JPH08225457A - Composition for inhibiting cancer metastasis - Google Patents

Abstract

PURPOSE: To provide a composition comprising a specific lipid and a specific compound containing an adhesive core peptide sequence which is the basic unit of the adhesive function of a cell adhesive protein, exhibiting an excellent cancer metastasis-inhibiting action over a long time in vivo, and low in toxicity. CONSTITUTION: This composition comprises (A) a compound selected from among compounds of formulas: R<1> -Q-Z and H-Q-W-R<2> and a compound of the formula [Q is a fragment having a cell adhesive activity; R<2> is a 10-25C branched alkyl substituted on the terminal amino group of Q; R<1> is a 10-25C branched alkyl; R<3> is a 10-25C branched alkyl, a branched alkanoyl; W is O or NH substituted on the terminal carbonyl group of Q; Z is OH or (substituted) amino substituted on the C-terminal carbonyl group of Q], and (B) a lipid selected from among sphingolipids, cholesterol compounds, and phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine, phosphatidyl glycerol and phosphatidic acid which have 14-24C fatty acid residues, respectively.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a composition for suppressing cancer metastasis. More specifically, it relates to a composition for suppressing cancer metastasis, which comprises a compound containing a part or all of an adhesion core peptide sequence or an analog thereof, which is a basic unit of the adhesion function of a cell adhesive protein, and a lipid such as phosphatidylcholine. .

[0002]

BACKGROUND OF THE INVENTION Proteins such as fibronectin, laminin, and vitronectin are involved in the binding between cells and connective tissues and have various biological activities related to the cell function of animal cells. Has been done.
For example, fibronectin is a glycoprotein that is biosynthesized in the liver and is present in human plasma at a concentration of about 0.3 mg / ml.

The primary structure of fibronectin has been determined using molecular cloning (Koarnblihtt, AR, et.
al., EMBO Journal, 4, 2519, 1985), it has been clarified that the A chain, which is a polypeptide having a molecular weight of about 250K, and the B chain, which has a molecular weight of about 240K, are disulfide-bonded with a disulfide bond near the C terminus. . The primary structure of laminin has also been determined (Sasaki, M., et al., Proc. Natl. Acad. Sci.
USA., 81, 935, 1987; and Sasaki, M., et al., J.
Biol. Chem., 262, 17111, 1987), A chain, B1 chain, B2
It is known that it is composed of three polypeptide chains called chains and has a cross-shaped structure.

[0004] The binding sites of these cell adhesion proteins involved in cell adhesion have also been studied, and the core sequence of the cell adhesion part of fibronectin is Arg-Gly-Asp-Ser (indicated by RGDS in single letter code). , Hereinafter, this sequence may be referred to as "RGDS sequence" in the present specification) (Pierschbacher, M.
D., et al., Nature, 309, 30, 1984), that the core sequence of the cell adhesion site of laminin is Tyr-Ile-Gly-Ser-Arg (YIGSR
It has been elucidated to be a pentapeptide consisting of (sequence) (Graf, J., et al., Cell, 48, 989, 1987).

Cell-adhesive proteins such as fibronectin and laminin transmit various information to cells by binding to cell receptors through the above core sequences. On the other hand, the cell adhesive protein binds to biopolymers such as heparin, collagen and fibrin through the above core sequence, and is involved in adhesion between cells and connective tissue, differentiation and proliferation of cells, etc. It is believed that.

In recent years, cell adhesion proteins have been attracting attention as biomolecules involved in cancer metastasis. In cancer metastasis, cancer cells released from a primary cancer tissue that has invaded the blood vessel migrate to the vascular endothelial cells in distant tissues by flowing in the bloodstream, and then the cancer cells that adhere to the vascular endothelial cells and implant are proliferated. It is thought to be completed by escaping from the vascular endothelium to extravascular tissue and proliferating to form metastatic tissue. In the process of such cancer metastasis, cancer cells come into contact with various host cells and biopolymers, but when they come into contact with cell adhesive molecules such as fibronectin and laminin, multicellular masses are formed and cancer cells grow or grow. It is believed to increase the chances of survival.

In the process of forming this multicellular nucleus, the adhesion between the cancer cell and the cell adhesive molecule is essential, and such adhesion is caused by the receptor (generally called integrin) existing on the surface of the cancer cell. It is considered to be carried out by specifically binding the core sequence on the surface of the cell adhesive molecule as a ligand. Further, when an oligopeptide containing a sequence corresponding to the core sequence of the adhesion site of fibronectin is coexisted in the adhesion process of the above-mentioned cancer cells, this oligopeptide competitively binds to the fibronectin receptor on the surface of cancer cells, resulting in cell adhesion. Have been reported to be blocked by cancer metastasis inhibition (Science, Vol. 23).
8, 467, 1986).

[0008] However, when a tetrapeptide having the RGDS sequence (or a tripeptide having a part of the RGD sequence) is administered as a cancer metastasis inhibitor, the Arg-Gly bond is rapidly enzymatically hydrolyzed. Or, since the tetrapeptide itself is a small molecule and is rapidly excreted, it is not possible to maintain an effective blood concentration,
There is a problem that its effectiveness as a medicine can hardly be expected. In order to solve such problems, attempts have been made to maintain effective blood levels by using modified polypeptides containing these core sequences and to further enhance the binding force (cell adhesion) to cancer cell surface receptors. .

For example, a method for controlling cancer metastasis using an oligopeptide containing the above core sequence, a cyclic oligopeptide, or a peptide having a repeating sequence thereof has been proposed (Int. J. Biol. Macromol., Vol. .11, 23, 198
9: ibid, Vol.11, 226, 1989: Jpn. J. Cancer Res., Vo
l.60, 722, 1989; and JP-A-2-174798. In addition, a method for preventing tumor recurrence with such a modified peptide (Japanese Patent Laid-Open No. 2-240020) or cancer using a peptide having a cell adhesion peptide and a heparin-binding peptide in the fibronectin molecule as constituent units A method of suppressing metastasis (Japanese Patent Laid-Open No. 3-127742) has also been proposed. However, the cancer metastasis inhibitory action of these modified peptides alone has not been satisfactory from the viewpoint of receptor affinity and pharmacokinetics (blood concentration half-life, etc.).

On the other hand, many methods of using molecular aggregates such as liposomes and micelles as drug carriers have been studied (for example, Cancer Res., Vol. 43, 5328, 1983; J.
Controlled Release, Vol., 269, 1990;
"Liposome", published by Nankodo, pp.245-271, 1988). However, an example in which these molecular assemblies are combined with the above-mentioned cancer metastasis inhibitor and used as a medicine has not yet been known. For example, a compound obtained by introducing myristic acid into an RGD sequence-containing peptide is disclosed in PCT International Publication WO 90/11297, but its utility as a cancer metastasis inhibitor is unknown.

[0011]

An object of the present invention is to provide a composition for suppressing cancer metastasis. More specifically, one of the objects of the present invention is to use a compound containing the core sequence as a partial structure capable of specifically binding to a cancer cell surface receptor having the core sequence as a ligand. It is intended to provide a composition for suppressing cancer metastasis, which is included as one of the components. Another object of the present invention is to suppress cancer metastasis, which comprises one of the active ingredients as a compound having the above-mentioned characteristics and capable of exhibiting an excellent cancer metastasis suppressing action when administered to a living body. To provide a composition.

From another point of view, the object of the present invention is to suppress cancer metastasis by containing, as an active ingredient, the above-mentioned compound having a cancer metastasis suppressing action and a substance which enhances the cancer metastasis suppressing action of such a compound. An object is to provide a useful pharmaceutical composition. Further, it is an object of the present invention to provide an action enhancer for enhancing the cancer metastasis inhibiting action of the above compound having a cancer metastasis inhibiting action, and a method for inhibiting cancer metastasis using the above pharmaceutical composition.

[0013]

As a result of the inventors' earnest efforts to solve the above-mentioned problems, the partial structure of a middle or higher alkyl chain having at least one branch in the molecule and the above structure
It was found that a compound having an RGDS peptide sequence or a partial structure consisting of a repeating sequence thereof has an excellent cancer metastasis inhibitory action, and that a specific lipid remarkably enhances the cancer metastasis inhibitory action of the above compound. . Furthermore, the present inventor has found that a composition containing the above compound and a specific lipid exhibits an excellent cancer metastasis inhibitory action and is useful as a cancer metastasis inhibitory composition. The present invention has been completed based on the above findings.

That is, the present invention provides a composition for suppressing cancer metastasis, which comprises the following components: (a) the following formulas: R ¹ -QZ (I) HQWR ² (II) and HQ-NHCH ₂ CH ₂ O-. PO (OH) -0CH ₂ CH (OR ³ ) CH ₂ OR ³ (III) (In the formula, Q represents a fragment having cell adhesion activity, and R ¹ represents 10 carbon atoms substituted on the terminal amino group of the fragment. ~ 25 represents an alkanoyl group having 1 or 2 or more branches; R ² represents an alkyl group having 1 or 2 or more branches having 10 to 25 carbon atoms; and R ³ independently represents a carbon number.
10 to 25 represents an alkyl group or alkanoyl group having 1 or 2 or more branches; W represents -O- group or -NH- group substituted on the terminal carbonyl group of the above fragment; Z
Represents a hydroxyl group substituted on the C-terminal carbonyl group of the above fragment or a substituted or unsubstituted amino group), and a compound (b).
Phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylserine having a fatty acid residue having 14 to 24 carbon atoms, fatty acid residue having 14 to 24 carbon atoms Group-containing phosphatidylglycerol, phosphatidic acid having a C14-24 fatty acid residue, sphingolipids,
The present invention provides a composition containing a lipid selected from the group consisting of cholesterol.

