阅读说明：本技术 含有1,4-苯并硫氮杂*-1-氧化物衍生物的光学异构体的肾功能障碍的改善药 (Renal dysfunction improving agent containing optical isomer of 1, 4-benzothiazepine-1-oxide derivative ) 是由 金子升 于 2018-12-11 设计创作，主要内容包括：本发明的课题是提供一种用以治疗伴随肾功能障碍的各种疾病的医药组合物。通过含有下述通式[II]所示的1,4-苯并硫氮杂<Image he="59" wi="55" file="DDA0002520367710000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>-1-氧化物衍生物的光学异构体或其药学上可接受的盐而构成的医药组合物,可改善肾功能障碍。<Image he="211" wi="700" file="DDA0002520367710000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(式中,R表示氢原子或羟基。*表示光学异构体)。(The present invention addresses the problem of providing a pharmaceutical composition for treating various diseases associated with renal dysfunction. By containing the following general formula [ II]1, 4-benzothiazepines of the formula A pharmaceutical composition comprising an optical isomer of an (E) -1-oxide derivative or a pharmaceutically acceptable salt thereof, which is capable of improving renal dysfunction. (wherein R represents a hydrogen atom or a hydroxyl group represents an optical isomer).)

1. A pharmaceutical composition for improving renal dysfunction, which comprises the following general formula [ II]1, 4-benzothiazepines of the formulaA pharmaceutical composition comprising an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,

wherein R represents a hydrogen atom or a hydroxyl group, and represents an optical isomer.

2. The pharmaceutical composition of claim 1, wherein the improvement in renal dysfunction is a decrease in serum creatinine level.

3. The pharmaceutical composition according to claim 1 or 2, wherein the improvement in renal dysfunction is an increase in Na and/or K excretion into the urine.

4. A pharmaceutical composition according to any one of claims 1-3 wherein the improvement in renal dysfunction is an increase in urine volume.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is a pharmaceutical composition for improving cardiac function against heart failure and/or arrhythmia complicated with renal dysfunction.

6. The pharmaceutical composition of claim 5, wherein the arrhythmia is atrial fibrillation and/or atrial flutter.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the pharmaceutically acceptable salt is a hydrochloride or citrate salt.

8. The pharmaceutical composition of any one of claims 1-7, wherein the renal dysfunction is acute kidney disease.

9. The pharmaceutical composition of any one of claims 1-7, wherein the renal dysfunction is chronic kidney disease.

10. A pharmaceutical composition according to any one of claims 1-7 wherein the renal dysfunction is a renal dysfunction selected from the group consisting of diabetic nephropathy, glomerulonephritis, renal dysfunction resulting from shock or bleeding, and renal dysfunction complicated by arrhythmia or heart failure.

11. The pharmaceutical composition according to any one of claims 1 to 10, which is a pharmaceutical composition for use in a patient with renal dysfunction.

12. The pharmaceutical composition according to any one of claims 1 to 11, which is a pharmaceutical composition for use in a patient suffering from renal dysfunction complicated by arrhythmia or heart failure.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein 1, 4-benzothiazepineThe optical isomer of the-1-oxide derivative is the 1 st component of the optical isomer.

Technical Field

The present invention relates to a pharmaceutical composition for improving renal dysfunction, which contains 1, 4-benzothiazepine-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof.

Background

The kidney is an organ that is present in the left and right dorsal lumbar regions and weighs about 130 g in an adult. The kidney mainly functions to (1) maintain the amount of water in the body, (2) discharge waste products such as urea nitrogen and creatinine, and (3) maintain the homeostasis of electrolytes such as sodium (Na), potassium (K), chlorine (Cl), and phosphorus (P) in the body by the production and discharge of urine.

There are many structures in the kidney called glomeruli (nephrons), which are blood vessels having almost the same thickness as capillaries, are in a spherical form, and are in the form of a hair coil. The glomeruli, which are present in about 100 ten thousand in 1 kidney, form a complex anastomosis with a size of about 0.1mm in diameter.

The glomeruli function to filter water, creatinine, urea nitrogen and other waste products, electrolytes and the like from the blood. These filtered substances are produced by reabsorbing or excreting water, electrolytes, and the like in proximal tubules, distal tubules, and collecting ducts connected to glomeruli as required by the living body, and excreted as urine, creatinine, urea nitrogen, and the like, which are unnecessary wastes in the living body. The kidney properly discharges these substances, thereby maintaining the concentration in the living body constant and maintaining the living environment.

The decrease in the amount of filtration causes an increase in creatinine and urea nitrogen in blood and an increase in potassium value in a living body.

Renal dysfunction can be classified according to the length of the disease process: acute diseases (hereinafter, also referred to as "acute kidney diseases") in less than 3 months from onset, and chronic diseases (hereinafter, also referred to as "chronic kidney diseases") in more than 3 months. With the increase in diabetic patients in recent years, diabetic renal disorder (diabetic nephropathy) has been the most cause of chronic kidney disease. Secondly, there are also many cases caused by chronic glomerulonephritis.

Acute kidney disease can be further classified from its site of occurrence as: acute renal diseases of the pre-, renal and postrenal nature. Prerenal acute kidney diseases are renal dysfunction that occurs as a result of a decrease in blood flow to the kidney due to bleeding, sudden blood pressure lowering (shock, etc.), or the like. When renal arteries become narrowed by arteriosclerosis, renal ischemia causes renal dysfunction. In addition, heart failure also causes renal dysfunction due to blood stasis in organs. Renal acute kidney disease is a disorder of the glomeruli themselves. It is a disorder of renal parenchyma caused by acute glomerulonephritis or drugs (e.g., anticancer agents or antibiotics). The acute renal disease after renal failure is renal dysfunction caused by an increase in the internal pressure of glomeruli or renal tubules due to suppression of urination caused by prostatic hypertrophy or urinary tract obstruction.

