JPH1192371A - Therapeutic agent for diabetic renal disease and hypolipidemic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a therapeutic agent useful for treatment of diabetic renal disease or the like by including, as the active ingredient, a 3-mercaptopicolinic acid derivative having a specific structure. SOLUTION: This therapeutic agent contains, as the active ingredient, at least one of 3-mercaptopicolinic acid derivatives selected from the group consisting of the compounds shown by formula I (R<1> is H or an alkyl; R<2> is H, an alkyl, aralkyl or the like; R<3> is H, a halogen, alkyl or the like; R<4> is H, an alkyl or (substituted)mercapto; and R<5> is H, a halogen, alkyl or the like) and formula II, preferably 3-mercaptopicolinic acid. It is contained at around 0.1 to 99.5 wt.%, preferably 0.5 to 95 wt.%, based on the whole agent composition, and is administered to a patient generally at 10 to 120 mg a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD [0001] The present invention relates to a therapeutic agent for diabetic renal disease and a lipid-lowering agent comprising a 3-mercaptopicolinic acid derivative (hereinafter referred to as a 3-MPA derivative) as an active ingredient.

[0002]

2. Description of the Related Art It has been reported that a 3-MPA derivative inhibits gluconeogenesis in rats fasted for 48 hours and lowers blood glucose [Journal of Medicinal Chem.
chemistry, 1974, vol. 17, p. 106
5-1071)]. However, it is not known that these derivatives have a therapeutic effect on diabetic kidney disease and a lipid-lowering effect. Conventionally, various therapeutic agents for diabetic renal diseases and lipid-lowering agents are known, but there is a drawback that some patients have serious side effects, and none of them is satisfactory.

[0003]

The present invention relates to 3-MPA
An object of the present invention is to provide a therapeutic agent for diabetic renal disease and a lipid-lowering agent comprising a derivative as an active ingredient.

[0004]

Means for Solving the Problems The present inventors have prepared various 3-
As a result of testing the MPA derivative, it was found that the 3-MPA derivative was useful as a therapeutic agent for diabetic renal disease and a lipid-lowering agent. The present invention has been made based on such findings. The present invention has the general formula

[0005]

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Wherein R ¹ is a hydrogen atom, an alkyl group,
R ² is a hydrogen atom, an alkyl group, an aralkyl group, an acyl group, R ³ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, an optionally substituted mercapto group, a phenoxy group, and R ⁴ is , A hydrogen atom, an alkyl group,
An optionally substituted mercapto group, R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group, or a —COOR ¹ group. ) And the general formula (II)

[0007]

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A therapeutic agent for renal diseases and a lipid-lowering agent comprising as an active ingredient at least one 3-mercaptopicolinic acid derivative selected from the group represented by

In the above general formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵
Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl and the like. Preferably, it is a methyl or ethyl group. As the acyl group for R ² , for example, adamantanecarbonylbenzoyl, p-pivaloylbenzoyl, p-
Propionylbenzoyl, p-methoxycarbonylbenzoyl, o-chlorobenzoyl, m-chlorobenzoyl, p-chlorobenzoyl, p-methylbenzoyl, m
-Methoxybenzoyl, p-methoxybenzoyl, m-
Trifluoromethylbenzoyl, p-trifluoromethylbenzoyl, p-acetylaminobenzoyl, p-dimethylaminobenzoyl, p-benzoylaminobenzoyl, p-carboxamidobenzoyl, p-aminosulfonylbenzoyl, p-cyanobenzoyl, p-nitrobenzoyl , P-fluorobenzoyl and the like.
Examples of the aralkyl group include a benzyl group and a p-methoxybenzyl group. The halogen atom for R ³ is chlorine, bromine, fluorine or the like, preferably chlorine. Examples of the alkoxy group for R ³ include methoxy, ethoxy, propoxy, and phenoxy groups. R ³ ,
The mercapto group which may be substituted for R ⁴ is a thiol, a carboxyl group for methylthio group R ⁵ is a —C at the 1-position.
OOR ¹ and it may be the same. And the like.

