WO2015152393A1 - 悪性腫瘍転移抑制用医薬 - Google Patents
悪性腫瘍転移抑制用医薬 Download PDFInfo
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- WO2015152393A1 WO2015152393A1 PCT/JP2015/060582 JP2015060582W WO2015152393A1 WO 2015152393 A1 WO2015152393 A1 WO 2015152393A1 JP 2015060582 W JP2015060582 W JP 2015060582W WO 2015152393 A1 WO2015152393 A1 WO 2015152393A1
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- WIPO (PCT)
- Prior art keywords
- amino
- malonamide
- metastasis
- naphthylsulfonyl
- benzyl
- Prior art date
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Definitions
- the present invention relates to a novel medicament for suppressing or preventing metastasis of malignant tumors such as cancer, which comprises a non-peptide angiotensin type 2 receptor agonist as an active ingredient.
- the present invention also relates to a vascular protective agent comprising a non-peptide angiotensin type 2 receptor agonist, and a novel medicament for suppressing or preventing metastasis of malignant tumors such as cancer containing this vascular protective agent as an active ingredient.
- the present invention further relates to a novel treatment or prevention method for suppressing or preventing metastasis of malignant tumors.
- the present invention further relates to a medicament for suppressing or preventing malignant tumor cell colonization or infiltration into the vascular endothelium, and a method for inhibiting or preventing malignant tumor cell colonization or infiltration into the vascular endothelium.
- Malignant tumors typified by cancer are diseases based on abnormal cell growth, but the greatest features of malignant tumors are invasion into surrounding tissues and metastasis to other organs. It has long been known that many causes of death in malignant tumor patients are not organ enlargement but multi-organ failure associated with distant metastasis of tumor cells. However, inhibitory control of malignant tumor metastasis has not been achieved in recent years, and is one of the most important issues in cancer treatment as a whole.
- the metastasis of epithelial malignant tumor is the acquisition of motility and invasion ability of cancer cells represented by epithelial to mesenchymal transition (hereinafter referred to as “EMT”), invasion of surrounding tissues, blood vessels It is thought to be caused by a variety of physiological phenomena such as migration and invasion into lymphatic vessels, colonization of distant tissues into the vascular endothelium and formation of metastases.
- EMT epithelial to mesenchymal transition
- Non-patent Document 1 inflammatory cytokines (IL-1 ⁇ , TNF- ⁇ ) promote the adhesion of tumor cells to vascular endothelial cells (Non-patent Documents 2 and 3).
- Non-Patent Documents 1 to 3 when inflammatory cytokines are produced by surgery or an infection caused thereby, systemic and local adhesion of tumor cells to vascular endothelial cells is promoted, and tumor metastasis to distant tissues Tumor recurrence is likely to occur at the primary site.
- angiotensinogen is converted into angiotensin I through renin, which is converted into angiotensin II (Ang II) having a variety of physiological functions by a converting enzyme such as angiotensin converting enzyme (ACE). Is done.
- AT1 receptor Angiotensin type 1 receptor
- AT2 receptor Angiotensin type 1 receptor
- AT2 receptor Angiotensin type 1 receptor
- Ang II receptor the actions of Ang II such as pressorization and vasoconstriction, which are well known from the past, are mainly mediated by the classic AT1 receptor.
- the function of the AT2 receptor is to antagonize the AT1 receptor in many cells / tissues, mainly to develop pathological conditions such as hypotension, suppression of cell proliferation, suppression of hypertrophy, promotion of apoptosis, inhibition of extracellular matrix production, and In recent years, it has been rapidly elucidated that it works in the direction of stopping progress.
- the AT2 receptor is expressed in a wide range and at a high level during fetal period, but its expression level decreases rapidly after birth.
- pathological conditions such as vascular disorders and cardiovascular remodeling after myocardial infarction, it has become known that tissue-specific re-expression is important, and the importance of the AT2 receptor involved in preventing the onset and progression of various diseases Sex is attracting attention.
- Non-patent Document 4 A general pharmacological action predicted by activating the AT2 receptor has also been reported in a paper by de Gasparo et al. (Non-patent Document 4).
- the target diseases include many disease groups involving the renin-angiotensin-aldosterone system (hereinafter referred to as RAAS), such as metabolic / circulatory diseases, cerebral infarction, kidney disease, heart disease, hypertension, diabetes , Metabolic syndrome and the like.
- RAAS renin-angiotensin-aldosterone system
- CGP44112A a peptide AT2 receptor agonist, suppresses cancer cell proliferation and promotes apoptosis, thereby suppressing colon cancer metastasis to the liver (Non-patent Document 7).
- malonic acid sulfonamide derivatives are known as AT2 receptor agonists, but they are not disclosed for suppressing cancer metastasis (Patent Document 10). Furthermore, malonic acid sulfonamide derivatives are known as herbicides (Patent Document 11).
- non-peptidic AT2 receptor ligands particularly non-peptidic AT2 receptor agonists, inhibit malignant tumor metastasis (especially, malignant tumors themselves are not targeted and malignant tumor metastasis is inhibited. ) Is not known.
- Patent Document 12 discloses a medicament for suppressing or preventing metastasis of malignant tumors, which contains a vascular endothelial cell cGMP enhancer such as a natriuretic peptide receptor GC-A agonist as an active ingredient. There is no disclosure of the action of non-peptidic AT2 receptor ligands, particularly non-peptidic AT2 receptor agonists, in metastasis of malignant tumors.
- the main object of the present invention is to provide a novel medicament for suppressing or preventing metastasis of malignant tumors such as cancer.
- Another object of the present invention is to provide a novel treatment or prevention method for suppressing or preventing metastasis of malignant tumors.
- the present invention also provides a medicament for suppressing or preventing malignant tumor cell colonization or infiltration into the vascular endothelium, and a method for inhibiting or preventing malignant tumor cell colonization or invasion into the vascular endothelium. Let it be an issue. Further, other purposes than the above will be apparent from the following description.
- the present inventors have found that distant metastasis of malignant tumors such as cancer can be exacerbated or increased by anticancer agent and / or antitumor agent treatment, and non-peptide type Angiotensin type 2 receptor ligands, particularly non-peptidic angiotensin type 2 receptor agonists, can effectively suppress the exacerbation or increase of metastasis of such malignant tumors, and such non-peptidic angiotensin 2
- the type-receptor agonist protects the host-side blood vessels by a mechanism that is completely different from the direct action on cancer cells as in Non-Patent Document 7, and thus metastasis of malignant tumors (and also by anticancer agents and / or antitumor agents).
- the non-peptide angiotensin type 2 receptor ligand of the present invention acts protectively on the vascular endothelium, so that malignant tumor cells can be transformed into the vascular endothelium during the metastasis process. It is possible to effectively inhibit fixing (adhesion) and infiltration into the skin. Adhesion and invasion of malignant tumor cells to the vascular endothelium is a process common to tumor cell metastasis. For this reason, by inhibiting colonization or infiltration of malignant tumor cells into the vascular endothelium, metastasis of all malignant tumors can be effectively suppressed or prevented.
- metastasis-inhibiting action acts to malignant tumor itself, for example, by inhibiting angiogenesis of malignant tumor cells or by inhibiting DNA synthesis, thereby suppressing tumor growth and metastasis. This is a different action.
- metastasis of malignant tumor includes distant metastasis (metastasis) of malignant tumor (cell) and recurrence of malignant tumor (recurrence at the site of primary tumor (primary tumor)).
- Suppression or prevention of metastasis of malignant tumor means suppressing or preventing distant metastasis of malignant tumor and / or suppressing or preventing recurrence of malignant tumor (recurrence at the primary lesion site).
- the medicament (or pharmaceutical composition, the same shall apply hereinafter) of the present invention comprises a non-peptide angiotensin type 2 receptor agonist (hereinafter sometimes referred to as AT2 receptor agonist) as an active ingredient.
- AT2 receptor agonist non-peptide angiotensin type 2 receptor agonist
- Such a medicament of the present invention is useful for suppressing or preventing metastasis of malignant tumors.
- the medicament of the present invention is also useful for suppressing or preventing metastasis (exacerbation and / or increase of metastasis) of a malignant tumor by an anticancer agent and / or an antitumor agent.
- the medicament of the present invention is also useful for suppressing or preventing exacerbation and / or increase of malignant tumor metastasis associated with vascular inflammation.
- the medicament of the present invention is also useful for suppressing or preventing exacerbation and / or increase of malignant tumor metastasis associated with vascular inflammation caused by surgical operation.
- the non-peptide angiotensin type 2 receptor agonist has a vascular protective action (vascular protective function)
- this vascular protective action can suppress or prevent the establishment or swelling of malignant tumor cells on the vascular endothelium, and is therefore effective. Metastasis of malignant tumors (and worsening and / or increase of metastasis of malignant tumors by anticancer agents and / or antitumor agents) can be suppressed or prevented. Therefore, the present invention includes a vascular protective agent containing a non-peptide angiotensin type 2 receptor agonist.
- Such a vasoprotective agent only needs to contain at least a non-peptidic angiotensin type 2 receptor agonist, and contains other components having a vascular protective function (for example, other metastasis inhibitors described later). Also good.
- non-peptidic angiotensin type 2 receptor agonists have various functions and provide new uses based on such functions. Therefore, the present invention includes the following inventions (i) to (v).
- a non-peptide angiotensin type 2 receptor agonist or vasoprotective agent for use in suppressing or preventing metastasis of malignant tumors.
- a non-peptide angiotensin type 2 receptor agonist or vasoprotective agent for use in suppressing or preventing aggravation and / or increase of malignant tumor metastasis by an anticancer agent and / or an antitumor agent.
- a medicament for suppressing or preventing malignant tumor cell colonization or infiltration into the vascular endothelium, which contains a non-peptide angiotensin type 2 receptor agonist as an active ingredient.
- a method of suppressing or preventing malignant tumor cell colonization or infiltration into a vascular endothelium comprising administering to a patient a non-peptide angiotensin type 2 receptor agonist or vascular protective agent (or an effective amount thereof).
- a non-peptide angiotensin type 2 receptor agonist for use in inhibiting or preventing malignant tumor cell colonization or invasion into the vascular endothelium.
- the non-peptide angiotensin type 2 receptor agonist may be, for example, a compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
- R 1 represents 2-naphthyl, trans- ⁇ -styryl, phenethyl, 3-phenoxypropyl, or 4-phenylbutyl;
- One of R 2 and R 3 represents a hydrogen atom, and the other one is isopropyl, isobutyl, neopentyl, allyl, —CH 2 —R 5 ⁇ wherein R 5 is an optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycle, or —CO—NR 6 R 7 (wherein R 6 and R 7 are the same or different, a hydrogen atom, C 1-6 alkyl, optionally substituted) Aryl or optionally substituted heteroaryl, or R 5 and R 6 together with the nitrogen atom to which they are attached may form an optionally substituted cyclic amino).
- R 4 is di (C 1-6 alkyl) amino or the following formula
- Z represents a hydrogen atom, a halogen atom or trifluoromethyl
- Y represents a nitrogen atom or CH
- R 8 represents ethyl, isopropyl, or 3-pentyl.
- Z represents a hydrogen atom.
