JPH11302177A - Medicine for treating nephritis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine for treating nephritis, having an action for inhibiting the excretion of urinary protein, scarcely accompanied with side effects such as a hemolytic action and excellent in safety, by compounding a specific phosphate derivative as an active ingredient. SOLUTION: This medicine for treating nephritis contains a phosphate derivative of the formula: R<1> -(A)1 -(O)n -(CH)m -PO(Z1 )Z2 [A is phenylene, thiophenediyl or pyrazinediyl; (1) is 0-1; (m) is 1-4; (n) is 0-1; Z1 and Z2 are simultaneously each OR<3> (R<3> is a lower alkyl), or either of Z1 and Z2 is a lower alkoxy and the other is phenyl; R<1> is a (substituted) lower alkylcarbonyl, a group of formula I (R<2> is H or a halogen; D is O or S), a group of formula II (E is carbonyl or methylene), a group of formula III (R<3> is a halogen, a lower alkoxy or the like), a (substituted) quinolyl, a (substituted) quinazolinyl or the like] as an active ingredient. The medicine is preferably administered at a daily dose of about 0.05-80 mg per kg of the body weight of an adult as the active ingredient compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic agent for nephritis.

[0002]

2. Description of the Related Art The present inventors have intensively studied active pharmaceutical ingredient compounds, and in the process, a series of carboxylic acid amide derivatives were useful as anti-inflammatory agents and calcium antagonists. (Japanese Patent Publication No. 4-19236 and EP Patent Publication No. 2734).
No. 44).

[0003] A series of carboxylic acid amide derivatives related to the above derivatives have excellent lipid-lowering effects and are also excellent in safety such as side effects, and are used as therapeutic agents for hyperlipidemia. Disease, hypertriglyceridemia,
It has been found that it is useful for treating and preventing various diseases (hyperlipidemia) such as hyperphospholipidemia and hyperfree fatty acidemia (see JP-A-3-68592).

Subsequently, various other compounds having the same pharmacological action as the above-mentioned carboxylic acid amide derivatives have been developed (for example, JP-A-4-243888, JP-A-4-3).
No. 56495, WO94 / 1821, WO9
5/0052, WO95 / 0605, JP-A-7-76591, JP-A-9-286792 and the like.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to develop a new pharmaceutical use of various compounds previously developed by the present applicant, particularly as a therapeutic agent for nephritis.

The present inventor has continued his research on the above object, and as a result, it has been found that the above-mentioned various compounds developed previously have pharmacological actions or activities for known pharmaceutical uses, ie, lipid lowering action, anti-inflammatory action, calcium Not related to antagonism, etc.
In addition, they have unexpectedly inhibited urinary protein excretion based on their known pharmacological actions and found that they are effective as a new therapeutic agent for nephritis. The present invention has been completed based on this finding.

[0007]

According to the present invention, there is provided a therapeutic agent for nephritis comprising a phosphoric acid derivative represented by the following general formula (1) as an active ingredient.

General formula (1): R ^1- (A) _l- (O) _n- (CH ₂ ) _m -PO (Z ₁ ) Z _{2 In the} above formula, R ¹ represents the following (1) to (13) ) Represents a group selected from

(1) a lower alkylcarbonyl group substituted by a phenyl group having 1 to 3 halogen atoms; (2) a group

[0010]

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(Wherein, R ² represents a hydrogen atom or a halogen atom, and D represents an oxygen atom or a sulfur atom);

[0012]

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(Wherein E represents a carbonyl group or a methylene group);

[0014]

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(Wherein R ³ represents a halogen atom, a lower alkoxy group or a phenyl lower alkoxy group); (5) 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group and a phenyl group A quinolyl group having a group; (6) from the group consisting of a halogen atom, a lower alkyl group, a phenyl group, a lower alkylthio group, a lower alkylamino group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group and an oxo group (7) a benzoxazinyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group and an oxo group; ) From the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups, hydroxyl groups, oxo groups and phenyl lower alkoxy groups (9) an indolyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a phenyl group and a lower alkoxy group; ) halogen atom, imidazopyridinyl group having 1 to 3 substituents selected from the group consisting of halogen-substituted lower alkyl group and a phenyl group; and (11) group -Z (R ¹¹⁾ R ¹² (base in And R ¹¹ are (a) a halogen atom, a lower alkoxy group, an N-lower alkylcarbamoyl group, a group 4-phenylmethyl-1-piperazinylcarbonyl group, a lower alkoxycarbonyl group, an aminosulfonyl group, an N-phenyl lower alkylcarbamoyl group A phenyl group which may have from 1 to 3 substituents selected from the group consisting of a group, an N-phenylcarbamoyl group and a carboxyl group; (b) lower A pyrazolyl group having 1 to 3 substituents selected from the group consisting of an alkyl group and a phenyl group which may have a halogen atom as a substituent; (c) a halogen atom, a lower alkyl group, a nitro group, a benzoyl as a substituent Group, benzoyl lower alkyl group, phenyl group, halogen atom or lower alkoxy group substituted phenyl group, lower alkoxycarbonyl group, lower alkoxycarbonyl lower alkyl group, lower alkoxycarbonylcarbonyl group and biphenyl group (D) thiazolyl group having three substituents; (d) thiadiazolyl group which may have a substituent selected from the group consisting of halogen atom, lower alkyl group, halogen-substituted lower alkyl group and phenyl group; (e) phenyl group and halogen-substituted phenyl At least one selected from the group consisting of (F) an oxazolyl group which may have at least one substituent; (f) a pyridyl group which may have at least one substituent selected from the group consisting of a cyano group and a halogen-substituted lower alkyl group; (g) a pyrazinyl group; h) a pyrimidinyl group which may have 1 to 3 halogen atoms; (i) a halogen atom, a lower alkyl group, a lower alkoxy group, an acyl group, a lower alkoxycarbonyl group, a halogen-substituted lower alkyl group and a phenyl lower alkoxy group A benzothiazolyl group which may have 1 to 3 substituents selected from the group consisting of: (j) a halogen-substituted benzoxazolyl group; and (k) a phenyl lower alkyl group which may have at least one of the substituents. Benzimidazolyl group; (l) thiazolopyridinyl group; (m) selected from the group consisting of halogen atoms and lower alkyl groups A quinolyl group which may have at least one substituent; (n) a naphthyridinyl group having at least one lower alkyl group as a substituent; (o) at least one substituent selected from a halogen atom and a lower alkyl group (P) a benzopyranothiazolyl group having at least one halogen atom as a substituent; or (q) a naphthoimidazolyl group having at least one lower alkyl group as a substituent. Represents a group. R ¹² represents a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group. Z represents a carbonyl group (= CO group) or = SO ₂ group.

