Patent EP-1577323-A1 (EP)
Inventor: KITADA CHIEKO
IPC: A61P43/00
Filed: 2003-12-26
Abstract: The present invention provides a metastin derivative having excellent blood
stability and exhibiting cancer metastasis inhibiting action or cancer growth inhibiting
action. Specifically, the present invention the metastin derivative (I), which is
represented by formula:
 
[wherein, Z 1 , Z 3 , Z 5  and Z 7  represent H or a C 1-3  alkyl group; Z 2 , Z 4 , Z 6  and Z 8 
represent H, O or S; R 1  represents (1) H, or (2) a C 1-8  alkyl group optionally
substituted with a substituent selected from the group consisting of a carbamoyl
group, a hydroxyl group and a aromatic cyclic group; R 2  represents (1) H 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 a C 1-8  alkyl group having a basic
group, an aralkyl group having a basic group, a C 1-4  alkyl group having a
non-aromatic cyclic hydrocarbon group of carbon atoms not greater than 7 having a
basic group, or a C 1-4  alkyl group having a non-aromatic heterocyclic group of
carbon atoms not greater than 7 having a basic group; R 4  represents a C 1-4  alkyl
group, which may optionally be substituted with a substituent selected from the
group consisting of a C 6-12  aromatic hydrocarbon group, an aromatic heterocyclic
group, a C 8-14  aromatic fused-ring group, an aromatic fused heterocyclic group, a
non-aromatic cyclic hydrocarbon group, and a non-aromatic heterocyclic group
having carbon atoms not greater than 7; X represents a group shown by formula:
-NHCH(Q 1 )YQ 2 C(=Z 9 )- (wherein, Q 1  represents a C 1-4  alkyl group, which may
optionally be substituted with a substituent selected from the group consisting of an
aromatic hydrocarbon group, an aromatic heterocyclic group, a C 8-14  aromatic
fused-ring group, an aromatic fused heterocyclic group, a non-aromatic cyclic
hydrocarbon group having carbon atoms not greater than 7, and a non-aromatic
heterocyclic group having carbon atoms not greater than 7; Q 2  represents CH 2 , NH
or O; Y represents -CONH-, -CSNH-, -CH 2 NH-, -NHCO-, -CH 2 O-, -CH 2 S- or
-CH 2 CH 2 -;
Z 9  represents H, O or S); and P represents (1) H; (2) an optional 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: 1; (3) a group
represented by formula: J 1 -J 2 -C(J 3 )(Q 3 )Y 1 C(J 4 )(Q 4 )Y 2 C(J 5 )(Q 5 )Y 3 C(J 6 )(Q 6 )C(=Z 10 )-(wherein,
J 1  represents (a) H or (b) (i) a C 1-15  acyl group, (ii) a C 1-15  alkyl group, (iii)
a carbamoyl group, (iv) a C 1-15  alkylcarbamoyl group, (v) a C 1-15  alkanoylcarbamoyl
group, (vi) an aminocarbamoyl group, (vii) a C 1-15  alkylaminocarbamoyl group,
(viii) an oxycarbonyl group, (ix) a C 1-15  alkoxylcarbonyl group, (x) a sulfonyl group,
(xi) an amidino group, (xii) a C 1-15  alkylamidino group, (xiii) a C 1-15  acylamidino
group, (xiv) a C 1-15  alkylsulfonyl group, or (xv) a oxaryl group, which group may
optionally be substituted with cyclic group; J 2  represents NH, CH 2 , O or S; J 3 
through J 6  represent H or a C 1-3  alkyl group; Q 3  through Q 6  represent a C 1-4  alkyl
group, which may optionally be substituted with a substituent selected from the
group consisting of a C 6-12  aromatic hydrocarbon group, an aromatic heterocyclic
group, a C 8-14  aromatic fused-ring group, an aromatic fused heterocyclic group, a
non-aromatic cyclic hydrocarbon group having carbon atoms not greater than 7, a
non-aromatic heterocyclic group having carbon atoms not greater than 7, an amino
group, a guanidino group, a hydroxyl group, a carboxyl group, a carbamoyl group,
and a sulfhydryl group, or H; 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; Y 1  through Y 3  represent 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 
represent H or a C 1-3  alkyl group); and Z 10  represents H, O or S); (4) a group
represented by formula: J 1 -J 2 -C(J 7 )(Q 7 )Y 2 C(J 8 )(Q 8 )Y 3 C(J 9 )(Q 9 )C(=Z 10 )- (wherein, J 1 
and J 2  have the same significance as described above; 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); (5) a group
represented by formula: 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 described above represents; 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 10  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); (6) a group represented by formula: 
J 1 -J 2 -C(J 12 )(Q 12 )C(=Z 10 )- (wherein, 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 ; Z 10  has the same significance as described above; and 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)], or a salt thereof.