The compound used in the present invention is a commercially available product or a compound synthesized by a known method. Specifically, (1) 3
-Mercaptopicolinic acid, (2) 3-methylthiopicolinic acid, (3) 3- (p-adamantanecarbonylbenzoylthio) picolinic acid, (4) 3- (o-chlorobenzoylthio) picolinic acid, (5) 3- (M-chlorobenzoylthio) picolinic acid, (6) 3- (p-chlorobenzoylthio) picolinic acid, (7) 3- (m-methoxybenzoylthio) picolinic acid, (8) 3- (p-methoxybenzoyl) Thio) picolinic acid, (9) 3- (m-trifluoromethylbenzoylthio) picolinic acid, (10) 3-
(P-trifluoromethylbenzoylthio) picolinic acid, (11) 3- (p-aminosulfonylbenzoylthio) picolinic acid, (12) 3- (p-benzoylaminobenzoylthio) picolinic acid, (13) 3- ( p-carboxamidobenzoylthio) picolinic acid, (14) 3-
(P-cyanobenzoylthio) picolinic acid, (15) 3
-(P-dimethylaminobenzoylthio) picolinic acid,
(16) 3- (p-fluorobenzoylthio) picolinic acid, (17) 3- (p-methoxycarbonylbenzoylthio) picolinic acid, (18) 3- (p-acetylaminobenzoylthio) picolinic acid, (19) 3- (p-methylbenzoylthio) picolinic acid, (20) 3- (p-nitrobenzoylthio) picolinic acid, (21) 3- (p-
(Pivaloylbenzoylthio) picolinic acid, (22) 3-
(P-propionylbenzoylthio) picolinic acid, (2
3) 3-mercapto-4-methylpicolinic acid, (24)
4-ethyl-3-mercaptopicolinic acid, (25) 3-
Mercapto-4-methoxypicolinic acid, (26) 3-mercapto-4-methylthiopicolinic acid, (27) 3-mercapto-4-phenoxypicolinic acid, (28) 4-amino-3-mercaptopicolinic acid, (29) 4-chloro-3-mercaptopicolinic acid, (30) 4-ethyl-3
-(P-methoxybenzoylthio) picolinic acid, (3
1) 4-ethyl-3-mercaptopicolinic acid, (32)
5-chloro-3-mercaptopicolinic acid, (33) 3-
Mercapto-5-methylpicolinic acid, (34) 6-chloro-3-mercaptopicolinic acid, (35) 3-mercapto-6-methylpicolinic acid, (36) 3,4-dimercaptopicolinic acid, (37) 3 , 5-Dimercaptopicolinic acid, (38) 3,5-dimercapto-2,6-pyridinedicarboxylic acid, (39) 3-mercapto-2,6-pyridinedicarboxylic acid, (40) 3,3′-dithiobis Picolinic acid and the like.

Examples of the ester derivative include ester derivatives of the above compound group, for example, methyl 3-methylthiopicolinate, ethyl 3-methylthiopicolinate and the like. Among the compounds of the present invention, more preferred is 3-mercaptopicolinic acid.

The 3-MPA derivative used in the present invention is a pharmacologically acceptable acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, or an organic acid, maleic acid, tartaric acid, citric acid, benzoic acid, or Bases such as organic bases such as amines and salts with inorganic bases such as alkali metal salts can be used.

[0013] A test for inhibiting the progress of renal disease, a test for lowering lipid, and examples of preparations of the present invention are shown below.

[0014]

【Example】

Example 1 Test method Streptozotocin (STZ) (40 mg / kg) was intravenously administered to male Wistar rats (8 weeks old) (day 1). Blood samples were collected on days 35-36, and serum biochemical tests were performed. Urine samples were collected on days 31-39, and urine tests were performed. After blood glucose, CHO, ALB in urine, and body weight were classified as indices, 3- Neutralize and dissolve MPA with baking soda,
It was orally administered at a dose of 0.3 mmol / kg, 5 days a week, and biochemical tests were periodically performed every 2 to 3 weeks until day 116, and BUN (mg / dl), CHO (mg
/ Dl), TG (mg / dl), GLU (mg / dl)
And urine ALB (mg / day) values were measured. Preparation method of drug: Neutral dissolve the drug in water using baking soda,
A 5 ml / kg aqueous solution was obtained. Water was administered to the control group.

Comparative Example 1 Metformin (commercially available product) was used as a test drug, and a test was conducted in the same manner as in Example 1. The test results of the above Examples and Comparative Examples were as shown in the following table. Table 1 [BUN (m
g / dl)], Table 2 [CHO (mg / dl)], Table 3
[TG (mg / dl)], Table 4 [GLU (mg / d
l)] and Table 5 [Urine ALB (mg / day)].

[0016]

[Table 1]

From the results shown in Table 1, it can be seen that the compound of the present invention significantly suppressed the increase in BUN value as compared with the control group.

