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

Compound No. 216: des (1) - [D-Asn2, Arg (Me) 9] MS10

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

Compound No. 217: des (1) - [D-Tyr2, Arg (Me) 9] MS10

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

Compound No. 218: [N ((CH ₂ ) 3Gn)] Gly9] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-N ((CH ₂ ) 3Gn) Gly-Phe-NH ₂

Compound No. 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 No. 223: des (1-2) - [D-Trp3, Arg (Me) 9] MS10

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

Compound No. 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 No. 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 No. 226: des (1) - [D-Tyr2, Ser3, Arg (Me) 9] MS10

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

Compound No. 227: des (1) - [D-Tyr2, Thr3, Arg (Me) 9] MS10

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

Compound No. 228: des (1) - [D-Tyr2, Ile3, Arg (Me) 9] MS10

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

Compound No. 229: [D-Tyr1, Val3, Arg (Me) 9] MS10

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

Compound No. 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, Ile3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Ile-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 234: [D-Tyr1, Val3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Val-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 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 No. 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 No. 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 No. 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 (4NH ₂ ) 3, AzaGly7, Arg (Me) 9] MS10

D-Tyr-Asn-Phe (4NH ₂ ) -Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 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 No. 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 No. 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 No. 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 No. 259: [D-Ala1, AzaGly7, Arg (Me) 9] MS10

D-Ala-Asn-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 261: [7Ψ8, CH ₂ NH] MS10

Tyr-Asn-Trp-Asn-Ser-Phe-GlyΨ (CH ₂ NH) Leu-Arg-Phe-NH ₂

Compound No. 265: des (1-3) -Indol-3-carbonyl- [AzaGly7, Arg (Me) 9] MS10

Indole-3-carbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 266: des (1-3) -Indol-3-acetyl- [AzaGly7, Arg (Me) 9] MS10

Indole-3-Acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 268: des (1-3) -Diphenylacetyl- [AzaGly7, Arg (Me) 9] MS10

Diphenylacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 271: des (1-2) - [AzaGly7, Arg (Me) 9] MS10

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

Compound No. 272: des (1-2) -acetyl- [AzaGly7, Arg (Me) 9] MS10

Acetyl-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 273: des (1-2) -Amidino [AzaGly7, Arg (Me) 9] MS10

Amidino-Trp-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 274: des (1-2) -acetyl- [Ala3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Ala-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 275: des (1-2) -acetyl- [Arg3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Arg-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 276: des (1-2) -acetyl- [Thr3, AzaGly7, Arg (Me) 9] MS10

Acetyl-Thr-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 277: des (1-3) -n-Hexanoyl- [AzaGly7, Arg (Me) 9] MS10

n-Hexanoyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 278: des (1-3) -cyclohexanecarbonyl- [AzaGly7, Arg (Me) 9] MS10

Cyclohexanecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 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 No. 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 No. 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 No. 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 No. 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 No. 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 No. 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 No. 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 No. 293: [4Ψ5, CH ₂ NH] MS10

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

Compound No. 294: [1Ψ2, CH ₂ NH] MS10

TyrΨ (CH ₂ NH) Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH ₂

Compound No. 295: [2Ψ3, CH ₂ NH] MS10

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

Compound No. 296: [6-7, 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 No. 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 No. 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 No. 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 No. 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 No. 310: [Nar9] MS10

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

Compound No. 311: [Nar (Me) 9] MS10

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

Compound No. 312: [Har (Me) 9] MS10

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

Compound No. 313: [Dab9] MS10

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

Compound No. 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 No. 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 No. 322: des (1-3) -3-Pyridylpropionyl- [AzaGly7, Arg (Me) 9] MS10

3-Pyridylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 323: des (1-3) -4-Imidazoleacetyl- [AzaGly7, Arg (Me) 9] MS10

4-Imidazoleacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 324: des (1-3) -4-Piperidinecarbonyl- [AzaGly7, Arg (Me) 9] MS10

Piperidinecarbonyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 325: des (1-3) -1-piperidinacetyl- [AzaGly7, Arg (Me) 9] MS10

Piperidine Acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 326: des (1-3) -1-Methylpiperidinio-1-acetyl- [AzaGly7, Arg (Me) 9]

Ms10

Methylpiperidino-1-acetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 327: des (1-3) -1-Pyridinioacetyl- [AzaGly7, Arg (Me) 9] MS10

1-Pyridinoacetyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 328: des (1-3) -D-Glucronyl- [AzaGly7, Arg (Me) 9] MS10

D-Glucronyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Phe-NH ₂

Compound No. 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 No. 386: des (1-3) -3-Pyridylpropionyl- [AzaGly7, Arg (Me) 9, Trp10] MS10

3-Pyridylpropionyl-Asn-Ser-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂

Compound No. 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 No. 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 ;

Compounds described in WO 2006/001499 (derivatives of metastin (ii) represented, for example, by the formula below or their salts:

[Where

V represents a group represented by the formula:

or a group represented by the formula:

n is 0 or 1;

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

W ² represents N or CH;

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

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

R ² represents (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) C _{1- 8} an alkyl group optionally substituted with a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxyl group, and an optionally substituted aromatic cyclic group;

R ³ represents (1) a C _1-8 alkyl group having an optionally substituted basic group and optionally having an additional substituent, (2) an aralkyl group having an optionally substituted basic group and optionally having an additional substituent, (3) C _1-4 alkyl a group having a non-aromatic cyclic hydrocarbon group of not more than 7 carbon atoms, having an optionally substituted basic group and optionally having an additional substituent, or (4) a C _1-4 alkyl group having a non-aromatic a heterocyclic group of not more than 7 carbon atoms having an optionally substituted basic group and optionally having an additional substituent;

R ⁴ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condensiro bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and (6) optionally substituted a non-aromatic heterocyclic group having no more than 7 carbon atoms;

Q ¹ represents a C _1-4 alkyl group which may optionally be substituted with a substituent selected from the group consisting of (1) optionally substituted C _6-12 aromatic hydrocarbon group, (2) optionally substituted 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic condensiro bath heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms, and (6) optionally substituted a non-aromatic heterocyclic group having no more than 7 carbon atoms;

Q ² represents (1) CH ₂ which optionally can be substituted with an optionally substituted C _1-4 alkyl group with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, (2) NH, which optionally can be substituted with optionally substituted A C _1-4 alkyl group with a substituent selected from the group consisting of a carbamoyl group and a hydroxyl group, or (3) O;

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

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

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

(1) a hydrogen atom;

(2) an optional amino acid residue continuously or non-continuously attached from the C-terminal end of the 1st to 48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;

(3) a group represented by the formula:

J ¹ -J ² -C (J ³ ) (Q ³ ) Y ¹ C (J ⁴ ) (Q ⁴ ) Y ² C (J ⁵ ) (Q ⁵ ) Y ³ C (J ⁶ ) (Q ⁶ ) C ( = Z ¹⁰ ) -

(Where

J ¹ represents (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) a sulfino group, (vii) an amidino group, (viii) a glyoxyloyl group or (ix) an amino group, which optionally can be substituted with a substituent containing an optionally substituted cyclic group;

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

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

Q ³ - Q ⁶ each represents 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 5-14 membered aromatic heterocyclic group consisting of 1-7 carbon atoms and heteroatoms 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 5-14 membered aromatic fused heterocyclic group consisting of 3-11 carbon atoms and heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,

(5) an optionally substituted non-aromatic cyclic hydrocarbon group having no more than 7 carbon atoms,

(6) an optionally substituted non-aromatic cyclic hydrocarbon group having at most 7 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) an optionally substituted sulfhydryl group,

or a hydrogen atom;

J ³ and Q ³ , J ⁴ and Q ⁴ , J ⁵ and Q ⁵ or J ⁶ and Q ⁶ can be combined together, 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 together to form a ring;

Y ¹ - Y ³ each represents a group represented by the formula:

—CON (J ¹³ ) -, —CSN (J ¹³ ) -, —C (J ¹⁴ ) N (J ¹³ ) -, or —N (J ¹³ ) CO— (where J ¹³ and J ¹⁴ each represents a hydrogen atom or C _1-3 alkyl group); and,

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

(4) a group represented by the formula:

J ¹ -J ² -C (J ⁷ ) (Q ⁷ ) Y ² C (J ⁸ ) (Q ⁸ ) Y ³ C (J ⁹ ) (Q ⁹ ) C (= Z ¹⁰ ) -

(Where

J ¹ and J ² each have the same meanings as above;

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

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

Y ² and Y ³ each have the same meanings as above;

Z ¹⁰ has the same meanings as above;

J ⁷ and Q ⁷ , J ⁸ and Q ⁸ or J ⁹ and Q ⁹ can be combined together, or, J ² and Q ⁷ , Y ² and Q ⁸ or Y ³ and Q ⁹ can be combined together to form a ring) ;

(5) a group represented by the formula:

J ¹ -J ² -C (J ¹⁰ ) (Q ¹⁰ ) Y ³ C (J ¹¹ ) (Q ¹¹ ) C (= Z ¹⁰ ) -

(Where

J ¹ and J ² have the same meanings as 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 meanings as above;

Z ¹⁰ has the same meanings as above; and,

J ¹⁰ and Q ¹⁰ or J ¹¹ and Q ¹¹ can be combined together, or J ² and Q ¹⁰ or Y ³ and Q ¹¹ can be combined together to form a ring);

(6) a group represented by the formula:

J ¹ -J ² -C (J ¹² ) (Q ¹² ) C (= Z ¹⁰ ) -

(Where

J ¹ and J ² have the same meanings as above;

J ¹² has the same meanings as for J ³ ;

Q ¹² has the same meanings as for Q ³ ;

Z ¹⁰ has the same meanings as above; and,

J ¹² and Q ¹² can be combined together, or J ² and Q ¹² can be combined together to form a ring); or,

(7) a group represented by the formula: J ¹ -

(Where

J ¹ has the same meanings as above)], preferably the following compounds:

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) NH2 (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 (symMe ₂ ) -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-Pyridine propionyl-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; and

The compounds described in WO 2007/072997 (metastin derivatives represented, for example, by the formula below or their salts:

A metastin derivative represented by the formula:

XX0-XX2-XX3-XX4-XX5-XX6-AzaGly-XX8-XX9-XX10-NH ₂

(Where

XX0 is formyl, C _1-20 alkanoyl, cyclopropanecarbonyl, 6- (acetyl-D-arginylamino) caproyl, 6 - ((R) -2,3-diaminopropionylamino) caproyl, 6- (D-norleucylamino) caproyl, 4- (D-arginylamino) butyryl, 3- (4-hydroxyphenyl) propionyl, glycyl, tyrosyl, acetylglycyl, acetyl tyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3- (pyridin-3-yl) propionyl, adipoyl, glycoloyl 6-aminocaproyl;

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

XX3 is:

D-Asp, D-Dap, D-Ser, D-Gln, D-His, D-NMeAla, D-NMePhe, Aze (2), Pic (2), Pic (3), Hyp, Thz, NMeAla, Gly , Aib, Abz (2), Abz (3), Sar, Leu, Lys, Glu, β-alanine, Pzc (2), Orn, His (3Me), Tyr (PO ₃ H ₂ ), Pro (4NH ₂ ) or Hyp (Bzl);

XX4 represents Asn, 2-amino-3-ureidopropionovuyu acid, N ^β formyl-β-diaminopropionic acid, N ^{β-acetyl-β-diaminopropionic} acid, N ^ω -pentilasparagin, N ^ω -tsiklopropilasparagin, N ^ω -benzilasparagin 2 4-diaminobutanoic acid, His, Gln, Cit or a chemical bond;

XX5 is Ser, Thr, Val, NMeSer, Gly, Ala, Hyp, D-Ala, D-Thr, D-Pro or a chemical bond;

XX6 is Phe, Tyr, Trp, Tyr (Me), Thi, Nal (2), Cha, Pya (4), threo-Ser (3Phenyl), erythro-Ser (3Phenyl), or optionally substituted phenylalanine;

AzaGly is azaglycin;

XX8 represents Leu, Nva or Val;

XX9 represents Arg, Orn, Arg (Me) or Arg (asymMe ₂ ); and,

XX10 represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine); or its salt, preferably the compounds presented below, or their salts:

Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu-D-Arg-Trp-NH ₂ (compound No. 708),

Ac-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 709),

Decanoyl-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 710),

Acp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 712),

Ac-Acp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 713),

Ac-D-Tyr-D-Trp-Asp (NHPen) -Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 714),

Ac-D-Tyr-D-Trp-Asp (NHcPr) -Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 715),

Ac-D-Tyr-D-Trp-Asp (NHBzl) -Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 716),

Ac-D-Tyr-D-Trp-Alb-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 717),

Ac-D-Tyr-D-Pya (4) -Alb-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 718),

Ac-D-Tyr-D-Trp-Asn-D-Pro-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 719),

Ac-D-Tyr-Aze (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 720),

Ac-D-Tyr-Pic (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 721),

Ac-D-Tyr-Pic (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 722)

Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 723),

Ac-D-Tyr-Thz-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 724),

Ac-D-Tyr-NMeAla-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 725)

Ac-D-Tyr-Gly-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 726)

Ac-D-Tyr-Aib-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 727),

Ac-D-Tyr-Abz (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 728)

Ac-D-Tyr-Aze (3) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 730)

Ac-D-Tyr-Sar-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 731)

Ac-D-Tyr-D-NMeAla-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 732),

Ac-D-Tyr-Izc-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 734),

Ac-D-Tyr-D-Asp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 735),

Ac-D-Tyr-D-Dap-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 736),

Ac-D-Tyr-D-Ser-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 737),

Ac-D-Tyr-D-Gln-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 738),

Ac-D-Tyr-D-His-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 739),

Ac-D-Tyr-D-Trp-Dab-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 740),

Ac-D-Tyr-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 742),

Ac-D-Tyr-Leu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 743),

Ac-D-Tyr-Ser-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 744),

Ac-D-Tyr-Lys-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 745),

Ac-D-Tyr-Glu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 746),

Ac-D-Tyr-β-Ala-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 747),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 748),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 749),

Ac-D-Tyr-D-Trp-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 750),

Ac-D-Tyr-Lys-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 754),

Ac-D-Tyr-Glu-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 755),

Ac-D-Tyr-Lys-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 756),

Ac-D-Tyr-Glu-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 757),

Ac-D-Tyr-Lys-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 758),

Ac-D-Tyr-Glu-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 759),

Ac-D-Tyr-Pzc (2) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 760),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 763),

Ac-D-Tyr-Trp-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 764),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 765),

Ac-D-Tyr-Trp-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 766),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 767),

Ac-D-Tyr-Trp-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 768),

Ac-D-Tyr-Gly-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 769),

Ac-D-Tyr-Aib-Asn-Thr-Phe (4Cl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 770),

Ac-D-Tyr-Orn-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 771),

Ac-D-Tyr-Thr-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 772),

Ac-D-Tyr-His (3Me) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 773),

Ac-D-Tyr-DL-Ala (Pip) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 774),

Ac-D-Tyr-Tyr (PO ₃ H ₂ ) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 775),

Glycoloyl-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 776)

Ac-D-Tyr-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 777),

Ac-D-Tyr-Pro (4NH ₂ ) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 780),

Ac-D-Tyr-Hyp (Bzl) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 781),

Ac-D-Tyr-D-NMePhe-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 782),

Ac-D-Tyr-Gly-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 783),

Ac-D-Tyr-Aib-Asn-Thr-Phe (2F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 784),

Ac-D-Tyr-Gly-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 785),

Ac-D-Tyr-Aib-Asn-Thr-Phe (3F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 786),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 787),

Ac-D-Tyr-Glu-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 788),

Ac-D-Tyr-Lys-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 789),

Ac-D-Tyr-Gly-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 790),

Ac-D-Tyr-Aib-Asn-Thr-Phe (4F) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 791),

Ac-D-Tyr-Hyp-Asn-Thr-D-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 794),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg-Trp-NH ₂ (compound No. 797),

Ac-D-Tyr-Hyp-Alb-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 800),

4- [Bis- (2-Pyridylmethyl) aminomethyl] benzoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 801),

Ac-D-Tyr-Hyp-Asn-NMeSer-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 809),

Ac-D-Tyr-Hyp-Asn-Hyp-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 810),

Ac-D-Tyr-Hyp-Asn-Gly-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 813),

Ac-D-Tyr-Hyp-Asn-Ala-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 814),

Ac-D-Tyr-Hyp-Asn-D-Ala-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 815),

Ac-D-Tyr-Hyp-His-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 816),

Ac-D-Tyr-Hyp-Gln-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 843),

Ac-D-Tyr-Hyp-D-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 844),

Ac-D-Tyr-Hyp-Cit-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 845),

Ac-D-Tyr-Hyp-Asn-D-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 846),

Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Ala (cPr) -Arg (Me) -Trp-NH ₂ (compound No. 856),

4-Ureidobenzoyl-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 860),

Ac-D-Tyr-Hyp-Arg-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 861),

Ac-D-Tyr-Hyp-Gly-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 862),

Ac-D-Tyr-Hyp-Dap-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 863),

Ac-D-Tyr-Hyp-Dab-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 864),

Ac-D-Tyr-Hyp-Asn-Thr-αMePhe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 868),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (2Me) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 870),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (3Me) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 872),

Ac-D-Tyr-Hyp-Asn-Thr-Phe (4Me) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 874),

Ac-D-Tyr-Hyp-Asn-Thr-threo-Ser (3Phenyl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 877),

Ac-D-Tyr-Hyp-Asn-Thr-erythro-Ser (3Phenyl) -AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 882),

Ac-D-Tyr-Hyp-Nva-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 886),

Ac-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 887),

3- (p-Hydroxyphenyl) propionyl-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 888),

pGlu-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 889),

Ac-D-Tyr-cisHyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 896),

Ac-D-Tyr-Pro (4F) -Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (compound No. 897),

Ac-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg (Me) -Trp-NH ₂ (Compound No. 899)

can also be used as agents for the prophylaxis / treatment of rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, gout and so on) or the like. Studies can be performed by well-known methods described above to determine that these compounds can be used in rheumatic diseases.

These compounds can also be used as agents for the prevention / treatment of autism, immunomodulation (regeneration of the thymus, repopulation of the thymus, enhanced growth of T cells), diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, arteriosclerosis, thrombotic disorders or lipotoxicity; agents for the prophylaxis / treatment of hyperlipemia, type II diabetes mellitus, hypertension, diabetic neuropathy, diabetic nephropathy or diabetic retinopathy; sedative; anti-stress agents; remedies for insomnia; agents for treating manic-depressive disease; agents for the prevention / treatment of hypertension (e.g., essential hypertension, renal hypertension, salt-sensitive hypertension, etc.), angina pectoris (e.g. stable angina pectoris, unstable angina pectoris, etc.), myocardial infarction, cerebrovascular disease (e.g. asymptomatic cerebrovascular disease) disorder, transient ischemic attack, apoplexy, cerebro-vascular dementia, hypertensive encephalopathy, cerebral infarction and so on), venous insufficiency, obliterative peripheral circulatory disorders, Raynaud's disease, arteriosclerosis, including atherosclerosis (e.g., aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosis, etc.), thickening of the walls of the vessels or occlusion and organ damage after the intervention (e.g., percutaneous coronary intervention, stent placement, coronary thrombolytic therapy and so on), portal hypertension, respiratory disorders (for example, asthma, pulmonary hypertension and so on); agents for the prophylaxis / treatment of impaired glucose tolerance (IGT); an agent that enhances the secretion of insulin, an inhibitor of the transition of IGT to diabetes;

agents for the prevention / treatment of diabetic complications [eg neuropathy, nephropathy, retinopathy, lens opacity, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infectious diseases (eg, respiratory tract infection, urinary tract infection, gastrointestinal infection, skin and soft infection tissue infection, lower leg infection), diabetic gangrene, xerostomia, hypoacusia, cerebrovascular disorder, peripheral circulatory disturbance], osteoporosis, cachexia (eg, p major cachexia, tuberculous cachexia, diabetic cachexia associated with blood disease cachexia associated with endocrine disease cachexia associated with infectious disease cachexia or cachexia due to acquired immunodeficiency syndrome), fatty liver infiltration, polycystic ovary syndrome, kidney disease (e.g. glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, the last stage of kidney disease), muscular dystrophy, myocardial infarction carditis, angina pectoris, cerebrovascular disease (e.g. cerebral infarction, apoplexy), Alzheimer's disease, Parkinson's disease, dementia, insulin resistance syndrome, X syndrome, metabolic syndrome, hyperinsulinemia, loss of sensitivity caused by hyperinsulinemia, leukemia tumors (e.g. skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., deforming spondylitis, deforming arthritis, lumbago, gout, postoperative or post-herbal atic inflammation, swelling, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including non-alcoholic steatohepatitis), pneumonia, enteritis, inflammatory bowel disorder (including inflammatory bowel disease), ulcerative colitis, damage to the gastric mucosa (including damage to the gastric mucosa caused by aspirin) ), damage to the mucous membrane of the small intestine, malabsorption, testicular functional disorder, visceral obesity, and so on; and,

to reduce visceral obesity, inhibit visceral fat accumulation, improve glucose metabolism, improve lipid metabolism, inhibit the production of oxidized LDL, improve lipoprotein metabolism, improve coronary artery metabolism, prevent or treat cardiovascular complications, prevent or treat heart failure complications, reduce residues in blood, prophylaxis or treatment of anovulation, prophylaxis or treatment of hirsutism, or prophylaxis or treatment of hyperandrogenism; as a means to improve the function of the pancreas (β-cells), regenerative means for the pancreas (β-cells), means to stimulate regeneration in the pancreas (β-cells), appetite regulator and so on.

