JPH06128155A - Agent for treating and / or preventing nephritis - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] A therapeutic and / or prophylactic agent for nephritis containing a 4H-1-benzopyran-4-one derivative represented by the general formula [1] or a salt thereof as an active ingredient. “In the formula, R ¹ is a lower (halo) alkyl group, a (halo) aryl group or the like; R ² is a hydrogen atom, an alkyl group or an acyl group; R ³ is a hydrogen atom, a halogen atom, a cyano group or a carboxyl group. , A hydroxyl group, an alkoxycarbonyl group or an optionally substituted alkyl, alkoxyphenyl, carbamoyl group or the like; R ⁴ is a hydrogen atom, a halogen atom, a carboxyl group, a hydroxyl group, an alkoxycarbonyl group or an optionally substituted group. Alkyl, phenyl, alkoxy, sulfamoyl, alkylsulfonyl, mono- or dialkylamino group and the like; R ⁵ is
An optionally substituted phenyl, thienyl, furyl or pyridyl group; Z represents O, S or NH. [Effect] The compound of the formula [1] or a salt thereof is a crescent type anti-G
It exhibits a BM nephritis inhibitory action and an ameliorating action of renal lesions in model animals of autoimmune disease, and is useful for the treatment and / or prevention of nephritis.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula [1]

[Chemical 4] "In the formula, R ¹ represents a lower alkyl, a lower alkenyl or an aryl group which may be substituted with a halogen atom;
² is a hydrogen atom, an alkyl group or an acyl group; R ³
Is a hydrogen atom, a halogen atom, a cyano group, an azido group, a carboxyl group, a hydroxyl group, a formyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R ⁴ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, an acyl group, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl , Alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic groups, or formulas

[Chemical 5] Or expression

[Chemical 6]

(Wherein R ⁶ is a hydrogen atom, a hydroxyl group, a cyano group or an alkoxycarbonyl group or an optionally substituted alkyl, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group. R ⁷ represents a hydrogen atom, an optionally substituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, and R ⁶ and R ⁷ together with the adjacent nitrogen atom are 3 to 7-membered ring which may form a heterocyclic group which may be substituted); R ⁵ is an optionally substituted phenyl, thienyl, furyl or pyridyl group; Z is , An oxygen atom, a sulfur atom or an imino group; and a broken line indicates a single bond or a double bond. The present invention relates to a novel therapeutic and / or preventive agent for nephritis, which comprises a 4H-1-benzopyran-4-one derivative represented by the formula or a salt thereof as an active ingredient.

[0003]

2. Description of the Related Art The 4H-1-benzopyran-4-one derivative of the general formula [1] is a known compound and has an anti-inflammatory effect,
It is known to have an antipyretic analgesic action, an anti-arthritic action and an anti-allergic action (Japanese Patent Laid-Open No. 2-49778), but it is known that it exerts a nephritis inhibitory action and is useful for the treatment and / or prevention of nephritis. Has not been done.

[0004]

At present, as a medicinal treatment for chronic renal diseases such as glomerulonephritis, non-steroidal anti-inflammatory agents, steroid agents, anticoagulants, antifibrinolytic agents, antiplatelet agents and Although immunosuppressants and the like are used, few drugs are effective for both treatment and / or prevention of nephritis. Steroids are relatively effective, but their use is limited due to side effects. Therefore, it has been desired to develop a drug that treats and / or prevents nephritis and has high safety.

[0005]

Under these circumstances, the inventors of the present invention have conducted diligent research, and as a result, the general formula [1]
It was found that the 4H-1-benzopyran-4-one derivative or a salt thereof achieves the above-mentioned object, and has completed the present invention. Hereinafter, the compound relating to the medicament of the present invention will be described in detail.

