WO2008050897A1 - Metastin derivatives and use thereof - Google Patents

Metastin derivatives and use thereof Download PDF

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Publication number
WO2008050897A1
WO2008050897A1 PCT/JP2007/071169 JP2007071169W WO2008050897A1 WO 2008050897 A1 WO2008050897 A1 WO 2008050897A1 JP 2007071169 W JP2007071169 W JP 2007071169W WO 2008050897 A1 WO2008050897 A1 WO 2008050897A1
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asn
arg
optionally substituted
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PCT/JP2007/071169
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English (en)
French (fr)
Inventor
Taiji Asami
Naoki Nishizawa
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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Priority to ES07830903.6T priority Critical patent/ES2539430T3/es
Priority to KR1020097010545A priority patent/KR101424306B1/ko
Priority to AU2007309969A priority patent/AU2007309969B2/en
Priority to HK09108616.8A priority patent/HK1130500B/en
Priority to EP20070830903 priority patent/EP2081955B1/en
Priority to MEP-2009-130A priority patent/ME00786B/me
Priority to CA2667537A priority patent/CA2667537C/en
Priority to US12/446,142 priority patent/US8765909B2/en
Priority to JP2009518179A priority patent/JP2010507565A/ja
Priority to RS20150413A priority patent/RS54083B1/sr
Priority to PL07830903T priority patent/PL2081955T3/pl
Priority to SI200731649T priority patent/SI2081955T1/sl
Priority to BRPI0717441A priority patent/BRPI0717441B8/pt
Priority to HRP20150819TT priority patent/HRP20150819T1/hr
Application filed by Takeda Pharmaceutical Co Ltd filed Critical Takeda Pharmaceutical Co Ltd
Priority to DK07830903.6T priority patent/DK2081955T3/da
Priority to CN200780039666.6A priority patent/CN101528772B/zh
Priority to MX2009004148A priority patent/MX2009004148A/es
Priority to NZ576375A priority patent/NZ576375A/en
Publication of WO2008050897A1 publication Critical patent/WO2008050897A1/en
Priority to IL198046A priority patent/IL198046A/en
Priority to TNP2009000140A priority patent/TN2009000140A1/fr
Priority to NO20091487A priority patent/NO341584B1/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Definitions

  • the present invention relates to metastin derivatives and use thereof.
  • metastin has an effect of suppressing cancer metastasis and is thus effective for preventing/treating cancers (for example, lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colonic cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, renal cancer, bladder cancer, brain tumor, etc.); metastin also has an effect of controlling the pancreatic function and is effective for preventing/treating pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, etc.); and metastin further has an effect of controlling placental function and is effective for preventing/treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or abnormal delivery (WO00/24890, WO01/75104, WO02/85399).
  • cancers for example, lung cancer, gastric cancer, liver cancer, pancreatic cancer,
  • the present invention aims at providing stable metastin derivatives having excellent biological activities (a cancer metastasis suppressing activity, a cancer growth suppressing activity, a gonadotropic hormone secretion stimulating activity, sex hormone secretion stimulating activity, a gonadotropic hormone secretion suppressing activity, sex hormone secretion suppressing activity, etc.)
  • the present inventors have made extensive studies to solve the foregoing problems and as a result, have found that by substituting the constituent amino acids of metastin with specific amino acids, unexpectedly blood stability, solubility, etc. are more improved, gelation tendency is reduced, pharmacokinetics are also improved, and an excellent cancer metastasis suppressing activity or a cancer growth suppressing activity is exhibited.
  • the present inventors have further found that unexpectedly these metastin derivatives have an effect of suppressing the gonadotropic hormone secretion, an effect of suppressing the sex hormone secretion, etc., which are totally different from the effects known so far. Based on these findings, the present inventors have continued further investigations and come to accomplish the present invention.
  • the present invention provides the following features, and so on.
  • V represents a group represented by formula:
  • n 0 orl
  • W 1 represents N, CH or O (provided that when W 1 is N or CH, n represents 1 and when W 1 is O, n represents 0);
  • W 2 represents N or CH; each of Z 1 , Z 5 and Z 7 represents hydrogen atom or a C 1-3 alkyl group; each of Z 2 , Z 4 , Z 6 and Z 8 represents hydrogen atom, O or S;
  • R 1 represents (1) 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) a cyclic or 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) 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) 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 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 carbon atoms not greater than 7 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 carbon atoms not greater than 7 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- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C 8-14 aromatic fused-ring group, (4) an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7, and, (6) an optionally substituted non-aromatic heterocyclic group having carbon atoms not greater than 7;
  • 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- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C 8-14 aromatic fused-ring group, (4) an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7, and (6) an optionally substituted non-aromatic heterocyclic group having carbon atoms not greater than 7;
  • A represents: (1) a nitrogen atom substituted with hydrogen atom or a C 1-3 alkyl group; (2) a carbon atom substituted
  • A' represents: (1) a carbon atom, which may optionally be substituted with hydrogen atom, O, S, a halogen atom, an optionally halogenated C 1-3 alkyl group, carbamoyl group or hydroxyl group;
  • (1) a group represented by 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 a C 1-6 alkyl group, hydroxyl group and a halogen atom; (2) an optionally substituted C 6-7 aromatic hydrocarbon group;
  • P and P' which may be the same or different, each may form a ring by combining P and P' or P and Q 1 together and represents: ( 1 ) hydrogen atom; (2) an optional amino acid residue continuously or discontinuously bound from the C-terminal end of the lst-48th amino acid sequence in the amino acid sequence represented by SEQ ID NO: 1;
  • J 1 represents (a) hydrogen atom or (b) (i) a C 1-20 acyl group, (ii) a C 1-20 alkyl group, (iii) a C O-14 aryl group, (iv) a carbamoyl group, (v) a carboxyl group, (vi) a sulf ⁇ no group, (vii) an amidino group, (viii) a glyoxyloyl group or (ix) an amino group, which 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 through J 6 represents hydrogen atom or a C 1-3 alkyl group; each of Q 3 through Q 6 represents a C 1-4 alkyl group, which may optionally be substituted with a substituent selected from the group consist
  • J 3 and Q 3 , J 4 and Q 4 , J 5 and Q 5 or J 6 and Q 6 may 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 may be combined together, to form a ring;
  • Y 1 through Y 3 each represents a group represented by formula: -CON(J 13 )-, -CSN(J 13 )-, -C(J 14 )N(J 13 )- or -N(J 13 )CO- (wherein J 13 and J 14 each represents hydrogen atom or a C 1-3 alkyl group); and Z 10 represents hydrogen atom, O or S);
  • 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 )- (wherein each of J 1 and J 2 has the same significance as defined above, J 7 through J 9 have the same significance as given for J 3 , Q 7 through Q 9 have the same significance as given for Q 3 , Y 2 and Y 3 have the same significance as defined above, Z 10 has the same significance as defined above, J 7 and Q 7 , J 8 and Q 8 or J 9 and Q 9 may be combined together, or J 2 and Q 7 , Y 2 and Q 8 or Y 3 and Q 9 may be combined together, to form a ring.);
  • J 1 -J 2 -C(J 10 )(Q 10 )Y 3 C(J 11 )(Q 11 )C( Z 10 )- (wherein J 1 and J 2 have the same significance as defined above, J 10 and J 11 have the same significance as given for J 3 , Q 10 and Q 11 have the same significance as given for Q 3 , Y 3 has the same significance as defined above, Z 10 has the same significance as defined above, J 10 and Q 10 or J 11 and Q 11 may be combined together, or J 2 and Q 10 or Y 3 and Q 11 may be combined together, to form a ring.);
  • J 1 and J 2 have the same significance as defined above, J 12 has the same significance as given for J 3 , Q 12 has the same significance as given for Q 3 , and Z 10 has the same significance as defined above; J 12 and Q 12 may be combined together, or J 2 and Q 12 may be combined together, to form a ring.); or,
  • J 1 a group represented by formula: J 1 - (wherein J 1 has the same significance as defined above); the bonds betweenY-Q 2 , Q 2 -A' and A'-A each independently represents a single or double bond.); provided that Ac-D-Tyr-D-Trp-Asn-Thr-Phe ⁇ (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-NH2 and Ac-D-Tyr-D-Trp-Asn-Thr-Phe-Gly-Aib-Arg(Me)-Trp-NH2 are excluded. [2] The metastin derivative according to [1]
  • Z 1 , Z 5 and Z 7 each represents hydrogen atom;
  • Z 2 , Z 4 , Z 6 and Z 8 each represents 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-S alkyl group having an optionally substituted basic group and optionally having an additional substituent;
  • R represents (4) a C 1-4 alkyl group, which may optionally be substituted with an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur 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- I 2 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • a substituent selected from the group consisting of (1) an optionally substituted C 6- I 2 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A' represents (1) a carbon atom substituted with hydrogen atom or O;
  • XXO represents formyl, C 1-20 alkanoyl, cyclopropanecarbonyl,
  • 3-(4-hydroxyphenyl)propionyl glycyl, tyrosyl, acetylglycyl, acetyltyrosyl, D-tyrosyl, acetyl-D-tyrosyl, pyroglutamyl, 3-(pyridin-3-yl)propionyl, adipoyl, glycoloyl or 6-aminocaproyl;
  • XX2 represents Tyr, D-Tyr, D-AIa, D-Leu, D-Phe, D-Lys, D-Trp or a chemical bond;
  • XX3 represents D- Asp, D-Dap, D-Ser, D-GIn, D-His, D-NMeAIa, D-NMePhe, Aze(2), Pic(2), Pic(3), Hyp, Thz, NMeAIa, GIy, Aib, Abz(2), Abz(3), Sar, Leu, Lys, GIu, ⁇ -alanine, Pzc(2), Orn, His(3Me), Tyr(PO 3 H 2 ), Pro(4NH 2 ), Hyp(Bzl), Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-AIa, D-Leu, D-Phe, D-Lys, D-GIu, D-2-pyridylalanine, D-3-pyridylalanine, D-4-pyridylalanine, Aad, Pro(4F) or a chemical bond;
  • XX4 represents Asn, 2-amino-3-ureidopropionic acid, N ⁇ -formyldiaminopropionic acid, N ⁇ -acetyldiaminopropionic acid, N ⁇ -pentylasparagine, N ⁇ -cyclopropylasparagine, N ⁇ -benzylasparagine, 2,4-diaminobutanoic acid, His, GIn, Cit or D-Asn;
  • XX5 represents Ser, Thr, VaI , NMeSer, GIy, Ala, Hyp, D-AIa, Dap or D-Thr;
  • T represents a group represented by formula II:
  • Z 4 represents hydrogen atom, O or S
  • R 2 represents (1) hydrogen atom or (2) a cyclic or linear C 1- I 0 alkyl group, (3) a C 1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) 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;
  • 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 Ce -12 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-menibered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C 8-14 aromatic fused-ring group, (4) an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7 and (6) an optionally substituted non-aromatic heterocyclic group having carbon atoms not greater than 7;
  • A represents:
  • a 1 represents:
  • a carbon atom which may optionally be substituted with hydrogen atom, O, S, a halogen atom, an optionally halogenated C 1-3 alkyl group, carbamoyl group or hydroxyl group,
  • (1) a group represented by 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 a C 1-6 alkyl group, hydroxyl group and a halogen atom, (2) an optionally substituted C 6-7 aromatic hydrocarbon group,
  • Q 2 may be a chemical bond; the bonds between Y-Q 2 , Q 2 - A 1 and A'-A each independently represents a single or double bond; XX9 represents Arg, Orn, Arg(Me) or Arg(asymMe 2 ); and,
  • XXlO represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine; provided that Ac-D-Tyr-D-Trp-Asn-Tlir-Phe ⁇ (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 are excluded.