According to a preferred embodiment of the present invention, the above fragment Q is represented by the following formula: ([X ¹ ] -Arg-Gly-Asp- [X ² ]) n (where Arg, Gly and Asp are each arginine. , Glycine, and aspartic acid residues; [X ¹ ] and [X ² ] indicate that X ¹ and X ² may or may not be present; X ¹ and X ² are each independently Represents an amino acid residue selected from the group consisting of serine, glycine, valine, asparagine, proline, cysteine, and threonine residues; n represents an integer of 1 to 5), and R ¹ is Substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is substituted on the C-terminal carbonyl group of the peptide chain. Composition; wherein the above fragment Q is represented by the following formula: ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n (wherein Ar g and Asp represent arginine and aspartic acid respectively; [Y ¹ ] and [Y ³ ] indicate that Y ¹ and Y ³ may or may not be present; Y ¹ represents aspartic acid Y ² represents leucine or isoleucine;
Y ³ represents serine or threonine; n represents an integer of 1 to 5), R ¹ is substituted on the N-terminal amino group of the peptide chain, and W is the peptide described above. The above composition substituted on the C-terminal carbonyl group of the chain and Z is substituted on the C-terminal carbonyl group of the above peptide chain; and the above fragment Q is represented by the following formula: ([Z] -Tyr-Ile -Gly-Ser-Arg) n (wherein Tyr, Ile, Gly, Ser, Arg represent tyrosine, isoleucine, glycine, serine and arginine, respectively; [Z] represents the presence or absence of Z. Is good; Z is aspartic acid or glutamic acid, n
Represents an integer of 1 to 5),
R ¹ is substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is on the C-terminal carbonyl group of the peptide chain. Substituted compositions as described above are provided.

Further, in a preferred embodiment of these inventions, R ¹ is an alkanoyl group having one or more methyl group branches, and R ² is an alkyl group having one or more methyl group branches, and / or Alternatively, the above composition in which R ³ is each independently an alkyl group having one or more methyl group branches or an alkanoyl group; R ¹ is H- [CH ₂ -CH
_{(CH 3) - (CH 2} ) 2] k -CH 2 -CH (CH 3) a -CH ₂ -CO- (k is an integer of 1 to 3), R ² is H- [CH ₂ - CH (CH ₃ )-(CH ₂ ) ₂ ] _l-
(l represents an integer of 2 to 4) and / or R ³ is H
_{- [CH 2 -CH (CH 3} ) - (CH 2) 2] m - (m is an integer of 2-4)
Or _{H- [CH 2 -CH (CH 3} ) - (CH 2) 2] s -CH 2 -CH (CH 3) -CH 2 -C
O- (s represents an integer of ¹ to 3); R ¹ is 3,
7,11-trimethyldodecanoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and a group selected from the group consisting of 5,9,13,17-tetramethyloctadecanoyl group,
R ² is a group selected from the group consisting of 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, and 5,9,13,17-tetramethyloctadecyl group, as well as/
Or R ³ are each independently 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, 5,9,13,1
7-tetramethyloctadecyl group, 3,7,11-trimethyldodecanoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and 5,9,13,17-tetramethyloctadecanoyl group There is provided the above composition, which is a group selected from the group.

In a preferred embodiment of these inventions, the lipid is a phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, a phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, and a fatty acid having 14 to 24 carbon atoms. Phosphatidylserine having a residue, phosphatidylglycerol having a fatty acid residue having 14 to 24 carbon atoms, 14 carbon atoms
To phosphatidic acid having a fatty acid residue of 24 to 24, and the above composition which is a lipid selected from the group consisting of cholesterol; phosphatidylcholine having a fatty acid residue of 14 to 24 carbon atoms, fatty acid residue of 14 to 24 carbon atoms The above composition, which is a lipid selected from the group consisting of phosphatidyl glycerol having: and cholesterol; the above composition wherein the lipid is a mixture of distearoylphosphatidyl choline, cholesterol, and dipalmitoyl phosphatidyl glycerol; Is provided.

According to another aspect of the invention, the following formulas: R ¹ -QZ (I) HQWR ² (II) and HQ-NHCH ₂ CH ₂ O-PO (OH) -0CH ₂ CH (OR ³ ) CH ₂ OR ³ (III) (In the formula, Q represents a fragment having a cell adhesion activity, and R ¹ represents one or more branches having 10 to 25 carbon atoms substituted on the terminal amino group of the fragment. Represents an alkanoyl group having; R ² represents an alkyl group having 10 to 25 carbon atoms and having 1 or 2 or more branches; R ³ independently represents the carbon number.
10 to 25 represents an alkyl group or alkanoyl group having 1 or 2 or more branches; W represents -O- group or -NH- group substituted on the terminal carbonyl group of the above fragment; Z
Is a hydroxyl group substituted on the C-terminal carbonyl group of the above fragment or a substituted or unsubstituted amino group), and is a potentiator of the cancer metastasis inhibitory action of a compound selected from the group consisting of compounds represented by Phosphatidylcholine having a fatty acid residue of 14 to 24, phosphatidylethanolamine having a fatty acid residue of 14 to 24 carbon atoms, 14 carbon atoms
Selected from the group consisting of phosphatidylserine having a fatty acid residue of 24 to 24, phosphatidylglycerol having a fatty acid residue of 14 to 24 carbon atoms, phosphatidic acid having a fatty acid residue of 14 to 24 carbon atoms, sphingolipids, and cholesterol. Provided is a potentiator containing a lipid as an active ingredient.

According to a preferred embodiment of the present invention, the above fragment Q is represented by the following formula: ([X ¹ ] -Arg-Gly-Asp- [X ² ]) n (where Arg, Gly and Asp are arginine, respectively). , Glycine, and aspartic acid residues; [X ¹ ] and [X ² ] indicate that X ¹ and X ² may or may not be present; X ¹ and X ² are each independently Represents an amino acid residue selected from the group consisting of serine, glycine, valine, asparagine, proline, cysteine, and threonine residues; n represents an integer of 1 to 5), and R ¹ is Substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is substituted on the C-terminal carbonyl group of the peptide chain. Enhancer; the above fragment Q is represented by the following formula: ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n (wherein Arg and Asp represent arginine and aspartic acid respectively; [Y ¹ ] and [Y ³ ] indicate that Y ¹ and Y ³ may or may not be present; Y ¹ represents aspartic acid Y ² represents leucine or isoleucine;
Y ³ represents serine or threonine; n represents an integer of 1 to 5), R ¹ is substituted on the N-terminal amino group of the peptide chain, and W is the peptide described above. The enhancer is substituted on the C-terminal carbonyl group of the chain and Z is substituted on the C-terminal carbonyl group of the peptide chain; the fragment Q is of the formula: ([Z] -Tyr-Ile- Gly-Ser-Arg) n (wherein Tyr, Ile, Gly, Ser, Arg represent tyrosine, isoleucine, glycine, serine and arginine respectively; [Z] may or may not be Z) Z is aspartic acid or glutamic acid, and n
Represents an integer of 1 to 5),
R ¹ is substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is on the C-terminal carbonyl group of the peptide chain. Substituted enhancers are provided.

According to a preferred embodiment of the above invention, R ¹ is an alkanoyl group having one or more methyl group branches, and R ² is an alkyl group having one or more methyl group branches. , And / or R ³ are each independently an alkyl group or an alkanoyl group having 1 or 2 or more methyl group branches; R ¹ is H- [CH ₂ -CH
_{(CH 3) - (CH 2} ) 2] k -CH 2 -CH (CH 3) a -CH ₂ -CO- (k is an integer of 1 to 3), R ² is H- [CH ₂ - CH (CH ₃ )-(CH ₂ ) ₂ ] _l-
(l represents an integer of 2 to 4) and / or R ³ is H
_{- [CH 2 -CH (CH 3} ) - (CH 2) 2] m - (m is an integer of 2-4)
Or _{H- [CH 2 -CH (CH 3} ) - (CH 2) 2] s -CH 2 -CH (CH 3) -CH 2 -C
The above-mentioned enhancer which is O- (s represents an integer of ¹ to 3); R ¹ is 3,
7,11-trimethyldodecanoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and a group selected from the group consisting of 5,9,13,17-tetramethyloctadecanoyl group,
R ² is a group selected from the group consisting of 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, and 5,9,13,17-tetramethyloctadecyl group, as well as/
Alternatively, R ³ are each independently 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, 5,9,13,1
7-tetramethyloctadecyl group, 3,7,11-trimethyldodecanoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and 5,9,13,17-tetramethyloctadecanoyl group Provided is the above enhancer, which is a group selected from the group.

Further, as preferred embodiments of these inventions, the lipid is a phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, a phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, and a fatty acid residue having 14 to 24 carbon atoms. Phosphatidylserine having a group, phosphatidylglycerol having a fatty acid residue having 14 to 24 carbon atoms, 14 carbon atoms
The above enhancer which is a lipid selected from the group consisting of phosphatidic acid having a fatty acid residue of 24 to 24 and cholesterol; phosphatidylcholine having a fatty acid residue of 14 to 24 carbon atoms, and a fatty acid residue of 14 to 24 carbon atoms The above-mentioned enhancer which is a lipid selected from the group consisting of phosphatidyl glycerol having: and cholesterol; A method for suppressing cancer metastasis, which comprises the step of administering to a mammal is provided.