Diseases accompanied by renal dysfunction can be classified into glomerular diseases, tubulointerstitial diseases, renal failure, renal diseases, polycystic kidney disease, and the like, depending on the disease state and the site of the disorder. The glomerular diseases include diseases associated with glomerular disorders such as acute nephritis syndrome, rapidly progressive nephritis syndrome, recurrent and persistent hematuria, chronic nephritis syndrome, nephrotic syndrome, and the like. The tubulointerstitial disease includes diseases accompanied by tubulointerstitial disorders such as tubulointerstitial nephritis (acute, chronic or not clearly defined which type). Among renal failure, acute renal failure and chronic renal failure are included. The renal diseases include viral nephropathy (HB virus nephropathy, HC virus nephropathy, HIV nephropathy, BK virus nephropathy, and the like), nephrosarcoidosis, diabetic nephropathy, hereditary nephropathy, familial nephritis, hypertensive nephropathy, hepatorenal syndrome, NSAID nephropathy, analgesic nephropathy, contrast-induced nephropathy, heavy metal-induced nephropathy, and the like.

When renal dysfunction is caused, the amount of renal filtration is reduced, resulting in an increase in creatinine and urea nitrogen in the blood. As renal dysfunction becomes more severe, the excretion of potassium (K) in the blood is impaired, increasing the blood K value. The increase of K in blood may also cause fatal arrhythmia such as ventricular tremor. Renal dysfunction also impairs sodium (Na) excretion. An increase in the amount of circulating blood due to an increase in Na in the blood causes a systemic edema. In this case, as the agent for ameliorating edema, for example, a loop diuretic (ループス diuretics) or thiazide diuretic which promotes Na excretion by inhibiting Na reabsorption in the renal tubules and increases the urine volume can be used. In addition, a potassium-retaining diuretic which promotes diuresis by inhibiting aldosterone in the renal tubule may also be used clinically. However, these agents do not have the effect of discharging waste products such as creatinine and urea nitrogen. In addition, loop diuretics and thiazide diuretics do not only have an effect of improving renal function but rather cause deterioration and thus cannot be given to cases of severe renal dysfunction.

It has been reported that 60% of patients with heart failure complicated with renal dysfunction in 90% of patients with heart failure (non-patent document 1). In the case of heart failure, systemic edema is caused, and therefore a loop diuretic or thiazide diuretic is used as an edema therapeutic agent. However, since these drugs further cause renal dysfunction, renal dysfunction complicated with heart failure is aggravated, resulting in poor prognosis of patients. It has been reported that the prognosis of heart failure patients is worse than that of general "cancer" (excluding pancreatic cancer and the like) (non-patent document 2). Accordingly, renal dysfunction is closely related to the prognosis of heart failure patients, and development of novel diuretics for improving renal dysfunction is desired.

Since there is no agent for increasing glomerular filtration and reducing creatinine in blood, renal dysfunction is currently treated by: 1) conservative treatments that do not put a burden on the kidneys as much as possible, such as, for example, limiting excessive water intake, 2) limiting salt (NaCl) intake, 4) limiting potassium salt (K) intake, 5) limiting protein intake, 6) stabilizing blood pressure (hypertension is a result of increased intraglomerular pressure and contributes to renal dysfunction), and 7) preventing dehydration. However, the effect of conservative treatment is limited, and the waste products such as creatinine and urea nitrogen cannot be sufficiently discharged, so that renal failure (renal dysfunction G5 described later) may end up, and artificial dialysis or kidney transplantation may be required.

Prognosis of patients with renal dysfunction, in acute renal diseases, half of patients feel mild/cured if the cause is removed. However, in chronic kidney diseases, since there is no drug for improving renal dysfunction, there are individual differences, but in many cases, the renal dysfunction deteriorates with time. Furthermore, renal arteriosclerosis with age also deteriorates renal function, and therefore renal dysfunction is likely to gradually progress with age. Eventually, when the renal dysfunction becomes G5, the kidney transplant is not obtained, and the artificial dialysis treatment has to be performed. At present, it is assumed that the number of dialysis patients in Japan is about 30 ten thousand. Dialysis has not only a problem in treatment but also a huge medical cost each year, and thus is a huge social problem such as personal loss and economic loss. In the future, development of renal function improving drugs is an urgent issue with aging and increase in diabetic patients. Currently, since there is no agent for reducing serum creatinine, an agent for reducing serum creatinine is an epoch-making agent for patients with renal dysfunction.

The present inventors have so far aimed at 4- [3- (4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineAnd derivatives thereof (see patent document 1 and patentDocument 2) was studied and reported. In addition, the above-mentioned compounds have also been found and reported, for example: has an effect of enhancing the effect on anticancer drugs (see patent document 3); inhibition of Ca from sarcoplasmic reticulum (tendon vesicles) by improvement and/or stabilization of the function of the Reynolds number receptor (リアノジン receptor)²⁺The action of leakage (see patent document 4); and a therapeutic agent for muscle relaxation, a therapeutic agent for left ventricular diastolic dysfunction, a therapeutic agent for angina pectoris, a therapeutic agent for acute emphysema, a blood flow improving agent for microcirculation, a therapeutic agent for hypertension, a therapeutic agent for ventricular tachycardia, a therapeutic agent for torsades de pointes (トルサドポアン), and the like (see patent document 5). However, with regard to the compounds belonging to 4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineJTV519 (also referred to as K201, corresponding to Compound [ III ] of the present description) and derivatives thereof]Compound), it has been reported that when JTV519 at 1.2mg/kg body weight is administered to a canine with a complete atrioventricular block, torsades de pointes, which is a lethal arrhythmia, is produced in some cases (non-patent document 3). Therefore, JTV519(K201) is not a compound that can be used directly in clinical applications in humans.