In the present specification, each term has the following meaning unless otherwise specified. Alkyl groups are, for example, methyl, ethyl, n-propyl, iso-propyl, n-
C _1-8 alkyl groups such as butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl; cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A C _3-8 cycloalkyl group such as; a lower alkyl group includes, for example, C _1- , such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl and pentyl. ₅ alkyl groups; lower alkenyl groups include, for example, vinyl,
Allyl, C _2-5 alkenyl groups such as 1-propenyl and 1-butenyl; and alkoxy groups, e.g., -O- alkyl group (the alkyl group, C _1-8 described above
Indicates an alkyl group. ); And an acyl group is, for example, a formyl group or a C _2-8 alkanoyl group such as acetyl, propionyl and butyryl group or an alkoxyoxalyl group such as methoxalyl and ethoxallyl,
C _3-8 cycloalkylcarbonyl group such as cyclohexanecarbonyl or aroyl group such as benzoyl group;

The alkoxycarbonyl group is, for example,
A -COO alkyl group (an alkyl group represents the above C _1-8 alkyl group); and an alkoxycarbonylamino group is, for example, a -NHCOO alkyl group (an alkyl group represents the above C _1-8 alkyl group). A halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; and an alkylthio group means, for example, —S—
An alkyl group (an alkyl group represents the above C _1-8 alkyl group); an alkylsulfinyl group, for example, a C _1-4 alkylsulfinyl group such as methylsulfinyl and ethylsulfinyl; an alkylsulfonyl group , For example, a C _1-4 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl;
An alkyl group is a group such as phenyl and naphthyl; an acylamino group is, for example, —NH—acyl group (acyl group has the same meaning as described above); and an alkylamino group is, for example, -NH-alkyl group (wherein the alkyl group represents the above C _1-8 alkyl group); and the dialkylamino group is, for example, —N (alkyl) ₂ group (wherein the alkyl group is the above C _1-8 alkyl group). Indicates an alkyl group.)
To;

The haloalkyl group is, for example, a halo-C _1-8 alkyl group such as chloromethyl, fluoromethyl, dichloromethyl, trifluoromethyl, dichloroethyl and trichloroethyl; and the lower alkynyl group is, for example, C such as ethynyl and 2-propynyl
_A heterocyclic group is, for example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 1,2,4. -Thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, quinolyl, isoquinolyl, pyrimidinyl, piperazinyl, pyrazinyl, pyridazinyl, 1,2,
Oxygen atoms, nitrogen atoms and sulfur atoms such as 3,4-tetrahydroquinolyl, 1,2,4-triazinyl, imidazo [1,2-b] [1,2,4] triazinyl, pyrrolidinyl, morpholinyl and quinuclidinyl 4 to 6-membered or condensed heterocyclic group containing at least one hetero atom selected from

In the general formula [1], when R ⁶ and R ⁷ together with the adjacent nitrogen atom form a 3- to 7-membered heterocyclic group, examples of the heterocyclic group include: Examples thereof include 3- to 7-membered nitrogen-containing heterocyclic groups such as azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, and pyrrol-1-yl.

[0010] The alkyl in R ^3, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino and phenyl groups; alkyl in R ^4, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino , phenyl and heterocyclic group; alkyl in R ^6, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl and amidino groups; alkyl in R ^7, alkoxy, phenyl, cycloalkyl and heterocyclic group; R ⁶ and R ⁷ are a 3- to 7-membered heterocyclic group formed together with the adjacent nitrogen atom, and R
Phenyl at ^5, thienyl, furyl and pyridyl groups, a halogen atom, alkoxy, alkylthio, phenoxy, carboxyl, acyl, alkoxycarbonyl, carbamoyl, sulfamoyl, cyano, alkylsulfonyl, hydroxyl, mercapto, acylamino, alkylamino, dialkylamino, alkyl , Cycloalkyl, oxo, nitro, haloalkyl, amino, phenyl, alkoxycarbonylamino, hydroxyimino and heterocyclic groups may be substituted with one or more substituents.

4H-1-benzopyran of the general formula [1]
The salts of 4-one derivatives include pharmaceutically acceptable salts, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; triethylamine and pyridine. Salts with organic amines; Salts with amino acids such as lysine, arginine and ornithine; Salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; Organic carboxylic acids such as fumaric acid, maleic acid, malic acid and citric acid Salts with acids; and salts with sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid and naphthalenedisulfonic acid.

4H-1-benzopyran of the general formula [1]
The 4-one derivative and its salt further include all isomers (geometrical isomers and optical isomers), hydrates, solvates and crystal forms. 4H of general formula [1]
-The 1-benzopyran-4-one derivative or its salt is
It can be produced by the method described in JP-A-2-49778.

The drug of the present invention is a capsule formulation by a conventional method.
It can be administered orally or parenterally as a powder, granules, pills, tablets, suspensions, emulsions, solutions, ointments, injections, syrups or suppositories. The administration method, dose, and frequency of administration may be appropriately adjusted depending on the age and symptoms of the patient, but usually about 5.0 to 1000 mg / day for adults
It may be given in divided doses from several times.

Representative compounds of the 4H-1-benzopyran-4-one derivative, which is an active ingredient of the therapeutic and / or prophylactic agent for nephritis of the present invention, are as follows. 1. 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-
On 2. 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 3. 6- (2,4-difluorophenoxy) -7-
Methylsulfonylamino-4H-1-benzopyran-4
-ON 4. 2-methyl-7-methylsulfonylamino-6
-Phenoxy-4H-1-benzopyran-4-one

5. 7-methylsulfonylamino-6
-Phenoxy-2-phenyl-4H-1-benzopyran-4-one 6. 7.-Phenylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 7. 7. 3-carbamoyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 8. 3-Acetylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-
on

9. 2-Ethyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-
4-on 10. 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 11. 7-Chloromethylsulfonylamino-3-formylamino-6-phenoxy-4H-1-benzopyran-4-one 12. 6- (2,4-difluorophenylamino)-
7-Methylsulfonylamino-4H-1-benzopyran-4-one

13. 3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-
4-on 14. 3-Methylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 15. 6 .- (2-Fluorophenoxy) -3-formylamino-7-methylsulfonylamino-4H-1-benzopyran-4-one 16. 6- (2,4-difluorophenoxy) -3-
Formylamino-7-methylsulfonylamino-4H-
1-benzopyran-4-one

17. 7-methylsulfonylamino-6
-Phenylthio-4H-1-benzopyran-4-one 18. 3-formylamino-2-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one 19. 2-Hydroxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one

Next, the pharmacological action of the therapeutic and / or prophylactic agent for nephritis of the present invention will be explained. 3-formylamino-7-methylsulfonylamino-6-phenoxy-
The following test was conducted using 4H-1-benzopyran-4-one as a test substance. Test Example 1 [Crescent Antiglomerular Basement Membrane Nephritis (Crescent AntiGBM
Nephritis)] Crescent GBM nephritis is similar to human progressive glomerulonephritis (RPGN) and is used as a model for screening drugs for glomerulonephritis [The Japanese Journal of・ Pharmacology (Japan.JP
harmacol.) Vol. 33, pp. 1145-1154 (1983)].

The test method was carried out according to the method described in the document. That is, Wistar weighing 180-220g
1 group of 8 r) male rats was used to induce nephritis by intravenous injection of 1 ml of anti-glomerular basement membrane rabbit serum. The test substance (3 mg / kg) suspended in a 0.5% (W / V) carboxymethylcellulose solution was orally administered while the antiserum was intravenously injected. After that,
Oral administration was carried out once a day for 9 consecutive days. Only the solvent was orally administered to the control group on the same schedule. A urinalysis from the 6th day to the 7th day of the administration, a laparotomy was performed under ether anesthesia on the day after the final administration,
Blood tests were performed using serum obtained by collecting blood from the descending abdominal vena cava. The results are shown in Table 1. In Table 1, CHO indicates total cholesterol; TG indicates triglyceride; BUN indicates blood urea nitrogen.