In the above general formula, Q is, for example, Arg-Gly.
-Peptide chains having cell adhesion activity such as Asp-Ser and peptide analogs having equivalent actions to these are shown. Examples of the peptide analog include those in which the nitrogen atom in the peptide bond is replaced with a carbon atom, and those in which the carbonyl group in the amide bond is a thiocarbonyl group. Preferably, Q is ([X ¹ ] -Arg-Gly-As
p- [X ² ]) n (where Arg, Gly, Asp are arginine, glycine, and aspartic acid residues, respectively; [X ¹ ] and [X ² ] are X ¹ and X ^2, respectively. Or X ¹ and X ² each independently represent an amino acid residue selected from the group consisting of serine, glycine, valine, asparagine, proline, cysteine, and threonine residues; n Is an integer of 1 to 5); ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n (wherein Arg and
Asp represents arginine and aspartic acid, respectively;
[Y ¹ ] and [Y ³ ] respectively indicate that Y ¹ and Y ³ may or may not be present; Y ¹ represents aspartic acid; Y ²
Represents leucine or isoleucine; Y ³ represents serine or threonine; n represents an integer of 1 to 5); or ([Z] -Tyr-Ile-Gly-Ser-Arg) n (In the formula, Tyr, Ile, Gly, Ser and Arg represent tyrosine, isoleucine, glycine, serine and arginine, respectively;
[Z] indicates that Z may or may not be present;
Z represents aspartic acid or glutamic acid, n is 1 to
(Indicates an integer of 5).

For these fragments-[X ¹ ] -Arg-
Taking Gly-Asp- [X ² ]-as an example, arginine,
It is shown that an amino acid residue represented by X and Y is optionally bonded to the N-terminal and C-terminal of the tripeptide to which glycine and an aspartic acid residue are bonded, and more specifically, -X ^1- Arg-Gly-Asp-X ^2- , -X ¹ -Arg-Gly-Asp-,
A peptide chain of either -Arg-Gly-Asp-X ^2- , or -Arg-Gly-Asp- is shown (in the present specification, when the peptide chain is described as above, the left end is the peptide chain. N
The end and the right end are the C-terminal of the peptide chain). Also, (-
[X ¹ ] -Arg-Gly-Asp- [X ² ]-) n is the above-X ¹ -Arg-Gly-Asp
-X ^2- , -X ¹ -Arg-Gly-Asp-, -Arg-Gly-Asp-X ^2- , or-
It shows a peptide chain to which n (n is an integer of 1 to 5) peptide chains independently selected from the group consisting of Arg-Gly-Asp- are bound. For example, a peptide chain in which n identical peptide chains are linked to form a repeating sequence is a preferred partial structure of the compound of the present invention.

If X ¹ and / or X ² are present, X ¹ and X ²
Can be the same or different, but X ¹ is Gly and Y is Se
It is preferably r, Thr or Val. The amino acid residues (excluding glycine residue) constituting these peptide chains may be in the D-form, the L-form, or the racemic form, but preferably the L-form can be used. For example, L-aspartic acid or D-aspartic acid can be used as Y ¹ , and Y ² is L-leucine, D-leucine,
Alternatively, it is preferably D-isoleucine, and Y ³ is L-serine or L-threonine. Furthermore, Z may be any of L-aspartic acid, D-alpartic acid, L-glutamic acid, or D-glutamic acid.

R ¹ is an alkanoyl group having 10 to 25 carbon atoms, which is substituted on the terminal amino group of the above fragment, preferably the N-terminal amino group of the above peptide chain, and which has one or more branches. Indicates. As a branch, a lower alkyl group having 1 to 4 carbon atoms, preferably a methyl group
Alternatively, 2 or more, preferably 1 to 4 alkanoyl groups can be used. As such an alkanoyl group, it is preferable to use an acyl group having a chain terpene-like structure. Such an alkanoyl group is, for example, H-
_{[CH 2 -CH (CH 3)} - (CH 2) 2] k -CH 2 -CH (CH 3) -CH 2 -CO- (k is 1
The integer of 3 to 3) can be shown, and as the chain terpene-like structure, those derived from natural chain terpenes as well as those derived from synthetic terpenes may be used. These are functional groups converted from the diterpene phytol and isophytol, the sesquiterpene farnesol and the like by a method well known to those skilled in the art, and are present in the terpene.
It can be prepared by reducing the heavy bonds, the details of which are given in the examples below. More specifically, as such an alkanoyl group, a 3,7,11-trimethyldodecanoyl group, a 3,7,11,15-tetramethylhexadecanoyl group,
A 5,9,13,17-tetramethyloctadecanoyl group or the like can be used.

R ² represents an alkyl group having 10 to 25 carbon atoms and having 1 or 2 or more branches. As a branch, a lower alkyl group having 1 to 4 carbon atoms, preferably an alkyl group having 1 or 2 or more, preferably 1 to 4 methyl groups can be used. As such an alkyl group, it is preferable to use an alkyl group having a chain-like terpene-like structure. Such an alkyl group is, for example, H- [CH ₂ -CH (CH ₃ )-(CH ₂ )
₂ ] _l- (l represents an integer of 2 to 4), and the chain terpene-like structure may be derived from a natural chain terpene or may be derived from a synthetic terpene. . These alkyl groups can be produced similarly to the above alkanoyl group. For example, 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group,
A 5,9,13,17-tetramethyloctadecyl group or the like can be used.

W represents a terminal carbonyl group of the above fragment, preferably a —O— group or an —NH— group substituted on the C-terminal carbonyl group of the above peptide chain, and more specifically,
When W represents an -O- group and the fragment is a peptide chain, the C-terminal of the peptide chain is esterified with R ^2.
When (-COOR ² ) is formed and W represents a -NH- group, the C-terminal of the above peptide chain represents an amide group (-CONHR ² ) in which R ² is substituted on the nitrogen atom. Z represents a hydroxyl group substituted on the C-terminal carbonyl group of the peptide chain or a substituted or unsubstituted amino group, and more specifically, when Z represents a hydroxyl group, the C terminal of the peptide chain is a carboxyl group. And when Z 2 represents a substituted or unsubstituted amino group, it represents a substituted or amide group having a substituent on the nitrogen atom. When Z represents a substituted amino group, a lower alkyl group having about 1 to 4 carbon atoms can be used as the substituent.

R ^3's each independently represent an alkyl group having 10 to 25 carbon atoms and having 1 or 2 or more branches, or an alkanoyl group. As a branch, a lower alkyl group having 1 to 4 carbon atoms, preferably 1 or 2 or more methyl groups, preferably 1 to 4
Alkyl groups each having one can be used. As the alkyl moiety of such an alkyl group or alkanoyl group,
It is preferable to use an alkyl group having a chain terpene-like structure. Such an alkyl group is, for example, H- [CH ₂ -C
H (CH ₃ )-(CH ₂ ) ₂ ] _m- (m represents an integer of 2 to 4). You may use what was induced. These alkyl groups can be produced similarly to the above alkanoyl group. As R ³ , for example, 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, 5,9,13,17-tetramethyloctadecyl group, 3,7,11-trimethyl Dodecanoyl group, 3,7,11,
15-tetramethylhexadecanoyl group or 5,9,13,17-
A tetramethyloctadecanoyl group or the like can be used.

A part of the group of compounds represented by the above formulas (I), (II), and (III) is disclosed in JP-A-4-208295, and can be easily prepared by the method described in this publication. It is possible to manufacture. Further, the above formulas (I), (II), and (II
Regarding the structure and properties of the fragment having the cell adhesion activity of the compound represented by I) and the production method,
4-208295 gazette, Japanese Patent Application No. 5-111716, Japanese Patent Application No.
It is described in detail in the specification of 5-111717 and the like. In addition,
The above-mentioned compound group of the present invention includes novel compounds, which are referred to by the above publications and publications described in the prior art, or by referring to the examples of the present specification. It is a compound that can be easily produced by a trader. It is obvious to those skilled in the art that the above compounds have a plurality of asymmetric carbons depending on the type of raw material amino acid used and the number and type of side chain branches. Therefore, the range of the compound includes all optically active isomers and isomers such as diastereoisomers, as well as arbitrary mixtures and racemates of these isomers.

Of the compounds included in the composition of the present invention,
The fragment with cell adhesion activity is ([X ¹ ] -Arg-Gly-As
Preferred compounds are exemplified as the compounds represented by p- [X ² ]) n, but the compounds contained in the composition of the present invention are not limited thereto. In addition, [-([X ¹ ] -Arg-Gly-Asp
-[X ² ]) n-], AA: -Arg-Gly-Asp-; BB: -Gly-Arg-
Gly-Asp- ； CC: -Arg-Gly-Asp-Ser- ； DD: -Arg-Gly-Asp-Th
r- ； EE: -Arg-Gly-Asp-Val- ； FF: -Gly-Arg-Gly-Asp-Ser
-； GG: -Gly-Arg-Gly-Asp-Thr- ； HH: -Gly-Arg-Gly-Asp-V
The abbreviation for al- is used.