  • the bond "-" between XXO-XXl denotes the bond between the alkanoyl group and the amino group in XX2;
  • the bond "-" between XXlO-NH 2 denotes the carbonyl group and the amino group in XXlO.
  • Specific examples of the bonds include those shown by the structural formulas in TABLE 1 later described.
  • XXO represents formyl, a C 1-6 alkanoyl or glycoloyl
  • XX2 represents D-Tyr or a chemical bond
  • XX3 represents Aze(2), Hyp, GIy, Aib, Leu, Lys, GIu, His(3Me), Tyr(PO 3 H 2 ), Pro(4F) or Hyp(Bzl);
  • XX4 represents Asn or 2-amino-3-ureidopropinonic 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) an optionally substituted C 6- I 2 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A represents (1) a nitrogen atom substituted with hydrogen atom, (2) a carbon atom substituted with hydrogen atom, or (4) S;
  • a 1 represents (1) a carbon atom substituted with hydrogen atom or O;
  • Co- 4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, a C 1-3 alkoxy group and an amino group;
  • XX9 represents Arg or Arg(Me);
  • XXlO represents Phe or Trp.
  • XXO represents C 1-12 alkanoyl
  • XX2 represents D-Tyr
  • XX3 represents Hyp, Pro(4F) or GIu
  • XX4 represents Asn or 2-amino-3-ureidopropionic acid
  • XX5 represents Thr
  • 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) an optionally substituted C 6-12 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A represents (1) a nitrogen atom substituted with hydrogen atom, (2) a carbon atom substituted with hydrogen atom, or (4) S;
  • A' represents (1) a carbon atom substituted with hydrogen atom or O;
  • C 1-4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, a C 1-3 alkoxy group and an amino group;
  • XX9 represents Arg or Arg(Me);
  • XXlO represents Trp.
  • [5 a] A compound below, 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.
  • a medicament comprising the metastin derivative according to [1] through [6] or a salt thereof, or a prodrug thereof.
  • the medicament according to [9] above which is an agent for suppressing cancer metastasis or an agent for suppressing cancer growth.
  • the medicament according to [9] above which is an agent for preventing/treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction.
  • the present invention further provides the following features, and so on.
  • a method for suppressing cancer metastasis or suppressing cancer growth which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for preventing/treating cancer which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for controlling the placental function which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method of preventing/treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for improving the gonadal function which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for preventing/treating hormone-dependent cancer, infertility, endometriosis, early puberty or myoma of the uterus which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for inducing or stimulating ovulation which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for inducing gonadotropic hormone secretion or inducing sex hormone secretion which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for preventing/treating Alzheimer's disease, moderate cognitive impairment or autism which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • [3 I] A method for down-regulation of gonadotropic hormone or sex hormone, which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • a method for preventing/treating hormone-dependent cancer which comprises administering to a mammal an effective dose of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof.
  • [37] Use of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof, to manufacture an agent for preventing/treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction.
  • [39] Use of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof, to manufacture an agent for preventing/treating hormone-dependent cancer, infertility, endometriosis, early puberty or myoma of the uterus.
  • [42] Use of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof, to manufacture an agent for preventing/treating Alzheimer's disease, moderate cognitive impairment or autism.
  • [44] Use of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof, to manufacture an agent for down-regulating human OT7T175 (metastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9.
  • An agent for controlling the pancreatic function (2) an agent for preventing/treating acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent, a pancreatic glucagon secretagogue agent or an agent for promoting urine formation, (4) an agent for preventing/treating, obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) an agent for suppressing gonadotropic hormone secretion or an agent for suppressing sex hormone secretion, or (6) an agent for inhibiting ovarian follicular maturation, a menstrual cycle-suspending agent or a contraceptive, which comprises the metastin derivative according to any one of [1] through [6] or a
  • a method for controlling the pancreatic function (2) a method for preventing/treating acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent, a pancreatic glucagon secretagogue agent or an agent for promoting urine formation, (4) an agent for preventing/treating, obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) an agent for suppressing gonadotropic hormone secretion or an agent for suppressing sex hormone secretion, or (6) an agent for inhibiting ovarian follicular maturation, a menstrual cycle-suspending agent or a contraceptive, which comprises administering to a mammal an effective dose of the metastin derivative
  • [48] Use of the metastin derivative according to any one of [1] through [6] or a salt thereof, or a prodrug thereof, to manufacture (1) an agent for controlling the pancreatic function, (2) an agent for preventing/treating acute or chronic pancreatitis or pancreatic cancer, (3) a hyperglycemic agent, a pancreatic glucagon secretagogue agent or an agent for promoting urine formation, (4) an agent for preventing/treating, obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity, (5) an agent for suppressing gonadotropic hormone secretion or an agent for suppressing sex hormone secretion, or (6) an agent for inhibiting ovarian follicular maturation, a menstru
  • the metastin derivative of the present invention, its salts, or prodrugs thereof have excellent blood stability, in addition to excellent cancer metastasis inhibiting action or cancer growth suppressing action and are useful as agents for preventing/treating cancers (e.g., lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colonic cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, etc.).
  • the metastin derivative of the present invention, its salts, or prodrugs thereof have the effects of regulating functions of the pancreas and are useful as medicaments for preventing/treating pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, etc.).
  • the metastin derivative of the present invention, its salts, or prodrugs thereof have the effects of regulating functions of the placenta and are useful as medicaments for preventing/treating choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction.
  • the metastin derivative of the present invention or its salts or prodrugs have the effects of increasing sugar level, promoting pancreatic glucagon secretion and promoting urine formation, and are useful as agents for preventing/treating obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes mellitus, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity.
  • the metastin derivative of the present invention or its salts or prodrugs have excellent activities of stimulating gonadotropic hormone secretion, stimulating sex hormone secretion, inducing ovulation or stimulating ovulation, and are useful as low toxic and stable agents, e.g., agents for improving gonadal function, agents for preventing/treating hormone-dependent cancer (e.g., prostate cancer, breast cancer, etc.), infertility, endometriosis, early puberty, myoma of the uterus, etc., agents for inducing or stimulating ovulation, gonadotropic hormone secretagogue agents, contraceptives, sex hormone secretagogue agents, or the like.
  • the metastin derivative of the present invention or its salts or prodrugs are useful as agents for preventing/treating Alzheimer's disease, moderate cognitive impairment, autism, etc.
  • the metastin derivative of the present invention or its salts or prodrugs are useful as agents for suppressing gonadotropic hormone secretion or suppressing sex hormone secretion; agents for down-regulating gonadotropic hormone or sex hormone; agents for down-regulating human OT7T175 (metastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9; agents for preventing/treating hormone-dependent cancers (e.g., prostate cancer, breast cancer, etc.; particularly, hormone- sensitive prostate cancer, hormone-sensitive breast cancer, etc.); agents for preventing/treating endometriosis; agents for inhibiting ovarian follicular maturation; menstrual cycle-suspending agents; agents for treating myoma of the uterus; agents for treating early puberty; contraceptives, etc.
  • hormone-dependent cancers e.g., prostate cancer, breast cancer, etc.; particularly, hormone- sensitive prostate cancer, hormone-sensitive breast cancer, etc.
  • metastin derivative of the present invention or its salts or prodrugs are useful as agents for potentiating immunity (e.g., prophylactic agents for infection after bone-marrow transplant, agents for potentiating immunity intended for cancer, etc); immunostimulators (e.g., regeneration of the thymus, regrowth of the thymus, enhancement of T cell development, etc); agents for preventing/treating bulbospinal muscular atrophy; agents for protecting ovary; agents for preventing/treating benign prostate hypertrophy (BPH); agents for preventing/treating gender identity disorder; or agents for in vitro fertilization (IVF).
