JP2009007290A - Advanced glycation end product formation inhibitor comprising phenylpropeneamide derivative as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new AGE (advanced glycation end product) formation inhibitor having excellent inhibitory actions on AGE production and useful as a prophylactic and/or a therapeutic agent for glomerular diseases, particularly as a medicine for prophylaxis and/or therapy of diabetic nephropathy. <P>SOLUTION: The AGE formation inhibitor comprises a phenylpropeneamide derivative represented by formula (1) (wherein, R<SP>1</SP>represents an alkylthio group), a salt thereof or a solvate thereof as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a drug useful for the prevention and / or treatment of the onset or progression of diabetic nephropathy due to irreversible protein modification in glomerular lesions.

  At present, it is said that there are about 20 million diabetic patients, suspected diabetic patients and pre-diabetes group in Japan. Among complications caused by diabetes, the incidence of diabetic nephropathy has been increasing year by year, already exceeding the incidence of chronic glomerulonephritis.

  The biggest problem when diabetic nephropathy develops is that the rate of transition to end-stage renal failure, that is, dialysis, is very high. Moreover, the shift to dialysis due to diabetic nephropathy has become a serious social problem such as a rise in medical costs. Therefore, a therapeutic agent related to diabetic nephropathy or a drug that can be expected to be prevented is strongly desired.

  The pathogenesis of diabetic nephropathy includes (1) genetic predisposition, (2) changes in glomerular hemodynamics, (3) advanced glycation end products caused by increased glycation and carbonyl / oxidative stress (Advanced Glycation End) The involvement of various factors such as accumulation of products (hereinafter referred to as “AGE”), (4) activation of protein Kinase C, and (5) enhancement of polyol metabolism are considered (Non-patent Document 1, Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5).

  Currently, in the treatment of diabetic nephropathy, angiotensin converting enzyme inhibitors (hereinafter referred to as “ACE inhibitors”) and angiotensin II type 1 receptor antagonists (hereinafter referred to as “ACE inhibitors”) mainly aimed at improving glomerular hemodynamics. , Referred to as “ARB”), and clinical evidence as well as basics have been reported (Non-Patent Document 6, Non-Patent Document 7). However, many of these have been approved as antihypertensive agents, and are hardly approved as therapeutic agents for diabetic nephropathy. Simply because many of the patients with diabetic nephropathy have high blood pressure, they are only widely used. Although the ACE inhibitor tanatril tablet (imidapril hydrochloride) was approved for the first time as a therapeutic agent for type 1 diabetic nephropathy, there are few drugs having a therapeutic or prophylactic effect on diabetic nephropathy, Appearance is anxious.

  Therefore, AGE formation inhibitors are attracting attention as therapeutic agents for the next diabetic nephropathy. AGE-modified proteins adversely affect many renal functions such as renal circulatory dynamics and filtration mechanism of the glomerular basement membrane, and AGE-related receptors that are present in many constitutive cells such as mesangial cells. It has been reported that it acts on (for example, Receptor for AGE: RAGE) to produce disorder factors such as cytokines and growth factors (Non-patent Document 8). Therefore, suppressing the formation of AGE is thought to lead to the suppression of the progression of diabetic nephropathy.

  Aminoguanidine is thought to inhibit the formation of AGEs by scavenging action of reactive carbonyl compounds (3-deoxyglucosone, methylglyoxal, etc.), scavenging action of oxygen radicals (particularly hydroxy radicals) and metal chelate forming action. It is a compound that was first fully studied as a therapeutic agent for diabetic nephropathy based on AGE inhibition. However, this clinical trial has already ended, but it has not yet been put into practical use. (Non-patent document 9, Non-patent document 10, Non-patent document 11).

Other AGE formation inhibitors include aminoguanidine derivatives OPB-9195, LR-90, ALT-946, natural compounds and their analogs thiamine (vitamin B ₁ ), thiamine pyrophosphate, benfotiamine. Although some compounds are known (Non-patent Document 12), none of them have been put into practical use.
On the other hand, an AGE formation inhibitor having a phenylpropenamide structure as a skeleton as represented by the following general formula (1) has not been known.

