WO1998043645A1

WO1998043645A1 - Inhibitors for the formation of glycosylated protein denaturation products

Info

Publication number: WO1998043645A1
Application number: PCT/JP1998/001250
Authority: WO
Inventors: Toru Kawamura; Tomoyuki Maruyama; Toshiaki Akira; Takashi Awata
Original assignee: Yoshitomi Pharmaceutical Industries, Ltd.; Senju Pharmaceutical Co., Ltd.
Priority date: 1997-03-31
Filing date: 1998-03-20
Publication date: 1998-10-08
Also published as: AU6421598A; JP2003119142A

Abstract

Inhibitors for the formation of glycosylated protein denaturation products containing as the active ingredient 1,4-benzothiazine-2-acetic acid compounds represented by general formula (I) or pharmceutically acceptable salts thereof (wherein R?1 and R2¿ represent each H, halogeno, lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or trifluoromethoxy; R3 represents optionally esterified carboxy; R?4, R5, R6 and R7¿ represent each H, halogeno, lower alkyl, lower alkoxy or trifluoromethyl; and X represents O or S) and preventives/remedies for diseases caused or worsened by the formation of glycosylated protein denaturation products.

Description

Specification

Glycoprotein denaturing substance formation inhibitor Technical field

The present invention relates to an inhibitor for the production of a modified glycated protein (Advanced Glycation Endproducts; hereinafter, referred to as “AGE”) containing a 1,4-benzothiazine-12-acetic acid compound or a pharmaceutically acceptable salt thereof as an active ingredient. . Background art

Non-enzymatic glycation of proteins in vivo causes direct protein modification and cell damage via receptors on cell membranes, resulting in diabetes, arteriosclerosis, collagen disease and Alzheimer's disease. It is known to cause various functional disorders such as senile diseases such as senile diseases.

That is, glucose in the blood non-enzymatically forms a Schiff base with an amino group of a protein, and further produces a translocation product by Amadori rearrangement. The Amadori rearrangement product releases active oxygen and is converted to a 3-deoxydalcosone-like active intermediate by the action of a trace amount of transition metal, and further reacts with the amino group of the protein, followed by oxidation and condensation. AGEs are formed through complex reactions such as, rearrangement and dehydration. AGE is considered to be a polymer in which a protein (or a degradation product thereof) is crosslinked with a structure derived from sugar. AGEs are also produced in healthy individuals and increase with age.For example, in diabetic patients, high blood glucose levels cause rapid glycation of proteins, which may lead to functional disorders of the target protein. It is said that this is one of the causes of various diabetic complications. In addition, active oxygen generated when AGE is generated is also considered to cause cell damage. More specifically, it has been recognized that diabetic cataract is caused by crystallin polymerization, insolubilization, fluorescence generation, and coloring accompanying glycation of crystallin in the eye lens (J. Biol. Chem., 256, 5176). , 1981), and diabetic neuropathy is a non-enzymatic glycation of neuronal myelin protein. Is thought to be the cause (Clin. Endocrinol. Metab., 11, 431, 1982). In addition, AGE production is not limited to diabetes-related diseases as described above, but is also considered to be a cause of aging.For example, senile cataract is associated with glycation of crystallin in the ocular lens, and atherogenic. AGEs are also involved in arteriosclerosis. Furthermore, it is known that AGE is also involved in the thickening of the basement membrane of blood vessels due to aging and the thickening of the glomerular basement membrane, which causes a decrease in renal function (Science, 232 ^ 1629, 1986). It is also known that AGE is involved in the formation of specific neurofibrillary tangles and senile plaques observed in Alzheimer's disease (Pro Natl. Acad. Sci. USA, 91, 4766, 1994 and Proc. Natl. Acad. Sci. USA, 91, 5710, 1994).