  • potentiating immunity e.g., prophylactic agents for infection after bone-marrow transplant, agents for potentiating immunity intended for cancer, etc
  • immunostimulators e.g., regeneration of the thymus, regrowth of the thymus, enhancement of T cell development, etc
  • agents for preventing/treating bulbospinal muscular atrophy agents for protecting ova
  • agents for preventing/treating infertility, hypogonadism, oligospermia, azoospermia, aspermia, asthenospermia, or necrospermia are also useful as agents for preventing/treating infertility, hypogonadism, oligospermia, azoospermia, aspermia, asthenospermia, or necrospermia.
  • hormone-dependent diseases e.g., sex hormone dependent cancer such as prostate cancer, uterine cancer, breast cancer, hypophyseal tumor, etc.
  • metastin per se or DNA encoding metastin, etc. are also useful as agents for suppressing gonadotropic hormone secretion or sex hormone secretion; down-regulating agents for gonadotropic hormone or suppressing sex hormone; down-regulating agents for human OT7T175 (metastin receptor) protein consisting of the amino acid sequence represented by SEQ ID NO: 9; agents for preventing/treating hormone-dependent cancers (e.g., prostate cancer, breast cancer, etc.; particularly, hormone- sensitive prostate cancer, hormone-sensitive breast cancer, etc.); agents for preventing/treating endometriosis; agents for inhibiting ovarian follicular maturation; menstrual cycle-suspending agents; agents for treating myoma of the uterus; agents for treating early puberty; contraceptives, etc.
  • hormone-dependent cancers e.g., prostate cancer, breast cancer, etc.; particularly, hormone- sensitive prostate cancer, hormone-sensitive breast cancer, etc.
  • n 0 or 1
  • W 1 represents N, CH or O
  • W 2 represents N or CH
  • each of Z 1 , Z 5 and Z 7 represents hydrogen atom or a C 1-3 alkyl group
  • each of Z 2 , Z 4 , Z 6 and Z 8 represents hydrogen atom, O or S.
  • the C 1-3 alkyl group used includes methyl group, ethyl group, propyl group and isopropyl group.
  • W 1 is preferably N and W 2 is preferably CH.
  • Z 1 is preferably hydrogen atom.
  • Z 2 is preferably O.
  • Z 4 is preferably O.
  • Z 5 is preferably hydrogen atom.
  • Z 6 is preferably O.
  • Z 7 is preferably 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 the cases where Z 1 is hydrogen atom and each of Z 5 and Z 7 represents hydrogen atom or a C 1-3 alkyl group and each of Z 2 , Z 4 , Z 6 and Z 8 represents O or S. More preferably, the combinations of Z 1 to Z 8 include: (a) the case where Z 1 is hydrogen atom, Z 5 is hydrogen atom, Z 7 is hydrogen atom, Z 2 is O, Z 4 is O, Z 6 is O and Z 8 is O;
  • R 1 represents (1) 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) a cyclic or linear C 1-10 alkyl group, (4) a Ci -10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group or (5) an optionally substituted aromatic cyclic group; inter alia, (1) 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) 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
  • the "C 1-8 alkyl group” 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, etc., a cyclic C 3-8 alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • a C 1-3 alkyl group such as methyl, ethyl, etc. are particularly preferred.
  • the "optionally substituted carbamoyl group” used includes, for example, carbamoyl, a mono-C 1-6 alkylcarbamoyl group (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), a di-Ci-6 alkylcarbamoyl group (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), a mono- or di-C6-i 4 arylcarbamoyl group (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), a mono- or di-5- or 7-membered heterocyclic carbamoyl group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon
  • the "optionally substituted hydroxyl group” used includes, for example, 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, etc.
  • 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 those given for the "optionally substituted C 1-6 alkoxy group,” “optionally substituted C 6-14 aryloxy group” and “optionally substituted C 7-16 aralkyloxy group” in Substituent Group A, which will be later described.
  • aromatic cyclic group in “optionally substituted aromatic cyclic group” used includes, for example, an aromatic hydrocarbon group, aromatic heterocyclic group, an aromatic fused-ring group, an aromatic fused heterocyclic group, etc.
  • aromatic hydrocarbon group used includes, for example, a C 6-14 aryl group such as phenyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, cyclooctatetraenyl, etc.
  • aromatic heterocyclic group used includes, for example, a 5- to 14-membered, preferably 5- to 10-membered, more preferably 5- or 6-membered aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
  • 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,
  • aromatic fused-ring group used includes a C 8-14 aromatic fused-ring group such as naphthyl (e.g., 1-naphthyl, 2-naphthyl), anthryl (e.g., 2-anthryl, 9-anthryl) and the like.
  • the "aromatic fused heterocyclic group” used includes, for example, a 5- to 14-memberd (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms, or a monovalent group formed by removing one optional hydrogen atom from a 7- to 10-membered aromatic bridged-hetero ring in 5- to 14-membered (preferably 5- to 10-membered) ring containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.
  • 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 e.g., 1-indolyl, 2-indolyl, 3-indolyl
  • 2-benzothiazolyl benzo[b]thienyl, (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl), benzo[b]furanyl (e.g., 2-benzo[b]furanyl, 3-benzo[b]furanyl) and the like.
  • the "substituent" used in the "aromatic cyclic group” includes a substituent selected from Substituent Group A, which will be later described.
  • R 1 there are used hydrogen atom, carbamoylmethyl, 2-carbamoylethyl, hydroxymethyl, 1 -hydroxy ethyl, benzyl, 4-hydroxybenzyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-naphthylmethyl,
  • R 2 represents (1) hydrogen atom, (2) a cyclic or linear C 1-10 alkyl group, (3) a
  • C 1-1 O alkyl group consisting of a cyclic alkyl group and a linear alkyl group, or (4) 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 hydroxy 1 group and an optionally substituted aromatic cyclic group.
  • a substituent selected from the group consisting of an optionally substituted carbamoyl group, an optionally substituted hydroxy 1 group and an optionally substituted aromatic cyclic group.
  • preferred are (1) hydrogen atom, (2) a cyclic or linear C 1-1 O alkyl group, or (3) a C 1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group.
  • 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 is preferred.
  • the cyclic C 1-10 alkyl group used includes, for example, a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cycl
  • linear C 1-10 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl, etc.
  • the C 1-10 alkyl group consisting of a cyclic alkyl group and a linear alkyl group used includes, for example, a C 3-7 cycloalkyl-C 1-3 alkyl group such as cyclopentylmethyl, cyclohexylmethyl, etc.
  • R 2 examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, benzyl, hydroxymethyl, 2-carbamoylethyl, tert-pentyl, etc.; among others, preferred are methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc., more preferably, propyl, isopropyl, isobutyl, cyclopropylmethyl, etc.
  • R 3 represents:
  • the "optionally substituted basic group" used includes, for example, (1) 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, etc.), etc., (2) an amino group optionally having 1 to 3 substituents from C 1-6 alkyl, C 1-6 acyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, acetyl, propionyl, etc.), etc., (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 ⁇ acyl (e.g., methyl, ethyl, propyl, isopropy
  • guanidino N-methylguanidino, N, N-dimethylguanidino, N, N'-dimethylguanidino, N-ethylguanidino, N-acetylguanidino, amino, N-methylamino, N, N-dimethylamino, aminoacetamido, guanidinoacetamido, amidino, and the like.
  • the "additional substituent” other than the “optionally substituted basic group” used includes a substituent selected from Substituent Group A later described.
  • Examples of the "C 1-8 alkyl group” used are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • aralkyl group used includes, for example, a C 7-16 aralkyl group such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl,
  • non-aromatic cyclic hydrocarbon group of carbon atoms not greater than 7 includes, for example, a C 3-7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the "non-aromatic heterocyclic group of carbon atoms not greater than 7" used includes, for example, a 5- to 10-membered non-aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, in addition to 1 to 7 carbon atoms, etc.
  • 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, 3-piperidinyl, 4-piperidinyl
  • piperazinyl e.g., 1 -piperazinyl, 2-piperazinyl
  • morpholino thiomorpholino, etc.
  • C 1-4 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • R 3 there are used, 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,
  • 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- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms,
  • C 1-4 alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • the "C 6-12 aromatic hydrocarbon group” used includes, for example, a monocyclic C 6-12 aromatic hydrocarbon group such as phenyl, cyclooctatetraenyl, etc.
  • the "5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms" used includes, for example, a 5- to 14-membered, preferably 5- to 10-membered, more preferably 5- or 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 7 carbon atoms.
  • 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,
  • the "C 8-14 aromatic fused-ring group” used includes, for example, naphthyl (e.g., 1-naphthyl, 2-naphthyl), anthryl (e.g., 2-anthryl, 9-anthryl), etc.
  • the "5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms" used includes, for example, a 5- to 14-memberd (preferably 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to 3 to 11 carbon atoms, or a monovalent group formed by removing one optional hydrogen atom from a 7- to 10-membered aromatic bridged-hetero ring in 5- to 14-membered (preferably 5- to 10-membered) ring containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, in addition to carbon atoms.
  • 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 e.g., 1-indolyl, 2-indolyl, 3-indolyl
  • 2-benzothiazolyl benzo[b]thienyl, (e.g., 2-benzo[b]thienyl, 3-benzo[b]thienyl), benzo[b]furanyl (e.g., 2-benzo[b]furanyl, 3-benzo[b]furanyl), etc.
  • cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • non-aromatic heterocyclic group of carbon atoms not greater than 7 includes, for example, a 5- or 10-membered non-aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms, in addition to 1 to 7 carbon 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, 3 -piperidinyl, 4-piperidinyl), piperazinyl (e.g., 1 -piperazinyl, 2-piperazinyl), morph
  • cycloalkylcarbonyl e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1 -methyl- cyclohexyl-carbonyl, etc.