(In the formula, R ¹ represents a C _{1 to} C ₆ alkylthio group, R ² represents a hydrogen atom or a C _{1 to} C ₆ alkyl group, and R ³ represents a hydrogen atom or a C _{6 to} C ₁₀ arylcarbonyl. _group, a C 2 -C ₆ acyl group, or a _C 1 -C ₆ alkyloxycarbonyl group.)

Cooper, ME. Etal .; Lancet, 352, 213-219, 1998. Hiroshi Kanno; Diabetes nephropathy onset and progression mechanism and treatment: 80-121, 1999; Diagnosis and treatment company Bohlender, J. et al .; Am. J. Physiol. Renal Physiol., 289, F645-F659, 2005 D, Jay.et al.; FreeRadical Biology & Medicine, 40,183-192,2006 Vinik, A .; Expert Opin. Investig. Drugs, 14 (12), 1547-1559, 2005 Masakuni, N. et al .; Jpn. J. Pharmacol., 85: 416-422,2001 Rossing, K. et al .; DiabetesCare., 28 (9): 2106-2112,2005 Locatelli, F. et al.; Nephrol.Dial.Transplant., 18 (9): 1716-25,2003 Price, DL. Et al .; J. Biol. Chem., 276, 48967-48972, 2001 Abdel-Rahman, E. et al .; ExpertOpin. Investig. Drugs., 11 (4): 565-574,2002 Mark E. et al.; Current Diabetes Reports., 4: 441-446,2004 Tsutomu Imaizumi et al .; AGEs research front: 209-217, 2004; Medical Review

  The present invention is to provide a novel AGE formation inhibitor. AGE formation inhibitors are useful for the prevention or treatment of the onset and progression of diabetic nephropathy due to irreversible protein modification in glomerular lesions. Even in patients whose primary disease has not been diagnosed with diabetic nephropathy, many patients who have undergone dialysis due to glomerular diseases such as chronic glomerulonephritis and hypertensive nephropathy have markedly increased plasma AGE. Due to the well-known fact that it has increased, AGE formation inhibitors are useful not only for diabetic nephropathy but also for the prevention or treatment of glomerular diseases including chronic glomerulonephritis and hypertensive nephropathy.

  In view of the above situation, as a result of searching for compounds having an AGE formation inhibitory activity, the present inventors have found that a compound represented by the following general formula (1) is an in vitro system using pentosidine, which is a kind of AGE as an index. In the inhibition test, it was found that it has a stronger AGE formation inhibitory action than aminoguanidine, and the present invention has been completed.

That is, the present invention is described in detail as follows.
<1> The following general formula (1)

（式中、Ｒ^１は、Ｃ_１〜Ｃ_６アルキルチオ基を示し、Ｒ^２は、水素原子、又はＣ_１〜Ｃ_６アルキル基を示し、Ｒ^３は、水素原子、Ｃ_６〜Ｃ_１０アリールカルボニル基、Ｃ_２〜Ｃ_６アシル基、又はＣ_１〜Ｃ_６アルキルオキシカルボニル基を示す。）で表されるフェニルプロペンアミド誘導体、若しくはその塩又はそれらの溶媒和物。
＜２＞ Ｒ^１は、メチルチオ基であり、Ｒ^２は、水素原子、又はメチル基であり、Ｒ^３は、水素原子、Ｃ_６〜Ｃ_１０アリールカルボニル基、又はＣ_１〜Ｃ_６アルキルオキシカルボニル基である＜１＞記載のフェニルプロペンアミド誘導体、若しくはその塩又はそれらの溶媒和物。
＜３＞ Ｎ−メチル−Ｎ−（ｏ−メチルチオフェニル）アクリルアミド、（Ｅ）−Ｎ−（ｏ−メチルチオフェニル）−３−メトキシカルボニルプロペンアミド、及び（Ｅ）−Ｎ−メチル−Ｎ−（ｏ−メチルチオフェニル）−３−ベンゾイルプロペンアミドからなる群から選ばれるフェニルプロペンアミド誘導体、若しくはその塩又はそれらの溶媒和物。
＜４＞ ＜１＞〜＜３＞のいずれかに記載のフェニルプロペンアミド誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とするＡＧＥ形成阻害剤。
＜５＞ ＜１＞〜＜３＞のいずれかに記載のフェニルプロペンアミド誘導体、若しくはその塩又はそれらの溶媒和物を有効成分とする糸球体疾患の予防及び／又は治療剤。
＜６＞ 糸球体疾患が、糖尿病性腎症である＜５＞記載の予防及び／又は治療剤。

