JP5020564B2 - Drugs for releasing drug resistance - Google Patents

Description

  The present invention relates to a medicine, and more particularly, to a medicine suitable for a drug resistance release agent in a drug resistance disease useful for infectious diseases and the like.

  In the chemotherapy such as infectious diseases, the biggest challenge is the emergence of drug resistant strains. Since drug pressure is applied in chemotherapy, the strain selectivity due to this increases, and the drug-resistant strains that have emerged tend to be widely distributed. For this reason, there is a problem that the effectiveness of the drug is remarkably reduced, and thus the therapeutic effect of the disease is remarkably reduced. In particular, in malaria, the problem of drug resistance is serious because there are few types of therapeutic drugs. In addition, if one drug has resistance, other drugs have acquired resistance. There is also a phenomenon of overcoming drug resistance. In other words, it can be said that development of means for releasing drug resistance is desired.

  For such drug resistance, a search for a drug that releases resistance is performed, and indole derivatives (see, for example, Patent Document 1), anthranilic acid derivatives (for example, see Patent Document 2), piperazine derivatives (for example, Patent Document 3, Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 7) are being studied. Since various compounds have a resistance release effect, it is expected that the mechanism of resistance development is intertwined with complex factors, and a new drug for releasing drug resistance is also required in order to identify the factors. It can be said that.

  On the other hand, many ligands of opioid receptors such as 7-benzylidenenaltrexon (BNTX), naltriben (NTB), naltolindole (NTI), and the like have already been known. Many manufacturing methods are also known. In these opioid receptor ligands, there are known opioid receptor-mediated actions such as anti-inflammatory analgesic action, immunosuppressive action, and anesthetic action (for example, Patent Document 8, Patent Document 9, Non-Patent Document 1). Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5, Non-patent document 6, and Non-patent document 7). In addition to the action on opioid receptors, the action on transporters at the cerebral blood flow barrier is known (see, for example, Patent Document 10). However, there is no known relationship between the opioid receptor ligand and the drug resistance release action.

Special table 2003-527308 gazette JP-T-2001-502683 JP 2005-272354 A JP 2004-339073 A JP 2002-060383 A Japanese Patent Laid-Open No. 06-271556 No. 02/042284 Japanese Patent Laid-Open No. 03-223288 Japanese National Patent Publication No. 09-505052 Special table 2004-528273 gazette Portoghese P.S. et.al., Eur. J. Pharmacol. 1992; 218 (1): 195-6 Sofuoglu M. et.al., J. Pharmacol. Exp. Ther. 1991; 257 (2): 676-80 Portoghese P.S. et.al., Eur. J. Pharmacol. 1988; 146 (1): 185-6 Coop A. et.al., Bioorganic & Medicinal Chemistry Letters (1999), 9 (3), 357-362 Ohkawa S. et.al., J. Med. Chem., (1998), 41 (3), 4177-4180 Palmer R.B. et.al., J. Med. Chem., (1997), 40 (5), 749-753 Nan y. Et.al., J. Heterocyclic Chemistry, (1996), 33 (2), 399-407

  The present invention has been made under such circumstances, and an object of the present invention is to provide a novel drug for releasing drug resistance.

In view of such a situation, the present inventors have sought for a new drug for releasing drug resistance and, as a result of intensive research, have found that an opioid receptor ligand has such an action. The present invention has been completed. That is, the present invention is as follows.
(1) A drug for releasing resistance of a drug resistant disease, characterized by comprising an opioid receptor ligand as an active ingredient.
(2) The drug for releasing resistance of a drug resistant disease according to (1) above, wherein the opioid receptor ligand is an opioid δ receptor antagonist.
(3) The medicament for releasing resistance of a drug resistant disease according to (1) or (2), wherein the opioid receptor ligand is administered together with a chemotherapeutic agent for treatment.
(4) The drug for releasing resistance of drug-resistant disease according to (3) above, wherein the chemotherapeutic drug administered together with the opioid receptor ligand is an infectious drug.
(5) The above (1) to (4), wherein the opioid receptor ligand is a compound selected from the group consisting of compounds represented by the following general formulas (1) to (3) and / or a salt thereof. ) A drug for releasing resistance of a drug resistant disease according to any one of the above.