These compounds can be used in combination with drugs other than these compounds.

As drugs that can be used in combination with these compounds (hereinafter sometimes simply referred to as “concomitant drugs”), drugs described as drugs that can be used in combination with the compounds of the present invention can be used similarly. way.

The compounds of the present invention can be used in combination with drugs, for example chemotherapeutic agents for treating cancer, hormonal therapeutic agents, immunotherapeutic agents, drugs for inhibiting the effects of cell growth factor and their receptors, and so on (hereinafter simply referred to as “concomitant agents” ) Examples of “chemotherapeutic agents” include alkylating agents, antimetabolites, anti-cancer antibiotics, anti-cancer agents derived from plants, and so on. In particular, the medications described below can be used.

In addition, the compound of the present invention has excellent blood stability, solubility and solution stability compared to untreated metastin, such as metastin 54 (1-54) or metastin 10 (45-54).

The metastin derivative of the present invention, or a salt or prodrug thereof, metastin per se, or DNA encoding metastin, and so on, is useful as an agent for suppressing the secretion of gonadotropin hormone (e.g. FSH, LH) or the secretion of sex hormone [e.g. androgen (such as testosterone, androstedione), estrogen (such as estradiol, estrone), progesterone]; and so on; in particular, it is used to suppress gonadotropin hormone secretion or sex hormone secretion by downregulating the gonadotropin hormone or sex hormone (where the downregulation of the gonadotropin hormone or sex hormone may be pulse loss LHRH or reduction in the amount of LHRH) or downregulation of the human OT7T175 protein (metastin receptor) consisting of the amino acid sequence represented by SEQ ID NO: 9; in particular, used as a means for the prevention or treatment of hormone-dependent cancers (for example, prostate cancer, breast cancer, and so on; in particular, prostate cancer, hormone-sensitive prostate cancer, and so on); agents for the prevention or treatment of endometriosis; means to prevent follicular suppuration of the ovaries; a means of stopping the menstrual cycle; funds for the treatment of uterine fibroids; agents for the treatment of early puberty; or as a contraceptive and so on. In the case where the metastin derivative of the present invention, or its salt or prodrug, metastin per se or DNA encoding metastin, and so on, has normal agonist activity, an effective dose of metastin derivative sufficient to suppress the secretion of gonadotropin hormone or sex hormone is administered in the area or tissue where the therapeutic effects are caused, so that the metastin derivative is present in a dose greater than necessary (i.e., the metastin derivative is administered in an amount exceeding normal w effective dose, at which the metastin derivative causes suppression effects of cancer metastasis, suppressing cancer growth, etc.; or the effect of stimulating the secretion of gonadotropic hormone effect of stimulating the secretion of sex hormones, etc.) to induce the effects of suppressing gonadotropic hormone secretion or sex hormone secretion. Specific examples include continuous or continuous administration of a normal effective dose (including a route of administration for the gradual release of pharmaceutical ingredients by bolus administration); etc. In addition, when the metastin derivative of the present invention, or its salt, or its prodrug, and so on, has sufficient agonist activity greater than necessary (super-agonist activity), it becomes possible to maintain activities greater than the required dose in the region or tissue where the therapeutic effect is manifested. Thus, to suppress the secretion of gonadotropin hormone or sex hormone, it is sufficient to introduce even a normal effective dose, thereby demonstrating the effect of suppressing the secretion of gonadotropic hormones or secretion of sex hormones.

In other words, an effective dose of a metastin derivative of the present invention, or a salt or prodrug thereof, metastin per se, or DNA encoding metastin, and so on, sufficient to suppress the secretion of gonadotropin hormone or sex hormone, is administered so that the metastin derivative is present in a dose greater than necessary in the area or tissue where therapeutic effects are manifested, or its activity may be longer than necessary, which allows us to show the effects of suppressing the secretion of gonadotropic hormones new or suppression of the secretion of sex hormones.

A drug containing a compound of the present invention is low toxic. Accordingly, the compound of the present invention can be safely administered either directly, as it is, or as a mixture with pharmaceutically acceptable carriers, orally or parenterally (e.g. topically, rectally, intravenously and so on), in the form of pharmaceutical preparations, such as tablets ( including dragees and coated tablets), powdered dosage forms, granules, capsules (including soft capsules), liquid dosage forms, injections, suppositories, sustained release dosage forms and so on, in accordance with widely known methods commonly used in the manufacture of pharmaceutical preparations.

The compound of the present invention is contained in the pharmaceutical preparation of the present invention in an amount of from about 0.01 to about 100 weight%, based on the total weight of the drug.

The dose of the compound of the present invention may vary depending on the subject of administration, the target organ, condition, route of administration, and so on, and when administered orally, the compound is usually administered to a patient (eg, body weight 60 kg) having a cancerous tumor with a daily dose of from about 0.01 to about 100 mg, preferably from about 0.1 to about 50 mg, and more preferably from about 0.1 to about 20 mg. When administered parenterally, a single dose of the compound may vary depending on the subject of administration, the target organ, the condition of the patient, the route of administration, and so on and in the form of an injectable dosage form, preferably the compound is administered to a patient (e.g., body weight 60 kg) having a cancerous tumor, usually a daily dose of from about 0.001 to about 30 mg, preferably from about 0.01 to about 20 mg, and more preferably from about 0.01 to about 10 mg. Other types of animals may be administered in an appropriate dose, calculated on 60 kg of weight.

Pharmaceutically acceptable carriers that can be used in the manufacture of the pharmaceutical preparation of the present invention include various organic or inorganic carriers commonly used as materials for pharmaceutical preparations. These substances include, for example, a filler, a lubricant, a binder and a disintegrant, in solid dosage form, a solvent, a dissolution aid, a suspending agent, an isotonic substance, a buffer, an analgesic, and so on, in liquid dosage form. In addition, commonly used additives, such as a preservative, antioxidant, colorant, sweetener, adsorbent, moisturizer, and so on, can be suitably used in suitable amounts, if necessary.

Examples of excipients include: lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and so on. Examples of lubricants include: magnesium stearate, calcium stearate, talc, colloidal silicon oxide and so on.

Examples of binders include: crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sugar, gelatin, methyl cellulose, sodium carboxymethyl cellulose and so on.

Examples of disintegrants include: starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and so on.

Examples of solvents include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and so on.

Examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and so on.

Examples of suspending agents include: surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzetonium chloride, glycerol monostearate and so on; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and so on.

Examples of isotonic agents include: glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and so on.

Examples of buffering agents include: buffers containing phosphate, acetate, carbonate, citrate, and so on.

Examples of painkillers include: benzyl alcohol and so on.

Examples of preservatives include: p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and so on.

Examples of antioxidants include sulfite, ascorbic acid, α-tocopherol, and so on.

Further, the compound of the present invention can be used in combination with drugs other than the compound of the present invention.

Examples of drugs that can be used in combination with a compound of the present invention (hereinafter sometimes simply referred to as “concomitant drugs”) include: chemotherapeutic agents for treating cancer, hormonal therapeutic agents, immunotherapeutic agents, drugs for inhibiting the effects of growth factor cells and their receptors and so on (hereinafter simply referred to as “concomitant substances”).

Examples of “chemotherapeutic agents” include: alkylating agents, antimetabolites, anti-cancer antibiotics, anti-cancer substances derived from plants, and so on.

Examples of “alkylating agents” include: nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboxyvone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, eacraminetriamine, dacarimin triaminetin, tricarbamide, dacarimin triamine carmustine, lomustine, streptozocin, pipobromane, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepos, temibromidine, tembromidine, ribomustine ofosfamide, zinostatin stimalamer, carboxyvone, adoselesin, cystemustine, biselezin and so on.

Examples of "antimetabolites" include: mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, enocytabine, cytarabine, cytarabine oxphosphate, anticytabine hydrochloride, 5-FU medications (for example, fluorouracil, tegafurfurfalcimfurcilfinfin, dokt, ginfin, tinfinurfilfurcimfurfalcitumfin further), aminopterin, calcium leucovorin, tabloid, butocin, calcium folinate, calcium levofolinate, cladribine, emitfur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin, pyritrexime, idoxuridine, mitoguazone, thiazofrin, ambamustine and so on.

Examples of “anticancer antibiotics” include: actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloricin chlorinocinocinocinocinocinaminocinocinocinocinocinocaminocin, pyracinocinocinocinocinocinocaminocin, , mitotan, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and so on.

Examples of “anti-cancer substances derived from plants” include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and so on.

Examples of “hormonal therapeutic agents” include phosphestrol, diethylstilbestrol, chlortrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, citromel torefen, tamelofenrefen, tamelofenrefen, tamelofenrefen, tamelofenrefen, tamelofenremen, tamelofenrefen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, tamelofenremen, further), dosage forms - pills, mepitiostan, testrolactone, aminoglutethimide, LH-RH agonists (for example, goserelin acetate, buserelin, leuprorelin and so on), droloxifene, epithiostanol, ethinyl ester adiol sulfonate, aromatase inhibitors (e.g. fadrozole hydrochloride, anastrozole, tetrozole, exemestane, vorozol, formestane and so on), antiandrogens (e.g. flutamide, bicartamide, nilutamide and so on), 5α-reductase inhibitors (e.g. phenasteride, eprist and so on), andrenocorticogormonal drugs (for example, dexamethasone, prednisone, betamethasone, triamcinolone and so on), androgen synthesis inhibitors (for example, abiraterone and so on), retinoid and drugs that delay the metabolism of the reti nooids (e.g., liarozole and so on), and among others, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin and so on) are preferred.

Examples of “immunotherapeutic substances (BRM)” include pitsibanil, baptism, sisofiran, lentinan, ubenimex, interferons, macrophage colony stimulation factor, granulocyte colony stimulation factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvolazole, leva, etc.

The “cell growth factor” in “drugs for inhibiting the action of cell growth factor and their receptors” can be any substance, provided that this substance is to stimulate cell growth and, usually, peptides that have a molecular weight can be used as factors equal to 20,000 or less, and bind to their receptors to demonstrate actions at the lower level. Specific examples are (1) EGF (epidermal growth factor) or substances having substantially similar EGF activity [for example, EGF, hereglin and so on], (2) insulin or substances having substantially similar insulin activity [for example, insulin, IGF (insulin-like growth factor) -1, IGF-2 and so on], (3) FGF (fibroblast growth factor) or substances with substantially similar FGF activity [for example, acidic FGF, basic FGF, KGF (keratinocyte growth factor) , FGF-10 and so on], (4) another cell growth factor [for example, CSF (factor stimulated I colonies), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor), VEGF (factor vascular endothelial growth) and so on] and the like.

“Cell growth factor receptors” can be any receptor because it is able to bind to the cell growth factor described above, and specific examples are the EGF receptor, hereglin receptor (HER2), insulin receptor, IGF receptor, FGF receptor-1 or FGF receptor -2 and so on.

A “substance that inhibits the effect of cell growth factor” includes HER2 antibody (trastuzumab (Herceptin (trademark)) and so on), imatinib mesylate, ZD1839 or EGFR antibody (cetuximab (Erbitux (trademark)) and so on), anti VEGF (e.g., Bevacizumab (Avastin (trademark))), VEGFR antibody, VEGFR inhibitor, EGFR inhibitor (erlotinib (Tarceva (trademark)), gefitinib (Iressa (trademark)) and so on).

In addition to the above substances, L-asparginase, aceglatone, procarbazine hydrochloride, protorphyrin-cobalt complex, mercury-hematoporphyrin sodium, topoisomerase I inhibitor (for example, irinotecan, topotecan and so on), topoisomerase II inhibitor (for example, soboxoxane and so on) are also used. differentiating agent (e.g. retinoid, vitamin D group and so on), angiogenesis inhibitor (e.g. thalidomide, SU11248 and so on), α-blocker (e.g. tamsulosin hydrochloride, naphthopidyl, urapidil, alfuzosin, terazosin, prazosin, sil dosine and so on), a serine-threonine kinase inhibitor, an endothelin receptor antagonist (e.g., atrazentan, and so on), a proteasome inhibitor (e.g., ortezomib, and so on), an Hsp90 inhibitor (e.g., 17-AAG and so on), spironolactone, minoxidil, 11α-hydroxyprogesterone, a bone resorption inhibitor / bone metastasis suppressor (e.g., zolendronic acid, alendronic acid, pamidronic acid, ethidronic acid, ibandronic acid, clodronic acid) and so on.

The combined use of a compound of the present invention and a concomitant drug exhibits the following excellent effects.

(1) The dose may be reduced compared to the dose when the compound of the present invention or the concomitant drug is administered separately.

(2) A drug concomitant with the administration of a compound of the present invention may be selected depending on the condition (mild, severe, etc.) of the patient.

(3) The concomitant drug, the mechanism of action of which is different from the mechanism of action of the compounds of the present invention, can be selected so as to extend the treatment period.

(4) The concomitant drug, the mechanism of action of which is different from the mechanism of action of the compounds of the present invention, can be selected so as to provide continuous therapeutic effects.

(5) A synergistic effect can be obtained by the concomitant use of a compound of the present invention and a concomitant drug.

In addition, the compound of the present invention can lower testosterone levels to an unaffected level immediately after drug therapy. Thus, when a concomitant drug, such as an LH-RH agonist (e.g., goserelin acetate, buserelin, leuprorelin and so on; preferably leuprorelin) is used in combination with the compound of the present invention, testosterone levels may decrease to a level that has no effect. immediately after drug therapy with the compound of the present invention. In addition, since the combined use of a concomitant drug, such as an LH-RH agonist (e.g., goserelin acetate, buzerelin, leuprorelin and so on; preferably leuprorelin) and the compounds of the present invention leads to a prolonged preservation of the hormone-dependent period, it can be successfully used.

The combined use of the compound of the present invention and the concomitant drug is hereinafter referred to as the “combination preparation of the present invention”.

When using the combination preparation of the present invention, the dosage period of the compound of the present invention and the concomitant drug is not limited; the compound of the present invention or its pharmaceutical composition and the concomitant drug or its pharmaceutical composition may be administered to the subject either simultaneously or at predetermined time intervals. The dose of the concomitant drug may vary depending on the clinically used dose and may accordingly be selected depending on the subject to whom the drug is administered, route of administration, disease, combination, and so on.

The route of administration of the combination preparation of the present invention is not particularly limited, however, it is sufficient that the compound of the present invention is used in combination with a concomitant drug during administration. Such a route of administration includes, for example, (1) administering a single dosage form obtained by mixing a compound of the present invention and a concomitant drug together at the same time, (2) co-administering two dosage forms obtained separately from a compound of the present invention and a concomitant drug, the same route of administration, (3) the administration of two dosage forms obtained separately from the compounds of the present invention, and the concomitant drug time intervals by the same route of administration, (4) co-administration of two dosage forms obtained separately from the compound of the present invention and the concomitant drug by various methods of administration, (5) administration of two dosage forms obtained separately from the compound of the present invention, and concomitant drug at certain intervals (for example, the introduction of the compounds of the present invention and the concomitant drug in this order, or ix backwards) by various routes of administration, and so forth.

The combination preparation of the present invention is low toxic and can thus be safely administered orally or parenterally (e.g. topically, rectally, intravenously and so on) in the form of pharmaceutical preparations such as tablets (including dragees and coated tablets), powdered dosage forms, granules, capsules (including soft capsules), liquid dosage forms, injections, suppositories, sustained release dosage forms and so on, which are obtained by mixing the compound according to the present invention or / and the concomitant medicament described above with pharmaceutically acceptable carriers well known in the art. Injectable dosage forms may be administered intravenously, intramuscularly or subcutaneously to an organ or directly to a lesion.

Pharmaceutically acceptable carriers that can be used to prepare the combination preparation of the present invention include various organic or inorganic carriers commonly used as materials for pharmaceutical preparations. These substances include, for example, a filler, a lubricant, a binder and a disintegrant in a solid dosage form, a solvent, a dissolution aid, a suspending agent, an isotonic substance, a buffer, an analgesic and the like, in a liquid dosage form. In addition, commonly used additives, such as a preservative, an antioxidant, a coloring agent, a sweetener, an adsorbent, a moisturizing agent and so on, can accordingly be used in suitable amounts, if necessary.

Examples of excipients include: lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and so on.

Examples of lubricants include: magnesium stearate, calcium stearate, talc, colloidal silicon oxide and so on.

Examples of binders include: crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sugar, gelatin, methyl cellulose, sodium carboxymethyl cellulose and so on.

Examples of disintegrants include: starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and so on.

Examples of solvents include: water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and so on.

Examples of dissolution aids include: polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and so on.

Examples of suspending agents include: surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzetonium chloride, glycerol monostearate and so on; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and so on.

Examples of isotonic agents include: glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and so on.

Examples of buffer substances include: buffer solutions of phosphate, acetate, carbonate, citrate, and so on.

Examples of painkillers include: benzyl alcohol and so on.

Examples of preservatives include: p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and so on.

Examples of antioxidants include sulfite, ascorbic acid, α-tocopherol, and so on.

In the combination preparation of the present invention, the ratio of the compound of the present invention to the concomitant drug may be appropriately selected depending on the subject to whom the drug is administered, route of administration, disease, and so on.

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 from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight and more preferably about 0.5 to 20% by weight of the total weight of the preparation.

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, and more preferably about 0.5 to 20% by weight of the total weight of the drug.

The amount of additives, such as a carrier and so on, contained in the combination preparation of the present invention varies depending on the dosage form of the preparation and is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight of the total mass of the drug.

These amounts may also be the same when the compound of the present invention and the concomitant drug are obtained separately, respectively.

These preparations can be obtained by themselves by well-known commonly used methods.

For example, a compound of the present invention or a concomitant drug can be presented as an injectable dosage form by combining with a dispersant (e.g. Tween 80 (manufactured by Atlas Powder Company, USA), HCO 60 (manufactured by Nikko Chemicals Co., Ltd), polyethylene glycol , carboxymethyl cellulose, sodium alginate, hydroxypropyl methyl cellulose, dextrin and so on), a stabilizer (e.g. ascorbic acid, sodium pyrosulfite), a surfactant (e.g. polysorbate 80, macrogol and so on), a loving agent (e.g., glycerin, ethanol, etc.), a buffering agent (e.g., phosphoric acid or an alkali metal salt thereof, citric acid or an alkali metal salt thereof, etc.), an isotonic agent (e.g., sodium chloride, potassium chloride, mannitol , sorbitol, glucose and so on), a pH regulating substance (e.g. hydrochloric acid, sodium hydroxide, etc.), a preservative (e.g. ethyl p-hydroxybenzoate, benzoic acid, methyl paraben, propyl paraben, benzyl alcohol and so on), a solubilizer ( e.g. con entrirovanny glycerin, meglumine, etc.), dissolution aids (e.g., propylene glycol, sucrose, etc.), soothing agent (e.g., glucose, benzyl alcohol and so on) to obtain an aqueous injection; or dissolving, suspending or emulsifying with a vegetable oil, such as olive oil, sesame oil, cottonseed oil, corn oil, and so on, with a dissolution promoting substance, such as propylene glycol or the like, to obtain an oil injection.

An oral dosage form can be prepared by the usual method of adding to a compound of the present invention or to a concomitant drug, for example, an excipient (e.g., lactose, sucrose, starch, etc.), a disintegrant (e.g., starch, calcium carbonate, etc.), a binder substances (e.g. starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose and so on), a lubricant (e.g. talc, magnesium stearate, polyethylene glycol 6000 and so on) and others their additives, compressing the resulting mixture and, if necessary, coating the compressed product for the purpose of taste correction, cleavage in the intestine or sustained release, well known methods per se. Coating agents include, e.g. colorants (e.g., iron oxide, titanium dioxide). The oral dosage form may be either a quick release dosage form of the active substance or a sustained release dosage form of the active substance.

For example, in suppositories, a compound of the present invention or a concomitant drug is presented in the form of an oily or aqueous, solid, semi-solid or liquid composition, by methods generally known per se. The oil bases used for the composition described above include higher fatty acid glycerides [eg, cocoa butter, witepsols (manufactured by Dynamite Nobel Company, Germany) and so on], medium fatty acids [eg, migliols (manufactured by Dynamite Nobel Company, Germany) and so on], vegetable oils (for example, sesame oil, soybean oil, cottonseed oil and so on) and the like. Aqueous bases include, for example, polyethylene glycols and propylene glycol. Basics for aqueous gels include, for example, natural rubber, cellulose derivatives, vinyl polymers, acrylic polymers and so on.

Examples of the above sustained release dosage forms include sustained release microcapsules and the like.

Slow-release microcapsules of the active substance can be made and administered by themselves by well-known methods, and, preferably, are made in the form, for example, of a dosage form with a slow release, by the method [2] described below.

Preferably, the compound of the present invention is formulated as an oral dosage form, such as a solid dosage form (e.g., a powdered dosage form, granules, tablets, capsules) or as a rectal dosage form, such as a suppository and so on. A dosage form for oral administration is particularly preferred.

Concomitant drug can be obtained in the form of a dosage form described above, depending on the type of drug.