(In the formula, R ¹ represents a C _{1 to} C ₆ alkylthio group, R ² represents a hydrogen atom or a C _{1 to} C ₆ alkyl group, and R ³ represents a hydrogen atom or a C _{6 to} C ₁₀ arylcarbonyl. _group, C 2 -C ₆ acyl group, or a _C 1 -C phenyl propenamide derivative represented by ₆ illustrates a alkyloxycarbonyl group.), or a salt or solvate thereof.
<2> R ¹ is a methylthio group, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a C ₆ -C ₁₀ arylcarbonyl group, or a C ₁ -C ₆ alkyloxycarbonyl. The phenylpropenamide derivative according to <1>, which is a group, or a salt thereof, or a solvate thereof.
<3> N-methyl-N- (o-methylthiophenyl) acrylamide, (E) -N- (o-methylthiophenyl) -3-methoxycarbonylpropenamide, and (E) -N-methyl-N- (o -Methylthiophenyl) -3-benzoylpropenamide A phenylpropenamide derivative selected from the group consisting of, or a salt thereof, or a solvate thereof.
<4> An AGE formation inhibitor comprising the phenylpropenamide derivative according to any one of <1> to <3>, a salt thereof, or a solvate thereof as an active ingredient.
<5> A prophylactic and / or therapeutic agent for glomerular diseases comprising the phenylpropenamide derivative according to any one of <1> to <3>, a salt thereof, or a solvate thereof as an active ingredient.
<6> The preventive and / or therapeutic agent according to <5>, wherein the glomerular disease is diabetic nephropathy.

  The compound represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof has an excellent AGE formation inhibitory action, as shown in Test Examples described later, and prevents glomerular disease and / or Or it is useful as a therapeutic agent, especially a preventive and / or therapeutic agent of diabetic nephropathy.

  As described in the Examples, in the evaluation using the plasma of a hemodialysis patient and adding aminoguanidine or each test drug, each test drug exhibits an AGE formation inhibitory activity equivalent to or better than aminoguanidine. It was. That is, with respect to the production of pentosidine, which is one of the main AGEs observed in a system to which aminoguanidine or each test drug was added at 37 ° C. for 7 days using plasma of a hemodialysis patient, All of the additions showed the same or better pentosidine production inhibitory effect than the addition of aminoguanidine.

In the present specification, the C ₁ -C ₆ alkyl group is a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, an n-pentyl group, and an n-hexyl group. .
In the present specification, specific examples of the C ₁ -C ₆ alkylthio group include methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, t-butylthio group, n -A pentylthio group, n-hexylthio group, etc. are mentioned, A methylthio group is preferable.
In the present specification, the C ₆ -C ₁₀ arylcarbonyl group is a group in which a carbonyl group is bonded to a C ₆ -C ₁₀ aryl group. Specific examples include a phenylcarbonyl group, a 1-naphthylcarbonyl group, a 2-naphthylcarbonyl group, an azulenyl group, and the like, and a phenylcarbonyl group is preferable.
In the present specification, C ₂ -C ₆ acyl groups include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, 2-methylpentanoyl group, and 3-methylpentanoyl group. Group, 4-methylpentanoyl group, 2,2-dimethylbutanoyl group, 2,3-dimethylbutanoyl group, 3,3-dimethylbutanoyl group and the like.
In the present specification, the C ₁ -C ₆ alkyloxycarbonyl group is a group in which an oxycarbonyl group is bonded to the above-mentioned C ₁ -C ₆ alkyl group. Specifically, methyloxycarbonyl group, ethyloxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxy Examples thereof include a carbonyl group and an n-hexyloxycarbonyl group, and a methyloxycarbonyl group is preferable.