In the general formula (1), A represents a phenylene group, a thiophendiyl group or a pyrazinediyl group. l represents 0 or 1. m shows the integer of 1-4. n
Represents 0 or 1. Z ₁ and Z ₂ are simultaneously an OR ³ group (R ³
Is a lower alkyl group) or one is a lower alkoxy group and the other is a phenyl group.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION Each group defined in the present specification is as follows.

[0018] In the general formula (1), represented by R ¹ (1) ~
Each group of (11) is as follows. That is, (1) a halogen atom in a lower alkylcarbonyl group substituted with a phenyl group having 1 to 3 halogen atoms includes a fluorine atom,
Includes chlorine, bromine and iodine atoms. below
The terms “(2) to (11)” and the term “halogen atom” contained in each group are used in the same meaning as described above. Examples of the phenyl group having 1 to 3 halogen atoms include 2-chlorophenyl, 3-chlorophenyl,
-Chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-fluorophenyl, 4-iodophenyl,
Examples thereof include a 2,4-dichlorophenyl, a 2,6-dichlorophenyl, a 2-chloro-4-bromophenyl, and a 2,4,6-trichlorophenyl group.

The lower alkylcarbonyl group substituted by the halogen-substituted phenyl group includes an alkyl-carbonyl group having 1 to 6 carbon atoms having the above-mentioned halogen-substituted phenyl group, for example, 2-chlorophenylacetyl, 4-chlorophenylacetyl, 4-chlorophenylacetyl, Bromophenylacetyl, 2,4
-Dichlorophenylacetyl, 2,6-dichlorophenylacetyl, 2-chloro-4-bromophenylacetyl, 2- (2-chlorophenyl) phenethyl, 2-
(2,4-dichlorophenyl) propionyl, 3-
(2,4-dichlorophenyl) propionyl, 4- (4
-Bromophenyl) butyryl, 5- (2,6-dichlorophenyl) valeryl, 6- (2-chlorophenyl) hexanoyl group and the like.

In the group represented by (4), the lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy and the like. Can be exemplified. Hereinafter, in the present specification, the term "lower alkoxy group" means an alkoxy group having 1 to 6 carbon atoms, as described above. Further, as the phenyl lower alkoxy group, an alkoxy group having 1 to 6 carbon atoms having a phenyl group as a substituent, for example, benzyloxy, 1-
Examples include phenylethoxy, 3-phenylpropoxy, 2-phenylisopropoxy, 4-phenylbutoxy, 5-phenylpentyloxy, 6-phenylhexyloxy and the like.

In the group represented by (5), examples of the lower alkyl group include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like. . In this specification, the term "lower alkyl group" means an alkyl group having 1 to 6 carbon atoms.

[0022] 1-3 selected from the group consisting of halogen atoms, lower alkyl groups and phenyl groups represented by the above (5)
Quinolyl groups having three substituents include 3-methyl-
2-quinolyl, 4-phenyl-2-quinolyl, 6-chloro-2-quinolyl, 3-methyl-4-phenyl-2-quinolyl, 4-phenyl-6-chloro-2-quinolyl,
-Phenyl-7-chloro-2-quinolyl, 3-methyl-
Examples thereof include a 4-phenyl-6-chloro-2-quinolyl, a 2-methyl-4-phenyl-7-chloro-3-quinolyl, and a 3-ethyl-4-phenyl-6-bromo-2-quinolyl group.

The lower alkylthio group as a substituent in the substituted quinazolinyl group represented by (6) includes an alkylthio group having 1 to 6 carbon atoms, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio. And the like. As the lower alkylamino group as the substituent,
Examples thereof include an alkylamino group having 1 to 6 carbon atoms, such as a methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino group. Examples of the lower alkoxycarbonyl lower alkyl group as the same substituent include methoxycarbonylmethyl, ethoxycarbonylmethyl, butoxycarbonylmethyl, 2- (methoxycarbonyl) ethyl, 3- (methoxycarbonyl) propyl, and 4- (methoxycarbonyl) butyl , 5
-(Methoxycarbonyl) pentyl, 6- (methoxycarbonyl) hexyl, ethoxycarbonylmethyl, 2-
(Ethoxycarbonyl) ethyl, 4- (ethoxycarbonyl) butyl, 6- (ethoxycarbonyl) hexyl,
Examples thereof include 2- (propoxycarbonyl) ethyl, 4- (butoxycarbonyl) butyl, 5- (hexyloxycarbonyl) pentyl, and 6- (hexyloxycarbonyl) hexyl group.

A halogen atom, a lower alkyl group, a phenyl group, a lower alkylthio group, a lower alkylamino group, a lower alkoxy group, a lower alkoxycarbonyl lower alkyl group and an oxo group represented by (6). The quinazolinyl group having four substituents includes
6-bromo-2-quinazolinyl, 7-bromo-2-quinazolinyl, 4-ethylthio-2-quinazolinyl, 5-bromo-4-ethylthio-2-quinazolinyl, 6-bromo-4-ethylthio-2-quinazolinyl, 6- Chloro-4
-Methylthio-2-quinazolinyl, 4-methoxy-2-
Quinazolinyl, 6-methoxy-2-quinazolinyl, 7-
Methoxy-2-quinazolinyl, 4,6-dimethoxy-2
-Quinazolinyl, 6,7-dimethoxy-2-quinazolinyl, 4,6,7-trimethoxy-2-quinazolinyl,
-Phenyl-2-quinazolinyl, 5-phenyl-2-quinazolinyl, 6-phenyl-2-quinazolinyl, 7-phenyl-2-quinazolinyl, 4,6-diphenyl-2-
Quinazolinyl, 4-methylamino-2-quinazolinyl,
4-propylamino-2-quinazolinyl, 5-methylamino-2-quinazolinyl, 7-ethylamino-2-quinazolinyl, 3-methyl-6,7-dimethoxy-4-oxo-3 [H] -quinazoline-2- Yl, 3-methyl-
6,8-dimethoxy-4-oxo-3 [H] -quinazolin-2-yl, 3-methyl-5-fluoro-4-oxo-3 [H] -quinazolin-2-yl, 3-methyl-7-
Fluoro-4-oxo-3 [H] -quinazolin-2-yl, 3-methyl-6-chloro-4-oxo-3 [H]-
Quinazolin-2-yl, 3-methyl-7-chloro-4-
Oxo-3 [H] -quinazolin-2-yl, 3-methoxycarbonylmethyl-6-bromo-4-oxo-3
[H] -quinazolin-2-yl, 3-ethoxycarbonylmethyl-6-bromo-4-oxo-3 [H] -quinazolin-2-yl, 3-ethoxycarbonylmethyl-7-
Bromo-4-oxo-3 [H] -quinazolin-2-yl, 2- (3-ethoxycarbonylethyl) -6-bromo-4-oxo-3 [H] -quinazolin-2-yl group and the like can be exemplified. .

The benzoxazinyl group having 1 to 3 substituents selected from the halogen atom, lower alkoxy group and oxo group represented by (7) includes 6-methoxy-4
H-3,1-benzoxazin-2-yl, 7-methoxy-4H-3,1-benzoxazin-2-yl, 6,
7-dimethoxy-4H-3,1-benzoxazine-2
-Yl, 4-oxo-4H-3,1-benzoxazin-2-yl, 6-methoxy-4-oxo-4H-3,1
-Benzoxazin-2-yl, 6,7-dimethoxy-
4-oxo-4H-3,1-benzoxazin-2-yl, 6-bromo-4H-3,1-benzoxazin-2
-Yl, 6-bromo-4-oxo-4H-3,1-benzoxazin-2-yl, 7-bromo-4-oxo-4
H-3,1-benzoxazin-2-yl, 6-fluoro-4-oxo-4H-3,1-benzoxazin-2
-Yl, 7-fluoro-4-oxo-4H-3,1-benzoxazin-2-yl group and the like.

The chromenyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, an oxo group and a phenyl lower alkoxy group represented by (8) includes 6 -Hydroxy-4H-chromen-2-yl, 7-hydroxy-4H-
Chromen-2-yl, 8-hydroxy-4H-chromen-2-yl, 6-hydroxy-4-oxo-4H-chromen-2-yl, 7-hydroxy-4-oxo-4H-
Chromen-2-yl, 8-hydroxy-4-oxo-4
H-chromen-2-yl, 3-methoxy-4H-chromen-2-yl, 5-methoxy-4H-chromen-2-yl, 7-methoxy-4H-chromen-2-yl, 5-methoxy-4- Oxo-4H-chromen-2-yl, 6-
Methoxy-4-oxo-4H-chromen-2-yl, 8
-Methoxy-4-oxo-4H-chromen-2-yl,
3-chloro-4H-chromen-2-yl, 6-chloro-
4H-chromen-2-yl, 8-chloro-4H-chromen-2-yl, 6-chloro-3-methoxy-4-oxo-4H-chromen-2-yl, 8-chloro-3-ethoxy-4- Oxo-4H-chromen-2-yl, 6-bromo-3-methoxy-4-oxo-4H-chromen-2-
Yl, 3-methyl-4H-chromen-2-yl, 6-methyl-4H-chromen-2-yl, 6-chloro-3-methyl-4-oxo-4H-chromen-2-yl, 7-chloro- 3-methyl-4-oxo-4H-chromen-2-
Yl, 7-chloro-3-ethyl-4-oxo-4H-chromen-2-yl, 5-benzyloxy-4H-chromen-2-yl, 7-benzyloxy-4H-chromen-
2-yl, 6-benzyloxy-3-chloro-4-oxo-4H-chromen-2-yl, 7-benzyloxy-
3-chloro-4-oxo-4H-chromen-2-yl,
8-benzyloxy-3-chloro-4-oxo-4H-
Chromen-2-yl, 7- (2-phenethyloxy)-
Examples thereof include a 3-chloro-4-oxo-4H-chromen-2-yl group.

The indolyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, lower alkyl group, phenyl group and lower alkoxy group represented by (9) includes 4-chloro-2-indolyl, 5-chloro-2-indolyl, 6-chloro-2-indolyl, 7-chloro-
2-indolyl, 5-bromo-2-indolyl, 3-phenyl-2-indolyl, 5-chloro-3-phenyl-
2-indolyl, 5-promo-3-phenyl-2-indolyl, 6-bromo-3-phenyl-2-indolyl,
3-methyl-2-indolyl, 4-methyl-2-indolyl, 5-methyl-2-indolyl, 6-methyl-2-
Indolyl, 7-methyl-2-indolyl, 5-methyl-3-phenyl-2-indolyl, 6-methyl-3-phenyl-2-indolyl, 7-methyl-3-phenyl-
2-indolyl, 5-ethyl-3-phenyl-2-indolyl, 3,4-dimethyl-2-indolyl, 3,5-
Dimethyl-2-indolyl, 3,6-dimethyl-2-indolyl, 4-methoxy-2-indolyl, 5-methoxy-2-indolyl, 6-methoxy-2-indolyl,
7-methoxy-2-indolyl, 4-methoxy-3-phenyl-2-indolyl, 5-methoxy-3-phenyl-2-indolyl, 6-methoxy-3-phenyl-2-
Examples thereof include indolyl, 7-methoxy-3-phenyl-2-indolyl, and 5-ethoxy-3-phenyl-2-indolyl.

In the group represented by (10), the halogen-substituted lower alkyl group includes a halogeno- (C _1-6 ) alkyl group,
For example, chloromethyl, bromomethyl, fluoromethyl,
Examples thereof include iodomethyl, dichloromethyl, difluoromethyl, trifluoromethyl, tribromomethyl, 2-chloroethyl, 3-chloropropyl, 4-bromobutyl, 1-chloro-2-bromoethyl, 1-chloro-4-fluorobutyl, and the like. .

The imidazopyridinyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a halogen-substituted lower alkyl group and a phenyl group represented by (10) includes 4-trifluoromethyl- Imidazo [1,2-
a] pyridin-2-yl, 5-trifluoromethyl-imidazo [1,2-a] pyridin-2-yl, 6-trifluoromethyl-imidazo [1,2-a] pyridin-2-
Yl, 7-trifluoromethyl-imidazo [1,2-
a] pyridin-2-yl, 5-tribromomethyl-imidazo [1,2-a] pyridin-2-yl, 4-chloro-
Imidazo [1,2-a] pyridin-2-yl, 5-chloro-imidazo [1,2-a] pyridin-2-yl, 6-
Chloro-imidazo [1,2-a] pyridin-2-yl,
7-chloro-imidazo [1,2-a] pyridin-2-yl, 5-bromo-imidazo [1,2-a] pyridin-2
-Yl, 7-bromo-imidazo [1,2-a] pyridin-2-yl, 2-phenyl-imidazo [1,2-a] pyridin-2-yl, 3-phenyl-imidazo [1,2-
a] pyridin-2-yl, 4-chloro-3-phenyl-
Imidazo [1,2-a] pyridin-2-yl, 5-chloro-3-phenyl-imidazo [1,2-a] pyridine-
2-yl, 6-chloro-3-phenyl-imidazo [1,
2-a] pyridin-2-yl, 7-chloro-3-phenyl-imidazo [1,2-a] pyridin-2-yl group and the like.

In the group represented by (11), the groups defined by R ¹¹ and R ¹² are as follows. That is, R ¹¹ is the following (a)
Each group represented by-(q) is shown. In addition, each group used as a substituent in each group is as follows.

Examples of the N-lower alkylcarbamoyl group include an N- (C _1-6 ) alkylcarbamoyl group, for example,
N-methylcarbamoyl, N-ethylcarbamoyl, N
-Propylcarbamoyl, N-butylcarbamoyl and the like.

As the lower alkoxycarbonyl group,
(C _1-6 ) alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Examples include pentyloxycarbonyl and hexyloxycarbonyl groups.

As the N-phenyl lower alkylcarbamoyl group, an N-phenyl (C _1-6 ) alkyl-carbamoyl group, for example, N-benzylcarbamoyl, N- (1-
Phenethyl) carbamoyl, N- (2-phenethyl) carbamoyl, N- (3-phenylpropyl) carbamoyl, N- (4-phenylbutyl) carbamoyl, N-
Examples thereof include (5-phenylpentyl) carbamoyl and N- (6-phenylhexyl) carbamoyl.

As the benzoyl lower alkyl group, a benzoyl- (C _1-6 ) alkyl group such as benzoylmethyl, 2-benzoylethyl, 2-benzoylpropyl,
3-benzoylpropyl, 4-benzoylbutyl, 5-
Examples thereof include a benzoylpentyl and a 6-benzoylhexyl group.

As the acyl group, (C _1-6 ) alkyl-
Examples include carbonyl groups such as acetyl, propionyl, butyryl, valeryl, and hexanoyl groups.

Examples of the phenyl lower alkyl group include a phenyl- (C _1-6 ) alkyl group such as benzyl, 1-phenethyl, 2-phenethyl, 3-phenylpropyl, and 4-phenylethyl.
Examples thereof include phenylbutyl, 5-phenylpentyl, and 6-phenylhexyl group.

The phenyl group which may have a substituent represented by the above (a) includes, in addition to an unsubstituted phenyl group,
2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,
4,5-trimethoxyphenyl, 2-bromophenyl,
3-bromophenyl, 4-bromophenyl, 3,5-dibromophenyl, 3,4,5-tribromophenyl, 2
-Chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3,4,5-trichlorophenyl, 2- (N-methylcarbamoyl) phenyl, 3- (N-methylcarbamoyl) phenyl, 4-
(N-methylcarbamoyl) phenyl, 4-bromo-2
-(N-methylcarbamoyl) phenyl, 2- (N-methylcarbamoyl) 5-chlorophenyl, 2- (N-methylcarbamoyl) -3-chlorophenyl, 2-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonyl Phenyl, 4-ethoxycarbonylphenyl, 4-bromo-2-methoxyphenyl, 4-chloro-2-methoxycarbonylphenyl,
-Aminosulfonylphenyl, 3-aminosulfonylphenyl, 4-aminosulfonylphenyl, 2-aminosulfonyl-4-bromophenyl, 2-aminosulfonyl-5-bromophenyl, 2- (N-benzylcarbamoyl) phenyl, 3- ( N-benzylcarbamoyl) phenyl, 4- (N-benzylcarbamoyl) phenyl, 2
-(N-phenethylcarbamoyl) phenyl, 4-bromo-2- (N-benzylcarbamoyl) phenyl, 4-
Chloro-2- (N-benzylcarbamoyl) phenyl,
2- (N-phenylcarbamoyl) phenyl, 3- (N
-Phenylcarbamoyl) phenyl, 4- (N-phenylcarbamoyl) phenyl, 4-bromo-2- (N-phenylcarbamoyl) phenyl, 4-chloro-2- (N
-Phenylcarbamoyl) phenyl, 2-carboxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3,5-dicarboxyphenyl, and the like.

The substituted pyrazolyl group represented by (b) includes 2-methyl-3-pyrazolyl, 4-methyl-3-pyrazolyl, 2-ethyl-3-pyrazolyl, 2,4,5-
Trimethyl-3-pyrazolyl, 2-phenyl-3-pyrazolyl, 4-phenyl-3-pyrazolyl, 4-phenyl-5-pyrazolyl, 2,5-diphenyl-3-pyrazolyl, 2,4-diphenyl-3-pyrazolyl, 1- (4-
(Chlorophenyl) -3-pyrazolyl, 5- (4-chlorophenyl) -3-pyrazolyl, 2-methyl-5- (4-
(Chlorophenyl) -3-pyrazolyl, 2-ethyl-5-
Examples thereof include a (2-chlorophenyl) -3-pyrazolyl group.

The substituted thiazolyl group represented by (c) includes 4-methyl-2-thiazolyl, 5-methyl-2-thiazolyl, 4-ethyl-2-thiazolyl, 4-propyl-2-thiazolyl, 4-butyl -2-thiazolyl, 4-
Pentyl-2-thiazolyl, 4-isopentyl-2-thiazolyl, 4-hexyl-2-thiazolyl, 4-chloro-2-thiazolyl, 5-chloro-2-thiazolyl, 4-
Bromo-2-thiazolyl, 5-bromo-2-thiazolyl, 2-nitro-4-thiazolyl, 4-nitro-2-thiazolyl, 5-nitro-2-thiazolyl, 4-benzoyl-2-thiazolyl, 5-benzoyl- 2-thiazolyl, 4-benzoylmethyl-2-thiazolyl, 4-benzoylmethyl-2-thiazolyl, 5-benzoylmethyl-2-thiazolyl, 2-benzoylmethyl-4-thiazolyl, 4-phenyl-2-thiazolyl, 5- Phenyl-
2-thiazolyl, 4,5-diphenyl-2-thiazolyl, 4-phenyl-5-bromo-2-thiazolyl, 4-
Phenyl-5-chloro-2-thiazolyl, 5-benzoyl-4-phenyl-2-thiazolyl, 4- (4-methoxyphenyl) -2-thiazolyl, 5- (3,4-dimethoxyphenyl) -2-thiazolyl, 4- (2,3,4-
Trimethoxyphenyl) -2-thiazolyl, 4- (3,
4,5-trimethoxyphenyl) -2-thiazolyl, 4
-(4-bromophenyl) -2-thiazolyl, 4- (4
-Fluorophenyl) -2-thiazolyl, 4- (4-fluorophenyl) -5-methyl-2-thiazolyl, 4-
(2-chlorophenyl) -2-thiazolyl, 5- (3-
(Chlorophenyl) -2-thiazolyl, 5- (4-fluorophenyl) -4-methyl-2-thiazolyl, 5- (4
-Fluorophenyl) -4-ethyl-2-thiazolyl,
4-methoxycarbonylmethyl-2-thiazolyl, 4-
Ethoxycarbonylmethyl-2-thiazolyl, 2-methoxycarbonyl-4-thiazolyl, 4-ethoxycarbonyl-2-thiazolyl, 5-ethoxycarbonyl-2-
Thiazolyl, 5-ethoxycarbonyl-4-methyl-2
-Thiazolyl, 4-ethoxycarbonyl-5-methyl-
Examples thereof include 2-thiazolyl, 4- (4-biphenyl) -2-thiazolyl, and 5- (4-biphenyl) -2-thiazolyl group.

Examples of the thiadiazolyl group having a substituent represented by (d) include 1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, -Ethyl-1,3,4-thiadiazol-2-yl, 5-propyl-1,3,4-thiadiazol-2-yl, 5-chloro-1,3,4-thiadiazol-2-yl, 5-bromo -1,3,4-thiadiazol-2-yl, 5-fluoro-1,3,4-thiadiazol-2-yl, 5-iodo-1,3,4-thiadiazol-2-yl, 5-trifluoromethyl -1, 3,
4-thiadiazol-2-yl, 5-dibromomethyl-
Examples thereof include a 1,3,4-thiadiazol-2-yl, 3-phenyl-1,2,4-thiadiazol-5-yl, and a 5-phenyl-1,2,4-thiadiazol-3-yl group.

The oxazolyl group which may have a substituent represented by (e) includes 5-isoxazolyl,
Phenyl-5-isoxazolyl, 4-phenyl-5-
Isoxazolyl, 5-phenyl-3-isoxazolyl, 3- (4-chlorophenyl) -5-isoxazolyl, 3- (2-chlorophenyl) -5-isoxazolyl, 4- (4-chlorophenyl) -5-isoxazolyl, 5- (4 -Chlorophenyl) -4-isoxazolyl, 3- (4-bromophenyl) -5-isoxazolyl group and the like.

The pyridyl group which may have a substituent represented by (f) includes 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl,
Trifluoromethyl-2-pyridyl, 5-trifluoromethyl-3-pyridyl, 3-cyano-2-pyridyl,
-Cyano-2-pyridyl, 5-cyano-2-pyridyl,
Examples thereof include a 3-cyano-4-pyridyl group.

The pyrazinyl group represented by (g) includes a 2-pyrazinyl group.

The pyrimidinyl group having 1 to 3 halogen atoms represented by (h) includes unsubstituted pyrimidinyl groups such as 2-pyrimidinyl and 4-pyrimidinyl, 5-bromo-2-pyrimidinyl, 5-chloro-2-
Examples thereof include a pyrimidinyl, 6-bromo-2-pyrimidinyl, 2-bromo-4-pyrimidinyl group and the like.

The benzothiazolyl group which may have a substituent represented by (i) includes an unsubstituted benzothiazol-2-yl group and 4-chloro-benzothiazole-
2-yl, 5-chloro-benzothiazol-2-yl,
6-chloro-benzothiazol-2-yl, 7-chloro-benzothiazol-2-yl, 6-bromo-benzothiazol-2-yl, 7-bromo-benzothiazol-
2-yl, 4-methoxy-benzothiazol-2-yl, 5-methoxy-benzothiazol-2-yl, 6-
Methoxy-benzothiazol-2-yl, 7-methoxy-benzothiazol-2-yl, 4,6-dimethoxy-
Benzothiazol-2-yl, 6-bromo-4-methoxy-benzothiazol-2-yl, 4-acetyl-benzothiazol-2-yl, 5-acetyl-benzothiazol-2-yl, 6-acetyl-benzothiazole -2
-Yl, 7-acetyl-benzothiazol-2-yl,
4-acetyl-6-bromo-benzothiazol-2-yl, 5-methoxycarbonyl-benzothiazol-2-
Yl, 7-methoxycarbonyl-benzothiazole-2
-Yl, 7-ethoxycarbonyl-benzothiazole-
2-yl, 4-methyl-benzothiazol-2-yl,
6-methyl-benzothiazol-2-yl, 4-trifluoromethyl-benzothiazol-2-yl, 6-trifluoromethyl-benzothiazol-2-yl, 7-trifluoromethyl-benzothiazol-2-yl, 4-
Examples thereof include a benzyloxy-benzothiazol-2-yl group and a 6-benzyloxy-benzothiazol-2-yl group.

The halogen-substituted benzoxazolyl group represented by (j) includes 4-chloro-benzoxazole-
2-yl, 5-chloro-benzoxazol-2-yl, 6-chloro-benzoxazol-2-yl, 7-
Chloro-benzoxazol-2-yl, 5-bromo-
Benzoxazol-2-yl, 6-bromo-benzoxazol-2-yl group and the like can be exemplified.

The benzoimidazolyl group which may have a substituent represented by (k) includes benzoimidazolyl-
2-yl, 1-benzyl-benzimidazolyl-2-yl, 4-benzyl-benzimidazolyl-2-yl, 6
-Benzyl-benzimidazolyl-2-yl group and the like.

Examples of the thiazolopyridinyl group represented by (l) include a thiazolo [5,4-b] pyridin-2-yl group.

Examples of the quinolyl group which may have a substituent represented by (m) include unsubstituted 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 7-quinolyl group and the like. Bromo-2-quinolyl, 4-bromo-3-quinolyl, 3-bromo-4-quinolyl, 2-methyl-4-
Quinolyl, 3-methyl-4-quinolyl, 7-methyl-5
-Quinolyl group and the like.

The substituted naphthyridinyl group represented by (n) includes 2-methyl-1,8-naphthyridin-7-yl,
4-methyl-1,8-naphthyridin-7-yl, 2,4
-Dimethyl-1,8-naphthyridin-7-yl group and the like.

The indenothiazolyl group which may have a substituent represented by (o) includes 8H-indeno [1,
2-d] thiazol-2-yl, 4-methyl-8H-indeno [1,2-d] thiazol-2-yl, 4-ethyl-8H-indeno [1,2-d] thiazol-2-yl, 5-methyl-8H-indeno [1,2-d] thiazol-2-yl, 7-methyl-8H-indeno [1,2
-D] thiazol-2-yl, 4-bromo-8H-indeno [1,2-d] thiazol-2-yl, 6-bromo-8H-indeno [1,2-d] thiazol-2-yl, -Chloro-8H-indeno [1,2-d] thiazol-2-yl, 7-chloro-8H-indeno [1,2
-D] thiazol-2-yl group and the like.

The halogen-substituted benzopyranothiazolyl group represented by (p) includes 6-fluoro-4H- (1) benzopyrano [3,4-d] thiazol-2-yl,
Fluoro-4H- (1) benzopyrano [3,4-d] thiazol-2-yl, 8-fluoro-4H- (1) benzopyrano [3,4-d] thiazol-2-yl, 8-bromo-4H- (1) Benzopyrano [3,4-d] thiazol-2-yl, 6-chloro-4H- (1) benzopyrano [3,4-d] thiazol-2-yl group and the like can be exemplified.

The lower alkyl-substituted naphthimidazolyl group represented by (q) includes 1-methyl-1H-naphtho [1,2-d] imidazol-2-yl and 1-ethyl-
1H-naphtho [1,2-d] imidazol-2-yl,
Examples thereof include a 1-propyl-1H-naphtho [1,2-d] imidazol-2-yl group.

The compounds as active ingredients of the therapeutic agent for nephritis of the present invention are classified into the above formulas (1) to (11) according to the type of the group represented by R ¹ in the general formula (1). Among them,
In particular, the compound represented by (11) can be exemplified as a preferable one because it can exhibit an excellent therapeutic effect on nephritis. The active compound of the present invention having the group represented by (11) is also divided into the above-mentioned 17 groups (a) to (q) according to the type of the R ¹¹ group in the group. . Each of these groups can exert an excellent therapeutic effect on nephritis.

The active ingredient compound of the therapeutic agent for nephritis of the present invention is characterized in that it has an excellent therapeutic effect on nephritis as described above, and also has excellent safety with almost no side effects such as hemolysis. From these aspects, it is extremely useful as a therapeutic agent for nephritis.

The compounds represented by the general formula (1) as active ingredients in the therapeutic agent for nephritis of the present invention are all known compounds (for example, see the above-mentioned patent publications such as JP-A-3-68592).

The above-mentioned active ingredient compound is usually prepared in the form of a general pharmaceutical preparation, and used as the therapeutic agent for nephritis of the present invention.
The pharmaceutical preparation is prepared by a general method using a commonly used diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant, and a lubricant. You. Various forms can be selected as the pharmaceutical preparation to be adjusted depending on the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules,
Suppositories, injections (solutions, suspensions, etc.) and the like can be mentioned.

In forming into tablets, carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, binder such as polyvinylpyrrolidone, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, sodium alginate, agar powder, laminaran powder, Disintegrating agents such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, sucrose, stearin,
Disintegration inhibitors such as cocoa butter and hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, purified talc, stearates, powdered boric acid, lubricants such as polyethylene glycol and the like can be used. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the case of molding into a pill form, carriers such as excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol, etc. Agent,
Disintegrators such as laminaran and agar can be used. For molding into a suppository form, for example, polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like can be used as carriers.

Capsules are usually prepared by mixing the active ingredient compound of the present invention with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like in accordance with a conventional method.

When prepared as an injection, the liquid preparations, emulsions and suspensions are preferably sterilized and isotonic with blood, and when formed into these forms, diluents such as water and ethyl alcohol , Macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be included in the pharmaceutical preparation, and a usual solubilizer, buffer, soothing agent and the like may be added. You may.

Further, the remedy for nephritis of the present invention may contain a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.

The amount of the active ingredient compound to be contained in the preparation of the present invention is not particularly limited and can be appropriately selected from a wide range. Usually, the amount is preferably 1 to 70% by weight in the pharmaceutical preparation.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the form of the preparation, the age, gender and other conditions of the patient,
It is determined according to the degree of the disease. For example, tablets, pills,
Solutions, suspensions, emulsions, granules and capsules are administered orally. The injection is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally.
Suppositories are administered rectally.

The dose of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, gender and other conditions, the degree of the disease and the like. Usually, the amount of the active ingredient compound is about 0. It is good to be about 0.5 to 80 mg,
The formulation can be administered in 1 to 4 divided doses per day.

[0066]

EXAMPLES Hereinafter, in order to explain the present invention in more detail, pharmacological tests performed on the active ingredient compound of the present invention will be described.
Next, preparation examples of the therapeutic agent for nephritis of the present invention will be given.

[0067]

[Pharmacological test example 1] (1) Test compound When using the test compound, dimethyl sulfoxide (DMSO,
It was dissolved in Wako Pure Chemical Industries, Ltd.) and adjusted to a concentration of 2 × 10 ⁻² M, and this was added to 2% fetal bovine serum (FBS, BioWhittake).
r) Dulbecco's modified Eagle's medium (DMEM, manufactured by Nissui Pharmaceutical Co., Ltd.) was diluted 2,000-fold to 10 ^-5 M,
It was diluted with 2% FBS-DMEM containing 0.05% DMSO to prepare a 10 ^-6 M test compound solution.

(2) Test cells glomerular mesangial cells (NHM) which are normal human cells
C, manufactured by Clonetics) from Sanko Junyaku
Growth medium (Brett Kit MsGM, manufactured by Sanko Junyaku)
The cells were incubated at 37 ° C. under 5% CO 2 gas, and when the cell density became almost conflict, trypsin /
Harvest using EDTA solution, about 5 × 10 ³ cells /
subculture by diluting with the above medium so as to be cm ² ,
Cells in the 5th to 7th cultures were subjected to the experiment.

(3) Measurement of Cell Proliferation Inhibitory Activity The above-mentioned mesangial cells harvested using trypsin / EDTA solution were seeded on a 24-well plate at 2 × 10 ⁴ cells / 1.0 ml / well and used for growth. The cells were cultured for 3 days using a medium (Brett Kit MsGM). After washing three times with FBS-free DMEM (2 ml / well), a CCMD180 medium containing 50 μg / ml gentamicin sulfate and 50 ng / ml amphotericin B (Brett kit MsBM (FBS-free MsG
M), manufactured by Sanko Junyaku Co., Ltd.) at 1 ml / well, followed by further culturing for 4 days to effect arrest.

After the arrest, MsBM was removed and ³ H
1 μC of thymidine (5 Ci / mmol, manufactured by Amersham)
i / ml of the test compound solution added to 1 ml /
Wells were added.

As a control, DMEM containing 2% FBS without addition of the test compound and 0.05% DMSO was used as a blank, and 0.05% without addition of the test compound and FBS.
DMEM containing% DMSO was used respectively.

The experiment was performed in quadruplicate measurement using 4 wells of each chemical solution added.

After culturing for 18 hours, the medium was removed, and PBS was removed.
Washed twice with (+) (manufactured by Nissui Pharmaceutical) and ice-cooled 10%
1 ml / well of trichloroacetic acid (TCA) was added. After allowing to stand at about 4 ° C. for about 30 minutes, the supernatant was removed and further washed three times with PBS (−) (manufactured by Nissui Pharmaceutical). After sufficiently removing the washing solution by suction, 0.5N NaOH 0.5 ml
/ Well was added and left at 37 ° C. overnight to lyse the cells. Transfer 0.3 ml of the well mixed cell lysate to a counting vial by pipetting, and add 5N
After neutralization by adding 30 μl of HCl, Scintisol EX
Add 4 ml of -H (ScintisolEX-H, Dojindo Laboratories), mix well, measure with a liquid scintillation counter (Tri-Carb ^™ 2500TR, Packard) for 4 minutes, and collect the acid-insoluble fraction of the cells. The amount of incorporated ³ H-thymidine was measured.

The average of quadruplicate measurements of the amount of ³ H-thymidine incorporation measured for each well was calculated, and the cell growth inhibition rate was determined from this value according to the following equation.

Cell growth inhibition rate (%) = (CA) / (C
-B) × 100 A: Average dpm value of the test reagent group at each concentration B: Average dpm value of the blank group C: Average dmp value of the control group Fig. 3 shows the cell growth inhibition rates obtained using the test compounds.

[0076]

[Table 1]

[0077]

[Table 2]

[0078]

[Table 3]

[0079]

[Table 4]

[0080]

[Table 5]

[0081]

[Table 6]

[0082]

[Table 7]

[0083]

[Table 8]

[0084]

[Table 9]

[0085]

[Table 10]

[0086]

[Table 11]

[0087]

[Table 12]

[0088]

[Table 13]

[0089]

[Table 14]

[0090]

[Table 15]

From the above Table 1, it is clear that the active ingredient compound of the therapeutic agent for nephritis of the present invention generally exerts an excellent growth inhibitory effect. Therefore, the active ingredient compound is effective as a therapeutic agent for nephritis. I understand.

[0092]

Formulation Example 1 Preparation of Tablets Tablets (1000 tablets) containing 250 mg of the compound prepared in Production Example 1 per tablet were prepared according to the following formulation.

Compound of Compound No. 21 250 g Lactose (Japanese Pharmacopoeia) 33.3 g Corn Starch (Japanese Pharmacopoeia) 16.4 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 12.8 g Methylcellulose (Japanese Pharmacopoeia) 0 g Magnesium stearate (Japanese Pharmacopoeia) 1.5 g Total amount 320.0 g That is, the active ingredient compound, lactose, corn starch and carboxymethylcellulose are sufficiently mixed according to the above-mentioned formulation, granulated using methylcellulose aqueous solution, and granulated into 24 mesh. The mixture was passed through a sieve, mixed with magnesium stearate, and pressed into tablets.

[0094]

Formulation Example 2 Preparation of Capsules Hard gelatin capsules (1000) containing 250 mg per capsule of the compound of Compound No. 108 as an active ingredient compound of the present invention were prepared according to the following formulation.

