Therapeutic or prophylactic agent for cachexia

Abstract

The present invention addresses the problem of providing a therapeutic or prophylactic agent for cachexia, which has few side effects in the treatment of cachexia and exhibits a significant drug effect. The present invention provides a therapeutic or prophylactic agent for cachexia, which is obtained by combining a compound having a morphinane skeleton represented by the following compound or a pharmacologically acceptable acid addition salt thereof with a starvation receptor agonist.

Description

technical field

[0001] The present invention relates to a therapeutic or preventive agent for cachexia. Background technique

[0002] Cachexia is a syndrome of complex metabolic abnormalities associated with underlying diseases, and is defined as a decrease in muscle mass regardless of the presence or absence of a decrease in fat mass. Chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases, acquired immunodeficiency syndrome, etc. are mentioned as the underlying diseases that develop cachexia, and it is known that significant weight loss, anemia, edema, appetite Systemic syndrome in which lack of energy, general weakness, and fatigue are the main symptoms (Non-Patent Document 1).

[0003] Among them, cachexia with malignant tumor as the underlying disease is called cancer cachexia, and it is said to account for about 20% of deaths from malignant tumors.

[0004] In the case of cancer cachexia, as the sympt...

Examples

Embodiment 1）

[0119] (Example 1) (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α in a mouse cancer-bearing model (a ghrelin-resistant non-small cell lung cancer model) -Effect of combined use of epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinane hydrochloride (below, compound 1) and emmorelin hydrochloride:

[0120] Using A549 cells, which are human alveolar basal epithelial adenocarcinoma cells, transplanted into nude mice, the effect on food intake and body weight when compound 1 was combined with emerin hydrochloride (MedChemExpress) was studied. the medicinal effect.

[0121] Passaging of A549 cells was performed using RPMI1640 medium containing 10% FBS. For the efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (SLC from Japan) were purchased and used after one week of acclimation. The preparation of cancer-bearing model animals was carried out as follows. That is, A549 cells were subcutaneously transplanted into the right abdomen of mice, 2.5 × 10 per mouse. 7 ind...

Embodiment 2）

[0126] (Example 2) Combination effect of compound 1 and emmorelin hydrochloride in a mouse cancer-carrying model (non-small cell lung cancer model):

[0127] Using a cancer-bearing model animal obtained by transplanting A549 cells, which are human alveolar basal epithelial adenocarcinoma cells, into nude mice, the pharmacological effects on food intake and body weight when Compound 1 was combined with emmorelin hydrochloride were studied.

[0128] Passaging of A549 cells was performed using RPMI1640 medium containing 10% FBS. For the efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (SLC from Japan) were purchased and used after one week of acclimation. The preparation of cancer-bearing model animals was carried out as follows. That is, A549 cells were subcutaneously transplanted into the right abdomen of mice, 2.5 × 10 per mouse. 7 indivual. On the 22nd day after cell transplantation, grouping was performed in such a way that the mean tumor volume of each group ...

Embodiment 3）

[0132] (Example 3) Combination effect of compound 1 and emmorelin hydrochloride in a mouse cancer-carrying model (skin cancer model):

[0133] Using a cancer-bearing model animal obtained by transplanting B16 / F10 cells, which are mouse malignant melanoma cells, into mice, the pharmacological effects on food intake and body weight when compound 1 was combined with emerin hydrochloride were studied .

[0134] Passaging of B16 / F10 cells was performed using DMEM medium containing 10% FBS and penicillin-streptomycin. For the efficacy evaluation, female C57BL / 6J mice (Charles River, Japan) at the age of 6 weeks at the time of introduction were used, and they were used after acclimation for one week. The preparation of cancer-bearing model animals was carried out as follows. That is, B16 / F10 cells were subcutaneously transplanted into the right abdomen of mice, 5 × 10 per mouse. 6 indivual. On the 5th day after cell transplantation, the groups were divided in such a way that the ...

technical field

[0001] The present invention relates to a therapeutic or preventive agent for cachexia. Background technique

[0002] Cachexia is a syndrome of complex metabolic abnormalities associated with underlying diseases, and is defined as a decrease in muscle mass regardless of the presence or absence of a decrease in fat mass. Chronic diseases such as malignant tumors, tuberculosis, diabetes, blood diseases, endocrine diseases, infectious diseases, acquired immunodeficiency syndrome, etc. are mentioned as the underlying diseases that develop cachexia, and it is known that significant weight loss, anemia, edema, appetite Systemic syndrome in which lack of energy, general weakness, and fatigue are the main symptoms (Non-Patent Document 1).

[0003] Among them, cachexia with malignant tumor as the underlying disease is called cancer cachexia, and it is said to account for about 20% of deaths from malignant tumors.

[0004] In the case of cancer cachexia, as the sympt...

Examples

Embodiment 1）

[0119] (Example 1) (-)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α in a mouse cancer-bearing model (a ghrelin-resistant non-small cell lung cancer model) -Effect of combined use of epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide]morphinane hydrochloride (below, compound 1) and emmorelin hydrochloride:

[0120] Using A549 cells, which are human alveolar basal epithelial adenocarcinoma cells, transplanted into nude mice, the effect on food intake and body weight when compound 1 was combined with emerin hydrochloride (MedChemExpress) was studied. the medicinal effect.

[0121] Passaging of A549 cells was performed using RPMI1640 medium containing 10% FBS. For the efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (SLC from Japan) were purchased and used after one week of acclimation. The preparation of cancer-bearing model animals was carried out as follows. That is, A549 cells were subcutaneously transplanted into the right abdomen of mice, 2.5 × 10 per mouse. 7 ind...

Embodiment 2）

[0126] (Example 2) Combination effect of compound 1 and emmorelin hydrochloride in a mouse cancer-carrying model (non-small cell lung cancer model):

[0127] Using a cancer-bearing model animal obtained by transplanting A549 cells, which are human alveolar basal epithelial adenocarcinoma cells, into nude mice, the pharmacological effects on food intake and body weight when Compound 1 was combined with emmorelin hydrochloride were studied.

[0128] Passaging of A549 cells was performed using RPMI1640 medium containing 10% FBS. For the efficacy evaluation, 7-week-old female BALB / C slc / nu / nu mice (SLC from Japan) were purchased and used after one week of acclimation. The preparation of cancer-bearing model animals was carried out as follows. That is, A549 cells were subcutaneously transplanted into the right abdomen of mice, 2.5 × 10 per mouse. 7 indivual. On the 22nd day after cell transplantation, grouping was performed in such a way that the mean tumor volume of each group ...

Embodiment 3）

[0132] (Example 3) Combination effect of compound 1 and emmorelin hydrochloride in a mouse cancer-carrying model (skin cancer model):

[0133] Using a cancer-bearing model animal obtained by transplanting B16 / F10 cells, which are mouse malignant melanoma cells, into mice, the pharmacological effects on food intake and body weight when compound 1 was combined with emerin hydrochloride were studied .

[0134] Passaging of B16 / F10 cells was performed using DMEM medium containing 10% FBS and penicillin-streptomycin. For the efficacy evaluation, female C57BL / 6J mice (Charles River, Japan) at the age of 6 weeks at the time of introduction were used, and they were used after acclimation for one week. The preparation of cancer-bearing model animals was carried out as follows. That is, B16 / F10 cells were subcutaneously transplanted into the right abdomen of mice, 5 × 10 per mouse. 6 indivual. On the 5th day after cell transplantation, the groups were divided in such a way that the ...

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