Agents for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic disorders

Abstract

The present invention addresses the problem of providing an ameliorating agent or a prophylactic agent for a muscle weakness symptom in a disease or a syndrome associated with a metabolic disorder. The present invention provides an ameliorating agent or a prophylactic agent for a muscle weakness symptom in a disease or a syndrome associated with a metabolic disorder, the agent containing a compound having a morphinan backbone structure typified by the below-mentioned compound or a pharmacologically acceptable acid addition salt thereof as an active ingredient.

Description

[Technical Field]

[0001] The present invention relates to an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities. [Background technology]

[0002] Declining muscle strength leads to declines in mobility, balance, and physical strength, leading to a shorter healthy lifespan and the risk of transitioning to a state requiring nursing care. For example, weakened muscle strength in the lower back and thighs makes it difficult to stand up or climb stairs, weakened muscle strength around the shoulders makes it difficult to lift heavy objects, and weakened muscle strength in the hands makes it difficult to perform delicate movements such as holding chopsticks, resulting in interference with daily activities. Furthermore, weakened muscle strength below the knees causes the legs to droop, making the toes more likely to catch on small protrusions, leading to the risk of falls and subsequent fractures, leading to a state requiring nursing care.

[0003] Symptoms of muscle weakness are known to occur, for example, in myogenic muscular atrophy, which is caused by a disease in the muscles themselves, and in neurogenic muscular atrophy, which is caused by a disease in the nervous system that controls muscle movement (Non-Patent Document 1). Symptoms of muscle weakness are also known to occur in diseases and syndromes involving metabolic abnormalities, even when there is no direct cause in the muscles or nervous system (Non-Patent Document 1).

[0004] To treat muscle weakness symptoms associated with diseases or syndromes involving metabolic abnormalities, for example, therapeutic drugs for the underlying disease or syndrome can be used. Meanwhile, as for drugs for improving muscle weakness symptoms without treatment of the underlying disease or syndrome, for example, nonsteroidal tricyclic compounds that are selective androgen receptor modulators (Patent Document 1) have been reported to have an effect of improving muscle weakness symptoms, but no such products are currently on the market. Therefore, exercise therapy and nutritional intake therapy are currently used as methods for improving or preventing muscle weakness symptoms associated with diseases or syndromes involving metabolic abnormalities (Non-Patent Document 2).

[0005] On the other hand, compounds having a morphinan skeleton or pharmacologically acceptable acid addition salts thereof have been disclosed to have opioid κ receptor agonism and to be used as analgesics and diuretics (Patent Document 2). In addition, their use as antipruritics (Patent Document 3), cachexia treatment agents (Patent Document 4), and hypoalbuminemia ameliorating agents (Patent Document 5) has also been disclosed. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 02 / 066475 [Patent Document 2] International Publication No. 93 / 015081 [Patent Document 3] International Publication No. 98 / 023290 [Patent Document 4] WO 12 / 105475 [Patent Document 5] WO 16 / 152965 [Non-patent literature]

[0007] [Non-Patent Document 1] Lynch et al., Pharmacology & Therapeutics, 2007, Vol. 113, pp. 461-487 [Non-patent document 2] Cruz-Jentoft et al., Age and Ageing, 2014, Vol. 43, pp. 748-759 Summary of the Invention [Problem to be solved by the invention]

[0008] However, clinical trials have only reported that androgen receptor modulators have a short-term effect of improving muscle weakness. Furthermore, exercise therapy, which is expected to improve muscle weakness, carries the risk of musculoskeletal disorders due to inappropriate training, and patients suffering from chronic diseases such as cardiac disease, respiratory disease, and orthopedic disease cannot implement or continue exercise therapy. Furthermore, the long-term improvement effect of nutritional intake therapy on muscle weakness has not yet been clarified. In other words, existing therapies are only applicable to a limited number of patients, and there is little evidence to support their therapeutic effects. Therefore, there is currently no therapy that can satisfactorily improve muscle weakness. Therefore, there is a strong need for the development of new agents for improving or preventing muscle weakness in diseases and syndromes associated with metabolic abnormalities.

[0009] Therefore, an object of the present invention is to provide an agent for improving or preventing the symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities. [Means for solving the problem]

[0010] As a result of extensive research aimed at solving the above-mentioned problems, the present inventors have found that compounds having a morphinan skeleton or pharmacologically acceptable acid addition salts thereof have excellent ameliorative and preventive effects on symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities, and have thus completed the present invention.