  • C 6-14 aryl-carbonyl e.g., benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
  • C7-16 aralkyl-carbonyl e.g., phenylacetyl, 3-phenylpropionyl, etc.
  • optionally substituted 5- to 7-membered heterocyclic carbonyl containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms e.g., nicotinoyl, isonicotinoyl, thenoyl, furoyl, morpholinocarbonyl, thiomorpholinocarbonyl
  • the "optionally esterified carboxyl group" in Substituent Group A includes, for example, an optionally substituted C 1-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), an optionally substituted C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl, etc.), an optionally substituted C 7-16 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, etc.), and the like.
  • C 1-6 alkoxy-carbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.
  • C 6-14 aryloxy-carbonyl e.g., phenoxycarbonyl, etc.
  • C 1-6 alkyl in the "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, etc.
  • the "C 2 -6 alkenyl” in the “optionally substituted C 2-6 alkenyl” in Substituent Group A includes, for example, vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5-hexen-l-yl, etc.
  • Group A includes, for example, 2-butyn-l-yl, 4-pentyn-l-yl, 5-hexyn-l-yl, etc.
  • the "C 3-8 cycloalkyl” in the “optionally substituted C 3-8 cycloalkyl” in Substituent Group A includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • the "C 6-14 aryl” in the “optionally substituted C 6-14 aryl” in Substituent Group A includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • A includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl, etc.
  • C 7-16 aralkyl in the "optionally substituted C 7-16 aralkyl" in Substituent Group A includes, for example, benzyl, phenethyl, diphenyllmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl, etc.
  • the "C 1-6 alkoxy” in the "optionally substituted Ci -6 alkoxy” in Substituent Group A includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
  • Group A includes, for example, phenyloxy, 1-naphthyloxy, 2-naphthyloxy, etc.
  • C 7- I 6 aralkyloxy in the "optionally substituted C 7-16 aralkyloxy" in Substituent Group A includes, for example, benzyloxy, phenethyloxy, etc.
  • C -6 alkylthio in the "optionally substituted C 1-6 alkylthio" in Substituent Group A includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.
  • C 6- I 4 arylthio in the "optionally substituted C 6-14 arylthio" in Substituent Group A includes, for example, phenylthio, 1-naphthylthio, 2-naphthylthio, etc.
  • C 7-16 aralkylthio in the "optionally substituted C 7-16 aralkylthio" in Substituent Group A includes, for example, benzylthio, phenethylthio, etc.
  • 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 aryl-amino,” “C 3-8 cycloalkyl-carbonyl,” “C 6-14 aryl-carbonyl,” “C 7-16 aralkyl-carbonyl,” “5- to 7-membered heterocyclic carbonyl containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms," “C 6-14 arylsulfonyl,” “C 6-14 arylsulfinyl,” “C 3-8 cycloalkyl-carbonylamino,” “C 6-14 aryl-carbonylamino,” “C 6-14 arylsulf
  • the "optionally substituted heterocyclic group" in Substituent Group A includes, for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which may optionally be substituted with a halogen atom, hydroxy, carboxy, nitro, cyano, the optionally substituted C 1-6 alkyl described above, the optionally substituted C 2-6 alkenyl described above, the optionally substituted C 2-6 alkynyl described above, the optionally substituted C 3-8 cycloalkyl described above, the optionally substituted C 6-14 aryl described above, the optionally substituted C 1-6 alkoxy described above, the optionally substituted C 1-6 alkylthio described above, the optionally substituted C 6-14 arylthio described above, the optionally substituted C 7-16 aralkylthio described above, the optional
  • 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
  • the "optionally substituted carbamoyl group" in Substituent Group A includes a carbamoyl group, which may optionally be substituted with the optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, an optionally substituted C 2-6 alkynyl, an optionally substituted C 3-8 cycloalkyl, an optionally substituted C 6-14 aryl, an optionally substituted heterocyclic group described above, etc., and specific examples are carbamoyl, thiocarbamoyl, InOnO-C 1-6 alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), di-C 1-6 alkylcarbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), C 1-6 alkyl (C 1-6 alkoxy
  • the "optionally substituted amino" in Substituent Group A includes an amino, which may optionally be substituted with 1 or 2 groups selected from the optionally substituted C 1-6 alkyl described above, the optionally substituted C 2-6 alkenyl described above, the optionally substituted C 2-6 alkynyl described above, the optionally substituted C 3-8 cycloalkyl described above, the optionally substituted C 6-14 aryl described above, the optionally substituted C 1-6 alkoxy described above, formyl, the optionally substituted C 1-6 alkyl-carbonyl described above, the optionally substituted C 3-8 cycloalkyl-carbonyl described above, the optionally substituted C 6-14 aryl-carbonyl described above, the optionally substituted C 1-6 alkoxy-carbonyl described above, the optionally substituted C 1-6 alkylsulfonyl described above, the optionally substituted C 6-14 arylsulfonyl, and the like.
  • R 4 used examples include:
  • a 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, etc.;
  • a C 1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms 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, etc.;
  • a C 1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms such as 3-indolemethyl, l-formylindol-3-ylmethyl, 3-benzo[b]thienylmethyl, 2-quinolylmethyl, etc.;
  • a C 1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group of carbon atoms not greater than 7 such as cyclohexylmethyl, cyclop entylmethyl, indan-2-ylmethyl, etc.;
  • a C 1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group of carbon atoms not greater than 7 such as 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin-3-yl, etc.; among others, preferred are benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4-cyanobenzyl,
  • 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:
  • Q 1 examples include:
  • a 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, etc.,
  • a C 1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms 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, etc.
  • 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, etc.
  • a C 1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms such as 3-indolemethyl, l-formylindol-3-ylmethyl, 3-benzo[b]thienylmethyl, 2-quinolylmethyl, etc.
  • a C 1-4 alkyl group having an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7 such as cyclohexylmethyl, cyclopentylmethyl, indan-2-ylmethyl, etc.
  • a C 1-4 alkyl group having an optionally substituted non-aromatic heterocyclic group having carbon atoms not greater than 7 such as 3-piperidylmethyl, 4-piperidinylmethyl, tetrahydrofurfuryl, tetrahydrofuran-2-yl, tetrahydropyran-3-yl, indolin-3-yl, etc.; among others, preferably used are cyclohexylmethyl, benzyl, 4-fluorobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, pentafluorobenzyl, 2-pyridylmethyl, 4-pyridylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 3-indolemethyl, 3-piperidylmethyl, 2-thienylmethyl, etc.; more preferably, benzyl, 4-fluorobenzyl, 4-pyridylmethyl, cyclohexylmethyl, 3-piperidylmethyl,
  • the "C 0-4 alkyl group” is used to mean a bond or a C 1-4 alkyl group.
  • the "C 0 alkyl group” refers to a bond (e.g., a chemical bond "-").
  • CH 2 substituted with a C 0 alkyl group which is substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, a C 1-3 alkoxy group and amino group represents CH 2 substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, a C 1-3 alkoxy group and amino group.
  • the "C 0-4 alkyl group” is preferably a C 1-4 alkyl group.
  • C 1-4 alkyl group used includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • the "C 1-3 alkoxy group” used includes, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, etc.
  • Preferred Q 2 are CH 25 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 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 a C 1-6 alkyl group, hydroxyl group and a halogen atom; (2) an optionally substituted C 6-7 aromatic hydrocarbon group;
  • the "Ci-6 alkyl group” used includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • Y includes (1) a group represented by formula: -CONH-, -CSNH-, -NHCO-,
  • A preferably includes (1) a nitrogen atom substituted with hydrogen atom or a C 1-3 alkyl group (among others, a nitrogen atom substituted with hydrogen atom); (2) a carbon atom substituted with hydrogen atom or a C 1-3 alkyl group (among others, a carbon atom substituted with hydrogen atom); or (4) S.
  • A' represents: (1) a carbon atom, which may optionally be substituted with hydrogen atom, O, S, a halogen atom, an optionally halogenated Ci -3 alkyl group, carbamoyl group or hydroxyl group;
  • A' includes (1) a carbon atom, which may optionally be substituted with hydrogen atom, O, S, a halogen atom, an optionally halogenated C 1-3 alkyl group, carbamoyl group or hydroxyl group (among others, a carbon atom substituted with hydrogen atom or O).
  • V is the group represented by the formula below.
  • P and P' which may be the same or different, each may form a ring by combining P and P 1 or P and Q 1 together and represents: (1) hydrogen atom,
  • amino acid residue continuously or discontinuously bound from the C-terminal end of the 1-48 amino acid sequence in the amino acid sequence represented by SEQ ID NO: 12 include: (l) Asn-
  • J 1 represents (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) carbamoyl group, (v) carboxyl group, (vi) sulfino group or (vii) amidino group, (viii) glyoxyloyl group or (ix) amino group, which groups may optionally be substituted with a substituent containing an optionally substituted cyclic group;
  • the "cyclic group” used includes, for example, “an optionally substituted aromatic hydrocarbon group,” “an optionally substituted aromatic heterocyclic group,” “an optionally substituted aromatic fused-ring group,” “an optionally substituted aromatic fused heterocyclic group,” “an optionally substituted non-aromatic cyclic hydrocarbon group,” “an optionally substituted non-aromatic heterocyclic group,” etc., and examples of the “aromatic hydrocarbon group,” “aromatic heterocyclic group,” “aromatic fused-ring group” and “aromatic fused heterocyclic group” used are the same as those given above.