- non-peptide angiotensin type 2 receptor agonists are: N, N-diethyl-2- ⁇ 4-[(2,6-difluorobenzoyl) amino] benzyl ⁇ -N ′-(2-naphthylsulfonyl) malonamide, (2S) -2- [4- (Benzoylamino) benzyl] -N, N-diethyl-N ′-(2-naphthylsulfonyl) malonamide, (2S) -N, N-diethyl-2- ⁇ 4-[(2-fluorobenzoyl) amino] benzyl ⁇ -N ′-(2-naphthylsulfonyl) malonamide, (2S) -N, N-diethyl-2- ⁇ 4-[(3-fluorobenzoyl) amino] benzyl ⁇ -N ′-(2-naphthylsulfonamide
- metastasis of malignant tumor may be, for example, metastasis to at least one selected from lung, bone, liver and brain (for example, metastasis to at least one selected from lung and liver).
- the malignant tumor may be at least one malignant tumor (for example, melanoma) selected from, for example, epithelial malignant tumor, non-epithelial malignant tumor, and melanoma.
- the patient to be administered may be a patient who has undergone resection surgery for a malignant tumor or who has undergone resection surgery.
- the administration target patient may be a patient who has been or has been administered an anticancer agent and / or an antitumor agent.
- a non-peptide angiotensin type 2 receptor agonist can be used with an anticancer agent and / or an antitumor agent. Therefore, the medicament (non-peptide angiotensin type 2 receptor agonist or vascular protective agent) of the present invention may be used together with an anticancer agent and / or an antitumor agent (for example, a platinum antitumor agent). Good. Further, as described above, the non-peptide angiotensin type 2 receptor agonist is useful for suppressing or preventing metastasis exacerbation and / or increase by an anticancer agent and / or an antitumor agent.
- non-peptide property is administered to the patient to be administered before administration of the anticancer agent and / or antitumor agent (for example, from 1 day or more before the start of administration of the anticancer agent and / or antitumor agent).
- an angiotensin type 2 receptor agonist is administered.
- the angiotensin type 2 receptor agonist of the present invention is non-peptidic, it can be administered orally, and the above function can be effectively expressed even by oral administration. Therefore, the medicament (non-peptide angiotensin type 2 receptor agonist or vascular protective agent) of the present invention may be particularly for oral administration (oral administration medicament, oral preparation).
- the target tissue in the present invention is , Blood vessels and perivascular tissues (preferably vascular endothelium, but not limited to vascular endothelial cells), which exert a metastasis-inhibiting action against malignant tumors by controlling the host side, Is a therapy with completely different mechanisms, and is a new technique that can be applied to all malignant tumors without depending on the type and nature of the malignant tumor itself.
- the present invention can suppress or prevent the establishment or infiltration of malignant tumor cells into the vascular endothelium, and can effectively suppress or prevent metastasis of malignant tumors by such vascular protective action. It is.
- the medicament and the treatment or prevention method of the present invention have an excellent effect that metastasis of malignant tumor can be effectively suppressed or prevented.
- the medicament and the treatment or prevention method of the present invention can effectively suppress or prevent metastasis of malignant tumors by vasoprotective action.
- the medicament and the treatment or prevention method of the present invention can suppress or prevent the establishment or infiltration of malignant tumor cells into the vascular endothelium in metastasis of malignant tumors. For this reason, the metastasis
- an anticancer agent and / or an antitumor agent for example, a platinum-based antitumor agent such as cisplatin (CDDP)
- an antitumor agent for example, a platinum-based antitumor agent such as cisplatin (CDDP)
- CDDP cisplatin
- metastasis of malignant tumors is likely to be promoted by the promotion of anti-cancer agents and / or anti-tumors due to their vascular protective action.
- the use of the medicament of the present invention can effectively suppress or prevent the deterioration and / or increase of malignant tumor metastasis caused by the anticancer agent and / or antitumor agent.
- the pharmaceutical agent of the present invention is capable of suppressing the adhesion of vascular endothelial cells to the vascular endothelial cells of the surgical operation or the systemic and local tumors promoted by the surgical operation due to its vascular protective action.
- the medicament of the present invention can effectively prevent metastasis (exacerbation and / or increase in metastasis) of malignant tumors associated with inflammation of blood vessels (for example, inflammation of blood vessels by surgical operation) due to its vascular protective action. It has an effect that can be suppressed.
- FIG. 1 is a micrograph of lungs 2 weeks after tumor cell injection when CDDP injection and / or compound A was orally administered in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells.
- FIG. 2 is formed by metastasis to the lung two weeks after tumor cell infusion when injecting CDDP and / or oral ingestion of Compound A in the mouse tail vein infusion metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 3 is a micrograph of the lung 2 weeks after tumor cell injection when LPS injection and / or compound A was orally ingested in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells.
- FIG. 4 is a micrograph of lungs 2 weeks after tumor cell injection when LPS injection and / or oral intake of compounds BE were performed in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells.
- FIG. 5 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound A was orally ingested in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 5 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound A was orally ingested in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 6 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound B was orally administered in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 7 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound C was orally ingested in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 7 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound C was orally ingested in a mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 8 is formed by metastasis to the lung two weeks after tumor cell injection when LPS injection and / or compound D was orally administered in the mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 9 is formed by metastasis to the lung 2 weeks after tumor cell injection when LPS injection and / or compound E was orally administered in the mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 9 is formed by metastasis to the lung 2 weeks after tumor cell injection when LPS injection and / or compound E was orally administered in the mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells. It is a graph showing the number of nodules.
- FIG. 10 shows an angiotensin type 2 receptor knockout mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells, and LPS injection and / or oral intake of compound A, 2 weeks after tumor cell injection. It is a micrograph.
- FIG. 11 shows an angiotensin type 2 receptor knockout mouse tail vein injection metastasis test of mouse melanoma B16-F10 cells into the lung 2 weeks after tumor cell injection when LPS injection and / or compound A was orally administered. It is a graph showing the number of nodules formed by the transition of.
- non-peptidic agonists are used.
- the molecular weight of such an agonist is, for example, 1000 or less, preferably 800 or less, and particularly preferably an AT2 receptor agonist having a molecular weight of 300 to 700.
- the non-peptide angiotensin type 2 receptor agonist in the present invention is not particularly limited, and examples thereof include sulfonamide compounds [for example, 3-phenyl-2-thiophene sulfonamide compound, biphenyl sulfonamide compound, malonic acid sulfonamide. Compound] and the like.
- Specific examples of the AT2-type receptor agonist include compounds described in International Publication WO 2008/156142 pamphlet, compounds described in International Publication WO 2002/096883 pamphlet, and the like.
- a malonic acid sulfonamide compound is preferable, and in particular, the following compound (I) described in International Publication WO 2008/156142 or a pharmacologically acceptable salt thereof. Can be preferably used.
- R 1 represents 2-naphthyl, trans- ⁇ -styryl, phenethyl, 3-phenoxypropyl, or 4-phenylbutyl;
- One of R 2 and R 3 represents a hydrogen atom, and the other one is isopropyl, isobutyl, neopentyl, allyl, —CH 2 —R 5 ⁇ wherein R 5 is an optionally substituted C 3-10 Cycloalkyl, optionally substituted heterocycle, or —CO—NR 6 R 7 (wherein R 6 and R 7 are the same or different, a hydrogen atom, C 1-6 alkyl, optionally substituted) Aryl or optionally substituted heteroaryl, or R 5 and R 6 together with the nitrogen atom to which they are attached may form an optionally substituted cyclic amino).
- R 4 is di (C 1-6 alkyl) amino or the following formula
- Z represents a hydrogen atom, a halogen atom or trifluoromethyl
- Y represents a nitrogen atom or CH
- R 8 represents ethyl, isopropyl, or 3-pentyl.
- Z represents a hydrogen atom.
- C 1-6 alkyl means a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.
- the C 2-6 alkenyl described below means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon double bonds. Allyl, 1-propenyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-methyl-2-propenyl, prenyl, isopentenyl, 2-hexenyl and the like.
- the C 2-6 alkynyl described below means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon triple bonds, such as ethynyl, Examples include 2-propynyl, 2-butynyl, 3-butynyl, 3-pentynyl, 5-hexynyl and the like.
- C 1-6 alkoxy is synonymous with the above “C 1-6 alkyl” and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
- C 3-10 cycloalkyl means a cyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- the cycloalkyl is condensed with a benzene ring to form indan (eg, indan-1-yl, indan-2-yl, etc.), tetrahydronaphthalene (eg, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, etc.) Etc. may be formed.
- the C 3-10 cycloalkyl C 1-6 alkyl described later means a group in which the “C 3-10 cycloalkyl” is substituted on the “C 1-6 alkyl”.
- the “C 1-6 alkyl” is preferably an alkyl having 1 to 3 carbon atoms, such as cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, cycloheptylmethyl. Etc.
- Aryl preferably means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include phenyl and naphthyl.
- the group includes ortho-fused bicyclic groups having 8 to 10 ring atoms and at least one ring being an aromatic ring (for example, indenyl).
- the aryl C 1-6 alkyl described later means a group in which the above “C 1-6 alkyl” is substituted with the above “aryl”.
- the aryl C 2-6 alkenyl described later means a group obtained by substituting the above “C 2-6 alkenyl” with the above “aryl”.
- the “C 2-6 alkenyl” is preferably alkenyl having 2 to 4 carbon atoms, such as trans- ⁇ -styryl, cinnamyl, 3- (1-naphthyl) -2-propenyl, 3- (2-naphthyl). -2-propenyl and the like.
- the heteroaryl means an aromatic group containing one or more (preferably 1 to 4) heteroatoms selected from an oxygen atom, a sulfur atom or a nitrogen atom in addition to the carbon atom.
- These groups include 5- or 6-membered monocyclic groups, or ortho-fused bicyclic groups having 8 to 10 ring atoms derived therefrom (especially benzo derivatives), and propenylene, trimethylene or tetramethylene As well as the stable N-oxide thereof.
- Examples of the group include pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -Oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1, 3,5-triazinyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, oxazolopyridyl, imidazopyridazin
- the heteroaryl C 1-6 alkyl described later means a group in which the above “C 1-6 alkyl” is substituted with the above “heteroaryl”.
- the “C 1-6 alkyl” is preferably alkyl having 1 to 5 carbon atoms, such as 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-pyridyl) ethyl, 2- ( 3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, 3- (2-pyridyl) propyl, 3- (3-pyridyl) propyl, 3- (4-pyridyl) propyl, 2-thienylmethyl, 3-thienyl Methyl, 2- (2-thienyl) ethyl, 3- (2-thienyl) propyl, 4-pyrazolylmethyl, 2- (4-pyrazolyl) ethyl, 3- (4-pyrazolyl) propyl, 2-
- the heterocycle means a cyclic hydrocarbon group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, a sulfur atom and the like.
- the group is non-aromatic and may be saturated or partially unsaturated.
- the group includes not only a single ring but also a spiro ring, and a 4- to 7-membered monocyclic group or a 10- or 11-membered spiro ring group is preferable.
- Examples of the group include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, 1,4-diazepanyl, 1,2,5,6-tetrahydropyridyl, tetrahydropyranyl, cyclopentanespiro-4′-piperidinyl and the like.
- the heterocycle may be condensed with an aromatic ring.
- condensed ring examples include indolinyl, isoindolinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, spiro [indan-1,4′-piperidine] -1 '-Ile and the like can be mentioned.
- Cyclic amino means a cyclic hydrocarbon group containing at least one nitrogen atom, and the nitrogen atom is a bond of the group.
- the ring may contain 1 to 3 of the same or different heteroatoms selected from, for example, a further nitrogen atom, oxygen atom and sulfur atom.
- the group is non-aromatic and may be saturated or partially unsaturated.
- the group includes not only a single ring but also a spiro ring, and a 4- to 7-membered monocyclic group or a 10- or 11-membered spiro ring group is preferable.
- Examples of the group include azetidino, pyrrolidino, piperidino, piperazino, morpholino, 1,4-diazepan-1-yl, 1,2,5,6-tetrahydropyridino, tetrahydroimidazolino, cyclopentanespiro-4′-piperidino Etc.
- the cyclic amino may be condensed with an aromatic ring.
- the fused ring include indolino, isoindolino, 1,2,3,4-tetrahydroquinolino, 1,2,3,4-tetrahydroisoquinolino, spiro [indan-1,4′-piperidine] -1 '-Ile and the like can be mentioned.
- halogen atom examples include a chlorine atom, a bromine atom, a fluorine atom, and an iodine atom.
- Substituent group A halogen atom (as defined above), hydroxyl group, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 3-10 cycloalkyl (as defined above), C 3-10 cycloalkyl C 1- 6 alkyl (as defined above), aryl (as defined above), aryloxy, aryl C 1-6 alkyl (as defined above), aryl C 2-6 alkenyl (as defined above), aryl C 2-6 alkynyl, hetero Aryl (as defined above), heteroaryloxy, heteroarylC 1-6 alkyl (as defined above), heterocycle (as defined above), oxo , -COOR a,
- substituent may further have 1 to 3 substituents selected from the substituent group B at substitutable positions.
- Substituent group B halogen atom (as defined above), hydroxyl group, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 3-10 cycloalkyl (as defined above), C 3-10 cycloalkyl C 1- 6 alkyl (as defined above), aryl (as defined above), aryloxy, aryl C 1-6 alkyl (as defined above), aryl C 2-6 alkenyl (as defined above), aryl C 2-6 alkynyl, hetero Aryl (as defined above), heteroaryloxy, heteroarylC 1-6 alkyl (as defined above), heterocycle (as defined above), oxo , —COOR a
- C 1-6 alkyl portion of the C 1-6 alkoxy has the same meaning as the above-mentioned "C 1-6 alkyl” ,, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyl Examples include oxy.
- C 1-6 alkyl part of C 1-6 alkylthio has the same meaning as the above “C 1-6 alkyl”, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like.
- C 1-6 alkyl portion of the C 1-6 alkylsulfinyl has the same meaning as the above-mentioned "C 1-6 alkyl", for example, methylsulfinyl, ethylsulfinyl, propyl sulfinyl, isopropyl sulfinyl, butylsulfinyl, pentylsulfamoyl alkylsulfonyl, And hexylsulfinyl.
- aryl part of aryloxy has the same meaning as the above “aryl”, and examples thereof include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
- Aryl C 2-6 alkynyl means a group obtained by substituting the above “aryl” for the above “C 2-6 alkynyl”.
- the “C 2-6 alkynyl” is preferably alkynyl having 2 to 4 carbon atoms, and examples thereof include phenylethynyl.
- heteroaryl part of heteroaryloxy has the same meaning as the above “heteroaryl”, and examples thereof include 2-pyridyloxy, 2-benzothiazolyloxy and the like.
- R a to R j are each a hydrogen atom, C 1-6 alkyl (as defined above), aryl (as defined above), aryl C 1-6 alkyl (as defined above), heteroaryl (as defined above) Or a heteroaryl C 1-6 alkyl (as defined above), and these groups may further have 1 to 3 substituents selected from Substituent Group A at substitutable positions. Good.
- R b and R c , R e and R f , R i and R j in —NR b R c , —NR e R f , —NR i R j , and cyclic nitrogen may further have 1 to 3 substituents selected from the substituent group A at substitutable positions.
- the cyclic amino formed by —NR e R f is an oxo-containing cyclic amino (for example, 2-pyrrolidinon-1-yl, 1-oxoisoindoline-2-yl, succinimide, oxazolidine-2-one-3-yl, 2-benzoxazolinon-3-yl, phthalimide, 4-quinazolinone-3-yl, etc.).
- oxo-containing cyclic amino for example, 2-pyrrolidinon-1-yl, 1-oxoisoindoline-2-yl, succinimide, oxazolidine-2-one-3-yl, 2-benzoxazolinon-3-yl, phthalimide, 4-quinazolinone-3-yl, etc.
- T 1 to T 3 are each C 1-6 alkyl (as defined above), C 2-6 alkenyl (as defined above), C 2-6 alkynyl (as defined above), C 3-10 cycloalkyl (as defined above) Synonyms), C 3-10 cycloalkyl C 1-6 alkyl (as defined above), aryl (as defined above), aryl C 1-6 alkyl (as defined above), heteroaryl (as defined above), heteroaryl C 1-6 alkyl (as defined above), cyclic amino (as defined above), or heterocycle (as defined above), and these groups are further substituted with 1 to 3 substituents selected from substituent group A
- substituent group A For example, as aryl or heteroaryl having 1 to 3 substituents selected from Substituent Group A, 2-aminophenyl, 2-amino-5- Fluoroph Alkenyl, 2-amino-6-fluorophenyl, 2-fluorophenyl, 4-methoxy
- non-peptide angiotensin type 2 receptor agonist in the present invention include the following Example compounds 1 to 588 described in the pamphlet of International Publication No. WO2008 / 156142.
- non-peptide angiotensin type 2 receptor agonist in the present invention, the following compounds or pharmacologically acceptable salts thereof are particularly preferable.
- non-peptide angiotensin type 2 receptor agonist in the present invention, the following compounds or pharmacologically acceptable salts thereof are preferable.
- the AT2 receptor agonist may be in the form of a pharmacologically acceptable salt.
- salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), organic acid addition salts (for example, methanesulfonic acid, benzenesulfonic acid).
- P-toluenesulfonic acid formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, Salts with methyl sulfate, etc.), inorganic base addition salts (for example, salts with sodium, potassium, calcium, magnesium, etc.), salts with amino acids (for example, salts with glutamic acid, aspartic acid, arginine, lysine, etc.), etc. Can be mentioned.
- the AT2 receptor agonist may exhibit polymorphism, and when the molecule contains an asymmetric carbon, an optical isomer or a stereoisomer may exist.
- the AT2 receptor agonist may be in the form of a hydrate or a solvate. . Furthermore, it can exist as more than one tautomer depending on the presence of an unsaturated bond, the type of substituent, pH and the like. Accordingly, AT2 receptor agonists include any stereoisomers, optical isomers, polymorphs, tautomers, and any mixtures thereof as described above.
- AT2 receptor agonists may be used alone or in combination of two or more.
- the AT2 receptor agonist can be produced by a known method (for example, a method described in International Publication WO2008 / 156142 pamphlet).
- the medicament of the present invention is not limited as long as it contains the above-mentioned AT2 receptor agonist (or vascular protective agent) as an active ingredient.
- AT2 receptor agonist or vascular protective agent
- known pharmacologically acceptable inert carriers and excipients and may contain a diluent and the like.
- metastasis of malignant tumor can be preferably suppressed or prevented.
- the present invention also exhibits an excellent metastasis-suppressing effect even for malignant tumors whose metastasis has worsened or increased by administration of an anticancer agent and / or an antitumor agent (for example, a platinum antitumor agent such as cisplatin). It also has excellent effects on metastasis of malignant tumors in patients who have undergone tumor resection surgery and malignant tumors in patients who have received treatment by radiotherapy or laser ablation. Therefore, according to the present invention, metastasis of malignant tumor can be suppressed or prevented.
- the metastasis-suppressing action according to the present invention is usually an action that suppresses metastasis of malignant tumors without being based on the cell-killing effect or cell growth inhibition on the malignant tumor itself.
- the effect is different from that obtained by acting on the malignant tumor side like normal anticancer agents and antitumor agents, and acts on the host (for example, malignant tumor patient) side to protect blood vessels or vessels. It is obtained by action. Since it acts on the host side as described above, the present invention can exert an excellent metastasis inhibitory effect on all malignant tumors regardless of the type of malignant tumor (for example, cancer).
- the AT2 receptor agonist (or pharmaceutical or vascular protective agent, hereinafter the same in the same description) for suppressing or preventing metastasis of malignant tumors of the present invention suppresses or prevents malignant tumor cell colonization or infiltration into vascular endothelium. It is also preferably used as an AT2 receptor agonist for prevention.
- the method for inhibiting or preventing malignant tumor metastasis and the method for treating or preventing the present invention are also suitable as a method for suppressing or preventing malignant tumor cell colonization or infiltration into the vascular endothelium.
- the medicament (or AT2 receptor agonist) of the present invention a method for suppressing or preventing malignant tumor metastasis, and a method for treating or preventing can be preferably used for suppressing or preventing metastasis of any malignant tumor.
- it is suitable for suppressing or preventing the establishment (adhesion) or infiltration of malignant tumor cells to the vascular endothelium in hematogenous metastasis.
- the present invention is effective not only for the suppression and prevention of metastasis of malignant tumors and the prevention of metastasis after treatment by tumor resection, but also for metastasis of malignant tumors that are difficult to excise. It can be effectively suppressed or prevented.
- the purpose of the present invention is to suppress or prevent metastasis of malignant tumors, but the target patients are usually malignant tumor patients.
- the type of malignant tumor is not particularly limited, and examples thereof include various types of malignant tumors such as epithelial malignant tumors such as cancer, non-epithelial malignant tumors such as sarcoma, and melanoma.
- Such malignant tumors include, for example, lung cancer (non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), stomach cancer, colon cancer, liver cancer, kidney cancer, bladder cancer, pancreatic cancer, thyroid cancer, breast cancer, Examples include uterine cancer, ovarian cancer, prostate cancer, bone tumor, and brain tumor.
- lung cancer non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.
- stomach cancer colon cancer
- liver cancer kidney cancer
- bladder cancer pancreatic cancer
- thyroid cancer breast cancer
- Examples include uterine cancer, ovarian cancer, prostate cancer, bone tumor, and brain tumor.
- the object of the present invention is to suppress or prevent metastasis of malignant tumors.
- malignant tumor cells are released from the primary tumor (primary focus), blood flow, or lymphatic system.
- primary tumor primary focus
- blood flow or lymphatic system.
- tumor cells spread to other parts of the body and thus include any organ and tissue throughout the body.
- malignant tumor cells are thin blood vessels such as capillaries, and are likely to metastasize to organs or tissues with a large blood flow.
- the most common metastatic sites include lung, bone, liver and brain, among which lung and liver are important as metastatic sites.
- metastasis to tissues or organs such as lung, bone, liver and brain, more preferably lung or liver, can be effectively suppressed or prevented.
- Such a malignant tumor may be a primary tumor or a metastatic tumor, and administration of the medicament of the present invention (or an AT2 receptor agonist or a vascular protective agent, hereinafter the same in the same description).
- administration of the medicament of the present invention or an AT2 receptor agonist or a vascular protective agent, hereinafter the same in the same description.
- the timing it can be administered at any time after a malignant tumor such as cancer is found in the patient, but from the viewpoint of normal metastasis suppression, it may be administered continuously or at regular intervals. It is preferable.
- the medicament of the present invention is preferably administered, for example, to a patient who has undergone resection surgery of a malignant tumor or who has undergone resection surgery.
- a patient who is or has been administered with an anticancer agent and / or an antitumor agent is also preferred as a subject patient of the medicament of the present invention.
- An anticancer agent and an antitumor agent are 1 type (s) or 2 or more types of the other anticancer agent and / or antitumor agent which are used with the pharmaceutical of this invention mentioned later, for example.
- the administration of the medicament of the present invention is started about 1 week or more before surgery, preferably about 10 days or more, and is continued after about 1 week or more, preferably about 10 days or more after excision surgery. It is preferable to do this.
- the dosage form and administration route of the medicament of the present invention are not particularly limited, and one or more oral or parenteral agents can be selected according to the patient's situation. Two or more kinds can be used in combination.
- the medicament of the present invention can be used as an oral medicament (oral preparation), it can be easily administered.
- the medicament of the present invention can be used in combination with at least one of other metastasis inhibitor.
- other metastasis suppressors include, for example, the GC-A agonist, GC-B agonist, NEP inhibitor, PDE5 inhibitor, NO supply agent, eNOS activator, GC- C agonists, cGMP analogs and the like can be preferably used.
- metastasis inhibitor When other metastasis inhibitor is administered parenterally, for example intravenously, it is preferably administered continuously using an infusion pump, a catheter, etc. for several hours to several days (for example, 3 to 14 days, (Preferably about 3 to 7 days).
- examples of other metastasis inhibitors include (i) an angiotensin II receptor antagonist described in International Application No. PCT / JP2013 / 077140, (ii) HMG-CoA reductase inhibitor, (iii) It is also possible to suitably use at least one vascular protective agent selected from ghrelin or a derivative thereof, (iv) adrenomedullin or a derivative thereof, or a pharmaceutically acceptable salt thereof.
- Angiotensin II receptor antagonist An angiotensin II receptor antagonist has the effect
- An angiotensin II receptor antagonist used as an active ingredient of other metastasis inhibitors may be any as long as it has the above action.
- angiotensin II receptor antagonist for example, one or more of eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan-medoxomil, azilsartan are preferable, and valsartan, telmisartan, irbesartan, azilsartan One or more of olmesartan medoxomil are more preferable.
- angiotensin II receptor antagonist in the other metastasis inhibitor is particularly preferably telmisartan.
- HMG-CoA reductase inhibitors The HMG-CoA reductase inhibitor has an action of specifically inhibiting HMG-CoA reductase.
- the HMG-CoA reductase inhibitor used as an active ingredient of other metastasis inhibitors may be any as long as it has the above action.
- HMG-CoA reductase inhibitors used as active ingredients of other metastasis inhibitors include all natural substances derived from microorganisms, semisynthetic substances derived therefrom, and total synthetic compounds, such as pravastatin, lovastatin, Simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, rosuvastatin and the like can be mentioned.
- pravastatin, simvastatin, fluvastatin, rivastatin, atorvastatin, pitavastatin, and rosuvastatin are preferable, and pitavastatin is particularly preferable.
- angiotensin II receptor antagonist and HMG-CoA reductase inhibitor for example, commercially available drugs or compounds can be used.
- Ghrelin acts on growth hormone secretagogue-receptor 1a (GHS-R1a) and has an action of enhancing secretion of growth hormone (Growth Hormone: GH) from the pituitary gland.
- Ghrelin usually has an amino acid sequence consisting of 28 amino acid residues (or 27 amino acid residues), and has a structure in which the third amino acid residue from the amino terminus of the sequence is acylated with a fatty acid. It is a peptide.
- ghrelin of human and non-human mammals eg, rat, mouse, pig, cow, horse, sheep, dog, etc.
- amino acid sequence and acylation structure as shown below are known.
- International pamphlet of WO01 / 07475 International pamphlet of WO01 / 07475.
- GSS (n-octanoyl) FLSPEHQRVQQRKESKKPPAKLQPR (SEQ ID NO: 1) GSS (n-octanoyl) FLSPEHQRVQRKESKKPPAKLQPR (SEQ ID NO: 2)
- Rat GSS (n-octanoyl) FLSPEHQKAQQRKESKKPPAKLQPR (SEQ ID NO: 3) : GSS (n-octanoyl) FLSPEHQKAQRKESKKPPAKLQPR (SEQ ID NO: 4)
- Mouse GSS (n-octanoyl) FLSPEHQKAQQRKESKKPPAKLQPR (SEQ ID NO: 5)
- Pig Porcine
- Bovine GSS (n-octanoyl) FLS
- ghrelin has a structure in which the side chain hydroxyl group of the amino acid residue at position 3 (serine residue (S), etc.) is acylated with a fatty acid such as octanoic acid or decanoic acid.
- a fatty acid such as octanoic acid or decanoic acid.
- human ghrelin is a peptide having the amino acid sequence shown in SEQ ID NO: 1 or 2, and the third amino acid residue (serine residue) from the amino terminus has a side chain (hydroxyl group) of a fatty acid (n- It is a modified amino acid residue acylated with octanoic acid.
- ghrelin ghrelin derived from mammals is preferable, and for example, ghrelin from other animals such as human, ghrelin, rat, mouse, pig, cow, horse, sheep, dog and the like can be used.
- ghrelin derived from the species to which the individual belongs is preferably used.
- human ghrelin is preferably used for humans.
- ghrelin As a derivative of ghrelin, it has a structure similar to that of ghrelin and has the same action as ghrelin, that is, an agonistic action on growth hormone secretagogue receptor 1a, and it secretes growth hormone from the pituitary gland. The thing which has the effect
- ghrelin and derivatives thereof include, for example, peptides having a structure selected from the following (1) to (3), and having an agonistic action on the growth hormone secretion promoting factor receptor 1a, etc. Is mentioned.
- a peptide having an amino acid sequence in which one to several amino acids are deleted, substituted and / or added in a portion other than the conserved sequence, and further from the amino terminus Is a modified amino acid residue whose side chain is acylated with a fatty acid.
- amino acid sequence represented by any one of SEQ ID NOS: 1 to 10 is, for example, “when any of the pharmaceuticals of the present invention is applied to humans”
- the amino acid sequence shown is preferred.
- examples of the fatty acid introduced into the side chain include fatty acids having any of 2, 4, 6, 8, 10, 12, 14, 16 and 18 carbon atoms.
- octanoic acid, decanoic acid or its monoene fatty acid or its polyene fatty acid is used, and more preferably octanoic acid (e.g., having 8 carbon atoms and n-octanoic acid).
- substitution, substitution and / or addition is also referred to as “substitution etc.”.
- the number of amino acids to be substituted is not particularly limited as long as the peptide consisting of the amino acid sequence or a derivative thereof has a desired action (that is, an agonistic action on the growth hormone secretion promoting factor receptor 1a).
- a desired action that is, an agonistic action on the growth hormone secretion promoting factor receptor 1a.
- about 9 preferably about 1 to 4, more preferably about 1 to 3, more preferably about 1 to 2, particularly preferably about 1.
- addition includes insertion.
- substitution in the case of substitution with an amino acid having similar properties (charge and / or polarity), the desired function is not usually lost even if a large number of amino acids are substituted.
- substitution is made at a plurality of locations, any one of deletion, substitution, and addition may be used, or two or more may be combined.
- the amino acid sequence of the ghrelin derivative (eg, (2) and (3) above) is preferably at least from the amino terminus to the fourth in the amino acid sequence of natural ghrelin (eg, those shown in SEQ ID NOs: 1 to 10). It is preferable that the sequence up to the 5th, more preferably the sequence up to the 10th is conserved.
- amino acid sequence of the ghrelin derivative (for example, (2) and (3) above) is usually about 70% or more, preferably about 80% or more, more preferably about 80% or more compared to the amino acid sequence of natural ghrelin. It is preferred to have a sequence identity of 90% or more, particularly preferably about 95% or more, and most preferably about 97% or more.
- Examples of other ghrelin derivatives include those obtained by amidating the peptide bond from the structure exemplified above, further amidating the carboxyl terminal without terminating with a carboxylic acid. By adopting such a form, it becomes possible to find the minimum activity unit with a shorter amino acid sequence. In addition to these, those obtained by adding a basic amino acid to the carboxyl terminus as desired, or those introduced with an amino acid that is an amide such as -Lys-NH 2 may be used.
- Other derivatives of ghrelin include, for example, Matsumoto et al. (Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues.
- ghrelin and its derivatives have an agonistic effect on the growth hormone secretagogue receptor 1a is determined by Matsumoto et al.
- Structure-activity relationship of ghrelin pharmacological study of ghrelin peptides. Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y, Kangawa K. Biochem Biophys Res Commun. 2001 Sep 14; 287 (1): 142-6.
- Physiological actions via growth hormone secretion promoting factor receptor 1a such as an increase in ion concentration can be determined as an index.
- ghrelin or a derivative thereof is contacted with the growth hormone secretagogue receptor 1a, and it is tested whether it increases intracellular calcium ion concentration by binding to the receptor. If the ion concentration is increased, it can be determined that there is an agonistic effect.
- nucleic acids encoding ghrelin or ghrelin derivatives having the above peptide structure
- Such a nucleic acid may be designed so as to express ghrelin or a ghrelin derivative having the above peptide structure by being administered in vivo.
- Ghrelin and its derivatives can be produced by chemical synthesis or the like by conventional methods.
- an amino acid having a protecting group is condensed by a liquid phase method and / or a solid phase method, the peptide chain is extended, all protecting groups are removed with an acid, and the resulting crude product is subjected to, for example, gel filtration, limiting It can be obtained by purification by separation and purification methods such as external filtration, dialysis, SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), and various chromatography.
- the side chain of the amino acid at the target position can be selectively acylated with an acylating enzyme or an acyltransferase.
- a method using a combination of recombinant DNA technology and chemical synthesis may be used.
- fragments containing modified amino acid residues are produced by chemical synthesis, and other fragments not containing modified amino acid residues are produced by recombinant DNA technology.
- Ghrelin and its derivatives can also be isolated from natural sources.
- amino acid includes all amino acids such as L-amino acid, D-amino acid, ⁇ -amino acid, ⁇ -amino acid, ⁇ -amino acid, natural amino acid, synthetic amino acid and the like. Preferably, it is a natural amino acid.
- Adrenomedullin is a polypeptide having a vasodilatory action and a hypotensive action (blood pressure lowering action).
- adrenomedullin active adrenomedullin
- PAMP broadrenomedullin N-terminal 20 peptide
- Adrenomedullin exerts an action of increasing intracellular cAMP of platelets, vascular endothelial cells and smooth muscle cells, as well as a platelet aggregation inhibitory action, a strong vasodilatory action and a hypotensive action.
- adrenomedullin means active adrenomedullin unless otherwise specified.
- SEQ ID NO: 11 shows the nucleotide sequence of adrenomedullin precursor cDNA.
- SEQ ID NO: 12 shows the amino acid sequence of the adrenomedullin precursor.
- the amino acid sequence of SEQ ID NO: 12 is an amino acid sequence encoded by the base sequence of SEQ ID NO: 11.
- SEQ ID NO: 13 shows the amino acid sequence of adrenomedullin (active form).
- SEQ ID NO: 14 shows the amino acid sequence of PAMP.
- adrenomedullin human adrenomedullin and other animal adrenomedullin such as rat, mouse, pig and cow can be used.
- adrenomedullin derived from a mammal is used.
- human adrenomedullin is preferably used for humans.
- a derivative of adrenomedullin a derivative having a structure similar to that of adrenomedullin and having the same action as adrenomedullin (the action of increasing cAMP in blood platelets, or the vasodilating action and / or the antihypertensive action), etc.
- the derivative of adrenomedullin is preferably a polypeptide having an action of increasing cAMP in platelets, a vasodilatory action and a hypotensive action.
- precursors of adrenomedullin are also included.
- PAMP is also included.
- adrenomedullin and derivatives thereof in the present invention include, for example, a polypeptide having a structure selected from the following (1) to (3), and an effect of increasing cAMP in platelets: Alternatively, a polypeptide having a vasodilatory action and / or an antihypertensive action may be mentioned.
- polypeptide having an amino acid sequence represented by SEQ ID NO: 12, 13, or 14 (2) a polypeptide having an amino acid sequence in which one to several amino acids are deleted, substituted and / or added in the amino acid sequence shown in SEQ ID NO: 12, 13 or 14; and (3) shown in SEQ ID NO: 11
- the nucleic acid may be either RNA or DNA, but DNA is preferred.
- adrenomedullin As the adrenomedullin or a derivative thereof in the present invention, adrenomedullin (active form) is preferable, and mammalian adrenomedullin is more preferable.
- the above (1) is preferably a polypeptide having the amino acid sequence shown in SEQ ID NO: 13.
- the number of amino acids to be substituted when “one to several amino acids are deleted, substituted and / or added” is the polypeptide comprising the amino acid sequence Is usually not more than about 30 amino acids (about 1 to 30 amino acids), preferably about 15 amino acids (about 1 to 15 amino acids), more preferably about 5 amino acids. (About 1 to 5 amino acids) (for example, preferably within about 3 amino acids (about 1 to 3 amino acids)), more preferably about 1 to 2, particularly preferably about 1.
- substitution of amino acids with similar properties (charge and / or polarity) or the like does not usually lose the desired function even if a large number of amino acids are substituted.
- substitution is made at a plurality of locations, any one of deletion, substitution and addition may be used, or two or more may be combined.
- the amino acid sequence of the adrenomedullin derivative is usually about 70% or more, preferably about 80% or more, more preferably about 90% or more, especially compared to the natural amino acid sequence (for example, SEQ ID NO: 12, 13, or 14). Preferably it has a sequence identity of about 95% or more, most preferably about 97% or more.
- stringent conditions generally refer to 6M urea, 0.4% SDS, 0.5xSSC conditions, or equivalent hybridization conditions of stringency. Isolation of DNA with higher homology can be expected by using conditions with higher stringency, for example, conditions of 6M urea, 0.4% SDS, 0.1xSSC, and the like. The isolated DNA has high homology or identity with the amino acid sequence of the target protein at the amino acid level.
- a nucleic acid capable of hybridizing under stringent conditions with a nucleic acid consisting of the base sequence shown in SEQ ID NO: 11 is usually about 90% or more, preferably with a DNA consisting of a base sequence complementary to SEQ ID NO: 11, Is a DNA encoding a polypeptide having a sequence identity of about 95% or more, more preferably about 98% or more, and an effect of increasing cAMP in platelets or having a vasodilatory action and / or a hypotensive action. preferable.
- Kitamura et al. (Adrenomedullin (11-26): a novel endogenous hypertensive peptide isolated from bovine adrenal medulla.Kitamura K, Matsui E, Kato J, Katoh F, Kita T, Tsuji T, Kangawa K, Eto T. Peptides. 2001 Nov; 22 (11): 1713-8.) and Champion et al. Can be determined by testing by the method described in Structure-activity relationships of adrenomedullin in the circulation and adrenal gland.
- adrenomedullin derivative for example, adrenomedullin or a form of nucleic acid encoding an adrenomedullin derivative having the above polypeptide structure can be mentioned.
- a nucleic acid may be designed to express adrenomedullin or an adrenomedullin derivative having the above peptide structure by being administered in vivo.
- Adrenomedullin and its derivatives can be produced by ordinary recombinant DNA technology or chemical synthesis, or a combination thereof. It can also be isolated from natural raw materials.
- Adrenomedullin or a derivative thereof can be obtained by purification by separation and purification methods such as gel filtration, ultrafiltration, dialysis, SDS-PAGE (sodium dodecyl sulfate polyacrylamide gel electrophoresis), and various chromatography.
- the active ingredient in the pharmaceutical composition described in International Application No. PCT / JP2013 / 077140 may be in free form or in the form of a pharmacologically acceptable salt.
- salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
- the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt.
- salts with organic bases include salts with organic bases such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, and the like. Can be mentioned.
- salts with inorganic acids include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.
- salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with organic acids such as toluenesulfonic acid.
- salts with basic amino acids include salts with basic amino acids such as arginine, lysine and ornithine.
- Suitable examples of salts with acidic amino acids include aspartic acid and glutamic acid. And a salt with an acidic amino acid.
- an angiotensin II receptor antagonist or HMG-CoA reductase inhibitor which is an active ingredient in other metastasis inhibitors
- it is preferably administered once to 3 times a day.
- an angiotensin II receptor antagonist or an HMG-CoA reductase inhibitor it is preferable to orally administer about 1 to 100 mg / kg per day as an active ingredient per body weight. It can be administered at a dose below that used for hypercholesterolemia.
- the administration rate of the active ingredient is about 0.1 ⁇ g / kg / min or less, preferably about 0.08 ⁇ g / kg / min or less. Etc. can be adopted.
- the administration rate of the active ingredient is usually about 0.1 ⁇ g / kg / min or less, preferably about 0.05 ⁇ g / kg / min or less. Continuous administration or the like can be employed.
- the administration period in the case of continuous administration of ghrelin, adrenomedullin and their derivatives is usually about 1 day or longer, preferably about 1 day to 2 weeks.
- the administration method is preferably intravenous administration.
- ghrelin When orally administering ghrelin, adrenomedullin or a derivative thereof, for example, it is preferable to formulate at a dose of about 4 times or less per day, and for parenteral administration such as intravenous administration, an infusion pump, a catheter, etc. It is preferable to administer continuously using.
- the medicament of the present invention and other metastasis inhibitor can be used by applying the above-mentioned administration period according to the administration method.
- the active ingredient is usually mixed with known pharmacologically acceptable inert carriers, excipients, diluents and the like into a pharmaceutical composition, which is generally used in medicine. It can be administered to an individual by a method, that is, an oral administration method, or a parenteral administration method such as transmucosal administration, intravenous administration, intramuscular administration, or subcutaneous administration.
- the active ingredient of another metastasis inhibitor when the active ingredient of another metastasis inhibitor is a peptidic substance, it can be orally administered as a preparation that is not easily degraded in the digestive tract, for example, a microcapsule encapsulating the active ingredient peptide in liposomes. is there.
- the administration method which absorbs from mucous membranes other than digestive tracts, such as a rectum, a nose, and a sublingual is also possible. In this case, for example, it can be administered to an individual in the form of a suppository, a nasal spray, an inhalant, or a sublingual tablet.
- the active ingredient of another metastasis inhibitor is in the form of a nucleic acid encoding a peptide substance
- a nucleic acid a gene encoding a peptide substance, etc.
- the vector can be introduced into a patient by intravenous injection, intramuscular injection, local injection or the like using the vector as a vector or in the form of a plasmid or the like.
- the dosage of the medicament of the present invention varies depending on the administration route, target disease, patient symptom, body weight, age, etc., and can be appropriately set according to the purpose of administration.
- the dose or dose (for example, the dose when orally administered to an adult) is 0.01 to 1000 mg / kg, more preferably 0.05 to 500 mg / kg per day as an AT2 receptor agonist. It is preferable to administer an appropriately set dose once to several times a day.
- the administration frequency of the active ingredient in the pharmaceutical or therapeutic or preventive method of the present invention is not particularly limited, and varies depending on the active ingredient used, the administration route, and the specific disease to be treated.
- the pharmaceutical or therapeutic or preventive method of the present invention can be used in combination with at least one of other commonly used anticancer agents and / or antitumor agents to more efficiently treat malignant tumors.
- Examples of the form of such combination therapy include a form in which the medicament of the present invention is administered to a patient who has been or has been administered an anticancer agent and / or an antitumor agent. Since the medicament of the present invention can control the metastasis and invasion of tumor cells, it can be appropriately administered during treatment with an anticancer agent and / or antitumor agent, so that the treatment with the anticancer agent and / or antitumor agent can be performed. It can increase efficiency and improve treatment prognosis.
- the medicament of the present invention together with at least one of a commonly used anticancer agent and / or antitumor agent, the deterioration and / or increase of malignant tumor metastasis by the anticancer agent and / or antitumor agent is effectively suppressed or prevented.
- the effect that it can do is also acquired.
- the medicament of the present invention is suitably used for suppressing or preventing the exacerbation and / or increase of malignant tumor metastasis by an anticancer agent and / or an antitumor agent.
- the present invention also includes a method for suppressing or preventing exacerbation and / or increase of metastasis of malignant tumors by an anticancer agent and / or an antitumor agent, which comprises administering the medicament (or an effective amount thereof) to a patient.
- the dosage of the anticancer agent and the antitumor agent is not particularly limited, and the type of drug, the type of disease (malignant tumor), What is necessary is just to set according to the age of an individual (patient), a body weight, the grade of a symptom, an administration route, etc., and can use it by the normally used dose.
- the dosage of the medicament of the present invention is determined depending on the type of disease (malignant tumor), age of individual (patient), body weight, It may vary depending on the symptom level and administration route, and may be appropriately selected.
- the AT2 receptor agonist is, for example, about 0.01 to 1000 mg / kg, preferably 0.05 to 500 mg / kg per day, and an appropriately set dose (or dose) once to several times a day. It is preferable to administer separately (for example, oral administration).
- the medicament of the present invention When the medicament of the present invention is used together with an anticancer agent and / or an antitumor agent, the medicament is preferably administered before (or prior to administration) the anticancer agent and / or antitumor agent.
- the pharmaceutical of this invention should just be administered before administering an anticancer agent and / or an antitumor agent, and can be continuously administered for the period required for a treatment after that.
- an anticancer agent and / or an antitumor agent for example, a platinum antitumor agent such as cisplatin
- the anticancer agent and / or after the blood vessel is protected beforehand by administering the medicament of the present invention to the patient.
- an antitumor agent for example, a platinum antitumor agent such as cisplatin
- the anticancer agent and / or after the blood vessel is protected beforehand by administering the medicament of the present invention to the patient.
- an antitumor agent for example, a platinum antitumor agent such as cisplatin
- the medicament of the present invention is administered about 1 day or more before the start of administration of an anticancer agent and / or antitumor agent (for example, 3 days or more), preferably 1 week or more, more preferably about 10 days or more ( Or administration of a medicine may be started). Further, after the administration of the anticancer agent and / or antitumor agent, the administration of the medicament of the present invention is continued for about 1 day or more (for example, 3 days or more), preferably for 1 week or more, preferably about 10 days or more. preferable.
- an anticancer agent and / or an antitumor agent for example, a platinum antitumor agent such as cisplatin
- one or more oral or parenteral agents are used as the medicament of the present invention in accordance with the patient's situation.
- the medicament of the present invention can be used in combination with at least one of the other metastasis inhibitors.
- an anticancer agent and / or an antitumor agent for example, a platinum antitumor agent such as cisplatin
- an antitumor agent for example, a platinum antitumor agent such as cisplatin
- the combination of the medicament of the present invention and another metastasis inhibitor can be administered simultaneously or separately.
- the pharmaceutical agent of the present invention in such a combination usually starts administration of the pharmaceutical agent of the present invention from about 1 week or more before starting the administration of the anticancer agent and / or antitumor agent, preferably about 10 days or more before the anticancer agent and / or The administration is preferably continued for about 1 week or more, preferably about 10 days or more after the end of the administration of the antitumor agent.
- the dosage form and administration route of the medicament of the present invention in such a combination are not particularly limited, and one or more oral or parenteral agents can be selected according to the patient's situation. Two or more oral preparations can be used in combination.
- metastasis inhibitor when other metastasis inhibitor is administered parenterally, for example, intravenously, it is preferably administered continuously using an infusion pump, a catheter, etc., for several hours to several days ( (For example, about 3 to 14 days, preferably about 3 to 7 days).
- the medicament of the present invention and other metastasis inhibitor can be used by applying the above-mentioned administration period according to the administration method.
- the medicament of the present invention or other metastasis inhibitor When administering the medicament of the present invention or other metastasis inhibitor, depending on the condition of the patient, for example, before the operation and before administration of the anticancer agent and / or antitumor agent, the medicament of the present invention or the above other metastasis inhibitor is administered. Orally administered, and after the surgery or after the administration of the anticancer agent and / or antitumor agent, or the like, the pharmaceutical of the present invention or the other metastasis inhibitor is administered parenterally, and after recovery, the pharmaceutical or It is preferable to administer other metastasis inhibitors orally.
- Examples of the anticancer agent and antitumor agent used together with the medicament of the present invention include alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant components, BRM (biological response regulator), hormones, vitamins , Antitumor antibodies, molecular target drugs, platinum antitumor agents, other anticancer agents and antitumor agents.
- a platinum-type antitumor agent is preferable.
- the alkylating agent includes, for example, an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl; an aziridine alkylating agent such as carbocone or thiotepa; dibromomannitol or dibromodarsi Epoxide-based alkylating agents such as Thor; nitrosourea-based alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin or ranimustine; busulfan, improsulfan tosylate or dacarbazine.
- an alkylating agent such as nitrogen mustard, nitrogen mustard N-sodium oxide or chlorambutyl
- an aziridine alkylating agent such as carbocone or thiotepa
- dibromomannitol or dibromodarsi Epoxide-based alkylating agents such as Thor
- antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine; antipyrimidine metabolism such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine Agents: antifolate antimetabolites such as methotrexate or trimetrexate.
- purine antimetabolites such as 6-mercaptopurine, 6-thioguanine or thioinosine
- antipyrimidine metabolism such as fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine or enocytabine Agents
- antifolate antimetabolites such as methotrexate or trimetrexate.
- Antitumor antibiotics include, for example, anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, pepromycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin; chromomycin A3 Or actinomycin D etc. are mentioned.
- anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, pepromycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin or epirubicin
- chromomycin A3 Or actinomycin D etc. are mentioned.
- antitumor plant component examples include vinca alkaloids such as vindesine, vincristine or vinblastine; taxanes such as paclitaxel and docetaxel; or epipodophyllotoxins such as etoposide or teniposide.
- BRM examples include tumor necrosis factor and indomethacin.
- hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, phosfestol, ethinylestradiol, chlormadinone, or medroxyprogesterone.
- vitamins examples include vitamin C and vitamin A.
- Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, etc.
- platinum antitumor agent examples include cisplatin, carboplatin, oxaliplatin and the like. Of these, cisplatin is preferable.
- anticancer agents and / or antitumor agents examples include tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, piperobroman, neocartinostatin, hydroxyurea, Ubenimex or Krestin is exemplified.
- the pharmaceutical agent of the present invention When the pharmaceutical agent of the present invention is administered in combination with an anticancer agent / antitumor agent (and / or metastasis inhibitor), the pharmaceutical agent and anticancer agent / antitumor agent (and / or metastasis inhibitor) are contained in a single preparation. They may be contained as active ingredients of different preparations.
- the combination of the medicament and anticancer agent and / or antitumor agent is not particularly limited.
- the platinum antitumor agent combined with the medicament of the present invention is preferably cisplatin.
- “administered in combination” with a plurality of active ingredients or drugs means that the administration subject takes all the active ingredients or drugs to be combined into the body for a certain period of time. All active ingredients may be administered as a preparation (so-called combination drug) contained in a single preparation, and each active ingredient is formulated separately and all of them are administered separately (so-called combination) Administration). When formulated separately, the timing of administration is not particularly limited, and may be administered at the same time, and may be administered at different times or on different days. When a plurality of active ingredients are administered at different times or days, the order of administration of the active ingredients is not particularly limited. Usually, since each formulation is administered according to each administration method, the administration may be the same number of times or may be different times.
- each active ingredient when each active ingredient is formulated separately, the administration method (administration route) of each preparation may be the same, or may be administered by different administration methods (administration route). Also, it is not necessary for all active ingredients to be present in the body at the same time, and all the active ingredients are effective for a certain period of time (for example, one month, preferably one week, more preferably several days, even more preferably one day). It is only necessary that an ingredient is taken into the body, and another active ingredient may disappear from the body upon administration of one active ingredient.
- Example 1 Inhibition of pulmonary metastasis (CDDP) by administration of drugs to hematogenous metastasis model by mouse tail vein injection of mouse melanoma
- CDDP pulmonary metastasis
- Mouse melanoma B16-F10 was purchased from ATCC and cultured in Dulbecco's Modified Eagle Medium (DMEM) (Life Technologies Corporation) containing 10% Fetal calf serum (FCS) under conditions of 37 ° C and 5% CO 2.
- DMEM Dulbecco's Modified Eagle Medium
- FCS Fetal calf serum
- mice After treatment with EDTA-trypsin (0.01-0.125% solution) in a confluent state, the mixture was centrifuged and suspended in serum free DMEM to 3 ⁇ 10 6 cells / mL. At a dose of 100 ⁇ L / mouse, 3 ⁇ 10 5 melanoma cell suspensions were injected from the tail vein of mice.
- pretreatment was performed by injecting cisplatin (CDDP) 2.5 mg / kg from the tail vein.
- Compound A was used as an angiotensin type 2 receptor agonist.
- 0.5% carboxymethylcellulose aqueous solution adjusted to a dose of 30 mg / kg of Compound A was administered from 4 days before CDDP administration until the end of the experiment (14 days after melanoma cell injection). Ingested continuously.
- the CDDP injection was not performed, and only the same aqueous solution containing no drug was orally ingested for the experiment.
- Control is the lung (number of nodule) of control mice (no CDDP injection or compound A was ingested)
- AT2A is the lung and nodule number of mice that received only CDDP injection
- CDDP is the lung and nodule number of mice that received only CDDP injection
- AT2A + CDDP is the CDDP injection and compound A It is the number of lungs and nodules of mice ingested orally.
- a black part is a nodule (metastasis) formed by the metastasized melanoma.
- CDDP cisplatin
- Lung metastasis inhibitory effect by drug administration on hematogenous metastasis model by mouse tail vein injection of mouse melanoma
- LPS Lung metastasis inhibitory effect
- Mouse melanoma B16-F10 was purchased from ATCC, cultured in DMEM (Life Technologies Corporation) containing 10% FCS under conditions of 37 ° C and 5% CO 2 , and EDTA-trypsin (0.01-0.125) in a semi-confluent state. % Solution) and then centrifuged.
- DMEM Life Technologies Corporation
- EDTA-trypsin 0.01-0.125
- As angiotensin type 2 receptor agonist using compound A ⁇ E, so as to be 3 ⁇ 10 6 cells / mL in compound A administration group, also to 2 ⁇ 10 6 cells / mL in compound B ⁇ E administered group Each was suspended in serum free DMEM.
- mice respectively Injection was made from the tail vein.
- angiotensin type 2 receptor agonist group a 0.5% carboxymethylcellulose aqueous solution (0.2 mg / mL) adjusted so that the drug (compounds A to E) was dosed at 30 mg / kg / day was tested 4 days before LPS administration. The dose was continuously taken orally until the end (14 days after the injection of melanoma cells).
- LPS was not injected and only the same aqueous solution containing no drugs (compounds A to E) was orally ingested for the experiment.
- the first lung from the upper left is the lung of a control mouse (no LPS injection or oral ingestion of Compound A), and the second to fifth lungs from the upper left are LPS.
- a black part is a nodule (metastasis) formed by the metastasized melanoma.
- “Control” is the lung of a control mouse (no LPS injection or oral administration of drugs (compounds B to E)), and “LPS” is a mouse of only LPS injection.
- “LPS + AT2B” represents the lungs of mice that received LPS injection and oral intake of Compound B
- “LPS + AT2C” represents the lungs of mice that received LPS injection and oral intake of Compound C.
- “LPS + AT2D” is the lungs of mice that received LPS infusion and oral intake of Compound D
- “LPS + AT2E” is the lungs of mice that received LPS injection and oral intake of Compound E.
- a black part is a nodule (metastasis) formed by metastasized melanoma.
- Control is the number of nodules in the control mice (no LPS injection or drug ingestion)
- AT2A is the nodules in the mice with only compound A oral ingestion
- LPS is the number of nodules in mice that received only LPS injection
- LPS (AT2A) is the number of nodules in mice that received LPS injection and oral intake of Compound A.
- Control indicates the number of nodules of the control mice (no LPS injection or drug ingestion)
- LPS indicates the number of nodules of the mice that received only LPS injection
- LPS (AT2B) is the number of nodules of mice that received LPS injection and orally ingested Compound B.
- Control indicates the number of nodules of the control mice (no LPS injection or oral administration of the drug)
- LPS indicates the number of nodules of the mice that received only LPS injection
- LPS (AT2C) is the number of nodules of mice that received LPS injection and orally ingested Compound C.
- Control indicates the number of nodules of the control mice (no LPS injection or oral administration of the drug)
- LPS indicates the number of nodules of the mice that received only LPS injection
- LPS (AT2D) is the number of nodules in mice that received LPS injection and oral intake of Compound D.
- Control indicates the number of nodules of the control mice (no LPS injection or oral administration of the drug)
- LPS indicates the nodules of the mice that received only LPS injection.
- the number “LPS (AT2E)” is the number of nodules in mice that received LPS infusion and oral intake of Compound E.
- the medicament of the present invention can be expected to suppress the deterioration and / or increase of malignant tumor metastasis associated with vascular inflammation (for example, vascular inflammation by surgical operation).
- LPS lung metastasis
- mice 4-week-old male wild-type C57BL6 mice and angiotensin type 2 receptor C57BL6 knockout mice (both purchased from Charles River Japan) were used.
- Lipopolysaccharide (LPS) was injected at 1 mg / kg from the tail vein, and 4-5 hours later, mouse melanoma B16-F10 was injected from the tail vein of the mouse. At this time, mouse melanoma was injected into the tail vein on the side different from the tail vein to which LPS was administered.
- Mouse melanoma B16-F10 was purchased from ATCC, cultured in DMEM (Life Technologies Corporation) containing 10% FCS under conditions of 37 ° C and 5% CO2, and EDTA-trypsin (0.01-0.125%) in a semi-confluent state. Solution) After the treatment, it was centrifuged and suspended in serum free DMEM to 2.5 ⁇ 10 6 cells / mL. At a dose of 100 ⁇ L / mouse, 2.5 ⁇ 10 5 melanoma cell suspensions were injected from the tail vein of mice. Compound A was used as an angiotensin type 2 receptor agonist.
- WT is the lung of a wild-type mouse of a control (in which neither LPS injection nor drug ingestion was performed), and “WT (LPS)” was ingested only by LPS injection.
- Wild type mice lungs, WT (AT2agonist + LPS) is the lungs of wild type mice injected with LPS and orally ingested drug (Compound A), and AT2R-KO (cont) is the control (AT2R-KO (LPS) is an angiotensin type 2 receptor that was ingested only by LPS infusion in the lungs of angiotensin type 2 receptor knockout mice (no LPS injection or drug ingestion)
- the lung of a knockout mouse, “AT2R-KO (AT2agonist + LPS)” is the lung of an angiotensin type 2 receptor knockout mouse that has been injected with LPS and orally ingested with a drug (compound A).
