WO2016152965A1 - Agent for improving hypoalbuminemia - Google Patents

Agent for improving hypoalbuminemia Download PDF

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Publication number
WO2016152965A1
WO2016152965A1 PCT/JP2016/059350 JP2016059350W WO2016152965A1 WO 2016152965 A1 WO2016152965 A1 WO 2016152965A1 JP 2016059350 W JP2016059350 W JP 2016059350W WO 2016152965 A1 WO2016152965 A1 WO 2016152965A1
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hypoalbuminemia
agent
compound
administration
improving
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PCT/JP2016/059350
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French (fr)
Japanese (ja)
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知比古 鈴木
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東レ株式会社
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Priority to JP2016518228A priority Critical patent/JP6702184B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine

Definitions

  • the present invention relates to an agent for improving hypoalbuminemia.
  • Serum albumin is a protein synthesized in the liver and occupies about 50 to 65% of protein in blood.
  • the reference value (normal value) of serum albumin concentration in blood is about 3.5 to 5.3 g / dL, although there is a range depending on the measurement method.
  • serum albumin concentration is lower than the reference value, low albumin
  • the value of 3.0 g / dL is regarded as important clinically (Non-patent Document 1).
  • causes of hypoalbuminemia include lack of amino acid supply due to nutritional disorders and decreased albumin synthesis due to liver damage, loss of albumin from blood due to renal failure such as nephrotic syndrome and trauma such as burns, dilution of plasma due to heart failure, etc. It is caused by increased catabolism of proteins such as albumin due to hyperthyroidism. When albumin in the blood decreases, the osmotic pressure of the blood decreases and edema and ascites develop.
  • dietary therapy with a high protein diet drug therapy with an amino acid preparation or a blood preparation containing serum albumin itself, and the like are performed.
  • the compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof, which is an active ingredient of the present invention has opioid ⁇ receptor agonist activity and reports on its use as an analgesic and diuretic.
  • Patent Document 1 the compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof, which is an active ingredient of the present invention, has opioid ⁇ receptor agonist activity and reports on its use as an analgesic and diuretic.
  • Patent Document 2 uses include antitussives (Patent Document 2), brain cell protective drugs (Patent Document 3), antidiarrheals (Patent Document 4), hyponatremia drugs (Patent Document 5), ORL-1 Receptor antagonist (Patent Document 6), neuropathic pain therapeutic drug (Patent Document 7), corneal or conjunctival antidiarrheal drug (Patent Document 8), neuropsychiatric disease therapeutic drug (Patent Document 9), drug-dependent therapeutic drug (Patent document 10), septic drug (patent document 11), itch treatment drug associated with multiple sclerosis (patent document 12), schizophrenia drug (patent document 13), skin property improving drug (patent document) 14), dyskinesia treatment (patent document 15), fibromyalgia treatment (patent document 16), biliary tract disease treatment (patent document 17) and cachexia treatment (patent document 18). ing.
  • amino acid preparations and blood preparations for intravenous injection are mainly used to improve hypoalbuminemia.
  • acid-base imbalance and high ammonia are used when amino acid preparations are administered intravenously. Attention must be paid to the development of side effects such as blood glucose, amino acid imbalance, and high nitrogen plasma, and blood products also have risks inherent to blood products such as virus contamination.
  • a preparation containing albumin itself has a problem that it cannot be administered orally because albumin is degraded in the stomach. Therefore, a drug that is highly safe and can be administered orally is desired.
  • an object of the present invention is to provide a hypoalbuminemia ameliorating agent that is highly safe and can be administered orally.
  • the present invention provides a hypoalbuminemia-improving agent comprising a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
  • a double line consisting of a dotted line and a solid line represents a double bond or a single bond
  • R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms
  • R 2 represents a straight chain having 1 to 5 carbon atoms.
  • B represents —CH ⁇ CH—.
  • R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl
  • R 2 is methyl, is preferably ethyl or propyl.
  • R 1 is cyclopropylmethyl
  • R 2 is methyl
  • B is trans —CH ⁇ CH—.
  • the hypoalbuminemia ameliorating agent is ( ⁇ )-17- (cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - [N-methyl-trans-3- (3 -Furyl) acrylamide] morphinan or a pharmacologically acceptable acid addition salt thereof is most preferably the active ingredient.
  • hypoalbuminemia-improving agent is preferably an agent for improving hypoalbuminemia associated with liver disease, and more preferably an agent for improving hypoalbuminemia associated with chronic liver disease.
  • the present invention also provides a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for use in improving hypoalbuminemia.
  • Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
  • the present invention also provides use of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for improving hypoalbuminemia.
  • Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
  • the present invention also provides use of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for improving hypoalbuminemia.
  • Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
  • the present invention also relates to a method for improving hypoalbuminemia, comprising an effective amount of a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for a patient in need of improvement.
  • Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
  • the hypoalbuminemia-improving agent of the present invention is a highly safe drug that can be administered orally and can be used for the treatment of hypoalbuminemia, and can particularly improve hypoalbuminemia associated with liver disease.
  • the agent for improving hypoalbuminemia of the present invention comprises a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
  • a double line consisting of a dotted line and a solid line represents a double bond or a single bond
  • R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms
  • R 2 represents a straight chain having 1 to 5 carbon atoms.
  • B represents —CH ⁇ CH—.
  • R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl
  • R 2 is methyl, is preferably ethyl or propyl.
  • R 1 is cyclopropylmethyl
  • R 2 is methyl
  • B is trans —CH ⁇ CH—.
  • the hypoalbuminemia-improving agent is a compound represented by the following formula (II): ( ⁇ )-17- (cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - Most preferably, [N-methyl-trans-3- (3-furyl) acrylamide] morphinan or a pharmacologically acceptable acid addition salt thereof is the active ingredient.
  • hydrochloride nalfurafine hydrochloride (( ⁇ )-17- (cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - [N-methyl-trans-3- (3-furyl) acrylamide) ] Morphinan hydrochloride) is already used as a drug for oral administration as an antidiarrheal agent (efficacy / effect: improvement of pruritus in hemodialysis patients or chronic liver disease patients). It is most preferable as an agent for improving hypoalbuminemia that can be administered.
  • Examples of the “pharmacologically acceptable acid addition salt” include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, acetate, lactate, Organic carboxylates such as citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate, or methanesulfonic acid And organic sulfonates such as salts, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like. Of these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, and the like are preferably used.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be produced according to the method described in WO 93/015081.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an action to improve hypoalbuminemia.
  • the above-mentioned hypoalbuminemia improving agent is preferably used as an improving agent for hypoalbuminemia associated with liver disease.
  • the “hypoalbuminemia ameliorating agent” is also called a therapeutic agent for hypoalbuminemia, and the hypoalbuminemia ameliorating agent can also be used as a therapeutic agent for hypoalbuminemia.
  • “Hypoalbuminemia” means the case where the serum albumin level is lower than the reference value. Clinically, a serum albumin level of 3.0 g / dL is regarded as important, and mortality is significantly increased in hypoalbuminemia of less than 3.0 g / dL (Sato et al. 2009, Vol. 18, pp. 26-28).
