JP6702184B2 - Hypoalbuminemia improver - Google Patents

Description

  The present invention relates to an agent for improving hypoalbuminemia.

  Serum albumin is a protein synthesized in the liver and accounts for about 50 to 65% of proteins in blood. The standard value (normal value) of serum albumin concentration in blood is about 3.5 to 5.3 g/dL although there is a difference due to the difference in the measuring method, and when albumin concentration is lower than the standard value, low albumin level is obtained. The value is 3.0 g/dL, which is clinically regarded as important (Non-patent document 1).

  Hypoalbuminemia is caused by insufficient nutritional supply of amino acids due to malnutrition and decreased albumin synthesis due to liver damage, loss of albumin from the blood due to renal failure such as nephrotic syndrome, trauma such as burns, and plasma dilution due to heart failure. , Is caused by enhancement of catabolism of proteins such as albumin due to hyperthyroidism. When albumin in the blood is lowered, the osmotic pressure of blood is lowered, and edema, ascites, etc. occur.

  As a treatment method for hypoalbuminemia, diet therapy with a high protein diet, drug therapy with a blood product containing an amino acid preparation or serum albumin itself, and the like are performed.

  On the other hand, with regard to the compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof, which is the active ingredient of the present invention, it is reported that it has opioid κ receptor agonism and its use as an analgesic and a diuretic. (Patent Document 1).

  In addition, as other uses, an antitussive drug (Patent Document 2), a brain cell protective drug (Patent Document 3), an antipruritic drug (Patent Document 4), a hyponatremia therapeutic drug (Patent Document 5), ORL-1 Receptor antagonist (Patent Document 6), neuropathic pain therapeutic drug (Patent Document 7), corneal or conjunctival antipruritic drug (Patent Document 8), neuropsychiatric disease therapeutic drug (Patent Document 9), drug dependence therapeutic drug (Patent Document 10), therapeutic drug for sepsis (Patent Document 11), therapeutic drug for pruritus associated with multiple sclerosis (Patent Document 12), therapeutic drug for schizophrenia (Patent Document 13), therapeutic drug for improving skin properties (Patent Document) 14), therapeutic agents for dyskinesia (Patent Document 15), therapeutic agents for fibromyalgia (Patent Document 16), therapeutic agents for biliary tract diseases (Patent Document 17) and cachexia therapeutic agents (Patent Document 18). ing.

International Publication No. 93/015081 International Publication No. 95/001178 International Publication No. 95/003307 International Publication No. 98/023290 International Publication No. 99/005146 JP 2000-53572 A International Publication No. 01/014383 JP 2001-163784 A International Publication No. 02/078744 International Publication No. 99/011289 International Publication No. 02/089845 International Publication No. 06/095836 International Publication No. 09/001764 International Publication No. 09/044883 International Publication No. 08/133297 JP, 2011-074018, A International Publication No. 11/093441 International Publication No. 12/105475

Sato et al., Koseiren Medical Journal, 2009, Vol. 18, p. 26-28

  At present, however, intravenous amino acid preparations and blood preparations are mainly used to improve hypoalbuminemia, but in the case of intravenous administration of amino acid preparations, acid-base imbalance and high ammonia content are high. It is necessary to pay attention to the occurrence of side effects such as blood pressure, amino acid imbalance, and high-nitrogen plasma, and blood products have risks peculiar to blood products such as virus contamination. In addition, a preparation containing albumin itself has a problem that it cannot be orally administered because albumin is decomposed in the stomach. Therefore, a highly safe drug that can be orally administered is desired.

  Therefore, an object of the present invention is to provide an agent for improving hypoalbuminemia which is highly safe and can be orally administered.

  The present inventors have conducted extensive studies to solve the above problems, and as a result, a specific compound having a morphinan skeleton or a pharmaceutically acceptable acid addition salt thereof has an excellent improving effect on hypoalbuminemia. The present invention has been completed and the present invention has been completed.

That is, the present invention provides an agent for improving hypoalbuminemia, which comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
[In the formula, a double line 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 is a straight chain having 1 to 5 carbon atoms. Or represents branched alkyl, and B represents -CH=CH-. ]

It is preferred that R ¹ is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl and R ² is methyl, ethyl or propyl.

More preferably, R ¹ is cyclopropylmethyl, R ² is methyl, and B is trans —CH═CH—.

