METASTIN DERIVATIVE AND USE THEREOF

摘要

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:
<Chemistry id="chema01" num="0001"><Image id="ia01" he="34" wi="138" file="IMGA0001.TIF" imgContent="chem" imgFormat="TIFF" /></Chemistry> [wherein, Z<Sup>1</Sup>, Z<Sup>3</Sup>, Z<Sup>5</Sup> and Z<Sup>7</Sup> represent H or a C<Sub>1-3</Sub> alkyl group; Z<Sup>2</Sup>, Z<Sup>4</Sup>, Z<Sup>6</Sup> and Z<Sup>8</Sup> represent H, O or S; R<Sup>1</Sup> represents (1) H, or (2) a C<Sub>1-8</Sub> 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<Sup>2</Sup> represents (1) H or (2) a cyclic or linear C<Sub>1-10</Sub> alkyl group, or (3) a C<Sub>1-10</Sub> alkyl group consisting of a cyclic alkyl group and a linear alkyl group; R<Sup>3</Sup> represents a C<Sub>1-8</Sub> alkyl group having a basic group, an aralkyl group having a basic group, a C<Sub>1-4</Sub> alkyl group having a non-aromatic cyclic hydrocarbon group of carbon atoms not greater than 7 having a basic group, or a C<Sub>1-4</Sub> alkyl group having a non-aromatic heterocyclic group of carbon atoms not greater than 7 having a basic group; R<Sup>4</Sup> represents a C<Sub>1-4</Sub> alkyl group, which may optionally be substituted with a substituent selected from the group consisting of a C<Sub>6-12</Sub> aromatic hydrocarbon group, an aromatic heterocyclic group, a C<Sub>8-14</Sub> 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<Sup>1</Sup>)YQ<Sup>2</Sup>C(=Z<Sup>9</Sup>)- (wherein, Q<Sup>1</Sup> represents a C<Sub>1-4</Sub> 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<Sub>8-14</Sub> 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<Sup>2</Sup> represents CH<Sub>2</Sub>, NH or O; Y represents -CONH-, -CSNH-, -CH<Sub>2</Sub>NH-, -NHCO-, -CH<Sub>2</Sub>O-, -CH<Sub>2</Sub>S- or -CH<Sub>2</Sub>CH<Sub>2</Sub>-; Z<Sup>9</Sup> represents H, O or S); and P represents (1) H; (2) an optional amino acid residue<!-- EPO <DP n="8001"> --> 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<Sup>1</Sup>-J<Sup>2</Sup>-C(J<Sup>3</Sup>)(Q<Sup>3</Sup>)Y<Sup>1</Sup>C(J<Sup>4</Sup>)(Q<Sup>4</Sup>)Y<Sup>2</Sup>C(J<Sup>5</Sup>)(Q<Sup>5</Sup>)Y<Sup>3</Sup>C(J<Sup>6</Sup>)(Q<Sup>6</Sup>)C(=Z<Sup>10</Sup>)-(wherein, J<Sup>1</Sup> represents (a) H or (b) (i) a C<Sub>1-15</Sub> acyl group, (ii) a C<Sub>1-15</Sub> alkyl group, (iii) a carbamoyl group, (iv) a C<Sub>1-15</Sub> alkylcarbamoyl group, (v) a C<Sub>1-15</Sub> alkanoylcarbamoyl group, (vi) an aminocarbamoyl group, (vii) a C<Sub>1-15</Sub> alkylaminocarbamoyl group, (viii) an oxycarbonyl group, (ix) a C<Sub>1-15</Sub> alkoxylcarbonyl group, (x) a sulfonyl group, (xi) an amidino group, (xii) a C<Sub>1-15</Sub> alkylamidino group, (xiii) a C<Sub>1-15</Sub> acylamidino group, (xiv) a C<Sub>1-15</Sub> alkylsulfonyl group, or (xv) a oxaryl group, which group may optionally be substituted with cyclic group; J<Sup>2</Sup> represents NH, CH<Sub>2</Sub>, O or S; J<Sup>3</Sup> through J<Sup>6</Sup> represent H or a C<Sub>1-3</Sub> alkyl group; Q<Sup>3</Sup> through Q<Sup>6</Sup> represent a C<Sub>1-4</Sub> alkyl group, which may optionally be substituted with a substituent selected from the group