  • liver diseases include fulminant hepatitis, chronic or acute hepatitis, viral hepatitis, fatty liver, cirrhosis, liver cancer, alcoholic liver disease, obstructive jaundice, cholestasis, or primary biliary cirrhosis. It is done. As the liver disease, chronic liver disease is preferable.
  • hypoalbuminemia ameliorating agent is used as a hypoalbuminemia ameliorating agent for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs or monkeys). Particularly, it is preferably used when administered to humans.
  • mammals eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs or monkeys.
  • it is preferably used when administered to humans.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is purified to a pharmaceutical use, and after passing a necessary safety test, as it is or as a known pharmacological agent.
  • the dosage form for oral administration is tablets, capsules, buccal disintegrants, powders or granules, etc.
  • parenteral administration intravenous rapid infusion, intravenous continuous infusion, intramuscular injection, subcutaneous injection, intradermal injection
  • a tape agent or a patch agent can be selected.
  • the content of the compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof in the pharmaceutical composition is not particularly limited, and is usually adjusted to be 0.1 ⁇ g to 100 mg per dose. obtain.
  • the dosage can be appropriately selected according to the patient's symptoms, age, sex, body weight, administration method, and the like.
  • the amount of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof per day for an adult is 0.1 ⁇ g to 20 mg, preferably 1 ⁇ g to 1 mg, more preferably 1 ⁇ g to About 40 ⁇ g can be administered, and each can be administered once or divided into several times.
  • the agent for improving hypoalbuminemia is a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof alone, or treatment or prevention of a disease, reduction or suppression of symptoms.
  • the drug to be combined may be a low molecular compound, a high molecular protein, a polypeptide or an antibody, a vaccine, or the like.
  • the drugs to be combined can be administered simultaneously or with a time difference.
  • the method of combining may use each chemical
  • the dose of the drug to be combined can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the hypoalbuminemia-improving agent and the drug to be combined is appropriately selected depending on the subject to be administered, age of the subject to be administered, body weight and symptom, administration time, dosage form, administration method, drug combination, etc. can do.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is effective for the improvement of hypoalbuminemia is, for example, the above-mentioned general Evaluation can be made by administering a compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof, and comparing serum albumin levels before and after administration. Alternatively, it can be evaluated using a model animal in a hypoalbuminemia state.
  • Example 1 Effect on serum albumin level of pruritus patients with chronic liver disease exhibiting low albumin level: The effect of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof on serum albumin levels of pruritus patients with chronic liver disease exhibiting low albumin levels was evaluated.
  • subjects Patients with pruritus due to chronic liver disease (hereinafter referred to as subjects) were orally administered Compound 1 at 2.5 ⁇ g / day or 0 ⁇ g / day (where 0 ⁇ g / day is a placebo that does not contain Compound 1; hereinafter referred to as a placebo).
  • a control experiment was conducted. For subjects whose serum albumin level before the start of administration was 3.0 g / dL or less, the serum albumin levels before the start of administration and on the 15th and 29th days after the start of administration were compared. Serum albumin levels were measured by the BCG method.
  • Statistical analysis used an unpaired t-test (unpaired t-test). As a result of statistical analysis, when the P value was less than 0.05, it was judged to be statistically significant.
  • the vertical axis in FIG. 1 shows the compound 1 (2.5 ⁇ g / day) or placebo as the reference value of the serum albumin level (g / dL) before administering Compound 1 (2.5 ⁇ g / day) or placebo to the subject.
  • 15 shows the change in serum albumin level (g / dL) on the 15th day after the start of administration, indicating how much it has changed from the reference value before administration, where “placebo” on the horizontal axis is the placebo-administered group, and “compound 1” is the compound One administration group is shown.
  • the symbol * (asterisk) in the figure indicates that it is statistically significant (unpaired t-test; P ⁇ 0.05) compared to the placebo-administered group.
  • FIG. 2 shows the serum albumin value (g / dL) before administration of Compound 1 (2.5 ⁇ g / day) or placebo to each subject and the serum albumin value 15 days after the start of administration ( g / dL), “placebo” in the left figure represents the placebo-administered group, and “compound 1” in the right figure represents the compound-1 administration group.
  • FIG. 2 is a diagram in which serum albumin levels of each subject before administration of “placebo” or “Compound 1” and 15 days after the start of administration are connected by a single straight line. It shows how the serum albumin level fluctuates.
  • the results on the 29th day after the start of administration are shown in FIGS.
  • the vertical axis in FIG. 3 shows compound 1 (2.5 ⁇ g / day) or placebo as the reference value, which is the serum albumin level (g / dL) before administering Compound 1 (2.5 ⁇ g / day) or placebo to the subject.
  • the serum albumin level (g / dL) on the 29th day after the start of administration shows how much it has changed from the reference value before administration.
  • the “placebo” on the horizontal axis is the placebo-administered group, and “compound 1” is the compound One administration group is shown.
  • the symbol * (asterisk) in the figure indicates that it is statistically significant (unpaired t-test; P ⁇ 0.05) compared to the placebo-administered group.
  • FIG. 4 The vertical axis in FIG. 4 indicates the serum albumin value (g / dL) before administration of Compound 1 (2.5 ⁇ g / day) or placebo to each subject and the serum albumin value on the 29th day after administration ( g / dL), “placebo” in the left figure represents the placebo-administered group, and “compound 1” in the right figure represents the compound-1 administration group.
  • FIG. 4 is a diagram in which serum albumin levels of each subject before administration of “placebo” or “Compound 1” and 29 days after the start of administration are connected by a single straight line. It shows how the serum albumin level fluctuates.
  • the serum albumin level in the compound 1 administration group increased on both the 15th and 29th days after the start of administration, and the compound compared with the serum albumin change value in the placebo administration group.
  • the serum albumin change value of one administration group increased statistically significantly. Therefore, administration of Compound 1 showed an improvement effect on hypoalbuminemia. In the case of subjects exhibiting normal serum albumin levels, no change in serum albumin levels was observed even when Compound 1 was administered.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an action of improving hypoalbuminemia.
  • Example 2 Action on hypoalbuminemia model mice: According to the method of Huynh et al. (Molecular cancer therapeutics, 2007, Vol. 6, P. 2959-2966), hypoalbuminemia model mice by peritoneal seeding of ovarian cancer cells were prepared, The action of the compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof was evaluated.
  • Compound 1 was started 37 days after cell suspension transplantation (this day is taken as the administration start date).
  • Plasma was obtained after adding EDTA as an anticoagulant to the collected blood.
  • the plasma albumin concentration was measured with a biochemical analyzer (DRY-CHEM 4000S, Fuji Film). Plasma that had been frozen and stored once was thawed on the day of the measurement, 10 ⁇ L of the stock solution was dropped onto Fuji Dry Chemslide (ALB-PS, Fuji Film Co., Ltd.), and the albumin concentration was measured according to the manual.
  • the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is hypoalbuminemia caused by peritoneal dissemination of ovarian cancer cells, which is a disease different from chronic liver disease. It has been shown to have an effect of improving hypoalbuminemia.