[Table 1] Compound of formula (I) ──────────────────────────────────── No. Peptide moiety ZR ¹ ─────────────────────────────────── I-1 AA OH CH ₃ -CH (CH ₃ )- (CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-2 FF OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I- 3 AA-AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-4 AA-FF OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-5 AA-EE-AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I -6 HH-AA-AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-7 AA-AA-FF-AA OH CH ₃ -CH ( CH ₃ )-(CH ₂ ) _3- CH (CH ₃ ) -CH ₂ -CO- I-8 AA-AA-AA-AA-AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-9 AA-BB-AA-CC-AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I -10 AA-BB-DD-AA-FF OH CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -CH ₂ -CO- I-11 AA OH H- [CH ₂ -CH _{(CH 3) - (CH 2} ) 2] 2 -CH 2 -CH (CH 3) -CH 2 -CO- I-12 AA-FF OH H- [CH 2 _{-CH (CH 3) - (CH} 2) 2] 2 -CH 2 -CH (CH 3) -CH 2 -CO- I-13 GG-FF OH H- [CH 2 -CH (CH 3) - (CH _{2) 2] 2 -CH 2 -CH} (CH 3) -CH 2 -CO- I-14 AA OH H- [CH 2 -CH (CH 3) - (CH 2) 2] 3 -CH 2 -CH ( CH ₃ ) -CH ₂ -CO- I-15 BB OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I- 16 CC OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-17 DD OH H- [CH ₂ -CH ( CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-18 EE OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _{3 -CH 2 -CH (CH 3) -CH} 2 -CO- I-19 FF OH H- [CH 2 -CH (CH 3) - (CH 2) 2] 3 -CH 2 -CH (CH 3) -CH ₂ -CO- I-20 GG OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-21 HH OH H- _{[CH 2 -CH (CH 3)} - (CH 2) 2] 3 -CH 2 -CH (CH 3) -CH 2 -CO- I-22 AA-CC OH H- [CH 2 -CH (CH 3) -(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-23 GG-FF OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _{3- CH 2 -CH (CH 3) -CH} 2 -CO- I-24 AA-CC-GG OH H- [CH 2 -CH (CH 3) - (CH 2) 2] 3 -CH 2 -CH (CH 3 ) -CH ₂ -CO- I-25 AA-DD-BB-CC OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH _2- CO- I -26 CC-DD-AA-GG-HH OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-27 CC -CC-CC-CC-CC OH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-28 FF OH C _{2 H 5 -CH (C 2 H 5} ) - (CH 2) 3 -CH (CH 3) -CH 2 -CO- I-29 FF OH C 2 H 5 -CH (CH 3) - (CH 2) 3 - CH (CH ₃ ) -CH ₂ -CO- I-30 AA OH CH ₃ -CH (CH ₃ )-(CH ₂ ) _3- CH (C ₂ H ₅ ) -CH ₂ -CO- I-31 CC NH _{2 H- [CH 2 -CH (CH 3} ) - (CH 2) 2] 3 -CH 2 -CH (CH 3) -CH 2 -CO- I-32 DD NH 2 H- [CH 2 -CH (CH 3 )-(CH ₂ ) ₂ ] ₃ -CH ₂ -CH (CH ₃ ) -CH ₂ -CO- I-33 EE NH ₂ H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _3- CH ₂ -CH (CH ₃ ) -CH ₂ -CO- ────────────────────────────────────

[0031]

[Table 2] Compound of formula (II) ─────────────────────────────────── No. Peptide part WR ² ─────────────────────────────────── II-1 AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) _3- CH (CH ₃ )-(CH ₂ ) ₂ -II-2 FF -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-3 AA-AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) _3- CH (CH ₃ )-(CH ₂ ) ₂ -II-4 AA-FF -O- CH _{3 -CH (CH 3) - (} CH 2) 3 -CH (CH 3) - (CH 2) 2 - II-5 AA-EE-AA -O- CH 3 -CH (CH 3) - (CH 2) _{3 -CH (CH 3) - (} CH 2) 2 - II-6 HH-AA-AA -O- CH 3 -CH (CH 3) - (CH 2) 3 -CH (CH 3) - (CH 2) ₂ -II-7 AA-AA-FF-AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-8 AA-AA-AA -AA-AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-9 AA-BB-AA-CC-AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-10 AA-BB-DD-AA-FF -O- CH ₃ -CH (CH ₃ )- (CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-11 AA -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -II-12 AA-FF -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -II-13 GG-FF -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -II-14 AA -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-15 BB -O- H- [CH ₂ -CH (CH ₃ ) -(CH ₂ ) ₂ ] ₄ -II-16 CC -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-17 DD -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-18 EE -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-19 FF -O- H- [ CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-20 GG -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-21 HH -O _{- H- [CH 2 -CH (CH} 3) - (CH 2) 2] 4 - II-22 AA-CC -O- H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - II-23 GG-FF -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-24 AA-CC-GG -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-25 AA-DD-BB-CC -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-26 CC-DD- AA-GG-HH -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-27 CC-CC-CC-CC-CC -O- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-28 FF -O- C ₂ H ₅ -CH (C ₂ H ₅ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-29 FF -O-C ₂ H ₅ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -II-30 AA -O- CH ₃ -CH (CH ₃ )-(CH ₂ ) _3- CH (C ₂ H ₅ )- (CH ₂ ) ₂ -II-31 CC -NH- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-32 DD -NH- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -II-33 EE -NH- H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -────────────── ──────────────────────

[0032]

[Table 3] Compound of Formula (III) ──────────────────────────────────── No. Peptide moiety R ³ (Glycerol 2-position; lower 3-position) ──────────────────────────────────── III -1 AA CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ ) -(CH ₂ ) ₂ -III-2 FF CH ₃ -CH (CH ₃ )-(CH ₂ ) _3- CH (CH ₃ )-(CH ₂ ) ₂ -H- [CH ₂ -CH (CH ₃ )- (CH ₂ ) ₂ ] ₃ -III-3 AA-AA CH ₃ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -CH ₃ -CH (CH ₃ )- (CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -III-4 AA H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -H- [CH ₂ -CH ( CH ₃ )-(CH ₂ ) ₂ ] ₃ -III-5 AA-FF H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -H- [CH ₂ -CH (CH ₃ )- (CH ₂ ) ₂ ] ₄ -III-6 GG-FF-BB H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -H- [CH ₂ -CH (CH ₃ )-(CH _{2) 2] 3 - III-} 7 AA H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - III-8 AA H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -III-9 AA H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₃ -H- [ CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-10 BB H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-11 CC H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-12 DD H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III -13 EE H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-14 FF H- [ _{CH 2 -CH (CH 3) -} (CH 2) 2] 4 - H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - III-15 GG H- [CH 2 -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-16 HH H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-17 AA-CC H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _{4 - H- [CH 2 -CH (CH} 3) - (CH 2) 2] 4 - III-18 AA-CC-GG H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - H _{- [CH 2 -CH (CH 3} ) - (CH 2) 2] 4 - III-19 AA-DD-BB-CC H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 - H _{- [CH 2 -CH (CH 3} ) - (CH 2) 2] 4 - III-20 CC-DD-AA-GG-HH H- [CH 2 -CH (CH 3) - (CH 2) 2] 4 -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-21 CC-CC-CC-CC-CC H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-22 FF H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -C ₂ H ₅ -CH (C ₂ H ₅ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -III-23 FF C ₂ H ₅ -CH (C ₂ H ₅ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] ₄ -III-24 FF C ₂ H ₅ -CH (CH ₃ )-(CH ₂ ) ₃ -CH (CH ₃ )-(CH ₂ ) ₂ -C ₂ H ₅ -CH (CH ₃ )-(CH ₂ ) _3- CH (CH ₃ )-(CH ₂ ) ₂ -─────────── ─────────────────────────

As the peptide chain represented by ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n, Asp-Arg-Leu-Asp-Ser (all amino acid residues are L-form ) And the like are preferred, and ([Z] -Tyr-Ile-Gly
-Ser-Arg) n peptide chain is Asp-Tyr-Ile
-Gly-Ser-Arg- r (all amino acid residues are L-form) and the like are preferable. In the compounds shown in Tables 1 to 3 above, the peptide moiety is Asp-Arg-Leu-Asp-Ser (all amino acid residues are L-forms) or Asp-Tyr-Ile-Gly-Ser-Arg-. Substituted compounds are preferred compounds of the invention. The composition for suppressing cancer metastasis of the present invention has the above formulas (I), (II), and (I
II) one or more compounds selected from the group of compounds, phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, carbon number Phosphatidylserine having 14 to 24 fatty acid residues, 14 to 24 carbon atoms
A phosphatidylglycerol having a fatty acid residue, a phosphatidic acid having a fatty acid residue having 14 to 24 carbon atoms, sphingolipids, and one or more lipids selected from the group consisting of cholesterol. It is a composition. The above formula in the composition of the present invention
(I), (II), and the content of the compound represented by (III) (wt%) is not particularly limited, in the usual case, 0.1 to 80% relative to the total weight of the composition, preferably 1 to 40 %, More preferably 3 to 25%.

The action enhancer of the present invention is used to enhance the cancer metastasis inhibitory action of the compounds represented by the above formulas (I), (II), and (III), and has 14 carbon atoms. ~ Phosphatidylcholine having a fatty acid residue of 24, carbon number of 14-24
Phosphatidylethanolamine having fatty acid residues, phosphatidylserine having fatty acid residues having 14 to 24 carbon atoms, phosphatidyl glycerol having fatty acid residues having 14 to 24 carbon atoms, phosphatididine having fatty acid residues having 14 to 24 carbon atoms It is characterized by containing one or more lipids selected from the group consisting of acids, sphingolipids and cholesterol. The action enhancer of the present invention is the above formula (I), (II), with respect to the total weight of the compound of the present invention and the action enhancer of the present invention represented by the formula (I), (II) ),
And the compound represented by (III) is 0.1 to 80%, preferably
It is used in the range of 1 to 40%, more preferably 3 to 25%.

