JP2003238408A - Therapeutic agent or prophylactic agent for tissue fibrosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an orally administrable therapeutic or prophylactic agent for tissue fibrosis. <P>SOLUTION: The therapeutic agent or the prophylactic agent for tissue fibrosis comprises a compound having a pyrimidone skeleton represented by formula (II) and having a chymase inhibiting activity or its pharmacologically acceptable salt as an active ingredient. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic or prophylactic agent for tissue fibrosis using a compound that effectively inhibits chymase activity in vivo by oral administration or the like.

[0002]

2. Description of the Related Art Tissues constituting a living body often cause a phenomenon called fibrosis with a disease. Fibrosis is the rigidity of tissue accompanied by excessive deposition of fibrous proteins such as collagen and infiltration / proliferation of fibroblasts, which is essentially unnecessary as a result of inflammation or the like occurring in the tissue.

[0003] Tissue fibrosis can occur in all tissues, and the resulting phenomenon is the same even though the site of occurrence and the stimulus that triggers it are different. The details of the onset mechanism of fibrosis are unknown, but it is considered as follows. When parenchymal cells are lost or tissue function declines, the body may migrate and supplement fibroblasts unrelated to the original function of the tissue, but fibroblasts recover the function of the tissue. However, the accumulation of fibroblasts and the accumulation of the intercellular matrix such as collagen produced by the fibroblasts cause the rigidity of the tissue. Such rigidification is fibrosis, and it becomes difficult for the fibrotic tissue to function normally, resulting in a pathological condition often called fibrosis.
Tissues that have once become fibrotic do not return to their original state, and the condition may progress further and cause serious disability.

About fibrosis in major visceral tissues,
A brief description is given below. As one of pulmonary fibrosis, pulmonary fibrosis, which is a side effect of administration of bleomycin, which is an anticancer agent, is known. This is considered to be because radicals generated by bleomycin damage lung tissue, infiltrate and proliferate fibroblasts to compensate for the damage, deposit collagen protein, and impair lung function. In addition, lung tissue damage that causes pulmonary fibrosis is not limited to chemical substances such as anticancer agents, but may also occur due to blood pressure overload in pulmonary hypertension and chronic inflammatory reaction in asthma. As a result of such fibrosis of the lungs, the ventilation capacity of the lungs is reduced, which further aggravates the condition. Although many treatments to suppress pulmonary fibrosis induced by bleomycin have been studied so far, a satisfactory treatment has not been found yet. Further, there is no known treatment for pulmonary fibrosis caused by pulmonary hypertension or asthma, and it is particularly difficult to restore the function of the lung with advanced fibrosis.

The bladder is also a tissue that contacts the outside world through the urethra and is exposed to various stimuli including infection, and it is known that the inflammatory reaction induced by such stimulus leads to fibrosis of the bladder. There is. In bladder fibrosis, urine collection and urination become difficult, leading to cystitis with frequent urination and difficulty urinating. That is, the occurrence of fibrosis of the bladder in cystitis such as urinary tract tuberculosis, interstitial cystitis, and radiation cystitis is described in "Urology" (edited by Takashi Kurita, p177 (1995).
Year), Nanzando) ”. In particular, it has become clear that interstitial cystitis is a disease in which fibrosis accompanied by an increase in chymase is a problem (T. Yamada).
et al. , Int. J. Urol. , 7,292
(2000)). Treatment for interstitial cystitis due to fibrosis of the bladder tissue has not been established, and symptomatic treatment is repeated, and in many cases, cystectomy is finally performed.

Also in the kidney, various factors cause fibrosis. Kidney disease is called various names depending on its cause and place of occurrence, such as IgA nephropathy caused by immune complex deposition, diabetic nephropathy resulting from diabetes mellitus, and pyelonephritis occurring in the renal pelvis. A decrease in function associated with tissue fibrosis is observed in. It is also known that as a result of chronic rejection after kidney transplantation, fibrosis may occur and renal dysfunction may occur again. There is currently no effective treatment to prevent such dysfunction in the kidney. Further, although dialysis is widely used as a means for compensating for the deterioration of renal function, the kidneys of patients who have once undergone renal dialysis treatment do not recover their functions, and dialysis treatment must be continued for life.