consisting of a C<Sub>6-12</Sub> aromatic hydrocarbon group, an aromatic heterocyclic group, a C<Sub>8-14</Sub> 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<Sup>3</Sup> and Q<Sup>3</Sup>, J<Sup>4</Sup> and Q<Sup>4</Sup>, J<Sup>5</Sup> and Q<Sup>5</Sup> or J<Sup>6</Sup> and Q<Sup>6</Sup> may be combined together, or, J<Sup>2</Sup> and Q<Sup>3</Sup>, Y<Sup>1</Sup> and Q<Sup>4</Sup>, Y<Sup>2</Sup> and Q<Sup>5</Sup>, or Y<Sup>3</Sup> and Q<Sup>6</Sup> may be combined together, to form a ring; Y<Sup>1</Sup> through Y<Sup>3</Sup> represent a group represented by formula: -CON(J<Sup>13</Sup>)-, -CSN(J<Sup>13</Sup>)-, -C(J<Sup>14</Sup>)N(J<Sup>13</Sup>)- or -N(J<Sup>13</Sup>)CO- (wherein J<Sup>13</Sup> and J<Sup>14</Sup> represent H or a C<Sub>1-3</Sub> alkyl group); and Z<Sup>10</Sup> represents H, O or S); (4) a group represented by formula: J<Sup>1</Sup>-J<Sup>2</Sup>-C(J<Sup>7</Sup>)(Q<Sup>7</Sup>)Y<Sup>2</Sup>C(J<Sup>8</Sup>)(Q<Sup>8</Sup>)Y<Sup>3</Sup>C(J<Sup>9</Sup>)(Q<Sup>9</Sup>)C(=Z<Sup>10</Sup>)- (wherein, J<Sup>1</Sup> and J<Sup>2</Sup> have the same significance as described above; J<Sup>7</Sup> through J<Sup>9</Sup> have the same significance as J<Sup>3</Sup>; Q<Sup>7</Sup> through Q<Sup>9</Sup> have the same significance as Q<Sup>3</Sup>; Y<Sup>2</Sup> and Y<Sup>3</Sup> have the same significance as described above; Z<Sup>10</Sup> has the same significance as described above; J<Sup>7</Sup> and Q<Sup>7</Sup>, J<Sup>8</Sup> and Q<Sup>8</Sup> or J<Sup>9</Sup> and Q<Sup>9</Sup> may be combined together, or, J<Sup>2</Sup> and Q<Sup>7</Sup>, Y<Sup>2</Sup> and Q<Sup>8</Sup> or Y<Sup>3</Sup> and Q<Sup>9</Sup> may be combined together, to form a ring); (5) a group represented by formula: J<Sup>1</Sup>-J<Sup>2</Sup>-C(J<Sup>10</Sup>)(Q<Sup>10</Sup>)Y<Sup>3</Sup>C(J<Sup>11</Sup>)(Q<Sup>11</Sup>)C(=Z<Sup>10</Sup>)- (wherein, J<Sup>1</Sup> and J<Sup>2</Sup> have the same significance as described above represents; J<Sup>10</Sup> and J<Sup>11</Sup> have the same significance as J<Sup>3</Sup>; Q<Sup>10</Sup> and Q<Sup>11</Sup> have the same significance as Q<Sup>3</Sup>; Y<Sup>3</Sup> has the same significance as described above; Z<Sup>10</Sup> has the same significance as described above; and J<Sup>10</Sup> and Q<Sup>10</Sup> or J<Sup>11</Sup> and Q<Sup>11</Sup> may be combined together, or J<Sup>2</Sup> and Q<Sup>10</Sup> or Y<Sup>3</Sup> and Q<Sup>11</Sup> may be combined together, to form a ring); (6) a group represented by formula:<!-- EPO <DP n="8002"> --> J<Sup>1</Sup>-J<Sup>2</Sup>-C(J<Sup>12</Sup>)(Q<Sup>12</Sup>)C(=Z<Sup>10</Sup>)- (wherein, J<Sup>1</Sup> and J<Sup>2</Sup> have the same significance as described above; J<Sup>12</Sup> has the same significance as J<Sup>3</Sup>; Q<Sup>12</Sup> has the same significance as Q<Sup>3</Sup>; Z<Sup>10</Sup> has the same significance as described above; and J<Sup>12</Sup> and Q<Sup>12</Sup> may be combined together, or J<Sup>2</Sup> and Q<Sup>12</Sup> may be combined together, to form a ring); or (7) a group represented by formula: J<Sup>1</Sup>- (wherein, J<Sup>1</Sup> has the same significance as described above)], or a salt thereof.