Against this background, a search has been made for substances that inhibit AGE formation of proteins, and aminoguanidine has been reported as such a compound (Science, 23 1629, 1986). Aminoguanidine is thought to block the transfer of the protein to AGE because it blocks the active carbonyl group of the Amadori rearrangement product and inhibits cross-linking polymerization of the Amadori rearrangement product. However, aminoguanidine has a problem not only in its degree of efficacy but also in the occurrence of serious side effects (nephrotoxicity). To date, no AGE generation inhibitor that can be clinically used has been found yet. . Disclosure of the invention

The present inventors have proposed various diseases caused by the generation of AGE by inhibiting the generation of AGE or diseases in which the progress of the disease state is caused by the generation of AGE, for example, diabetes-induced diseases, that is, diabetic complications. (Neuropathy, retinopathy, nephropathy, cataract, etc.), non-diabetic diseases (neuropathy, retinopathy, nephropathy, cataract, coronary heart disease, peripheral circulatory disorders, cerebrovascular disorders, arteriosclerosis, As a result of examining compounds useful for preventing and treating arthriosclerosis, rheumatoid arthritis, cancer, Alzheimer's disease, etc., 1,4-benzthiazine-2-acetic acid compound represented by the following general formula (I) was examined. Alternatively, a pharmaceutically acceptable salt thereof is not limited to the type of protein, but is an excellent inhibitor of AGE formation. It was found to have harmful activity. The present invention can be made based on such findings.

An object of the present invention is to provide an AGE production inhibitor. Another object of the present invention is to provide a prophylactic / therapeutic agent for the various diseases as described above, which develops due to the generation of AGE or whose disease state is advanced by the generation of AGE.

The present invention relates to the following.

The following general formula (I)

(In the formula, R ¹ and R ² may be the same or different, and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group, and R ³ is an ester And R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group. And X represents an oxygen atom or a sulfur atom.

An AGE formation inhibitor comprising, as an active ingredient, a 1,4-benzothiazine-2-acetic acid compound or a pharmaceutically acceptable salt thereof (hereinafter, referred to as “1,4-benzothiazine-12-acetic acid compounds”).

1, 4 A method for inhibiting AGE production, which comprises administering a benzothiazine-12-acetic acid compound. -

Use of 1,4-monobenzothiazine-2-acetic acid compounds for the production of AGE formation inhibitors. A pharmaceutical composition for inhibiting SAGE production, comprising a 1,4-benzothiazine-12-acetic acid compound and a pharmaceutically acceptable carrier.

A commercial package comprising the pharmaceutical composition and a description of the pharmaceutical composition, which states that the pharmaceutical composition can or should be used for inhibiting AGE production.

A preventive / therapeutic agent for diseases caused by the production of AGE containing 1,4-benzothiazine-12-acetic acid compounds as an active ingredient or for diseases whose progress is caused by the production of AGE.

A method for preventing or treating a disease that develops due to the generation of AGE or a disease in which the progression of the disease state is caused by the generation of AGE, which comprises administering 1,4-benzothiazine-2-acetic acid compounds.

Use of 1,4-benzothiazine-2-acetic acid compounds for the manufacture of a prophylactic / therapeutic agent for a disease that develops due to the generation of AGE or a disease whose progress is caused by the generation of AGE.

Pharmaceutical composition for prevention and treatment of diseases caused by AGE generation or diseases in which AGE generation leads to progression of AGEs containing 1,4-benzothiazine-2-acetic acid compounds and pharmaceutically acceptable carrier object.

The above-mentioned pharmaceutical composition and the composition can be used or should be used for the prevention and treatment of diseases caused by AGE production or diseases in which AGE production leads to progression of disease state A commercial package containing a description of the pharmaceutical composition, wherein

In the compound represented by the general formula (I), the definition of each substituent is as follows: ο

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. The lower alkyl group is preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. , Sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

As the lower alkoxy group, a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms is preferable. For example, methoxy, ethoxy, propoxy, isopropoxy, putoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, iso Pentyloxy, hexyloxy, isohexyloxy and the like. As the lower alkylthio group, a linear or branched alkylthio group having 1 to 6 carbon atoms is preferable, and methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, O isopentylthio, hexylthio, isohexylthio, etc.

Examples of the esterified carboxyl group include lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, and tert-butoxycarbonyl; cyclohexyloxycarbonyl, cyclopentyl A cycloalkyloxycarbonyl having 5 to 10 carbon atoms in the cycloalkyl moiety such as an oxycarbonyl; or a substituent such as a halogen atom, a lower alkyl group, a lower alkoxy group, or a nitro group on the benzene ring; Aryloxycarbonyl or benzyloxycarbonyl, which may have the following.

The compound represented by the general formula (I) has an asymmetric carbon atom, and therefore can exist as a stereoisomer, and can be separated into a pure isomer if necessary.

The pharmaceutically acceptable salt of the compound represented by the general formula (I) is not particularly limited as long as it is pharmaceutically acceptable and non-toxic. Examples thereof include a lithium salt, a sodium salt, and a potassium salt. Alkali metal salts such as calcium salts, magnesium salts and the like Al earth metal salts; aluminum salts; salts with organic bases such as triethylamine salts and pyridine salts; salts with basic amino acids such as lysine salts and arginine salts No. In the general formula (I), R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different, and a compound which is a hydrogen atom, a fluorine atom or a chlorine atom is preferable as the compound of the present invention.

In the present invention, the compound represented by the general formula (I) is a known compound, and the compound including its preparation method is described in, for example, JP-A-5-92961. Representative examples of the compound represented by the general formula (I) include, for example, the following 3,4-dihydro-13-oxo_4 — [(4,5,7-trifluoro-2-benzothiazolyl) methyl ] — 2 H-1,4-benzothiazine-2-acetic acid.

The pharmaceutical composition of the present invention comprises a preparation of 1,4-benzothiazine-12-acetic acid compound as an active ingredient and an appropriate pharmaceutically acceptable carrier (eg, excipient, diluent, etc.). Contains pharmaceutically necessary ingredients. The pharmaceutical composition can be administered orally in the form of powder, granules, tablets, capsules and the like, or parenterally in the form of injections, eye drops and the like. An effective amount of the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is blended in the above pharmaceutical composition.

In the preventive treatment method of the present invention, the dose of 1,4-benzothiazine-2-acetic acid compound varies depending on the administration route, symptoms, patient weight or age, etc., for example, oral administration to an adult patient In this case, it is desirable to administer 1 to 200 OmgZkg body weight / day, especially 10 to 60 OmgZkg body weight daily, once to several times a day. Brief description of the drawings

FIG. 1 is a graph showing the results of Test Example 1, and shows the inhibitory effect of Compound A on the production of AGE-modified hemoglobin.

FIG. 2 is a graph showing the results of Test Example 2, and shows the inhibitory effect of Compound A on the generation of AGE-lysozyme. Example

Hereinafter, the present invention will be described in more detail based on test examples, but the present invention is not limited to these examples.

Formulation Example 1

Tablets

(1) Compound A 10 mg

(2) Fine particles for direct hit No. 209 (Fuji Chemical Co., Ltd.) 46. o mg Magnesium aluminate metasilicate 20%

Tumor corn starch 30% lactose 50%

(3) Microcrystalline cellulose 24.0 mg

(4) CarboxymethylcelluloseCalcium 4.0 mg

(5) Magnesium stearate 0.4 mg Compound A: 3,4-dihydro-3-oxo-4 [(4,5,7-trifluoro- mouth-2-benzothiazolyl) methyl] 1-2H-1 monobenzothiazine 2-acetic acid (the same applies to the following formulation examples)

(1), (3) and (4) are all passed through a 100 mesh sieve in advance. After drying (1), (3) and (4) and (2), respectively, to reduce the water content to a certain level, the above weight ratios are mixed using a mixer. At the end of the mixture, ) Was added and mixed for a short time (30 seconds), and the mixed powder was tabletted (punches: 6.3 mm, 6. OmmR) to give a tablet of 85 mg per tablet. The tablet may be coated with a commonly used gastrosoluble film coating agent (for example, polyvinyl acetate or ethyl acetate) or an edible colorant, if necessary. Formulation Example 2

Capsule

(1) Compound A 50 g

(2) Lactose 9 3 5 g

(3) Magnesium stearate 15 g Each of the above components was weighed and mixed uniformly, and the mixed powder was filled into a hard gelatin capsule at 20 Omg. Formulation Example 3

Injection

(1) Compound A 50 mg

(2) Glucose 100 mg

(3) 10 ml of physiological saline The above mixture was filtered with a membrane filter, sterilized and filtered again, and the filtrate was aseptically dispensed into vials, filled with nitrogen gas and injected intravenously. Agent. Formulation Example 4

Eye drops 1

(1) Compound A 0.1

(2) Sodium dihydrogen phosphate, dihydrate 0.1 S

(3) 2.6 g concentrated glycerin

(4) Methyl paraoxybenzoate 0.02 g (5) Propyl paraoxybenzoate 0.O lg

(6) Suitable amount of hydrochloric acid

(7) Appropriate amount of sterilized purified water About 80 ml of sterilized purified water was heated to about 80 ° C to dissolve (4) and (5). The solution was cooled to room temperature, and (1), (2) and (3) were added and dissolved. (6) and p

H was adjusted to 7.5, and the total amount was adjusted to 10 Om 1 in (7). Formulation Example 5

Eye drops 2

(1) Compound A 1.0 g

(2) boric acid 1.0 g

(3) Sodium edetate 0.O l g

(4) Sodium hydroxide

(5) Sterile purified water

The above components were added and dissolved in about 70 ml of sterilized purified water. The pH was adjusted to 8.0 ί with (4), and the total volume was adjusted to 100 ml with (5). Formulation Example 6

Eye ointment

(1) Compound A 3.0 g

(2) White serine

(3) Liquid paraffin 10 g

(4) Methyl paraoxybenzoate 0.02 g

(5) Propyl paraoxybenzoate 0.1 g After weighing each of (1), (3), (4) and (5) above, mix them evenly so that the total amount of (2) is 100 g. And mixed evenly. In order to show the usefulness of the AGE production inhibitor of the present invention, the results of pharmacological tests of typical compounds are shown below.

Test Example 1 (AGE hemoglobin production inhibitory action)

Test compound

3,4-dihydro-3-oxo-1-4-1 [(4,5,7-trifluoro-1-2-benzothiazolyl) methyl] -12H-1, 4-benzothiazine-2-acetic acid (Compound A)

Test method

To male male Sprague-Dawley rats (8 weeks old), streptozotocin (STZ, 60 mgZkg body weight) dissolved in citrate buffer (pH 4.5) was intravenously administered to the tail vein. Three weeks after the administration of STZ, Compound A (30 mgZkg body weight) was suspended in 0.5% carboxymethylcellulose and orally administered once a day for 2 weeks. The control group was orally administered with 5 ml of a vehicle (0.5% carboxymethylcellulose) and a body weight of 5 kg. On the last day of drug administration, blood samples were collected using a syringe containing heparinized saline and centrifuged at 2000 rpm for 10 minutes at 4 ° C to extract hemoglobin.

AGE-hemoglobin (Hb_AGE) in blood was measured by a competitive ELISA method (J. Biol. Chem., 267, 5133 (1992)) modified from a conventionally established protocol. Briefly, the hemoglobin solution 5 extracted above was combined with an equal volume of polyclonal anti-AGE antibody (diluted 1: 400) together with AGE-modified ribonuclease (10 μg in phosphate buffered saline). (/ mL). After incubating at room temperature for 2 hours, add a horseradish peroxidase-labeled secondary antibody, incubate again at room temperature for 1 hour, and add o-phenylenediamine. The bound anti-AGE antibody was detected by. AGE immunoreactivity was measured twice in serially diluted samples. AGE unit is calculated as a relative value to synthetic AGE-ribonuclease standard (1 AGE unit = AGE—10 〃 g of ribonuclease).

All data were expressed as mean value S.E. with 8 to 10 cases. Dunnett's method was used to test for significant differences.

Result

The results are shown in Table 1 and FIG. 1 (#p 0.05, for the normal group; ** p 0.01, for the control group receiving vehicle).

table 1

# p <0.05, for normal group

** P <0.01, Hb-AGE levels in the control group were significantly higher than those in the normal group compared to the control group receiving vehicle (Δ% = 45, ρ < 0.05, relative to normal group). In contrast, the administration of Compound II significantly reduced the Hb_AGE level (ρ 0.01; Δ% = 48 compared to the vehicle-treated control group). As shown in Table 1 and FIG. 1, Compound 示し showed a high inhibitory action on AGE-modified hemoglobin production. Test Example 2 (aged lysozyme production inhibitory effect)

Test compound

3,4-Dihydro-3-oxo-l 4-[(4,5,7-trifluoro-2--benzothiazolyl) methyl] -l2H-l, 4-bene-2-acetic acid (Compound A) Test method

Compound A (dissolved in dimethyl sulfoxide, final concentration: 0.5 mM) was added to 500 t / L of the incubation buffer described below, and the mixture was incubated at 37 ° C for 14 days. The control group (vehicle-administered group) was treated in the same manner as above except that the solvent excluding Compound A (dimethyl sulfoxide, 5% final concentration) was added to the incubation buffer. The control group was incubated at 37 ° C for 14 days with a buffer in which only the concentration of fructoses was 5 mM in the following incubation buffer.

Incubation buffer (final concentration)

Phosphate buffer (pH 7.4) 0.5M

Chicken egg white lysozyme 10 mg / ml

Fructose 250 mM

Pepstatin A 0.1 μg / ml

Leptin 0.5 g / mL

Penicillin + streptomycin 100 units + 100 g / mL ethylenediaminetetraacetic acid 1 mM

Sodium azide 3 mM

After completion of the incubation, AGE-lysozyme (lysozyme-AGE) was measured by a competitive ELISA method modified from a conventionally established protocol. Briefly, 50 L of the above reaction solution was mixed with the same volume of polyclonal anti-AGE antibody (diluted 1: 400) together with AGE-modified lysozyme (1〃 gZmL in phosphate buffered saline). It was added to the sized microtiter plate. After incubation at room temperature for 2 hours, a horseradish peroxidase-labeled secondary antibody was added, incubated again at room temperature for 1 hour, and bound anti-AGE antibody by adding o-phenylenediamine. Was detected. AGE was calculated as absolute value using synthetic AGE-lysozyme standard product

All data were expressed as mean SE of 5 cases. Dunnet to test for significance The t method was used.

Result

The results are shown in Table 2 and FIG. 2 (# #p 0.01 for the control group; * p <0.05 for the control group with vehicle).

Table 2

# # p く 0.01, for the control group

* p <0.05, lysozyme-AGE level in control group was significantly higher than lysozyme-AGE level in control group compared to control group with vehicle addition (Δ% = 808, ρ < 0.01, relative to control group). On the other hand, the AGE level of lysozyme was significantly reduced by the addition of Compound II (p <0.05, Δ% == 14.5 compared to the control group to which vehicle was added). As shown in Table 2 and FIG. 2, Compound 示し exhibited a high inhibitory action on AGE-lysozyme production. Industrial applicability

The 1,4-benzothiazine-2-acetic acid compounds, which are the active ingredients of the present invention, are limited to the types of proteins in mammals (eg, mice, rats, rabbits, dogs, cats, humans, etc.). In addition, it has an excellent AGE production inhibitory effect on plasma proteins such as albumin-globulin and hemoglobin, and has low toxicity. Therefore, AGE Various diseases caused by the generation or diseases whose disease state is progressed by the generation of AGE, such as diabetes-induced diseases, ie, diabetic complications (neuropathy, retinopathy, nephropathy, cataract, etc.) , Non-diabetic diseases (neuropathy, retinopathy, nephropathy, cataract, coronary heart disease, peripheral circulatory disorders, cerebrovascular disorders, arteriosclerosis, arthrosclerosis, rheumatoid arthritis, cancer, Alzheimer's disease, etc.) Useful for prevention and treatment of In addition, the active ingredients of the present invention, 1,4-benzothiazine-12-acetic acid compounds, exhibit particularly excellent inhibitory effects on hemoglobin saccharification. Is useful for the above diseases based on

This application is based on Japanese Patent Application No. 1997-636 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

1. General formula (I)

1,4-Benzothiazine-2-acetate Compound or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The 1,4-benzothiazine-2-acetic acid compound represented by the general formula (I) is converted to 3,4-dihydro-3-oxo_4 — [(4,5,7-trifluoro-2-benzothiazolyl) 2. The glycated protein-denatured substance formation inhibitor according to claim 1, wherein the inhibitor is methyl [1-2H-1,4-benzothiazine-2-acetic acid].

3. General formula (I)

A method for inhibiting the production of denatured glycated protein, which comprises administering a 1,4-benzothiazine-2-acetic acid compound or a pharmaceutically acceptable salt thereof.

4. The 1,4-benzothiazine-12-acetic acid compound represented by the general formula (I) is 3,4-dihydro-13-oxo-1-[(4,5,7_trifluoro-2-benzothiazolyl) methyl 4. The method for inhibiting the production of a glycated protein-modified substance according to claim 3, wherein the method is mono 2H-1,4-benzothiazine_2-acetic acid.

5. General formula (I) for production of glycated protein denaturing substance production inhibitor

Use of 1,4-benzothiazine-12-acetic acid compounds or pharmaceutically acceptable salts thereof.

6. The 1,4-benzothiazine-2-acetic acid compound represented by general formula (I) is 3,4-dihydro-3-oxo-l 4-[(4,5,7_trifluoro-2-benzothiazolyl) methyl ] — 2H—1,4-Monobenzothiazine—2-acetic acid.

7. General formula (I)

A pharmaceutical composition for inhibiting formation of denatured glycated protein, comprising a 1,4-benzothiazine-12-acetic acid compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The 1,4-benzothiazine-2-acetic acid compound represented by the general formula (I)

The compound according to claim 7, which is 4-dihydro-3-oxo-1-41 [(4,5,7-trifluoro-2-benzothiazolyl) methyl] —2H—1,4-benzothiazine-12-acetic acid. A pharmaceutical composition for inhibiting the production of denatured glycated protein.

9. The pharmaceutical composition according to claim 7 or 8, and a statement that the pharmaceutical composition can or should be used for use in inhibiting the production of denatured glycated protein. A commercial package comprising a description of the pharmaceutical composition.

10. General formula (I)

I, —Benzothiazine— 2 —Acetic acid compound or a pharmaceutically acceptable salt thereof as an active ingredient. Prophylactic and therapeutic agents for diseases.

II. Claims that the disease caused by the production of the glycated protein-denatured substance or the disease caused by the production of the glycated protein-denatured substance leads to the development of the disease is the disease caused by the dysfunction of glycation of plasma proteins. [10] The prophylactic / therapeutic agent according to the above item [10].

1 2. A disease caused by the production of a modified glycated protein or a disease caused by the development of a modified glycated protein is a disease caused by an abnormal function due to glycation of hemoglobin. [10] The prophylactic / therapeutic agent according to [10].

13. The preventive treatment according to claim 10, wherein the disease caused by the production of a glycated protein-denatured substance or the disease caused by the development of a glycated protein-denatured substance to progress the disease state is a non-diabetic disease. Agent.

1 4. The 1,4-benzothiazine-2-acetic acid compound represented by the general formula (I) is 3 , 4-dihydro-1-3-oxo-4-[(4,5,7-trifluoro-1-2-benzothiazolyl) methyl] —2H—1,4_benzothiazine_2—acetic acid Claim 10 to Item 14. The prophylactic / therapeutic agent according to any one of Items 13 to 13.

1 5. General formula (I)

(In the formula, R ¹ and R ² may be the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, and R ³ represents Represents a carboxyl group which may be esterified; R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group; And X represents an oxygen atom or a sulfur atom.

Diseases caused by the formation of glycated protein denaturing substances, including the administration of 1,4-benzothiazine-2-acetic acid compounds or pharmaceutically acceptable salts thereof, or the development of disease states due to the formation of glycated protein denaturing substances For preventing or treating diseases resulting in

16. A disease caused by the production of a glycated protein-denatured substance or a disease caused by the development of a glycated protein-denatured substance to progress the disease state is a disease caused by a dysfunction of glycation of plasma proteins. 16. The method for prevention or treatment according to claim 15, wherein

1 7. The disease caused by the production of glycated protein-denatured substances or the disease whose progress is caused by the production of glycated protein-denatured substances is a function of hemoglobin glycation. 16. The method for prevention or treatment according to claim 15, wherein the disease is caused by an abnormality.

18. The prophylaxis or claim according to claim 15, wherein the disease caused by the production of the glycated protein-denatured substance or the disease in which the disease state progresses due to the production of the glycated protein-denatured substance is a non-diabetic-induced disease. Method of treatment.

1 9. The 1,4-monobenzothiazine—2-acetic acid compound represented by the general formula (I) is 3

, 4 — dihydro — 3 — oxo-1 4 _ [(4,5,7 — trifluoro-1-2-benzothiazolyl) methyl] 1 2 H—1,4,1-benzothiazine-2 —acetic acid 15. The prevention or treatment method according to any one of items 15 to 18.

20. General formula (I) for the manufacture of a prophylactic / therapeutic agent for a disease caused by the production of a glycated protein-denatured substance or a disease in which the disease state progresses due to the production of a glycated protein-modified substance

2 1. A disease caused by the production of a modified glycated protein or a disease caused by the development of a modified glycated protein is a disease caused by an abnormal function due to glycation of plasma proteins. Use according to item 20 of the range.

2 2. A disease caused by the production of a modified glycated protein or a disease caused by the development of a modified glycated protein is a disease caused by an abnormal function due to glycation of hemoglobin. Use according to scope 20.

23. The use according to claim 20, wherein the disease caused by the production of a glycated protein-denatured substance or the disease caused by the development of a glycated protein-denatured substance to progress the disease state is a non-diabetic disease.

2 4. The 1,4-benzothiazine-12-acetic acid compound represented by the general formula (I) is converted to 3,4-dihydro-3-oxo-1 4 _ [(4,5,7-trifluoro-2-benzo). The use according to any one of claims 20 to 23, which is thiazolyl) methyl] -2H-1,4-benzothiazine_2-acetic acid.

2 5. General formula (I)

(In the formula, R ¹ and R ² may be the same or different, and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a trifluoromethyl group, or a trifluoromethoxy group, and R ³ is an ester And R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different and represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group. And X represents an oxygen atom or a sulfur atom. 1,4-Benzothiazine-12-acetic acid compound or a pharmaceutically acceptable salt thereof, and a disease or a glycated protein modified substance caused by the formation of a glycated protein modified substance containing a pharmaceutically acceptable carrier. A pharmaceutical composition for the prophylaxis or treatment of a disease in which the development of a disease leads to the development of a disease state.

26. Claim that a disease caused by the production of a glycated protein-denatured substance or a disease caused by the development of a glycated protein-denatured substance leads to the development of a disease is a disease caused by a dysfunction due to glycation of plasma proteins. Item 25.The pharmaceutical composition for prophylactic treatment according to item 25.

27. A disease caused by the production of a modified glycated protein or a disease caused by the development of a modified glycated protein is a disease caused by an abnormal function due to glycation of hemoglobin. 26. The pharmaceutical composition for prophylactic treatment according to item 25.

28. The preventive treatment according to claim 25, wherein the disease caused by the production of a glycated protein-denatured substance or the disease caused by the development of a glycated protein-denatured substance leads to progression of a disease state is a non-diabetic disease. For pharmaceutical compositions.

2 9. — 1, 4-benzothiazine represented by the general formula (I) — 2-acetic acid compound is 3

, 4—Dihidro 3 _oxo-1 4-1 [(4,5,7—Trifluoro-1-2—benzothiazolyl) methyl] —2H—1,4—benzothiazine—2—acetic acid Claim 25 29. The pharmaceutical composition for prophylactic treatment according to any one of -28.

30. The pharmaceutical composition according to any one of claims 25 to 29, and a disease or a glycated protein denaturing substance that develops the pharmaceutical composition due to the production of a glycated protein denaturing substance. A commercial package comprising a description of the pharmaceutical composition, which describes or can be used for the prevention or treatment of a disease whose production leads to the development of a disease state.