[0011] That is, the present invention provides an agent for improving or preventing symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities, which agent contains, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof: [ka] [In the formula, the double line consisting 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, and R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms, and B represents -CH=CH-.

[0012] The compound represented by the general formula (I) is R 1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexylmethyl, and R 2 is preferably methyl, ethyl or propyl.

[0013] The compound represented by the general formula (I) is R 1 is cyclopropylmethyl, and R 2 More preferably, is methyl and B is trans -CH=CH-.

[0014] 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, which has the following structural formula: [ka]

[0015] In this case, an excellent effect of improving or preventing the symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities can be expected.

[0016] Examples of the metabolic abnormalities include anabolic resistance and hypercatabolism. That is, one aspect of the present invention provides an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by anabolic resistance, which comprises, as an active ingredient, a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof. Also provided is an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by hypercatabolism, which comprises, as an active ingredient, a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof. The preferred aspects of the compound represented by the above general formula (I) also apply to the above aspects.

[0017] In another aspect, the present invention provides a pharmaceutical composition for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities, comprising a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof and a pharmacologically acceptable carrier. The above-mentioned preferred aspects regarding the compound represented by the above general formula (I) also apply to this aspect.

[0018] In another aspect, the present invention provides use of a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for improving or preventing muscle weakness symptoms in diseases or syndromes associated with metabolic abnormalities. The preferred aspects of the compound represented by the above general formula (I) also apply to this aspect.

[0019] In another aspect, the present invention provides a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for use in improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities. The above-mentioned preferred aspects of the compound represented by the above general formula (I) also apply to this aspect.

[0020] Furthermore, in another aspect, the present invention provides use of a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities (for example, an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities). The above-mentioned preferred aspects regarding the compound represented by the above general formula (I) also apply to this aspect.

[0021] In yet another aspect, the present invention provides a method for improving or preventing muscle weakness symptoms associated with a disease or syndrome accompanied by metabolic abnormality, the method comprising the step of administering a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof to a patient in need of improvement or prevention of muscle weakness symptoms associated with a disease or syndrome accompanied by metabolic abnormality. The above-mentioned preferred aspects regarding the compound represented by the above general formula (I) also apply to this aspect. [Effects of the Invention]

[0022] The compound of the present invention or a pharmacologically acceptable acid addition salt thereof can improve the symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities.

[0023] This specification includes the contents described in the specifications and / or drawings of Japanese Patent Applications Nos. 2020-112486 and 2021-097684, which are priority documents of this application. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 shows the effect of Compound 1 on tumor volume in a malignant tumor model exhibiting symptoms of muscle weakness. [Figure 2] FIG. 1 shows the muscle weakness symptom suppressing effect of Compound 1 in a malignant tumor model exhibiting muscle weakness symptoms. [Figure 3] FIG. 1 shows the suppressive effect of Compound 1 on symptoms of muscle weakness in an accelerated aging model exhibiting symptoms of muscle weakness. DETAILED DESCRIPTION OF THE INVENTION

[0025] The agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities of the present invention is characterized by containing, as an active ingredient, a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof: [ka] [In the formula, the double line consisting 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, and R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms, and B represents -CH=CH-.

[0026] In the above general formula (I), R 1is preferably cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, more preferably cyclopropylmethyl.

[0027] R 2 is preferably methyl, ethyl or propyl, more preferably methyl.

[0028] B is preferably -CH=CH- in the trans form.

[0029] In the compound represented by general formula (I), the double line of the dotted line and the solid line represents a single bond, and R 1 is cyclopropylmethyl, and R 2 is methyl, and B is a trans -CH=CH- and is in the (-) form, i.e., (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan, which is represented by the following structural formula: [ka]

[0030] In a preferred embodiment, the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof may be (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan or a pharmacologically acceptable acid addition salt thereof, and one embodiment of the (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan or a pharmacologically acceptable acid addition salt thereof is (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride.

[0031] As used herein, the following terms have the definitions set forth below unless otherwise specified.

