Treatment or prevention of cachexia

Abstract

The present invention addresses the problem of providing a therapeutic or prophylactic agent that is for cachexia and that exhibits significant efficacy in therapy of cachexia with few side effects. The present invention provides a therapeutic or prophylactic agent that is for cachexia and that contains a combination of a ghrelin receptor agonist and a compound having a morphinan backbone, represented by the following compounds, or a pharmaceutically acceptable acid addition salt thereof.

Description

[Technical field]

[0001] The present invention relates to an agent for treating or preventing cachexia. [Background technology]

[0002] Cachexia is defined as a syndrome of complex metabolic disorders associated with underlying diseases, characterized by a decrease in muscle mass regardless of the presence or absence of a decrease in fat mass. Cachexia is known to be a systemic syndrome with major symptoms such as significant weight loss, anemia, edema, anorexia, generalized weakness, and fatigue (Non-Patent Document 1).

[0003] In particular, cachexia caused by malignant tumors is called cancer cachexia, and is said to account for approximately 20% of deaths from malignant tumors.

[0004] In cancer cachexia, the patient's physical strength is significantly weakened as the symptoms progress, making it impossible to continue treatment with antitumor agents, and the patient's responsiveness to the antitumor agents is also reduced. Conversely, if nutrition is provided to improve the symptoms of cachexia, it will actually accelerate the progression of malignant tumors, so the onset of cancer cachexia is a serious hindrance to the treatment of malignant tumors. It has been reported that even if the patient has the physical strength to administer antitumor agents, side effects such as bone marrow toxicity will occur, and cachexia will not improve (Non-Patent Document 2).

[0005] To date, there is no standard effective treatment for cachexia. Known substances that have an effect of improving cachexia include ghrelin receptor agonists (Patent Document 1) and androgen receptor modulators (Patent Document 2).

[0006] Ghrelin is a peptide hormone discovered as an endogenous ligand (GHSR agonist) of the growth hormone secretagogue receptor (GHSR). Ghrelin is produced mainly in the stomach in humans and animals and enhances growth hormone secretion via the ghrelin receptor (Non-Patent Document 3). In addition, it has been reported that ghrelin has various effects such as feeding enhancement (improvement of eating disorders), gastric acid secretion and gastric peristalsis enhancement, and skeletal muscle mass increase (Non-Patent Document 3). Anamorelin, a ghrelin receptor agonist, showed a significant increase in lean body mass in a phase 3 clinical trial and is expected to be a therapeutic drug for cachexia (Patent Document 3).

[0007] However, in patients with cancer cachexia, increased ghrelin concentrations in the blood are observed, resulting in decreased ghrelin responsiveness, i.e., ghrelin resistance (Non-Patent Document 4). Rikkunshito, a traditional Chinese medicine, has been shown to partially improve ghrelin resistance and has been shown to have potential as a treatment for cancer cachexia (Non-Patent Document 5).

[0008] On the other hand, it has been disclosed that compounds having a morphinan skeleton or pharmacologically acceptable acid addition salts thereof have opioid κ receptor agonist activity and are used as analgesics and diuretics (Patent Document 4).It has also been disclosed that they are used as drugs for treating cachexia (Patent Document 5). [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO 05 / 097261 [Patent Document 2] WO 02 / 066475 [Patent Document 3] WO 16 / 036598 [Patent Document 4] International Publication No. 93 / 015081 [Patent Document 5] WO 12 / 105475 [Non-patent literature]

[0010] [Non-Patent Document 1] Kern et al., Journal of Parenteral and Enteral Nutrition, 1988, Vol. 12, pp. 286-298 [Non-Patent Document 2] Nelson et al., Journal of Clinical Oncology, 1994, Vol. 12, pp. 213-225 [Non-Patent Document 3] Kojima, Kangawa, Physiological Reviews, 2005, Vol. 85, pp. 495-522 [Non-Patent Document 4] Nakazato et al., Nature, 2001, Vol. 409, pp. 194-198 [Non-Patent Document 5] Terawaki et al., PLos One, 2017, Vol. 12, p. e0173113 Summary of the Invention [Problem to be solved by the invention]

[0011] However, appetite stimulants such as ghrelin receptor agonists used to treat cachexia have no effect on improving metabolic disorders and have limited therapeutic efficacy due to ghrelin resistance in patients, and steroidal anti-inflammatory drugs are difficult to use long-term due to their strong side effects.

[0012] Furthermore, there have been no reports of a reduction in the dosage, an enhancement of the therapeutic effect for cachexia, or a reduction in side effects when a compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof is used in combination with a ghrelin receptor agonist, and there has been no suggestion of an effect for treating cachexia in a ghrelin-resistant state. Thus, in the treatment of cachexia, there is currently a need to develop medicines based on new mechanisms.

[0013] Therefore, an object of the present invention is to provide a therapeutic or preventive agent for cachexia which has few side effects and exhibits remarkable efficacy in the treatment of cachexia. [Means for solving the problem]

[0014] As a result of extensive research aimed at solving the above problems, the inventors have discovered that the use of a specific compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist has excellent therapeutic or preventive effects against cachexia, and have thus completed the present invention.

[0015] That is, the present invention provides an agent for treating or preventing cachexia, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist.