  • the present invention can be used as an agent for improving hypoalbuminemia in the field of medicine.

Abstract

The purpose of the present invention is to provide a highly safe agent for improving hypoalbuminemia, it being possible to administer the agent orally. The present invention provides an agent for improving hypoalbuminemia, the agent containing, as an active ingredient, a compound that has a morphinan skeleton represented by the following compound or a pharmacologically acceptable acid addition salt thereof.

Description

低アルブミン血症の改善剤Hypoalbuminemia improver
　本発明は、低アルブミン血症の改善剤に関する。 The present invention relates to an agent for improving hypoalbuminemia.
　血清アルブミンは肝臓で合成されるタンパク質であり、血中のタンパク質の約５０～６５％を占める。血中の血清アルブミン濃度の基準値（正常値）は、その測定法の違いにより幅はあるものの約３．５～５．３ｇ／ｄＬであり、血清アルブミン濃度が基準値より低い場合に低アルブミン血症とされ、臨床的には３．０ｇ／ｄＬという値が重要視されている（非特許文献１）。 Serum albumin is a protein synthesized in the liver and occupies about 50 to 65% of protein in blood. The reference value (normal value) of serum albumin concentration in blood is about 3.5 to 5.3 g / dL, although there is a range depending on the measurement method. When serum albumin concentration is lower than the reference value, low albumin The value of 3.0 g / dL is regarded as important clinically (Non-patent Document 1).
　低アルブミン血症の原因としては、栄養障害によるアミノ酸供給不足や肝障害によるアルブミン合成の低下、ネフローゼ症候群等の腎不全や火傷等の外傷による血中からのアルブミンの喪失、心不全等による血漿の希釈、甲状腺機能亢進によるアルブミンなどのタンパク質の異化作用の亢進等によって引き起こされる。血中のアルブミンが低下することにより、血液の浸透圧が下がり、浮腫や腹水などを発症する。 Causes of hypoalbuminemia include lack of amino acid supply due to nutritional disorders and decreased albumin synthesis due to liver damage, loss of albumin from blood due to renal failure such as nephrotic syndrome and trauma such as burns, dilution of plasma due to heart failure, etc. It is caused by increased catabolism of proteins such as albumin due to hyperthyroidism. When albumin in the blood decreases, the osmotic pressure of the blood decreases and edema and ascites develop.
　低アルブミン血症の治療方法としては、高蛋白食による食事療法や、アミノ酸製剤又は血清アルブミンそのものを含む血液製剤による薬物療法などが行われている。 As a method for treating hypoalbuminemia, dietary therapy with a high protein diet, drug therapy with an amino acid preparation or a blood preparation containing serum albumin itself, and the like are performed.
　一方、本発明の有効成分である、モルヒナン骨格を有する化合物又はその薬理学的に許容される酸付加塩については、オピオイドκ受容体作動性を有すること並びに鎮痛薬及び利尿薬としての用途が報告されている（特許文献１）。 On the other hand, the compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof, which is an active ingredient of the present invention, has opioid κ receptor agonist activity and reports on its use as an analgesic and diuretic. (Patent Document 1).
　また、その他の用途としては、鎮咳薬（特許文献２）、脳細胞保護薬（特許文献３）、止痒薬（特許文献４）、低ナトリウム血症治療薬（特許文献５）、ＯＲＬ－１受容体拮抗薬（特許文献６）、神経因性疼痛治療薬（特許文献７）、角膜又は結膜用止痒薬（特許文献８）、精神神経疾患治療薬（特許文献９）、薬物依存治療薬（特許文献１０）、敗血症治療薬（特許文献１１）、多発性硬化症に伴う痒みの治療薬（特許文献１２）、統合失調症治療薬（特許文献１３）、皮膚性状改善治療薬（特許文献１４）、ジスキネジア治療薬（特許文献１５）、線維筋痛症治療薬（特許文献１６）、胆道疾患治療薬（特許文献１７）及び悪液質治療薬（特許文献１８）としての用途が報告されている。 Other uses include antitussives (Patent Document 2), brain cell protective drugs (Patent Document 3), antidiarrheals (Patent Document 4), hyponatremia drugs (Patent Document 5), ORL-1 Receptor antagonist (Patent Document 6), neuropathic pain therapeutic drug (Patent Document 7), corneal or conjunctival antidiarrheal drug (Patent Document 8), neuropsychiatric disease therapeutic drug (Patent Document 9), drug-dependent therapeutic drug (Patent document 10), septic drug (patent document 11), itch treatment drug associated with multiple sclerosis (patent document 12), schizophrenia drug (patent document 13), skin property improving drug (patent document) 14), dyskinesia treatment (patent document 15), fibromyalgia treatment (patent document 16), biliary tract disease treatment (patent document 17) and cachexia treatment (patent document 18). ing.
国際公開第９３／０１５０８１号International Publication No. 93/015081 国際公開第９５／００１１７８号International Publication No. 95/001178 国際公開第９５／００３３０７号International Publication No. 95/003307 国際公開第９８／０２３２９０号International Publication No. 98/023290 国際公開第９９／００５１４６号International Publication No. 99/005146 特開２０００－５３５７２号公報JP 2000-53572 A 国際公開第０１／０１４３８３号International Publication No. 01/014383 特開２００１－１６３７８４号公報JP 2001-163784 A 国際公開第０２／０７８７４４号International Publication No. 02/078744 国際公開第９９／０１１２８９号International Publication No. 99/011289 国際公開第０２／０８９８４５号International Publication No. 02/0889845 国際公開第０６／０９５８３６号International Publication No. 06/095836 国際公開第０９／００１７６４号International Publication No. 09/001764 国際公開第０９／０４４８８３号International Publication No. 09/044883 国際公開第０８／１３３２９７号International Publication No. 08/133297 特開２０１１－０７４０１８号公報JP 2011-074018 A 国際公開第１１／０９３４４１号International Publication No. 11/094411 国際公開第１２／１０５４７５号International Publication No. 12/105475
　しかしながら、現在、低アルブミン血症の改善に主に用いられているのは、静注用のアミノ酸製剤や血液製剤であるが、アミノ酸製剤の静脈内投与の場合は、酸塩基平衡失調、高アンモニア血症、アミノ酸不均衡、高窒素血漿等の副作用の発現に注意を払う必要があり、血液製剤もウイルス混入等の血液製剤特有のリスクがある。また、アルブミンそのものを含む製剤は胃でアルブミンが分解されるため、経口投与できないという問題がある。したがって、安全性が高く経口投与が可能な薬剤が望まれている。 However, currently, amino acid preparations and blood preparations for intravenous injection are mainly used to improve hypoalbuminemia. However, when amino acid preparations are administered intravenously, acid-base imbalance and high ammonia are used. Attention must be paid to the development of side effects such as blood glucose, amino acid imbalance, and high nitrogen plasma, and blood products also have risks inherent to blood products such as virus contamination. In addition, a preparation containing albumin itself has a problem that it cannot be administered orally because albumin is degraded in the stomach. Therefore, a drug that is highly safe and can be administered orally is desired.