（但し、式（１）中、Ｒ¹は水素原子、アルキル基又はアルケニル基を表し、Ｒ²は水素原子、水酸基又はアルキルオキシ基を表し、Ｒ³は水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキルオキシ基、ニトロ基、アミノ基、アシルアミノ基を表し、Ｒ⁴は水素原子又は水酸基を表し、Ｘは酸素原子又は（ＣＨ₂）₀で表される基（Ｘそのものが存在しないでＸを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表し、Ｙは（ＣＨ₂）_n（ｎは０または１を表す。）で表される基（（ＣＨ₂）₀はＹそのものが存在しないでＹを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表す。点線の結合はあってもなくても良く、Ｒ³の結合位置は縮合環を含む環内であれば特定されない。）に表される化合物。 General formula (1)

(In the formula (1), R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group, R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and R ³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group. A group, an alkyloxy group, a nitro group, an amino group, and an acylamino group, R ⁴ represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or a group represented by (CH ₂ ) ₀ (X itself does not exist and X Represents a group in which carbons to be bonded to each other directly form a single bond to form a ring), and Y represents a group represented by (CH ₂ ) _n (n represents 0 or 1) (( CH ₂ ) ₀ represents a group that represents that carbons to be bonded through Y without Y itself being directly bonded to each other to form a ring). bonding position of R ³ is not specified as long as the ring containing fused ring Compounds represented).

（但し、式（２）中、Ｒ¹は水素原子、アルキル基又はアルケニル基を表し、Ｒ²は水素原子、水酸基又はアルキルオキシ基を表し、Ｒ³は水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキルオキシ基、ニトロ基、アミノ基、アシルアミノ基を表し、Ｒ⁴は水素原子又は水酸基を表し、Ｘは酸素原子又は（ＣＨ₂）₀で表される基（Ｘそのものが存在しないでＸを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表し、Ｙは（ＣＨ₂）_n（ｎは０または１を表す。）で表される基（（ＣＨ₂）₀はＹそのものが存在しないでＹを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表す。点線の結合はあってもなくても良く、Ｒ³の結合位置は縮合環を含む環内であれば特定されない。）に表される化合物。 General formula (2)

(In the formula (2), R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group, R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and R ³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group. A group, an alkyloxy group, a nitro group, an amino group, and an acylamino group, R ⁴ represents a hydrogen atom or a hydroxyl group, X represents an oxygen atom or a group represented by (CH ₂ ) ₀ (X itself does not exist and X Represents a group in which carbons to be bonded to each other directly form a single bond to form a ring), and Y represents a group represented by (CH ₂ ) _n (n represents 0 or 1) (( CH ₂ ) ₀ represents a group that represents that carbons to be bonded through Y without Y itself being directly bonded to each other to form a ring). bonding position of R ³ is not specified as long as the ring containing fused ring Compounds represented).

（但し、式（３）中、Ｒ¹は水素原子、アルキル基又はアルケニル基を表し、Ｒ²は水素原子、水酸基又はアルキルオキシ基を表し、Ｒ³は水素原子、ハロゲン原子、アルキル基、アルケニル基、アルキルオキシ基、ニトロ基、アミノ基、アシルアミノ基を表し、Ｒ⁴は水素原子又は水酸基を表し、Ｒ⁵は水素原子、アルキル基又はアシル基を表し、Ｘは酸素原子又は（ＣＨ₂）₀で表される基（Ｘそのものが存在しないでＸを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表し、Ｙは（ＣＨ₂）_n（ｎは０または１を表す。）で表される基（（ＣＨ₂）₀はＹそのものが存在しないでＹを介して結合すべき炭素同士が直接単結合して環を形成することを表す基）を表す。点線の結合はあってもなくても良く、Ｒ³の結合位置は縮合環を含む環内であれば特定されない。）に表される化合物。 General formula (3)

(In the formula (3), R ¹ represents a hydrogen atom, an alkyl group or an alkenyl group, R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and R ³ represents a hydrogen atom, a halogen atom, an alkyl group or an alkenyl group. A group, an alkyloxy group, a nitro group, an amino group, an acylamino group, R ⁴ represents a hydrogen atom or a hydroxyl group, R ⁵ represents a hydrogen atom, an alkyl group, or an acyl group, and X represents an oxygen atom or (CH ₂ ) Represents a group represented by ₀ (a group representing that a carbon to be bonded through X without X itself being directly bonded to form a ring), and Y is (CH ₂ ) _n (n is (Representing 0 or 1)) ((CH ₂ ) ₀ represents a group in which Y is not present and carbons to be bonded via Y are directly single-bonded to form a ring). The dotted bond may or may not be present, and the R ³ bond A compound position is not specified as long as it is within a ring containing a condensed ring.

(6) The opioid receptor ligand is selected from 7-benzylidenenaltrexon (BNTX; 7-Benzylidenenaltrexon), naltriben (NTB; Naltriben), naltolindole (NTI; Naltrindole) and physiologically acceptable salts thereof. The medicament for releasing resistance of a drug resistant disease according to any one of (1) to (5), which is an opioid δ receptor antagonist.

BNTX: Formula (4)

NTB: Formula (5)

NTI: Formula (6)

(7) The drug for releasing resistance of a drug resistant disease according to any one of (1) to (6), wherein the drug resistant disease is drug resistant malaria.

  According to the present invention, a novel drug for releasing drug resistance can be provided.

  The medicament for releasing resistance of a drug resistant disease of the present invention is characterized by comprising an opioid receptor ligand as an active ingredient. Through research into the mechanism of action of analgesics such as morphine, it is known that various organs including the brain have sites where these substances specifically bind, that is, opioid receptors. A compound that binds to this receptor and expresses a pharmacological action such as an analgesic action is called an agonist. A substance that has an affinity for the opioid receptor but does not have an opioid action by itself and antagonizes the action of the opioid substance is called an opioid antagonist. Such agonists and antagonists of opioid receptors are collectively referred to as ligands. In the present invention, this opioid receptor ligand is used as an active ingredient. There are three subtypes of the opioid receptor, μ, κ, and δ, each of which has a ligand. Any of these can be used for the medicament of the present invention. Among these, a δ receptor ligand is preferable, and an antagonist of δ receptor is particularly preferable in releasing resistance of drug-resistant malaria.

  As such δ receptor antagonists, compounds represented by the general formulas (1) to (3) and / or salts thereof are known, and any of these can be used.

In the general formula (1), R ¹ is a hydrogen atom, an alkyl group, preferably an alkyl group or an alkenyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, preferably an alkenyl having 2 to 5 carbon atoms. R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, and the alkyl group Examples of preferable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like. R ³ is a hydrogen atom, a halogen atom, an alkyl group, preferably a straight chain of 1 to 6 carbon atoms, branched or cyclic Al Group, an alkenyl group, preferably an alkenyl group having 2 to 5 carbon atoms, a nitro group, an amino group, an acylamino group, and an acyl group in the acylamino group preferably has 2 to 10 carbon atoms, specifically an acetyl group , A propanoyl group, a butanoyl group, a pentanoyl group, a benzoyl group, etc., or an alkyloxy group, wherein the alkyl group in the alkyloxy group may have a linear, branched or cyclic structure having 1 to 6 carbon atoms The alkyl group is preferably a methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, etc. And R ⁴ represents a hydrogen atom, a hydroxyl group or an alkyl group. Represents an oxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group. Group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and X is represented by an oxygen atom or (CH ₂ ) ₀ . And Y represents (CH ₂ ) _n (where n is 0 or 1). Represents a group ((CH ₂ ) ₀ represents a group in which Y is not present and carbons to be bonded via Y directly form a single bond to form a ring). Examples of the linear, branched or cyclic alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, and cyclopropylmethyl. Group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, Suitable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like. Suitable examples of halogen atoms include chlorine, bromine and iodine atoms. It can be. Examples of these salts include mineral acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate, organic acid salts such as citrate, acetate, oxalate and tartrate, and mesylate Physiologically acceptable salts such as tosylate are preferable.

（但し、式（１）中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｘ、およびＹは、前記と同じ。）に示す化合物は、一般式（１)ｓ

（但し、式（１)ｓ中、Ｒ¹、Ｒ²、Ｒ⁴、Ｘ、およびＹは、一般式（１）中と同じ意味を表す。）に示すカルボニル化合物を、例えば、対応する置換基を有する芳香族アルデヒド化合物と反応させて脱水縮合させる公知の方法により、一般式（１)ａ

（但し、式（１)ａ中、Ｒ³は、一般式（１）中と同じ意味を表す。）に示す芳香族アルデヒド化合物と反応させて製造することができる。なお、この製造方法の詳細は、非特許文献１〜７に記載されている。 General formula (1)

(In the formula (1), R ¹ , R ² , R ³ , R ⁴ , X, and Y are the same as described above.) The compound represented by the general formula (1) s

(In the formula (1) s, R ¹ , R ² , R ⁴ , X, and Y represent the same meaning as in the general formula (1)), for example, a corresponding substituent By a known method of dehydration condensation by reacting with an aromatic aldehyde compound having the general formula (1) a

(In the formula (1) a, R ³ represents the same meaning as in the general formula (1)), and can be produced by reacting with an aromatic aldehyde compound shown in FIG. Details of this manufacturing method are described in Non-Patent Documents 1 to 7.

In the general formula (2), R ¹ is a hydrogen atom, an alkyl group, preferably an alkyl group or an alkenyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, preferably an alkenyl having 2 to 5 carbon atoms. R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, and the alkyl group Suitable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and the like. , R ³ is a hydrogen atom, a halogen atom, an alkyl group, preferably a straight chain of 1 to 6 carbon atoms, branched or cyclic a Kill groups, alkenyl groups, preferably alkenyl groups having 2 to 5 carbon atoms, nitro groups, amino groups, acylamino groups, and acyl groups in the acylamino groups preferably have 2 to 10 carbon atoms, specifically acetyl groups , A propanoyl group, a butanoyl group, a pentanoyl group, a benzoyl group, etc., or an alkyloxy group, wherein the alkyl group in the alkyloxy group may have a linear, branched or cyclic structure having 1 to 6 carbon atoms The alkyl group is preferably a methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, etc. And R ⁴ represents a hydrogen atom, a hydroxyl group or an alkyl. Represents an oxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group. Group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and X is represented by an oxygen atom or (CH ₂ ) ₀ . And Y represents (CH ₂ ) _n (where n is 0 or 1). Represents a group represented by (CH ₂ ) ₀ is a group representing that a carbon to be bonded through Y without a single Y is directly bonded to form a ring). . Examples of the linear, branched or cyclic alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, and cyclopropylmethyl. Group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, Suitable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like. Suitable examples of halogen atoms include chlorine, bromine and iodine atoms. It can be. Examples of these salts include mineral acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate, organic acid salts such as citrate, acetate, oxalate and tartrate, and mesylate Physiologically acceptable salts such as tosylate are preferable.

（但し、式（２）中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｘ、およびＹは、前記と同じ。）に示す化合物は、前記一般式（１)ｓに示すカルボニル化合物を、例えば、対応する置換基を有するＯ−アリールヒドロキシルアミン化合物（またはその塩）と反応させてベンゾフラン環を生成させる公知の方法により、一般式（１)ｂ

（但し、式（１)ｂ中、Ｒ³は、一般式（２）中と同じ意味を表す。）に示すＯ−アリールヒドロキシルアミン化合物（またはその塩）と反応させて製造することができる。なお、この製造方法の詳細は、非特許文献１〜７に記載されている。 General formula (2)

(In the formula (2), R ¹ , R ² , R ³ , R ⁴ , X, and Y are the same as described above.) The compound represented by the general formula (1) s is represented by the following formula: For example, by a known method of reacting with an O-arylhydroxylamine compound (or a salt thereof) having a corresponding substituent to form a benzofuran ring, a compound represented by the general formula (1) b

(In the formula (1) b, R ³ represents the same meaning as in the general formula (2)), and can be produced by reacting with an O-arylhydroxylamine compound (or a salt thereof). Details of this manufacturing method are described in Non-Patent Documents 1 to 7.

In the general formula (3), R ¹ is a hydrogen atom, an alkyl group, preferably an alkyl group or an alkenyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, preferably an alkenyl having 2 to 5 carbon atoms. R ² represents a hydrogen atom, a hydroxyl group or an alkyloxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, and the alkyl group Examples of preferable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like. R ³ is a hydrogen atom, a halogen atom, an alkyl group, preferably a straight chain of 1 to 6 carbon atoms, branched or cyclic Al Group, an alkenyl group, preferably an alkenyl group having 2 to 5 carbon atoms, a nitro group, an amino group, an acylamino group, and an acyl group in the acylamino group preferably has 2 to 10 carbon atoms, specifically an acetyl group , A propanoyl group, a butanoyl group, a pentanoyl group, a benzoyl group, etc., or an alkyloxy group, wherein the alkyl group in the alkyloxy group may have a linear, branched or cyclic structure having 1 to 6 carbon atoms The alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, an isopropyl group, an isobutyl group, a tertiary butyl group, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, or a cyclopentylmethyl group. And R ⁴ represents a hydrogen atom, a hydroxyl group or an alkyl. Represents an oxy group, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group. Group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and X is represented by an oxygen atom or (CH ₂ ) ₀ . R ⁵ represents a hydrogen atom, an alkyl group, or an acyl group, and represents a group that represents that a carbon to be bonded through X without X itself is directly bonded to form a ring. Examples of the alkyl group include methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclohexane A propyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group and the like can be suitably exemplified, and the acyl group preferably has 2 to 10 carbon atoms, specifically, an acetyl group, a propanoyl group, a butanoyl group , A pentanoyl group, a benzoyl group, and the like, and Y represents (CH ₂ ) _n (n represents 0 or 1). ) ((CH ₂ ) ₀ represents a group in which Y itself does not exist and carbons to be bonded via Y directly form a single bond to form a ring). Examples of the linear, branched or cyclic alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, butyl group, isopropyl group, isobutyl group, tertiary butyl group, cyclopropyl group, and cyclopropylmethyl. Group, cyclobutylmethyl group, cyclopentylmethyl group and the like can be suitably exemplified, and the alkyl group in the alkyloxy group is preferably an alkyl group having a linear, branched or cyclic structure having 1 to 6 carbon atoms, Suitable examples include methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, cyclopropyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and the like. Suitable examples of halogen atoms include chlorine, bromine and iodine atoms. It can be. Examples of these salts include mineral acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate, organic acid salts such as citrate, acetate, oxalate and tartrate, and mesylate Physiologically acceptable salts such as tosylate are preferable.

（但し、式（３）中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵、Ｘ、およびＹは、前記と同じ。）に示す化合物は、前記一般式（１)ｓに示すカルボニル化合物を、例えば、対応する置換基を有する芳香族ヒドラジン化合物（またはその塩）と反応させてインドール環を生成させる公知の方法により、一般式（１)ｃ

（但し、式（１)ｃ中、Ｒ³、およびＲ⁵は、一般式（３）中と同じ意味を表す。）に示す芳香族ヒドラジン化合物（またはその塩）と反応させて製造することができる。なお、この製造方法の詳細は、非特許文献１〜７に記載されている。 General formula (3)

(In the formula (3), R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X, and Y are the same as described above.) The compound represented by the general formula (1) s For example, by a known method in which a compound is reacted with an aromatic hydrazine compound having a corresponding substituent (or a salt thereof) to form an indole ring, the compound represented by the general formula (1) c

(However, in the formula (1) c, R ³ and R ⁵ represent the same meaning as in the general formula (3)) and can be produced by reacting with an aromatic hydrazine compound (or a salt thereof). it can. Details of this manufacturing method are described in Non-Patent Documents 1 to 7.

  Specific ligands represented by the general formulas (1) to (3) include, for example, 7-benzylidenenaltrexone (BNTX; 7-Benzylidenenaltrexon), naltriben (NTB; Naltriben), naltolindole (NTI; Naltrindole) Etc., and their derivatives are preferably exemplified. Particularly preferred is BNTX or a derivative thereof, such as 7- (9-anthrylmethylene) naltrexone, 7- (4-phenylbenzylidene) naltrexone, 7- (2-naphthylmethylene) naltrexone, 7- (1-naphthylmethylene) naltrexone, 7-[(1-methyl-1H-imidazol-2-yl) methylene] naltrexone, 7- (4-pyridinylmethylene) naltrexone, 7- (3-pyridinyl Methylene) naltrexone, 7- (p-fluorobenzylidene) naltrexone, 7- (p-chlorobenzylidene) naltrexone, 7-[(p-methoxycarbonyl) benzylidene] naltrexone, 7- (o-chlorobenzylidene) naltrexone, 7- ( o-Fluorobenzylidene) Naruto Xone, 7- (m-chlorobenzylidene) naltrexone, 7- (m-fluorobenzylidene) naltrexone, 7- (o-methoxybenzylidene) naltrexone, 7- (p-methylbenzylidene) naltrexone, 7- (m-methoxybenzylidene) Preferred examples include naltrexone, 7- (p-methoxybenzylidene) naltrexone, 7- (m-nitrobenzylidene) naltrexone, 7- (p-nitrobenzylidene) naltrexone and the like. Such a derivative can be produced by dehydrating condensation of naltrexone and an aromatic aldehyde having a corresponding substituent, like BNTX. Details of this manufacturing method are described in Non-Patent Documents 4 to 7. BNTX can be purchased from Tcris Cookson Inc. (Ellisville MO, USA), and naltrexone, NTI and NTB can be purchased from Aldrich Japan.

  Such a ligand for an opioid receptor acts on a disease-causing foreign organism that has acquired resistance to a therapeutic agent, and has the effect of reducing the resistance. Examples of the causative organism include protozoa such as malaria protozoa, trypanosoma protozoa, dysentery amoeba, leishmania protozoa, and the like. Among these, it is more preferable to target malaria because of the importance of formulating countermeasures against tolerance. For the causal heterogeneous diseases that have acquired resistance to these therapeutic agents, the medicament of the present invention is administered together with usual chemotherapeutic agents for such diseases. As the chemotherapeutic agent, an infection therapeutic agent can be preferably exemplified, and an antiprotozoal agent such as chloroquine, mefloquine, primaquine, quinine, tafenokine, proguanil, pentostam, mebendazole, nitrobendazole, doxycycline, metronidazole, sulfoxamine is preferably used. It can be illustrated. The pharmaceutical administration for releasing the resistance may be performed in advance, simultaneously with the administration of the therapeutic agent, or may be performed subsequent to the administration of the therapeutic agent. They can be administered as the same preparation, or the preparation of the therapeutic agent and the preparation of the drug for releasing resistance can be administered separately. The dose of the ligand for the opioid receptor varies depending on the type of disease, but it is preferably exemplified by administering 0.01 to 100 times, more preferably 0.1 to 10 times the amount of the therapeutic agent. it can. The daily dose can be 1 to 10000 mg divided into 1 or several times.

  The medicament of the present invention can be produced by using the above-mentioned opioid receptor ligand as an active ingredient, adding an optional ingredient on the formulation to this, and processing according to a conventional method. Examples of optional ingredients in the preparation include excipients such as sucrose, lactose, croscarmellose and maltose, disintegrants such as starch and crystalline cellulose, binders such as hydroxypropylcellulose and gum arabic, talc, magnesium stearate Lubricants such as polyoxyethylene hydrogenated castor oil, coating agents such as hydroxypropylcellulose caprylate and polyacrylic acid dimethylamide, colorants, flavoring agents, pH adjusting agents such as buffer salts Suitable examples include osmotic pressure adjusting agents such as sodium chloride. Using such ingredients, granulation can be processed into a granule form, which can be made into a preparation, or the granule can be filled into a capsule to form a capsule, or tableted to form a tablet. Alternatively, it can be dissolved in an aqueous carrier together with a buffer salt and an osmotic pressure adjusting agent, sterilized, and lyophilized as desired, or filled in a vial and sealed to give an injection or infusion.

  Hereinafter, the present invention will be described in more detail with reference to examples, but it is needless to say that the present invention is not limited to such examples.