  • the "non-aromatic cyclic hydrocarbon group” used includes a C 3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • non-aromatic heterocyclic group used includes a 5- to 10-membered non-aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to 1 to 7 carbon 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-iniidazolinyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl), morpholino, thiomorpholino, etc.
  • the substituent optionally present on
  • C 1-2 O acyl group used includes, for example, formyl, C 1-18 alkyl-carbonyl (e.g., C 1-18 alkyl-carbonyl such as acetyl, propionyl, pivaloyl, octanoyl, decanoyl, palmitoyl, etc.) and the like.
  • C 1-18 alkyl-carbonyl e.g., C 1-18 alkyl-carbonyl such as acetyl, propionyl, pivaloyl, octanoyl, decanoyl, palmitoyl, etc.
  • C 1-20 alkyl group used include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonanyl, decanyl, tridecyl, pentadecyl, etc.
  • C 6-14 aryl group used includes, for example, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, etc.
  • the C 1-15 acyl group which may optionally be substituted with a substituent containing a cyclic group, includes (i) formyl, (ii) C 1-14 alkyl-carbonyl (e.g., C 1-6 alkyl-carbonyl such as acetyl, propionyl, pivaloyl, etc.), (iii) C 3-8 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, 1-methylcyclohexylcarbonyl, etc.), (iv) C 3-8 cycloalkyl-C t - 6 alkyl-carbonyl (e.g., cyclopropylacetyl, cyclopentylacetyl, cyclohexylacetyl, etc.), (v) C 6-14 aryl-carbonyl (e.g., benzoyl, 1-na
  • the 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, etc.), (iii) mono- or di-C 3-8 cycloalkyl-C 1-12 (preferably,
  • the C 6-14 aryl group which may optionally be substituted with a substituent containing a cyclic group, includes, for example, a C 6-14 aryl group (e.g., phenyl, naphthyl, biphenyl), which may optionally be substituted with (i) a C 6-I4 carbocyclic group (e.g., cycloalkyl, phenyl, 1-naphthyl, 2-naphthyl, etc.), (ii) a 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms (e.g., 3-pyridyl, 2-thienyl, etc.), (iii) a 5- to 14-membered (preferably, 5- to 10-membered) bicyclic or tricyclic aromatic heterocyclic group containing 1 to 4 hetero atoms of 1 or 2 species selected from nitrogen,
  • the optionally substituted carbamoyl group which may optionally be substituted with a substituent containing a cyclic group, includes (i) carbamoyl, (ii) mono- or di-Ci-is alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl), (iii) mono- or di-C3_8 cycloalkylcarbamoyl (e.g., cyclopropylcarbamoyl, cyclopentylcarbamoyl, cyclohexylcarbamoyl, etc.), (iv) mono- or di-C 3-8 cycloalkyl-C 1-6 alkyl-carbamoyl (e.g., cyclopropylmethylcarbamoyl, cyclopentylmethylcarbamoyl, 2-cyclohexylethylcarbamoyl, etc.)
  • the carboxyl group which may optionally be substituted with a substituent containing a cyclic group, includes (i) C 1-15 alkyloxycarbonyl (C 1-15 alkyl herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), (ii) C 6-14 aryloxycarbonyl (C 6-14 aryl herein has the same significance as the "C 6-14 aryl group” in the "C 6-14 aryl group, which may optionally be substituted with a substituent containing a cyclic group,” e.g., phenoxycarbonyl), etc.
  • C 1-15 alkyl herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 al
  • the sulfino group which may optionally be substituted with a substituent containing a cyclic group, includes (i) C 1-15 alkylsulfonyl (C 1-15 alkyl as used herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., benzylsulfonyl), (ii) C 6-14 arylsulfonyl (C 6-14 aryl as used herein has the same significance as the "C 6-14 aryl group” in the "C 6-14 aryl group, which may optionally be substituted with a substituent containing a cyclic group,” e.g., tosyl), etc.
  • the 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 as used herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., N-methylamidino), (iii) C 1-15 acylamidino (C 1-15 acyl as used herein has the same significance as the "C 1-15 acyl group” in the "C 1-15 acyl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., N-acetylamidino), etc.
  • the glyoxyloyl group which may optionally be substituted with a substituent containing a cyclic group, includes (i) C 1-15 alkyloxalyl (C 1-15 alkyl as used herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., ethyloxalyl), (ii) C 6-14 aryloxalyl (C 6-14 aryl as used herein has the same significance as the "C 6-14 aryl group” in the "C 6-14 aryl group, which may optionally be substituted with a substituent containing a cyclic group," e.g., phenyloxalyl), etc.
  • the amino group which may optionally be substituted with a substituent containing a cyclic group, includes (i) C 1-15 alkylamino (C 1-15 alkyl as used herein has the same significance as the "C 1-15 alkyl group” in the "C 1-15 alkyl group, which may optionally be substituted with a substituent containing a cyclic group”).
  • J 1 used include hydrogen atom, formyl, acetyl, 3-indolecarbonyl, 3-(indol-3-yl)propionyl, 3-phenylpropionyl, diphenylacetyl, 3-(pyridin-3-yl)propionyl, 4-imidazoleacetyl, cyclohexanecarbonyl, 1-piperidineacetyl, 1 -methyl- 1-piperidinioacetyl, 4-piperidinecarbonyl, hexanoyl, amino-(4-hydroxyphenyl)acetyl, D-glucuronyl, 2-(indol-3-yl)ethylcarbamoyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl, amidino, 4-guanidomethylbenzoyl, benzoyl, 3-indoleacetyl, benzyloxycarbonyl
  • 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.
  • C 1-6 alkyl group used includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
  • J 2 is NH.
  • Each of J 3 through J 12 represents hydrogen atom or a C 1-3 alkyl group.
  • C 1-3 alkyl group used includes methyl, ethyl, propyl, isopropyl, etc.
  • J 3 is hydrogen atom.
  • J 4 is hydrogen atom.
  • J 5 is hydrogen atom.
  • J 6 is hydrogen atom.
  • J 7 is hydrogen atom.
  • J 8 is hydrogen atom.
  • J 9 is hydrogen atom.
  • J 10 is hydrogen atom.
  • J 11 is hydrogen atom.
  • J 12 is hydrogen atom.
  • Each of Q 3 through Q 12 represents a C 1-4 alkyl group, which may optionally be substituted with a substituent selected from the group consisting of:
  • Q 3 to Q 9 are a C 1-4 alkyl group having a substituent selected from the group consisting of:
  • C 1-4 alkyl group having an optionally substituted C 6-12 aromatic hydrocarbon group there are used, for example, benzyl, 4-hydroxybenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 4-aminobenzyl, etc.
  • 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, there are used, for example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 4-imidazolemethyl, etc.
  • the C 1-4 alkyl group having an optionally substituted Cs -14 aromatic fused-ring group there are used, for example, 1-naphthylmethyl, 2-naphthylmethyl, etc.
  • C 1-4 alkyl group having an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms there are used, for example, 3-indolemethyl, l-formylindol-3-ylmethyl, 2-quinolylmethyl, etc.
  • C 1-4 alkyl group having an optionally substituted amino group there are used, for example, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 4-acetamidobutyl, etc.
  • C 1-4 alkyl group having an optionally substituted guanidino group there are used, for example, 3-guanidinopropyl, 3-(N-tosyl)guanidinopropyl, etc.
  • C 1-4 alkyl group having an optionally substituted hydroxyl group there are used, for example, hydroxymethyl, 1 -hydroxy ethyl, benzyloxymethyl, etc.
  • C 1-4 alkyl group having an optionally substituted carboxyl group there are used, for example, carboxylmethyl, 2-carboxylethyl, benzyloxycarbonylmethyl, etc.
  • C 1-4 alkyl group having an optionally substituted carbamoyl group there are used, for example, carbamoylmethyl, 2-carbamoylethyl, xanthylcarbamoyl, etc.
  • C 1-4 alkyl group having an optionally substituted sulfhydryl group there are used, for example, sulfhydrylmethyl, 2-(methylsulfhydryl)ethyl, etc.
  • the unsubstituted C 1-4 alkyl group there are used, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.
  • Q 3 used include hydrogen atom, 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl, methyl, isobutyl, hydroxymethyl, carboxymethyl, 4-aminobutyl, etc., particularly preferably, 4-hydroxybenzyl, 3-pyridylmethyl, 4-pyridylmethyl, etc.
  • Q 4 used include carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl, 4-imidazolemethyl, isobutyl, hydroxymethyl, 1-hydroxyethyl, carboxymethyl, 4-aminobutyl, etc., particularly preferably, carbamoylmethyl, 2-carbamoylethyl, 4-hydroxybenzyl, etc.
  • Q 5 used include benzyl, 2-chlorobenzyl, 3-chlorobenzyl,
  • Q 6 used are methyl, hydroxymethyl, 1-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, etc., particularly preferably, carbamoylmethyl, etc.
  • Q 7 used are 4-hydroxybenzyl, carbamoylmethyl, 3-pyridylmethyl, methyl, isobutyl, benzyl, 4-aminobutyl, 3-indolemethyl, etc., particularly preferably, 4-hydroxybenzyl, etc.
  • Preferred examples of Q 8 used include benzyl, 2-pyridylmethyl,
  • Q 9 used include hydrogen atom, methyl, ethyl, hydroxymethyl, 1 -hydroxy ethyl, carbamoylmethyl, 2-carbamoylethyl, ureidomethyl, acetamidomethyl, diethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, etc., particularly preferably, carbamoylmethyl, ureidomethyl, etc.
  • Q 10 used include 4-hydroxybenzyl, 3-indolemethyl, methyl, 1-hydroxyethyl, 3-guanidinopropyl, etc., particularly preferably, 3-indolemethyl, etc.
  • Q 11 used include carbamoylmethyl, etc.