  Preferred examples of the present invention include N-methyl-N- (o-methylthiophenyl) acrylamide, (E) -N- (o-methylthiophenyl) -3-methoxycarbonylpropenamide, or (E) -N-methyl. -N- (o-methylthiophenyl) -3-benzoylpropenamide is mentioned.

The compound represented by the general formula (1) of the present invention can be converted into a salt.
Preferred salts include, for example, acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate; benzoate, methanesulfonate, ethanesulfonic acid Salt, benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate, tartrate, citrate, acetate, etc. The salt is not particularly limited as long as it is a salt.
Moreover, the compound represented by General formula (1) can form arbitrary solvates represented by the hydrate, and these solvates are also included by this invention.
Furthermore, when optical isomers and geometric isomers exist in the compound represented by the general formula (1), all these isomers are included in the present invention.

The compound represented by the general formula (1) of the present invention can be produced by, for example, the following method 1).
1)

[In the figure, R ¹ , R ² and R ³ represent the same substituents as described above, R ⁴ and R represent C _{1 to} C ₆ alkyl groups, PG represents a protecting group, and X represents halogen. ]

The compound represented by the general formula (1) can be produced from the benzothiazin-3-one derivative (II) or (V). For these, commercially available products can be used.
The alkoxybenzothiazin-3-one derivative (III) can be produced by treating the benzothiazin-3-one derivative (II) with an alcohol in the presence of a base after the reaction with the halogenating agent. As the halogenating agent, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like can be used, and the base is not particularly limited, but for example, lithium hydride, sodium hydride, etc. Alkali metal hydrides such as potassium hydride, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate, heavy metal Alkali metal bicarbonates such as sodium carbonate and potassium bicarbonate, metal salts of alcohols such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide, triethylamine, pyridine, Imidazole, 4- It can be used organic bases such as dimethylaminopyridine. As the alcohol, methanol, ethanol, propanol, butanol and the like can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, acetone, butanone, acetonitrile, propionitrile, etc. can be used individually or in combination. The reaction temperature is −78 ° C. to 100 ° C., preferably −30 ° C. to 50 ° C., and the reaction time is 5 minutes to 24 hours, preferably 1 to 5 hours.

  (V) can be produced by subjecting the alkoxybenzothiazin-3-one derivative (III) to acid treatment after the nucleophilic substitution reaction in the presence of a base. As the base, the same ones as described above can be used. As the nucleophilic species, active methylene (IV) such as acetoacetate derivative, meldrum acid, malonate derivative and the like can be used. Although there is no restriction | limiting in particular as an acid, For example, organic acids, such as mineral acids, such as hydrochloric acid, hydrobromic acid, a sulfuric acid, nitric acid, or acetic acid, trifluoroacetic acid, and methanesulfonic acid, can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene etc. can be used individually or in combination. The reaction temperature is −78 to 100 ° C., preferably 0 to 100 ° C., and the reaction time is 5 minutes to 5 days, preferably 1 hour to 1 day to obtain (V).

The phenylpropenamide derivative (1) can be produced by treating (V) with an alkyl halide and then reacting with a base.
Examples of the alkyl halide include methyl iodide, ethyl iodide, n-propyl iodide, n-propyl chloride, n-propyl bromide, aryl iodide, aryl chloride, aryl bromide, n-butyl iodide, n-butyl bromide, C ₁ -C ₆ alkyl halides such as n-butyl chloride, n-pentane iodide, n-pentane chloride, n-pentane bromide, n-hexane iodide, n-hexane chloride, n-hexane bromide may be used. it can. As the base, the same ones as described above can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, acetone, butanone, acetonitrile, propionitrile, etc. can be used individually or in combination. The reaction temperature is −78 ° C. to 100 ° C., preferably −30 ° C. to 50 ° C., and the reaction time is 12 hours to 5 days, preferably 1 to 3 days.