Further, the present inventors have found that 4- [3- (4-benzylpiperidin-1-yl) propionyl group is a specific oxide of the above compound]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineA general formula [ I ] represented by (E) -1-oxide]1, 4-benzothiazepines of the formulaThe 1-oxide derivative has also been found and reported to be useful as a therapeutic or prophylactic agent for myocardial relaxation disorder in atrial arrhythmia accompanied by heart failure and hypertension, diastolic disorder, angina pectoris and myocardial infarction, hypertension, ischemic heart disease, heart failure, ventricular arrhythmia (see patent documents)Document 6).

(wherein R represents a hydrogen atom or a hydroxyl group)

Patent document 6 describes an effect of improving cardiac function, but does not describe an effect of improving renal function with respect to the effect of the compound.

Furthermore, the general formula [ II]1, 4-benzothiazepines of the formulaThe-1-oxide derivative has a central chirality in which the sulfur atom becomes a chiral center in the S-oxide moiety.

(wherein R represents a hydrogen atom or a hydroxyl group, and R represents an optical isomer).

The present inventors aimed at the compounds belonging to the general formula [ II]4- [3- (4-benzylpiperidin-1-yl) propanoyl group of one of the compounds shown]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine1-oxide, which can be stably separated even at 40 ℃ when attempting to separate a stereoisomer of the central chirality, and each enantiomer can be successfully separated (patent document 7). In the present specification, as in patent document 7, the present inventors refer to an enantiomer eluted first among 2 enantiomers separated by using a chiral column as component 1 (or, in some cases, compound (a)), and refer to an enantiomer eluted next as component 2 (or, in some cases, compound (B)). The ratio of the amount of the separated 1 st component to the 2 nd component was almost 1: 1. Next, the present inventors collected 2 enantiomers (hereinafter, also referred to as optical isomers) separately.

Then, when the pharmacological activities of the two were examined, it was found that the properties of the 1 st component (compound (a)) and the 2 nd component (compound (B)) which are optical isomers have opposite effects, and particularly regarding atrial fibrillation, only the 1 st component has very specific pharmacological activities which are expected to have a high anti-atrial fibrillation effect and an effect of reducing the proarrhythmic action (patent document 7). However, no renal function improving effect is described as an effect of any of the optical isomers. Further, it was confirmed by crystal structure analysis that the 1 st component was (R) form and the 2 nd component was (S) form.

Disclosure of Invention

Technical problem to be solved by the invention

The technical problem of the present invention is to provide a pharmaceutical composition useful for improving renal dysfunction, which has the effects of increasing urine volume, increasing the amount of sodium in urine, increasing the amount of potassium in urine, and/or decreasing the amount of serum creatinine.

Means for solving the problems

The inventors are directed to the general formula [ I]1, 4-benzothiazepines of the formulaVarious pharmacological actions of the-1-oxide derivatives have been studied elaborately.

(wherein R represents a hydrogen atom or a hydroxyl group)

As a result, the present inventors have found that the compound represented by the general formula [ II ]]Optically active 1, 4-benzothiazepines-1-oxide derivative, i.e., optically active 4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineOne optical isomer of (E) -1-oxide (Compound (A)) has an effect of improving renal dysfunction, i.e., increasing urine volume at a low dose, and also has a surprising effect of promoting the excretion of creatinine in blood and reducing the excretion of creatinine in blood in addition to Na excretion and K excretion, thereby completing the present invention.

(wherein R represents a hydrogen atom or a hydroxyl group, and represents an optical isomer)

Namely, the present invention relates to a pharmaceutical composition comprising the following general formula [ II]1, 4-benzothiazepines of the formula-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof. More particularly, the present invention relates to a composition comprising [ II ] as defined above]1, 4-benzothiazepines of the formulaOptical isomer of 1-oxide derivative component 1 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention has the effect of increasing urine volumeThe effects of increasing the amount of sodium in urine, increasing the amount of potassium in urine, and/or decreasing the amount of serum creatinine are useful pharmaceutical compositions for improving renal dysfunction, and are useful for the treatment of various diseases associated with renal dysfunction.

(wherein R represents a hydrogen atom or a hydroxyl group, and represents an optical isomer)

The present invention will be described in more detail below.

(1) A pharmaceutical composition for improving renal dysfunction, which comprises the following general formula [ II]1, 4-benzothiazepines of the formulaA pharmaceutical composition comprising an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,

(wherein R represents a hydrogen atom or a hydroxyl group, and R represents an optical isomer).

(2) The pharmaceutical composition according to the above (1), wherein the improvement in renal dysfunction is a decrease in the creatinine level in blood.

(3) The pharmaceutical composition according to the above (1) or (2), wherein the improvement in renal dysfunction is an increase in Na and/or K excretion in urine.

(4) The pharmaceutical composition according to any one of the above (1) to (3), wherein the improvement in renal dysfunction is an increase in urine volume.