　そこで本発明は、安全性が高く経口投与が可能な低アルブミン血症の改善剤を提供することを目的とする。 Therefore, an object of the present invention is to provide a hypoalbuminemia ameliorating agent that is highly safe and can be administered orally.
　本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、モルヒナン骨格を有する特定の化合物又はその薬理学的に許容される酸付加塩が、低アルブミン血症に対する優れた改善効果を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found that a specific compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof has an excellent improvement effect on hypoalbuminemia. As a result, the present invention has been completed.
　すなわち、本発明は、下記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を有効成分として含有する、低アルブミン血症の改善剤を提供する。
Figure JPOXMLDOC01-appb-C000002
 ［式中、点線と実線の二重線は、二重結合又は単結合を表し、Ｒ１は、炭素数４～７のシクロアルキルアルキルを表し、Ｒ２は、炭素数１～５の直鎖又は分岐アルキルを表し、Ｂは、－ＣＨ＝ＣＨ－を表す。] That is, the present invention provides a hypoalbuminemia-improving agent comprising a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
Figure JPOXMLDOC01-appb-C000002
 [In the formula, a double line consisting of a dotted line and a solid line represents a double bond or a single bond, R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms, and R 2 represents a straight chain having 1 to 5 carbon atoms. Alternatively, it represents a branched alkyl, and B represents —CH═CH—. ]
　Ｒ１は、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル又はシクロヘキシルメチルであり、Ｒ２は、メチル、エチル又はプロピルであることが好ましい。 R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl, R 2 is methyl, is preferably ethyl or propyl.
　Ｒ１は、シクロプロピルメチルであり、Ｒ２は、メチルであり、Ｂは、トランス型の－ＣＨ＝ＣＨ－であることがより好ましい。 More preferably, R 1 is cyclopropylmethyl, R 2 is methyl, and B is trans —CH═CH—.
　また、上記の低アルブミン血症の改善剤は、（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン又はその薬理学的に許容される酸付加塩が有効成分であることが最も好ましい。 The hypoalbuminemia ameliorating agent is (−)-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 most preferably the active ingredient.
　また、上記の低アルブミン血症の改善剤は、肝疾患に伴う低アルブミン血症の改善剤であることが好ましく、慢性肝疾患に伴う低アルブミン血症の改善剤であることがより好ましい。 In addition, the hypoalbuminemia-improving agent is preferably an agent for improving hypoalbuminemia associated with liver disease, and more preferably an agent for improving hypoalbuminemia associated with chronic liver disease.
　また本発明は、低アルブミン血症の改善に使用するための、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を提供する。低アルブミン血症は、肝疾患に伴う低アルブミン血症であることが好ましく、慢性肝疾患に伴う低アルブミン血症であることがより好ましい。 The present invention also provides a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for use in improving hypoalbuminemia. Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
　また本発明は、低アルブミン血症を改善するための、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の使用を提供する。低アルブミン血症は、肝疾患に伴う低アルブミン血症であることが好ましく、慢性肝疾患に伴う低アルブミン血症であることがより好ましい。 The present invention also provides use of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for improving hypoalbuminemia. Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
　また本発明は、低アルブミン血症の改善用医薬の製造における、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の使用を提供する。低アルブミン血症は、肝疾患に伴う低アルブミン血症であることが好ましく、慢性肝疾患に伴う低アルブミン血症であることがより好ましい。 The present invention also provides use of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof in the manufacture of a medicament for improving hypoalbuminemia. Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
　また本発明は、低アルブミン血症を改善する方法であって、改善の必要のある患者に有効量の上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を投与することを含む方法を提供する。低アルブミン血症は、肝疾患に伴う低アルブミン血症であることが好ましく、慢性肝疾患に伴う低アルブミン血症であることがより好ましい。 The present invention also relates to a method for improving hypoalbuminemia, comprising an effective amount of a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof for a patient in need of improvement. Is provided. Hypoalbuminemia is preferably hypoalbuminemia associated with liver disease, and more preferably hypoalbuminemia associated with chronic liver disease.
　本発明の低アルブミン血症の改善剤は、安全性が高く経口投与が可能な薬剤として、低アルブミン血症の治療に利用でき、特に肝疾患に伴う低アルブミン血症を改善できる。 The hypoalbuminemia-improving agent of the present invention is a highly safe drug that can be administered orally and can be used for the treatment of hypoalbuminemia, and can particularly improve hypoalbuminemia associated with liver disease.
低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する化合物１の作用を示す図（投与開始後１５日目：投与前値からの変化）である。It is a figure which shows the effect | action of the compound 1 with respect to the serum albumin level of the pruritus patient with the chronic liver disease which shows a low albumin level (15 days after administration start: Change from the value before administration). 低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する化合物１の作用を示す図（投与開始後１５日目：投与前及び後の血清アルブミン値）である。It is a figure which shows the effect | action of the compound 1 with respect to the serum albumin level of the pruritus patient with the chronic liver disease which shows a low albumin level (15 days after administration start: serum albumin level before and after administration). 低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する化合物１の作用を示す図（投与開始後２９日目：投与前値からの変化）である。It is a figure which shows the effect | action of the compound 1 with respect to the serum albumin level of the pruritus patient with the chronic liver disease which shows a low albumin level (29 days after administration start: Change from the value before administration). 低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する化合物１の作用を示す図（投与開始後２９日目：投与前及び後の血清アルブミン値）である。It is a figure which shows the effect | action of the compound 1 with respect to the serum albumin level of the pruritus patient with the chronic liver disease which shows a low albumin level (29 days after administration start: serum albumin level before and after administration). 低アルブミン血症モデルマウスにおける血漿中アルブミン値に対する化合物１の作用を示す図である。It is a figure which shows the effect | action of the compound 1 with respect to the albumin level in plasma in a hypoalbuminemia model mouse.
　本発明の低アルブミン血症の改善剤は、下記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を有効成分として含有することを特徴とする。
Figure JPOXMLDOC01-appb-C000003
 ［式中、点線と実線の二重線は、二重結合又は単結合を表し、Ｒ１は、炭素数４～７のシクロアルキルアルキルを表し、Ｒ２は、炭素数１～５の直鎖又は分岐アルキルを表し、Ｂは、－ＣＨ＝ＣＨ－を表す。] The agent for improving hypoalbuminemia of the present invention comprises a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
Figure JPOXMLDOC01-appb-C000003
 [In the formula, a double line consisting of a dotted line and a solid line represents a double bond or a single bond, R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms, and R 2 represents a straight chain having 1 to 5 carbon atoms. Alternatively, it represents a branched alkyl, and B represents —CH═CH—. ]
　Ｒ１は、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル又はシクロヘキシルメチルであり、Ｒ２は、メチル、エチル又はプロピルであることが好ましい。 R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl, R 2 is methyl, is preferably ethyl or propyl.
　Ｒ１は、シクロプロピルメチルであり、Ｒ２は、メチルであり、Ｂは、トランス型の－ＣＨ＝ＣＨ－であることがより好ましい。 More preferably, R 1 is cyclopropylmethyl, R 2 is methyl, and B is trans —CH═CH—.
　上記の低アルブミン血症の改善剤は、下記の式（ＩＩ）で示される化合物である、（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン又はその薬理学的に許容される酸付加塩が有効成分であることが最も好ましい。
Figure JPOXMLDOC01-appb-C000004
 The hypoalbuminemia-improving agent is a compound represented by the following formula (II): (−)-17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- Most preferably, [N-methyl-trans-3- (3-furyl) acrylamide] morphinan or a pharmacologically acceptable acid addition salt thereof is the active ingredient.
Figure JPOXMLDOC01-appb-C000004
　（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナンの一般名は、ナルフラフィンである。その塩酸塩であるナルフラフィン塩酸塩（（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン塩酸塩）は、止痒薬（効能・効果：血液透析患者又は慢性肝疾患患者におけるそう痒症の改善）として経口投与用の薬剤として既に用いられていることから、安全性が高く経口投与が可能な低アルブミン血症の改善剤として最も好ましい。 The general name of (−)-17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan is nalflaphine is there. Its hydrochloride, nalfurafine hydrochloride ((−)-17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide) ] Morphinan hydrochloride) is already used as a drug for oral administration as an antidiarrheal agent (efficacy / effect: improvement of pruritus in hemodialysis patients or chronic liver disease patients). It is most preferable as an agent for improving hypoalbuminemia that can be administered.
　「薬理学的に許容される酸付加塩」としては、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩若しくはリン酸塩等の無機酸塩、酢酸塩、乳酸塩、クエン酸塩、シュウ酸塩、グルタル酸塩、リンゴ酸塩、酒石酸塩、フマル酸塩、マンデル酸塩、マレイン酸塩、安息香酸塩若しくはフタル酸塩等の有機カルボン酸塩、又は、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩若しくはカンファースルホン酸塩等の有機スルホン酸塩等が挙げられる。その中でも、塩酸塩、臭化水素酸塩、リン酸塩、酒石酸塩又はメタンスルホン酸塩等が好ましく用いられる。 Examples of the “pharmacologically acceptable acid addition salt” include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, acetate, lactate, Organic carboxylates such as citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate, or methanesulfonic acid And organic sulfonates such as salts, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like. Of these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate, and the like are preferably used.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩は、国際公開第９３／０１５０８１号に記載の方法に従って製造することができる。 The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof can be produced according to the method described in WO 93/015081.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩は、低アルブミン血症の改善作用を有する。上記の低アルブミン血症の改善剤は、肝疾患に伴う低アルブミン血症の改善剤として好ましく用いられる。 The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an action to improve hypoalbuminemia. The above-mentioned hypoalbuminemia improving agent is preferably used as an improving agent for hypoalbuminemia associated with liver disease.
　「低アルブミン血症の改善剤」とは、低アルブミン血症の治療剤ともいい、低アルブミン血症の改善剤は低アルブミン血症の治療剤として用いることもできる。 The “hypoalbuminemia ameliorating agent” is also called a therapeutic agent for hypoalbuminemia, and the hypoalbuminemia ameliorating agent can also be used as a therapeutic agent for hypoalbuminemia.
　「低アルブミン血症」とは、血清アルブミン値が基準値より低い場合を意味する。臨床的には、血清アルブミン値が３．０ｇ／ｄＬという値が重要視されており、３．０ｇ／ｄＬ未満の低アルブミン血症では、死亡率が顕著に増加する（佐藤ら、厚生連医誌、２００９年、第１８巻、ｐ．２６－２８）。 “Hypoalbuminemia” means the case where the serum albumin level is lower than the reference value. Clinically, a serum albumin level of 3.0 g / dL is regarded as important, and mortality is significantly increased in hypoalbuminemia of less than 3.0 g / dL (Sato et al. 2009, Vol. 18, pp. 26-28).
　肝疾患としては、例えば、劇症肝炎、慢性若しくは急性肝炎、ウイルス性肝炎、脂肪肝、肝硬変、肝がん、アルコール性肝疾患、閉塞性黄疸、胆汁うっ滞又は原発性胆汁性肝硬変などが挙げられる。肝疾患としては、慢性肝疾患が好ましい。 Examples of liver diseases include fulminant hepatitis, chronic or acute hepatitis, viral hepatitis, fatty liver, cirrhosis, liver cancer, alcoholic liver disease, obstructive jaundice, cholestasis, or primary biliary cirrhosis. It is done. As the liver disease, chronic liver disease is preferable.
　上記の低アルブミン血症の改善剤は、哺乳動物（例えば、ヒト、マウス、ラット、ウサギ、イヌ、ネコ、ウシ、ウマ、ブタ又はサル等）に対して低アルブミン血症の改善剤として用いることができ、特にヒトに対して投与する場合に好ましく用いられる。 The above-mentioned hypoalbuminemia ameliorating agent is used as a hypoalbuminemia ameliorating agent for mammals (eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs or monkeys). Particularly, it is preferably used when administered to humans.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩は、医薬品用途にまで純化され、必要な安全性試験に合格した後、そのまま、又は公知の薬理学的に許容される酸、担体及び／又は賦形剤等と混合した医薬組成物として、経口的又は非経口的に投与することができる。経口投与における剤型は、錠剤、カプセル剤、口腔内崩壊剤、散剤又は顆粒剤等、非経口的な投与としては静脈内急速注入、静脈内持続注入、筋肉内注射、皮下注射、皮内注射、テープ剤又はパッチ剤等を選択できる。 The compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is purified to a pharmaceutical use, and after passing a necessary safety test, as it is or as a known pharmacological agent. Can be administered orally or parenterally as a pharmaceutical composition mixed with an acceptable acid, carrier and / or excipient. The dosage form for oral administration is tablets, capsules, buccal disintegrants, powders or granules, etc. For parenteral administration, intravenous rapid infusion, intravenous continuous infusion, intramuscular injection, subcutaneous injection, intradermal injection A tape agent or a patch agent can be selected.
　医薬組成物中の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の含量は、特に限定されず、一服用あたり通常０．１μｇ～１００ｍｇとなるように調製され得る。また、投与量は、患者の症状、年齢、性別及び体重並びに投与方法等に応じて適宜選択することができる。通常、成人一日当り、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の量として、０．１μｇ～２０ｍｇ、好ましくは１μｇ～１ｍｇ、より好ましくは１μｇ～４０μｇ程度を投与することができ、それぞれ一回又は数回に分けて投与することができる。 The content of the compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof in the pharmaceutical composition is not particularly limited, and is usually adjusted to be 0.1 μg to 100 mg per dose. obtain. The dosage can be appropriately selected according to the patient's symptoms, age, sex, body weight, administration method, and the like. Usually, the amount of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof per day for an adult is 0.1 μg to 20 mg, preferably 1 μg to 1 mg, more preferably 1 μg to About 40 μg can be administered, and each can be administered once or divided into several times.
　上記の低アルブミン血症の改善剤は、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を単独で、又は疾患の治療若しくは予防、症状の減少若しくは抑制に対して用いられる一種類又はそれ以上の薬剤と組み合わせて投与することができる。組み合わせる薬剤は、低分子化合物、高分子のタンパク質、ポリペプチド若しくは抗体又はワクチン等であってもよい。この際、組み合わせる薬剤と同時又は時間差をおいて投与することもできる。なお、組み合わせる方法はそれぞれの薬剤を併用しても良いし、合剤とすることも可能である。組み合わせる薬剤の投与量は、それぞれ臨床上用いられる用量を基準として適宜選択することができる。また、上記の低アルブミン血症の改善剤と、組み合わせる薬剤との配合比は、投与対象、投与対象の年齢、体重及び症状、投与時間、剤形、投与方法並びに薬剤の組み合わせ等により、適宜選択することができる。 The agent for improving hypoalbuminemia is a compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof alone, or treatment or prevention of a disease, reduction or suppression of symptoms. Can be administered in combination with one or more drugs used for. The drug to be combined may be a low molecular compound, a high molecular protein, a polypeptide or an antibody, a vaccine, or the like. At this time, the drugs to be combined can be administered simultaneously or with a time difference. In addition, the method of combining may use each chemical | medical agent together, and can also be set as a mixture. The dose of the drug to be combined can be appropriately selected based on the clinically used dose. The mixing ratio of the hypoalbuminemia-improving agent and the drug to be combined is appropriately selected depending on the subject to be administered, age of the subject to be administered, body weight and symptom, administration time, dosage form, administration method, drug combination, etc. can do.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩が、低アルブミン血症の改善に有効であることは、例えば、低アルブミン値を示す患者に上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を投与して、投与前後の血清アルブミン値を比較することで評価できる。又は、低アルブミン血症状態にあるモデル動物を用いて評価することもできる。 The fact that the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is effective for the improvement of hypoalbuminemia is, for example, the above-mentioned general Evaluation can be made by administering a compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof, and comparing serum albumin levels before and after administration. Alternatively, it can be evaluated using a model animal in a hypoalbuminemia state.
　以下の実施例により、本発明をさらに詳細に説明するが、本発明は、これらによって限定されるものではない。 The present invention will be described in more detail by the following examples, but the present invention is not limited thereto.
　（実施例１）低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する作用：
　低アルブミン値を示す慢性肝疾患によるそう痒症患者の血清アルブミン値に対する、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の作用を評価した。 (Example 1) Effect on serum albumin level of pruritus patients with chronic liver disease exhibiting low albumin level:
The effect of the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof on serum albumin levels of pruritus patients with chronic liver disease exhibiting low albumin levels was evaluated.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩として、（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン塩酸塩（以下の化合物１）を用いた。
Figure JPOXMLDOC01-appb-C000005
 As the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, (−)-17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β -[N-methyl-trans-3- (3-furyl) acrylamide] morphinan hydrochloride (compound 1 below) was used.
Figure JPOXMLDOC01-appb-C000005
　慢性肝疾患によるそう痒症患者（以下、被験者）に、化合物１を２．５μｇ／日又は０μｇ／日（０μｇ／日は、化合物１を含まない偽薬；以下、偽薬）をそれぞれの被験者に経口投与し、対照実験を行った。投与開始前の血清アルブミン値が３．０ｇ／ｄＬ以下を示す被験者について、投与開始前と投与開始後１５日目及び２９日目の血清アルブミン値を比較した。血清アルブミン値はＢＣＧ法にて測定した。統計解析は、対応のないｔ検定（ｕｎｐａｉｒｅｄ　ｔ検定）を用いた。統計解析の結果、Ｐ値が０．０５未満の場合に統計学的に有意であると判断した。 Patients with pruritus due to chronic liver disease (hereinafter referred to as subjects) were orally administered Compound 1 at 2.5 μg / day or 0 μg / day (where 0 μg / day is a placebo that does not contain Compound 1; hereinafter referred to as a placebo). A control experiment was conducted. For subjects whose serum albumin level before the start of administration was 3.0 g / dL or less, the serum albumin levels before the start of administration and on the 15th and 29th days after the start of administration were compared. Serum albumin levels were measured by the BCG method. Statistical analysis used an unpaired t-test (unpaired t-test). As a result of statistical analysis, when the P value was less than 0.05, it was judged to be statistically significant.
　投与開始後１５日目の結果を図１及び図２に示す。図１の縦軸は、被験者に化合物１（２．５μｇ／日）又は偽薬を投与する前の血清アルブミン値（ｇ／ｄＬ）を基準値として、化合物１（２．５μｇ／日）又は偽薬を投与開始後１５日目の血清アルブミン値（ｇ／ｄＬ）が投与前の基準値からどの程度変化したかの変化値を示し、横軸の「偽薬」は偽薬投与群、「化合物１」は化合物１投与群を示す。また、図中の記号＊（アスタリスク）は、偽薬投与群と比較して統計学的に有意（対応のないｔ検定；Ｐ＜０．０５）であることを示す。 The results on the 15th day after the start of administration are shown in FIGS. The vertical axis in FIG. 1 shows the compound 1 (2.5 μg / day) or placebo as the reference value of the serum albumin level (g / dL) before administering Compound 1 (2.5 μg / day) or placebo to the subject. 15 shows the change in serum albumin level (g / dL) on the 15th day after the start of administration, indicating how much it has changed from the reference value before administration, where “placebo” on the horizontal axis is the placebo-administered group, and “compound 1” is the compound One administration group is shown. In addition, the symbol * (asterisk) in the figure indicates that it is statistically significant (unpaired t-test; P <0.05) compared to the placebo-administered group.
　また、図２の縦軸は、化合物１（２．５μｇ／日）又は偽薬を、それぞれの被験者に投与する前の血清アルブミン値（ｇ／ｄＬ）及び投与開始後１５日目の血清アルブミン値（ｇ／ｄＬ）を示し、左図の「偽薬」は偽薬投与群、右図の「化合物１」は化合物１投与群を示す。図２は、「偽薬」又は「化合物１」を投与する前及び投与開始後１５日目の各被験者の血清アルブミン値の点を一本の直線で繋いだ図であり、各被験者の投与前後の血清アルブミン値の変動の様子を示す。 The vertical axis in FIG. 2 shows the serum albumin value (g / dL) before administration of Compound 1 (2.5 μg / day) or placebo to each subject and the serum albumin value 15 days after the start of administration ( g / dL), “placebo” in the left figure represents the placebo-administered group, and “compound 1” in the right figure represents the compound-1 administration group. FIG. 2 is a diagram in which serum albumin levels of each subject before administration of “placebo” or “Compound 1” and 15 days after the start of administration are connected by a single straight line. It shows how the serum albumin level fluctuates.
　投与開始後２９日目の結果を図３及び図４に示す。図３の縦軸は、被験者に化合物１（２．５μｇ／日）又は偽薬を投与する前の血清アルブミン値（ｇ／ｄＬ）を基準値として、化合物１（２．５μｇ／日）又は偽薬を投与開始後２９日目の血清アルブミン値（ｇ／ｄＬ）が投与前の基準値からどの程度変化したかの変化値を示し、横軸の「偽薬」は偽薬投与群、「化合物１」は化合物１投与群を示す。また、図中の記号＊（アスタリスク）は、偽薬投与群と比較して統計学的に有意（対応のないｔ検定；Ｐ＜０．０５）であることを示す。 The results on the 29th day after the start of administration are shown in FIGS. The vertical axis in FIG. 3 shows compound 1 (2.5 μg / day) or placebo as the reference value, which is the serum albumin level (g / dL) before administering Compound 1 (2.5 μg / day) or placebo to the subject. The serum albumin level (g / dL) on the 29th day after the start of administration shows how much it has changed from the reference value before administration. The “placebo” on the horizontal axis is the placebo-administered group, and “compound 1” is the compound One administration group is shown. In addition, the symbol * (asterisk) in the figure indicates that it is statistically significant (unpaired t-test; P <0.05) compared to the placebo-administered group.
　また、図４の縦軸は、化合物１（２．５μｇ／日）又は偽薬を、それぞれの被験者に投与する前の血清アルブミン値（ｇ／ｄＬ）及び投与開始後２９日目の血清アルブミン値（ｇ／ｄＬ）を示し、左図の「偽薬」は偽薬投与群、右図の「化合物１」は化合物１投与群を示す。図４は、「偽薬」又は「化合物１」を投与する前及び投与開始後２９日目の各被験者の血清アルブミン値の点を一本の直線で繋いだ図であり、各被験者の投与前後の血清アルブミン値の変動の様子を示す。 The vertical axis in FIG. 4 indicates the serum albumin value (g / dL) before administration of Compound 1 (2.5 μg / day) or placebo to each subject and the serum albumin value on the 29th day after administration ( g / dL), “placebo” in the left figure represents the placebo-administered group, and “compound 1” in the right figure represents the compound-1 administration group. FIG. 4 is a diagram in which serum albumin levels of each subject before administration of “placebo” or “Compound 1” and 29 days after the start of administration are connected by a single straight line. It shows how the serum albumin level fluctuates.
　図１～４に示した結果から、投与開始後１５日目及び２９日目のいずれにおいても、化合物１投与群の血清アルブミン値は増加し、偽薬投与群の血清アルブミン変化値と比較して化合物１投与群の血清アルブミン変化値は統計学的に有意に増大した。したがって、化合物１の投与により低アルブミン血症の改善作用が示された。なお、正常血清アルブミン値を示す被験者の場合には、化合物１を投与しても血清アルブミン値の変動は認められなかった。 From the results shown in FIGS. 1 to 4, the serum albumin level in the compound 1 administration group increased on both the 15th and 29th days after the start of administration, and the compound compared with the serum albumin change value in the placebo administration group. The serum albumin change value of one administration group increased statistically significantly. Therefore, administration of Compound 1 showed an improvement effect on hypoalbuminemia. In the case of subjects exhibiting normal serum albumin levels, no change in serum albumin levels was observed even when Compound 1 was administered.
　したがって、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩は、低アルブミン血症を改善する作用を有することが示された。 Therefore, it was shown that the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof has an action of improving hypoalbuminemia.
　（実施例２）低アルブミン血症モデルマウスに対する作用：
　Ｈｕｙｎｈらの方法（Ｍｏｌｅｃｕｌａｒ　ｃａｎｃｅｒ　ｔｈｅｒａｐｅｕｔｉｃｓ、２００７年、第６巻、Ｐ．２９５９－２９６６）に従って、卵巣癌細胞の腹膜播種による低アルブミン血症モデルマウスを作製し、低アルブミン血症に対する、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩の作用を評価した。 (Example 2) Action on hypoalbuminemia model mice:
According to the method of Huynh et al. (Molecular cancer therapeutics, 2007, Vol. 6, P. 2959-2966), hypoalbuminemia model mice by peritoneal seeding of ovarian cancer cells were prepared, The action of the compound represented by the formula (I) or a pharmacologically acceptable acid addition salt thereof was evaluated.
　上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩として、（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン塩酸塩（以下の化合物１）を用いた。
Figure JPOXMLDOC01-appb-C000006
 As the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof, (−)-17- (cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β -[N-methyl-trans-3- (3-furyl) acrylamide] morphinan hydrochloride (compound 1 below) was used.
Figure JPOXMLDOC01-appb-C000006
　ヒト卵巣癌細胞株ＯＶ－９０（ＣＲＬ－１１７３２；Ａｍｅｒｉｃａｎ　ｔｙｐｅ　ｃｕｌｔｕｒｅ　ｃｏｌｌｅｃｔｉｏｎ）を、１５％ウシ胎仔血清を含むＭＥＭ培地を用いて、３７℃、５％ＣＯ２インキュベータで培養し維持した。ＯＶ－９０細胞をトリプシン／ＥＤＴＡにて剥離し回収した後、ＰＢＳ（－）で洗浄した。ＯＶ－９０細胞をＰＢＳ（－）に懸濁して、ＯＶ－９０細胞懸濁液を調製した。雌性ＳＣＩＤマウス（Ｃ．Ｂ．－１７/ｌｃｒ－ｓｃｉｄ／ｓｃｉｄ－ｊｃｌ、７～８週齢；日本クレア株式会社）の腹腔内に、ＯＶ－９０細胞懸濁液（５×１０６細胞／匹）を移植した。なお、ヒト卵巣癌細胞を移植しなかった同一週齢の雌性ＳＣＩＤマウスを、対照群とした（ｎ＝３）。 Human ovarian cancer cell line OV-90 (CRL-11732; American type culture collection) was cultured and maintained in a MEM medium containing 15% fetal calf serum at 37 ° C. in a 5% CO 2 incubator. OV-90 cells were detached and collected with trypsin / EDTA, and then washed with PBS (−). OV-90 cell suspension was prepared by suspending OV-90 cells in PBS (−). An OV-90 cell suspension (5 × 10 6 cells / mouse) was intraperitoneally injected into female SCID mice (CB-17 / lcr-scid / scid-jcl, 7-8 weeks old; CLEA Japan, Inc.). ) Was transplanted. In addition, the female SCID mouse of the same age which did not transplant a human ovarian cancer cell was made into the control group (n = 3).
　細胞懸濁液移植の３７日後から化合物１の投与を開始した（この日を投与開始日とする）。化合物１の投与液は、生理食塩水に溶解して調製し、３０μｇ／ｋｇの用量で、皮下隔日投与した（ｎ＝６；化合物１投与群）。溶媒投与群として、化合物１の代わりに、同容量の溶媒を同様に投与した（ｎ＝７）。 Administration of Compound 1 was started 37 days after cell suspension transplantation (this day is taken as the administration start date). Compound 1 administration solution was prepared by dissolving in physiological saline and administered subcutaneously every other day at a dose of 30 μg / kg (n = 6; Compound 1 administration group). As a solvent administration group, the same volume of solvent was administered in the same manner instead of Compound 1 (n = 7).
　４回目の投与が終了した１日後（投与開始日から４４日後）に、対照群、溶媒投与群及び化合物１投与群の各個体の腋下静脈からイソフルラン吸入麻酔下にて採血した。採取した血液に抗凝固剤としてＥＤＴＡを添加した後、血漿を得た。 One day after the completion of the fourth administration (44 days after the start of administration), blood was collected under the anesthesia by inhalation of isoflurane from the arm of each individual of the control group, the solvent administration group and the compound 1 administration group. Plasma was obtained after adding EDTA as an anticoagulant to the collected blood.
　血漿中のアルブミン濃度測定は、生化学分析装置（ＤＲＹ－ＣＨＥＭ　４０００Ｓ、富士フィルム）により測定した。血漿は一旦凍結保存したものを測定当日に融解し、原液１０μＬを富士ドライケムスライド（ＡＬＢ－ＰＳ、富士フィルム株式会社）に滴下し、マニュアルに従いアルブミン濃度を測定した。 The plasma albumin concentration was measured with a biochemical analyzer (DRY-CHEM 4000S, Fuji Film). Plasma that had been frozen and stored once was thawed on the day of the measurement, 10 μL of the stock solution was dropped onto Fuji Dry Chemslide (ALB-PS, Fuji Film Co., Ltd.), and the albumin concentration was measured according to the manual.
　統計解析は、溶媒投与群と化合物１投与群との間の２群間で行い、等分散性の検定（Ｆ検定）によりＳｔｕｄｅｎｔのｔ検定を行った。統計解析の結果、Ｐ値が０．０５未満の場合に統計学的に有意であると判断した。 Statistical analysis was performed between two groups between the solvent-administered group and the compound 1-administered group, and Student's t-test was performed by an equal dispersion test (F test). As a result of statistical analysis, when the P value was less than 0.05, it was judged to be statistically significant.
　その結果を図５に示す。図５の縦軸は、血漿中アルブミン濃度（ｇ／ｄＬ）（平均値±標準誤差；ｎ＝３～７）を示し、横軸の「対照」は対照群、「溶媒」は溶媒投与群、「化合物１」は化合物１投与群を示す。また、図中の記号＊（アスタリスク）は、溶媒投与群と比較して統計学的に有意（Ｓｔｕｄｅｎｔのｔ検定；Ｐ＜０．０５）であることを示す。 The result is shown in FIG. The vertical axis in FIG. 5 shows the albumin concentration in plasma (g / dL) (mean ± standard error; n = 3 to 7), “control” on the horizontal axis is the control group, “solvent” is the solvent administration group, “Compound 1” indicates a compound 1 administration group. Moreover, the symbol * (asterisk) in the figure indicates that it is statistically significant (Student's t test; P <0.05) compared to the solvent administration group.
　溶媒投与群は、対照群と比較して血漿中アルブミン濃度の低下が認められ、低アルブミン血症であることが示された。化合物１の投与により、この血漿中アルブミン濃度の低下は抑制された（溶媒投与群の血漿中アルブミン濃度と比較して化合物１投与群の血漿中アルブミン濃度は、統計学的に有意に増大した（Ｐ＜０．０５））。したがって、化合物１は、低アルブミン血症を改善することが示された。 In the solvent administration group, a decrease in plasma albumin concentration was observed compared to the control group, indicating hypoalbuminemia. The decrease in plasma albumin concentration was suppressed by administration of Compound 1 (the plasma albumin concentration in the Compound 1 administration group was statistically significantly increased compared to the plasma albumin concentration in the vehicle administration group ( P <0.05)). Thus, Compound 1 was shown to improve hypoalbuminemia.
　したがって、上記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩は、慢性肝疾患とは異なる疾患である卵巣癌細胞の腹膜播種による低アルブミン血症においても、低アルブミン血症を改善する作用を有することが示された。 Therefore, the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is hypoalbuminemia caused by peritoneal dissemination of ovarian cancer cells, which is a disease different from chronic liver disease. It has been shown to have an effect of improving hypoalbuminemia.
　本発明は、医薬の分野において、低アルブミン血症の改善剤として利用できる。
  The present invention can be used as an agent for improving hypoalbuminemia in the field of medicine.

Claims (5)

  1. 　下記の一般式（Ｉ）で示される化合物又はその薬理学的に許容される酸付加塩を有効成分として含有する、低アルブミン血症の改善剤。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、点線と実線の二重線は、二重結合又は単結合を表し、Ｒ１は、炭素数４～７のシクロアルキルアルキルを表し、Ｒ２は、炭素数１～５の直鎖又は分岐アルキルを表し、Ｂは、－ＣＨ＝ＣＨ－を表す。]     An agent for improving hypoalbuminemia, comprising a compound represented by the following general formula (I) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, a double line consisting of a dotted line and a solid line represents a double bond or a single bond, R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms, and R 2 represents a straight chain having 1 to 5 carbon atoms. Alternatively, it represents a branched alkyl, and B represents —CH═CH—. ]
  2. 　Ｒ１は、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル又はシクロヘキシルメチルであり、Ｒ２は、メチル、エチル又はプロピルである、請求項１記載の低アルブミン血症の改善剤。 R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl, R 2 is methyl, ethyl or propyl, improving agents of hypoalbuminemia of claim 1.
  3. 　Ｒ１は、シクロプロピルメチルであり、Ｒ２は、メチルであり、Ｂは、トランス型の－ＣＨ＝ＣＨ－である、請求項１記載の低アルブミン血症の改善剤。 The agent for improving hypoalbuminemia according to claim 1 , wherein R 1 is cyclopropylmethyl, R 2 is methyl, and B is trans form -CH = CH-.
  4. 　（－）－１７－（シクロプロピルメチル）－３，１４β－ジヒドロキシ－４，５α－エポキシ－６β－［Ｎ－メチル－トランス－３－（３－フリル）アクリルアミド］モルヒナン又はその薬理学的に許容される酸付加塩が有効成分である、請求項１記載の低アルブミン血症の改善剤。 (−)-17- (Cyclopropylmethyl) -3,14β-dihydroxy-4,5α-epoxy-6β- [N-methyl-trans-3- (3-furyl) acrylamide] morphinan or a pharmacologically acceptable salt thereof The agent for improving hypoalbuminemia according to claim 1, wherein the acid addition salt is an active ingredient.
  5. 　肝疾患に伴う低アルブミン血症の改善剤である、請求項１～４のいずれか一項記載の低アルブミン血症の改善剤。 The agent for improving hypoalbuminemia according to any one of claims 1 to 4, which is an agent for improving hypoalbuminemia associated with liver disease.
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WO2022004788A1 (en) 2020-06-30 2022-01-06 東レ株式会社 Ameliorating agent or prophylactic agent for muscle weakness symptom in disease or syndrome associated with metabolic disorder
KR20230031207A (en) 2020-06-30 2023-03-07 도레이 카부시키가이샤 Agents for improving or preventing symptoms of muscle weakness in diseases or syndromes accompanying metabolic abnormalities

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