In (V), a protecting group can be introduced as necessary. That is, (V ′) can be produced by a known method (such as the method described in Protective groups in organic synthesis third edition, John Wiley & Sons, Inc.). As the protecting group, known ones (the method described in Protective groups in organic synthesis third edition, John Wiley & Sons, Inc.) can be used, and preferably an acetyl group, a pivaloyloxymethyl group, or the like is used. it can. After treating with (V ′) with an alkyl halide, the phenylpropenamide derivative (1) can be produced by reacting with a base and removing the protecting group.
As the alkyl halide, the same ones as described above can be used. As the base, the same ones as described above can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, acetone, butanone, acetonitrile, propionitrile, etc. can be used individually or in combination. The reaction temperature is −78 ° C. to 100 ° C., preferably −30 ° C. to 50 ° C., and the reaction time is 12 hours to 5 days, preferably 1 to 3 days. Removal of the protecting group is in accordance with a known method (such as the method described in Protective groups in organic synthesis third edition, John Wiley & Sons, Inc.).

Moreover, the compound represented by General formula (1) can also be manufactured by the method of 2).
2)

[In the figure, R ¹ , R ² and R ³ represent the same substituents as described above, and X represents halogen. ]

The phenylpropenamide derivative (VIII) can be produced by reacting the aniline derivative (VI) with the halogenated alkenyl derivative (VII) in the presence of a base. As the alkenyl halide derivative, acrylic acid chloride, crotonic acid chloride, cinnamoyl chloride and the like can be used. As the base, the same ones as described above can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene etc. can be used individually or in combination. The reaction temperature is −78 ° C. to 100 ° C., preferably −30 ° C. to 50 ° C., and the reaction time is 5 minutes to 24 hours, preferably 1 to 6 hours to produce the phenylpropenamide derivative (VIII). Can do. A commercial item can be used for the aniline derivative (VI).
An alkylphenylpropenamide derivative (1) can be produced by reacting the phenylpropenamide derivative (VIII) with an alkyl halide (IX) in the presence of a base. As the base, the same ones as described above can be used. As the alkyl halide, the same ones as described above can be used. Although there is no restriction | limiting in particular as a solvent, For example, a methylene chloride, chloroform, carbon tetrachloride, benzene, toluene etc. can be used individually or in combination. The reaction temperature is −78 ° C. to 100 ° C., preferably −30 ° C. to 50 ° C., and the reaction time is 30 minutes to 24 hours, preferably 30 minutes to 6 hours to produce the alkylphenylpropenamide derivative (1). can do.

  The compound represented by the general formula (1) of the present invention can be obtained by the above-described method, and can be further purified by a usual purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired solvate can be obtained by a conventional method.

  The pharmaceutical composition of the present invention contains a compound represented by the general formula (1) or a solvate thereof, and may be used alone, but is usually a pharmaceutically acceptable carrier, Used in combination with additives. The administration form of the pharmaceutical composition is not particularly limited and can be appropriately selected depending on the purpose of treatment. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections and the like.

  These preparations include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers used in pharmacology depending on the dosage form. It can be mixed with a pharmaceutical additive such as a dispersant, a stabilizer, a solubilizing agent, etc., appropriately mixed, diluted or dissolved, and manufactured according to a conventional method.

  For example, in the case of powders, in addition to the essential components, an appropriate excipient, lubricant and the like may be added and mixed as necessary. In the case of a tablet, it may be prepared by adding an appropriate excipient, disintegrant, binder, lubricant, etc. as necessary, and tableting according to a conventional method. Tablets can be coated as necessary to form film-coated tablets, sugar-coated tablets, and the like.

  In the case of an injection, it can be in the form of a solution (sterile water or non-aqueous solution), an emulsion and a suspension. Examples of the non-aqueous carrier, diluent, solvent, or vehicle used for these include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic acid esters such as ethyl oleate. In addition, auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents can be appropriately blended in the composition.