(5) The pharmaceutical composition according to any one of the above (1) to (4), which is a pharmaceutical composition for improving cardiac function against heart failure and/or arrhythmia complicated with renal dysfunction.

(6) The pharmaceutical composition according to the above (5), wherein the arrhythmia is atrial fibrillation and/or atrial flutter.

(7) The pharmaceutical composition according to any one of the above (1) to (6), wherein the pharmaceutically acceptable salt is a hydrochloride or citrate.

(8) The pharmaceutical composition according to any one of the above (1) to (7), wherein the renal dysfunction is acute kidney disease.

(9) The pharmaceutical composition according to any one of the above (1) to (7), wherein the renal dysfunction is chronic kidney disease.

(10) The pharmaceutical composition according to any one of the above (1) to (7), wherein the renal dysfunction is a renal dysfunction selected from the group consisting of diabetic nephropathy, glomerulonephritis, renal dysfunction due to shock or hemorrhage, and renal dysfunction complicated by arrhythmia or heart failure.

(11) The pharmaceutical composition according to any one of the above (1) to (10), which is a pharmaceutical composition for use in a patient suffering from renal dysfunction.

(12) The pharmaceutical composition according to any one of the above (1) to (11), which is a pharmaceutical composition for use in a patient suffering from renal dysfunction complicated by arrhythmia or heart failure.

(13) The pharmaceutical composition according to any one of the above (1) to (12), wherein 1, 4-benzothiazepineThe optical isomer of the-1-oxide derivative is the 1 st component of the optical isomer.

(14) The pharmaceutical composition according to the above (13), wherein the 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1.

(15) A method for improving renal dysfunction, the method comprising administering to a subject having renal dysfunction an effective amount of a pharmaceutical composition comprising the foregoing general formula [ II]1, 4-benzothiazepines of the formulaA step of preparing a pharmaceutical composition comprising an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof.

(16) The method according to (15) above, wherein the subject is a subject suffering from heart failure and/or arrhythmia complicated by renal dysfunction.

(17) The method according to the preceding (16), wherein the arrhythmia is atrial fibrillation and/or atrial flutter.

(18) The method according to any one of the preceding (15) to (17), wherein the pharmaceutically acceptable salt is a hydrochloride or citrate.

(19) The method according to any one of the above (15) to (18), wherein the 1, 4-benzothiazepineThe optical isomer of the-1-oxide derivative is the 1 st component of the optical isomer.

(20) The process as described in the above (19), wherein 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1.

(21) A compound of the general formula [ II]1, 4-benzothiazepines of the formula-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof, which is used for the improvement or treatment of renal dysfunction.

(22) 1, 4-Benzothiazepine as described in the aforementioned (21)-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof for use in the amelioration or treatment of renal dysfunction and the amelioration or treatment of heart failure and/or arrhythmia complicated with renal dysfunction.

(23) 1, 4-Benzothiazepine as described in the aforementioned (22)-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof, wherein the arrhythmia is atrial fibrillation and/or atrial flutter.

(24) The 1, 4-benzothiazepine as described in any one of the preceding (21) to (23)-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride or citrate.

(25) The 1, 4-benzothiazepine as described in any one of the preceding (21) to (24)An optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof, wherein the aforementioned 1, 4-benzothiazepineThe optical isomer of the-1-oxide derivative is the 1 st component of the optical isomer.

(26) 1, 4-Benzothiazepine as described in the aforementioned (25)An optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof, wherein, 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1.

(27) A compound of the general formula [ II]1, 4-benzothiazepines of the formula-use of an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the improvement or treatment of renal dysfunction.

(28) The use according to (27) above for producing a pharmaceutical composition for improving or treating renal dysfunction and heart failure and/or arrhythmia associated with renal dysfunction.

(29) The use as described in (27) above, wherein the arrhythmia is atrial fibrillation and/or atrial flutter.

(30) The use according to any one of the preceding (27) to (29), wherein the pharmaceutically acceptable salt is a hydrochloride or citrate.

(31) The use as described in any of the above (27) to (30), wherein the aforementioned 1, 4-benzothiazepineThe optical isomer of the-1-oxide derivative is the 1 st component of the optical isomer.

(32) The use as described in the aforementioned (31), wherein 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1-oxidationThe optical isomer of the compound 1.

Effects of the invention

The above general formula [ II]1, 4-benzothiazepines of the formulaOptical isomers of 1-oxide derivatives component 1 or pharmaceutically acceptable salts thereof improve renal dysfunction. By administration of the general formula [ II]Optically active 1, 4-benzothiazepines-1-oxide derivative, i.e. optically active 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineAn optical isomer of 1-oxide (compound (A)), as specifically shown in examples 3 to 5 described later, an increase in urine volume, Na excretion and K excretion and a decrease in the amount of creatinine in blood can be obtained. Also, compound (a) did not cause torsade de pointes, which is an adverse event, in fully atrioventricular conduction-blocked dogs. Torsade de pointes leads to fatal arrhythmias, and the absence of lethal arrhythmia from pharmaceutical compounds is a clinically beneficial property.

By administering a pharmaceutical composition containing compound (a), improvement of renal dysfunction, which could not be provided by previously effective treatment methods, can be achieved, whereby patients suffering from renal dysfunction can be prevented from developing renal failure, or the number of years in which renal failure develops can be prolonged. As a result, artificial dialysis can be avoided, or the development of years requiring artificial dialysis can be extended. In addition, since the current loop diuretics and thiazide diuretics do not have the effect of improving renal function, even block renal function, the prognosis of patients with renal dysfunction due to heart failure is poor, but the renal dysfunction improving drugs containing compound (a) having diuretic effect and creatinine reduction are good news for patients with renal dysfunction due to or complicated with heart failure.