[0016] [ka] [In the formula, the double line of a dotted line and a solid line represents a double bond or a single bond, and R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms; R 2 represents a linear or branched alkyl group having 1 to 5 carbon atoms, and B represents -CH=CH-.

[0017] In addition, as one embodiment of the above-mentioned agent for treating or preventing cachexia, the present invention provides an agent for treating or preventing cachexia, which comprises, as active ingredients, a compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist.

[0018] The compound represented by the above general formula (I) is R 1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, and R 2 is preferably methyl, ethyl or propyl, R 1 is cyclopropylmethyl, R 2It is more preferred that is methyl and B is the trans -CH=CH-.

[0019] It is more preferable that the compound represented by the above general formula (I) is (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan, as exemplified below, and the ghrelin receptor agonist is more preferably anamorelin or a pharmacologically acceptable salt thereof.

[0020] The above-mentioned therapeutic or preventive agent for cachexia is preferably a therapeutic or preventive agent for cancer cachexia, and can also be suitably used as a therapeutic or preventive agent for cancer cachexia in a ghrelin-resistant state.

[0021] As an embodiment of the agent for treating or preventing cachexia, the present invention provides a pharmaceutical composition for treating or preventing cachexia, which comprises a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist, and further comprises one or more pharma- ceutical acceptable carriers.

[0022] As an embodiment of the agent for treating or preventing cachexia, the present invention provides a pharmaceutical combination or kit for treating or preventing cachexia, which comprises a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist.

[0023] As an embodiment of the above-mentioned agent for treating or preventing cachexia, the present invention provides use of a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist in the manufacture of a medicament for treating or preventing cachexia (e.g., an agent for treating or preventing cachexia). Also, as an embodiment of the above-mentioned agent for treating or preventing cachexia, the present invention provides a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist for treating or preventing cachexia.

[0024] As an embodiment of the above-mentioned agent for treating or preventing cachexia, the present invention provides an agent for treating or preventing cachexia, which contains, as an active ingredient, a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof, to be used in combination (concomitant use) with the above-mentioned ghrelin receptor agonist, and also provides use of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for treating or preventing cachexia (e.g., an agent for treating or preventing cachexia) to be used in combination (concomitant use) with the above-mentioned ghrelin receptor agonist.

[0025] Furthermore, the present invention provides, as an embodiment of the above-mentioned agent for treating or preventing cachexia, an agent for treating or preventing cachexia containing a ghrelin receptor agonist as an active ingredient, which is used in combination (concomitant use) with the compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable acid addition salt thereof, and also provides use of a ghrelin receptor agonist in the manufacture of a medicament for treating or preventing cachexia (e.g., an agent for treating or preventing cachexia), which is used in combination (concomitant use) with the compound represented by the above-mentioned general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[0026] Furthermore, as an embodiment of the agent for treating or preventing cachexia, the present invention provides a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof for use in combination (concomitant use) with the above-mentioned ghrelin receptor agonist for the treatment or prevention of cachexia, and also provides a ghrelin receptor agonist for use in combination (concomitant use) with the above-mentioned compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof for the treatment or prevention of cachexia.

[0027] Furthermore, as an embodiment of the agent for treating or preventing cachexia, the present invention provides a method for treating or preventing cachexia, which comprises administering to a patient in need of treatment or prevention of cachexia a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist. Effect of the Invention

[0028] The therapeutic or preventive agent for cachexia of the present invention can reduce the dose of the compound having a morphinan skeleton and / or the ghrelin receptor agonist, reduce the risk of side effects, and improve systemic syndrome in patients with cachexia, the main symptoms of which are significant weight loss, anemia, edema, anorexia, general weakness, fatigue, etc. Furthermore, the therapeutic or preventive agent for cachexia of the present invention can also improve cachectic symptoms in a ghrelin-resistant state. [Brief description of the drawings]

[0029] [Figure 1] FIG. 1 shows the cumulative food intake increasing effect of combined administration of Compound 1 and anamorelin in a mouse cancer-bearing model (a non-small cell lung cancer model in which ghrelin resistance has developed). [Diagram 2] FIG. 1 shows the effect of combined administration of Compound 1 and anamorelin on increasing body weight in a mouse cancer model (a non-small cell lung cancer model in which ghrelin resistance has developed). [Diagram 3] FIG. 1 shows the cumulative food intake increasing effect by combined administration of Compound 1 and anamorelin in a mouse cancer-bearing model (non-small cell lung cancer model). [Figure 4] FIG. 1 shows the effect of combined administration of Compound 1 and anamorelin on increasing body weight in a mouse cancer model (non-small cell lung cancer model). [Diagram 5] FIG. 1 shows the cumulative food intake increasing effect by combined administration of Compound 1 and anamorelin in a mouse cancer-bearing model (skin cancer model). [Figure 6] FIG. 1 shows the effect of combined administration of Compound 1 and anamorelin on increasing body weight in a mouse cancer-bearing model (skin cancer model).

[0030] This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2019-193743, which is the priority basis of this application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] The present invention is characterized by a therapeutic or preventive agent for cachexia comprising a compound represented by the following general formula (II) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist.