  • Q 12 used include methyl, carbamoylmethyl, etc., particularly preferably, carbamoylmethyl, etc.
  • Each of Y 1 through Y 3 represents a group shown by formula: -CON(J 13 )-, -CSN(J 13 )-, -C(J 14 )N(J 13 )- or -N(J 13 )CO- (wherein each of J 13 and J 14 represents hydrogen atom or a C 1-3 alkyl group).
  • J 13 is preferably hydrogen atom.
  • J 14 is preferably hydrogen atom.
  • Y 1 is preferably a group shown by formula: -CONH- or -CH 2 NH-, etc.
  • Y 2 is preferably a group shown by formula: -CONH- or -CH 2 NH-, etc., particularly preferably a group shown by formula: -COCN-.
  • Y 3 is preferably a group shown by formula: -CONH-, etc.
  • J 3 and Q 3 , J 4 and Q 4 , J 5 and Q 5 , J 6 and Q 6 , J 7 and Q 7 , J 8 and Q 8 , J 9 and Q 9 , J 10 and Q 10 , J 11 and Q 11 , and J 12 and Q 12 may be combined together to form a ring.
  • C(J 3 )(Q 3 ), C(J 4 )(Q 4 ), C(J 5 )( Q5 ), C(J 6 )(Q 6 ), C(J 7 )(Q 7 ), C(J 8 )(Q 8 ), C(J 9 )(Q 9 ), C(J 10 XQ 10 ), C(J 11 XQ 11 ) or C(J 12 XQ 12 ) may form, for example, cyclopentane, cyclohexane, piperidine, etc.
  • 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 ⁇ ,and J 2 and Q 12 (preferably, J 2 and Q 3 , Y 1 and Q 4 , Y 2 and Q 5 , Y 3 and Q 6 , J 2 and Q 7 , Y 2 and Q 8 , Y 3 and Q 9 , J 2 and Q 10 , Y 3 and Q 11 , and J 2 and Q 12 ) may be combined together to form a ring. Also, the ring formed may be substituted or form a fused ring.
  • the ring is shown by Z ⁇ 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, e.g., azetidine, pyrrolidine, piperidine or thiazolidine. Also, the ring formed may be substituted or may form a fused ring. As Z 1 ⁇ -N-CH-R 1 , azetidine, pyrrolidine, 4-hydroxypyrrolidine, piperidine, etc. are preferably used.
  • the ring is shown by Y 1 C(J 4 XQ 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 XQ 9 ) or Y 3 C(J 11 XQ 11 ) including, e.g., pyrrolidine-2-carbonyl, piperidine-2-carbonyl or thiazolidine-4-carbonyl. Also, the ring formed may be substituted or may form a fused ring.
  • Z 10 represents hydrogen atom, O or S; O and S are preferred among others, and
  • O is particularly preferred.
  • Preferred examples of the group represented by formula: J 1" include: hydrogen atom
  • preferred P is Ac-D-Tyr-Hyp-Asn, Ac-D-Tyr-Glu-Asn orAc-D-Tyr-Hyp-Alb-.
  • metastin derivatives of the present invention or salts thereof are preferably compounds represented by formula I described above, or salts thereof, wherein:
  • Z 1 , Z 5 and Z 7 each represents hydrogen atom;
  • Z 2 , Z 4 , Z 6 and Z 8 each represents 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 may optionally be substituted with an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur 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- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A represents (1) a nitrogen atom substituted with hydrogen atom, (2) a carbon atom substituted with hydrogen atom;
  • A' represents (1) a carbon atom substituted with hydrogen atom or O;
  • Y represents (1) a group represented by 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, hydroxyl group or a halogen atom.
  • metastin derivatives of the present invention or salts thereof are compounds represented by the formula below, or salts thereof:
  • XXO represents 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,
  • XX2 represents Tyr, D-Tyr, D-AIa, D-Leu, D-Phe, D-Lys, D-Trp or a chemical bond;
  • XX3 represents D- Asp, D-Dap, D-Ser, D-GIn, D-His, D-NMeAIa, D-NMePhe, Aze(2), Pic(2), Pic(3), Hyp, Thz, NMeAIa, GIy, Aib, Abz(2), Abz(3), Sar, Leu, Lys, GIu, ⁇ -alanine, Pzc(2), Orn, His(3Me), Tyr(PO 3 H 2 ), Pro(4NH 2 ), Hyp(Bzl), Trp, Pro, 4-pyridylalanine, Tic, D-Trp, D-AIa, D-Leu, D-Phe, D-Lys, D-GIu, D-2-pyridylalanine, D-3-pyridylalanine, D-4-pyridylalanine, Aad, Pro(4F) or a chemical bond;
  • XX4 represents Asn, 2-amino-3-ureidopropionic acid
  • N ⁇ -formyldiaminopropionic acid N ⁇ -acetyldiaminopropionic acid, N ⁇ -pentylasparagine, N ⁇ -cyclopropylasparagine, N ⁇ -benzylasparagine, 2,4-diaminobutanoic acid, His, GIn, Cit or D-Asn;
  • XX5 represents Ser, Thr, VaI , NMeSer, GIy, Ala, Hyp, D-AIa, Dap or D-Thr (more preferably, Ser, Thr, VaI , NMeSer, GIy, Ala, Hyp, D-AIa or D-Thr);
  • T represents a group represented by formula II:
  • Z 4 represents hydrogen atom, O or S
  • R 2 represents (1) 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) a C 1- S 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) an optionally substituted C 6-12 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (3) an optionally substituted C 8-14 aromatic fused-ring group, (4) an optionally substituted 5- to 14-membered aromatic fused heterocyclic group consisting of 3 to 11 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7, and (6) an optionally substituted non-aromatic heterocyclic group having carbon atoms not greater than 7;
  • A represents: (1) a nitrogen atom substituted with hydrogen atom or a C 1-3 alkyl group
  • A' represents: (1) a carbon atom, which may optionally be substituted with hydrogen atom, O, S, a halogen atom, an optionally halogenated C 1-3 alkyl group, carbamoyl group or hydroxyl group;
  • NH which may optionally be substituted with an optionally substituted Ci -4 alkyl group with a substituent selected from the group consisting of carbamoyl group and hydroxyl group; or,
  • (1) a group represented by 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 a C 1-6 alkyl group, hydroxyl group and a halogen atom; (2) an optionally substituted C 6-7 aromatic hydrocarbon group;
  • Q 2 may be a chemical bond; the bonds between Y-Q 2 , Q 2 - A 1 and A' -A each independently represents a single or double bond; XX9 represents Arg, Orn, Arg(Me) or Arg(asy InMe 2 ); and,
  • XXlO represents Phe, Trp, 2-naphthylalanine, 2-thienylalanine, tyrosine or 4-fluorophenylalanine; provided that
  • metastin derivatives of the present invention or salts thereof are compounds represented by the following formula, or salts thereof:
  • XXO represents formyl, Ci -6 alkanoyl or glycoloyl
  • XX2 represents D-Tyr or a chemical bond
  • XX3 represents Aze(2), Hyp, GIy, Aib, Leu, Lys, GIu, His(3Me), Tyr(PO 3 H 2 ), Pro(4F) or Hyp(Bzl);
  • XX4 represents Asn or 2-amino-3-ureidopropinonic acid
  • XX5 represents Ser or Thr
  • T represents the 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) an optionally substituted C ⁇ -12 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A represents (1) a nitrogen atom substituted with hydrogen atom, (2) a carbon atom substituted with hydrogen atom;
  • A' represents (1) a carbon atom substituted with hydrogen atom or O
  • C 0-4 alkyl groups which may optionally be substituted with a substituent selected from the group consisting of carbamoyl group, hydroxyl group, a C 1-3 alkoxy group and an amino group;
  • XX9 represents Arg or Arg(Me);
  • XXlO represents Phe or Trp.
  • metastin derivatives of the present invention or salts thereof, which are particularly preferred, are compounds represented by the following formula, or salts thereof:
  • XXO represents C 1-12 alkanoyl
  • XX2 represents D-Tyr
  • XX3 represents Hyp, Pro(4F) or GIu;
  • XX4 represents Asn, 2-amino-3-ureidopropionic acid
  • XX5 represents Thr
  • T represents the 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) an optionally substituted CO -12 aromatic hydrocarbon group, (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group consisting of 1 to 7 carbon atoms and hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, and, (5) an optionally substituted non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7;
  • A represents (1) a nitrogen atom substituted with hydrogen atom, (2) a carbon atom substituted with hydrogen atom;
  • a 1 represents (1) a carbon atom substituted with hydrogen atom or O;
  • XX9 represents Arg or Arg(Me); and, XXlO represents Trp.
  • Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH 2 (SEQ ID NO: 16) is referred to as metastin 10 (MetastinlO), i.e., MSlO.
  • N-terminal Tyr and the C-terminal Phe in MSlO are counted as 1- and 10-positions, respectively.
  • Compound No. 796 (EXAMPLE 1): des(l)-Ac-[D-Tyr2,Hyp3 5 Thr5,Arg(Me)9,Trpl0]MS10 means a peptide wherein the N-terminal Tyr (1-position) is deleted, Asn at the 2-position is replaced by D-Tyr, Trp at the 3 -position is replaced by Hyp, Ser at the 5-position is replaced by Thr, Arg at the 9 -position is replaced by Arg(Me), the C-terminal (10-position) is replaced by Trp, and the amino group on the D-Tyr at the 2-position is modified to Ac.
  • the chemical bond "-" in the formula "XX5-T” represents the bond between the carboxyl group ( ⁇ -carboxyl group) in XX5 and a group represented by the group represented by T. More specifically, -OH in the carboxyl group (-COOH) contained in XX5 is substituted with the group represented by T.