  The dose of the compound represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc., but usually 1 to 1000 mg per day is given once or several times per adult. It is preferable to administer orally or parenterally in divided doses.

Hereinafter, the present invention will be described in more detail with reference to examples. The present invention is not limited to these examples.
[Production Example 1]
Production of N- (o-methylthiophenyl) acrylamide (o-methylthio) aniline (4.55 g, manufactured by Tokyo Chemical Industry Co., Ltd.) is dissolved in anhydrous methylene chloride (25 mL) and cooled to 0 ° C. Slowly add propenyl chloride (5.9 g) and triethylamine (9.12 mL). The reaction mixture was stirred at 0 ° C. for 2.5 hours, then washed with water, 1M hydrochloric acid, 5% sodium hydroxide and dried over magnesium sulfate. Filtration and concentration were performed, and the residue was quickly purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain a product (2.5 g, 40%).
¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 5.80 (1H, d, J = 10 Hz), 6.32 (1H, dd, J = 10, 17 Hz), 6 .44 (1H, d, J = 10 Hz), 6.49 (1H, d, J = 8 Hz), 7.05-7.15 (1H, m), 7.28-7.35 (1H, m), 7.50 (1H, d, J = 8 Hz).

Preparation of N-methyl-N- (o-methylthiophenyl) acrylamide N- (o-methylthiophenyl) acrylamide (2.65 g) was dissolved in anhydrous methylene chloride (30 mL), and sodium hydride (60% in mineral oil) (548 mg) was added. After stirring for 30 minutes, methyl iodide (1.95 g) was added and stirred for 2.5 hours. The reaction mixture was washed with water, extracted with methylene chloride, and dried over magnesium sulfate. Filtration and concentration were performed, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain a product (2.5 g, 88%).
¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.26 (3H, s), 5.48 (1H, dd, J = 2, 10 Hz), 5.89 (1H, dd, J = 10, 17 Hz), 6.37 (1H, dd, J = 2, 17 Hz), 7.12 (1H, dd, J = 1, 8 Hz) 7.15-7.32 (2H , M), 7.35-7.42 (1H, m).

[Production Example 2]
Preparation of methyl 4-acetyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazinyl acetate Methyl 3-oxo-3,4-dihydro-2H-1,4-benzothiazinyl acetate (1.18 g Sigma Aldrich Japan) was dissolved in acetic anhydride (2 mL) and refluxed for 5 hours. After cooling to room temperature, the reaction mixture was washed with water, sodium bicarbonate was added, extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to obtain the product (490 mg, 35%).
¹ H-NMR (CDCl ₃ ) δ: 2.55-2.70 (1H, m), 2.68 (3H, s), 3.05-3.17 (1H, m), 3.75 (3H , S), 3.80-3.90 (1H, m), 7.15-7.20 (1H, m), 7.21-7.35 (2H, m), 7.42-7.50. (1H, m).

(E) Preparation of -N- (o-methylthiophenyl) -3-methoxycarbonylpropenamide Methyl 4-acetyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazinyl acetate (450 mg) was anhydrous The mixture was dissolved in methylene chloride (10 mL), methyl iodide (2.06 g) and silver tetrafluoroborate (343 mg) were added under ice cooling, and the mixture was stirred at room temperature for 15 hours. The precipitated crystals were filtered and the filtrate was concentrated. The residue was dissolved in methylene chloride (15 mL), 5% aqueous sodium hydroxide solution-methylene chloride (5 mL-5 mL) was added dropwise, and the mixture was stirred at room temperature for 30 min. The reaction solution was extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by thin layer silica gel column chromatography to obtain the product (40 mg, 10%).
¹ H-NMR (CDCl ₃ ) δ: 2.39 (3H, s), 3.83 (3H, s), 6.95 (1H, d, J = 15 Hz), 7.11 (1H, d, J = 15 Hz), 7.05-7.20 (1 H, m), 7.30-7.38 (1 H, m), 7.51 (1 H, d, J = 8 Hz), 8.43 ( 1H, d, J = 8 Hz), 8.67 (1H, br s).