Next, [1] an injectable preparation based on a compound of the present invention or a concomitant drug and its preparation, [2] a sustained release or quick release preparation of a compound of the present invention or a concomitant drug and its preparation, and [3] sublingual will be specifically described , buccal or rapidly orally disintegrating preparations of a compound of the present invention or a concomitant drug and its preparation.

[1] Injectable drug and its preparation

An injectable preparation obtained by dissolving a compound of the present invention or a concomitant drug in water is preferred. The injectable preparation may contain benzoate and / or salicylate.

An injectable preparation is prepared by dissolving a compound of the present invention or a concomitant drug and optionally benzoate and / or salicylate in water.

Examples of the benzoate and / or salicylate described above include an alkali metal salt such as sodium and potassium salts and so on, an alkaline earth metal salt such as calcium and magnesium salts and so on, an ammonium salt, a meglumine salt, an organic acid salt such as trometamol , etc.

The concentration of the compound of the present invention or the concomitant drug in the injectable preparation is from about 0.05 to 50 mass / volume%, preferably from about 0.3 to 20 mass / volume%. The concentration of benzoate and / or salicylate is from 0.5 to 50 mass / volume%, preferably from 3 to 20 mass / volume%.

Then, respectively, additives are added to the preparation that are usually used in the injected preparation, such as a stabilizer (ascorbic acid, sodium pyrosulfite and so on), a surfactant (polysorbate 80, macrogol, etc.), a solubilizing substance (glycerin, ethanol and so on), a buffering agent (phosphoric acid and its alkali metal salt, citric acid and its alkali metal salt and so on), an isotonic substance (sodium chloride, potassium chloride and so on), a dispersing agent (hydroxypropyl methylcellulose oza, dextrin), pH regulating substance (hydrochloric acid, sodium hydroxide and so on), preservative (ethyl p-hydroxybenzoate, benzoic acid and so on), solubilizer (concentrated glycerin, meglumin and so on), a substance that promotes dissolution (propylene glycol , sucrose and so on), a painkiller (glucose, benzyl alcohol and so on). Any of these additives are added in the amount usually used in the injectable preparation.

The pH of the injectable preparation is adjusted to a value of 2-12, preferably 2.5-8.0, by the addition of a pH of a regulatory substance.

An injectable preparation is prepared by dissolving in water both a compound of the present invention, or a concomitant drug, and optionally benzoate and / or salicylate, and, if necessary, the above additives. These components can be dissolved in any order, in a manner similar to that commonly used to prepare an injectable preparation.

The aqueous solution for injection is preferably heated and used as an injectable preparation after sterilization by filtration or autoclaving, as in the conventional method for preparing the injectable preparation.

The aqueous injectable preparation is preferably autoclaved, for example, at a temperature of 100-121 ° C for 5-30 minutes.

In addition, the drug may be in the form of a solution that is given antibacterial activity for use as a dosage form for repeated administration with fractional dosing.

[2] A preparation for the sustained release of an active component or rapid release of an active component and its preparation

A preferred sustained release formulation comprises a core containing a compound of the present invention or a concomitant drug that is optionally coated with a water-insoluble substance or a swellable polymer. For example, a sustained release oral preparation having a single dose daily dosage form is preferred.

Examples of a water-insoluble substance used as a shell-forming substance include cellulose ethers such as ethyl cellulose, butyl cellulose and so on, cellulose esters such as cellulose acetate, cellulose propionate and so on, polyvinyl esters such as polyvinyl acetate, polyvinyl butyrate and so on, acrylic acid polymers such as acrylic acid / methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacry copolymer lat, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate), polymethacrylate, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, in particular the Eudragits series (Rohm & Pharma), such as E-100 , RL-100, RS-30D, RL-30D, RL-PO and RS-PO (ethyl acrylate / methyl methacrylate / chlorotrimethyl methacrylate / ethylammonium copolymer) and Eudragit NE-30D (methyl methacrylate / ethyl acrylate copolymer) and so on, hydrogenated oils such as hydrogenated castor oil (e.g. LUBRI WAX (Freund Indust rial Co., Ltd) and so on), waxes such as carnauba wax, fatty acid glycerin ester, paraffin and so on, polyglycerol fatty acid esters and so on.

The swellable polymer is preferably a polymer having an acidic removable group and exhibiting a pH dependent swelling, and a polymer having an acidic removable group that is less swellable at an acidic pH, such as in the stomach, but intensively swells at a neutral, is preferred. pH level of the medium, such as in the small and large intestines.

Examples of such an acid containing a removable acid group and exhibiting a pH dependent swelling include a crosslinked polyacrylic acid polymer such as 934P, 940, 941, 974P, 980, 1342 carbomers and so on, polycarbophil and calcium polycarbophil (all manufactured by BF Goodrich Chemicals) , Hivis Wakos 103, 104, 105 and 304 (all manufactured by Wako Pure Chemical Industries, Ltd) and so on.

The coating agent used in the sustained release formulation may further comprise a hydrophilic agent.

Examples of a hydrophilic substance include: a polysaccharide which may have a sulfate group such as pullulan, dextrin, alkali metal alginates and so on, a polysaccharide having a hydroxyalkyl group or carboxyalkyl group such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. methyl , polyvinyl alcohol, polyethylene glycol and so on.

The amount of water-insoluble substance contained in the coating substance of the sustained release preparation is from about 30 to about 90% (w / w), preferably from about 35 to about 80% (w / w), more preferably from about 40 to about 75% (mass / mass), and the content of the swellable polymer is from about 3 to about 30% (mass / mass), preferably from about 3 to about 15% (mass / mass). The coating agent may further comprise a hydrophilic substance, and the amount of hydrophilic substance contained in the coating agent is about 50% (w / w) or less, preferably from about 5 to about 40% (w / w), more preferably from about 5 to about 35% (w / w). Used in the present invention, the symbol% (w / w) indicated above is used to denote% by weight of the composition of the shell-forming substance that is the remainder of the solution of the shell-forming substance after removing any solvent (e.g., water, lower alcohol, such as methanol, ethanol and so on).

A sustained release preparation is prepared by preparing a core containing a drug, as illustrated below, then coating the resulting core with a coating solution obtained by melting by heating a water-insoluble substance or a swellable polymer, or by dissolving or dispersing such a substance in a solvent.

I. Obtaining a core containing a drug

The shape of the core containing the drug for coating the coating forming material (hereinafter sometimes referred to simply as the core) is not specifically limited, but it is preferable to obtain a specific shape such as granules, small granules, or the like.

When the core is granules or small granules, they have an average size of preferably from about 150 to about 2000 microns, more preferably from about 500 to about 1400 microns.

The core can be obtained in the usual way. For example, the drug is mixed with a suitable excipient, binder, disintegrant, lubricant, stabilizer, etc., then wet granulated by extrusion, fluidized bed granulation, or the like.

The content of the drug substance in the core is from about 0.5 to about 95% (mass / mass), preferably from about 5.0 to about 80% (mass / mass), more preferably from about 30 to about 70% (mass / mass) )

Examples of a core filler include a saccharide such as sucrose, lactose, mannitol, glucose and so on, starch, crystalline cellulose, calcium phosphate, corn starch and so on. Among others, crystalline cellulose and corn starch are preferred.

Examples of a binder used include: polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F68, gum arabic, gelatin, starch and so on. Examples of a disintegrant include: calcium carboxymethyl cellulose (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinylpyrrolidone (crospovidone), low substituted hydroxypropyl cellulose (L-HPC), and so on. Among others, hydroxypropyl cellulose, polyvinyl pyrrolidone and low substituted hydroxypropyl cellulose are preferred. Examples of a lubricant and anticoagulant include: talc, magnesium stearate and its inorganic salts, and examples of a lubricant include polyethylene glycol and so on. Examples of the stabilizer include an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, and so on.

In addition to the method described above, the core can be obtained using other methods, such as milling granulation, a coating method in a special boiler, fluidized-bed coating, and melting granulation, where the drug or a mixture of a drug with a filler, a lubricant and so on then added in parts to the particles of an inert carrier as seed for the core by spraying a binder dissolved in an appropriate solvent such as water, n higher alcohol (e.g. methanol, ethanol and so on) or the like. Examples of particles of an inert carrier include particles derived from sucrose, lactose, starch, crystalline cellulose and wax, and preferably these carriers have an average particle size of from about 100 μm to about 1500 μm.

To separate the drug contained in the core from the coating agent, the surface of the core may be coated with a protective substance. Examples of the protective substance include the hydrophilic substance described above and a water-insoluble substance. A preferred protective substance is a polyethylene glycol or polysaccharide having a hydroxyalkyl group or a carboxyalkyl group, more preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose. The protective substance may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid and so on, and a lubricant such as talc. When using a protective substance, its applied amount is from about 1 to about 15% (mass / mass), preferably from about 1 to about 10% (mass / mass), more preferably from about 2 to about 8% (mass / mass) relative to the mass of the core.

The protective substance can be applied by the commonly used coating method, and specifically, a protective substance is sprayed onto the core using a fluidized-bed coating method, a coating method in a special boiler, and so on.

II. Coating core

The core obtained in step I above is coated with a solution of a coating-forming substance obtained by melting by heating a water-insoluble substance and a pH-dependent swellable polymer described above, and a hydrophilic substance, by dissolving or dispersing them in a solvent to obtain a slow release preparation active substance.

An example of a method for applying a solution of a shell-forming substance to a core is, for example, spray coating and so on.

The ratio in the composition of the water-insoluble substance, the swellable polymer, and the hydrophilic substance in the solution of the coating-forming substance can be suitably selected from the amounts of the respective components contained in the coating.

The amount of the substance forming the shell is from about 1 to about 90% (mass / mass), preferably from about 5 to about 50% (mass / mass), more preferably from about 5 to about 35% (mass / mass) by weight nuclei (except for the coating with a protective substance).

As a solvent for the solution of the shell-forming substance, water and an organic solvent can be used, either alone or as a mixture thereof. When using the mixture, the ratio of water to organic solvent (water / organic solvent: mass ratio) can vary from 1 to 100% and preferably from 1 to about 30%. The organic solvent is not particularly limited since it can dissolve a substance insoluble in water, and examples of the solvent include: a lower alcohol such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and so on, lower alkanone, such as acetone, acetonitrile, chloroform, methylene chloride and so on. In particular, lower alcohol is preferred, however, ethyl alcohol and isopropyl alcohol are more preferred. Water and a mixture of water and an organic solvent are preferably used as solvents for the solution of the shell-forming substance. In this case, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, and so on, if necessary, can be added to the solution of the shell-forming substance to stabilize the solution of the shell-forming substance.

For spray coating, the coating may be performed by a commonly used coating method. Specifically, a solution of a coating agent is sprayed onto the core, by a coating method in a fluidized bed, a coating method in a special boiler, or the like. A lubricant such as talc, titanium oxide, magnesium stearate, calcium stearate, light silicon anhydride and so on, and a plasticizer such as fatty glycerol ester, hardened castor oil, triethyl citrate, cetyl alcohol, stearyl can also be added at this stage. alcohol and so on.

After applying the sheathing agent, if necessary, an antistatic agent such as talc may also be added.

The drug for the rapid release of the active component may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, and so on). An oral preparation and a parenteral preparation such as an injectable preparation can be used, and an oral preparation is preferred.

In addition to the drug, which is the active ingredient, the quick release preparation may usually contain a carrier, additives and excipient (hereinafter sometimes referred to as simply excipients), which are commonly used in the pharmaceutical field. Pharmaceutical excipients are not particularly limited as they are excipients commonly used in the pharmaceutical field. Examples of an oral solid drug excipient include lactose, starch, corn starch, crystalline cellulose (Avicel PH101, manufactured by Asahi Kasei Corporation, etc.), powdered sugar, granulated sugar, mannitol, light silicon anhydride, magnesium carbonate, calcium carbonate, L- cysteine and so on, however, corn starch and mannitol are preferred. Any of these excipients may be used alone or in combination with each other. The amount of fillers is, for example, from about 4.5 to about 99.4 mass / mass%, preferably from about 20 to about 98.5 mass / mass%, more preferably from about 30 to about 97 mass / mass% of the total mass rapid release drug component. The drug content of the quick release preparation may suitably be in the range of about 0.5% to about 95%, preferably about 1% to about 60% of the total amount of the quick release preparation of the active component.

When the preparation for rapid release of the active ingredient is a solid preparation for oral use, the preparation contains a disintegrant, in addition to the components described above. Examples of disintegrant include: calcium carboxymethyl cellulose (ECG505 manufactured by GOTOKU CHEMICAL Co., Ltd), croscarmellose sodium (e.g. Ac-Di-Sol manufactured by Asahi Kasei Corporation), crospovidone (e.g. COLIDON CL manufactured by BASF), low-substituted hydroxypropylcellulose Etsu chemical Co., Ltd), carboxymethyl starch (MATSUTANI CHEMICAL INDUSTRY Co., Ltd), sodium carboxymethyl starch (EXORITAB manufactured by KIMURA SANGYO), incomplete α starch (PCS manufactured by Asahi Kasei Corporation) and so on. For example, a loosening agent can be used that breaks the granules by absorbing water or swelling when in contact with water, or forming a channel between the active component, including the core, and the filler. Any of these disintegrants can be used alone or in combination with each other. The amount of disintegrant used can be appropriately selected depending on the type and amount of the drug or particular preparation used, for a given release of the active ingredient. For example, the amount is from about 0.05 to about 30 mass / mass%, preferably from about 0.5 to about 15 mass / mass% of the total mass of the preparation for the rapid release of the active component.

When the rapid release preparation of the active ingredient is an oral solid preparation, the oral solid preparation may optionally contain additives commonly used in solid preparations, in addition to the components described above. Examples of additives include: binders (e.g. sucrose, gelatin, gum arabic powder, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, pulran, dextrin, etc.), lubricants (polyethylene glycol, silicon, silicon, Aerosil (NIPPON AEROSIL)), surfactants (e.g. anionic surfactants, such as sodium alkyl sulfate, non-ionic surfactants, such as polyoxyethylene fatty ester, polyoxyethylene sorbitan fatty ester, castor oil polyoxyethylene derivatives and so on), colorants (e.g. resinous colorants, caramel, crocus, titanium oxide, riboflavins), if necessary, modifiers (e.g. sweeteners, flavorings and so on) , adsorbents, preservatives, moisturizers, antistatic agents, etc. In addition, an organic acid such as tartaric acid, citric acid, succinic acid can also be added as a stabilizer. , Fumaric acid or the like.

As the binder mentioned above, hydroxypropyl cellulose, polyethylene glycol and polyvinylpyrrolidone and so on are preferably used.

A rapid release preparation of the active component can be obtained by mixing the components described above, and kneading the mixture, if necessary, and then molding in accordance with a commonly used pharmaceutical preparation method. The above mixing can be performed in the usual way, for example, by stirring, kneading and so on. Specifically, in the case when the preparation for the rapid release of the active component is in the form of particles, the preparation can be obtained by mixing the components using a vertical type granulator, a universal mixer (manufactured by HATA IRON WORKS CO., LTD), FD-5S fluid bed granulation apparatus (manufactured by POWREX CORPORATION) or the like, and then granulating obtained by wet extrusion or granulation in a fluidized bed in a manner analogous to obtaining a sustained release drug core described wow above.

A drug with a quick release of the active ingredient and a drug with a slow release of the active ingredient, thus obtained, can be combined into a mixture as it is or together with suitable pharmaceutical excipients in pharmaceutical preparations separately, by the usual method of preparing the corresponding preparations, for administration in combination with each other , simultaneously or at certain intervals. Alternatively, both formulations may be combined in a unitary dosage form for oral administration (e.g., granules, fine granules, tablets, capsules) as they are or together with appropriate pharmaceutical excipients. Also, a separate capsule for oral administration can be filled with both drugs in the form of granules or small granules.

[3] Sublingual, buccal or rapidly disintegrating oral drug and its preparation

The sublingual, buccal, or rapidly disintegrating oral drug may be in the form of a solid preparation, such as a tablet, or may be in the form of an oral mucosal patch (film) or an oral disintegrating film.

The sublingual, buccal or rapidly disintegrating oral drug is preferably a preparation containing a compound of the present invention or a concomitant drug and excipient. The preparation may also contain auxiliary agents, such as a lubricant, an isotonic substance, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, and so on. In addition, in order to promote absorption and enhance bioavailability, the preparation may also contain β-cyclodextrin or derivatives of β-cyclodextrin (for example, hydroxypropyl-β-cyclodextrin and so on) and the like.

Examples of the above excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silicon anhydride and so on. Examples of the lubricant include: magnesium stearate, calcium stearate, talc, colloidal silicon oxide and so on, however, magnesium stearate and colloidal silicon oxide are preferred. Examples of the isotonic substance include: sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, sucrose, glycerin and urea, however, mannitol is particularly preferred. As the hydrophilic carrier, there are, for example, a swellable hydrophilic carrier, such as crystalline cellulose, ethyl cellulose, cross-linked polyvinyl pyrrolidone, light silicon anhydride, silicic acid, dicalcium phosphate, calcium carbonate and so on, and crystalline cellulose (for example, microcrystalline cellulose and ) is preferred. As the water-dispersible polymer, for example, resin (e.g. tragacanth gum, gum arabic, guar gum), alginate (e.g. sodium alginate), cellulose derivatives (e.g. methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose, for example, can be used) starch, polyacrylic acid (e.g. carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbate palmitate sol b and so on, however, hydroxypropyl methyl cellulose, polyacrylic acid, alginate, gelatin, carboxymethyl cellulose, polyvinyl pyrrolidone and polyethylene glycol are preferred. Hydroxypropyl methyl cellulose is particularly preferred. As a stabilizer, for example, cysteine, thiosorbite, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and so on can be used, however, citric acid and ascorbic acid are particularly preferred.

A sublingual, buccal or rapidly disintegrating oral drug can be prepared by mixing a compound of the present invention or a concomitant drug and excipient as such in a known manner. In addition, if desired, excipients described above can also be included in the mixture, such as a lubricant, an isotonic substance, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a colorant, a sweetener, a preservative, and so on. After mixing the components described above, simultaneously or at predetermined intervals, the mixture is compressed into tablets to obtain sublingual, buccal or rapidly disintegrating oral tablets. To obtain the appropriate hardness, a solvent, such as water, alcohol, and so on, can be used to moisten or wet the components before or after tableting, followed by drying.

Upon receipt of an oral mucosal patch (film), a compound of the present invention or a concomitant drug and a water-dispersible polymer (preferably hydroxypropyl cellulose, hydroxypropyl methyl cellulose), a filler, and the like described above are dissolved in a solvent such as water and so on, then the resulting solution cast into a film. In addition, additives such as plasticizer, stabilizer, antioxidant, preservative, coloring agent, buffering agent, sweeteners and so on may be added to the preparation. Glycol, such as polyethylene glycol, propylene glycol, etc., can be added to the film to impart appropriate elasticity, and, to enhance the adhesion of the film to the oral mucosal lining, a bioadhesive polymer (e.g., polycarbophil, carbopol) can also be added. Watering can be done by pouring the solution on a non-adhesive surface, spreading the solution over the surface using a coating device, such as a knife device, with a uniform thickness (preferably about 10 to 1000 microns), and then drying the solution to form a film. The film thus obtained is dried at room temperature or by heating, then cut into pieces, each of which has a desired surface area.

A preferred fast disintegrating drug for oral administration is, for example, a rapidly penetrating solid product that contains a compound of the present invention or a concomitant drug and a water-soluble or water-diffusing carrier that is inert to the compound of the present invention or a concomitant drug. The product is formed by distilling off the solvent from a solid composition containing a solution of a compound of the present invention or a concomitant drug in an appropriate solvent.

In addition to the compound of the present invention or the concomitant drug, the rapidly disintegrating oral drug composition may preferably contain a matrix-forming substance and secondary components.

Examples of a matrix forming substance include gelatins, dextrins, and animal or vegetable proteins of soy, wheat, plantain seeds, and so on; resinous substances such as gum arabic, guar gum, agar, xanthan gum and so on; polysaccharides; alginates; carboxymethyl cellulose; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidones; substances obtained from gelatin-gum arabic complexes and so on. The matrix-forming substance further includes saccharides such as mannitol, dextrose, lactose, galactose, trehalose and so on; cyclic saccharides such as cyclodextrins and so on; inorganic salts such as sodium phosphate, sodium chloride, aluminum silicate and so on; amino acids containing from 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 so on.

One or more matrix forming substances may be introduced into the solution or suspension before hardening. Matrix-forming substances may be present in addition to the surfactant, or may be present in the absence of surfactants. Matrix-forming substances serve not only to form the matrix itself, but also help maintain the diffusion of the compound of the present invention or the concomitant drug in a solution or suspension.

The composition may contain an auxiliary component, such as a preservative, an antioxidant, a surfactant, a thickening agent, a coloring agent, a pH adjusting agent, a flavoring agent, a sweetener, a flavoring agent, and so on. Examples of suitable colorants include, for example: red, black and yellow iron oxide, FD & C dyes available from ERIS & EVERALD, such as FD & C Blue No. 2 and FD & C Red No. 40 and so on. Examples of a suitable flavor include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, grape flavor, and combinations thereof. Examples of an appropriate pH adjusting agent include: citric acid, tartaric acid, phosphoric acid, hydrochloric acid, and maleic acid. Examples of a suitable sweetener include: aspartame, asulfam K, and thaumatin. Examples of suitable flavoring agents include: sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbents, and microencapsulated apomorphine.