  Further, the above-mentioned agent for improving hypoalbuminemia is (−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3 Most preferably, -furyl)acrylamide]morphinan or a pharmaceutically acceptable acid addition salt thereof is the active ingredient.

  Further, the above-mentioned agent for improving hypoalbuminemia 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 pharmaceutically 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 the use of the compound represented by the above general formula (I) or a pharmaceutically 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 the use of the compound represented by the general formula (I) or a pharmaceutically 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, which is an effective amount of a compound represented by the above general formula (I) or a pharmaceutically 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.

  INDUSTRIAL APPLICABILITY The hypoalbuminemia-improving agent of the present invention is a highly safe and orally administrable drug and can be used for the treatment of hypoalbuminemia, and in particular, can improve hypoalbuminemia associated with liver disease.

It is a figure which shows the effect of the compound 1 with respect to the serum albumin level of the pruritus patient with chronic liver disease which shows a low albumin level (the 15th day after administration: change from the value before administration). 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 chronic liver disease which shows a low albumin level (15th day after administration: serum albumin level before and after administration). 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 chronic liver disease which shows a low albumin level (29 days after administration start: change from the value before administration). 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 chronic liver disease which shows a low albumin level (29th day after administration start: serum albumin level before and after administration). It is a figure which shows the effect of the compound 1 with respect to the plasma albumin level in a hypoalbuminemia model mouse.

The agent for improving hypoalbuminemia of the present invention is characterized by containing a compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
[In the formula, a double line 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 is a straight chain having 1 to 5 carbon atoms. Or represents branched alkyl, and B represents -CH=CH-. ]

It is preferred that R ¹ is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl and R ² is methyl, ethyl or propyl.

More preferably, R ¹ is cyclopropylmethyl, R ² is methyl, and B is trans —CH═CH—.

The above-described 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 pharmaceutically acceptable acid addition salt thereof is the active ingredient.

  The general name for (−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan is nalfurafine. is there. Its hydrochloride salt, nalfurafine hydrochloride ((−)-17-(cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamide] Morphinan hydrochloride) is a highly safe oral drug because it is already used as an antipruritic drug (potency/effect: improvement of pruritus in hemodialysis patients or patients with chronic liver disease). Most preferred as an administrable agent for improving hypoalbuminemia.

  Examples of the "pharmacologically acceptable acid addition salt" include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates and other inorganic acid salts, acetates, lactates, Organic carboxylic acid salts such as citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate, or methanesulfonic acid Examples thereof include salts, organic sulfonates such as ethane sulfonate, benzene sulfonate, p-toluene sulfonate, and camphor sulfonate. Among them, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate and the like are preferably used.

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

  The compound represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an action of improving hypoalbuminemia. The above-mentioned agent for improving hypoalbuminemia is preferably used as an agent for improving hypoalbuminemia associated with liver disease.

  The "improving agent for hypoalbuminemia" is also called a therapeutic agent for hypoalbuminemia, and the improving agent for hypoalbuminemia can also be used as a therapeutic agent for hypoalbuminemia.

  "Hypoalbuminemia" means that the serum albumin level is lower than the standard value. Clinically, a serum albumin level of 3.0 g/dL is regarded as important, and the mortality rate increases remarkably in hypoalbuminemia of less than 3.0 g/dL (Sato et al. , 2009, Vol. 18, p.26-28).

  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. Be done. Chronic liver disease is preferred as the liver disease.

  Use of the above-described hypoalbuminemia-improving agent for mammals (for example, human, mouse, rat, rabbit, dog, cat, cow, horse, pig or monkey) as hypoalbuminemia-improving agent It can be used, and 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 passed a necessary safety test, as it is or after a known pharmacological action. Can be orally or parenterally administered as a pharmaceutical composition mixed with a pharmaceutically acceptable acid, a carrier and/or an excipient. The dosage form for oral administration is tablets, capsules, orally disintegrating agents, powders or granules. Parenteral administration includes rapid intravenous infusion, continuous intravenous infusion, intramuscular injection, subcutaneous injection, and 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 pharmaceutically acceptable acid addition salt thereof in the pharmaceutical composition is not particularly limited, and is usually adjusted to 0.1 μg to 100 mg per dose. obtain. Further, the dose can be appropriately selected according to the symptoms, age, sex and weight of the patient, the administration method and the like. Usually, the amount of the compound represented by the general formula (I) or a pharmaceutically acceptable acid addition salt thereof per day for adults 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 in several divided doses.