  • T-XX9 represents the bond between the group represented by T and the amino group ( ⁇ -amino group) in XX9. More specifically, hydrogen atom in the amino group (NH 2 ) contained in XX9 is substituted with the group represented by T.
  • the chemical bond "-" in the formula "XXlO-NH 2 " represents the bond between the carboxyl group ( ⁇ -carboxyl group) contained in XXlO and -NH 2 . More specifically, -OH in the carboxyl group (-COOH) contained in XXlO is substituted with -NH 2 .
  • metastin derivatives of the present invention all compounds that the groups described above are optionally combined are preferably used. Among others, the following compounds are preferred.
  • the metastin derivatives of the present invention can be prepared by publicly known methods for peptide synthesis.
  • the methods for peptide synthesis for example, either solid phase synthesis or liquid phase synthesis may be used. That is, the partial peptide or amino acids that can constitute the peptide of the present invention are repeatedly condensed with the remaining part to give the product having a desired sequence. Where the product has protecting groups, these protecting groups are removed to give the desired peptide.
  • Publicly known methods for condensation and removal of the protecting groups includes those, e.g., described in (1) to (5) below. (1) M. Bodanszky & M.A. Ondetti: Peptide Synthesis, Interscience Publishers, New York (1966)
  • the product may be purified and isolated by a combination of conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography and recrystallization to give the peptide of the present invention.
  • conventional purification methods such as solvent extraction, distillation, column chromatography, liquid chromatography and recrystallization to give the peptide of the present invention.
  • the peptide obtained by the above methods is in a free form, the peptide can be converted into an appropriate salt by a publicly known method; conversely when the peptide is obtained in a salt form, it can be converted into its free form by publicly known methods.
  • trisphosphonium salts examples include benzotriazol-l-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolidino) phosphonium hexafluorophosphate (PyBroP) and
  • tetramethyluronium salts examples include 2-(lH-benzotriazol-l-yl)-l,l,3,3-hexafluoro ⁇ hosphate (HBTU), 2-(7-azabenzotriazol-l-yl)-l, 1,3,3-hexafluorophosphate (HATU), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetraflluoroborate (TBTU), 2-(5-norbornene-2,3-dicarboxyimido)-l,l,3,3-tetramethyluronium tetrafiuoroborate (TNTU) and O-(N-succinimidyl)-l,l,3,3-tetramethyluronium tetramethyluronium tetramethyluronium tetrafluetrafluetrafluetrafluiuoroborate (TNTU) and O-(N-s
  • racemization inhibitors e.g., HONB, HOBt, HOAt, HOOBt, etc.
  • Solvents used in condensation may be appropriately chosen from solvents that are known to be usable for condensation.
  • acid amides such as anhydrous or hydrous N,N-dimethylfbrmamide, N,N-dimethylacetamide, N-methylpyrrolidone, etc., halogenated hydrocarbons such as methylene chloride, chloroform, etc., alcohols such as trifluoroethanol, phenol, etc., sulfoxides such as dimethyl sulfoxide, etc., tertiary amines such as pyridine, etc., ethers such as dioxane, tetrahydrofuran, etc., nitriles such as acetonitrile, propionitrile, etc., esters such as methyl acetate, ethyl acetate, etc., or suitable mixtures thereof, etc.
  • halogenated hydrocarbons such as methylene chloride, chloroform, etc.
  • alcohols such as trifluoroethanol, phenol, etc.
  • sulfoxides such as dimethyl sulfoxide, etc
  • the reaction temperature is appropriately chosen from the range known to be applicable to peptide binding reactions and is normally suitably chosen from the range of about -2O 0 C to 5O 0 C.
  • the activated amino acid derivatives are used generally in 1.5 to 6 times excess.
  • the condensation is examined using the ninhydrin reaction; when the condensation is insufficient, the condensation can be completed by repeating the condensation reaction without removal of the protecting groups. When the condensation is yet insufficient even after repeating the reaction, the unreacted amino acids are acylated with acetic anhydride or acetylimidazole to cancel any adverse effect on the subsequent reaction.
  • Examples of the protecting groups used to protect amino groups in the starting amino acids include Z, Boc, tert-pentyloxycarbonyl, isoborayloxycarbonyl, 4-methoxybenzyloxycarbonyl, Cl-Z, Br-Z, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulphenyl, diphenylphosphinothioyl, Fmoc, trityl, etc.
  • Examples of protecting groups for a carboxyl group include, in addition to the C 1-6 alkyl group, C 3-8 cycloalkyl group and C 7-14 aralkyl group for R described above, allyl, 2-adamantyl, 4-nitrobenzyl, 4-methoxybenzyl, 4-chlorobenzyl, phenacyl group, benzyloxycarbonylhydrazide, tert-butoxycarbonylhydrazide, tritylhydrazide, etc.
  • the hydroxyl group of serine and threonine can be protected, for example, by esterification or etherification.
  • groups suitable for this esterification include a group derived from organic acid such as a lower (C 2-4 ) alkanoyl group such as acetyl group, an aroyl group such as benzoyl group, etc.
  • Examples of a group suitable for the etherification include benzyl group, tetrahydropyranyl group, tert-butyl group, trytyl group (Trt), etc.
  • Examples of groups for protecting the phenolic hydroxyl group of tyrosine include BzI, 2,6-dichlorobenzyl (Cl 2 -BzI), 2-nitrobenzyl, Br-Z, tert-butyl, etc.
  • Examples of groups used to protect the imidazole moiety of histidine include Tos, 4-methoxy-2,3,6-trimethylbenzenesulfonyl (Mtr), DNP, Bom, Bum, Boc, Trt, Fmoc, etc.
  • 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 , etc.
  • Mtr 4-methoxy-2,3,6-trimethylbenzenesulfonyl
  • MSS p-methoxybenzenesulfonyl
  • Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl
  • Mts mesitylene-2-sulfonyl
  • Pbf 2,2,4,6,7-pentamethyld
  • protecting groups for side chain amino group of lysine include Z, Cl-Z, trifluoroacetyl, Boc, Fmoc, Trt, Mtr, 4,4-dimethyl-2,6-dioxocyclohexylideneyl (Dde), etc.
  • protecting groups for indolyl of tryptophan include formyl (For), Z, Boc, Mts, Mtr, etc.
  • Examples of protecting groups for asparagine and glutamine include Trt, xanthyl (Xan), 4,4-dimethoxybenzhydryl (Mbh), 2,4,6-trimethoxybenzyl (Tmob), etc.
  • Examples of the activated carboxyl groups in the starting material 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 the amino groups in the starting material include the corresponding phosphorous amides.
  • the elimination of protecting groups by the acid treatment described above is carried out generally at a temperature of approximately -20°C to 40°C.
  • a cation scavenger such as anisole, phenol, thioanisole, m-cresol, p-cresol, etc., dimethylsulf ⁇ de, 1,4-butanedithiol, 1,2-ethanedithiol, etc.
  • 2,4-dinitrophenyl group used as the protecting group for the imidazole of histidine is removed by a treatment with thiophenol.
  • Formyl group used as the protecting group of the indole of tryptophan is removed by the aforesaid acid treatment in the presence of 1,2-ethanedithiol, 1,4-butanedithiol, etc. as well as by a treatment with an alkali such as a dilute sodium hydroxide solution, dilute ammonia, etc.
  • Protection of functional groups that should not be involved in the reaction of the starting materials, protecting groups, removal of the protecting groups and activation of functional groups involved in the reaction may be appropriately chosen from publicly known groups and publicly known means.
  • Methods for obtaining the amide of the peptide include, for example, solid phase synthesis using resins for the formation of peptide amide.
  • the ⁇ -carboxyl group of the carboxy terminal amino acid is first protected by amidation; the peptide chain is then extended from the amino group side to a desired length. Thereafter, a peptide in which only the protecting group of the N-terminal ⁇ -amino group in the peptide chain has been removed from the peptide and a peptide (or an amino acid) in which only the protecting group of the C-terminal carboxyl group has been eliminated are prepared.
  • the two peptides are condensed in a mixture of the solvents described above.
  • the metastin derivative of the present invention when present in the form of a configurational isomer, a diastereomer, a conformer, or the like, each can be isolated by the separating and purifying means described above, if desired.
  • the compound of the present invention when the compound of the present invention is racemic, it can be separated into an S isomer and an R isomer by the conventional optical resolving means.
  • the present invention includes both of these isomers alone and the isomers present as a mixture thereof.
  • metastin derivative of the present invention may also be hydrated or non-hydrated.
  • the metastin derivative of the present invention may also be labeled with an isotope (e.g., 3 H, 14 C, 33 S), etc.
  • the peptides are represented in accordance with the conventional way of describing peptides, that is, the N-terminus (amino terminus) at the left hand and the C-terminus (carboxyl terminus) at the right hand.
  • the C-terminus is usually in the form of an amide (-CONH 2 ), a carboxyl group (-COOH), a carboxylate (-COO " ), an alkylamide (-C0NHR) or an ester (-COOR) and the amide (-CONH 2 ) is particularly preferred.
  • R in the ester or alkylamide examples include a C 1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.; a C 3-8 cycloalkyl group such as cyclopentyl, cyclohexyl, etc.; a C 6 - I2 aryl group such as phenyl, ⁇ -naphthyl, etc.; a C 7 -I 4 aralkyl group such as a phenyl-C ⁇ -alkyl group, e.g., benzyl, phenethyl, etc., or an ⁇ -naphthyl-d-2-alkyl group such as ⁇ -naphthylmethyl, etc.; pivaloyloxymethyl group, which are widely used as an ester for oral use, and the like.
  • salts of the metastin derivative of the present invention include a metal salt, an ammonium salt, a salt with an organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid, and the like.