Typically, the preparation contains a compound of the present invention or a concomitant drug in an amount of from about 0.1 to about 50% by weight, preferably from about 0.1 to about 30% by weight, and preferably the preparation (sublingual tablet, buccal and so on further described above) allows 90% or more of the compound of the present invention or concomitant drug to dissolve (in water) within about 1 to about 60 minutes, preferably from about 1 minute to about 15 minutes, more preferably from about 2 minutes to about 5 minutes, or is a rapidly disintegrating oral drug that disintegrates for about 1 to about 60 seconds, preferably about 1 to about 30 seconds, more preferably about 1 to about 10 seconds, after placing it in the oral cavity.

The amount of the above filler is from about 10 to about 99% by weight, preferably from about 30 to about 90% by weight of the total weight of the preparation. The amount of β-cyclodextrin or a derivative of β-cyclodextrin is from about 0 to about 30% by weight of the total weight of the preparation. The amount of lubricant is from about 0.01 to about 10% by weight, preferably from about 1 to about 5% by weight of the total weight of the preparation. The amount of isotonic substance is from about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight of the total weight of the preparation. The amount of hydrophilic carrier is from about 0.1 to about 50% by weight, preferably from about 10 to about 30% by weight of the total weight of the preparation. 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 of the total weight of the preparation. The amount of stabilizer is from about 0.1 to about 10% by weight, preferably from about 1 to about 5% by weight of the total weight of the preparation. If necessary, the preparation described above may further contain additives such as a coloring agent, sweetener, preservative, and so on.

The dose of the combined preparations of the present invention varies depending on the type of compound of the present invention, age, body weight, condition, dosage form, route of administration, dosage period and so on.

The dose of the compound of the present invention may vary depending on the subject to whom the compound is administered, its condition, route of administration, and so on, and when administered orally, the compound is usually administered to a patient (e.g., body weight 60 kg) having a cancer tumor, in a daily dose, component from about 0.01 to about 100 mg, preferably from about 0.1 to about 50 mg, and more preferably from about 0.1 to about 20 mg. With parenteral administration, a single dose of the compound may vary depending on the subject to whom the compound is administered, its condition, route of administration and so on, and when the dosage form is injectable, preferably for intravenous administration, the compound to a patient (e.g., body weight 60 kg) having the cancer is usually administered in a daily dose of from about 0.001 to about 30 mg, preferably from about 0.01 to about 20 mg, and more preferably from about 0.01 to about 10 mg. Other types of animals may be administered in an appropriate dose, calculated on 60 kg of weight. Of course, the dose may vary depending on the condition of the patient, as described above; in this case, a dose lower than the dose defined above may be sufficient or a higher dose than the above limit may be used.

You can set any dose limit for the concomitant drug, as this will not cause harmful side effects. The daily dose of the concomitant drug may vary depending on the severity of the disease, age, gender, body weight and susceptibility of the subject, the dosage period and intervals, features, composition, type and active components of the pharmaceutical preparation, and so on, and is not specifically limited. For example, when administered orally, the dose is from about 0.001 to 2000 mg, preferably from about 0.01 to 500 mg, and more preferably from about 0.1 to 100 mg of the preparation per kg body weight of a mammal; usually this dose is administered, dividing it 1-4 times a day.

When the pharmaceutical preparations of the present invention are administered, they can be administered sequentially. Alternatively, the concomitant drug is first administered, and then the compound of the present invention is administered, or the compound of the present invention is first administered, and then the concomitant drug. When they are administered at certain time intervals, the intervals vary depending on the active ingredient to be administered, the dosage form and the route of administration; for example, when a concomitant drug is first administered, the compound of the present invention can 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 a compound of the present invention is first administered, the concomitant drug can 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.

A preferred route of administration is, for example, oral administration of about 0.001 to 200 mg / kg of the concomitant drug as an oral drug and, after about 15 minutes, parenteral administration of about 0.005 to 0.5 mg / kg of the compound of the present invention in the form of a preparation for parenteral administration as a daily dose.

As metastins, for example, human metastin described in WO 00/24890, a mouse or rat metastin described in WO 01/75104, and so on are used.

Specific examples of human metastin include a peptide containing the N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 and consisting of 8-54 amino acid residues, and the like.

"A peptide containing an N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 and consisting of 8-54 amino acid residues" may be any peptide, since it is a peptide containing an N-terminal 47-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1, and consisting of 8-54 amino acid residues, however, it means that these peptides have substantially similar physiological activity (e.g., receptor binding activity, signaling flax transduction, an action that increases sugar levels, an action that stimulates the secretion of glucagon in the pancreas, an effect that stimulates urination, and so on). Specifically, using (i) a peptide having the amino acid sequence represented by SEQ ID NO: 1, (ii) a peptide containing the N-terminal 47-54 amino acid sequence at the C end in the amino acid sequence represented by SEQ ID NO: 1, and consisting of 8-15 amino acid residues and so on.

More specifically, the human metastin used includes (i) a peptide consisting of the amino acid sequence represented by SEQ ID NO: 1 (human metastin 54 (1-54)), (ii) a peptide consisting of an N-terminal 40-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 15 (40-54); SEQ ID NO: 15), (iii) a 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); SEQ ID NO: 16), (iv) a peptide consisting of N-co the terminal 46-54 amino acid sequence in 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 the sequence represented by SEQ ID NO: 1 (human metastin 8 (47-54); SEQ ID NO: 18) and so on.

As mouse metastin (A), for example, (i) a peptide containing the N-terminal 134-141 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 3 and consisting of 8-52 amino acid residues is used. Specific examples of the mouse metastin (A) used include (i) a peptide consisting of an N-terminal 90-141 amino acid sequence represented by SEQ ID NO: 3, (ii) a peptide consisting of an N-terminal 132-141 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 3, (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 containing the N-terminal 138-145 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 5 and consisting of 8-52 amino acid residues is used. Specific examples of murine metastin (B) used include a peptide consisting of the N-terminal 94-145 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 5, and the like. As rat metastin, for example, (i) a peptide containing the N-terminal 112-119 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 7 and consisting of 8-52 amino acid residues is used. Specific examples of rat rat metastin used include (i) a peptide consisting of an N-terminal 68-119 amino acid sequence represented by SEQ ID NO: 7, (ii) a peptide consisting of an N-terminal 110-119 amino acid sequence represented by SEQ ID NO: 7, (iii) a peptide consisting of the N-terminal 105-119 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 7, and the like.

Throughout the description, metastins are presented in accordance with the usual method of describing peptides, that is, the N-terminus (amino terminus) on the left side and the C-terminus (carboxyl end) on the right side. In the peptide represented by SEQ ID NO: 1, the C-terminus may be any form of a carboxyl group (—COOH), a carboxylate (—COO ^- ), an amide (—CONH ₂ ), and an ester (—COOR). Here, examples of R in an ester or alkylamide group include a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and so on; A C _3-8 cycloalkyl group such as cyclopentyl, cyclohexyl and so on; A C _6-12 aryl group such as phenyl, α-naphthyl and so on; C _7-14 aralkyl, such as phenyl-C _1-2 alkyl group, for example, benzyl, phenethyl, benzhydryl and so on, or α-naphthyl-C _1-2 alkyl group, such as α-naphthylmethyl and so on; pivaloyloxymethyl group, which is widely used as an ester for oral administration, and the like.

Further, metastins include peptides where the amino group on the N-terminal methionine residue is protected by a protecting group (for example, a C _1-6 acyl group such as a C _2-6 alkanoyl group, for example a formyl group, acetyl group and so on); such peptides where the N-terminal portion is cleaved in vivo and the glutamyl group thus formed undergoes pyroglutamination; such peptides, where the substituent (e.g., -OH, -SH, amino group, imidazole group, indole group, guanidino group and so on), in the side chain of an amino acid in the molecule, is protected by an appropriate protecting group (e.g., C _1-6 acyl group, such as a C _2-6 alkanoyl group, for example, a formyl group, an acetyl group and so on), or conjugated peptides, such as glycopeptides linked to sugar chains.

For the metastin salts of the present invention, salts of physiologically acceptable bases (e.g., alkali metal salts) or acids (e.g., organic acids or inorganic acids) are preferred, and so on, physiologically acceptable acid addition salts are particularly preferred. Examples of such salts include salts, for example, inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid); organic acid salts (e.g., 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) and the like.

As encoding DNA metastins, for example, DNA encoding a human metastin described in WO 00/24890, DNA encoding a murine or rat metastin described in WO 01/75104 and so on are used.

Encoding DNA metastins can be any genomic DNA, library genomic DNA, cDNA derived from cells and tissues described above, library cDNA derived from cells and tissues described above, and synthetic DNA. The vector used for the library can be any bacteriophage, plasmid, cosmid and phagemid. DNA can also be directly amplified by reverse transcriptase polymerase chain reaction (hereinafter abbreviated RT-PCR) using the total RNA or mRNA fraction obtained from the cells and tissues described above.

The DNA encoding human metastin, the precursor of mouse metastin (A), the precursor of mouse metastin (B) or the precursor of rat metastin can be any DNA, since each is a DNA containing the base sequence represented by SEQ ID NO: 2, SEQ ID NO: 4 , SEQ ID NO: 6 or SEQ ID NO: 8, or DNA having a base sequence that can be hybridized to a base sequence represented by any base sequence represented by SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 under extreme conditions iah and encoding human metastin, mouse metastin (A), mouse metastin (B) or rat metastin as described above.

Specific examples of DNA that can be hybridized to the base sequence represented by any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8 include DNA containing a base sequence having at least about 70% degree of homology, preferably at least about 80% degree of homology, more preferably at least about 90% degree of homology, and most preferably at least about 95% degree of homology, to the base sequence represented by any of SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6 or SEQ ID NO: 8.

Homology in the base sequence can be determined using the NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) homology algorithm under the following conditions (expected value = 10; spaces allowed; filtering = enabled; compatibility = 1; incompatibility = -3 )

Hybridization can be performed as such by well-known methods or modifications of these methods, for example, in accordance with the method described in Molecular Cloning, 2nd (J. Sambrook et al., Cold Spring Harbor Lab. Press, 1989). A commercially available library may also be used in accordance with the instructions of the attached manufacturer's protocol. Preferably, hybridization can be performed under extremely harsh conditions.

The extremely stringent conditions used here are, for example, a sodium concentration of about 19-40 mm, preferably about 19-20 mm at a temperature of about 50-70 ° C, preferably about 60-65 ° C. In particular, hybridization conditions are most preferred at a sodium concentration of about 19 mM at a temperature of about 65 ° C.

Specifically, as the DNA encoding a human metastin consisting of the amino acid sequence represented by SEQ ID NO: 1, a DNA containing the base sequence represented by SEQ ID NO: 2 is used. Accordingly, for a base sequence encoding a human metastin consisting of the various amino acid sequences described above, the base sequence corresponding to each partial amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 can be selected from the base sequence represented by SEQ ID NO: 2.

As the DNA encoding the mouse metastin precursor (A) containing the amino acid sequence represented by SEQ ID NO: 3, a DNA containing the base sequence represented by SEQ ID NO: 4 and the like is used. Accordingly, for a base sequence encoding a 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 can be selected from the base sequence, represented by SEQ ID NO: 4.

As the DNA encoding the mouse metastin precursor (B) containing the amino acid sequence represented by SEQ ID NO: 5, a DNA containing the base sequence represented by SEQ ID NO: 6 and the like is used. Accordingly, for a base sequence encoding a mouse metastin precursor (B) containing 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 can be selected from the base sequence represented by SEQ ID NO: 6.

As the DNA encoding rat metastin containing the amino acid sequence represented by SEQ ID NO: 7, a DNA containing the base sequence represented by SEQ ID NO: 8 and the like is used. Accordingly, for a base sequence encoding a mouse metastin 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: 7 can be selected from the base sequence represented by SEQ ID NO :8.

More specifically, for a peptide consisting of the amino acid sequence represented by SEQ ID NO: 1 (human metastin 54 (1-54)), a DNA containing the base sequence represented by SEQ ID NO: 2 and so on is used.

For a peptide consisting of an N-terminal 40-54 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1 (human metastin 15 (40-54); SEQ ID NO: 15), a DNA containing the base sequence represented by SEQ ID is used NO: 19 and so on.

For a peptide consisting of an 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), a DNA containing the base sequence represented by SEQ is used ID NO: 20 and so on.

For a peptide consisting of an 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), a DNA containing the base sequence represented by SEQ is used ID NO: 21 and so on.

For a peptide consisting of an 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), a DNA containing the base sequence represented by SEQ is used ID NO: 22 and so on.

As the metastin receptor, its partial peptides or their salts, for example, the human metastin receptor, its partial peptides or their salts described in WO 00/24890, the human, mouse or rat metastin receptor, its partial peptides or their salts described in WO 01/75104 and so on.

Specifically, a protein containing a similar or substantially similar amino acid sequence as the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 and so on is used as a metastin receptor.

An amino acid sequence that is essentially the same as an amino acid sequence, such as, for example, the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, includes, for example, an amino acid sequence having at least about 70 % homology degree, preferably at least about 80% homology degree, more preferably at least about 90% homology degree and most preferably at least about 95% homo degree ogii to the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13.

The amino acid sequence homology can be determined using the NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) homology algorithm under the following conditions (expected value = 10; spaces allowed; matrix = BLOSUM62; filtering = off).

As a protein containing a substantially similar amino acid sequence, for example, the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, a protein having a substantially similar amino acid sequence, for example, the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, and having an activity of the same nature as the activity of a protein having the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 and so on.

As an activity of essentially a single nature, there is, for example, ligand binding activity, signal transduction activity, and the like. The term “essentially single nature” means that the nature of these activities is equivalent in terms of quality. Thus, activities such as ligand binding activity, signal transduction activity and so on are preferably equivalent (e.g., from about 0.01 to 100 times, preferably from about 0.5 to 10 times, more preferably from 0.5 to 2 times), but differ in quantitative parameters, such as the level of these activities, or, such as the molecular weight of the protein may be present and be acceptable.

Activities such as ligand binding activity, signal transduction activity and so on can be tested per se in a well-known manner with modifications and can be determined in accordance with ligand determination methods or screening methods described, for example, in WO 00/24890 or WO 01/75104.

Examples of the metastin receptor used include proteins containing (i) the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 in which at least 1 or 2 (preferably about 1 to about 30, more preferably from about 1 to about 10 and most preferably several (1 or 2)) amino acids; (ii) the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 to which at least 1 or 2 (preferably from about 1 to about 30, more preferably from about 1 to about 10 and most preferably several (1 or 2)) amino acids; (iii) the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, in which at least 1 or 2 (preferably about 1 to about 30, more preferably from about 1 to about 10, and most preferably, several (1 or 2)) amino acids are substituted with other amino acids; or (iv) a combination of these amino acid sequences; etc.

Throughout the description, metastin receptors are presented in accordance with the usual method of describing peptides, that is, the N-terminus (amino terminus) on the left side and the C-terminus (carboxyl end) on the right side. In metastin receptors, including a metastin receptor, consisting of the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13, the C-terminus may be any form of a carboxyl group (-COOH), carboxylate (- COO-), amide (-CONH ₂ ) and ester (-COOR). Here, examples of R in the ester group include a C _1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and so on; A C _3-8 cycloalkyl group such as cyclopentyl, cyclohexyl and so on; A C _6-12 aryl group such as phenyl, α-naphthyl and so on; C _7-14 aralkyl, such as phenyl-C _1-2 alkyl group, for example, benzyl, phenethyl and so on, or α-naphthyl-C _1-2 alkyl group, such as α-naphthylmethyl and so on; and pivaloyloxymethyl group, which is widely used as an ester for oral administration, and the like.

In the case where the metastin receptors contain a carboxyl group (or carboxylate) at a position other than the C-terminus, the carboxyl group may be amidated or esterified, and such amides or esters are also included in the receptor protein of the present invention. In this case, the ester group used may be the same group as, for example, the C-terminal esters described above.

Further, metastin receptors include receptors where the amino group at the N-terminal methionine residue is protected by a protecting group (eg, a C _1-6 acyl group, such as a C _2-6 alkanoyl group, for example, a formyl group, an acetyl group and so on); receptors where the N-terminal region is cleaved in vivo and the glutamyl group thus formed is pyroglutaminized; receptors where the substituent (e.g., -OH, -SH, amino group, imidazole group, indole group, guanidino group and so on) on the side chain of an amino acid in a molecule is protected by an appropriate protecting group (e.g., C _1-6 acyl group such as C _{2 -6} alkanoyl group, for example, formyl group, acetyl group and so on), or conjugated proteins, such as glycoproteins associated with sugar chains.

Specific examples of metastin receptors include a human metastin receptor consisting of the amino acid sequence represented by SEQ ID NO: 9, a rat metastin receptor consisting of the amino acid sequence represented by SEQ ID NO: 11, a mouse metastin receptor consisting of the amino acid sequence represented by SEQ ID NO : 13 and so on.

Incomplete peptides of the metastin receptor (hereinafter sometimes referred to simply as an incomplete peptide) can be any peptide, since they are incomplete peptides of the metastin receptor described above; use peptides, such as metastin receptor protein molecules, which are sites located outside the cell membrane and having ligand binding activity.

Specifically, an incomplete metastin receptor peptide consisting of the amino acid sequence represented by SEQ ID NO: 9, SEQ ID NO: 11 or SEQ ID NO: 13 is a peptide containing regions considered as extracellular domains (hydrophilic domains) in a hydrophobic plotting analysis . A peptide partially containing a hydrophobic domain may also be used. In addition, the peptide may contain each domain separately or multiple domains together.

In the metastin receptor, preferred incomplete peptides are those containing at least 20 amino acids, preferably at least 50 and more preferably at least 100 in the amino acid sequence described above, forming the metastin receptor.

An incomplete peptide may be a peptide having the amino acid sequence described above, in which at least 1 or 2 (preferably from about 1 to about 10 and more preferably several (1 or 2)) amino acids are deleted; to which at least 1 or 2 (preferably from about 1 to about 10 and more preferably several (1 or 2)) amino acids are added; or, in which at least 1 or 2 (preferably from about 1 to about 10 and more preferably several (1 or 2)) amino acids are substituted with other amino acids. In an incomplete peptide, the C terminus may be any form of a carboxyl group (—COOH), a carboxylate (—COO ^- ), an amide (—CONH ₂ ), and an ester (—COOR), such as, for example, in the metastin receptor described above.

In addition, partial peptides include peptides where the amino group at the N-terminal methionine residue is protected by a protecting group; peptides where the N-terminal region is cleaved in vivo and the glutamyl group thus formed is pyroglutaminated; peptides, where the substituent on the side chain of the amino acid in the molecule is protected by an appropriate protecting group, or conjugated peptides, such as glycopeptides linked to sugar chains, such as, for example, in the metastin receptors described above.

For metastin receptor salts or partial peptide salts, physiologically acceptable acid salts, especially physiologically acceptable acid addition salts, are preferred. Examples of salts include salts, for example, inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid); organic acid salts (e.g., 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) and the like.

As DNA encoding a metastin receptor or its partial peptides, for example, DNA encoding a human metastin receptor or its partial peptides described in WO 00/24890, DNA encoding a mouse or rat metastin receptor or its partial peptides described in WO are used. 01/75104 and so on.

The DNA encoding the metastin receptor or its partial peptides can be any genomic DNA, a genomic library DNA, cDNA derived from cells and tissues described above, a library cDNA derived from cells and tissues described above, and synthetic DNA. The vector used for the library can be any bacteriophage, plasmid, cosmid and phagemid. DNA can also be directly amplified by reverse transcriptase polymerase chain reaction (hereinafter abbreviated RT-PCR) using the total RNA or mRNA fraction obtained from the cells and tissues described above.

Specifically, the DNA encoding the human metastin receptor, mouse metastin receptor, or rat metastin receptor may be any DNA, as it is a DNA containing each base sequence represented by SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14, or DNA containing a base sequence that can be hybridized to the base sequence represented by SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14, under extremely stringent conditions, and encoding a receptor having an activity of essentially the same nature ( e.g. act ligand binding, signal transduction activity, etc.), such as, for example, human metastin receptor, mouse metastin receptor or rat metastin receptor consisting of the amino acid sequence represented by SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 12 :fourteen.

Examples of DNA capable of hybridization to the base sequence represented by any of SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14 include DNA containing a base sequence having at least about 70% homology, preferably at least at least about 80% degree of homology, more preferably at least about 90% degree of homology, and most preferably at least about 95% degree of homology, to the base sequence represented by any of SEQ ID NO: 10, SEQ ID NO: 12 or SEQ ID NO: 14.

Homology in the base sequence can be determined using the NCBI BLAST (National Center for Biotechnology Information Basic Local Alignment Search Tool) homology algorithm under the following conditions (expected value = 10; spaces allowed; filtering = enabled; compatibility = 1; incompatibility = -3 )

Hybridization can be carried out per se by widely known methods or modifications of these methods, for example, in accordance with the method described in Molecular Cloning, 2nd (J. Sambrook et al., Cold Spring Harbor Lab. Press, 1989) and so on. A commercially available library may also be used in accordance with the instructions of the manufacturer's attached protocol. Preferably, hybridization can be performed under extremely harsh conditions.