Formulas (I), (II), included in the composition of the present invention,
And a compound represented by (III), and a phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, 14 to 14 carbon atoms
Phosphatidyl ethanolamine having 24 fatty acid residues, phosphatidyl serine having 14 to 24 carbon fatty acid residues, phosphatidyl glycerol having 14 to 24 carbon fatty acid residues, and 14 to 24 carbon fatty acid residues The ionic group present in phosphatidic acid and sphingolipids may form a salt with a suitable counter ion, or may form a salt in the molecule. As the salt, those which are physiologically and pharmacologically acceptable should be used, and more specifically, salts with inorganic acids such as hydrochloride, sulfate, nitrate and phosphate, acetate and lactic acid. Salts, salts with organic acids such as tartrate, sodium salts, potassium salts and the like may be used. Of these, hydrochloride, acetate and sodium salt are preferable. Such conversion to a salt can be done by conventional means.

Without being bound to any particular theory, the action of the composition for suppressing cancer metastasis of the present invention can be explained as follows. The above lipids form micelles having a bilayer structure after being administered to blood, and the long chain alkyl moiety (a part of R ¹ , R ² or R ² ) of the compound represented by the above formulas (I) to (III) is formed. as well as
R ³ ) is embedded in the hydrophobic part of the lipid bilayer. The compound is transported to peripheral blood vessels together with the micelle while being kept semi-fixed in the micelle. On the other hand, a fragment part of the above compound semi-fixed to the micelle (eg peptide chain)
Is exposed to the outside of the micelle, and the cell adhesive peptide or its analog present in this fragment portion binds to a receptor on the surface of cancer cells, blocks cell adhesion and exhibits a cancer metastasis inhibitory action.

Further, although not limited to any particular theory, the cancer metastasis suppressing composition of the present invention has the following characteristics in exerting such an action. Since the long-chain alkyl moiety (a part of R ¹ , R ² , and R ³ ) of the above compound has a branch, it has a larger steric hindrance than linear alkyl and is once embedded in the micelle. And will not fall off easily. Therefore, the fragment portion is not easily hydrolyzed by the peptide-degrading enzyme in blood, and the cancer metastasis inhibitory action is maintained in vivo for a long period of time. On the other hand, the long-chain alkyl part of the above compound embedded in the hydrophobic part in the micelle (a part of R ¹ , R ² ,
Since R and R ³ ) have a branch, the action of this branch weakens the structure of the micelle and reduces the surfactant activity of the micelle itself. Therefore, the toxicity of the micelles due to the surface-active effect can be reduced. Furthermore, the fragment portion exposed on the surface of the micelle (preferably the peptide chain)
Has a plurality of cell-adhesive peptide sequences, and is characterized in that it can act on receptors on cancer cells at multiple points.

Therefore, the composition for suppressing cancer metastasis of the present invention comprises
By inhibiting the binding of cancer cells to fibronectin, it inhibits cancer cell adhesion, colonization, and destructive erosion, and exhibits a cancer metastasis-suppressing action. Therefore, a drug for suppressing cancer metastasis in mammals including humans Is useful as For example, breast cancer, epidermal cancer, muscle line mela
noma), epidermal neuroblastoma x epidermal li
ne neuroblastoma x glioma), chondrocytes, and fibrosarcoma, which are effective in inhibiting adhesion and metastasis of various cells. Further, the composition for suppressing cancer metastasis of the present invention,
No toxicity was observed in a toxicity test using mice, and it is extremely low in toxicity.

The dose of the composition for suppressing cancer metastasis of the present invention is
It may be appropriately increased or decreased depending on the purpose of use, the age and weight of the patient to be applied, the type of cancer for which metastasis is to be suppressed, etc., but in general, the formula (I), (II) per adult day , Or
The dose of the compound represented by (III) is from 0.2 μg / kg to 200
It can be administered in the range of mg / kg. The route of administration is preferably parenteral administration such as intravenous administration or intraperitoneal administration. Further, in the operation for removing the primary cancer tissue, for the purpose of suppressing implantation of cancer cells that are separated from the primary cancer tissue, the composition for suppressing cancer metastasis of the present invention is continuously or once or in a surgical field. It may be administered in divided doses.

The preparation for parenteral administration is generally used as a liquid unit dose preparation in which the above-mentioned two components are dissolved in distilled water for injection, sterile physiological saline, sterile buffer and the like. Such a preparation can be produced, for example, by dissolving the above-mentioned two components in the above-mentioned medium, performing sterile filtration, filling a suitable vial or ampoule and sealing. In addition, in order to enhance stability, a formulation in which a lyophilized composition is filled in a vial may be used.
Such a formulation can be used by adding a predetermined medium such as distilled water for injection, sterilized physiological saline, and sterilized buffer at the time of use. The parenteral suspension is produced in substantially the same manner as the parenteral solution, but it can be suitably produced by suspending the active ingredient in a medium and sterilizing with ethylene oxide or the like. If necessary, a surfactant, a wetting agent, etc. may be added so that the active ingredient has a uniform distribution.

The composition for inhibiting cancer metastasis of the present invention is used in water
Since a micelle (molecular assembly) based on a molecular membrane structure is formed, a compound having another pharmacological action in the aqueous phase in the micelle or the hydrophobic portion of the lipid bilayer, more specifically, anticancer It is also possible to retain a sex compound. Therefore, the above composition containing one or more anticancer compounds is also preferable as the composition of the present invention. For example, as the anti-cancer compound, an anti-cancer antibiotic such as adriamycin or mitomycin commonly used in cancer chemotherapy, or an anti-cancer platinum derivative such as cisplatin can be used. In conventional chemotherapy, anticancer drugs with strong side effects may be used for the purpose of suppressing cancer metastasis,
By administering the composition of the present invention in the above aspect, it is possible to effectively suppress cancer metastasis, reduce the dose of the anticancer drug, and reduce the side effects of the anticancer drug.
Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

[0042]

【Example】

Example 1: Synthesis of compounds 1 and 2 Compounds 1 and 2 represented by the following formulas were produced as follows in order to be used as an active ingredient of the composition for suppressing cancer metastasis of the present invention.

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The synthetic scheme of Compound 1 is shown in the following scheme. The abbreviations in the scheme are as follows. Boc: t-butoxycarbonyl Bn: benzyl AcoEt: ethyl acetate Z: benzyloxycarbonyl HOBt: 1-hydroxybenzotriazole DCC: dicyclohexylcarbodiimide iPr ₂ NEt: diisopropylethylamine Et ₃ N: triethylamine AcOH: acetic acid DMF: dimethylformamide CDI: carbonyl Diimidazole TFA: trifluoroacetic acid EtOH: ethanol p-TsCl: p-toluenesulfonyl chloride t-BuOK: t-butoxypotassium Ph: phenyl

[0044]

Embedded image

[0045]

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Synthesis of Compound 1 (1) Synthesis of Intermediate 1 Boc-Ser (Bn) -OH (20.4 g, 69 mmol), benzyl bromide
(13 g, 76 mmol), diisopropylethylamine (9.8
g, 76 mmol) was dissolved in ethyl acetate (100 ml), and the reaction mixture was heated under reflux for 5 hours. After allowing to cool to room temperature, the generated salt was removed by filtration, and the filtrate was washed with water, 1 M citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to give Intermediate 1 as a colorless oil, which was used in the next reaction without purification.

(2) Synthesis of Intermediate 2 To a solution of Intermediate 1 in methylene chloride (80 ml) was added trifluoroacetic acid (80 ml), and the reaction mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, the residue was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the amine compound as a colorless oil.
The obtained amine compound and Boc-Asp (Bn) -OH (22.6 g, 70 mmo
l), 1-hydroxybenzotriazole (10.7 g, 70 mmo
l) was dissolved in a mixed solvent of DMF (80 ml) and methylene chloride (80 ml), and DCC (14.4 g, 70 mmol) was added while cooling with ice. The reaction mixture was stirred under ice cooling for 2 hours, and further stirred overnight while warming to room temperature. The reaction mixture was filtered through Celite to remove the formed precipitate. The filtrate was diluted with an appropriate amount of ethyl acetate, washed successively with water, 5% sodium carbonate solution, 1 M citric acid solution, and saturated saline, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give an oily substance. Purify by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1), and then use Intermediate 2 (35.
8 g) was obtained as colorless crystals (yield 87% in 3 steps).

(3) Synthesis of Intermediate 3 Intermediate 2 (35.7 g, 60.5 mmol) of methylene chloride (100 m
l) Trifluoroacetic acid (100 ml) was added to the solution, and the reaction mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the solvent was distilled off, and the residue was crystallized from ether to give trifluoroacetic acid salt (32.5 g). Obtained trifluoroacetate (18.9
g, 31.3 mmol), Boc-Gly-OH (5.75 g, 33 mmol), 1-hydroxybenzotriazole (5.04 g, 33 mmol) and diisopropylethylamine (4.45 g, 34.4 mmol) in DMF (2
0 ml) and methylene chloride (50 ml) dissolved in a mixed solvent,
DCC (6.8 g, 33 mmol) was added while cooling with ice. The reaction mixture was stirred under ice-cooling for 2 hours, further stirred overnight while warming to room temperature, and then filtered through Celite to remove the formed precipitate.
The filtrate was diluted with an appropriate amount of ethyl acetate, washed successively with water, a 5% sodium carbonate solution, a 1 M citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to give a colorless solid, and hexane / ethyl acetate (2
Recrystallization from (1/1) gave Intermediate 3 (17.9 g) (87%).