Compound of Compound No. 108 250 g Microcrystalline cellulose (Japanese Pharmacopoeia) 30 g Corn starch (Japanese Pharmacopoeia) 17 g Talc (Japanese Pharmacopoeia) 2 g Magnesium stearate (Japanese Pharmacopoeia) 1 g Total amount 300 g Then, each component was finely powdered and thoroughly mixed so as to form a uniform mixture, and then filled into a gelatin capsule for oral administration having desired dimensions to obtain a desired capsule.

[0096]

Formulation Example 3 Preparation of Granules Compound No. 38 as an active ingredient was added in an amount of 5 per gram.
A granule (1000 g) containing 00 mg was prepared according to the following formulation.

Compound No. 38 Compound 500 g Corn starch (Japanese Pharmacopoeia) 250 g Lactose (Japanese Pharmacopoeia) 100 g Microcrystalline cellulose (Japanese Pharmacopoeia) 100 g Carboxymethylcellulose calcium (Japanese Pharmacopoeia) 40 g Hydroxypropylcellulose (Japanese Pharmacopoeia) In other words, after mixing the active ingredient compound, corn starch, lactose, crystalline cellulose, and potassium carboxymethylcellulose according to the above-mentioned formulation, an aqueous solution of hydroxypropylcellulose was added to the mixture, kneaded, and the mixture was granulated by an extrusion granulator. After drying at 50 ° C. for 2 hours, the target granules were obtained.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Yasuhisa Kuroki 189-5 Villa Sezon, 5 Iwa-ji, Nadu-cho, Naruto City, Tokushima Prefecture 72) Inventor, J. Mukai 1-9, Marusu, Hiroshima, Matsushimo-cho, Itano-gun, Tokushima (72) Inventor Kenji Hashimoto 83 east of Kitahama, Miyako, Naruto, Tokushima Kitajima Town

Claims (3)

[Claims] 1. A general formula ^{(1): R 1 - (} A) l - (O) n - (CH 2) m -PO (Z 1) Z 2 wherein, R ¹ is the following (1) to It represents a group selected from (11). (1) a lower alkylcarbonyl group substituted by a phenyl group having 1 to 3 halogen atoms; (2) a group (Wherein, R ² represents a hydrogen atom or a halogen atom, and D represents an oxygen atom or a sulfur atom); (3) a group (Wherein E represents a carbonyl group or a methylene group); (Wherein R ³ represents a halogen atom, a lower alkoxy group or a phenyl lower alkoxy group); (5) having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group and a phenyl group A quinolyl group; (6) 1 to 4 substituents selected from the group consisting of halogen atoms, lower alkyl groups, phenyl groups, lower alkylthio groups, lower alkylamino groups, lower alkoxy groups, lower alkoxycarbonyl lower alkyl groups, and oxo groups. A quinazolinyl group having a group; (7) a benzoxazinyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkoxy group and an oxo group; (8) a halogen atom, a lower alkyl group and a lower Chromemen having 1 to 3 substituents selected from the group consisting of an alkoxy group, a hydroxyl group, an oxo group and a phenyl lower alkoxy group (9) an indolyl group having 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a phenyl group and a lower alkoxy group; (10) a halogen atom, a halogen-substituted lower alkyl group and phenyl imidazopyridinyl group having 1 to 3 substituents selected from the group consisting of groups; and (11) group -Z-N (R ¹¹⁾ in R ¹² (base, R ¹¹ is (a) a halogen atom A lower alkoxy group, an N-lower alkylcarbamoyl group, a 4-phenylmethyl-1-piperazinylcarbonyl group, a lower alkoxycarbonyl group, an aminosulfonyl group, an N-phenyl lower alkylcarbamoyl group, an N-phenylcarbamoyl group and a carboxyl group A phenyl group which may have 1 to 3 substituents selected from the group consisting of: (b) a lower alkyl group and a halogen atom as a substituent A pyrazolyl group having 1 to 3 substituents selected from the group consisting of a phenyl group which may have; (c) a halogen atom, a lower alkyl group, a nitro group, a nitro group, a benzoyl group, a benzoyl lower alkyl group, a phenyl group as a substituent; A thiazolyl group having 1 to 3 groups selected from the group consisting of a halogen atom or a lower alkoxy group-substituted phenyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a lower alkoxycarbonylcarbonyl group and a biphenyl group; (d ) A thiadiazolyl group which may have a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group and a phenyl group; (e) at least one selected from the group consisting of a phenyl group and a halogen-substituted phenyl group Oxazoly having two substituents (F) a pyridyl group which may have at least one substituent selected from the group consisting of a cyano group and a halogen-substituted lower alkyl group; (g) a pyrazinyl group; (h) 1 to 3 halogen atoms (I) 1 to 3 selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups, acyl groups, lower alkoxycarbonyl groups, halogen-substituted lower alkyl groups, and phenyl lower alkoxy groups; (J) halogen-substituted benzooxazolyl group; (k) benzimidazolyl group which may have at least one phenyl lower alkyl group as a substituent; (l) thiazolopyro A dinyl group; (m) having at least one substituent selected from the group consisting of a halogen atom and a lower alkyl group; (N) a naphthyridinyl group having at least one lower alkyl group as a substituent; (o) an indenothiazolyl group which may have at least one substituent selected from a halogen atom and a lower alkyl group (P) a benzopyranothiazolyl group having at least one halogen atom as a substituent; or (q) a naphthoimidazolyl group having at least one lower alkyl group as a substituent. R ¹² represents a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group. Z represents a carbonyl group (= CO group) or = SO ₂ group. A represents a phenylene group, a thiophendiyl group or a pyrazinediyl group. l represents 0 or 1. m shows the integer of 1-4. n represents 0 or 1. Z ₁ and Z ₂ simultaneously represent an OR ³ group (R ³ is a lower alkyl group) or one is a lower alkoxy group and the other is a phenyl group. ] A therapeutic agent for nephritis, comprising a phosphoric acid derivative represented by the formula [1] as an active ingredient. 2. The therapeutic agent for nephritis according to claim 1, wherein a phosphoric acid derivative in which R ¹ is a group represented by (11) in the general formula (1) is an active ingredient. 3. The therapeutic agent for nephritis according to claim 1, wherein a phosphoric acid derivative in which R ¹ is a group represented by any of (1) to (10) in the general formula (1) is an active ingredient.