[0032] [ka] [In the formula, A double line consisting of a dotted line and a solid line indicates a double bond or a single bond; R 1 represents an alkyl group having 1 to 5 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms, a cycloalkenylalkyl group having 5 to 7 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aralkyl group having 7 to 13 carbon atoms, an alkenyl group having 4 to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group (wherein the alkyl portion has 1 to 5 carbon atoms) or a thiophen-2-ylalkyl group (wherein the alkyl portion has 1 to 5 carbon atoms), R 14 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, or NR 9 R 10 (where R 9 represents hydrogen or alkyl having 1 to 5 carbon atoms; R 10 is hydrogen, alkyl having 1 to 5 carbon atoms, or -(C=O)R 11 (where R 11 represents hydrogen, phenyl, or alkyl having 1 to 5 carbon atoms; R 3 represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms, A is -XC(=Y)-, -XC(=Y)Z-, -X-, or -XSO2- (wherein X, Y, and Z are each independently NR 4 (where R 4 represents hydrogen, linear or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms, 4 When two or more are present, they may be the same or different, and represent S or O; B is a valence bond, a straight-chain or branched alkylene having 1 to 14 carbon atoms (which may be substituted with at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and 1 to 3 methylenes may be replaced with carbonyl), a straight-chain or branched acyclic unsaturated hydrocarbon having 2 to 14 carbon atoms and containing 1 to 3 double bonds and / or triple bonds (which may be substituted with at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and 1 to 3 methylenes may be replaced with carbonyl), or a thioether bond, an ether bond, and / or an amino bond. a linear or branched, saturated or unsaturated hydrocarbon having 1 to 14 carbon atoms and containing 1 to 5 carbon atoms (provided that the heteroatom is not directly bonded to A and 1 to 3 methylenes may be replaced by carbonyls), a linear or branched, acyclic, unsaturated hydrocarbon having 2 to 14 carbon atoms and containing 1 to 3 double bonds and / or triple bonds (provided that the ... may be substituted with at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and 1 to 3 methylenes may be replaced by carbonyls), or a linear or branched, saturated or unsaturated hydrocarbon having 1 to 14 carbon atoms and containing 1 to 5 thioether bonds, ether bonds, and / or amino bonds (provided that the heteroatom is not directly bonded to A and 1 to 3 methylenes may be replaced by carbonyls), R 5 is hydrogen or the following basic structure [ka] (wherein, in these formulas, Q represents N, O, or S; T represents CH2, NH, S, or O; 1 represents an integer from 0 to 5; m and n each independently represent an integer from 0 to 5, the sum of m and n is 5 or less, and each organic group may be substituted with at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy), R 6 is hydrogen, R 7 represents hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms, R 6 and R 7 taken together represent -O-, -CH2- or -S-, R 8 represents hydrogen, alkyl having 1 to 5 carbon atoms, or alkanoyl having 1 to 5 carbon atoms, R 12 and R 13 are both hydrogen, or one of them is hydrogen and the other is hydroxy, or are together oxo, General formula (II) includes (+), (-) and (±) forms.]

[0033] In the above-mentioned therapeutic or preventive agent for cachexia, among the compounds represented by general formula (II) or their pharmacologically acceptable acid addition salts, the compound having a morphinan skeleton represented by the above-mentioned general formula (I) or its pharmacologically acceptable acid addition salts is preferred.

[0034] The double line consisting of a dotted line and a solid line in the general formula (I) represents a double bond or a single bond, and preferably a single bond.

[0035] In the general formula (I), R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms. 1As the aryl group, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl are preferred, and cyclopropylmethyl is particularly preferred.

[0036] R 2 represents a linear or branched alkyl group having 1 to 5 carbon atoms. 2 As the aryl group, methyl, ethyl and propyl are preferable, and methyl is particularly preferable.

[0037] B represents -CH=CH-. B is preferably a trans-form -CH=CH-.

[0038] In the compound represented by general formula (I), the double line of the dotted line and the solid line is a single bond, and R 1 is cyclopropylmethyl, R 2 is methyl and B is a trans -CH=CH-, i.e., a compound in the (-) form, i.e., (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan, is particularly preferred. [ka]

[0039] The compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof can be prepared according to the method described in WO 93 / 015081.

[0040] Among the compounds represented by general formula (II), R 12 and R 13 Compounds in which R are both hydrogen can be prepared according to the method described in WO 93 / 015081. 12 and R 13The compound in which R is taken together to form an oxo group can be produced, for example, from a compound prepared according to the methods described in Horikiri and Kawamura's paper (Heterocycles, 2004, Vol. 63, p. 865-870) and Sagara et al.'s paper (Bioorg. Med. Chem. Lett., 1995, Vol. 5, p. 1505-1508) according to the methods described in Horikiri et al.'s paper (Chem. Pharm. Bull., 2004, Vol. 52, No. 6, p. 664-669) and International Publication No. WO 93 / 015081. 12 is hydroxy and R 13 Compounds in which represents hydrogen can be prepared according to the method described in the above-mentioned Horikiri et al. paper.