[Production Example 3]
Preparation of 2-ethoxy-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6 0.72 g, Sigma-Aldrich Japan) was dissolved in anhydrous carbon tetrachloride (60 mL), N-chlorosuccinimide (5.18 g) was added at 0 ° C., and the solution was gradually warmed to room temperature and stirred for 3 hours. . Subsequently, ethanol (8.0 g) and pyridine (4.0 g) were slowly added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature, washed twice with water, dried over magnesium sulfate, and concentrated to give the product (8.35 g, 98%).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7 Hz), 3.52 (3H, s), 3.80 (2H, q, J = 7 Hz), 5.10 (1H, s), 7.06 (1H, dd, J = 1, 8 Hz), 7.15 (1H, d, J = 7 Hz), 7.25-7.32 (1H, m), 7 .37 (1H, dd, J = 1, 8 Hz).
MS m / z: 223 (M +). Anal. Calcd. _{for C 11 H 13 NO 2 S} : C, 59.17; H, 5.87; N, 6.27. Found: C, 59.20; H, 5.935; N, 6.31.

[Production Example 4]
Preparation of 2-benzoylmethyl-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine 2-ethoxy-4-methyl-3-oxo-3,4-dihydro-2H-1, 4-Benzothiazine (2.0 g) was dissolved in anhydrous methylene chloride (30 mL) and methyl benzoyl acetate (3.45 g) was added. Trifluoroborane etherate (1.3 mL) was added at 0 ° C., the temperature was gradually returned to room temperature, warmed to 50 ° C., and stirred for 4 hours. The reaction mixture was cooled to room temperature, washed with water, extracted with methylene chloride, dried over magnesium sulfate, and concentrated. Ethanol (5 mL) and water (5 mL) were added to the residue and dissolved, concentrated sulfuric acid (2.4 mL) was slowly added, and the mixture was refluxed for 16 hours. The mixture was cooled to room temperature, washed with water, extracted with ethyl acetate, and dried over magnesium sulfate. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 10) to obtain the product (2.01 g, 75%).
¹ H-NMR (CDCl ₃ ) δ: 3.12 (1H, dd, J = 6, 17 Hz), 3.46 (3H, s), 3.84 (1H, dd, J = 7, 17 Hz) , 4.21 (1H, dd, J = 6, 7 Hz), 7.02-7.11 (2H, m), 7.12-7.20 (1H, m), 7.27-7.35. (2H, m), 7.35-7.40 (1H, m), 7.45-7.53 (1H, m), 7.53-7.63 (1H, m), 7.98 (1H , D, J = 7 Hz).
HRMS m / z: 297.0821 Calcd. _{for C 17 H 15 NO 2 S} Observed 297.0820.

(E) Preparation of -N-methyl-N- (o-methylthiophenyl) -3-benzoylpropenamide 2-Benzoylmethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (2.0 g ) Was dissolved in anhydrous methylene chloride (80 mL), and methyl iodide (9.3 g) was added. Silver tetrafluoroborate (1.4 g) was added at 0 ° C., and the mixture was returned to room temperature and stirred overnight. The precipitated crystals were filtered and washed with acetonitrile, and then the filtrate was concentrated to obtain sulfonium salt crystals (2.0 g). The sulfonium salt was dissolved in acetonitrile, 2 equivalents of triethylamine was added at 0 ° C., and the mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride: ethyl acetate = 10: 1) to obtain the product (1.0 g, 48%).
¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.32 (3H, s), 6.72 (1H, d, J = 15 Hz), 7.13-7.26 ( 3H, m), 7.36-7.46 (3H, m), 7.54-7.58 (1H, m) 7.94 (2H, d, J = 8 Hz), 7.96 (1H, d, J = 15 Hz).
HRMS m / z: 311.0978 Calcd. for C ₁₈ H ₁₇ NO ₂ S. Observed 311.0977.