[0032] Examples of the "pharmacologically acceptable acid addition salts" of the compound represented by the general formula (I) include salts with inorganic acids and salts with organic acids. Examples of salts with inorganic acids include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate. Examples of salts with organic acids include oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate, and cinnamate. Among these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, and the like are preferably used.

[0033] The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof may be an anhydride, or may form a solvate or a crystalline polymorph. The solvate may be either a hydrate or a non-hydrate, but a pharmacologically acceptable solvate is preferred.

[0034] The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be produced, for example, according to a known synthesis method (WO 93 / 015081).

[0035] The compound represented by the above general formula (I) or its pharmacologically acceptable acid addition salt can be used as an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities. Examples of the diseases or syndromes accompanied by metabolic abnormalities include, but are not limited to, stroke, chronic heart failure, chronic obstructive pulmonary disease, chronic kidney disease, type 2 diabetes, sepsis, osteoarthritis, osteoporosis, sarcopenia (primary sarcopenia, secondary sarcopenia), malignant tumors, cachexia, disuse syndrome, musculoskeletal syndrome, geriatric syndrome, and acquired immune deficiency syndrome.

[0036] As used herein, an agent for improving muscle weakness symptoms in a disease or syndrome associated with metabolic abnormality refers to a pharmaceutical administered to a patient for the purpose of improving muscle weakness symptoms in a disease or syndrome associated with metabolic abnormality. Furthermore, an agent for preventing muscle weakness symptoms in a disease or syndrome associated with metabolic abnormality refers to a pharmaceutical administered to a patient for the purpose of preventing the onset or worsening of muscle weakness. For example, when a pharmaceutical containing a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient is administered to a patient with a malignant tumor, type 2 diabetes, stroke, or the like who exhibits mild muscle weakness symptoms, or a patient with a musculoskeletal syndrome or the like who exhibits reduced walking speed, for the purpose of preventing the progression of muscle weakness symptoms, the pharmaceutical is included in the category of an agent for preventing muscle weakness symptoms. Muscle weakness leads to reduced mobility, balance, and physical strength, making it difficult to independently perform even minimal daily activities such as walking, putting on and taking off clothes, and using the toilet, and is associated with a risk of shortening healthy life expectancy and transitioning to a state requiring nursing care. It is expected that the pharmacological action of the agent for improving or preventing the symptoms of muscle weakness in the diseases or syndromes accompanied by the above-mentioned metabolic abnormalities will reduce these risks.

[0037] As used herein, metabolic abnormalities refer to a state in which the balance between muscle protein synthesis and degradation is disrupted. Examples of metabolic abnormalities include anabolic resistance, which is a decrease in muscle protein synthesis, and catabolic hyperactivity, which is an increase in muscle protein degradation. Among metabolic abnormalities, diseases or syndromes associated with anabolic resistance include, but are not limited to, stroke, chronic obstructive pulmonary disease, chronic kidney disease, sarcopenia, malignant tumors, cachexia, acquired immune deficiency syndrome, chronic heart failure, disuse syndrome, musculoskeletal syndrome, geriatric syndrome, etc. Furthermore, among metabolic abnormalities, diseases or syndromes associated with catabolic hyperactivity include, but are not limited to, stroke, chronic obstructive pulmonary disease, chronic kidney disease, sarcopenia, malignant tumors, cachexia, acquired immune deficiency syndrome, type 2 diabetes, sepsis, osteoarthritis, osteoporosis, etc. As described above, some diseases or syndromes may exhibit both anabolic resistance and catabolic hyperactivity.

[0038] Anabolic resistance refers to a state in which muscle protein synthesis is reduced. Anabolic resistance is said to be caused by a decrease in muscle protein synthesis capacity or a lack of amino acids, the substrate for muscle protein, due to malnutrition. Therefore, improving symptoms of muscle weakness can be expected to improve anabolic resistance by increasing maximum oxygen uptake through increased daily activity (Chronic Respiratory Disease, 2014, Vol. 11, pp. 247-255), and by suppressing the signal that inactivates the muscle protein synthesis pathway caused by hypoxia (The Journal of Physiology, 2006, Vol. 574, pp. 85-93). Furthermore, improvement in muscle weakness symptoms will allow for an increase in food intake due to an increase in basal metabolic rate (Japanese Journal of Nutrition and Food Science, 1993, Vol. 46, pp. 451-458; The American Journal of Clinical Nutrition, 2013, Vol. 97, pp. 7-14), and an improvement in anabolic resistance due to an increase in amino acid intake from food is expected.

[0039] Hypercatabolism refers to a state in which the breakdown of muscle proteins is accelerated. Hypercatabolism is thought to be caused by systemic inflammation, a biological response aimed at recovery from disease or invasion. Therefore, improving muscle weakness symptoms is expected to improve catabolism by increasing daily activity levels, increasing exercise load, and increasing basal metabolic rate, thereby increasing food intake. This, in turn, suppresses systemic inflammatory responses through improved immune function (Science Advances, 2019, Vol. 5, eaau7802).

[0040] As mentioned above, the improvement of muscle weakness symptoms is expected to improve metabolic abnormalities by increasing daily activity and basal metabolic rate, thereby further improving muscle weakness symptoms. Therefore, the compound represented by the above general formula (I) or its pharmacologically acceptable acid addition salt is more preferably used in, for example, stroke, sarcopenia, malignant tumor, cachexia, acquired immune deficiency syndrome, disuse syndrome, musculoskeletal syndrome, geriatric syndrome, etc., in which daily activity and basal metabolic rate are reduced, but is not limited to the following.

[0041] The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can improve symptoms of skeletal muscle weakness, where skeletal muscle refers to trunk muscles such as those in the head, neck, chest, abdomen, and back, and limb muscles such as those in the upper and lower limbs.

[0042] The effectiveness of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof in improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities can be evaluated, for example, by using an animal model of the disease or syndrome as an indicator of the improving effect on muscle weakness symptoms. Note that the effectiveness of the improving effect on muscle weakness symptoms found by this method in improving muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities can be explained by the relationship between muscle weakness symptoms and metabolic abnormalities, as described above. Examples of animal models of diseases or syndromes exhibiting muscle weakness include accelerated aging models (Lipids, 2013, Vol. 48, pp. 1135-1143), malignant tumor models (Oncology Reports, 2011, Vol. 25, pp. 189-193), type 2 diabetes models (Journal of Applied Physiology, 2019, Vol. 126, pp. 170-182), cerebral ischemia models (Disease Models & Mechanisms, 2017, Vol. 10, pp. 787-796), and tail suspension models in which muscle use in normal animals is restricted (Bioscience, 1979, Vol. 29, pp. 168-172). Furthermore, in patients, grip strength and physical function (walking distance in a specified time) can be used as indicators to evaluate the effectiveness of the drug in improving or preventing muscle weakness symptoms.

[0043] Previous studies have shown that in patients, a decline in forelimb muscle strength (grip strength) after disease onset is highly correlated with a decline in lower limb and respiratory muscle strength (Physical Therapy Science, 2011, Vol. 26, pp. 255-258; Annals of Rehabilitation Medicine, 2017, Vol. 41). Furthermore, in disease model animals, the decline in forelimb muscle strength (grip strength) coincides with the decline in motor ability and hindlimb muscle strength (Journal of Cachexia, Sarcopenia and Muscle, 2018, Vol. 9, pp. 975-986; Neurotoxicology and Teratolog, 2003, Vol. 25, pp. 543-553). Therefore, grip strength can be used as an indicator of overall muscle strength. Therefore, by using the above-mentioned model animals, etc., and evaluating the therapeutic effect on symptoms of muscle weakness using, for example, the grip strength of the forelimbs measured with a grip test device as an indicator, the effect of improving symptoms of muscle weakness throughout the body can be evaluated.

[0044] As will be shown in the Examples below, the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof does not inhibit the increase in tumor volume in a malignant tumor model in which A549 cells, a human alveolar basal epithelial adenocarcinoma cell line, are transplanted into nude mice.

[0045] Cancer cachexia, a common complication in patients with malignant tumors, is a condition characterized by muscle weakness. Anamorelin, a drug intended for the treatment of cancer cachexia, has been shown to increase lean body mass and improve symptoms in patients with cancer cachexia, but has not been shown to improve muscle weakness (The Lancet Oncology, 2016, Vol. 17, pp. 519-531). Similarly, enobosarm, a drug intended for the treatment of cancer cachexia, has also increased lean body mass in patients with cancer cachexia, but this effect was not confirmed in a study evaluating muscle weakness (improvement in physical function) (The Lancet Oncology, 2013, Vol. 14, pp. 335-345). These results suggest that therapeutic agents for weight loss (a diagnostic criterion) in cancer cachexia may not improve muscle weakness.

[0046] The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be used as an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.).

[0047] When the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is used clinically as an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities, the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof may be used as is, or may be administered orally or parenterally after being appropriately mixed with an additive such as an excipient, capsule shell, stabilizer, preservative, buffer, solubilizer, emulsifier, diluent, isotonicity agent, disintegrant, lubricant, coating agent, plasticizer or colorant as a pharmacologically acceptable carrier.

[0048] Examples of the excipient include D-mannitol, erythritol, lactose, macrogol, etc. Examples of the capsule shell include gelatin and succinated gelatin, etc. Examples of the stabilizer include sodium thiosulfate hydrate, etc. Examples of the disintegrant include crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, etc. Examples of the lubricant include magnesium stearate, sodium stearyl fumarate, sucrose fatty acid esters, etc. Examples of the coating agent include hydroxypropylmethylcellulose, polyvinyl alcohol, etc. Examples of the plasticizer include concentrated glycerin and macrogol 400, etc. Examples of the colorant include titanium oxide, red ferric oxide, yellow red ferric oxide, talc, etc.

[0049] In addition, the agent for improving or preventing the symptoms of muscle weakness in the above-mentioned diseases or syndromes accompanied by metabolic abnormalities can be produced by a conventional method using the above-mentioned carrier as appropriate. Pharmaceutical compositions containing the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof and a pharmacologically acceptable carrier can also be produced in the same manner.

[0050] When the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is orally administered as an agent for improving or preventing muscle weakness symptoms in diseases or syndromes accompanied by metabolic abnormalities, examples of the dosage form include tablets, capsules, orally disintegrating agents, powders, granules, etc., and examples of parenteral administration include rapid intravenous infusion, continuous intravenous infusion, intramuscular injection, subcutaneous injection, intradermal injection, inhalants, suppositories, ointments, creams, patches, etc. Also, known sustained-release preparations may be used.

[0051] The content of the compound represented by formula (I) or its pharmacologically acceptable acid addition salt in the agent for improving or preventing muscle weakness symptoms in the above-mentioned diseases or syndromes accompanied by metabolic abnormalities is not particularly limited, but it can be prepared so that it usually contains 0.1 μg to 100 mg per dose. The dosage can be appropriately selected depending on 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 preferably 0.1 μg to 20 mg, more preferably 1 μg to 10 mg, and even more preferably 1 μg to 100 μg, and can be administered once or in divided doses.

[0052] The agent for improving or preventing muscle weakness symptoms in diseases or syndromes associated with metabolic abnormalities described above can be administered in combination with one or more other drugs used to treat, prevent, or reduce or suppress symptoms of diseases or syndromes associated with metabolic abnormalities, in order to complement or enhance the improving or preventing effect or to reduce the dosage. The combined drug may be a low-molecular-weight compound, or a high-molecular-weight protein, polypeptide, antibody, vaccine, or the like. In this case, the combined drug may be administered simultaneously or at a later time. The combination method may simply involve using each drug in combination, or a combination drug may be used. The dosage of the combined drug can be appropriately selected based on the clinically used dose of each drug. The blending ratio of the agent for improving or preventing muscle weakness symptoms in diseases or syndromes associated with metabolic abnormalities described above to the combined drug can be appropriately selected depending on the recipient, the recipient's age, weight, symptoms, administration time, dosage form, administration method, etc. [Example]

[0053] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0054] Example 1: Effect of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride in malignant tumor models: Using a malignant tumor animal model in which human alveolar basal epithelial adenocarcinoma cells, A549 cells, were transplanted into nude mice, the ameliorative effect on muscle weakness of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (hereinafter referred to as Compound 1), produced according to WO 93 / 015081, was evaluated. Note that since this model exhibits symptoms of muscle weakness due to malignant tumors, a disease accompanied by metabolic abnormalities, it is believed that the ameliorative and preventive effects on muscle weakness symptoms can be evaluated.

[0055] A549 cells were passaged using RPMI1640 medium containing 10% FBS. For efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (Japan SLC Co., Ltd.) were purchased and used after one week of acclimation. Malignant tumor model animals were created as follows: A549 cells were injected into the right flank of each mouse at a concentration of 2.5 × 10 cells per mouse. 7 Each cell was subcutaneously injected and transplanted (suspended in FBS-free RPMI1640 medium). On day 41 after cell transplantation, the mice were divided into groups so that the average tumor volume of each group was equal. Tumor volume was calculated by measuring the diameter of the tumor with a digital caliper and using the following formula: Tumor volume (mm 3 ) = "Long diameter (mm)" x "Short diameter (mm)" x "Short diameter (mm)" x 1 / 2

[0056] To clarify that this model is a muscle weakness model, we used control animals with malignant tumors, which were transplanted with A549 cells and FBS-free RPMI1640 medium.

[0057] Compound 1 was orally administered to malignant tumor model animals daily for 28 days, from day 43 to day 70 after cell transplantation. The dose of Compound 1 was 0.125 mg / kg (9 animals) or 0.25 mg / kg (9 animals). Distilled water was administered in the same manner as a control for Compound 1 (9 animals). Additionally, distilled water was administered to control animals (10 animals) to confirm muscle strength decline in the malignant tumor model animals. Muscle strength was evaluated by measuring the grip strength of the forelimbs on day 28 (the final day of administration) after the start of Compound 1 administration using a grip test device (Muromachi Kikai Co., Ltd.). The group of malignant tumor model animals administered Compound 1 at 0.125 mg / kg was designated the Compound 1 0.125 mg / kg administration group, and the group of malignant tumor model animals administered Compound 1 at 0.25 mg / kg was designated the Compound 1 0.25 mg / kg administration group. A group of malignant tumor model animals administered with distilled water was designated as the distilled water administration group, and a group transplanted with A549 cells and FBS-free RPMI1640 medium and administered with distilled water was designated as the model control group.

[0058] The results of Compound 1 on tumor volume are shown in Figure 1. The vertical axis shows the tumor volume (mean ± standard error) 28 days after the start of Compound 1 administration. On the horizontal axis, "Model control" indicates the model control group, "Distilled water" indicates the distilled water administration group, "Compound 1 0.125 mg / kg" indicates the Compound 1 0.125 mg / kg administration group, and "Compound 1 0.25 mg / kg" indicates the Compound 1 0.25 mg / kg administration group. * indicates a statistically significant difference between the model control group and the distilled water administration group (t-test) (*: p<0.05).

[0059] The results of Compound 1 on grip strength are shown in Figure 2. The vertical axis shows grip strength (mean ± standard error) 28 days after the start of Compound 1 administration. On the horizontal axis, "Model control" indicates the model control group, "Distilled water" indicates the distilled water administration group, "Compound 1 0.125 mg / kg" indicates the Compound 1 0.125 mg / kg administration group, and "Compound 1 0.25 mg / kg" indicates the Compound 1 0.25 mg / kg administration group. * indicates statistical significance in the comparison (t-test) between the model control group and the distilled water administration group (*: p<0.05). # indicates statistical significance in the comparison (Dunnett's multiple test) between the distilled water administration group and each concentration of Compound 1 administration group (#: p<0.05).

[0060] The results in Figure 1 show that the distilled water-administered group showed a statistically significant increase in tumor volume compared to the model control group. Compound 1-administered groups did not exhibit any inhibitory effect on this increase in tumor volume, regardless of the dose.

[0061] The results in Figure 2 show that the distilled water-administered group showed a statistically significant decrease in grip strength (muscle strength) compared to the model control group. Therefore, it was revealed that the malignant tumor model in which A549 cells were transplanted into nude mice exhibits symptoms of decreased grip strength (muscle strength). In contrast to this significant decrease in grip strength (muscle strength), the Compound 1-administered groups at all doses showed a statistically significant increase in grip strength (muscle strength) compared to the distilled water-administered group, improving to the point where they exhibited grip strength (muscle strength) equivalent to that of the model control group.

[0062] Example 2: Effect of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride in an accelerated aging model: Using SAMP8 mice, a model of accelerated aging, we evaluated the ameliorative effect on muscle weakness of (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (hereinafter referred to as Compound 1), which was prepared according to WO 93 / 015081. Note that since this model exhibits symptoms of muscle weakness due to geriatric syndrome, a disease accompanied by metabolic abnormalities, we believe that it is possible to evaluate the ameliorative and preventive effects on muscle weakness symptoms.