[0041] In the above-mentioned cachexia treatment or prevention agent, the ghrelin receptor agonist can be a known peptide compound or non-peptide compound. For example, the peptide compound includes pralmorelin and the like in addition to ghrelin, which is an endogenous ligand, and the non-peptide compound includes anamorelin, macimorelin, ibutamoren methanesulfonate, urimorelin, capromorelin, SM-130686, and the like. If it is a salt, its salt form can be included, and if it can form a salt, its pharmacologically acceptable salt can be included. If it is a non-peptide compound, anamorelin or its pharmacologically acceptable salt can be included.

[0042] Among ghrelin receptor agonists, anamorelin can be used as 2-amino-N-[(1R)-2-[(3R)-3-benzyl-3-(N,N',N'-trimethylhydrazinocarbonyl)piperidin-1-yl]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]-2-methylpropionamide, which can be prepared according to the method described in U.S. Pat. No. 6,576,659.

[0043] In the above-mentioned therapeutic or prophylactic agent for cachexia, the preferred embodiment of the compound represented by formula (I) or its pharmacologically acceptable acid addition salt and the preferred embodiment of the ghrelin receptor agonist can be combined in any manner, for example, (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan or its pharmacologically acceptable acid addition salt and anamorelin or its pharmacologically acceptable salt can be combined.

[0044] As used herein, the following terms are defined below unless otherwise indicated.

[0045] Examples of the "pharmacologically acceptable acid addition salt" in the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, etc., organic carboxylates such as acetate, lactate, citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, etc., and organic sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Among these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, etc. are preferably used.

[0046] In the present invention, the "pharmacologically acceptable salt" includes, in addition to the above-mentioned acid addition salts, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and ammonium salt, and organic base salts such as methylamine salt, diethylamine salt, trimethylamine salt, triethylamine salt, pyridinium salt, triethanolamine salt, ethylenediamine salt, and guanidine salt.

[0047] The "ghrelin receptor" in the present invention is also referred to as GHSR, GHDP, GHS-R, etc., and in humans refers to a protein (UniProtID: Q92847) encoded by a gene (Ensembl ID: ENSG00000121853).

[0048] In the present invention, the term "ghrelin receptor agonist" refers to a peptide-based compound or a non-peptide-based compound that acts on the ghrelin receptor and exhibits a function similar to that of ghrelin.

[0049] In the present invention, "cachexia" includes systemic syndromes with major symptoms such as significant weight loss, anemia, edema, loss of appetite, generalized weakness, fatigue, etc., in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases, and acquired immune deficiency syndrome. Examples include cancer cachexia, tuberculous cachexia, diabetic cachexia, blood disease cachexia, endocrine disease cachexia, infectious disease cachexia, and cachexia due to acquired immune deficiency syndrome. The above-mentioned therapeutic or preventive agent for cachexia is preferably used for cancer cachexia due to malignant tumors, among other cachexia.

[0050] In the present invention, the term "malignant tumor" (also called cancer or malignant neoplasm) includes "cancer (also called carcinoma)" derived from epithelial tissue, "sarcoma" derived from non-epithelial tissue, and those derived from the hematopoietic organs. Examples include malignant melanoma, malignant bone tumor, gastric cancer, hepatocellular carcinoma, acute myeloid leukemia, acute lymphocytic leukemia, cervical cancer, uterine cancer, esophageal cancer, pancreatic cancer, prostate cancer, colon cancer, breast cancer, lung cancer, bladder cancer, and ovarian cancer.

[0051] The above-mentioned therapeutic or preventive agent for cachexia has an effect of improving cachexia, i.e., an effect of improving a systemic syndrome whose main symptoms are significant weight loss, anemia, edema, loss of appetite, general weakness, fatigue, etc., which occur in chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases, and acquired immune deficiency syndrome.

[0052] The above-mentioned therapeutic or preventive agent for cachexia is used as a therapeutic or preventive agent for cachexia in mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).

[0053] A therapeutic or preventive agent for cachexia, which is a combination of a compound represented by formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist, can be administered orally or parenterally as a mixture of the two, i.e., a combination drug, either as is or with a medicament-acceptable carrier. However, the two can also be prepared individually, i.e., as a single drug, rather than as a combination drug, and administered simultaneously as is or with a medicament-acceptable additive or the like that is commonly used in the field of formulations. Furthermore, each single drug can be administered before or after an appropriate interval. In these cases, the dosage form and administration route of each single drug do not need to be the same, and may be different from each other. The above-mentioned "appropriate interval" can be confirmed by clinical or animal experiments.

[0054] The above-mentioned therapeutic or preventive agent for cachexia comprises a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist, and may optionally comprise one or more medicament-acceptable carriers, and in particular may comprise a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist.

[0055] In another embodiment of the present invention, the above-mentioned therapeutic or prophylactic agent for cachexia contains, as active ingredients, a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist. The above-mentioned therapeutic or prophylactic agent for cachexia contains, as active ingredients, a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist, and may optionally contain one or more medicament-acceptable carriers, and may in particular consist of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist.

[0056] As one embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing cachexia, which comprises a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist, and contains one or more pharmacologic acceptable carriers. The pharmaceutical composition of this embodiment preferably contains a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist as active ingredients, and further contains one or more pharmacologic acceptable carriers.

[0057] As another embodiment of the present invention, a pharmaceutical combination for treating or preventing cachexia is provided, which comprises a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist. The pharmaceutical combination of this embodiment preferably contains a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in combination with a ghrelin receptor agonist. For example, the pharmaceutical combination of this embodiment may be provided in the form of a single preparation (i.e., a combination drug) containing the above active ingredients together, or in the form of multiple single agents in which the above active ingredients are separately formulated. When the pharmaceutical combination of this embodiment is in the form of multiple single agents, the pharmaceutical combination of this embodiment may be provided in the form of a kit containing multiple pharmaceutical preparations each containing the above active ingredients, and optionally instructions for administering the pharmaceutical preparations.

[0058] In another embodiment of the present invention, there is provided a use of a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist in the manufacture of a medicament for treating or preventing cachexia (e.g., a therapeutic or prophylactic agent for cachexia).In another embodiment of the present invention, there is provided a combination of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist for treating or preventing cachexia.

[0059] When the compound represented by formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist are orally administered as a single agent or a combination agent, the dosage form may be, for example, a tablet, a capsule, an orally disintegrating agent, a powder, or a granule. When the compound is administered parenterally, for example, a rapid intravenous infusion, a continuous intravenous infusion, an intramuscular injection, a subcutaneous injection, an intradermal injection, a tape, a patch, or the like can be selected.

[0060] The compound represented by formula (I) or its pharmacologically acceptable acid addition salt and a ghrelin receptor agonist may be prepared as a single agent or a combination agent in the above dosage form according to a known manufacturing method generally used in the pharmaceutical field. In this case, if necessary, excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, etc. that are generally used in the pharmaceutical field and are medicamentously acceptable may be added.

[0061] The content of the compound represented by formula (I) or its pharmacologically acceptable acid addition salt in the above-mentioned cachexia treatment or prevention agent is not particularly limited, but can be prepared so that it is usually 0.1 μg to 100 mg per dose. The dosage can be appropriately selected according to the patient's symptoms, age, sex, weight, administration method, etc., but usually, the amount of the compound represented by formula (I) or its pharmacologically acceptable acid addition salt per day for an adult is 0.1 μg to 20 mg, preferably 1 μg to 10 mg, more preferably 1 μg to 40 μg, and each can be administered once or several times. In addition, when it is prepared as a kit, each pharmaceutical preparation may be administered simultaneously or at intervals.

[0062] The content of anamorelin or its pharmacologically acceptable salt in the above-mentioned cachexia treatment or prevention agent is not particularly limited, but can be prepared so that it is usually 10 μg to 10000 mg per dose. The dosage can be appropriately selected according to the patient's symptoms, age, sex, weight, administration method, etc., but the amount of anamorelin or its pharmacologically acceptable salt per adult is usually about 10 μg to 2000 mg, preferably 100 μg to 1000 mg, more preferably about 100 μg to 400 mg, and can be administered once or several times. In addition, when it is made into a kit, each pharmaceutical preparation may be administered simultaneously or at intervals.

[0063] In the above-mentioned agents for treating or preventing cachexia, the mixing ratio of the compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof to the ghrelin receptor agonist can be appropriately selected depending on the subject, age and weight of the subject, symptoms, administration time, dosage form, administration method, combination of drugs, etc.

[0064] The above-mentioned therapeutic or preventive agent for cachexia can be preferably used as a therapeutic or preventive agent for cancer cachexia (e.g., caused by malignant melanoma, malignant bone tumor, gastric cancer, hepatocellular carcinoma, acute myeloid leukemia, acute lymphocytic leukemia, cervical cancer, uterine cancer, esophageal cancer, pancreatic cancer, prostate cancer, colon cancer, breast cancer, lung cancer, bladder cancer, or ovarian cancer).

[0065] The above-mentioned therapeutic or preventive agent for cachexia can also be suitably used as a therapeutic or preventive agent for cancer cachexia in a ghrelin-resistant state.

[0066] When the above-mentioned therapeutic or preventive agent for cachexia is prepared as a kit, the pharmaceutical preparation containing the compound represented by formula (I) or its pharmacologically acceptable acid addition salt prepared by the above-mentioned method and the pharmaceutical preparation containing a ghrelin receptor agonist can be separately packaged, and each pharmaceutical preparation can be taken out from each package at the time of administration. Also, each pharmaceutical preparation can be packaged in a form suitable for combined administration at each time.

[0067] The above-mentioned therapeutic or preventive agent for cachexia can be administered in combination with one or more other drugs used for the treatment, prevention, or reduction or suppression of symptoms of a disease. The combined drug may be a low molecular weight compound, or may be a high molecular weight protein, polypeptide, antibody, or vaccine. In this case, the combined drug may be administered simultaneously or at a time lag. The combination method may involve the use of each drug in combination, and may also involve the use of a combination drug. The dosage of the combined drug may be appropriately selected based on the respective clinically used doses. The mixing ratio of the above-mentioned therapeutic or preventive agent for cachexia to the combined drug may be appropriately selected depending on the subject of administration, the age, weight, and symptoms of the subject of administration, the administration time, the dosage form, the administration method, the combination of drugs, and the like.