(4) Synthesis of Intermediate 4 To a solution of Intermediate 3 (17.9 g, 27 mmol) in methylene chloride (60 ml) was added trifluoroacetic acid (60 ml), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was distilled off and the residue was crystallized from ether to give trifluoroacetate 15.9.
got g. Meanwhile, Boc-Arg (Z) ₂ -OH (5.0 g, 9.2 mmol) was added to DM.
Dissolve it in F (20 ml) and chill with CDI (1.5
A solution of 1 g, 9.3 mmol) in DMF (10 ml) was added. The reaction mixture was stirred with ice cooling for 1 hour, and then trifluoroacetic acid salt (6.22 g, 9.2 mmol) obtained by the above operation and diisopropylethylamine (1.32 g, 9.5 mmol) in DMF (20 m
l) The solution was added. The reaction mixture was stirred under ice-cooling for 2 hours and further stirred overnight while warming to room temperature, and then the solvent was distilled off under reduced pressure. The obtained solid was recrystallized from ether to give Intermediate 4 (10.8 g) as colorless crystals (quantitative). FAB-
MS: (M + H) ⁺ 1072.

(5) Synthesis of Intermediate 5 To a solution of Intermediate 4 (11.5 g, 11 mmol) in methylene chloride (40 ml) was added trifluoroacetic acid (40 ml), and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off and the residue was dissolved in ethyl acetate. The ethyl acetate layer is saturated aqueous sodium hydrogen carbonate,
The organic layer was washed successively with saturated brine and dried over anhydrous sodium sulfate, and the solution was concentrated under reduced pressure. The residue was recrystallized from ether to give Intermediate 5 (11.5 g) (quantitative). FAB-MS: (M +
H) ⁺ 972, (M + Na) ⁺ 994.

(6) Synthesis of Intermediate 6 Natural diterpene phytol (200 g) was added to ethanol.
After dissolving in (1000 ml) and adding platinum oxide (1 g), the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After the reaction was completed, insoluble substances were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to obtain 201 g of phytanol as an oily substance. IR
ν _max (film) 3340 (br s), 2960 (s), 2930 (s), 2870
(s), 1465 (s), 1380 (s), 1370 (m), 1060 (s), 735
(w) cm ^-1

Phytanol (40 g) was dissolved in a mixed solvent (700 ml) of carbon tetrachloride: acetonitrile: water = 2: 2: 3, and ruthenium trichloride n hydrate (500 mg) and metaperoxide were added to this solution. After adding sodium iodate (70 g), the reaction mixture was vigorously stirred at room temperature for 4 hours. After the reaction was completed, insoluble substances were removed by filtration through Celite, the filtrate was diluted with methylene chloride, the organic layer was separated, and then the aqueous layer was extracted with methylene chloride. The organic layers were combined, washed once with water, and then dried over anhydrous sodium sulfate. Sodium sulfate is filtered off,
The filtrate was concentrated under reduced pressure to obtain 39 g of phytanic acid as an oily substance. IR ν _max (film) 3600-2400 (br m), 2960 (s), 2
930 (s), 2870 (s), 1715 (s), 1465 (m), 1380 (m), 1
370 (w), 1300 (m), 940 (w) cm ^-1

Phytanic acid (30 g) in toluene (150 ml)
Thionyl chloride (18 g) was added to the solution and the reaction mixture was stirred for 40 hours. After the gas generation stopped and the reaction was completed, the solvent and excess thionyl chloride were distilled off at atmospheric pressure. The residue was dried under reduced pressure to obtain Intermediate 6 (phytanoyl chloride) 32 g as an oil. IR ν _max (film) 2960 (s), 2930
(s), 2870 (s), 1800 (s), 1465 (s), 1380 (s), 1370
(m), 990 (m), 825 (s) cm ^-1

(7) Synthesis of Intermediate 7 Intermediate 5 (1.5 g, 1.5 mmol) and diisopropylethylamine (1 ml) in a methylene chloride (15 ml) solution were treated with Intermediate 6
A solution of (550 mg) in methylene chloride (5 ml) was added. The reaction mixture was stirred under ice-cooling for 2 hours, then allowed to stand overnight while warming to room temperature. The solvent was distilled off under reduced pressure, and the residue was crystallized from ether to obtain 1.8 g (quantitative) of a desired intermediate 7 as a colorless waxy solid. FAB-MS: (M + H) ⁺ 1266.

(8) Synthesis of Compound 1 A solution of Intermediate 7 (1.5 g) in acetic acid (40 ml) was added with 10% Pd-C (200
mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at 40 ° C. for 20 hours. The catalyst was removed by filtration through Celite, and the Celite layer was washed with a small amount of acetic acid. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting aqueous solution of the residue was freeze-dried to give compound 1 (8
00 mg) was obtained as a colorless powder. FAB-MS: (M + H) ⁺ 728.

Synthesis of Compound 2 The synthetic route of Compound 2 is shown below.

[0057]

[Chemical 4]

[0058]

Embedded image

(9) Synthesis of Intermediate 8 A solution of phytanol (30.5 g, 0.1 mol) and triethylamine (15 g, 0.15 mol) in chloroform (200 ml) was added,
A chloroform (150 ml) solution of p-toluenesulfonyl chloride (22.9 g, 0.12 mol) was added dropwise. The reaction mixture was stirred under ice-cooling for 2 hours, then allowed to stand overnight while warming to room temperature. Water was added to the reaction mixture and the mixture was stirred for 1 hour, then diluted with an appropriate amount of chloroform and the organic layer was separated. The organic layer was washed successively with water, 1M citric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tosylate as an oil.

Sodium iodide (12 g, 80 m) was added to a solution of the obtained tosylate (24 g, 53 mmol) in acetone (250 ml).
mol) was added and the reaction mixture was heated to reflux for 6 hours. After cooling to room temperature, the formed precipitate was removed by filtration through Celite, and the Celite layer was washed with hexane. The filtrate and washings were combined and concentrated under reduced pressure. The residue was diluted with hexane, washed with water, 5% sodium thiosulfate solution, and saturated saline,
The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification by silica gel column chromatography (eluent: hexane) gave 21 g of the desired iodide as a colorless oil.

The resulting iodide (4.1 g, 10 mmol) and 3-benzyl-sn-glycerol (720 mg, 4 mmol, literature [Synth
esis page 503, 1985] prepared by the method described in DMF (10
ml) and tetrahydrofuran (10 ml) solution, potassium
t-Butoxide (1.1 g, 10 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with an appropriate amount of hexane, washed successively with water, a 5% sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate.
The solution was concentrated under reduced pressure to give an oily substance. Purification by silica gel column chromatography (eluent: hexane / ethyl acetate = 40/1) gave 2.5 g of the desired alkylated product as a colorless oil.

Obtained alkylated product (2.5 g, 3.4 mmol)
10% Pd-C (300 mg) was added to the ethyl acetate (50 ml) solution of and the reaction mixture was stirred under hydrogen atmosphere at 40 ° C. for 16 hours.
The catalyst was removed by filtration through Celite, and the Celite layer was washed with ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure to obtain the intended intermediate 8 (2.1 g) as a colorless oil. FAB-MS: M ⁺ 652.

(10) Synthesis of Intermediate 9 3-Nitro-1H-1,2,4-triazole (960 mg, 8.4 mmol) was added to a solution of phenylphosphoric dichloride (890 mg, 4.2 mmol) in tetrahydrofuran (10 ml). A solution of triethylamine (850 mg, 8.4 mmol) in tetrahydrofuran (20 ml) was added dropwise while cooling with ice. The reaction mixture was stirred for 30 minutes while warming to room temperature, then Intermediate 8 (2.5 g, 3.8 mmol)
Tetrahydrofuran (15 ml) solution was added over 10 minutes,
The reaction mixture was stirred at room temperature for 1 hour. Then, with Nt-butoxycarbonylethanolamine (620 mg, 3.8 mmol)
A solution of N-methylimidazole (330 mg, 4.0 mmol) in tetrahydrofuran (15 ml) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then an appropriate amount of water was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, and then this solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 40/1 → 8/1) to obtain intermediate 9 (3.3 g) (yield
91.3%). FAB-MS: (M + Na) ⁺ 974.

(11) Synthesis of Intermediate 10 Intermediate 9 (1.45 g, 1.5 mmol) in methylene chloride (10 ml)
Trifluoroacetic acid (5 ml) was added to the solution and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with an appropriate amount of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to obtain an amine compound as an oily substance. The obtained amine compound (1.33 g) and Boc-As
Dissolve p (Bn) -OH (550 mg, 1.7 mmol) and 1-hydroxybenzotriazole (260 mg, 1.7 mmol) in a mixed solvent of DMF (5 ml) and methylene chloride (5 ml) and cool with ice. DC
C (350 mg, 1.6 mmol) was added. The reaction mixture was stirred under ice-cooling for 2 hours and further stirred overnight while warming to room temperature,
The precipitate formed was removed by filtration through Celite. The Celite layer was washed with ethyl acetate, and the filtrate and washings were combined and washed with water, 5
% Sodium carbonate solution, 1 M citric acid solution, saturated brine, and then dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10/1
→ 4/1), and intermediate 10 (1.7 g) was obtained (yield 96.7%). FAB-MS: (M + Na) ⁺ 1179.

(12) Synthesis of Intermediate 11 Intermediate 10 (1.15 g, 1.0 mmol) in methylene chloride (10 ml)
Trifluoroacetic acid (5 ml) was added to the solution and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with an appropriate amount of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the amine compound as an oil. The obtained amine compound (940 mg) and Boc-Gly-OH (180 m
g, 1.0 mmol), 1-hydroxybenzotriazole (155
mg, 1.0 mmol) to DMF (5 ml) and methylene chloride (5 ml)
Dissolve it in the mixed solvent of DCC (210 mg, 1.0 mm
ol) was added. The reaction mixture was stirred under ice cooling for 2 hours, further stirred overnight while warming to room temperature, and then filtered through Celite to remove the formed precipitate. The Celite layer was washed with ethyl acetate, and the filtrate and washings were combined, washed successively with water, 5% sodium carbonate solution, 1 M citric acid solution, and saturated saline, and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 5/1 → 1/1) to obtain Intermediate 11 (950 mg) (yield 78.3% ). FAB-MS: (M + H) ⁺ 1214.

(13) Synthesis of Intermediate 12 Intermediate 11 (940 mg, 0.75 mmol) in methylene chloride (10 ml)
Trifluoroacetic acid (5 ml) was added to the solution and the reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the solution was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with an appropriate amount of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the amine compound as an oil. The obtained amine compound (920 mg) and Boc-Arg (Z) 2-OH (49
0 mg, 0.9 mmol) and 1-hydroxybenzotriazole (140 mg, 0.9 mmol) were dissolved in a mixed solvent of DMF (5 ml) and methylene chloride (5 ml), and DCC (190 m
g, 0.9 mmol) was added. The reaction mixture was stirred under ice-cooling for 2 hours, further stirred overnight while warming to room temperature, and then filtered through Celite to remove the formed precipitate. The Celite layer was washed with ethyl acetate, and the filtrate and washings were combined, washed successively with water, 5% sodium carbonate solution, 1 M citric acid solution, and saturated saline, and then dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4/1
→ 2/1) and intermediate 12 (970 mg) were obtained (yield 79.0%). FAB-MS: (M + H) ⁺ 1638.

(14) Synthesis of Compound 2 Intermediate 12 (900 mg, 0.55 mmol) in methylene chloride (10 ml)
Trifluoroacetic acid (5 ml) was added to the solution, and the reaction mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent. The residue was diluted with an appropriate amount of chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to obtain an amine compound. Platinum oxide (80 mg) was added to a solution of the obtained amine compound in acetic acid (40 ml), and the reaction mixture was stirred under a hydrogen atmosphere at 40 ° C. for 20 hours. The catalyst was removed by filtration through Celite, and the Celite layer was washed with a small amount of acetic acid. The filtrate and washings were combined and concentrated under reduced pressure, and the resulting residue was freeze-dried as an aqueous solution to obtain Compound 2 (540 mg) as a colorless powder. FAB-MS: (M + H) ⁺ 1136.

Example 2: Preparation of a composition according to the invention Distearoylphosphatidylcholine / cholesterol / dipalmitoylphosphatidylglycerol / compound 1 (weight ratio = 20/20/5/6) were mixed thoroughly and composition 1 according to the invention Was prepared. Similarly, distearoylphosphatidylcholine / cholesterol / dipalmitoylphosphatidylglycerol / compound 2 (weight ratio = 20/20/5 /
Composition 2 of the present invention was prepared from 6). Moreover, distearoylphosphatidylcholine / cholesterol / dipalmitoylphosphatidylglycerol / compound 1 (weight ratio = 20/20/5 / 1.5) are thoroughly mixed to prepare the composition 3 of the present invention.
Was prepared. Similarly, distearoylphosphatidylcholine / cholesterol / dipalmitoylphosphatidylglycerol / compound 2 (weight ratio = 20/20/5 / 1.5)
Composition 4 of the present invention was prepared from Furthermore, distearoylphosphatidylcholine / cholesterol / dipalmitoylphosphatidylglycerol / compound 1 / adriamycin (Kyowa Hakko Kogyo Co., Ltd. adriacin injection) (weight ratio = 20/20/5 / 1.5 / 0.5) is thoroughly mixed to form the composition of the present invention. Item 5 was prepared.

Example 3: Inhibitory effect on cancer metastasis by experimental lung metastasis model system using melanoma cells Using the above composition of the present invention, the inhibitory effect on cancer metastasis was examined by an experimental lung metastasis model system. Arg-Gl, a fibronectin adhesion core sequence tetrapeptide, for comparison
y-Asp-Ser was used. The composition 1, composition 2 and the comparative compound Arg-Gly-Asp-Ser were 200 μg each, and B16-BL6 melanoma cells (logarithmic growth phase 5 × 10 ⁴ cells), which are highly metastatic cancer cells. ) Were mixed with each other in PBS.
Each mixture was administered to 5 C57BL / 6 female mice (5 weeks old) by tail vein injection. Fourteen days after the administration, the mice were sacrificed and dissected, and the number of colonies of cancer metastasized to the lung was counted and compared with the control PBS administration group. The results of cancer metastasis inhibition are shown in Table 4 below.

[0070]

[Table 4] ────────────────────── Administered drug Cancer metastasis inhibition rate (%) ──────────────── ─────── PBS (untreated) -Composition 1 83.1 Composition 2 47.7 Arg-Gly-Asp-Ser 0 ───────────────────── ─

According to these results, the cancer metastasis to the lung was significantly suppressed by the administration of the composition for suppressing cancer metastasis (compositions 1 and 2) of the present invention. In contrast, the adhesion core sequence peptide of fibronectin, Arg-Gly-Asp-Ser, showed no metastasis-suppressing effect at the dose of this experiment.

Example 4 Cancer Metastasis Suppressing Effect by Spontaneous Lung Metastasis Model System Using Melanoma Cells The metastasis suppressing effect of the composition for suppressing cancer metastasis of the present invention is a more realistic model for treating pathological conditions, a natural lung metastasis suppressing test. It was examined by. Composition 3 and composition 4 as the composition of the present invention
Was used as a comparative compound, Arg-Gly-Asp-Ser, which is an adhesion core sequence tetrapeptide of fibronectin.
B16-BL6 melanoma cells (5 × 1 in logarithmic growth phase) in the right heel of 7 female C57BL / 6 mice (5 weeks old) per group.
0 ⁴ / 50μl) were transplanted. After transplant 7, 10, 13, 16, 19, 2
5 or 2 times by injection of the test drug by tail vein injection on the 2nd and 25th days
The dose was 00 μg, and the transplanted cancer was surgically excised on the 21st day. Mice were sacrificed 35 days after melanoma transplantation,
After dissection, count the number of cancer colonies that have spread to the lungs
It was compared with the PBS administration group. The results of cancer metastasis inhibition are shown in Table 5 below.

[0073]

[Table 5] ────────────────────── Administered drug Cancer metastasis inhibition rate (%) ──────────────── ─────── PBS (untreated) -Composition 1 58.5 Composition 2 76.1 Arg-Gly-Asp-Ser 0 ───────────────────── ─

These results show that the administration of the cancer metastasis suppressors (compositions 3 and 4) of the present invention markedly suppressed the number of cancer metastases even in the natural lung metastasis suppression test which is a realistic model for treating pathological conditions. Which indicates that. On the other hand, Arg-Gly-Asp-Ser, which is a conventionally known adhesion core sequence peptide of fibronectin, had no inhibitory effect on cancer metastasis. Therefore, the metastasis-suppressing effect of the cancer metastasis-suppressing agent of the present invention and its usefulness are clear.

[0075]

INDUSTRIAL APPLICABILITY The composition of the present invention exerts an excellent cancer metastasis inhibitory action in vivo for a long period of time, and is therefore useful as a pharmaceutical for suppressing cancer metastasis of mammals such as humans. Further, the composition of the present invention has reduced toxicity and is extremely useful as a medicine.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area C07K 5/09 C07K 5/103 5/103 5/11 5/11 7/06 7/06 7/08 7 / 08 A61K 37/22 // (A61K 38/00 ADU 31: 685 31: 575) (A61K 38/00 ADU 31:66 31: 575) (72) Inventor Naoto Oku 21-11 Kawaramachi, Shimizu City Shizuoka Prefecture

Claims (19)