Drawings

FIG. 1 shows the preparation of optically active 4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1-oxide elution profile for use in chromatography using a chiral column. The 1 st component of the optical isomer of the present invention was eluted at about 8.1 minutes, and the 2 nd component of the optical isomer belonging to the enantiomer thereof was eluted at about 11.4 minutes, showing that the two were completely separated.

FIG. 2 shows the elution profile of the separately collected 1 st component of the optical isomer of the present invention when used for chromatography using the same chiral column when separately collected.

FIG. 3 shows the elution profile of the optical isomer of the enantiomer which belongs to the optical isomer component 1 of the present invention, component 2, when used for chromatography using the same chiral column when collected alone.

FIG. 4 shows a compound belonging to 4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineOptical isomer of 1-oxide component 1 (compound (A)) on canine urine volume. Compound (a) showed a dose-dependent urine volume increasing effect. In the figure, a indicates that there is a significant difference of p < 0.01.

FIG. 5 shows the effect of Compound (A) on Na excretion in dog urine. Compound (a) showed a dose-dependent increase in urinary Na excretion. In the figure, a indicates that there is a significant difference of p < 0.05.

FIG. 6 shows the effect of Compound (A) on K excretion in dog urine. Compound (a) shows an increase in urinary K excretion. In the figure, a indicates that there is a significant difference of p < 0.01.

FIG. 7 shows the effect of Compound (A) on serum creatinine levels in dogs. Compound (a) showed a dose-dependent decrease in serum creatinine values. In the figure, a indicates that there is a significant difference of p < 0.05.

FIG. 8 shows the effect of Compound (A) on creatinine clearance in rat ischemia reperfusion injury experiments. Compound (a) significantly improved creatinine clearance 24-48 hours after ischemia reperfusion. In the figure, a indicates that there is a significant difference of p < 0.05.

FIG. 9 shows the effect of Compound (A) on the creatinine level in blood in rat ischemia reperfusion injury experiments. Compound (a) showed a significant reduction in serum creatinine values. In the figure, a indicates that there is a significant difference of p < 0.05.

Figure 10 shows the concentration of compound (a) in the blood when compound (a) was administered to adults and the amount of urine from just after administration to 8 hours after administration, the amount of urine is in terms of the height of the bar and is shown along with the standard deviation the concentration of compound (a) in the plasma is plotted as ◇ and is shown along with the standard deviation indicating that there is a significant difference of p < 0.05.

Detailed Description

One embodiment of the present invention is a pharmaceutical composition for improving renal dysfunction, which comprises [ II ]]1, 4-benzothiazepines of the formulaAn optical isomer of the 1-oxide derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. As used herein, 1, 4-benzothiazepinesPreferable examples of the optical isomer of the (E) -1-oxide derivative include the optical isomer component 1. Further, an example of the preferable optical isomer component 1 is 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1. Herein, the optical isomer 1 st component is an isomer of R configuration. Herein, preferred examples of the pharmaceutically acceptable salt include hydrochloride and citrate.

Another embodiment of the present invention is a method for improving renal dysfunction, the method comprising administering to a subject having renal dysfunction an effective amount of a pharmaceutical composition comprising the foregoing general formula [ II [ ]]1, 4-benzothiazepines of the formulaA step of preparing a pharmaceutical composition comprising an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof. As used herein, 1, 4-benzothiazepinesPreferable examples of the optical isomer of the (E) -1-oxide derivative include the optical isomer component 1. Further, an example of the 1 st component which is a preferable optical isomer is 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1. Herein, the optical isomer 1 st component is an isomer of R configuration. Herein, preferred examples of the pharmaceutically acceptable salt include hydrochloride and citrate.

Yet another embodiment of the present invention is a method for improving or treating renal dysfunction of the aforementioned general formula [ II ]]1, 4-benzothiazepines of the formula-an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof. As used herein, 1, 4-benzothiazepinesPreferable examples of the optical isomer of the (E) -1-oxide derivative include the optical isomer component 1. Further, an example of the 1 st component which is a preferable optical isomer is 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1. Herein, the optical isomer 1 st component is an isomer of R configuration. Herein, preferred examples of the pharmaceutically acceptable salt include hydrochloride and citrate.

Another embodiment of the present invention is a composition of the above general formula [ II ]]1, 4-benzothiazepines of the formula-use of an optical isomer of a 1-oxide derivative or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the improvement or treatment of renal dysfunction. As used herein, 1, 4-benzothiazepinesPreferable examples of the optical isomer of the (E) -1-oxide derivative include the optical isomer component 1. Further, a preferable example of the optical isomer component 1 is 1, 4-benzothiazepineThe optical isomer of the (E) -1-oxide derivative is 4- [3- (4-benzylpiperidin-1-yl) propanoyl]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1. Herein, the optical isomer 1 st component is an isomer of R configuration. In this contextPreferable examples of the pharmaceutically acceptable salt include hydrochloride and citrate.