[0068] The above-mentioned therapeutic or preventive agents for cachexia can be used in combination with other drugs such as chemotherapeutic agents, immunotherapeutic agents, and diuretics.

[0069] Examples of chemotherapeutic agents include alkylating agents such as cyclophosphamide, ifosfamide, melphalan, busulfan, nimustine, ranimustine, and temozolomide; nucleic acid metabolic antagonists such as methotrexate, fluorouracil, tegafur, carmofur, doxifluridine, capecitabine, cytarabine, ancitabine, enocitabine, cytarabine ocfosfate, gemcitabine, mercaptopurine, and fludarabine; doxorubicin, daunorubicin, pirarubicin, Examples of such agents include antitumor antibiotics such as epirubicin, idarubicin, mitoxantrone, mitomycin C, bleomycin, and peplomycin; microtubule inhibitors such as vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, and docetaxel; platinum preparations such as cisplatin, carboplatin, and nedaplatin; topoisomerase inhibitors such as irinotecan, nogitecan, and etoposide; and molecular targeted therapeutic agents such as trastuzumab, rituximab, and imatinib.

[0070] Immunotherapeutic agents include muramyl dipeptide derivatives, lentinan, sizofiran, ubenimex, picibanil, krestin, interferon, interleukin, granulocyte colony-stimulating factor, erythropoietin, and the like.

[0071] Examples of diuretics include xanthine derivative preparations such as theobromine sodium salicylate and theobromine calcium salicylate; thiazide preparations such as ethiazide, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penflutizide, polythiazide, and methyclothiazide; anti-aldosterone preparations such as spironolactone and triamterene; carbonic anhydrase inhibitors such as acetazolamide; chlorbenzenesulfonamide preparations such as chlorthalidone, mefruside, and indapamide; azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, and furosemide.

[0072] Examples of embodiments of the above-mentioned therapeutic or preventive agent for cachexia include a therapeutic or preventive agent for cachexia containing, as an active ingredient, a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof, which is used in combination (concomitant use) with the above-mentioned ghrelin receptor agonist, and a therapeutic or preventive agent for cachexia containing, as an active ingredient, a ghrelin receptor agonist, which is used in combination (concomitant use) with the above-mentioned compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[0073] Examples of embodiments of the above-mentioned therapeutic or preventive agent for cachexia include the use of a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for treating or preventing cachexia (e.g., a therapeutic or preventive agent for cachexia) to be used in combination (concomitant use) with the above-mentioned ghrelin receptor agonist, and the use of a ghrelin receptor agonist in the manufacture of a medicament for treating or preventing cachexia (e.g., a therapeutic or preventive agent for cachexia) to be used in combination (concomitant use) with the above-mentioned compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof.

[0074] Examples of embodiments of the therapeutic or preventive agent for cachexia include a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof for use in combination with the above-mentioned ghrelin receptor agonist for the treatment or prevention of cachexia, and a ghrelin receptor agonist for use in combination with the above-mentioned compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof for the treatment or prevention of cachexia.

[0075] Further, an embodiment of the above-mentioned cachexia treatment or prevention agent can be a method for treating or preventing cachexia, which comprises administering a compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and a ghrelin receptor agonist in combination (concomitant use) to a patient in need of cachexia treatment or prevention. In this embodiment, the compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and the ghrelin receptor agonist can be administered to the patient in effective amounts (e.g., the content in the cachexia treatment or prevention agent exemplified above). In this embodiment, the compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof and the ghrelin receptor agonist can be administered simultaneously or in tandem with an appropriate interval (e.g., continuously or sequentially at a fixed interval). EXAMPLES

[0076] The present invention will be described in detail below by showing examples, but the present invention is not limited to these.

[0077] Example 1: Effect of combined use of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (hereinafter, Compound 1) and anamorelin hydrochloride in a mouse tumor-bearing model (non-small cell lung cancer model with ghrelin resistance): The efficacy of compound 1 in combination with anamorelin hydrochloride (MedChemExpress) on food intake and body weight was examined using a tumor-bearing animal model in which A549 cells, a type of human alveolar basal epithelial adenocarcinoma, were transplanted into nude mice.

[0078] A549 cells were subcultured using RPMI1640 medium containing 10% FBS. For efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (Japan SLC) were purchased and used after 1 week of acclimation. Cancer-bearing animal models were created as follows. A549 cells were injected into the right flank of each mouse at a dose of 2.5 × 10 7 On the 41st day after cell transplantation, the mice were divided into groups so that the average tumor volume of each group was equal.

[0079] The effects of various compounds on food intake and body weight were examined as follows. That is, from the 43rd day to the 70th day after cell transplantation, various compounds were orally administered every day for 28 days, and food intake and body weight were measured at the same time. The doses of various compounds were 0.25 mg / kg (9 cases) for compound 1 and 30 mg / kg (9 cases) for anamorelin hydrochloride. For the co-administration of compound 1 and anamorelin hydrochloride, 0.25 mg / kg of compound 1 and 30 mg / kg of anamorelin hydrochloride were used (9 cases), which were prepared by mixing compound 1 and anamorelin hydrochloride dissolved in distilled water in advance. As a control, distilled water was administered in the same manner (9 cases). The food intake was calculated by subtracting the weight of the lid of the single cage containing food on the previous day from the weight of the lid of the single cage containing food on the measurement day.

