Metastin derivatives and use thereof

Abstract

The present invention provides a metastin derivative in which the amino acids comprising metastin were modified by alternative chemical substituents resulting in metastin derivatives, having excellent blood stability and exhibiting cancer metastasis inhibiting action or cancer growth inhibiting action.

1 . A metastin derivative represented by formula (I): 
       
         
           
                 
                 
               
                     
                   Tyr-Asn-Trp-Asn-Ser-Phe-Ala-Leu-Arg-Phe-NH 2   
                 
             
                
               
            
           
         
       
     
     
         2 - 6 . (canceled) 
     
     
         7 . The pharmaceutical according to claim  4 , which is an agent for regulating a function of the pancreas. 
     
     
         8 . The pharmaceutical according to claim  4 , which is an agent for preventing/treating acute or chronic pancreatitis or pancreatic cancer. 
     
     
         9 . The pharmaceutical according to claim  4 , which is an agent for regulating a function of the placenta. 
     
     
         10 . The pharmaceutical according to claim  4 , which is an agent for preventing/treating choriocarcinoma, hydatid mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction. 
     
     
         11 . The pharmaceutical according to claim  4 , which is an agent for improving gonadal function. 
     
     
         12 . (canceled) 
     
     
         13 . The pharmaceutical according to claim  4 , which is an agent for inducing or stimulating ovulation. 
     
     
         14 . The pharmaceutical according to claim  4 , which is a gonadotropic hormone secretagogue agent or a sex hormone secretagogue agent. 
     
     
         15 . The pharmaceutical according to claim  4 , which is an agent for preventing/treating Alzheimer's disease or moderate cognitive impairment. 
     
     
         16 . A method for suppressing cancer metastasis or cancer proliferation, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         17 . A method for preventing/treating cancer, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         18 . A method for regulating a function of the pancreas, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         19 . A method for preventing/treating acute or chronic pancreatitis or pancreatic cancer, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         20 . A method for regulating a function of the placenta, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         21 . A method for preventing/treating choriocarcinoma, hydatid 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 (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         22 . A method for improving gonadal function, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         23 . A method for preventing/treating hormone-dependent cancer, infertility, endometriosis or myoma of the uterus, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         24 . A method for inducing or stimulating ovulation, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         25 . A method for promoting gonadotropic hormone secretion or promoting sex hormone secretion, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         26 . A method for preventing/treating Alzheimer's disease or moderate cognitive impairment, which comprises administering to a mammal an effective dose of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         27 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for suppressing cancer metastasis or an agent for suppressing cancer proliferation. 
     
     
         28 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for preventing/treating cancer. 
     
     
         29 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for regulating a function of the pancreas. 
     
     
         30 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for preventing/treating acute or chronic pancreatitis or pancreatic cancer. 
     
     
         31 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for regulating a function of the placenta. 
     
     
         32 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for preventing/treating choriocarcinoma, hydatid mole, invasive mole, miscarriage, fetal hypoplasia, abnormal glucose metabolism, abnormal lipid metabolism or labor induction. 
     
     
         33 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for improving gonadal function. 
     
     
         34 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for preventing/treating hormone-dependent cancer, infertility, endometriosis or myoma of the uterus. 
     
     
         35 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for inducing or stimulating ovulation. 
     
     
         36 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture a gonadotropic hormone secretagogue agent or a sex hormone secretagogue agent. 
     
     
         37 . Use of the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof to manufacture an agent for preventing/treating Alzheimer's disease or moderate cognitive impairment. 
     
     
         38 . A pancreatic glucagon secretagogue agent, comprising an agonist for a metastin receptor. 
     
     
         39 . An agent for promoting urine formation, comprising an agonist for a metastin receptor. 
     
     
         40 . 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, comprising an agonist for a metastin receptor. 
     
     
         41 . The agent according to  claim 38  through  40 , wherein the agonist for a metastin receptor is the metastin derivative (I) according to  claim 1  or a salt thereof, or a prodrug thereof. 
     
     
         42 . A method for promoting pancreatic glucagon secretion, which comprises administering to a mammal an effective dose of the agonist for a metastin receptor. 
     
     
         43 . A method for promoting urine formation, which comprises administering to a mammal an effective dose of the agonist for a metastin receptor. 
     
     
         44 . A method 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, which comprises administering to a mammal an effective dose of the agonist for a metastin receptor. 
     
     
         45 . Use of the agonist for a metastin receptor to manufacture a pancreatic glucagon secretagogue agent. 
     
     
         46 . Use of the agonist for a metastin receptor to manufacture an agent for promoting urine formation. 
     
     
         47 . Use of the agonist for a metastin receptor to manufacture 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. 
     
     
         48 . A pharmaceutical composition comprising the metastin derivative of  claim 1 .