[0063] For efficacy evaluation, 7-week-old male SAMP8 / TaSlc mice (Japan SLC, Inc.) were purchased and bred for 9 months before use. For a total of 3 days, starting 3 days before administration of the test substance and ending 1 day before, the forelimb grip strength was measured using a grip test device. The average value for the 3 days was calculated, and the mice were divided into groups so that the average muscle strength of each group was equal. To clarify that this model is a muscle weakness model, a control animal of the senescence-accelerated model was established. As a control animal of the senescence-accelerated model, 7-week-old male SAMPR1 / TaSlc mice (Japan SLC, Inc.) were purchased and bred under the same conditions as the SAMP8 mice. They were used in the study.

[0064] Compound 1 was orally administered to SAMP8 mice daily for 28 days. The dose of Compound 1 was 0.125 mg / kg (10 mice) or 0.25 mg / kg (13 mice). Distilled water was administered in the same manner as a control for Compound 1 (11 mice). Additionally, distilled water was administered to control animals (13 mice) to confirm muscle strength decline in the malignant tumor model animals. Muscle strength was assessed by measuring the grip strength of the forelimbs using a grip test device on the 28th day (the final day of administration) after the start of Compound 1 administration. The group of SAMP8 mice administered Compound 1 at 0.125 mg / kg was designated the Compound 1 0.125 mg / kg administration group, and the group of SAMP8 mice administered Compound 1 at 0.25 mg / kg was designated the Compound 1 0.25 mg / kg administration group. The group of SAMP8 mice administered distilled water was designated the distilled water administration group, and the group of SAMR1 mice administered distilled water was designated the model control group.

[0065] The results of Compound 1 on grip strength are shown in Figure 3. The vertical axis shows grip strength (mean ± standard error) 28 days after the start of Compound 1 administration. On the horizontal axis, "Model control" indicates the model control group, "Distilled water" indicates the distilled water administration group, "Compound 1 0.125 mg / kg" indicates the Compound 1 0.125 mg / kg administration group, and "Compound 1 0.25 mg / kg" indicates the Compound 1 0.25 mg / kg administration group. * indicates a statistically significant difference between the model control group and the distilled water administration group (t-test) (*: p<0.05). # indicates a statistically significant difference between the distilled water administration group and each concentration of Compound 1 administration group (Williams' multiple comparison) (#: p<0.05).

[0066] The results in Figure 3 show that the distilled water-administered group showed a statistically significant decrease in grip strength (muscle strength) compared to the model control group. Therefore, it was revealed that SAMP8 mice, a model of accelerated aging, exhibit symptoms of decreased grip strength (muscle strength). In contrast to this significant decrease in grip strength (muscle strength), all doses of Compound 1 administered groups showed a statistically significant increase in grip strength (muscle strength) compared to the distilled water-administered group.

[0067] From the above results, it has become clear that the compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof exhibits a remarkable symptom-improving effect on muscle weakness symptoms. Furthermore, since the ameliorating effect on muscle weakness symptoms can improve metabolic disorders, it has become clear that the compound represented by general formula (I) or a pharmacologically acceptable acid addition salt thereof can improve the effect of improving muscle weakness symptoms in diseases or syndromes accompanied by metabolic disorders. [Industrial Applicability]

[0068] The compound of the present invention or a pharmacologically acceptable acid addition salt thereof has an effect of improving symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities, and is therefore useful in the pharmaceutical field.

[0069] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. An agent for improving or preventing symptoms of muscle weakness in diseases or syndromes accompanied by metabolic abnormalities, which comprises a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient: 【Chemical 1】 [In the formula, the double line consisting 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, and R ２ represents a linear or branched alkyl group having 1 to 5 carbon atoms, and B represents —CH═CH—.

2. R １ is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R ２ The ameliorating or preventing agent according to claim 1, wherein is methyl, ethyl or propyl.

3. R １ is cyclopropylmethyl, and R ２ The ameliorating or preventing agent according to claim 1, wherein is methyl and B is -CH=CH- in trans form.

4. The ameliorating or preventing agent according to claim 1, wherein the compound represented by the 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 2】

5. The improving or preventing agent according to any one of claims 1 to 4, wherein the metabolic disorder is anabolic resistance.

6. The improving or preventing agent according to any one of claims 1 to 4, wherein the metabolic disorder is hypercatabolism.

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