The extremely stringent conditions used here are, for example, a sodium concentration of about 19-40 mm, preferably about 19-20 mm at a temperature of about 50-70 ° C, preferably about 60-65 ° C. In particular, hybridization conditions are most preferred at a sodium concentration of about 19 mM, at a temperature of about 65 ° C.

More specifically, as a DNA encoding a human metastin receptor consisting of the amino acid sequence represented by SEQ ID NO: 9, a DNA containing the base sequence represented by SEQ ID NO: 10 is used.

As a DNA encoding a rat metastin receptor, consisting of the amino acid sequence represented by SEQ ID NO: 11, a DNA containing the base sequence represented by SEQ ID NO: 12 is used.

As the DNA encoding the mouse metastin receptor, consisting of the amino acid sequence represented by SEQ ID NO: 13, a DNA containing the base sequence represented by SEQ ID NO: 14 is used.

Metastin receptors, their partial peptides or their salts and DNA encoding metastin receptors or their partial peptides can be obtained or produced by the methods described in WO 00/24890 or WO 01/75104.

The present invention will be described in more detail using examples, composition examples and test examples, however, it is not intended that the invention be limited to them and any modification may be made without departing from the scope of the present invention.

In the following examples, the term "room temperature" usually means a temperature equal to from about 10 ° C to about 35 ° C. In percentage terms, the yield is presented as mol / mol% and the solvent used in chromatography is in the form of vol.%, And the rest is in the form of wt.%. In the proton NMR spectrum, data for OH, NH protons and so on, which are wide and unidentified, are not presented.

Other abbreviations used in the description have the following meanings.

Abbreviation Description 10Ψ, CSNH: C-terminal-CONH ₂ at position 10 is substituted with -CSNH ₂ . 1Ψ2, CH ₂ NH: -CONH- the bond between the 1- and 2-positions is substituted
-CH ₂ NH bond. 2Ψ3, CH ₂ NH: -CONH- the bond between the 2- and 3-positions is substituted
-CH ₂ NH bond. 3-4, CH ₂ NH: -CONH- the bond between the 3- and 4-positions is substituted
-CH ₂ NH- bond. 4-5, CH ₂ NH: -CONH- the bond between the 4- and 5-positions is substituted
-CH ₂ NH- bond. 6-7, CSNH: -CONH- the bond between the 6- and 7-positions is substituted
-CSNH-bond. 6Ψ7, NHCO: -CONH- the bond between the 6- and 7-positions is substituted
-NHCO- bond. 6Ψ7, CH ₂ NH: -CONH- the bond between the 6- and 7-positions is substituted
-CH ₂ NH- bond. 6Ψ7, CH ₂ O: -CONH- the bond between the 6- and 7-positions is substituted
-CH ₂ O- bond. 7Ψ8, CH ₂ NH: -CONH- the bond between the 7- and 8-positions is substituted
-CH ₂ NH- bond. 8Ψ9, CH ₂ NH: -CONH- the relationship between the 8- and 9-positions is replaced
-CH ₂ NH- bond. 9Ψ10, CH ₂ NH: -CONH- the bond between the 9- and 10-positions is replaced
-CH ₂ NH- bond. Aad: 2-aminoadipic acid Abu: 2-aminobutanoic acid Abz (2): 2-aminobenzoic acid Abz (3): 3-aminobenzoic acid Ac: acetyl AcONB: N-acetoxy-5-nonbornen-2,3-dicarboximide Acp: 6-aminocaproic acid AcOEt: ethyl acetate AcOH: acetic acid Aib: α-aminoisobutanoic acid Ala (2-Qui): 2-quinolylalanine Ala (3-Bzt): 3-benzothienylalanine Ala (cBu): cyclobutylalanine Ala (cPr): cyclopropylalanine Ala (Pip): (4-piperidin-1-yl) alanine Alb: Albizzin (2-amino-3-ureidopropionic acid) Ambz (4): 4-aminomethylbenzoyl Arg (Ac): N ^ω -acetylarginine Arg (Boc ₂ , Me): N ^{ω, ω '} bis-tert-butoxycarbonyl-N ^ω -methylarginine Arg (Et): N ^ω -ethylarginine Arg (Me): N ^ω -methylarginine 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 -} nitroarginine Arg (Pbf): N ^ω -2,2,4,6,7-pentamethyldihydrobenzofuransulfonyl arginine Arg (n-Pr): N ^ω -propylarginine Arg (Tos): N ^ω -tosylarginine Asp (NHMe): N ^ω -methylasparagin Asp (NMe ₂ ): N ^{ω, ω-} dimethyl asparagine Asp (NHPen): N ^ω -pentylasparagin Asp (NHcPr): N ^ω -cyclopropyl asparagine Asp (NHBzl): N ^{ω -} benzyl asparagine AzaGly: azaglycin 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-dimethylimimidazolium 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- acetyl-β-diaminopropionic acid Dap (For): N ^β- Formyl-β-diaminopropionic acid Dap (Gly): N ^β- glycyl-β-diaminopropionic acid Dap (GnGly): N ^β - (N-guanidino-glycyl) -β-diaminopropionic acid DCM: dichloromethane DEA: diethylamine DIEA: N, N-diisopropylethylamine DIPCDI: 1,3-diisopropylcarbodiimide DMAP: 4-dimethylaminopyridine DMF: N, N-dimethylformamide EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide EDT: 1,2-ethanedithiol Fmoc: 9-fluorenylmethoxycarbonyl For: formed γ-Abu: 4-aminobutanoic acid γ-MeLeu, Leu (Me): γ-methylleucine GlyΨ ((E) CH = CH) Leu: - CONH- between Gly and Leu is replaced by an alkene of type (E). GlyΨ (CH ₂ CH ₂ ) Leu: The —CONH— between Gly and Leu is substituted with the —CH ₂ CH ₂ - bond. GlyΨ (CH ₂ S) Leu: The —CONH— between Gly and Leu is substituted with the —CH ₂ S— bond. Gn: guanidino GuAmb: 4-guanidinomethylbenzoyl Har: homoarginine Har (Me): N ^ω -methyl homoarginine His (3Me): 3-methylhistidine π-methylhistidine HOAt: 1-hydroxy-7-azabenzotriazole Hobt: 1-hydroxybenzotriazole HOOBt: 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine HONB: N-hydroxy-5-nonbornen-2,3-dicarboximide Hph: homophenylalanine Hyp: trans-4-hydroxyproline Hyp (Bzl): O-benzyl-trans-4-hydroxyproline IndPr: 3- (indol-3-yl) propionyl Izc: imidazolidine-2-carboxylic acid Lys (Me ₂ ): N ^{ε, ε-} dimethyl lysine MBHA: p-methylbenzhydrylamine MeOH: methanol Mtt: 4-methyl trityl N ((CH ₂ ) ₃ Gn) Gly: N- (3-guanidinopropyl) glycine Nal (1): 1-naphthylalanine Nal (2): 2-naphthylalanine Nar: norarginine Nar (Me): N ^ω -methylnorginine Nle: norleucine NMeAla: N ^α- methylalanine 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- methyl tyrosine Nva: norvaline OBu ^t : tert-butoxy Orn: ornithine Orn (Mtt): N ^δ - (4-methyltrityl) ornithine PAL: 5- (4- (9-fluorenylmethoxycarbonyl) aminomethyl-3,5-dimethoxyphenoxy) valerianic 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 Phe (2Me): 2-methylphenylalanine Phe (3Me): 3-methylphenylalanine Phe (4Me): 4-methylphenylalanine PheΨ (CH ₂ CH ₂ ) AzaGly: The —CONH— between Phe and AzaGly is substituted with the —CH ₂ CH ₂ - bond. PheΨ ((E) CH = CH) Gly: The —CONH— bond between Phe and Gly is substituted with a type (E) alkene. PheΨ (CH ₂ CH ₂ ) Gly: -CONH- bond between Phe and Gly is substituted
-CH ₂ CH ₂ is a bond. PheΨ (CH ₂ S) Gly: -CONH- bond between Phe and Gly is substituted
-CH ₂ S- bond. PheΨ ((R) CH (OH) - (E) CH =) Gly: The —CONH— bond between Phe and Gly is replaced by the —CH (OH) —CH— bond, the —CH (OH) —fragment has an (R) configuration, and the group between the carbon atom in the —CH — fragment and the α carbon atom in Gly is alkene type (E). PheΨ ((S) CH (OH) - (E) CH =) Gly: The —CONH— bond between Phe and Gly is substituted with the —CH (OH) —CH— bond, the —CH (OH) —fragment has an (S) configuration, and the group between the carbon atom in the —CH — fragment and the α carbon atom in Gly is alkene type (E). PheΨ ((R) CH (OH) -CH ₂ ) Gly: The —CONH— bond between Phe and Gly is substituted with the —CH (OH) —CH ₂ - bond, and
-CH (OH) - the fragment has a (R) configuration. PheΨ ((S) CH (OH) -CH ₂ ) Gly: The —CONH— bond between Phe and Gly is substituted with the —CH (OH) —CH ₂ - bond, and
-CH (OH) - the fragment has a (S) configuration. PheΨ (CH ₂ O) Gly: The —CONH— bond between Phe and Gly is substituted with the —CH ₂ O— bond. PheΨ (COCH ₂ ) Gly: The —CONH— bond between Phe and Gly is substituted with the —COCH ₂ - bond. PheΨ (CSNH) -NH ₂ : The C-terminal phenylalanilamide is substituted with phenylalanylthioamide. Phg: phenyl glycine PhOH: phenol PhSMe: thioanisole Pic (2): pipecolic acid Pic (3): 3-piperidinecarboxylic acid Pip: pipecolic acid Pro: proline Pro (4F): trans-4-fluoroproline Pro (4NH ₂ ): cis-4-aminoproline 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 Pzc (2): piperazine-2-carboxylic acid Sar: N-methylglycine Ser (Ac): O-acetylserine Ser (Me): O-methylserine Thi: 2-thienylalanine Thz: thioproline Tic: 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid TIS: triisopropylsilane Tle: tert-leucine Tos: tosil Trp (For): N ⁱⁿ formyl tryptophan Trt: trityl Tyr (Me): O-methyl tyrosine Tyr (PO ₃ H ₂ ): O-phosphotyrosine TyrΨ (CH ₂ NH) Asn: The —CONH— between Tyr and Asn is substituted with the —CH ₂ NH— bond. Tfu: trifluoroacetic acid TFE: trifluoroethanol Z: benzyloxycarbonyl

In the description and figures, where the designations of bases and amino acids are indicated by abbreviations, they are based on abbreviations in accordance with the IUPAC-IUB Commission on Biochemical Nomenclature or designations accepted in this field, examples of which are given below. Amino acids, which may have an optical isomer, are presented in L form, unless otherwise indicated.

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: template 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

The sequence identification numbers in the sequence listing in the description represent the following sequence, respectively.

[SEQ ID NO: 1]

Represents the amino acid sequence of human metastin (metastin).

[SEQ ID NO: 2]

Represents the base sequence of a DNA encoding human metastin.

[SEQ ID NO: 3]

Represents the amino acid sequence of the mouse metastin precursor (A).

[SEQ ID NO: 4]

Represents the base sequence of the DNA encoding the mouse metastin precursor (A), which is the base sequence in plasmid pCMV-mKiSS-1, hiding in the Escherichia Coli transform DH10B / pCMV-mKiSS-1.

[SEQ ID NO: 5]

Represents the amino acid sequence of the mouse metastin precursor (B).

[SEQ ID NO: 6]

Represents the base sequence of the DNA encoding the mouse metastin precursor (B), which is the base sequence in the plasmid pCR2,1-mKiSS-1,4A, hiding in the Escherichia Coli transformant DH5α / pCR2,1-mKiSS-1,4A.

[SEQ ID NO: 7]

Represents the amino acid sequence of rat metastin precursor.

[SEQ ID NO: 8]

Represents the base sequence of DNA encoding a rat metastin precursor.

[SEQ ID NO: 9]

Represents the amino acid sequence of human OT7T175 (metastin receptor).

[SEQ ID NO: 10]

Represents the base sequence of the DNA encoding the human OT7T175 (metastin receptor).

[SEQ ID NO: 11]

Represents the amino acid sequence of rat OT7T175 (metastin receptor).

[SEQ ID NO: 12]

Represents the base sequence of DNA encoding rat OT7T175 (metastin receptor).

[SEQ ID NO: 13]

Represents the amino acid sequence of mouse OT7T175 (metastin receptor).

[SEQ ID NO: 14]

Represents the base sequence of a DNA encoding mouse OT7T175 (metastin receptor).

[SEQ ID NO: 15]

Represents the amino acid sequence of human metastin 15 (40-54).

[SEQ ID NO: 16]

Represents the amino acid sequence of human metastin 10 (45-54) (MS10).

[SEQ ID NO: 17]

Represents the amino acid sequence of human metastin 9 (46-54).

[SEQ ID NO: 18]

Represents the amino acid sequence of human metastin 8 (47-54).

[SEQ ID NO: 19]

Represents the base sequence of the DNA encoding human metastin 15 (40-54).

[SEQ ID NO: 20]

Represents the base sequence of the DNA encoding human metastin 10 (45-54).

[SEQ ID NO: 21]

Represents the base sequence of the DNA encoding human metastin 9 (46-54).

[SEQ ID NO: 22]

Represents the base sequence of the DNA encoding human metastin 8 (47-54)

The transformant Escherichia Coli DH10B / pCMV-mKiSS-1 has been deposited since January 24, 2000 at the International Patent Organisms Depository, National Institute of Advanced Industrial Science and Technology (the former Ministry of International Trade and Industry, Agency of Industrial Science and Technology, National Institute of Bioscience and Human Technology (NIBH)), located at Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki (postal code 305-8566), Japan, as the Accession Number FERM BP-7003 and from December 16, 1999 in Institute for Fermentation (IFO), located at 2-17-85, Juso-Honmachi, Yodogawa-ku, Osaka-shi, Osaka, Japan, as the Accession IFO Number 16348.

The transformant Escherichia Coli DH5α / pCR2.1-mKiSS-1.4A was deposited from March 6, 2000 at the International Patent Organisms Depository, National Institute of Advanced Industrial Science and Technology (the former Ministry of International Trade and Industry, Agency of Industrial Science and Technology , National Institute of Bioscience and Human Technology (NIBH)), located at Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki (postal code 305-8566), Japan, as the Accession Number FERM BP-7073 and since February 16 , 2000 with Institute for Fermentation (IFO), located at 2-17-85 Juso-Honmachi, Yodogawa-ku, Osaka-shi, Osaka, Japan, as the Accession IFO Number 16360.

REFERENCE EXAMPLE 1

Obtaining N-methyl-N, N'-bis-Boc-1-guanylpyrazole

In a nitrogen atmosphere, 720 mg of 60% NaH in oil was dissolved in 20 ml of dry DMF and 20 ml of a solution of dry DMF 5.59 g of commercially available N, N'-bis-Boc-1-guanylpyrazole was added to the solution at 0 ° C then mixed for 10 minutes. After adding 1.68 ml of methyl iodide, the mixture was stirred at room temperature for 24 hours. After removing the solvent by distillation, the residue was dissolved in AcOEt and the solution was washed with 1N. aqueous HCl, saturated aqueous NaHCO ₃ and then saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated and the concentrate was purified by flash column chromatography (ethyl acetate / n-hexane = 1/4) using silica gel 60 (200 ml) to obtain 5.35 g (yield 91.6 %) N-methyl-N, N'-bis-Boc-1-guanylpyrazole.

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.00 (br s, 1H), 7.69 (br s, 1H), 6.42 (dd, 1H, J = 2.7, 1, 5 Hz), 3.25 (s, 3H), 1.53 (s, 9H), 1.30 (s, 9H)

Elemental analysis for C ₁₅ H ₂₄ N ₄ O ₄

Calculated: 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)

HPLC elution time: 26.7 min.

Elution Conditions:

Column: Wakosil-II 5C18 HG (4.6 × 100 mm)

Eluent: Linear density gradient of elution with eluents A / B = 100 / 0-20 / 80 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (40 min)

Flow rate: 1.0 ml / min.

REFERENCE EXAMPLE 2

Obtaining N-methyl-N, N'-bis-Z-1-guanylpyrazole

In an argon atmosphere, 40 mg of 60% NaH in oil was dissolved in 5 ml of dry DMF and 5 ml of a dry DMF solution of commercially available 380 mg of N, N'-bis-Z-1-guanylpyrazole was added to the solution at 0 ° C, then stirred for 10 minutes. After adding 125 μl of methyl iodide, the mixture was stirred at room temperature for 15 hours. Then, the solvent was distilled off, the residue was dissolved in AcOEt, and the solution was washed with 1 N. aqueous HCl, saturated aqueous NaHCO ₃ and then saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated to give 393 mg of a crude product. The crude product, 170 mg, was purified by flash column chromatography (ethyl acetate / n-hexane = 1/4) using silica gel 60 (75 ml) to give 152 mg (89.5% yield) N-methyl-N, N'-bis-Z-1-guanylpyrazole.

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.97 (br s, 1H), 7.61 (d, 1H, J = 1.0 Hz), 7.37-7.32 (m, 4H ), 7.29-7.26 (m, 4H), 7.16-7.13 (m, 2H), 6.36 (dd, 1H, J = 2.8, 1.6 Hz), 5, 18 (s, 2H), 5.04 (s, 2H), 3.22 (s, 3H)

Elemental analysis for C ₂₁ H ₂₀ N ₄ O ₄

Calculated: 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)

HPLC elution time: 28.9 min.

Elution Conditions:

Column: Wakosil-II 5C18 HG (4.6 × 100 mm)

Eluent: Linear density gradient of elution with eluents A / B = 100 / 0-20 / 80 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (40 min)

Flow rate: 1.0 ml / min.

EXAMPLE 1

(Synthesis A): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Arg (Me) 9, Trp10] MS10 (Compound No. 796)

After 5 g (0.4 mmol / g) of the commercially available Rink amide MBHA polymer was allowed to swell in DMF, the polymer was treated with 50 ml of a 20% piperidine / DMF solution for 20 minutes to remove the Fmoc group. The resulting resin was washed with DMF and treated with 4.213 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.272 ml (8 mmol) of DIPCDI and 16 ml (8 mmol) of 0.5 M HOAt / DMF solution at room temperature for 90 minutes, whereby Trp (Boc) was introduced to give the Fmoc-Trp (Boc) -Rink amide MBHA polymer. Orn (Mtt) was introduced in a similar manner to obtain 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink amide MBHA polymer. Then, the obtained polymer was washed and allowed to swell in DCM, 50 ml of TFA / TIS / DCM (1/5/94) were added, then they were shaken for 10 minutes and the solution was removed by filtration. This procedure was repeated until the yellow tint acquired as a result of the presence of the free Mtt group in the TFA / TIS / DCM solution (1/5/94) disappears when the solution is added; thus the Mtt group was removed. The resulting polymer Fmoc-Orn-Trp (Boc) -Rink amide MBHA was neutralized with a solution of 5% -DIEA / DCM. 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 were added to the polymer. the resulting solution to a value of 10; DIEA was added to the mixture. The solution was shaken for 15 hours to obtain 6.195 g of a polymer Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. By the method described above, Fmoc-Leu was introduced into the obtained polymer. In the obtained polymer Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA, 859 mg (0.25 mmol) of the polymer was used as starting material, which acted on ABI 433A (Fmoc / DCC / HOBt 0.25 mmol protocol) for administering Gly, Phe, Thr (Bu ^t ), Asn (Trt), Hyp (Bu ^t ) and D-Tyr (Bu ^t ), in that order. Thus, the polymer HD-Tyr (Bu ^t ) -Hyp (Bu ^t ) -Asn (Trt) -Thr (Bu ^t ) -Phe-Gly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. The polymer was then treated for 20 minutes in DMF with 94.4 μl (1 mmol) of Ac ₂ O and 174.2 μl (1 mmol) of DIEA for N-terminal acetylation to obtain Ac-D-Tyr (Bu ^t ) -Hyp ( Bu ^t ) -Asn (Trt) -Thr (Bu ^t ) -Phe-Gly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. To the resulting polymer was added 6 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5), then stirred for 90 minutes. Diethyl ether was added to the reaction solution, the resulting precipitate was centrifuged, and then the supernatant was removed. This procedure was repeated twice. After washing, the residue was extracted with an aqueous solution of acetic acid and the polymer was removed by filtration. Then linear density gradient elution was performed (60 minutes) to A / B: 74 / 26-64 / 36 at a flow rate of 15 ml / min, using: eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized. The resulting white powder, 114.6 mg, was dissolved in 100 ml of water, and 390 μl of BioRAD AG1 × 8 AcO ^- ion exchange resin was added to the solution, followed by stirring for one hour. The resin was removed by filtration through silica wool, a similar amount of resins was added again, and the mixture was stirred for one hour. The solution was filtered through a membrane filter to remove the resin and lyophilized to obtain 93.4 mg of a white powder as an acetate.

Mass spectrum (M + H) ⁺ 1224.6 (calc. 1224.6)

HPLC elution time: 11.8 min.

Elution Conditions:

Column: YMC ODS-AM301 (4.6 × 100 mm)

Eluent: linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Amino acid analysis (20% hydrochloric acid containing 4% thioglycolic acid, 110 ° C, hydrolysis for 24 hours; the numbers in parentheses represent theoretical values): Asp 0.98 (1); Thr 0.95 (1); Gly 0.99 (1); Leu 0.99 (1); Tyr 0.98 (1); Phe 1.00 (1)

EXAMPLE 2

(Synthesis B): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ O) Gly7, Arg (Me) 9, Trp10] MS10 (Compound No. 834)

After dissolving 1.80 g of Z-Phe in 20 ml of MeOH, 73 mg of DMAP, 1.38 g of WSCD HCl were added at 0 ° C, then stirred at 4 ° C for 12 hours. The solvent was evaporated and the concentrate was dissolved in AcOEt, then washed with 1N. aqueous HCl, saturated aqueous HCO ₃ , and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated to give Z-Phe-OMe as an oil. After dissolving in 20 ml of dry THF, 196 mg of LiBH _{4 was} added and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated and the concentrate was dissolved in AcOEt, the residue was washed with 1N. aqueous HCl, saturated aqueous NaHCO ₃ , and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated and diethyl ether-petroleum ether mixture was added to obtain 1.45 g (85% yield) of Z-Phe-ol as a precipitate. After 60 mg of 60% NaH was 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 were added at 0 ° C. While warming to room temperature, the mixture was stirred for 15 hours.

After the solvent was removed by distillation under reduced pressure, the residue was dissolved in AcOEt and then washed with 1 N aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated and the concentrate was purified by flash column chromatography to give 217 mg (54% yield) of Z-PheΨ (CH ₂ O) Gly-OBu ^t as an oil. After 160 mg of Z-PheΨ (CH ₂ O) Gly-OBu ^{t was} dissolved in 20 ml of MeOH, 10% Pd-C was added, then it was subjected to catalytic hydrogenation for 3 hours in a stream of hydrogen. The catalyst was removed by filtration and the solvent was evaporated to dryness. The residue was dissolved in 15 ml of DCM and 114 mg of Fmoc-Cl and 139 μl of DIEA were added. The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was dissolved in AcOEt and the solution was washed with 1N. aqueous HCl, saturated aqueous NaHCO ₃ and saturated aqueous NaCl. After drying over Na ₂ SO ₄ , the solvent was evaporated and the concentrate was purified using flash column chromatography. A diethyl ether-petroleum ether mixture was added to give 150 mg (yield 77%) of Fmoc-PheΨ (CH ₂ O) Gly-OBu ^t as a precipitate. The polymer Fmoc-Leu-Arg (Me, Boc ₂ ) -Trp (Boc) -Rink amide MBHA, 86 mg (25 μmol) obtained in Example 1, 32 mg Fmoc-PheΨ (CH ₂ O) Gly-OH (obtained by treating with Fmoc-PheΨ (CH ₂ O) Gly-OBu ⁽ 50% TFA / DCM for one hour), 200 μl 0.5M HOAt / DMF, 52 mg PyBrop and 53 μl DIEA and the mixture was shaken for 24 hours. The resin was washed and 5 ml of 20% piperidine / DMF was added, then it was shaken at room temperature for 30 minutes. After the resin was washed, Thr (Bu ^t ), Asn (Trt), Hyp (Bu ^t ) and D-Tyr (Bu ^t ) were sequentially introduced in this order on ABI 433A equipment (Fmoc / DCC / HOBt 0.25 mmol protocol ) sequentially to obtain the polymer HD-Tyr (Bu ^t ) -Hyp (Bu ^t ) -Asn (Trt) -Thr (Bu ^t ) -PheΨ (CH ₂ O) Gly-Leu-Arg (Boc ₂ , Me) -Trp ( Boc) -Rink amide MBHA. The resin was then treated in DMF with 9.4 μl (0.1 mmol) of Ac ₂ O and 17.4 μl (0.1 mmol) of DIEA for 20 minutes to acetylate the N-terminus to give Ac-D-Tyr polymer (Bu ^t ) -Hyp (Bu ^t ) -Asn (Trt) -Thr (Bu ^t ) -PheΨ (CH ₂ O) Gly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. To the resulting polymer was added 1 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) and the mixture was stirred for 90 minutes. Diethyl ether was added to the reaction solution to obtain a precipitate. For washing, the centrifugation procedure with removal of the supernatant was repeated twice. The residue was extracted with an aqueous solution of acetic acid. After the resin was removed by filtration, linear density gradient elution was performed (60 minutes) to A / B: 75 / 25-65 / 35 at a flow rate of 15 ml / min using: eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized. The resulting white powder, 2.5 mg, was dissolved in 100 ml of water, and 10 μl of BioRAD AG1 × 8 AcO form ion exchange resin was added. The mixture was stirred for one hour. To remove the resin, the solution was filtered through a membrane filter and lyophilized to give 2.0 mg of a white powder as an acetate.

Mass spectrum (M + H) ⁺ 1211.3 (calculated 1211.6)

HPLC elution time: 19.4 min.

Elution Conditions:

Column: Wakosil-II 5C18 HG (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 100 / 0-0 / 50, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 3

(Synthesis C): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ CH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10 (Compound No. 850)

After 4.44 g of a commercially available polymer (0.45 mmol / g) of Rink amide MBHA was allowed to swell in DMF to remove the Fmoc group, the polymer was treated with 50 ml of 20% piperidine / DMF for 20 minutes. The resulting polymer was washed with DMF and treated in DMF with 4.21 g (8 mmol) of Fmoc-Trp (Boc) -OH, 1.27 ml (8 mmol) of DIPCDI and 1.31 g (8 mmol) of HOOBt at room temperature for 90 minutes, whereupon Trp (Boc) was introduced to obtain the Fmoc-Trp (Boc) -Rink amide MBHA polymer. Orn (Mtt) was introduced in a similar manner to obtain 2 mmol of Fmoc-Orn (Mtt) -Trp (Boc) -Rink amide MBHA polymer. After the obtained polymer was washed and expanded in toluene, 30 ml of TFA / TIS / TFE / toluene (1/5/47/47) was added, then it was shaken for 30 minutes and the solution was removed by filtration. This procedure was repeated until the yellow tint acquired as a result of the presence of the free Mtt group in the TFA / TIS / TFE / toluene solution (1/5/47/47) disappears when the solution is added; whereby the Mtt group was removed. The resulting polymer Fmoc-Orn-Trp (Boc) -Rink amide MBHA was neutralized with a solution of 5% -DIEA / toluene. After washing with toluene, 15 ml of toluene-TFE (4: 1) and 1.95 g (6 mmol) of N-methyl-N, N'-bis-Boc-1-guanylpyrazole obtained in Reference Example 1 were added to the polymer. adjusting the pH of the solution to 10; DIEA was added to the mixture. The solution was shaken for 15 hours to obtain the polymer Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA (2 mmol). After drying the obtained polymer in MeOH, 0.03 mmol was measured and expanded again in DMF. Leu was introduced in the same manner as described above to obtain 0.03 mmol of the polymer Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. After deprotection with Fmoc in a 20% piperidine / DMF solution, the polymer was treated in DMF with 51.5 mg (0.12 mmol) of Fmoc-Phe-Ψ (CH ₂ CH ₂ ) -Gly-OH obtained in Reference Example 3 , 19.1 μl (0.12 mmol) of DIPCDI and 240 μl of a 0.5 M HOAt / DMF solution at room temperature for 150 minutes. The polymer was washed with DMF and then treated with 10.9 μl (0.12 mmol) of Ac ₂ O and 20.9 μl (0.12 mmol) of DIEA to cap the remaining amino groups. Then the polymer was shaken overnight in 2 ml of a DMF solution of Ac-D-Tyr-Hyp-Asn-Thr-OH (0.06 mmol), synthesized in the usual way of the liquid phase process, 31.2 mg (0.06 mmol) PyAOP, 120 μl (0.06 mmol) of a 0.5 M HOAt / DMF solution and 10.5 μl (0.06 mmol) of DIEA to give Ac-D-Tyr-Hyp-Asn-Thr-Phe-полим (CH ₂ CH) polymer ₂ ) -Gly-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. After drying, 1.5 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5/5 / 2.5 / 2.5) was added to the polymer and stirred for 90 minutes.

Diethyl ether was added to each reaction solution to obtain a precipitate and then centrifuged, the supernatant was removed; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the polymer. Then, linear density gradient elution was performed (60 minutes) to A / B: 71.5 / 28.5-61.5 / 38.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to give 5.5 mg of a white powder.

Mass spectrum (M + H) ⁺ 1209.7 (calc. 1209.6)

HPLC elution time: 12.2 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

REFERENCE EXAMPLE 3

Synthesis of Fmoc-Phe-Ψ (CH ₂ CH ₂ ) -Gly-OH

After dissolved in 10 ml of AcOEt, 97.4 mg (0.269 mmol) of Boc-Phe-Ψ [(E) CH = CH] -Gly-OBu ^t , which is a compound described in the literature, was added 10 mg of 10% Pd / C and the mixture was stirred in a stream of hydrogen gas at room temperature for 4 hours. The Pd catalyst was removed by filtration through celite, and the filtrate was evaporated under reduced pressure. Then the residue was dissolved in 4 ml of TFA and the solution was stirred at room temperature for 2 hours. TFA was distilled off under reduced pressure, and the residue was dissolved in 2.25 ml of a mixture of acetonitrile: H ₂ O (2: 1). Under ice-cooling, 236 μl (1.69 mmol) of TEA and 95.1 mg (0.282 mmol) of Fmoc-OSu in acetonitrile (3 ml) were successively added dropwise, and the mixture was stirred at the same temperature for 2 hours. After adding 20 ml of 0.1 N. HCl aqueous solution, all extracted with AcOEt. The organic layer was washed twice with 0.1 n. aqueous HCl and then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, the product was purified by flash column chromatography (ethyl acetate / n-hexane = 3/2) using Wakosil C-300 to give 118 mg (quantitative) Fmoc-Phe-Ψ (CH ₂ CH ₂ ) - Gly-OH.

EXAMPLE 4

(Synthesis D): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (COCH ₂ ) Gly7, Arg (Me) 9, Trp10] MS10 (Compound No. 851)

Using Boc-Phe-Ψ (COCH ₂ ) -Gly-OBu ^t , which is a known compound from the literature, Fmoc-Phe-Ψ (COCH ₂ ) -Gly-OH, synthesized in accordance with the method described in reference Example 3 as a crude substance, was treated in a similar manner to that described in Reference Example 3 to obtain Ac-D-Tyr-Hyp-Asn-Thr-Phe-полим (COCH ₂ ) -Gly-Leu-Arg (Boc ₂ , Me) polymer -Trp (Boc) -Rink amide MBHA. After drying the polymer, 1.5 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS (80/5/5/5/5) was added and the mixture was stirred for 90 minutes. Diethyl ether was added to each reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed; for washing, this procedure was repeated twice. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the resin. Then, linear density gradient elution was performed (60 minutes) to A / B: 72.5 / 27.5-62.5 / 37.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to obtain 4.0 mg of a white powder.

Mass spectrum (M + H) ⁺ 1224.2 (calc. 1223.6)

HPLC elution time: 11.8 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 5

(Synthesis E): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ NH) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 854)

Fmoc-Gly-OH, 1 g (3.36 mmol), 361.0 mg (3.70 mmol) of CH ₃ ONHCH ₃ and 447.3 mg (3.53 mmol) of HOBt were dissolved in DMF. Under ice-cooling, 677 mg (3.53 mmol) of WSCI.HCl and 1.94 ml (11.1 mmol) of DIEA were added to the solution, then stirred overnight. After evaporation of the reaction solution, 10% aqueous citric acid solution was added and the precipitated solid was extracted with AcOEt. The organic layer was washed with a 10% aqueous citric acid solution, a 5% aqueous NaHCO ₃ solution and a saturated aqueous sodium chloride solution, and dried over anhydrous Na ₂ SO ₄ . The oily Fmoc-Gly-N (CH ₃ ) OCH ₃ product obtained by concentration of the solvent was dissolved in THF. Under ice cooling, 332 mg (0.726 mmol) of LiAlH ₄ were added in small portions over a period of 15 minutes. After stirring at 0 ° C for 30 minutes, 150 ml of diethyl ether and 150 ml of a 20% aqueous citric acid solution were successively added to the reaction solution, which were then vigorously stirred for an hour. The organic layers were collected and the aqueous layer was again extracted with 150 ml of diethyl ether. The combined organic layer was washed successively with 5% aqueous NaHCO ₃ solution, water, 10% aqueous citric acid solution, water, then saturated aqueous sodium chloride and dried over anhydrous Na ₂ SO ₄ . The resulting organic layer was evaporated to give Fmoc-Gly-al as an oily substance.

After removal of the N-terminal Fmoc group in (0.291 mmol / g) 171.8 mg (0.05 mmol) of the polymer Fmoc-Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA, 56.2 was added mg (0.2 mmol) of Fmoc-Gly-al dissolved in DMF and 50 μl of AcOH and the mixture was stirred for 10 minutes. Then, 12.3 mg (0.2 mmol) of NaBH ₃ CN was added and the mixture was stirred overnight. The reaction process was monitored using a Kaiser test and was determined to be insufficient. Binding was performed again. After completion of the reaction, the capping of unreacted amino groups and the protection of the reducing amino fragments were performed by treatment with 107.7 mg (0.5 mmol) of Boc-OSu and 87.1 μl (0.5 mmol) of DIEA. Phe, Thr (Bu ^t ), Asn (Trt), Hyp (Bu ^t ) and D-Tyr (Bu ^t ) were introduced into the obtained polymer using an ABI peptide synthesizer. Then, the N-terminal amino group was treated with 9.5 μl (0.1 mmol) of Ac ₂ O and 17.4 μl (0.1 mmol) of DIEA in DMF for 20 minutes for acetylation. The polymer was then washed and dried to obtain 162.3 mg of Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ NH) Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA polymer . After drying the polymer, 1 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 each reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the polymer. Then, linear density gradient elution was performed (60 minutes) to A / B: 77 / 23-67 / 33 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1 % TFA-containing acetonitrile in preparative HPLC using a Daisopak-SP100-5-ODS-P column 2 × 25 cm, 120A (20 × 250 mm). The product containing fractions was collected and lyophilized to give 0.6 mg of a white powder.

Mass spectrum (M + H) ⁺ 1210.6 (calc. 1210.6)

HPLC elution time: 10.9 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 6

(Synthesis F): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ [(S) CHOH-CH ₂ ] Gly7, Arg (Me) 9, Trp10] MS10 (compound No. 857)

10% Pd / C (3 mg) was added to a MeOH solution (3 ml) of compound 858 (1.02 mg) synthesized by the method described in example 3. After stirring in a stream of hydrogen gas for 6 hours, the mixture was precipitated overnight in an atmosphere of hydrogen. After removing Pd / C by filtration, linear density gradient elution was performed (60 minutes) to A / B: 72 / 28-62 / 38 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to obtain 0.3 mg of a white powder.

Mass spectrum (M + H) ⁺ 1226.2 (calc. 1225.6)

HPLC elution time: 11.9 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 7

(Synthesis G): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 892)

HCl.H-Ser-OMe, 3.5 g (22.6 mmol), were suspended in (40 ml) chloroform. Under ice cooling, DIEA (8.7 ml, 49.7 mmol) and Pbf-Cl (5.86 g, 20.3 mmol) were successively added and stirred overnight while gradually raising the temperature to room temperature. After the reaction was stopped by the addition of an aqueous solution of saturated citric acid, chloroform was distilled off under reduced pressure and everything was extracted with AcOEt. The organic layer was washed successively with saturated aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, and then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1: 1 to give Pbf-Ser-OMe (6.94 g, 82.7%).

Under argon under ice cooling, 923 μl (2.03 mmol) of a toluene solution of 2.2 M diethyl azodicarboxylate was added to a solution of 500 mg (1.35 mmol) of Pbf-Ser-OMe, 522 mg (2.03 mmol) of PPh ₃ in THF (20 ml). The mixture was stirred overnight at room temperature and then THF was distilled off under reduced pressure. Flash chromatography was performed using AcOEt: n-hexane = 1: 1 to obtain 481 mg of aziridine methyl ester (quantitative).

In an argon atmosphere, 429 μl (0.644 mmol) of a solution of 1.5 M DIBAL-H was added dropwise to a toluene (10 ml) solution of aziridine methyl ester (198 mg, 0.56 mmol) at a temperature of -78 ° C. After stirring for 20 minutes at the same temperature, the reaction was stopped 0.1 n. aqueous solution of HCl. All was extracted with diethyl ether, and the organic layer was washed successively with 0.1 N. aqueous HCl and saturated aqueous sodium chloride. After drying over anhydrous MgSO ₄ , the reaction mixture was evaporated under reduced pressure to give the aldehyde as an oily substance. At the same time, 146 μl (0.84 mmol) of DIEA and 197 μl (0.84 mmol) of (EtO) ₂ P (O) CH ₂ CO ₂ Bu ^{t were} successively added under ice-cooling to a suspension of 35.6 mg (0, 84 mmol) of anhydrous LiCl in acetonitrile (2 ml). The mixture was stirred at the same temperature for 20 minutes, and then the acetonitrile (4 ml) aldehyde solution obtained above was added dropwise, then it was stirred at 0 ° C for 3 hours. After AcOEt was extracted, the organic layer was washed successively with a saturated aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous MgSO ₄ . The mixture was evaporated under reduced pressure and the concentrate was recrystallized from diethyl ether / n-hexane to give 86.5 mg of the desired aziridine enoate. The mother liquor was evaporated under reduced pressure and flash chromatographed using AcOEt: n-hexane = 1:19 to give another 82.4 mg of the desired aziridine enoate (total yield: 71.5%).

In an argon atmosphere, to an anhydrous THF (6 ml) solution of 284 mg (3.17 mmol) of CuCN and 269 mg (6.34 mmol) of anhydrous LiCl was added dropwise 1.59 ml (3.17 mmol) of 2.0 M THF i-BuMgCl solution at -78 ° C. The temperature was raised to 0 ° C and the mixture was stirred for 10 minutes. The mixture was again cooled to −78 ° C. and 402 μl (3.17 mmol) of BF ₃ .Et ₂ O and anhydrous THF (6 ml) of a 334 mg (0.792 mmol) aziridine enoate solution were added dropwise successively. The mixture was stirred at the same temperature for 20 minutes. After quenching with a saturated aqueous solution of ammonium chloride: a 28% aqueous solution of ammonia (1: 1), the mixture was stirred at room temperature until the reaction solution turned blue. It was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, the residue was dissolved in a 95% aqueous solution of TFA (10 ml) and stirred at room temperature for 3 hours. TFA was removed by distillation under reduced pressure and azeotropically distilled off twice with diethyl ether. The residue was recrystallized from diethyl ether / n-hexane to give 254 mg of Pbf-GlyΨ [(E) -CH = CH] Leu-OH as a white powder (75.7%).

After 180 mg (0.425 mmol) of Pbf-GlyΨ [(E) -CH = CH] Leu-OH and 352 μl (3 mmol) of thioanisole were dissolved in TFA (2.65 ml), the solution was stirred at room temperature for 24 hours. TFA was distilled off under reduced pressure, and the obtained residue was dissolved in a mixture of acetonitrile: H ₂ O (2: 1, 9 ml). While cooling with ice, triethylamine was added until the solution became basic, and 168 mg (0.446 mmol) of Fmoc-OSu were further added thereto. As the temperature rose to room temperature, the mixture was stirred for 4 hours and all was extracted with AcOEt. The organic layer was washed successively with 0.1 N. aqueous HCl and saturated aqueous sodium chloride and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 3.5: 6.5 to give 145 mg of Fmoc-GlyΨ [(E) -CH = CH] Leu-OH (89%).

After 287 mg (0.1 mmol) of the Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA polymer (0.349 mmol / g) was expanded in DMF, the mixture was treated with a 20% piperidine / DMF solution to cleave Fmoc group. The polymer was then treated in DMF with 133 mg (0.338 mmol) Fmoc-GlyΨ [(E) -CH = CH] Leu-OH, 58.9 μl (0.338 mmol) DIEA, 676 μl (0.338 mmol) of a 0.5 M HOAt / DMF and 176 mg (0.338 mmol) PyAOP at room temperature for 12 hours. After the polymer was washed with DMF, the N-terminal peptide was extended by Fmoc solid-phase synthesis to obtain Ac-D-Tyr (Bu ^t ) -Hyp (OBu ^t ) -Asn (Trt) -Thr (Bu ^t ) -Phe-GlyΨ [ (E) CH = CH] Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. After drying the polymer, 4 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 180 minutes. Diethyl ether was added to each reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the polymer. Then, linear density gradient elution was performed (60 minutes) to A / B: 71.5 / 28.5-61.5 / 38.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to give 19.6 mg of a white powder.

Mass spectrum (M + H) ⁺ 1207.5 (calc. 1207.6)

HPLC elution time: 14.6 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 8

(Synthesis of H): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 893)

After 9.9 mg of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 892) was dissolved in 4 ml of MeOH, 20 mg of 10% Pd / C was added to the solution and suspended in it. In a hydrogen atmosphere, the mixture was stirred for 9 hours and then the Pd catalyst was removed by filtration. MeOH was distilled off under reduced pressure. After dissolving the residue in 1.5 ml of a 50% aqueous solution of AcOH, linear density gradient elution was performed (60 minutes) to A / B: 72 / 28-62 / 38 at a flow rate of 15 ml / min using eluent A: 0.1 % TFA-water and Eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to obtain 4.1 mg of a white powder.