In the present invention according to the above-described various embodiments, the renal dysfunction is an acute renal disease or a chronic renal disease, and the therapeutic target of the present invention is, for example, diabetic nephropathy, glomerulonephritis, renal dysfunction due to shock or hemorrhage, and renal dysfunction accompanying arrhythmia or heart failure. In the present invention, the improvement of renal dysfunction is a case where a decrease in the creatinine level in blood, an increase in the excretion of Na and/or K into urine, or an increase in urine volume can be obtained. The patient to be treated by the present invention is a patient suffering from renal dysfunction. Herein, a patient suffering from renal dysfunction comprises a patient exhibiting renal circulatory failure complicated by arrhythmia or heart failure. The pharmaceutical composition of the present invention can also be used as a pharmaceutical composition for improving renal function and cardiac function in a patient suffering from heart failure and/or arrhythmia complicated with renal dysfunction. Herein, cardiac arrhythmia includes atrial fibrillation and/or atrial flutter.

(1) Evaluation subject of renal function

The effect of a drug on kidney function can be tested using humans or animals. The animal may be any animal such as mouse, rat, guinea pig, hamster, dog, cat, pig, goat, or sheep. The evaluation of the kidney function can be performed by collecting urine from a subject or a subject animal, and measuring the urine amount, the amount of sodium in urine, the amount of potassium in urine, and the like. In addition, renal function can also be evaluated by collecting blood and measuring the creatinine level in blood (serum or plasma). In addition, renal function and the degree of disorder of renal function can be evaluated or classified by the following methods.

(2) Assessment of renal dysfunction

Assessment of renal dysfunction can be assessed by the magnitude of glomerular filtration capacity (GFR) and the like. The amount of renal filtration in the glomerulus is the amount of creatinine output per unit time, i.e., almost coincides with creatinine clearance (Ccr), and therefore, determination of the Ccr value allows assessment of the degree of renal dysfunction.

The calculation formula for computing Ccr is as follows.

Ccr (m L/min) ═ creatinine concentration in urine (mg/d L) × urine outflow rate (m L/min)/creatinine concentration in serum (mg/d L)

In fact, as for a simpler measurement method, in recent years, the glomerular filtration amount is estimated from the age and the serum creatinine value: eGFR (esterified macromolecular filtration rate) is widely used clinically.

The calculation formula for calculating eGFR is as follows.

(situation in Male)

eGFR ═ 194 × Cr (serum creatinine value)^-1.094× age (year of age)^-0.287

(situation in female)

eGFR＝194×Cr^-1.094× age (year of age)^-0.287×0.739

(the units are m L/min/1.73 m²)

The severity of renal dysfunction in humans was classified into 6 stages as shown in the following table based on the calculated eGFR value.

TABLE 1

A reference value table for judging whether or not renal dysfunction is suspected is also created using the serum creatinine value (Cr) as an index.

TABLE 2

In short, the presence and extent of renal dysfunction can be assessed based on an increase in serum creatinine (Cr).

(3) The active ingredient of the pharmaceutical composition of the present invention

The active ingredient of the pharmaceutical composition of the present invention for improving renal dysfunction is represented by the general formula [ II]1, 4-benzothiazepines of the formula-optical isomers of 1-oxide derivatives. The invention has the general formula [ II]Shown inThe optical isomer of (A) has the general formula [ II]Wherein R is a hydrogen atom, and a compound wherein R is a hydroxyl group. Preferred examples of the compound as an active ingredient of the pharmaceutical composition of the present invention include the following formula [ IV]4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-optical isomer of 1-oxide component 1 or a pharmaceutically acceptable salt thereof.

(in the formula, symbol represents a chiral center)

In the compound of the present invention, since the bond (SO) between sulfur (S) and oxygen (O) of the heterocycle forms a polar atomic group exhibiting strong electronegativity as a coordinate bond, the bond between sulfur and oxygen can be represented by an arrow of heterocycle S → O to show that the bond is a coordinate bond, and in this case, the coordinate bond can be represented by heterocycle S⁺–O^-And (4) showing.

In general, R¹-S(O)-R²Among the sulfoxide compounds shown, R is known¹And R²When they are different groups, the sulfur atom becomes a chiral center and has central chirality. That is, it is known that two stereoisomers of a compound in which an oxygen atom is bonded from the lower side of the paper surface and a compound in which an oxygen atom is bonded from the upper side of the paper surface exist. Then, when a part of the electron pair of the sulfur atom is bonded to the virtual atom of the atom number 0, the electron pair can be represented as an R configuration or an S configuration according to the sequence rule of R-S nomenclature, regardless of the participation of the d orbital.

As shown in FIG. 1, it was revealed that the compound represented by the general formula [ I ] contained two compounds which were stably and definitely separated at a ratio of about 1:1 by passing through a chiral column at a temperature of 40 ℃. Then, the two compounds collected separately exhibited the same behavior in instrumental analysis, and were therefore considered as two stereoisomers distinguished chirally by chirality at a center. The stereoisomer designated as component 1 of the present invention was confirmed to have the R configuration by crystal structure analysis.

In the present specification, when a compound of formula [ IV ] which is one of the compounds represented by the general formula [ I ] is eluted at 40 ℃ at a flow rate of 1.0m L/min using MeOH/MeCN/DEA ═ 90/10/0.1(v/v) as a mobile phase through a chiral column (CHIRA L PAK AD-H (manufactured by japan) having an inner diameter of 0.46cm × and a length of 25cm), a component eluted from about 7 minutes to 9 minutes (retention time of about 8.1 minutes) is referred to as a 1 st component (or sometimes simply as compound (a)), and then a component eluted from about 10 minutes to 13 minutes (retention time of about 11.4 minutes) is referred to as a 2 nd component (or sometimes simply as compound (B)), and the compound (a) which is the 1 st component is an isomer as described above, and the compound (B) which is the 2 nd isomer (S) is also described in patent literature 7, as shown in fig. 2 and fig. 3.