[0080] The results are shown in Figures 1 and 2. The vertical axis of Figure 1 shows the cumulative food intake during the administration period of each compound (from the start of administration to the day after the final administration). The vertical axis of Figure 2 shows the body weight on the 29th day after the start of administration of each compound (the day after the final administration) (after 28 days of administration). On the horizontal axis of Figures 1 and 2, "distilled water" shows the distilled water administration group, "compound 1" shows the compound 1 administration group, "anamorelin" shows the anamorelin hydrochloride administration group, and "combined administration" shows the compound 1 and anamorelin hydrochloride administration group. The * marks in Figures 1 and 2 indicate statistical significance in comparison with the vehicle administration group (Dunnett's multiple test) (*: P<0.05).

[0081] In terms of cumulative food intake during the administration of various compounds, the compound 1 administration group or the anamorelin hydrochloride administration group did not show a statistically significant increase in food intake compared to the distilled water administration group, but the compound 1 and anamorelin hydrochloride combined administration group showed a statistically significant increase in food intake compared to the distilled water administration group. In terms of body weight after 28 days of administration of various compounds, the compound 1 administration group or the anamorelin hydrochloride administration group did not show a statistically significant increase in body weight compared to the distilled water administration group, but the compound 1 and anamorelin hydrochloride combined administration group showed a statistically significant increase in body weight compared to the distilled water administration group.

[0082] Furthermore, the above results show that anamorelin hydrochloride alone showed no effect on food intake or body weight, but the combined administration of compound 1 and anamorelin hydrochloride produced an effect, suggesting that ghrelin resistance had developed in this cancer-bearing animal model, and demonstrating that the combined use of compound 1 and anamorelin hydrochloride improved cancer cachexia in a ghrelin-resistant state.

[0083] Example 2: Effect of combined use of Compound 1 and anamorelin hydrochloride in a mouse tumor-bearing model (non-small cell lung cancer model): The efficacy of compound 1 in combination with anamorelin hydrochloride on food intake and body weight was examined using a tumor-bearing animal model in which A549 cells, a type of human alveolar basal epithelial adenocarcinoma, were transplanted into nude mice.

[0084] A549 cells were subcultured using RPMI1640 medium containing 10% FBS. For efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (Japan SLC) were purchased and used after 1 week of acclimation. Cancer-bearing animal models were created as follows. A549 cells were injected into the right flank of each mouse at a dose of 2.5 × 10 7 On the 22nd day after cell transplantation, the mice were divided into groups so that the average tumor volume of each group was equal.

[0085] The effects of various compounds on food intake and body weight were examined as follows. That is, from the 23rd day to the 50th day after cell transplantation, various compounds were orally administered every day for 28 days, and food intake and body weight were measured at the same time. The doses of various compounds were 0.25 mg / kg (13 cases) for compound 1 and 30 mg / kg (13 cases) for anamorelin hydrochloride. For the co-administration of compound 1 and anamorelin hydrochloride, 0.25 mg / kg of compound 1 and 30 mg / kg of anamorelin hydrochloride were used (13 cases), which were prepared by mixing compound 1 and anamorelin hydrochloride dissolved in distilled water in advance. As a control, distilled water was administered in the same manner (13 cases). The food intake was calculated by subtracting the weight of the lid of the single cage containing food on the previous day from the weight of the lid of the single cage containing food on the measurement day.

[0086] The results are shown in Figures 3 and 4. The vertical axis of Figure 3 shows the cumulative food intake during the administration period of each compound (from the start of administration to the day after the final administration). The vertical axis of Figure 4 shows the body weight on the 29th day after the start of administration of each compound (the day after the final administration) (after 28 days of administration). On the horizontal axis of Figures 3 and 4, "Distilled water" shows the distilled water administration group, "Compound 1" shows the Compound 1 administration group, "Anamorelin" shows the anamorelin hydrochloride administration group, and "Combined administration" shows the Compound 1 and anamorelin hydrochloride combination administration group. The * marks in Figures 3 and 4 indicate statistical significance in comparison with the vehicle administration group (Dunnett's multiple test) (*: P<0.05).

[0087] In terms of cumulative food intake during the administration of various compounds, the compound 1 administration group and the group administered with the combination of compound 1 and anamorelin hydrochloride showed a statistically significant increase in food intake compared to the distilled water administration group, and the anamorelin hydrochloride administration group showed a tendency to increase food intake compared to the distilled water administration group. The food intake increase effect was most remarkable in the group administered with the combination of compound 1 and anamorelin hydrochloride. In terms of body weight after administration of various compounds for 28 days, the compound 1 administration group, the anamorelin hydrochloride administration group, and the group administered with the combination of compound 1 and anamorelin hydrochloride all showed a statistically significant increase in body weight compared to the distilled water administration group, and the weight increase in the group administered with the combination of compound 1 and anamorelin hydrochloride was the most remarkable.

[0088] Example 3: Effect of combined use of Compound 1 and anamorelin hydrochloride in a mouse tumor-bearing model (skin cancer model): The efficacy of compound 1 in combination with anamorelin hydrochloride on food intake and body weight was examined using a tumor-bearing animal model in which mouse malignant melanoma cells, B16 / F10 cells, were transplanted into the mice.