  The above-mentioned hypoalbuminemia-improving agent is a compound represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof alone or for treating or preventing a disease, reducing or suppressing a symptom. Can be administered in combination with one or more agents used for The drug to be combined may be a low molecular weight compound, a high molecular weight protein, a polypeptide or an antibody, a vaccine or the like. At this time, the drug to be combined can be administered at the same time or at a time lag. In addition, as a method of combining, the respective drugs may be used in combination, or a combination drug may be used. The dose of the drug to be combined can be appropriately selected based on the dose clinically used. Further, the compounding ratio of the above-described hypoalbuminemia-improving agent and the drug to be combined is appropriately selected depending on the administration subject, age, weight and symptoms of administration subject, administration time, dosage form, administration method, combination of agents, etc. can do.

  The fact that the compound represented by the above general formula (I) or a pharmacologically acceptable acid addition salt thereof is effective in improving hypoalbuminemia means that, for example, in patients with low albumin levels, the above general It can be evaluated by administering the compound represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof, and comparing the serum albumin levels before and after administration. Alternatively, it can be evaluated using a model animal in a hypoalbuminemia state.

  The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

(Example 1) Effect on serum albumin level in pruritus patients with chronic liver disease showing low albumin level:
The effect of the compound represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof on the serum albumin level of pruritus patients with chronic liver disease showing low albumin level was evaluated.

As the compound represented by the above general formula (I) or a pharmaceutically 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.

  Compound 1 is orally administered to pruritus patients due to chronic liver disease (hereinafter referred to as subjects) at 2.5 μg/day or 0 μg/day (0 μg/day is a placebo without compound 1; hereinafter referred to as placebo). It was administered and a control experiment was conducted. The serum albumin levels before the start of administration and on the 15th day and the 29th day after the start of administration were compared for the subjects whose serum albumin level before the start of administration was 3.0 g/dL or less. The serum albumin value was measured by the BCG method. For the statistical analysis, unpaired t-test (unpaired t-test) was used. As a result of statistical analysis, it was judged to be statistically significant when the P value was less than 0.05.

  The results 15 days after the start of administration are shown in FIGS. 1 and 2. The vertical axis of FIG. 1 indicates Compound 1 (2.5 μg/day) or placebo with reference to the serum albumin level (g/dL) before administration of Compound 1 (2.5 μg/day) or placebo to the subject. The change value of the serum albumin level (g/dL) on the 15th day after the start of administration was changed from the reference value before administration. “Placebo” on the horizontal axis represents the placebo group, “Compound 1” represents the compound. 1 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.

  The vertical axis of FIG. 2 shows the serum albumin level (g/dL) before administration of Compound 1 (2.5 μg/day) or placebo to each subject and the serum albumin level 15 days after the start of administration ( g/dL), "placebo" in the left figure shows the placebo administration group, and "compound 1" in the right figure shows the compound 1 administration group. FIG. 2 is a diagram in which the points of the serum albumin level of each subject before administration of “placebo” or “Compound 1” and on the 15th day after the start of administration are connected by one straight line, and before and after administration of each subject. The change of the serum albumin level is shown.

  The results on day 29 after the start of administration are shown in FIGS. 3 and 4. The vertical axis of FIG. 3 indicates Compound 1 (2.5 μg/day) or placebo with reference to the serum albumin level (g/dL) before administration of Compound 1 (2.5 μg/day) or placebo to the subject. The change value of the serum albumin level (g/dL) on the 29th day after the start of administration was changed from the reference value before administration. “Placebo” on the horizontal axis represents the placebo group, “Compound 1” represents the compound. 1 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.

  The vertical axis of FIG. 4 indicates the serum albumin level (g/dL) before administration of Compound 1 (2.5 μg/day) or placebo to each subject and the serum albumin level 29 days after the start of administration ( g/dL), "placebo" in the left figure shows the placebo administration group, and "compound 1" in the right figure shows the compound 1 administration group. FIG. 4 is a diagram in which points of serum albumin level of each subject before and after administration of “placebo” or “Compound 1” are connected by one straight line, and before and after administration of each subject. The change of the serum albumin level is shown.

  From the results shown in FIGS. 1 to 4, the serum albumin level of the compound 1-administered group increased on both the 15th day and the 29th day after the start of administration, and the compound was compared with the serum albumin change value of the placebo-administered group. The change value of serum albumin in the 1-administered group was statistically significantly increased. Therefore, administration of Compound 1 was shown to improve hypoalbuminemia. In addition, in the case of a subject showing a normal serum albumin level, no change in the serum albumin level was observed even after administration of Compound 1.