(4) Optically active 1, 4-benzothiazepines of the inventionSalts and solvates of (E) -1-oxide derivatives

Due to the 1, 4-benzothiazepine of the inventionThe 1-oxide derivatives have a basic nitrogen atom and therefore form acid addition salts at this position. The acid used for forming the acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable acid. Preferred acid addition salts of the present invention include, for example: inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, or nitrate; organic acid addition salts such as oxalate, acetate, propionate, succinate, glycolate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and ascorbate; and amino acid addition salts such as aspartate and glutamate. Also, the compound of the present invention or an acid addition salt thereof may be waterAnd solvates such as hydrates.

(5) Optically active 1, 4-benzothiazepines of the inventionProcess for producing (1) -component which is an optical isomer of (1) -oxide derivative

The compound of the optical isomer component 1 of the present invention can be produced by separating and separately collecting the compound represented by the general formula [ I ] by a separation method using a chiral column or the like.

The compound represented by the general formula [ I ] can be produced by oxidizing the compound represented by the general formula [ III ] by the method described in patent document 6.

(wherein R represents a hydrogen atom or a hydroxyl group)

More specifically, for example, the oxide represented by the formula [ Ia ] can be produced by oxidizing a compound represented by the formula [ V ] in the following reaction formula with an appropriate oxidizing agent. As the oxidizing agent, a peracid, for example, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid (mCPBA), or the like can be used. As the solvent, a halogenated hydrocarbon such as dichloromethane or chloroform can be used as appropriate. The reaction temperature is low, for example, preferably about 0 ℃ to 5 ℃ in order to prevent oxidation to sulfone. The target substance can be isolated and purified from the reaction mixture by a known isolation and purification means such as extraction, chromatography, or distillation.

Can convert the compound [ V ]]4- [3- (4-benzylpiperidin-1-yl) propanoyl group of (1)]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineIn trichloromethane (CHCl)₃) In a solvent, m-chloroperbenzoic acid (mCPBA) as an oxidizing agent is oxidized.

Through the above reaction path, the formula [ V ]]A compound [ Ia ] produced by oxidizing the hydrochloride shown above with m-chloroperbenzoic acid (mCPBA) as an oxidizing agent in a chloroform solvent]4- [3- (4-benzylpiperidin-1-yl) propanoyl group]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineThe 1-oxide is separated by silica gel chromatography using a chloroform-methanol mixture as a mobile phase, and then the solvent is distilled off from the separated chloroform-methanol azeotropic solvent, and the residual solvent is further removed under argon gas to prepare the final product. The thus obtained compound of the formula [ Ia]The compound shown has a purity of 90% or more, has a molecular weight of 440.61, is amorphous, is stable to oxygen, humidity, and acids and bases at room temperature, is readily soluble in ethanol and dimethyl sulfoxide (DMSO), and is skin irritant. Further, compound [ Ia]The oxalate salt of (A) is a crystal having a molecular weight of 530.65, a purity of 90% or more, and a melting point of 167-168 ℃, and is soluble in water, ethanol and dimethylsulfoxide. By passing¹H-NMR measurement at room temperature confirmed that the stereoisomer of the amide moiety was present in a ratio of about 2: 3.

In addition, the general formula [ II ] of the present invention]In the compound, R is 4- {3- [4- (4-hydroxybenzyl) piperidin-1-yl of hydroxyl]Propionyl } -7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineThe (E) -1-oxide or a pharmaceutically acceptable salt thereof can be produced by protecting a hydroxyl group as required by the same oxidation reaction as described above. In addition, 1, 4-benzothiazepines which are parent compounds of these compounds may also be administered to rats or dogsDerivatives, obtained by adding water to urine and feces and homogenizing, using a reverse phase column using silica gel (ODS) chemically bonded with octadecyl, and mobile phase: as the a solution, water containing 0.1% trifluoroacetic acid (TFA); the content of the B solution is 0.1%TFA in acetonitrile, and separating the components of the supernatant by high performance liquid chromatography using gradient elution with a retention time of 19 minutes to 22 minutes. The mass-to-charge ratio (m/Z) of the separated components was 457 by mass spectrometry. Further, compound [ Ia]Also by the same means, by using gradient elution high performance liquid chromatography, can be retained for 27 minutes-30 minutes separation and obtain.

In addition, 7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine is also contemplatedOxidation was carried out by the same method as described above to give 7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepine-1-oxide, which is separated into stereoisomers by means of a chiral column, one enantiomer of which is collected separately and which is amidated under suitable reaction conditions to produce the general formula [ II ] of the invention]The method of (1).

(6) Mode of administration of the pharmaceutical composition of the present invention

The optical isomer component 1 of the compound represented by the general formula [ II ] or a salt thereof of the present invention has an effect of increasing urine volume, increasing sodium volume in urine, increasing potassium volume in urine and/or decreasing serum creatinine volume, and has an effect of improving renal function.

Therefore, the optical isomer 1-th component of the compound represented by the general formula [ II ] of the present invention or a salt thereof can be used as an active ingredient of a pharmaceutical composition. The pharmaceutical composition of the present invention can be administered orally, transmucosally, transdermally, intravenously, or the like.

(7) Dosage form and formulation of the pharmaceutical composition of the present invention

When the pharmaceutical composition of the present invention is prepared as a solid composition for oral administration, it may be in the form of tablets, pills, powders, granules, or the like. In such solid compositions, one or more active substances may be mixed with at least one inactive diluent, dispersant, adsorbent or the like, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminum metasilicate, anhydrous silicic acid powder or the like, and manufactured according to a conventional method.

In the case of tablets or pills, films of gastric or enteric substances such as white sugar, gelatin, hydroxypropyl cellulose, hydroxymethylcellulose phthalate, or the like may be coated as necessary, or two or more layers may be coated. Further, it can be made into gelatin or ethyl cellulose capsule.

When the composition is prepared into a liquid composition for oral administration, it may be in the form of pharmaceutically acceptable emulsions, solubilizers, suspensions, syrups, elixirs (elixir), and the like. Examples of the diluent used include: purified water, ethanol, vegetable oil or emulsifier, etc. Meanwhile, the composition may be mixed with adjuvants other than the diluent, such as wetting agent, suspending agent, sweetener, flavoring agent, aromatic agent, or preservative.

In the case of preparing an injection for parenteral administration, a sterile aqueous or nonaqueous solution, solubilizer, suspension or emulsifier is used. Examples of the aqueous solution, solubilizer, and suspension agent include: water for injection, distilled water for injection, physiological saline, cyclodextrin and its derivatives, organic amine or inorganic alkali solution such as triethanolamine, diethanolamine, monoethanolamine, triethylamine, etc.

In the case of aqueous solutions, for example, it is also possible to use: and vegetable oils such as propylene glycol, polyethylene glycol, and olive oil, and alcohols such as ethanol. Meanwhile, as the solubilizer, for example: polyoxyethylene hardened castor oil, surfactants such as sucrose fatty acid esters (forming mixed micelles), lecithin, and hydrogenated lecithin (forming liposomes). Also, an emulsion preparation containing a water-insoluble solubilizing agent such as vegetable oil and lecithin, polyoxyethylene hardened castor oil or polyoxyethylene polyoxypropylene glycol can be prepared.

As a dosage form for parenteral administration, a transdermal absorbent such as a patch can also be used. In the case of preparing a skin preparation for external use such as a patch, the preparation can be prepared in any form of an aqueous solution system, a solubilizing system, an emulsifying system, a powder dispersion system, a water-oil two-layer system, a water-oil-powder three-layer system, and the like. Since the compound (a) is water-soluble, it can be preferably prepared by dissolving it in water or emulsifying it after dissolving it in water in the preparation, but the preparation method is not limited thereto. The external preparation for skin may optionally contain components generally blended in pharmaceutical compositions, within a range not impairing the effects of the present invention, for example: alcohol, oil, surfactant, ultraviolet absorbent, humectant, thickener, antiseptic, inorganic powder, organic powder, perfume, etc. In addition, in the case of an external preparation for skin such as an ointment, it can be prepared by dissolving or dispersing the compound (a) in a lipophilic, water-soluble or emulsion-type base. Examples of the base include: examples of the solvent include, but are not limited to, petroleum jelly, lanolin, and polyethylene glycol.

When the administration route is transmucosal, it may be a dosage form such as sublingual tablet. The sublingual tablet can be produced by a method for producing a usual tablet, such as tableting at a lower pressure than a usual tablet. In addition, the transmucosal dosage forms such as suppositories, enteric tablets and enteric capsules can be appropriately formulated by a usual method.

(8) The dose of the pharmaceutical composition of the present invention

The general formula [ II ] of the invention]The compound or a salt thereof, as a free compound, varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is administered so that the blood concentration is 10 to 3000ng/m L, preferably 20 to 1500ng/m L, more preferably 30 to 1000ng/m L, preferably the blood concentration immediately after administration is 300ng/m L or more]The compound shown is preferably of the formula [ II]Optical isomer 1 of the compound shown. More preferably optically active 4- [3- (4-benzylpiperidin-1-yl) propionyl groupBase of]-7-methoxy-2, 3,4, 5-tetrahydro-1, 4-benzothiazepineComponent 1 (Compound (A)) which is an optical isomer in the-1-oxide.

(9) Medical use of the pharmaceutical composition of the present invention

The pharmaceutical composition of the present invention is useful for treating or ameliorating the symptoms of a disease accompanied by renal dysfunction.

Diseases associated with renal dysfunction are classified into glomerular diseases, tubulointerstitial diseases, renal failure, renal diseases, polycystic kidney disease, and the like, depending on the disease state or the site of the disorder. The glomerular diseases include diseases associated with glomerular disorders such as acute nephritis syndrome, rapidly progressive nephritis syndrome, recurrent and persistent hematuria, chronic nephritis syndrome, nephrotic syndrome, and the like. The tubulointerstitial disease includes diseases accompanied by tubulointerstitial disorders such as tubulointerstitial nephritis (acute, chronic or not clearly defined which type). Among renal failure, acute renal failure and chronic renal failure are included. The renal diseases include viral nephropathy (HB virus nephropathy, HC virus nephropathy, HIV nephropathy, BK virus nephropathy, and the like), nephrosarcoidosis, diabetic nephropathy, hereditary nephropathy, familial nephritis, hypertensive nephropathy, hepatorenal syndrome, NSAID nephropathy, analgesic nephropathy, contrast-induced nephropathy, heavy metal-induced nephropathy, and the like. These diseases can be the subjects of use of the pharmaceutical composition of the present invention. Renal dysfunction is an acute disease or a chronic disease, which is the subject of the pharmaceutical composition of the present invention. Preferred uses of the pharmaceutical composition of the present invention include: diabetic nephropathy, glomerulonephritis, renal dysfunction due to shock or hemorrhage, and renal dysfunction complicated by arrhythmia or heart failure are exemplified.