  • Preferred examples of the metal salts include alkali metal salts such as sodium salts, potassium salts, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, barium salts, etc.; aluminum salts; and the like.
  • Preferred examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.
  • Preferred examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • salts with organic acids include salts with 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, etc.
  • Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc.
  • preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.
  • salts pharmaceutically acceptable salts are preferable.
  • inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), ammonium salts, and the like are preferable.
  • salts with inorganic acids with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. are preferable.
  • the prodrug of the metastin derivative or salts thereof (hereinafter sometimes simply referred to as the metastin derivative of the present invention) is used to mean such a metastin derivative that is converted into the metastin derivative of the present invention under physiological conditions or by reactions with an enzyme, a gastric acid, etc., in vivo.
  • the prodrug of the present invention refers to the metastin derivative that undergoes enzymatic oxidation, reduction, hydrolysis, etc. to be converted into the metastin derivative of the present invention, or the metastin derivative that undergoes hydrolysis, etc. by gastric acid, etc. to be converted into the metastin derivative of the present invention.
  • Examples of the prodrug of the metastin derivative of the present invention include metastin derivatives wherein the amino group in the metastin derivative of the present invention is substituted with acyl, alkyl, phosphoric acid, etc. (e.g., metastin derivatives wherein the amino group in the metastin derivative of the present invention is substituted with eicosanoyl, alanyl, pentylaminocarbonyl (5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc); metastin derivatives wherein the hydroxy group in the metastin derivative of the present invention is substituted with acyl, alkyl, phosphoric acid, boric acid, etc.
  • metastin derivatives wherein the hydroxy group in the metastin derivative of the present invention is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl, alanyl, dimethylaminomethylcarbonyl, etc.
  • metastin derivatives wherein the carboxy group in the metastin derivative of the present invention is substituted with ester, amide, etc.
  • metastin derivatives wherein the carboxy group of the metastin derivative of the present invention is converted into the ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester,
  • metastin derivatives can be produced from the metastin derivatives of the present invention by per se known methods.
  • the prodrugs of the metastin derivative of the present invention may be those converted into the metastin derivatives of the present invention under the 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 salts thereof and their Prodrugs have the cancer metastasis suppressing activity or cancer growth suppressing activity and are useful as medicaments including preventive/therapeutic agents for all cancers (e.g., lung cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, rectal cancer, colonic cancer, prostate cancer, ovarian cancer, cervical cancer, breast cancer, etc.), as cancer metastasis inhibitors or cancer growth inhibitors.
  • the compound of the present invention has the effects of regulating functions of the pancreas and is useful as therapeutic/preventive agents for various pancreatic diseases (e.g., acute or chronic pancreatitis, pancreatic cancer, etc.).
  • the compound of the present invention has the effects of regulating the functions of placenta and is useful as medicaments such as preventive or therapeutic agents for choriocarcinoma, hydatidiform mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction.
  • the compound of the present invention has the effects of increasing sugar level, promoting pancreatic glucagon secretion and promoting urine formation, and, is useful as a hyperglycemic agent, a pancreatic glucagon secretagogue agent or an agent for promoting urine formation, e.g., as medicaments including agents for preventing or treating, obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes mellitus, fatty atrophy, insulin allergy, insulinoma, arteriosclerosis, thrombotic disorders or lipotoxicity.
  • medicaments including agents for preventing or treating, obesity, hyperlipemia, type II diabetes mellitus, hypoglycemia, hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, edema, urinary disturbances, insulin resistance, unstable diabetes mellitus, fatty
  • the compound of the present invention has the effects of stimulating gonadotropic hormone (e.g., FSH, LH, etc.) secretion, stimulating sex hormone [e.g., androgens (e.g., testosterone, androstenedione, etc.), estrogens (e.g., estradiol, estrone, etc.), progesterones, etc.] secretion, improving gonadal function and inducing or stimulating ovulation, as well as a sexual maturation effect, etc., and thus can be used as an agent for improving gonadal function, an agent for inducing or stimulating ovulation, a gonadotropic hormone secretagogue agent or a sex hormone secretagogue agent, or an agent for preventing/treating hormone-dependent cancers [e.g., prostate cancer, breast cancer, etc.], infertility [e.g., irregular menstruation, dysmenorrhea, amenorrhea, weight loss-induced amenorrhea, secondary am
  • the compound of the present invention is useful as an agent for preventing/treating rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, gout, etc.) or the like.
  • Test can be performed by publicly known procedures to determine that the compound is useful for rheumatic diseases.
  • One specific example of the test procedures is described below.
  • Bovine type II collagen is dissolved in 0.05 mol/L acetic acid solution, which is adjusted to a concentration of 3 mg/mL.
  • An equivolume of FIA (Freund's incomplete adjuvant) is added to prepare an emulsion.
  • the rats are inoculated with the emulsion intracutaneously in the back for sensitization (primary immunization). Seven days after the primary immunization, 0.2 mL of the same emulsion is inoculated intracutaneously at the tail base for booster immunization.
  • rat rear paw volume is measured using Plethysmometer (UGO BASILE) and the volumes for both rear paws are averaged to give a baseline size of the paws.
  • UGO BASILE Plethysmometer
  • the value obtained by subtracting the pre- value (Day 0) of each animal from the values on Days 4, 7, 11 and 14 is made the value of each animal and provided for statistic calculation.
  • the compound of the present invention is also useful as: an agent for preventing/treating autism, immunomodulation (regeneration of thymus, repopulation of thymus, enhanced T cell growth), hypertension, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, thrombotic disorders or lipotoxicity; an agent for preventing/treating hyperlipemia, type II diabetes mellitus, hypertension, diabetic neuropathy, diabetic nephropathy or diabetic retinopathy; an antianxiety agent; an antistress agent; an anti-insomnia agent; an antimanic-depressive agent; an agent for preventing/treating hypertension (e.g., essential hypertension, renal hypertension, salt sensitive hypertension, etc.), angina pectoris (e.g., stable angina, unstable angina, etc.), myocardial infarction, cerebrovascular disorders (e.g., asymptomatic cerebrovascular disorder, transient ischemic attack, apoplexy, cerebrovascular dementia, hyper
  • the compounds described in WO2004/063221, the compounds described in WO2006/001499 and the compounds described in WO2007/072997, or salts thereof, are also useful as agents for preventing/treating rheumatic diseases (e.g., rheumatoid arthritis, osteoarthritis, gout, etc.) or the like.
  • rheumatic diseases e.g., rheumatoid arthritis, osteoarthritis, gout, etc.
  • metastin derivatives (i) represented by, e.g., the formula below, or salts thereof:
  • each of Z , Z , Z and Z represents hydrogen atom or a C 1-3 alkyl group; each of Z 2 , Z 4 , Z 6 and Z 8 represents hydrogen atom, O or S;
  • R 1 represents (1) hydrogen atom, or (2) a Ci -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) 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:
  • 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- I 2 aromatic hydrocarbon group,
  • Q 1 represents a C 1-4 alkyl group, which may optionally be substituted with a substituent selected from the group consisting of:
  • Q 2 represents (1) CH 2 , which may optionally be substituted with a C 1-4 alkyl group optionally substituted with a substituent selected from the group consisting of carbamoyl group and hydroxyl group, (2) NH, which may optionally be substituted with a C 1-4 alkyl group optionally substituted with a substituent selected from the group consisting of carbamoyl group and hydroxyl group, or (3) O;
  • Y represents a group shown by formula: -CONH-, -CSNH-, -CH 2 NH-, -NHCO-, -CH 2 O-, -CH 2 S- or -CH 2 CH 2 -, which may optionally be substituted with a Ci-6 alkyi group;
  • Z 9 represents hydrogen atom, O or S
  • P represents: (1) hydrogen atom
  • J 1 represents (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 groups may optionally be substituted with a substituent containing an optionally substituted cyclic group;
  • J 2 represents (1) NH optionally substituted with a Ci -6 alkyl group, (2) CH 2 optionally substituted with a C 1-6 alkyl group, (3) O or (4) S; each of J 3 through J 6 represents hydrogen atom or a C 1-3 alkyl group; each of Q 3 through Q 6 represents a C 1-4 alkyl group, which may optionally be substituted with a substituent selected from the group consisting of:
  • J 3 and Q 3 , J 4 and Q 4 , J 5 and Q 5 or J 6 and Q 6 may 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 through Y 3 represents a group represented by formula: -CON(J 13 )-, -CSN(J 13 )-, -C(J 14 )N(J 13 )- or -N(J 13 )CO- (wherein each of J 13 and J 1 represents hydrogen atom or a C 1-3 alkyl group); and, Z 10 represents hydrogen atom, O or S);
  • J 7 through J 9 have the same significance as J 3 ; Q 7 through Q 9 have the same significance as Q 3 ; Y 2 and Y 3 have the same significance as described above; Z 10 has the same significance as described above; J 7 and Q 7 , J 8 and Q 8 or J 9 and Q 9 may be combined together, or, J 2 and Q 7 , Y 2 and Q 8 or Y 3 and Q 9 may be combined together, to form a ring);
  • J 10 and J 11 have the same significance as J 3 ; Q 10 and Q 11 have the same significance as Q 3 ; Y 3 has the same significance as described above; Z ° has the same significance as described above; and, J 10 and Q 10 or J 11 and Q 11 may be combined together, or J 2 and Q 10 or Y 3 and
  • Q 11 may be combined together, to form a ring
  • J 1 and J 2 have the same significance as described above; J 12 has the same significance as J 3 ; Q 12 has the same significance as Q 3 ;
  • J 12 and Q 12 may be combined together, or J 2 and Q 12 may be combined together, to form a ring); or, (7) a group represented by formula: J 1 - (wherein, J 1 has the same significance as described above)], preferably the following compounds, or salts thereof:

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