  Therefore, it was shown that the compound represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof has an action of improving hypoalbuminemia.

(Example 2) Action on hypoalbuminemia model mouse:
According to the method of Huynh et al. (Molecular cancer therapeutics, 2007, Volume 6, P. 2959-2966), a hypoalbuminemia model mouse was prepared by peritoneal dissemination of ovarian cancer cells, and the above-mentioned general albuminemia against hypoalbuminemia was prepared. The action of the compound represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof was evaluated.

As the compound represented by the above general formula (I) or a pharmaceutically 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.

The human ovarian cancer cell line OV-90 (CRL-11732; American type culture collection) was cultured and maintained in a MEM medium containing 15% fetal bovine serum at 37° C. in a 5% CO ₂ incubator. OV-90 cells were detached with trypsin/EDTA, collected, and then washed with PBS(-). OV-90 cells were suspended in PBS(-) to prepare an OV-90 cell suspension. Female SCID mice (CB-17/lcr-scid/scid-jcl, 7-8 weeks old; CLEA Japan, Inc.) were intraperitoneally injected into an OV-90 cell suspension (5×10 ⁶ cells/mouse). ) Was transplanted. In addition, female SCID mice of the same week without human ovarian cancer cells transplanted were used as a control group (n=3).

  The administration of Compound 1 was started 37 days after the cell suspension transplantation (this day is the administration start date). The administration liquid of Compound 1 was prepared by dissolving it in physiological saline, and was 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 similarly administered instead of Compound 1 (n=7).

  One day after the end of the fourth administration (44 days after the administration start date), blood was collected from the axillary vein of each individual in the control group, the solvent administration group, and the compound 1 administration group under isoflurane inhalation anesthesia. Plasma was obtained after adding EDTA as an anticoagulant to the collected blood.

  The albumin concentration in plasma was measured by a biochemical analyzer (DRY-CHEM 4000S, Fuji Film). The plasma was once frozen and stored, then thawed on the day of the measurement, and 10 μL of the stock solution was dropped on a Fuji Dry Chem Slide (ALB-PS, Fuji Film Co., Ltd.), and the albumin concentration was measured according to the manual.

  Statistical analysis was performed between the two groups, a solvent administration group and a compound 1 administration group, and Student's t-test was performed by a homoscedasticity test (F test). As a result of statistical analysis, it was judged to be statistically significant when the P value was less than 0.05.

  The result is shown in FIG. The vertical axis of FIG. 5 represents the plasma albumin concentration (g/dL) (mean±standard error; n=3 to 7), the “control” on the horizontal axis is the control group, the “solvent” is the solvent administration group, “Compound 1” indicates a compound 1 administration group. The symbol * (asterisk) in the figure indicates that it is statistically significant (Student's t-test; P<0.05) as compared with the solvent administration group.

  The vehicle-administered group showed a decrease in plasma albumin concentration as compared with the control group, which was shown to be hypoalbuminemia. This 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 as compared with the plasma albumin concentration in the solvent administration group ( P<0.05)). Therefore, Compound 1 was shown to improve hypoalbuminemia.

  Therefore, the compound represented by the above general formula (I) or a pharmaceutically acceptable acid addition salt thereof, even in hypoalbuminemia by peritoneal dissemination of ovarian cancer cells, which is a disease different from chronic liver disease, It was shown to have an effect of improving hypoalbuminemia.

INDUSTRIAL APPLICABILITY The present invention can be used as an agent for improving hypoalbuminemia in the field of medicine.

Claims (4)

An agent for improving hypoalbuminemia associated with liver disease, which comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.
[In the formula, a double line 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 is a straight chain having 1 to 5 carbon atoms. Or represents branched alkyl, and B represents -CH=CH-. ] The agent for improving hypoalbuminemia associated with liver disease according to claim ¹ , wherein R ¹ is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R ² is methyl, ethyl or propyl. The agent for improving hypoalbuminemia associated with liver disease according to claim ¹ , wherein R ¹ is cyclopropylmethyl, R ² is methyl, and B is trans -CH=CH-. (−)-17-(Cyclopropylmethyl)-3,14β-dihydroxy-4,5α-epoxy-6β-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan or its pharmacologically acceptable The agent for improving hypoalbuminemia associated with liver disease according to claim 1, wherein the acid addition salt is an active ingredient.