[0021]

Test Example 2 [Autoimmune disease model mouse MRL /
Action on lpr] MRL / lpr mouse, which is a model mouse for autoimmune disease, develops lupus nephritis such as glomerulonephritis and arteritis, and is therefore considered as a model animal for human systemic lupus erythematosus (SLE) [cellular immunology (Cell.Immuno.)
96, 312-326 (1985)]. Therefore, the effect of the test substance on the renal lesion of this mouse was examined.

Six-week-old male MRL / lpr mice (Charles River Japan) were preliminarily bred for 2 weeks and then grouped into 7 mice per group. A test substance (10 mg / kg) suspended in a 0.5% (W / V) carboxymethylcellulose solution was orally administered 5 times / week for 7 weeks. Only the solvent was orally administered to the control group on the same schedule. The day after the final administration, the animals were killed by exsanguination under ether anesthesia, the kidneys were removed, and HE (Hematoxylin and Eosin) and PAS (Perio
Histopathological examination was performed after staining with dic Acid Schiff. The effect was to randomly select 20 renal glomeruli from each animal, and examine their lesions in The Ryumachi Vol. 21,
Normal, proliferative (proliferation), membranous proliferative (membrane augmentation), membranous, lobulation (lobulation) by the method described on pages 165-171 (1981).
And the curability (curing) was graded into 6 levels and evaluated.
The results are shown in Table 2. The numbers in the table indicate the number of glomeruli showing the above lesions. (Below margin)

[0024]

[0025]

From the results of Test Examples 1 and 2 described above, the 4H-1-benzopyran-4-one derivative of the general formula [1] and the salt thereof show excellent crescentic anti-GBM nephritis inhibitory action, and It is clear that it improves renal lesions in model animals with autoimmune diseases. Therefore, the compound of the present invention is
It is useful as a therapeutic and / or preventive agent for nephritis. Further, it has already been reported that the compound of the present invention has high safety (JP-A-2-49778), and the value of the present invention is high.

[0026]

[Examples] The formulations of the present invention are specifically described below with reference to Examples, but the present invention is not limited thereto. The compounds used in the examples are the same as the test substances used in the above-mentioned test examples. (Below margin)

Example 1 A hard gelatin capsule is prepared by a conventional method using the following ingredients.

Example 2: A tablet is prepared by the usual method using the following ingredients. (Below margin)

Example 3: A tablet is prepared by a conventional method using the following ingredients.

Example 4 A tablet is prepared by a conventional method using the following ingredients.

Example 5: A tablet is prepared by a conventional method using the following ingredients.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shuntaro Takano 3-8-44 Inari Motomachi, Toyama City, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula: "In the formula, R ¹ represents a lower alkyl, a lower alkenyl or an aryl group which may be substituted with a halogen atom;
² is a hydrogen atom, an alkyl group or an acyl group; R ³
Is a hydrogen atom, a halogen atom, a cyano group, an azido group, a carboxyl group, a hydroxyl group, a formyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R ⁴ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, an acyl group, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl, lower alkenyl, sulfamoyl , An alkylsulfinyl, an alkylsulfonyl, an amidino, a phenyl or a heterocyclic group, or a compound of the formula Or the formula: (In the formula, R ⁶ is a hydrogen atom, a hydroxyl group, a cyano group or an alkoxycarbonyl group or an optionally substituted alkyl, cycloalkyl, phenyl, amino,
An acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group; R ⁷ represents a hydrogen atom, an optionally substituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group. R ⁶ and R ⁷ may form, together with the adjacent nitrogen atom, a 3- to 7-membered optionally substituted heterocyclic group. )
R ⁵ is an optionally substituted phenyl, thienyl, furyl or pyridyl group; Z is an oxygen atom, a sulfur atom or an imino group; and a broken line is a single bond or a double bond. Show. 4H-1-
A therapeutic and / or prophylactic agent for nephritis, which comprises a benzopyran-4-one derivative or a salt thereof as an active ingredient.