AGE formation inhibitory action using plasma of hemodialysis patients Plasma AGE (indicator: pentosidine) in hemodialysis patients was measured according to the report of Miyata et al. (Miyata, T. et al: J Am Soc Nephrol, 13, 2478-2487, 2002). 0.9 mL of plasma from a hemodialysis patient was reacted at 37 ° C. for 7 days in the presence of aminoguanidine or each test drug (added amount was 0.1 mL). The final concentration of aminoguanidine and each test drug was 5.0 mM. Aminoguanidine or each test drug was used after being dissolved in dimethyl sulfoxide (DMSO). The final concentration of DMSO was 10% in 1 mL of the reaction solution, which did not affect the oxidation reaction during the reaction. After the reaction for 7 days, the concentration of pentosidine in plasma to which aminoguanidine or each test drug was added was measured by the method shown below.

  An equal amount of 10% trichloroacetic acid (hereinafter referred to as “TCA”) was added to 0.05 mL of the reaction solution, and centrifuged at 5000 × g for 5 minutes. The supernatant was removed and the precipitate was washed with 0.3 mL of 5% TCA, then lyophilized and dried. Subsequently, 0.1 mL of 6N hydrochloric acid was added under nitrogen conditions at 110 ° C. for 16 hours to hydrolyze the dried product. Subsequently, 0.1 mL of 5N sodium hydroxide and 0.2 mL of 0.5M phosphate buffer (pH 7.4) were added for neutralization. The neutralized solution was passed through a filter having a diameter of 0.5 μm and diluted with a phosphate buffer to prepare a sample for measuring pentosidine. Pentosidine concentration was measured according to the method of Miyata et al.

Table 1 shows the inhibition intensity of pentosidine formation by each test drug as a relative value when the formation inhibition intensity by aminoguanidine is 1.0 (the formation inhibition intensity is in the control group. In the control group). Only DMSO was added).
Relative value = (test drug formation inhibition rate) ÷ (aminoguanidine formation inhibition rate)

  The final concentration of aminoguanidine and each test drug during the reaction was fixed at 5.0 mM.

  The relative values of each test drug were calculated as 2.36, 2.35 and 1.23, respectively, all of which were equal to or higher than the inhibition strength of pentosidine formation by aminoguanidine. From the above, the compound of the present invention represented by the general formula (1) has a potent AGE formation inhibitory action equal to or higher than that of aminoguanidine, and the possibility of being a more potent therapeutic agent is clear from the results of this experiment. became.

Claims (6)

The following general formula (1)

(In the formula, R ¹ represents a C _{1 to} C ₆ alkylthio group, R ² represents a hydrogen atom or a C _{1 to} C ₆ alkyl group, and R ³ represents a hydrogen atom or a C _{6 to} C ₁₀ arylcarbonyl. _group, C 2 -C ₆ acyl group, or a _C 1 -C phenyl propenamide derivative represented by ₆ illustrates a alkyloxycarbonyl group.), or a salt or solvate thereof. In the general formula (1), R ¹ is a methylthio group, R ² is a hydrogen atom or a methyl group, R ³ is a hydrogen atom, a C ₆ -C ₁₀ arylcarbonyl group, or a C ₁ -C The phenylpropenamide derivative according to claim 1, which is a ₆ alkyloxycarbonyl group, or a salt thereof, or a solvate thereof.   N-methyl-N- (o-methylthiophenyl) acrylamide, (E) -N- (o-methylthiophenyl) -3-methoxycarbonylpropenamide, and (E) -N-methyl-N- (o-methylthiophenyl) ) A phenylpropenamide derivative selected from the group consisting of -3-benzoylpropenamide, or a salt thereof, or a solvate thereof.   The AGE formation inhibitor which uses the phenylpropenamide derivative in any one of Claims 1-3, its salt, or those solvates as an active ingredient.   A prophylactic and / or therapeutic agent for glomerular diseases comprising the phenylpropenamide derivative according to any one of claims 1 to 3 or a salt thereof or a solvate thereof as an active ingredient. The preventive and / or therapeutic agent according to claim 5, wherein the glomerular disease is diabetic nephropathy.