- the black portion is a nodule (metastasis) formed by metastasized melanoma.
- Control indicates the number of nodules of the control mice (no LPS injection or drug ingestion was performed), and “LPS” indicates the nodules of the mice that received only LPS injection.
- the number “AT2agonist + LPS” is the number of nodules of mice that received LPS injection and orally ingested the drug (compound A).
- LPS administration increased lung metastasis of malignant tumors in both wild type mice and angiotensin type 2 receptor knockout mice.
- administration of an angiotensin type 2 receptor agonist suppresses lung metastasis of malignant tumors
- angiotensin type 2 receptor knockout mice administration of angiotensin type 2 receptor agonists does not cause malignant tumors. It was found that lung metastasis was not suppressed.
- angiotensin type 2 receptor is involved in the suppression of lung metastasis of malignant tumors, and angiotensin type 2 receptor agonists suppress the deterioration and / or increase of malignant tumor metastasis. Can be expected.
- the present invention is an excellent drug capable of suppressing metastasis of malignant tumor, a method of suppressing or preventing metastasis, and a method of treating or preventing malignant tumor.
- the present invention exhibits an excellent metastasis-suppressing effect even for malignant tumors whose metastasis has been exacerbated by administration of an anticancer agent and / or an antitumor agent. Therefore, the present invention is useful in the medical field and the like.
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Abstract
Description
また、上皮系以外の悪性腫瘍(肉腫など)においても、悪性化して、運動能・浸潤能を獲得した腫瘍細胞が、血管等へ侵入し、遠隔組織の血管内皮への定着、及び組織内への浸潤を経て、転移巣が形成されることとなる。
本発明の医薬は、また、血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するのに有用である。本発明の医薬は、また、外科的手術による血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するのに有用である。
(i)悪性腫瘍の転移の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
(ii)抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
(iii)非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有する、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防するための医薬(又は血管保護剤)。
(iv)非ペプチド性のアンジオテンシン2型受容体アゴニスト又は血管保護剤(又はその有効量)を患者に投与することを含む、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防する方法。
(v)血管内皮への悪性腫瘍細胞の定着又は浸潤の抑制又は予防に使用するための、非ペプチド性のアンジオテンシン2型受容体アゴニスト(又は血管保護剤)。
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、-CH2-R5{式中、R5は置換されていてもよいC3-10シクロアルキル、置換されていてもよいヘテロサイクル、または-CO-NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1-6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、-(CH2)2-R5’(式中、R5’はシアノ、またはC1-6アルコキシを示す。)、または-(CH2)n-Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
N,N-ジエチル-2-{4-[(2,6-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-[4-(ベンゾイルアミノ)ベンジル]-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(3-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2,4-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(4-メチルベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-チエノイル)アミノ]ベンジル}マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フロイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4,5-ジフルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-メチルベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
2-(4-フルオロベンジル)-N-イソプロピル-N-(3-ピリジル)-N’-((E)-スチリルスルホニル)マロンアミド、
2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド、
(2Sまたは2R)-2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-2-スチリルスルホニル)マロンアミド、
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、および
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド
から選択される少なくとも1種の化合物またはその薬理的に許容される塩であってもよい。
本発明において、投与対象患者は、悪性腫瘍の切除手術を受けるか又は切除手術を受けた患者であってもよい。また、投与対象患者は、抗癌剤及び/又は抗腫瘍剤の投与を受けているか又は投与を受けた患者であってもよい。
また、非ペプチド性のアンジオテンシン2型受容体アゴニストは、前記の通り、抗癌剤及び/又は抗腫瘍剤による転移の増悪及び/又は増大を抑制又は予防するのに有用であるが、このような抑制又は予防機能を有効に発現するためには、投与対象患者に、抗癌剤及び/又は抗腫瘍剤を投与する前から(例えば、抗癌剤及び/又は抗腫瘍剤投与開始の1日以上前から)非ペプチド性のアンジオテンシン2型受容体アゴニストを投与するのが好ましい。
そのため、本発明の医薬(非ペプチド性のアンジオテンシン2型受容体アゴニスト又は血管保護剤)は、特に、経口投与用(経口投与用医薬、経口剤)であってもよい。
一般式(I)
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、-CH2-R5{式中、R5は置換されていてもよいC3-10シクロアルキル、置換されていてもよいヘテロサイクル、または-CO-NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1-6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、-(CH2)2-R5’(式中、R5’はシアノ、またはC1-6アルコキシを示す。)、または-(CH2)n-Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
C1-6アルキルとは、炭素数1ないし6の直鎖状又は分岐鎖状の炭化水素基を意味し、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、イソヘキシル等が挙げられる。
さらに、上記ヘテロサイクルには芳香環が縮合していてもよい。該縮合環としては、例えば、インドリニル、イソインドリニル、1,2,3,4-テトラヒドロキノリル、1,2,3,4-テトラヒドロイソキノリル、スピロ[インダン-1,4’-ピペリジン]-1’-イル等が挙げられる。
N,N-ジエチル-2-{4-[(2,6-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-[4-(ベンゾイルアミノ)ベンジル]-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(3-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2,4-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(4-メチルベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-チエノイル)アミノ]ベンジル}マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フロイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4,5-ジフルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-メチルベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
2-(4-フルオロベンジル)-N-イソプロピル-N-(3-ピリジル)-N’-((E)-スチリルスルホニル)マロンアミド、
2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド、
(2Sまたは2R)-2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-2-スチリルスルホニル)マロンアミド、
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、または
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド。
なかでも、本発明における非ペプチド性のアンジオテンシン2型受容体アゴニストとして、好ましくは、以下の化合物またはその薬理的に許容しうる塩が好ましい。
(2S)-2-[4-(ベンゾイルアミノ)ベンジル]-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、または
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド。
このように宿主側へ作用することから、本発明は、悪性腫瘍(例えば癌)の種類によらず、全ての悪性腫瘍に対して優れた転移抑制効果を発揮することができる。
本発明の悪性腫瘍の転移を抑制又は予防する方法、及び治療若しくは予防方法は、血管内皮への悪性腫瘍細胞の定着又は浸潤を抑制又は予防するための方法としても好適である。
また、他の転移抑制薬としては、例えば、国際出願番号PCT/JP2013/077140号明細書に記載の(i)アンジオテンシンII受容体拮抗薬、(ii)HMG-CoA還元酵素阻害薬、(iii)グレリン又はその誘導体、(iv)アドレノメデュリン又はその誘導体から選択される少なくとも一種類の血管保護剤又はその薬理的に許容される塩を好適に用いることもできる。
アンジオテンシンII受容体拮抗薬は、アンジオテンシンII受容体(AT1受容体)にアンジオテンシンIIが結合するのを妨げる作用を有する。他の転移抑制薬の有効成分として用いるアンジオテンシンII受容体拮抗薬は、前記の作用を有するものであればよい。
HMG-CoA還元酵素阻害薬は、HMG-CoA還元酵素を特異的に阻害する作用を有する。他の転移抑制薬の有効成分として用いるHMG-CoA還元酵素阻害薬は、前記の作用を有するものであればよい。
グレリン(Ghrelin)は、成長ホルモン分泌促進因子レセプター1a(Growth Hormone Secretagogue- Receptor 1a:GHS-R1a)に作用し、下垂体からの成長ホルモン(Growth Hormone:GH)の分泌を亢進させる作用を有する。
: GSS(n-octanoyl)FLSPEHQRVQQRKESKKPPAKLQPR (配列番号1)
: GSS(n-octanoyl)FLSPEHQRVQRKESKKPPAKLQPR (配列番号2)
ラット(Rat)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号3)
: GSS(n-octanoyl)FLSPEHQKAQRKESKKPPAKLQPR (配列番号4)
マウス(Mouse)
: GSS(n-octanoyl)FLSPEHQKAQQRKESKKPPAKLQPR (配列番号5)
ブタ(Porcine)
: GSS(n-octanoyl)FLSPEHQKVQQRKESKKPAAKLKPR (配列番号6)
ウシ(Bovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEAKKPSGRLKPR (配列番号7)
ヒツジ(Ovine):
: GSS(n-octanoyl)FLSPEHQKLQRKEPKKPSGRLKPR (配列番号8)
イヌ(Canine)
: GSS(n-octanoyl)FLSPEHQKLQQRKESKKPPAKLQPR (配列番号9)
ウマ(Equine)
: GSS(n-butanoyl)FLSPEHHKVQHRKESKKPPAKLKPR (配列番号10)
(上記表記において、アミノ酸残基は一文字標記により表している。)
例えば、ヒトのグレリンは、配列番号1又は2に示されるアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基(セリン残基)はその側鎖(水酸基)が脂肪酸(n-オクタン酸)によりアシル化された修飾アミノ酸残基である。
(2)配列番号1~10のいずれか1つに示されるアミノ酸配列において1~数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであって、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド;及び
(3)配列番号1~10のいずれか1つに示されるアミノ酸配列において、アミノ末端から少なくとも4番目までの配列が保存されており、かつ、当該保存配列以外の部分において1~数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するペプチドであり、さらに、アミノ末端から3番目のアミノ酸残基はその側鎖が脂肪酸によりアシル化された修飾アミノ酸残基であるペプチド。
その他のグレリンの誘導体は、例えば、Matsumoto らの文献(Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S, Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K. Biochem Biophys Res Commun. 2001 Jun 15;284(3):655-9.)等を適宜参照して設計することが出来る。
より詳細には、例えば、グレリン又はその誘導体を成長ホルモン分泌促進因子レセプター1aに接触せしめ、それが当該レセプターに結合することにより細胞内カルシウムイオン濃度を上昇させるかどうか、を試験し、細胞内カルシウムイオン濃度を上昇があればアゴニスト作用があると判断できる。