[0089] B16 / F10 cells were subcultured using DMEM medium containing 10% FBS and penicilin-streptomycin. For efficacy evaluation, female C57BL / 6J mice (Charles River Japan) aged 6 weeks at the time of infusion were used after 1 week of acclimation. Cancer-bearing animal models were created as follows. B16 / F10 cells were injected into the right flank of each mouse at 5 × 10 6 On the fifth day after cell transplantation, the mice were divided into groups so that the average tumor volume of each group was equal.

[0090] The effects of various compounds on food intake and body weight were examined as follows. That is, from the 5th to 15th day after cell transplantation, various compounds were orally administered every day for 11 days, and food intake and body weight were measured at the same time. The doses of various compounds were 0.05 mg / kg (8 cases) for compound 1 and 30 mg / kg (8 cases) for anamorelin hydrochloride. For the co-administration of compound 1 and anamorelin hydrochloride, 0.05 mg / kg of compound 1 and 30 mg / kg of anamorelin hydrochloride were used (8 cases), which were prepared by mixing compound 1 and anamorelin hydrochloride dissolved in distilled water in advance. As a control, distilled water was administered in the same manner (8 cases). The food intake was calculated by subtracting the weight of the cage lid containing food on the previous day from the weight of the cage lid containing food on the measurement day. Each group of eight animals was divided into two cages of four animals each, and the total food intake in the two cages was divided by eight to calculate the amount of food intake per animal.

[0091] The results are shown in Figures 5 and 6. The vertical axis of Figure 5 shows the cumulative food intake during the administration period of various compounds (from the start of administration to the day after the final administration). The vertical axis of Figure 6 shows the body weight on the 12th day after the start of administration of various compounds (the day after the final administration) (after 11 days of administration). On the horizontal axis of Figures 5 and 6, "Distilled water" indicates the distilled water administration group, "Compound 1" indicates the Compound 1 administration group, "Anamorelin" indicates the anamorelin hydrochloride administration group, and "Combined administration" indicates the Compound 1 and anamorelin hydrochloride combination administration group. The * mark in Figure 5 indicates that the result is statistically significant in comparison with the vehicle administration group (Dunnett's multiple test) (*: P<0.05).

[0092] In the cumulative food intake during the administration of various compounds, the compound 1 and anamorelin hydrochloride groups did not show a statistically significant increase in food intake compared to the distilled water group, but the compound 1 and anamorelin hydrochloride combined administration group showed a statistically significant increase in food intake compared to the distilled water group. In addition, in the body weight after 11 days of administration of various compounds, the compound 1 group, the anamorelin hydrochloride group, or the compound 1 and anamorelin hydrochloride combined administration group did not show a tendency to increase in body weight compared to the distilled water group, but the compound 1 and anamorelin hydrochloride combined administration group showed a tendency to increase in body weight.

[0093] Furthermore, the above results show that the effect of increasing food intake and body weight by combined administration of compound 1 and anamorelin hydrochloride is observed not only in non-small cell lung cancer models but also in skin cancer models, demonstrating that combined use of compound 1 and anamorelin hydrochloride improves cancer cachexia caused by various types of cancer.

[0094] From the above results, it was revealed that the use of a compound represented by general formula (I) or its pharmacologically acceptable acid addition salt in combination with a ghrelin receptor agonist shows a significant symptom suppression effect against cachexia at an administration dose that does not show food intake and body weight increase effect by each alone. It was also shown that the use of a compound represented by general formula (I) or its pharmacologically acceptable acid addition salt in combination with a ghrelin receptor agonist can reduce the administration dose of both or either one of them, and reduce the concern of side effects. Furthermore, it was shown that this combination effect is applicable to malignant tumors in general. [Industrial Applicability]

[0095] The therapeutic or preventive agent for cachexia of the present invention has a high therapeutic effect against cachexia and is therefore useful in the medical field.

[0096] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A therapeutic or preventive agent for cachexia comprising a combination of a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof in a content ranging from 0.1 μg to 100 mg and a ghrelin receptor agonist which is anamorelin or a pharmacologically acceptable salt thereof in a content ranging from 10 μg to 10,000 mg. 【Chemistry 1】 [In the formula, the double line of a dotted line and a solid line represents a double bond or a single bond, and R １ represents cyclopropylmethyl, R ２ represents methyl, and B represents the trans form -CH=CH-.

2. An agent for treating or preventing cachexia, comprising as active ingredients a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof in a content ranging from 0.1 μg to 100 mg, and a ghrelin receptor agonist which is anamorelin or a pharmacologically acceptable salt thereof in a content ranging from 10 μg to 10,000 mg. 【Chemistry 2】 [In the formula, the double line of a dotted line and a solid line represents a double bond or a single bond, and R １ represents cyclopropylmethyl, R ２ represents methyl, and B represents the trans form -CH=CH-.

3. The therapeutic or prophylactic agent according to claim 1 or 2, wherein the compound represented by general formula (I) is (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan represented by the following structural formula. 【Chemistry 3】

4. The therapeutic or preventive agent according to any one of claims 1 to 3, wherein the cachexia is cancer cachexia.

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