[0018]

[Table 2]

From the results in Table 2, it can be seen that the compound of the present invention is CHO
It can be seen that the value has been reduced.

[0020]

[Table 3]

From the results shown in Table 3, it can be seen that the compound of the present invention significantly suppressed the increase in TG value as compared with the control group and metformin.

[0022]

[Table 4]

From the results in Table 4, it can be seen that the compounds of the present invention significantly reduce the GLU value as compared with the control group.

[0024]

[Table 5]

From the results shown in Table 5, it can be seen that the compounds of the present invention significantly suppressed the urinary ALB level as compared with the control group.

From the above results, it is clear that 3-MP used in the present invention
A derivative has BUN value, CH in STZ-induced renal injury
It shows an effect of remarkably improving values such as O value, TG value, GLU value and urinary ALB. These 3-MPA derivatives are useful as therapeutic agents for diabetic kidney disease. In addition, the compounds of the present invention significantly reduce CHO and TG values, and are therefore useful as lipid-lowering agents.

The 3-MPA derivative of the present invention can be used as a therapeutic agent for diabetic renal disease and a lipid-lowering agent by formulating it alone or with a compatible pharmaceutical carrier. Carrier materials include water, gelatin, gum arabic,
Lactose, starch, magnesium stearate, talc,
Organic or inorganic inert carrier materials suitable for intestinal, transdermal or parenteral administration, such as vegetable oils, polyalkylene glycols and petrolatum. Examples of the preparation include tablets, sugar-coated tablets, enteric-coated tablets, granules, powders, suppositories, capsules, solid preparations such as enteric capsules and liquid preparations such as solutions, suspensions and emulsions. Each of the above preparations can be produced according to a conventional method. In addition, auxiliary agents such as preservatives, stabilizers, setting agents, emulsifiers, flavor improvers, salts, and buffers can also be added.

When the compound of the present invention is used as a medicine, it can be used alone or in combination of two or more different compounds. The amount used is about 0.1 to 99.5%, preferably 0.5 to 95%, by total weight of the pharmaceutical composition. The daily dosage of the compound of the present invention for patients depends on the use, body weight, age,
Depending on the condition being treated, it is generally in the range of 10 to 120 mg per person.

Formulation Example 1 Tablets are prepared by the usual method with the following composition. Compound of Example 1 25 mg Lactose 60 mg Potato starch 40 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg

Formulation Example 2 Granules having the following composition are prepared by a conventional method. Compound of Example 1 50 mg Lactose 15 mg Maize starch 10 mg Hydroxypropyl cellulose 20 mg Polyvinyl alcohol 5 mg

Formulation Example 3 A powder having the following composition is prepared by a conventional method. Compound of Example 1 25 mg Lactose 275 mg

Formulation Example 4 The powder obtained in Formulation Example 3 is filled into a capsule container to prepare a capsule. Compound of Example 1 25 mg Lactose 275 mg

[0033]

According to the present invention, a therapeutic agent for diabetic renal disease and a lipid-lowering agent comprising the 3-mercaptopicolinic acid derivative of the present invention as an active ingredient can be provided.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Takeshi Endo 55 Yokohoonji Temple, Kamiichi-cho, Nakashinagawa-gun, Toyama Prefecture Fuji Chemical Industry Co., Ltd.

Claims (2)

[Claims] 1. A compound of the general formula (I) Wherein R ¹ is a hydrogen atom, an alkyl group, R ² is a hydrogen atom, an alkyl group, an aralkyl group, an acyl group, and R ³ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, An optionally substituted mercapto group, a phenoxy group, R ⁴ represents a hydrogen atom, an alkyl group, an optionally substituted mercapto group, and R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group, or a —COOR ¹ group. ) And the general formula (II) A therapeutic agent for renal disease, comprising as an active ingredient at least one 3-mercaptopicolinic acid derivative selected from the group represented by: 2. A compound of the general formula (I) Wherein R ¹ is a hydrogen atom, an alkyl group, R ² is a hydrogen atom, an alkyl group, an aralkyl group, an acyl group, and R ³ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an amino group, An optionally substituted mercapto group, a phenoxy group, R ⁴ represents a hydrogen atom, an alkyl group, an optionally substituted mercapto group, and R ⁵ represents a hydrogen atom, a halogen atom, an alkyl group, or a —COOR ¹ group. ) And the general formula (II) A lipid-lowering agent comprising as an active ingredient at least one 3-mercaptopicolinic acid derivative selected from the group consisting of: