JPH05949A - Kidney function improving and kidney protecting agent - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] (+)-(R) -3,4-dihydro-2-
[5-methoxy-2- [3- [N-methyl-N- [2-
[(3,4-Methylenedioxy) phenoxy] ethyl]
Amino] propoxy] phenyl] -4-methyl-3-oxo-2H-1,4-benzothiazine (Formula (I): R ^{1
_{= 5-OCH 3; R 2}} = R 4 = CH 3; R 3 = 3,4-
_{OCH 2 O-; A = (CH} 2) 3; B = (CH 2) 2;
A bonding position of OA = 2-) A renal function improving agent and a renal protective agent containing a benzothiazine derivative such as a fumarate. [Effect] Since the amount of urea nitrogen and creatinine in serum can be reduced, it is effective in improving renal dysfunction such as nephritis, diabetic nephropathy, and obstructive nephropathy, and preventing renal dysfunction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a renal function improving agent and a renal protective agent containing a benzothiazine derivative as an active ingredient.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 62-123181 discloses a 2-phenyl-3-oxo-2H-1,4-benzothiazine derivative containing hypertension and thrombosis. It has been shown to be useful as a therapeutic agent for diseases and arrhythmias. However, the action of these compounds on the kidney has not been known, and application to this field needs to be examined.

Then, the present inventors have examined the effects of these compounds on the kidney, and as a result, have found that they have a renal function improving effect and a renal protecting effect.

[Structure of the Invention] The present invention has the following general formula (I):
The present invention relates to a renal function-improving and renal-protecting agent, which comprises a compound represented by (1) or a salt thereof (hereinafter referred to as the present compound) as an active ingredient.

[0005]

[Chemical 2]

[Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group. R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, and R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group. , Halogen atom, nitro group, lower alkylenedioxy group, lower alkanoyl group,
Lower alkanoyloxy group, an amino group, lower alkylamino groups, one or more groups or is selected from lower alkanoylamino group or a lower alkoxycarbonyloxy group - (CH _{2) n} - indicates, R ⁴ is a hydrogen atom or a lower Represents an alkyl group, A and B are the same or different and each represents a lower alkylene group having 1 to 6 carbon atoms, and n represents 3 or 4. ]

The group defined above will be explained in more detail. The lower alkyl group means an alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group and hexyl group, and the halogen atom means Indicates fluorine, chlorine, bromine, etc., and the lower alkoxy group is a methoxy group, an ethoxy group,
The alkoxy group having 1 to 6 carbon atoms such as propoxy group and hexyloxy group is shown, and the lower alkanoyloxy group means 1 to 6 carbon atoms such as acetyloxy group, propionyloxy group and hexanoyloxy group. Shows an alkanoyloxy group having, and the lower alkylenedioxy group means a group having an alkylene group having 1 to 6 carbon atoms between two oxygen atoms such as methylenedioxy group and ethylenedioxy group. The lower alkanoyl group means an alkanoyl group having 1 to 6 carbon atoms such as an acetyl group, a propionyl group and a hexanoyl group.

The salts in this compound are not particularly limited as long as they are pharmaceutically acceptable salts.
Examples thereof include sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate, paratoluenesulfonate and the like. Moreover, stereoisomers exist in the present compound, and all of them are included in the present invention.

The renal dysfunction is, for example, nephritis, diabetic nephropathy, obstructive nephropathy and the like, which eventually causes renal failure and loses the function as a kidney. In order to examine the usefulness of the present compound on renal dysfunction, the effect on rat renal ischemia-reperfusion-induced acute renal failure model was examined. Although detailed data will be described in the section of pharmacological studies, those administered with this compound have a clear decrease in serum urea nitrogen and creatinine levels, which are indicators of renal failure, compared with controls. Became a renal function improving agent.

The results also show that administration of the present compound maintains renal function and has a renal protective effect. This renal protective effect not only prevents renal damage but also indicates that the function of the transplanted kidney in renal transplantation can be maintained.

The dose of the present compound in the present invention may be any as long as the therapeutic effect can be exerted, and the daily dose is preferably 1 to 1000 mg, but may be appropriately changed depending on the symptoms, age, dosage form and the like. Good. The compound may be administered orally or parenterally, and examples of the dosage form include tablets, capsules, granules, powders, injections and transdermal absorption agents. For example, JP-A-62-123181. The disclosed formulations can be used.

[0012]

EFFECTS OF THE INVENTION As shown in the section of the pharmacological test, this compound reduces the amounts of urea nitrogen and creatinine in serum, and is useful as a renal function improving agent and a renal protective agent.

[0013]

[Examples] Pharmacological test To examine the usefulness of drugs for renal dysfunction,
A method for administration to a rat of acute renal failure model induced by renal ischemia-reperfusion is known. (Lothar H.et a
l., The Journal of Urology, 134 , 1251 (19
85)) Then, as a representative example of this compound, (+)-
(R) -3,4-dihydro-2- [5-methoxy-2-
[3- [N-methyl-N- [2-[(3,4-methylenedioxy) phenoxy] ethyl] amino] propoxy]
Phenyl] -4-methyl-3-oxo-2H-1,4-
The effect was investigated using benzothiazine fumarate (hereinafter referred to as Compound 1).

Experimental Method An experiment was carried out as follows according to the method of Lothar H. et al. That is, the right kidney of Wistar / ST male rats (1 group, 7 rats) was removed under anesthesia. Next, a disposable clip is applied to the artery and vein of the left kidney to completely block the blood flow.
After 0 minutes, the clip was removed and blood flow was resumed. Compound 1
Was dissolved in a 0.5% methylcellulose solution 2 hours before the onset of ischemia and administered. Control does not include drug 0.5
% Methylcellulose solution alone was administered.

Blood was collected on the second and third days after ischemia to measure the amounts of urea nitrogen and creatinine in serum. Among the results obtained by the above experiment, the amount of urea nitrogen in serum on the second day after ischemia is shown in Table 1, and the amount of creatinine in serum on the third day after ischemia is shown in Table 2.

Table 1 Amount of urea nitrogen in serum 2 days after ischemia ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Urea Nitrogen amount (mg / dl) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Control 64.00 Compound 1 25 mg / Kg administration group 41. 74 Compound 1 50 mg / Kg administration group 26.33 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Table 2 Amount of creatinine in serum 3 days after ischemia ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ creatinine amount (Μg / ml) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Control 15.82 Compound 1 25 mg / Kg administration group 12.35 Compound 1 50 mg / Kg administration group 10.58 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

As shown in the table, the administration of the present compound clearly decreased the urea nitrogen level and creatinine level in the serum as compared with the control, and that the effect was increased by increasing the dose. I understood.

Claims (1)

Claims: 1. A renal function-improving and renal-protecting agent comprising a compound represented by the following general formula (I) or a salt thereof as an active ingredient. [Chemical 1] [Wherein R ¹ is selected from a hydrogen atom, a lower alkyl group, a halogen atom, a nitro group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an amino group, a lower alkylamino group or a lower alkoxycarbonyl group.
Or more groups, R ² represents a hydrogen atom, a lower alkyl group or a cycloalkyl group having 3 to 6 carbon atoms, R ³ represents a hydrogen atom, a lower alkyl group, a hydroxy group,
One or more selected from a lower alkoxy group, a halogen atom, a nitro group, a lower alkylenedioxy group, a lower alkanoyl group, a lower alkanoyloxy group, an amino group, a lower alkylamino group, a lower alkanoylamino group or a lower alkoxycarbonyloxy group. Group or-(C
H ₂ ) _n- , R ⁴ represents a hydrogen atom or a lower alkyl group, A and B represent the same or different lower alkylene groups having 1 to 6 carbon atoms, and n is 3 or 4 Indicates. ]