グレリン及びその誘導体は、天然の原料から単離することもできる。
アドレノメデュリンは、血管拡張作用及び降圧作用(血圧降下作用)を有するポリペプチドである。生体内で、アドレノメデュリンの前駆体より、生理活性を持つアドレノメデュリン(活性型アドレノメデュリン)及びPAMP(proadrenomedullin N-terminal 20 peptide)が生合成される(以下、PAMPはアドレノメデュリンの誘導体に含めることとする)。アドレノメデュリンは、血小板、血管内皮細胞及び平滑筋細胞の細胞内cAMPを増加させる作用、並びに血小板凝集抑制作用、強力な血管拡張作用及び降圧作用を発揮する。
配列番号11には、アドレノメデュリン前駆体のcDNAの塩基配列を示した。配列番号12には、アドレノメデュリン前駆体のアミノ酸配列を示した。配列番号12のアミノ酸配列は、配列番号11の塩基配列にコードされるアミノ酸配列である。また、配列番号13には、アドレノメデュリン(活性型)のアミノ酸配列を示した。また、配列番号14には、PAMPのアミノ酸配列を示した。
アドレノメデュリン誘導体の中には、アドレノメデュリンの前駆体も含まれる。また、アドレノメデュリン誘導体の中には、PAMPも含まれる。
(1)配列番号12、13又は14に示されるアミノ酸配列を有するポリペプチド;
(2)配列番号12、13又は14に示されるアミノ酸配列において1~数個のアミノ酸が欠失、置換及び/又は付加されたアミノ酸配列を有するポリペプチド;及び
(3)配列番号11に示される塩基配列からなる核酸とストリンジェントな条件下においてハイブリダイズし得る核酸によりコードされるポリペプチド。
上記(3)において、核酸は、RNA、DNAのいずれでもよいが、DNAが好ましい。
通常、抗癌剤及び/又は抗腫瘍剤投与開始の約1日以上前(例えば、3日以上前)、好ましくは1週間以上前、さらに好ましくは約10日以上前から、本発明の医薬を投与(又は医薬の投与を開始)してもよい。また、抗癌剤及び/又は抗腫瘍剤投与の終了後、約1日以上(例えば、3日以上)、好ましくは1週間以上、好ましくは約10日以上、本発明の医薬の投与を継続するのが好ましい。
シスプラチン(CDDP)はシスプラチン注「マルコ」(日医工ファーマ)を使用した。
また、アンジオテンシン2型受容体アゴニストとしては、以下の化合物を使用した。
化合物A:(2S)-2-[4-(ベンゾイルアミノ)ベンジル]-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド
化合物B:(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N, N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド
化合物C:2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド
化合物D:N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド
化合物E:(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N, N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド
マウスは8週齢の雄のC57BL6マウス(日本SLC株式会社より購入)を用いた。マウスメラノーマB16-F10はATCCより購入し、10% Fetal calf serum(FCS)を含む Dulbecco's Modified Eagle Medium(DMEM)(Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01~0.125%溶液)処理後、遠心し、3×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、3×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
アンジオテンシン2型受容体アゴニスト群には、化合物Aが30mg/kgの用量となるように調整された0.5%カルボキシメチルセルロース水溶液をCDDP投与4日前から実験終了(メラノーマ細胞の注入から14日後)まで前記用量で継続して経口摂取させた。
一方、コントロール群では、CDDPの注入を行わず、かつ薬剤が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、CDDPの注入を行わず、かつ化合物Aの経口摂取を行った実験、CDDPの注入を行い、かつ薬剤(化合物A)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=5。
なお、図1及び図2において、「Control」は、コントロールの(CDDPの注入及び化合物Aの経口摂取のいずれも行わなかった)マウスの肺及び結節数(number of nodule)を、「AT2A」は、化合物Aの経口摂取のみを行ったマウスの肺及び結節数を、「CDDP」は、CDDPの注入のみを行ったマウスの肺及び結節数を、「AT2A+CDDP」は、CDDPの注入及び化合物Aの経口摂取を行ったマウスの肺及び結節数である。また、図1において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
マウスは8週齢の雄のC57BL6マウス(日本SLC株式会社より購入)を用いた。リポポリサッカライド(LPS)を1mg/kgで尾静脈より注入し、その4-5時間後にマウスメラノーマB16-F10をマウスの尾静脈より注入した。この際、LPSを投与した尾静脈とは異なる側の尾静脈にマウスメラノーマを注入した。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01~0.125%溶液)処理後、遠心した。アンジオテンシン2型受容体アゴニストとして、化合物A~Eを使用し、化合物A投与群では3×106 cells/mLになるように、また、化合物B~E投与群では2×106 cells/mLになるように、それぞれserum free DMEMに懸濁した。100μL/mouseの用量で、化合物A投与群では3×105 個のメラノーマ細胞懸濁液を、また、化合物B~E投与群では2×105 個のメラノーマ細胞懸濁液を、それぞれマウスの尾静脈より注入した。
一方、コントロール群ではLPSの注入を行わず、かつ薬剤(化合物A~E)が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、LPSの注入を行わず、かつ化合物Aの経口摂取を行った実験、およびLPSの注入を行い、かつ薬剤(化合物A~E)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=5。
なお、図3において、上段左から1番目の肺はコントロール(LPSの注入及び化合物Aの経口摂取のいずれも行わなかった)のマウスの肺を、上段左から2~5番目の肺はLPSの注入のみを行ったマウスの肺を、下段左から1番目の肺は化合物Aの経口摂取のみを行ったマウスの肺を、下段左から2~5番目の肺はLPSの注入及び化合物Aの経口摂取を行ったマウスの肺である。また、図3において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
マウスは4週齢の雄の野生型C57BL6マウスおよびアンジオテンシン2型受容体C57BL6ノックアウトマウス(いずれも日本チャールスリバー社より購入)を用いた。リポポリサッカライド(LPS)を1mg/kgで尾静脈より注入し、その4-5時間後にマウスメラノーマB16-F10をマウスの尾静脈より注入した。この際、LPSを投与した尾静脈とは異なる側の尾静脈にマウスメラノーマを注入した。マウスメラノーマB16-F10はATCCより購入し、10% FCSを含む DMEM (Life Technologies Corporation)にて37℃、5%CO2の条件下で培養し、セミコンフルエントの状態でEDTA-trypsin(0.01~0.125%溶液)処理後、遠心し、2.5×106 cells/mLになるようserum free DMEMに懸濁した。100μL/mouseの用量で、2.5×105 個のメラノーマ細胞懸濁液をマウスの尾静脈より注入した。
アンジオテンシン2型受容体アゴニストとして、化合物Aを使用した。
一方、コントロール群ではLPSの注入を行わず、かつ薬剤が入っていない同水溶液のみを経口摂取させ、実験を行った。
また、比較のため、LPSの注入を行い、かつ薬剤(化合物A)が入っていない同水溶液の経口摂取を行った実験についても、あわせて行った。
各群の例数は、n=4。
なお、図10において、「WT」はコントロール(LPSの注入及び薬剤の経口摂取のいずれも行わなかった)の野生型マウスの肺を、「WT(LPS)」はLPSの注入のみ経口摂取を行った野生型マウスの肺を、「WT(AT2agonist+LPS)」はLPSの注入及び薬剤(化合物A)の経口摂取を行った野生型マウスの肺を、「AT2R-KO(cont)」はコントロールの(LPSの注入及び薬剤の経口摂取のいずれも行わなかった)アンジオテンシン2型受容体ノックアウトマウスの肺を、「AT2R-KO(LPS)」はLPSの注入のみ経口摂取を行ったアンジオテンシン2型受容体ノックアウトマウスの肺を、「AT2R-KO (AT2agonist+LPS)」はLPSの注入及び薬剤(化合物A)の経口摂取を行ったアンジオテンシン2型受容体ノックアウトマウスの肺である。また、図10において、黒い部分は転移したメラノーマにより形成された結節(転移巣)である。
以上の結果から、悪性腫瘍の肺転移の抑制にはアンジオテンシン2型受容体が関与していることが示唆され、アンジオテンシン2型受容体アゴニストは悪性腫瘍の転移の増悪及び/又は増大を抑制することが期待できる。
Claims (17)
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、悪性腫瘍の転移を抑制又は予防するための医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、抗癌剤及び/又は抗腫瘍剤による悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストを有効成分として含有することを特徴とする、血管の炎症に伴う悪性腫瘍の転移の増悪及び/又は増大を抑制又は予防するための医薬。
- 血管の炎症が外科的手術によるものである、請求項3に記載の医薬。
- 非ペプチド性のアンジオテンシン2型受容体アゴニストが、下記一般式(I)
R2、R3のいずれか一方は水素原子を示し、残りの一方はイソプロピル、イソブチル、ネオペンチル、アリル、-CH2-R5{式中、R5は置換されていてもよいC3-10シクロアルキル、置換されていてもよいヘテロサイクル、または-CO-NR6R7(式中、R6及びR7は、同一又は異なって水素原子、C1-6アルキル、置換されていてもよいアリール、または置換されていてもよいヘテロアリールを示し、あるいは、R5とR6はそれらが結合する窒素原子とともに、置換されていてもよい環状アミノを形成してもよい。)を示す。}、-(CH2)2-R5’(式中、R5’はシアノ、またはC1-6アルコキシを示す。)、または-(CH2)n-Ar(式中、nは1から3の整数を示し、Arは置換されていてもよいフェニルまたは置換されていてもよいヘテロアリールを示す。)を示し、あるいは、R2とR3はそれらが結合する炭素原子とともに、下式
R4はジ(C1-6アルキル)アミノまたは下式
で表される化合物またはその薬理的に許容される塩である請求項1~4のいずれか1項に記載の医薬。 - 非ペプチド性のアンジオテンシン2型受容体アゴニストが、
N,N-ジエチル-2-{4-[(2,6-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-[4-(ベンゾイルアミノ)ベンジル]-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(3-フルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2,4-ジフルオロベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(4-メチルベンゾイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-チエノイル)アミノ]ベンジル}マロンアミド、
(2S)-N,N-ジエチル-2-{4-[(2-フロイル)アミノ]ベンジル}-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-6-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-N,N-ジエチル-N’-(2-ナフチルスルホニル)-2-{4-[(2-ピリジルカルボニル)アミノ]ベンジル}マロンアミド、
(2S)-2-{4-[(2-アミノ-4-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-クロロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4,5-ジフルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-4-フルオロベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
(2S)-2-{4-[(2-アミノ-5-メチルベンゾイル)アミノ]ベンジル}-N,N-ジエチル-N’-(2-ナフチルスルホニル)マロンアミド、
2-(4-フルオロベンジル)-N-イソプロピル-N-(3-ピリジル)-N’-((E)-スチリルスルホニル)マロンアミド、
2-アリル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-((E)-スチリルスルホニル)マロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、
N-(4-フルオロフェニル)-2-イソブチル-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド、
(2Sまたは2R)-2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-((E)-2-スチリルスルホニル)マロンアミド、
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-フェネチルスルホニルマロンアミド、および
2-シクロプロピルメチル-N-(4-フルオロフェニル)-N-イソプロピル-N’-(2-ナフチルスルホニル)マロンアミド
から選択される少なくとも1種の化合物またはその薬理的に許容される塩である請求項1~5のいずれか1項に記載の医薬。 - 悪性腫瘍の転移が、肺、骨、肝臓及び脳から選択される少なくとも1種への転移である、請求項1~6のいずれか1項に記載の医薬。
- 悪性腫瘍の転移が、肺及び肝臓から選択される少なくとも1種への転移である、請求項1~7のいずれか1項に記載の医薬。
- 悪性腫瘍が、上皮系悪性腫瘍、非上皮系悪性腫瘍及びメラノーマから選択される少なくとも1種の悪性腫瘍である、請求項1~8のいずれか1項に記載の医薬。
- 悪性腫瘍が、メラノーマである、請求項1~9のいずれか1項に記載の医薬。
- 投与対象患者が、悪性腫瘍の切除手術を受けるか又は切除手術を受けた患者である、請求項1~10のいずれか1項に記載の医薬。
- 投与対象患者が、抗癌剤及び/又は抗腫瘍剤の投与を受けているか又は投与を受けた患者である、請求項1~11のいずれか1項に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤とともに用いられるためのものである、請求項1~12のいずれか1項に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤が白金系抗腫瘍剤である、請求項13に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤を投与する前から投与されるためのものである、請求項13または14に記載の医薬。
- 抗癌剤及び/又は抗腫瘍剤投与開始の1日以上前から投与されるためのものである、請求項15に記載の医薬。
- 経口投与用である、請求項1~16のいずれか1項に記載の医薬。
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WO2017061461A1 (ja) * | 2015-10-05 | 2017-04-13 | 国立研究開発法人国立循環器病研究センター | 急性腎障害の予防または抑制用医薬 |
WO2017204163A1 (ja) * | 2016-05-23 | 2017-11-30 | 国立研究開発法人国立循環器病研究センター | 肺障害の予防または抑制用医薬 |
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US10071099B2 (en) | 2018-09-11 |
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