Example 1
Using the P. chabaudi AS strain chloroquine resistant strain, the resistance release effect of the medicament of the present invention against chloroquine resistant malaria was examined. That is, 4 ICR crj mice (male; body weight 20-30 g) per group were used as animals, and on day 0, 5 × 10 ⁶ infected erythrocytes of P. chabaudi AS strain were injected from the tail vein and inoculated. On Day 0, Day 1, Day 2 and Day3, 10 mg / Kg of the sample was orally administered by dissolving in physiological saline, and 3 mg / Kg of chloroquine was dissolved in physiological saline and administered intraperitoneally. The untreated control is not administered, the chloroquine control is administered only chloroquine and the sample is not administered, and the sample control is blood sampled on Day 4 with the tip of the tail injured. Produced. The smear was fixed with methanol, stained with Giemsa, and the number of infected red blood cells per 10,000 red blood cells was counted with a microscope. In counting, 20 fields were averaged. Naltrexone, BNTX, and NTB were used as specimens. The results are shown in Table 1. All specimens show a resistance release effect, and it can be seen that BNTX and NTB have an excellent resistance release effect.

Example 2
As in Example 1, the specimen was replaced with NTI for examination. The results are shown in Table 2. It can be seen that NTI also has an excellent resistance release effect.

表１，２からも確認できるように、ＢＮＴＸ、ＮＴＢ、ＮＴＩ等のオピオイドδ受容体アンタゴニストをクロロキンとともに用いると、クロロキンに対するマラリア原虫の感受性が回復することが判る。

As can be confirmed from Tables 1 and 2, it can be seen that the use of opioid δ receptor antagonists such as BNTX, NTB and NTI together with chloroquine restores the sensitivity of the malaria parasite to chloroquine.

Example 3
As an effective mechanism, chloroquine is known to apply oxidative stress to protozoa in blood cells, thereby preventing the protozoa from converting from heme to hemozoin, and damaging the protozoa by the toxicity of heme. Therefore, the influence of the ligand of the opioid receptor, which is an active ingredient of the medicament of the present invention, on the production of glutathione, which is a defense system against oxidation, was examined. As a method, a glutathione total amount determination kit (manufactured by Dojindo Laboratories) was used. As a control, 10 μl of oxidized glutathione at 50 μg / ml was added to the system (final concentration 2.5 μg / ml). 10 μl of a 0.6 mg / ml sample solution was added (final concentration 30 μg / ml).

上式に従って、抑制率を求めたところ、ＢＮＴＸのグルタチオン生成抑制率は４７％であり、クロロキンの抑制率は４０．６％であった。これより、本発明の耐性解除用の医薬では、オピオイド受容体のリガンドは、酸化ストレスの負荷を介して、クロロキン耐性を解除していることが推測された。

When the inhibition rate was determined according to the above equation, the glutathione production inhibition rate of BNTX was 47%, and the inhibition rate of chloroquine was 40.6%. From this, it was speculated that the opioid receptor ligand released the resistance to chloroquine through the load of oxidative stress in the drug for releasing resistance of the present invention.

Example 4
According to the table | surface shown below, the pharmaceutical of this invention was manufactured. That is, the prescription ingredients were charged in a tumbling phase granulator, mixed with high speed, sprayed with 10% by mass of pure water, granulated, and then dried with warm air at 40 ° C. for 48 hours, and the resulting granules Was tableted to obtain the drug for releasing resistance of the present invention.

Example 5
According to the table | surface shown below, it operated similarly to Example 4 and obtained the pharmaceutical for tolerance cancellation of this invention.

Example 6
According to the table | surface shown below, it operated similarly to Example 4 and obtained the pharmaceutical for tolerance cancellation of this invention.

Example 7
According to the table | surface shown below, it operated similarly to Example 4 and obtained the pharmaceutical for tolerance cancellation of this invention.

The present invention can be applied to chemotherapy for infectious diseases such as malaria.

Claims (3)

An active ingredient is an opioid δ receptor antagonist selected from naltrexone (NTX), 7-benzylidenenaltrexone (BNTX), naltriben (NTB), naltolindole (NTI) and physiologically acceptable salts thereof. A feature- relieving drug for chloroquine-resistant malaria . The medicament for releasing resistance to chloroquine-resistant malaria according to claim 1, wherein the opioid receptor antagonist is administered together with a chemotherapeutic agent for treatment . The opioid receptor antagonist are both administered chemotherapeutic agents to be used in the treatment of infection therapeutic agent chloroquine resistant malaria resistant releasing medicament of claim 2 is.