[Claims] 1. A composition for suppressing cancer metastasis, comprising the following components: (a) the following formula: R ¹ -QZ (I) HQWR ² (II) and HQ-NHCH ₂ CH ₂ O-PO (OH). ) -0CH ₂ CH (OR ³ ) CH ₂ OR ³ (III) (wherein Q represents a fragment having cell adhesion activity, R ¹ represents a fragment having 10 to 25 carbon atoms substituted on the terminal amino group of the fragment). Represents an alkanoyl group having 1 or 2 or more branches; R ² represents an alkyl group having 1 or 2 or more branches having 10 to 25 carbon atoms; R ³ independently represents the number of carbon atoms
10 to 25 represents an alkyl group or alkanoyl group having 1 or 2 or more branches; W represents -O- group or -NH- group substituted on the terminal carbonyl group of the above fragment; Z
Represents a hydroxyl group substituted on the C-terminal carbonyl group of the above fragment or a substituted or unsubstituted amino group), and a compound (b).
Phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylserine having a fatty acid residue having 14 to 24 carbon atoms, fatty acid residue having 14 to 24 carbon atoms Group-containing phosphatidylglycerol, phosphatidic acid having a C14-24 fatty acid residue, sphingolipids,
A composition comprising a lipid selected from the group consisting of cholesterol. 2. The fragment Q is represented by the following formula: ([X ¹ ] -Arg-Gly-Asp- [X ² ]) n (wherein Arg, Gly and Asp are arginine, glycine and aspartic acid residues, respectively). Represents a group; [X ¹ ] and [X ² ] represent that X ¹ and X ² may or may not exist; X ¹ and X ² each independently represent serine, glycine, valine, Represents a amino acid residue selected from the group consisting of asparagine, proline, cysteine, and threonine residues; n represents an integer of 1 to 5), and R ¹ is the N-terminal of the peptide chain. The composition according to claim 1, wherein the amino group is substituted, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is substituted on the C-terminal carbonyl group of the peptide chain. . 3. The fragment Q is represented by the following formula: ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n (where Arg and Asp represent arginine and aspartic acid respectively; [Y ¹ ] and [Y ³ ] represent the presence or absence of Y ¹ and Y ^3, respectively; Y ¹ represents aspartic acid; Y ² represents leucine or isoleucine;
Y ³ represents serine or threonine; n represents an integer of 1 to 5), R ¹ is substituted on the N-terminal amino group of the peptide chain, and W is the peptide described above. Substitution on the C-terminal carbonyl group of the chain and Z is substituted on the C-terminal carbonyl group of the peptide chain.
The composition according to. 4. The fragment Q is represented by the following formula: ([Z] -Tyr-Ile-Gly-Ser-Arg) n (wherein Tyr, Ile, Gly, Ser, Arg are tyrosine, isoleucine, glycine, and Represents serine and arginine; [Z] represents the presence or absence of Z; Z represents aspartic acid or glutamic acid, n
Represents an integer of 1 to 5),
R ¹ is substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is on the C-terminal carbonyl group of the peptide chain. The substituted composition of claim 1. 5. R ¹ is an alkanoyl group having 1 or 2 or more methyl group branches, R ² is an alkyl group having 1 or 2 or more methyl group branches, and / or R ³ is independent of each other. 5. An alkyl group or an alkanoyl group having 1 or 2 or more methyl group branches in 5.
The composition according to any one of 1. 6. R ¹ is H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _k -CH ₂ -CH
(CH ₃ ) -CH ₂ -CO- (k represents an integer of 1 to 3) and R ²
There _{H- [CH 2 -CH (CH 3} ) - (CH 2) 2] l - a (l is an integer of 2-4), and / or, R ³ is H- [CH ₂ -CH ( CH ₃ )-(CH ₂ ) ₂ ]
_m - (m is an integer of 2-4) or _{H- [CH 2 -CH (CH 3} )
- (CH _{2) 2]} The composition according to _s -CH ₂ -CH (CH ₃₎ any one of -CH ₂ -CO- to (s is an integer of 1 to 3) claims 1 to 4 Stuff. 7. R ³ is 3,7,11-trimethyldodecanoyl group, 3,7,11,15-tetramethylhexadecanoyl group, and
A group selected from the group consisting of 5,9,13,17-tetramethyloctadecanoyl group, R ² is 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group , And 5,
A group selected from the group consisting of 9,13,17-tetramethyloctadecyl group, and / or R ³ are each independently 3,7,11
-Trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, 5,9,13,17-tetramethyloctadecyl group,
A group selected from the group consisting of a 3,7,11-trimethyldodecanoyl group, a 3,7,11,15-tetramethylhexadecanoyl group, and a 5,9,13,17-tetramethyloctadecanoyl group. A composition according to any one of claims 1 to 4. 8. A phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, a phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, and a lipid having 14 to 24 carbon atoms.
Phosphatidylserine with 14 fatty acids, carbon number 14
The composition according to any one of claims 1 to 7, which is a lipid selected from the group consisting of phosphatidylglycerol having a fatty acid residue of 24 to 24, phosphatidic acid having a fatty acid residue of 14 to 24 carbon atoms, and cholesterol. Stuff. 9. The lipid selected from the group consisting of phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, phosphatidylglycerol having a fatty acid residue having 14 to 24 carbon atoms, and cholesterol.
The composition according to any one of 1. 10. The composition according to any one of claims 1 to 9, further comprising an anticancer compound. 11. The following formulas: R ¹ -QZ (I) HQWR ² (II) and HQ-NHCH ₂ CH ₂ O-PO (OH) -0CH ₂ CH (OR ³ ) CH ₂ OR ³ (III) ( In the formula, Q represents a fragment having cell adhesion activity, R ¹ represents an alkanoyl group having 1 or 2 or more branched groups having 10 to 25 carbon atoms, which is substituted on the terminal amino group of the fragment; and R ² represents a carbon atom. An alkyl group having 1 or 2 or more branches of the number 10 to 25; R ³ independently represents the number of carbon atoms;
10 to 25 represents an alkyl group or alkanoyl group having 1 or 2 or more branches; W represents -O- group or -NH- group substituted on the terminal carbonyl group of the above fragment; Z
Is a hydroxyl group substituted on the C-terminal carbonyl group of the above fragment or a substituted or unsubstituted amino group), and is a potentiator of the cancer metastasis inhibitory action of a compound selected from the group consisting of compounds represented by Phosphatidylcholine having a fatty acid residue of 14 to 24, phosphatidylethanolamine having a fatty acid residue of 14 to 24 carbon atoms, 14 carbon atoms
Selected from the group consisting of phosphatidylserine having a fatty acid residue of 24 to 24, phosphatidylglycerol having a fatty acid residue of 14 to 24 carbon atoms, phosphatidic acid having a fatty acid residue of 14 to 24 carbon atoms, sphingolipids, and cholesterol. A cancer metastasis action enhancer comprising a lipid as an active ingredient. 12. The fragment Q is represented by the following formula: ([X ¹ ] -Arg-Gly-Asp- [X ² ]) n (wherein Arg, Gly and Asp are arginine, glycine and aspartic acid residues, respectively). Represents a group; [X ¹ ] and [X ² ] represent that X ¹ and X ² may or may not exist; X ¹ and X ² each independently represent serine, glycine, valine, Represents a amino acid residue selected from the group consisting of asparagine, proline, cysteine, and threonine residues; n is an integer of 1 to 5), and R ¹ is the N-terminal of the peptide chain. The enhancing agent according to claim 11, wherein the enhancer is substituted on the amino group, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is substituted on the C-terminal carbonyl group of the peptide chain. . 13. The fragment Q is represented by the following formula: ([Y ¹ ] -Arg-Y ² -Asp- [Y ³ ]) n (where Arg and Asp represent arginine and aspartic acid respectively; [Y ¹ ] and [Y ³ ] represent the presence or absence of Y ¹ and Y ^3, respectively; Y ¹ represents aspartic acid; Y ² represents leucine or isoleucine;
Y ³ represents serine or threonine; n represents an integer of 1 to 5), R ¹ is substituted on the N-terminal amino group of the peptide chain, and W is the peptide described above. Substitution on the C-terminal carbonyl group of the chain and Z is substituted on the C-terminal carbonyl group of said peptide chain.
The enhancer described in. 14. The fragment Q is represented by the following formula: ([Z] -Tyr-Ile-Gly-Ser-Arg) n (wherein Tyr, Ile, Gly, Ser and Arg are tyrosine, isoleucine, glycine, and Represents serine and arginine; [Z] represents that Z may or may not be present; Z represents aspartic acid or glutamic acid, n
Represents an integer of 1 to 5),
R ¹ is substituted on the N-terminal amino group of the peptide chain, W is substituted on the C-terminal carbonyl group of the peptide chain, and Z is on the C-terminal carbonyl group of the peptide chain. The enhanced agent according to claim 11, which is substituted. 15. R ¹ is an alkanoyl group having 1 or 2 or more methyl group branches, R ² is an alkyl group having 1 or 2 or more methyl group branches, and / or R ³
Is each independently an alkyl group having one or more methyl group branches or an alkanoyl group;
15. The enhancer according to any one of 14 above. 16. R ¹ is H- [CH ₂ -CH (CH ₃ )-(CH ₂ ) ₂ ] _k -CH ₂ -C.
H (CH ₃ ) -CH ₂ -CO- (k represents an integer of 1 to 3) and R ²
There _{H- [CH 2 -CH (CH 3} ) - (CH 2) 2] l - a (l is an integer of 2-4), and / or, R ³ is H- [CH ₂ -CH ( CH ₃ )-(CH ₂ ) ₂ ]
_m - (m is an integer of 2-4) or _{H- [CH 2 -CH (CH 3} )
- (CH _{2) 2]} enhanced according to item 1 one of _{s -CH 2 -CH (CH 3)} -CH 2 -CO- to (s is an integer of 1 to 3) claims 11 a 14 Agent. 17. R ¹ is a 3,7,11-trimethyldodecanoyl group, a 3,7,11,15-tetramethylhexadecanoyl group, and
A group selected from the group consisting of 5,9,13,17-tetramethyloctadecanoyl group, R ² is 3,7,11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group , And 5,
A group selected from the group consisting of 9,13,17-tetramethyloctadecyl group, and / or R ³ are each independently 3,7,
11-trimethyldodecyl group, 3,7,11,15-tetramethylhexadecyl group, 5,9,13,17-tetramethyloctadecyl group, 3,7,11-trimethyldodecanoyl group, 3,7,11, The enhancer according to any one of claims 11 to 14, which is a group selected from the group consisting of a 15-tetramethylhexadecanoyl group and a 5,9,13,17-tetramethyloctadecanoyl group. 18. A phosphatidylcholine having a fatty acid residue having 14 to 24 carbon atoms, a phosphatidylethanolamine having a fatty acid residue having 14 to 24 carbon atoms, and a lipid having 14 to 14 carbon atoms.
Phosphatidylserine having 24 fatty acid residues, carbon number
18. A lipid selected from the group consisting of phosphatidyl glycerol having a fatty acid residue of 14 to 24, phosphatidic acid having a fatty acid residue of 14 to 24 carbon atoms, and cholesterol. Enhancer. 19. The lipid selected from the group consisting of phosphatidylcholine having a C14-24 fatty acid residue, phosphatidylglycerol having a C14-24 fatty acid residue, and cholesterol.
The enhancer according to any one of 17 above.