Mass spectrum (M + H) ⁺ 1209.1 (calc. 1209.6)

HPLC elution time: 19.0 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 195 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 9

Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Ala (cPr) 8, Arg (Me) 9, Trp10] MS10 (compound No. 894)

Measured 2.744 g (0.952 mmol) of the polymer Fmoc-Arg (Me, Boc ₂ ) -Trp (Boc) -Rink amide MBHA and loaded into the reaction vessel, washed with DMF and then stirred in DMF for 20 minutes to swell the polymer. After deprotection in the N-terminal Fmoc group by treatment with 20% piperidine / DMF, the polymer was treated with 669.1 mg (1.904 mmol) of Fmoc-Ala (cPr) -OH, 7.616 ml (3.808 mmol) of a 0.5M HOAt / DMF solution and 0.454 ml (2.856 mmol) of DIPCDI for 150 minutes. After washing the polymer with DMF, the reaction process was monitored using a ninhydride test and found to be insufficient. Accordingly, the polymer was again treated in DMF with 233.0 mg (0.663 mmol) of Fmoc-Ala (cPr) -OH, 1.989 ml (0.995 mmol) of 0.5 M HOAt / DMF solution, 518.6 mg (0.995 mmol) of PyAOP and 0.578 ml (3.315 mmol) DIEA for 60 hours to complete the reaction. Gly, Cha, Thr (Bu ^t ), Asn (Trt), Hyp (Bu ^t ) and D-Tyr (Bu ^t ) were introduced in this order into the obtained polymer by Fmoc solid-phase synthesis using 4 mmol of each of the Fmoc amino acid / DIPCDI / HOOBt. From the N-terminal Fmoc group of the obtained polymer Fmoc-D-Tyr (Bu ^t ) -Hyp (Bu ^t ) -Asn-Thr (Bu ^t ) -Cha-Gly-Ala (cPr) -Arg (Me, Boc ₂ ) -Trp The (Boc) -Rink amide MBHA was removed from the protecting group by treatment with 20% piperidine / DMF to remove the N-terminal Fmoc group of the obtained polymer. The polymer was then suspended in about 10 ml of DMF and 377 μl (4 mmol) of Ac ₂ O and 697 μl (4 mmol) of DIEA were added to the suspension. The mixture was stirred for 20 minutes. The polymer was washed with DMF. After confirming the progress of the reaction, the polymer was washed in MeOH and dried.

To 3,5004 g of the obtained polymer, 35 ml of TFA: thioanisole: m-cresol: H ₂ O: EDT: TIS (80: 5: 5: 5: 2.5: 2.5) was added and the mixture was stirred for 90 minutes at room temperature. While removing the polymer by passing through a glass filter, a reaction solution was added dropwise to the cooled ether with stirring to give the crude peptide as a white powder. The polymer was thoroughly washed with a solution to remove the protective group and then returned to the reaction solution. The polymer was again treated with the same volume of solution to remove the protecting group at room temperature for 20 hours, and ether was similarly added dropwise to give the product as a white powder.

A mixture of white powder and ether was separated by centrifugation, respectively. The ether was removed by decantation and this procedure was repeated twice to remove acid and scavenger. The residue was dried and extracted with an aqueous solution of acetic acid. The extract was filtered through a 0.45 μm disk filter to remove fine particles, then concentrated on an evaporator. The residue was diluted in an aqueous solution of acetonitrile and lyophilized to give a total of 1.118 g of a whitish brown powder.

The resulting crude peptide was individually purified six times by preparative HPLC using a SHISEIDO CAPCELL PAK MGII column (50 × 250 mm). A linear density gradient elution was performed (60 minutes) to A / B: 72 / 28-62 / 38 at a flow rate of 45 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA- containing acetonitrile in preparative HPLC. The eluted product was fractionated into tubes of about 14 ml each. By examining each fraction using HPLC, only fractions containing the product were identified. Fractions were combined and lyophilized to give 389.3 mg of a white powder.

389.3 mg (316.9 μmol) of the obtained purified sample was dissolved in an AcCN-water mixture, and 1.320 ml (1.585 mmol equivalent) AG 1 × 8 AcO polymer was added to the solution. With periodic manual stirring, the solution was besieged for one hour and filtered through a PTFE membrane filter having a hole diameter of 3 μm. The filtrate was transferred to a flask for isolation and the solvent was distilled off. Then, 3 ml of acetic acid was added to the residue. After the mixture was dispersed with ultrasound for 5 minutes using an ultrasonic treatment apparatus, 12 ml of water was added to the solution. While cooling in a dry ice bath, the resulting 20% acetic acid solution was lyophilized to obtain 368.6 mg of a white powder.

Mass spectrum (M + H) ⁺ 1228.9 (calc. 1228.6)

HPLC elution time: 12.9 min.

Elution Conditions:

Column: YMC ODS-AM301 (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 80 / 20-30 / 70, using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Amino acid analysis (20% hydrochloric acid containing 4% thioglycolic acid, 110 ° C, hydrolysis for 24 hours; the numbers in parentheses show theoretical values): Asp 0.92 (1); Thr 0.89 (1); Gly 0.92 (1); Tyr 0.99 (1); Cha 1.00 (1)

EXAMPLE 10

Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 903)

After 4.32 g (1.5 mmol) of the polymer Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA (0.347 mmol / g) were equally divided into three and expanded in DMF, the mixture treated with a 20% piperidine / DMF solution to cleave the Fmoc group. Each polymer was then treated in DMF with 590 mg (1.5 mmol) Fmoc-GlyΨ [(E) -CH = CH] Leu-OH, 261 μl (1.5 mmol) DIEA, 3.0 ml (1.5 mmol) 0.5 M HOAt / DMF solution and 782 mg (1.5 mmol) PyAOP at room temperature for 12 hours. After the resin was washed with DMF and combined, Cha, Thr (Bu ^t ), Alb, Hyp (Bu ^t ) and D-Tyr (Bu ^t ) were introduced into the resulting polymer by Fmoc solid phase synthesis using Fmoc amino acid / DIPCDI / HOAt to obtain the polymer Fmoc-D-Tyr (Bu ^t ) -Hyp (OBu ^t ) -Asn (Trt) -Thr (Bu ^t ) -Cha-GlyΨ [(E) CH = CH] Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. The polymer thus obtained was stripped of the protective group by treatment with 20% piperidine / DMF and washed. The polymer was then suspended in DMF and 548 μl (6.0 mmol) of Ac ₂ O and 1.04 ml (6.0 mmol) of DIEA were added, respectively, then stirred for 20 minutes. The polymer was washed with DMF. After confirming the progress of the reaction, the polymer was washed in MeOH and dried to obtain Ac-D-Tyr (Bu ^t ) -Hyp (Bu ^t ) -Alb-Thr (Bu ^t ) -Cha-GlyΨ [(E) CH = CH] Leu polymer -Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. The resulting polymer was divided into 1 g, 2 g and 2.2 g, to which was added 25 ml, 50 ml and 50 ml of TFA: thioanisole: m-cresol: H ₂ O: EDT: TIS (80: 5: 5: 5: 2.5: 2.5), respectively. After stirring for 180 minutes at room temperature, the reaction solution was added dropwise to the cooled ether while removing the polymer by passing the polymer through a glass filter, thereby obtaining the crude peptide as a white powder. The resulting crude peptide was purified separately 10 times by preparative HPLC using a SHISEIDO CAPCELL PAK MGII column (50 × 250 mm). Linear density gradient elution (60 minutes) to A / B: 68 / 32-58 / 42 was performed at a flow rate of 45 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA- containing acetonitrile in preparative HPLC. The eluted product was fractionated into tubes of about 14 ml each. By examining each fraction by HPLC, only fractions containing the product were identified. Fractions were combined and lyophilized to give 352.2 mg of a white powder.

352.2 mg (286.7 μmol) of the obtained purified sample was dissolved in an AcCN-water mixture, and 1.195 ml (1.433 mmol equivalent) AG 1 × 8 AcO polymer was added to the solution. With periodic manual stirring, the solution was besieged for one hour and filtered through a PTFE membrane filter having a hole diameter of 3 μm. The filtrate was transferred to a flask for isolation and the solvent was distilled off. Then, 3 ml of acetic acid was added to the residue. After the mixture was dispersed with ultrasound for 5 minutes using an ultrasonic treatment apparatus, 12 ml of water was added to the solution. While cooling in a dry ice bath, the resulting 20% acetic acid solution was lyophilized to give 321.8 mg of a white powder.

Mass spectrum (M + H) ⁺ 1228.4 (calc. 1228.7)

HPLC elution time: 20.2 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Amino acid analysis (20% hydrochloric acid containing 4% thioglycolic acid, 110 ° C, hydrolysis for 24 hours; the numbers in parentheses show theoretical values): Thr 0.95 (1); Tyr 0.95 (1); Cha 1.00 (1)

EXAMPLE 11

Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10 (compound No. 926)

Using 3.33 g (1.5 mmol) of the Fmoc-Rink amide MBHA polymer (0.45 mmol / g) as the starting material, Fmoc solid-phase synthesis was performed to obtain the Fmoc-Arg (Pbf) -Trp (Boc) -Rink polymer amide MBHA. After the polymer Fmoc-Arg (Pbf) -Trp (Boc) -Rink amide MBHA in DMF was expanded, the mixture was treated with a 20% piperidine / DMF solution to cleave the Fmoc group. The polymer was then treated in DMF with 1.57 g (4.0 mmol) of Fmoc-GlyΨ [(E) -CH = CH] Leu-OH, 1.39 ml (8.0 mmol) of DIEA, 8.0 ml (4, 0 mmol) of a 0.5 M HOAt / DMF solution and 2.09 g (4.0 mmol) of PyAOP at room temperature for 24 hours. After washing the DMF polymer, the N-terminal peptide was extended by Fmoc solid phase synthesis to obtain the Fmoc-Cha-GlyΨ [(E) CH = CH] Leu-Arg (Pbf) -Trp (Boc) -Rink amide MBHA polymer. After deprotection of the N-terminal Fmoc group by treatment with 20% piperidine / DMF, the polymer was treated in DMF Ac-D-Tyr-Hyp-Asn-Thr-OH 2.48 g (4.5 mmol), 734 mg (4.5 mmol) HOOBt and 716 ml (4.5 mmol) of DIPCDI for 60 hours. The resulting polymer Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ [(E) CH = CH] Leu-Arg (Pbf) -Trp (Boc) -Rink amide MBHA was washed in MeOH and dried. To the resulting polymer, 60 ml of TFA: thioanisole: m-cresol: H ₂ O: EDT: TIS (80: 5: 5: 5: 5: 2.5: 2.5) was added. After stirring for 90 minutes at room temperature, the reaction solution was added dropwise to the cooled ether to remove the polymer by passing through a glass filter, thereby obtaining the crude peptide as a white powder.

The resulting crude peptide was separately purified five times by preparative HPLC using a SHISEIDO CAPCELL PAK MGII column (50 × 250 mm). A linear density gradient elution was performed (60 minutes) to A / B: 69 / 31-59 / 41 or 68 / 32-58 / 42 at a flow rate of 45 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC. The eluted product was fractionated into tubes of about 14 ml each. By examining each fraction using HPLC, only fractions containing the product were identified. Fractions were combined and lyophilized to give a white powder.

All dissolved in a mixture of acetonitrile-water and thereto was added 0.824 ml (1.005 mmol equivalent) AG 1 × 8 AcO ^- polymer. With periodic manual stirring, the solution was besieged for one hour and filtered through a PTFE membrane filter having a hole diameter of 3 μm. The filtrate was transferred to a flask for isolation and the solvent was distilled off. Then, 2 ml of acetic acid was added to the residue. After the mixture was dispersed with ultrasound for 5 minutes using an ultrasonic treatment apparatus, 8 ml of water was added to the solution. While cooling in a dry ice bath, the resulting 20% acetic acid solution was lyophilized to give 304.7 mg of a white powder.

Mass spectrum (M + H) ⁺ 1199.6 (calc. 1199.7)

HPLC elution time: 20.2 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Amino acid analysis (20% hydrochloric acid containing 4% thioglycolic acid, 110 ° C, hydrolysis for 24 hours; numbers in brackets show theoretical values): Asp: 0.93 (1); Thr 0.89 (1); Tyr 0.96 (1); Cha 1.00 (1); Arg 0.98 (1)

EXAMPLE 12

Obtaining des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10 (compound No. 927)

After 3.66 g (0.55 mmol) of the Fmoc-Rink amide MBHA polymer was expanded into DMF, the peptide chain was extended by Fmoc solid phase synthesis. With the N-terminal Fmoc group of the polymer thus obtained, Fmoc-D-Tyr (Bu ^t ) -Hyp (Bu ^t ) -Alb-Thr (Bu ^t ) -Cha-GlyΨ [(E) -CH = CH] Leu-Arg ( Pbf) -Trp (Boc) -Rink amide MBHA was removed from the protective group by treatment with 20% piperidine / DMF, and washed. The polymer was then suspended in about 10 ml of DMF and 208 μl (2.2 mmol) of Ac ₂ O and 383 μl (2.2 mmol) of DIEA were added, respectively, then mixed for 20 minutes. The polymer was washed with DMF. After confirming the progress of the reaction, the polymer was washed in MeOH and dried.

To 5.9695 g of the obtained polymer, 50 ml of TFA: thioanisole: m-cresol: H ₂ O: EDT: TIS (80: 5: 5: 5: 2.5: 2.5) was added and the mixture was stirred for 90 minutes at room temperature. While removing the polymer by passing through a glass filter, a reaction solution was added dropwise to the cooled ether with stirring to give the crude peptide as a white powder. The polymer was thoroughly washed with a solution to remove the protective group and then returned to the reaction solution. The polymer was again treated with the same volume of solution to remove the protecting group at room temperature for 20 hours, and ether was similarly added dropwise to give the product as a white powder.

A mixture of white powder and ether was separated by centrifugation, respectively. The ether was removed by decantation and this procedure was repeated twice to remove acid and scavenger. The residue was dried and extracted with an aqueous solution of acetic acid. The extract was passed through a 0.45 μm disk filter to remove fine particles, then concentrated on an evaporator. The residue was diluted in an aqueous solution of acetonitrile and lyophilized to give 1.646 g of a whitish-brown powder.

The resulting crude peptide was separately purified six times by preparative HPLC using a SHISEIDO CAPCELL PAK MGII column (50 × 250 mm). A linear density gradient elution was performed (60 minutes) to A / B: 68 / 32-58 / 42 at a flow rate of 45 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA- containing acetonitrile in preparative HPLC. The eluted product was fractionated into tubes of about 14 ml each. By examining each fraction using HPLC, only fractions containing the product were identified. Fractions were combined and lyophilized to give 436.9 mg of a white powder.

In a mixture of AcCN-water was dissolved 416.9 mg (343.3 umol) of the purified sample and to the solution was added 1.430 ml (1.717 mmol equivalent) AG 1 × 8 AcO ^- polymer. With periodic manual stirring, the solution was besieged for one hour and filtered through a PTFE membrane filter having a hole diameter of 3 μm. The filtrate was transferred to a flask for isolation and the solvent was distilled off. Then, 4 ml of acetic acid was added to the residue. After the mixture was dispersed with ultrasound for 5 minutes using an ultrasonic treatment apparatus, 16 ml of water was added to the solution. While cooling in a dry ice bath, the resulting 20% acetic acid solution was lyophilized to obtain 368.4 mg of a white powder.

Mass spectrum (M + H) ⁺ 1214.6 (calc. 1214.7)

HPLC elution time: 20.1 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Amino acid analysis (20% hydrochloric acid containing 4% thioglycolic acid, 110 ° C, hydrolysis for 24 hours; the numbers in parentheses show theoretical values): Thr 0.95 (1); Tyr 0.97 (1); Cha 1.00 (1); Arg 0.99 (1)

EXAMPLE 13

(Synthesis I): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Gly7Ψ (CH ₂ S) Leu8, Arg (Me) 9, Trp10] MS10 (compound No. 929)

To a solution in DCM (5 ml) of 289 mg (1.30 mmol) of benzyl L-leucinate, 2.1 ml (26 mmol) of pyridine and 1 ml (13 mmol) of methanesulfonyl chloride were successively added at 0 ° C. After stirring the mixture at the same temperature for 3 hours, a saturated aqueous solution of citric acid was added to terminate the reaction. After everyone was extracted with AcOEt, the organic layer was washed successively with a saturated aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was used using AcOEt: n-hexane = 1: 3 to obtain 636 mg of mesyl compound. The mesyloxy compound was dissolved in DMF (10 ml) and 535 mg (5.2 mmol) of NaBr was added. The mixture was heated for one hour at a temperature of 130 ° C in an oil bath. After cooling, everything was extracted with AcOEt, the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1:15 to give 266 mg of a bromine compound (71.7%). To a solution in DMF (2 ml) was added 61 mg (0.214 mmol) of bromine compound, 177 mg (1.28 mmol) of K ₂ CO ₃ and 108 μl (0.642 mmol) of BocNHCH ₂ CH ₂ SH and the mixture was stirred overnight at room temperature temperature. All were extracted with AcOEt. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1: 7 to obtain 75.1 mg of Boc-GlyΨ (CH ₂ S) Leu-OBzl as an oily substance (91.9%). 75.1 mg (0.197 mmol) of Boc-GlyΨ (CH ₂ S) Leu-OBn was dissolved in MeOH. They tried to remove the benzyl ester by treatment with HCONH ₄ solution in the presence of Pd / C. Since the reaction was carried out slightly, Pd / C was removed by filtration and the filtrate was extracted with AcOEt. The resulting residue was treated in MeOH (1 ml) 394 μl (0.394 mmol) of a 1 M aqueous NaOH solution at room temperature for 2 days. All was extracted with AcOEt, the organic layer was washed and dried over anhydrous MgSO ₄ . The residue obtained after concentration under reduced pressure was dissolved in 3 ml of TFA and the solution was stirred at room temperature for 2 hours. TFA was removed by distillation under reduced pressure and azeotropically distilled off twice with toluene. The resulting residue was dissolved in a mixture of acetonitrile: H ₂ O (2: 1, 3 ml). Under ice-cooling, Et ₃ N was added to the solution until the solution became basic, and 66.5 mg (0.446 mmol) of Fmoc-OSu was additionally added. While raising the temperature to room temperature, the mixture was stirred for 3 hours and then everything was extracted with AcOEt. The organic layer was washed successively with 0.1 N. aqueous HCl and saturated aqueous sodium chloride, then dried over anhydrous MgSO ₄ . The residue, 72 mg, obtained after concentration under reduced pressure, was used as Fmoc-GlyΨ (CH ₂ S) Leu-OH for the next step.

After 57.3 mg (0.02 mmol) of the Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA polymer (0.349 mmol / g) was expanded in DMF, the mixture was treated with a 20% piperidine / DMF solution for cleavage of the Fmoc group. The polymer was then treated in DMF with 36 mg (0.0871 mmol) of Fmoc-GlyΨ (CH ₂ S) Leu-OH, 15.2 μl (0.0871 mmol) of DIEA, 174 μl (0.0871 mmol) of a 0.5 M solution HOAt / DMF and 45.4 mg (0.0871 mmol) of PyAOP at room temperature for 12 hours. After the polymer was washed with DMF, the peptide chain was extended by condensation using 0.08 mmol of each Fmoc-Phe-OH, 0.5 M HOAt / DMF solution and DIPCDI and then 0.08 mmol of each Ac-D-Tyr-Hyp- Asn-Thr, PyAOP, 0.5 M HOAt / DMF solution and DIEA to obtain Ac-D-Tyr-Hyp-Asn-Thr-Phe-GlyΨ (CH ₂ S) Leu-Arg (Boc ₂ , Me) -Trp polymer (Boc) -Rink amide MBHA. After drying the polymer, 1.2 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added, then stirred for 180 minutes. Diethyl ether was added to each reaction solution to obtain a precipitate, and the supernatant was removed after centrifugation; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the polymer. Then, linear density gradient elution was performed (60 minutes) to A / B: 72.5 / 27.5-62.5 / 37.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The product containing fractions were collected and lyophilized to give 2.7 mg of a white powder.

Mass spectrum (M + H) ⁺ 1227.0 (calc. 1227.6)

HPLC elution time: 19.5 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 14

(Synthesis J): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ S) Gly7, Arg (Me) 9, Trp10] MS10 (compound No. 944)

After adding 157 mg (0.597 mmol) of PPh ₃ to a DCM (1.5 ml) solution of 100 mg (0.398 mmol) of Boc-Phe-ol and 165 mg (0.498 mmol) of CBr ₄ at 0 ° C, the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by flash chromatography using AcOEt: n-hexane = 1:10 to obtain 67 mg of the bromine compound as an oily substance (53.6%). To a DMF (1 ml) solution of 64 mg (0.204 mmol) of a bromine compound, 67.7 mg (0.49 mmol) of K ₂ CO ₃ and 21.9 μl (0.245 mmol) of HSCH ₂ CO ₂ Me were added, then stirred at room temperature for 3 hours. All were extracted with AcOEt, the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1: 5 to obtain 51.5 mg of Boc-PheΨ (CH ₂ S) Gly-OMe as an oily substance (74.4%). 51.5 mg (0.152 mmol) of Boc-PheΨ (CH ₂ S) Gly-OMe was dissolved in 1.2 ml of a mixture of THF: MeOH (3: 1) and 600 μl of a 1 M aqueous NaOH solution was added, then stirred at room temperature in within an hour. After adding 1 M aqueous HCl to terminate the reaction, everything was extracted with AcOEt and the organic layer was washed with 1 M aqueous HCl, dried over anhydrous MgSO ₄ and concentrated under reduced pressure. The residue was dissolved in 1.2 ml of TFA and the solution was stirred at room temperature for 2 hours. TFA was removed by distillation under reduced pressure and azeotropically distilled off twice with toluene. The resulting residue was dissolved in a mixture of acetonitrile: H ₂ O (2: 1, 2.25 ml). Under ice-cooling, Et ₃ N was added to the solution until the solution became basic, and 46.7 mg (0.152 mmol) of Fmoc-OSu was additionally added. While raising the temperature to room temperature, the mixture was stirred overnight and then everything was extracted with AcOEt. The organic layer was washed successively with 0.1 N. aqueous HCl and saturated aqueous sodium chloride, then dried over anhydrous MgSO ₄ . The residue, 62.5 mg, obtained after concentration under reduced pressure, was used as Fmoc-PheΨ (CH ₂ S) Gly-OH for the next step.

After 133 mg (0.045 mmol) of the Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA polymer (0.349 mmol / g) was expanded in DMF, the mixture was treated with a 20% piperidine / DMF solution to split the Fmoc group . The polymer was treated in DMF with 63.6 mg (0.18 mmol) of Fmoc-Leu-OH, 360 μl (0.18 mmol) of a solution of 0.5 M HOAt / DMF and 716 μl (0.18 mmol) of DIPCDI at room temperature within 1.5 hours. The polymer was then treated with a 20% piperidine / DMF solution to cleave the Fmoc group. The polymer was then treated in DMF with 62.5 mg (0.139 mmol) of Fmoc-PheΨ (CH ₂ S) Gly-OH, 24.2 μl (0.139 mmol) of DIEA, 278 μl (0.139 mmol) of a 0.5 M HOAt / DMF solution and 72.5 mg (0.139 mmol) of PyAOP at room temperature for 12 hours. The polymer was further treated with a 20% piperidine / DMF solution to cleave the Fmoc group. The polymer was then treated in DMF with 99.3 mg (0.18 mmol) Ac-D-Tyr-Hyp-Asn-Thr-OH, 31.4 μl (0.18 mmol) DIEA, 360 μl (0.18 mmol) 0.5 M HOAt / DMF solution and 93.9 mg (0.18 mmol) PyAOP at room temperature for 12 hours to obtain Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ S) Gly- polymer Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. After drying the resin, 1.5 ml of TFA / PhSMe / m-cresol / H ₂ O / TIS / EDT (80/5/5/5 / 2.5 / 2.5) was added, then stirred for 120 minutes. Diethyl ether was added to each reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the resin. Then, linear density gradient elution was performed (60 minutes) to A / B: 74 / 26-64 / 36 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA -containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to obtain 5.0 mg of a white powder.

Mass spectrum (M + H) ⁺ 1227.6 (calc. 1227.6)

HPLC elution time: 19.0 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 15

(Synthesis of K): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ (CH ₂ CH ₂ ) Leu8, Trp10] MS10 (compound No. 952)

After 15.7 mg of des (1) -Ac- [D-Tyr2, Hyp3, Alb4, Thr5, Cha6, Gly7Ψ ((E) CH = CH) Leu8, Trp10] MS10 (compound No. 927) was dissolved in 3 ml MeOH, 6.7 mg of 10% Pd / C was added to the solution and suspended in it. In a hydrogen atmosphere, the mixture was stirred overnight and then the Pd catalyst was removed by filtration. MeOH was distilled off under reduced pressure. After dissolving the residue in 1.5 ml of a 50% aqueous solution of AcOH, linear density gradient elution was performed (60 minutes) to A / B: 72.5 / 27.5-63.5 / 26.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm) . The fractions containing the product were collected and lyophilized to obtain 7.2 mg of a white powder.

Mass spectrum (M + H) ⁺ 1216.4 (calc. 1216.7)

HPLC elution time: 20.2 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

EXAMPLE 16

(Synthesis of L): Preparation of des (1) -Ac- [D-Tyr2, Hyp3, Thr5, Phe6Ψ (CH ₂ CH ₂ ) AzaGly7, Arg (Me) 9, Trp10] MS10 (compound No. 968)

Under a nitrogen atmosphere, 21.9 ml (32.8 mmol) of a 1.5 M DIBAL-H toluene solution was added dropwise to a toluene (150 ml) solution of 5.63 g (16.4 mmol) of Z-Phe-NMe (OMe ) at a temperature of -78 ° C. After stirring for 20 minutes at the same temperature, the reaction was stopped 0.1 n. aqueous solution of HCl. All was extracted with diethyl ether, and the organic layer was washed successively with 1 M aqueous HCl and saturated aqueous sodium chloride. After drying over anhydrous MgSO ₄ , the mixture was evaporated under reduced pressure to give the aldehyde as an oily substance. On the other hand, to a suspension of 869 mg (20.5 mmol) of anhydrous LiCl in acetonitrile (40 ml) under ice-cooling, 3.57 ml (20.5 mmol) of DIEA and 4.81 ml (20.5 mmol) were successively added ( EtO) ₂ P (O) CH ₂ CO ₂ Bu ^t . The mixture was stirred at the same temperature for 20 minutes, and then a solution of the above aldehyde in acetonitrile (4 ml) was added dropwise. As the temperature rose to room temperature, the mixture was stirred overnight. All were extracted with AcOEt and the organic layer was washed successively with a saturated aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous MgSO ₄ . It was then concentrated under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1: 8 to obtain 5.0 g of an α, β-unsaturated ester as a white powder (79.9%). After 1.29 g (3.38 mmol) of the α, β-unsaturated ester was dissolved in 10 ml of TFA, the solution was stirred at room temperature for 1.5 hours. TFA was removed by distillation under reduced pressure, and then azeotropically distilled off twice with toluene. The residue was dissolved in 15 ml of DMF and 771 mg (5.07 mmol) of HOBt.NH ₃ and 972 mg (5.07 mmol) of EDC.HCl were added, then stirred at room temperature overnight. The organic layer was washed successively with saturated aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, the residue was dissolved in 60 ml of MeOH and 10% Pd / C was added, then stirred overnight in a hydrogen atmosphere. Pd / C was removed by filtration through celite and the filtrate was evaporated under reduced pressure. The residue was dissolved in 6 ml of chloroform and 589 μl (3.38 mmol) of DIEA and 738 mg (3.38 mmol) of Boc ₂ O were added, then stirred at room temperature for 12 hours. All were extracted with AcOEt, the organic layer was washed successively with a saturated aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, the resulting powder was recrystallized from AcOEt / n-hexane / diethyl ether to give 611 mg of a carboxylic acid amide as a white powder (61.8%). After 200 mg (0.684 mmol) of the carboxylic acid amide was dissolved in THF, 111 μl (1.37 mmol) of pyridine and 589 mg of C ₆ H ₅ I (OCOCF ₃ ) ₂ were added to the solution. The mixture was then stirred at room temperature for 3 hours, and 477 μl (2.74 mmol) of DIEA and 307 mg (1.37 mmol) of HCl.H-Leu-OBu ^t were added sequentially. The mixture was further stirred at room temperature overnight. All were extracted with AcOEt, the organic layer was washed successively with a saturated aqueous solution of citric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over anhydrous MgSO ₄ . After concentration under reduced pressure, flash chromatography was performed using AcOEt: n-hexane = 1: 2 to give 200 mg of Boc-PheΨ (CH ₂ CH ₂ ) AzGly-Leu-OBu ^t as an oily substance (61.1%) . Then 200 mg (0.419 mmol) of Boc-PheΨ (CH ₂ CH ₂ ) AzGly-Leu-OBu ^{t was} dissolved in 4 ml of TFA and the solution was stirred at room temperature for 1.5 hours. TFA was distilled off under reduced pressure and then azeotroped twice. The resulting residue was dissolved in a mixture of acetonitrile: H ₂ O (2: 1, 4.5 ml). Under ice cooling, Et ₃ N was added until the solution became basic, and an additional 158 mg (0.419 mmol) of Fmoc-OSu was added. In the process of raising the temperature to room temperature, the mixture was stirred overnight. Then everything was extracted with AcOEt. H ₂ O was added to precipitate, and the precipitate was absorbed by filtration, washed successively with H ₂ O and n-hexane and dried under reduced pressure to obtain 250 mg of Fmoc-Phe P (CH ₂ CH ₂ ) AzaGly-Leu-OH.

After 86.5 mg (0.03 mmol) of the Fmoc-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA polymer (0.347 mmol / g) was expanded in DMF, the mixture was treated with a 20% piperidine / DMF solution for cleavage of the Fmoc group. The polymer was then treated in DMF with 65.2 mg (0.12 mmol) Fmoc-PheΨ (CH ₂ CH ₂ ) AzaGly-Leu-OH, 20.9 μl (0.12 mmol) DIEA, 240 μl (0.12 mmol) 0.5 M HOAt / DMF solution and 62.5 mg (0.12 mmol) PyAOP at room temperature for 12 hours. After washing with DMF, the polymer was treated with a 20% piperidine / DMF solution to cleave the Fmoc group. The polymer was then treated in DMF with 66.2 mg (0.12 mmol) Ac-D-Tyr-Hyp-Asn-Thr-OH, 20.9 μl (0.12 mmol) DIEA, 240 μl (0.12 mmol) 0.5 M HOAt / DMF solution and 62.5 mg (0.12 mmol) PyAOP at room temperature for 7 hours to obtain Ac-D-Tyr-Hyp-Asn-Thr-PheΨ (CH ₂ CH ₂ ) AzaGly polymer -Leu-Arg (Boc ₂ , Me) -Trp (Boc) -Rink amide MBHA. After washing the MeOH polymer and drying, 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 each reaction solution to obtain a precipitate, and after centrifugation, the supernatant was removed; this procedure was repeated twice for washing. The residue was extracted with an aqueous solution of acetic acid and the extract was filtered to remove the resin. Then, linear density gradient elution was performed (60 minutes) to A / B: 73.5 / 26.5-63.5 / 36.5 at a flow rate of 15 ml / min using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile in preparative HPLC using a YMC Pack R & D-ODS-5-B S-5, 120A column (30 × 250 mm). The fractions containing the product were collected and lyophilized to obtain 3.6 mg of a white powder.

Mass spectrum (M + H) ⁺ 1210.3 (calc. 1210.6)

HPLC elution time: 18.3 min.

Elution Conditions:

Column: SHISEIDO CAPCELL PAK C18 MGII (4.6 × 100 mm)

Eluent: Linear density gradient elution with eluents A / B = 95 / 5-45 / 55 using eluent A: 0.1% TFA-water and eluent B: 0.1% TFA-containing acetonitrile (25 min)

Flow rate: 1.0 ml / min.

Compounds synthesized in examples 1-16 and compounds synthesized by methods similar to those described in examples 1-16 are presented in table 2 below, depending on their structure, physicochemical properties and so on.

In the table, the heading "Synthesis" indicates that:

the compounds described in examples 1-16 were synthesized by the A-G method described in the Synthesis column of the corresponding compounds, or the compounds described in examples 1-16 were synthesized by the A-G method described in the Synthesis column of the corresponding compounds; and,

Compounds not described in Examples 1-16 were synthesized by the modified method described in "Synthesis" for the corresponding compounds.

The heading "HPLC condition" in the table indicates that:

the compounds described in examples 1-16 can be eluted under conditions a, b, c or d described in the column "HPLC conditions" for the corresponding compounds; and,

Compounds not described in Examples 1-16 were eluted under conditions a, b, c or d described in the “HPLC conditions” column for the corresponding compounds.

TEST EXAMPLE 1

Measurement of agonist activity by studying changes in the intracellular level of calcium ions

1) Obtaining cell lines stably expressing

human metastin and rat metastin

Cell lines stably expressing human metastin and rat metastin was obtained by transfection of an expression plasmid for animal cells into CHO / dhfr ^- cells using the transfection kit CellPhect (GE Healthcare manufacture). First, 240 μl of buffer A (attached to the CellPhect transfection kit) was added to 9.6 μg of plasmid DNA dissolved in 240 μl of distilled water, then mixed. After sedimenting the mixture for 10 minutes, 480 μl of buffer B (attached to the CellPhect transfection kit) was added to the mixture, which was vigorously mixed to form liposomes containing DNA. Then, 4 × ¹⁰ May CHO / dhfr ^- cells (obtained from ATCC) were inoculated on a 60 mM petri dish. After culturing the cells in Ham's F-12 medium (manufactured by Nissui Seiyaku Co., Ltd) supplemented with 10% fetal bovine serum (manufactured by BIO WHITTAKER, Inc) at 37 ° C. for 2 days in 5% carbon dioxide gas, dropwise 480 ml of liposomes were added to the cells in a petri dish. After culturing the cells in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 6 hours, the cells were washed twice with Ham's F-12 serum-free medium and 3 ml of 15% glycerol was added to the cells on the Petri dish, then treated for 2 minutes . The cells were again washed twice with Ham's F-12 serum-free medium, then incubated in Ham's F-12 medium, supplemented with 10% fetal bovine serum, in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 15 hours. Cells were dispersed by trypsin treatment to recover from a petri dish. The recovered cells were inoculated in a 6-well plate, 1.25 × 10 ⁴ cells per well, and incubation was initiated in a CO ₂ incubator (5% CO ₂ , 37 ° C) in Dulbecco-modified Eagle medium (DMEM, manufactured by Nissui Seiyaku) containing 10% dialyzed fetal bovine serum (manufactured by JRH BIOSCIENCES, Inc). Plasmid-transfected CHO transformants were grown in medium, however, non-transfected cells gradually died, respectively, the medium was changed on days 1 and 2 after incubation was initiated to remove dead cells. Approximately 20 colonies of CHO transformants that maintained growth on day 8-10 after incubation were separated. From the cells in these colonies, cells showing high reactivity with the ligand peptide metastin (hereinafter referred to simply as h175KB19 and h175KB29 strains) were selected to ensure the following experiment.

2) Sowing cells

The CHO cell line expressing human metastin (strain h175KB19 is described in a separate part) and the CHO cell line expressing rat metastin (strain h175KB29 is described in a separate part) were seeded in a 96-well plate (type 3904, manufactured by Corning) at 3 × 10 ⁴ cells per well, then incubated in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 24 hours. MEMα medium (without nucleic acid, manufactured by Nikken Bio Medical Laboratory) with the addition of dialyzed 10% fetal bovine serum (manufactured by Thermo, MultiSer) was used as the medium.

3) Introduction of Fluo-4 NW into cells

As an analytical buffer, 1 × Hanks' balanced saline solution (HBSS, manufactured by GIBCO) was added with the addition of 0.1% BSA, 20 mM HEPES (pH 7.4, manufactured by GIBCO) and 1 mM Probenecid (manufactured by Molecular Probes). The medium in the wells of the seeded cell plate was removed and 100 μl of assay buffer was added to each well (maintaining heat at 37 ° C). After 10 ml of assay buffer (volume for analysis of two plates) was loaded into one Fluo-4NW dye mix (Component A, Fluo-4 NW calcium assay kit (starter pack), manufactured by Molecular Probes) vessel, the mixture was carefully mixed to obtain Fluo -4 NW boot solution. This introduced solution was loaded into each well of 50 μl and subjected to interaction in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 30 minutes to load with Fluo-4 NW into the cells. Then the cells were besieged at room temperature (25 ° C) for 15 minutes, and then used for analysis.

4) Determination of agonist activity

To control the agonist activity of the test compound, the test compound diluted in the assay buffer described above was dispensed into a 96-well plate (type 3363, manufactured by Corning) 80 μl per well to obtain a compound plate. A cell plate in which a Fluo-4 NW and a compound plate were inserted were inserted into the Fluorometric Imaging Plate Reader (FLIPR, manufactured by Molecular Devices) and 50 μl was dispensed into each well using an automatic pipettor in FLIPR. The agonist response, when stimulated by the compound, was monitored by means of a CCD camera in FLIPR depending on changes in intracellular levels of calcium ions (changes in fluorescence of Fluo-4 NW).

The specific activity of the human metastin agonist (45-54) * is expressed by the value obtained by subtracting the change in fluorescence in the control group, without any addition, from the change in fluorescence caused by metastin (45-54). The specific agonist activity of the test compound is expressed by subtracting the change in fluorescence observed in the control group in the absence of any test compound from the observed change in fluorescence when the test compound is added. A compound content showing a 50% response agonist activity (EC ₅₀ value) is calculated from the dose response relationship. When the maximum response of the specific activity of a human metastin agonist (45-54) is 100%, the EC _{50 is} calculated from the test compound showing 70% or more of the maximum activity compared to the maximum response.

* The peptide used and synthesized from 45-54 in the amino acid sequence for human metastin [human metastin (45-54)] is a synthetic product from the Peptide Institute, Inc.

The agonist activity of each test compound [expressed by the specific activity of the EC _{50 of the} test compound based on metastin EC ₅₀ (45-54)] is shown in Table 3. The data show that the compounds of the present invention have excellent agonist activities with respect to metastin receptors.

TABLE 3 Compound No. Specific activity 796 1,2 803 0.5 804 0.6 811 1,5 818 1,0 822 0.3 823 0.5 827 1.3 828 1,2 834 0.5 839 1,2 847 1.7 848 0.9 849 0.9 850 1.3 851 1,1 852 0.5 853 0.6 854 2.9 855 1.9 857 1,2 858 1.7 859 0.7 866 1.4 867 0.8 869 3.8 871 0.7 873 0.8 875 0.9 885 0.5 892 0.6 893 0.8 894 0.5 895 0.4 902 0.6 903 0.4 904 0.5 905 0.5 906 0.6 907 0.6 908 0.5 909 2.5 910 1,1 911 0.7 912 0.6 913 1.4 914 0.9 915 4.6 916 0.8 917 0.8 918 0.7 919 1,0 920 0.5 921 0.5 923 0.5 924 0.4 925 0.4 926 0.6 927 0.5 929 1,2 931 1.7 932 0.6 933 1.4 934 3,5 940 0.5 942 0.4 944 0.7 945 0.7 946 0.5 947 0.5 948 0.5 949 0.7 951 0.7 952 1.3 953 0.5 956 1,1 957 1,1 959 0.4 968 0.6

TEST EXAMPLE 2

Evaluation of the effect of reducing the level of testosterone in the blood, derivatives of metastin peptide, using mature male rats

In the metastin peptide derivatives shown in Tables 1 and 2, blood testosterone-lowering effects were evaluated for compounds, with the exception of compound No. 828, 847, 854, 857, 866, 869, 915, 917 and 934.

A metastin peptide derivative (hereinafter simply a peptide) was dissolved in a 50% aqueous solution of DMSO (DMSO: Sigma-Aldrich, distilled water for injection: Otsuka Pharmaceutical) to obtain a peptide solution with a concentration of 0.1, 0.03 or 0.01 mM. Five ALZET osmotic pumps were filled with this peptide solution (Model 2001, 0.2 ml, injection rate: 0.001 ml / h, DURECT Corporation). An ALZET peptide-filled pump was subcutaneously implanted with 5 CD (SD) IGS male rats, 9 weeks after birth (Charles River Japan, Inc), in the back under ether anesthesia, one pump per animal. For down regulation, 5 ALZET osmotic pumps were filled with 50% aqueous DMSO solution, which were similarly implanted into 5 male rat CDS (SD) IGS (Charles River Japan, Inc), respectively. These rats were fed for 6 days under normal feeding conditions. After weighing, the animal was decapitated to collect blood. After 0.03 ml / ml blood of an aprotinin solution (Trasylol, Bayer) containing 0.1 g / ml EDTA, 2Na was added to the blood, the plasma was separated and recovered by centrifugation at 1800 × g for 30 minutes. For radioimmunoassay (DPC.Total Testosterone Kit, Diagnostic Products Corporation), 0.05 ml of the obtained plasma was used to measure the plasma testosterone level of each rat. Peptides were listed in Table 4 when the number of rats showing testosterone levels below the measurement limit (plasma level 0.04 ng / ml) in radioimmunoassay was 3 or more of 5 rats receiving peptides.

TABLE 4 Compound No. 822 853 892 894 895 902 903 904 905 907 910 912 924 925 926 927 931 956 957 959

Industrial applicability

In accordance with the present invention, stable metastin derivatives are provided having excellent biological activities (cancer metastasis suppression activity, cancer growth suppression activity, gonadotropin hormone secretion stimulating activity, sex hormone secretion stimulating activity, gonadotropin hormone secretion suppressing activity, secretion suppression activity sex hormones and so on).

Claims (5)

1. A compound selected from
Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ ,
Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ and
Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ (E) CH = CH) Leu-Arg-Trp-NH ₂ ,
or a pharmaceutically acceptable salt thereof. 2. A compound that is Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg (Me) -Trp-NH ₂ or a pharmaceutically acceptable salt thereof. 3. A compound that is Ac-D-Tyr-Hyp-Asn-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ or a pharmaceutically acceptable salt thereof. 4. A compound that is Ac-D-Tyr-Hyp-Alb-Thr-Cha-GlyΨ ((E) CH = CH) Leu-Arg-Trp-NH ₂ or a pharmaceutically acceptable salt thereof. 5. A drug that is an agonist of metastin receptors containing the compound according to claims 1-4, or a pharmaceutically acceptable salt thereof.

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