Adriamycin, which is an anticancer agent, is known to induce the side effects of cardiomyopathy. The heart is not limited to anticancer agents, but when stimulated by infection, pressure overload, etc., it may cause loss of myocardium or deterioration of cardiac function, compensatory migration of fibroblasts, and development of fibrosis. If it progresses excessively, the heart becomes rigid and the function as a pump deteriorates, and progresses to chronic heart failure due to fibrosis. Although ACE inhibitors and β-blockers are used as this treatment, they are not satisfactory treatments for suppressing or improving fibrosis.

It is known that the liver is fibrotic due to virus, tumor and alcohol stimulation. The fibrosis causes the liver to rapidly decline in function. If the cause is a virus or tumor, treatment with antiviral agents or anticancer agents is performed, and if the cause is dietary intake such as alcohol, diet therapy is taken, but active treatment methods for liver fibrosis are known. Not not.

As described above, fibrosis can occur in all organs in the living body, and it is closely related to the deterioration of tissue function. The fibrosis of the tissue inside the living body is confirmed by an examination such as echo or by collecting a part of the tissue and detecting a substance related to the fibrosis. For example, it is carried out by quantifying hydroxyproline, but it is technically complicated and requires a sample amount. A method of preparing a tissue specimen and analyzing it pathologically is also used. In addition, the recent development of gene manipulation technology has made it possible to use the expression level of a specific messenger RNA (mRNA) of a protein involved in fibrosis as an index. The fact that the mRNA expression level of proteins involved in fibrosis, such as collagen-3, changes with the fibrosis of the tissue is described in S. N. Iyer et al. Phar
macol. Exp. Therap. , 289, 211
(1999). That is, measuring the amount of collagen-3 mRNA expression is effective as a method of knowing tissue fibrosis. However, even if fibrosis of the tissue is discovered, an effective treatment method for fibrosis itself is not known and only symptomatic treatment for maintaining the function is taken.

Chymase, a protease present in mast cell granules, has been suggested by in vitro experiments to induce tissue fibrosis. That is, activation of matrix metalloprotease (J. Saarinen
et al. J. Biol. Chem. , 269,
18134 (1994)) and its inhibitor tis
sue inhibitor of metallop
Inactivation of Rotainase (BT Frank
et al. J. Immunol. , 166,27
There is also a view that it decomposes intercellular matrix proteins via 83 (2001) and triggers a fibrotic reaction. Chymase also has an action of inducing degranulation of non-degranulated mast cells, and interleukin 1β, c-
kit ligand, transforming glow
th factor-β (TGF-β; J. Taipa
le et al. J. Biol. Chem. , 27
0,4689 (1995)) and many other cytokines have been reported to be active, and it is considered to be involved in the inflammatory reaction and tissue destruction which are also said to be associated with fibrosis. Such a reaction promotes migration of fibroblasts into tissues, and in particular, activation of TGF-β is considered to be involved in expression of proteins such as collagen involved in fibrosis. Regarding the formation of fibrotic protein by the activation of chymase and type 1 collagen precursor,
M. W. Reported by Kofford and others (J. Bi
ol. Chem. , 272, 7127 (1997)).

Further, clinically, interstitial cystitis (T.
Yamada et al. , Int. J. Uro
l. , 7, 292 (2000)) and rejection kidney (M.Yam
ada et al. , Kidney Int. , 59,
It has been reported that chymase is enhanced in diseases associated with fibrosis, such as 1374 (2001)). The present inventors have previously reported that when bleomycin is administered into the hamster respiratory tract to cause pulmonary fibrosis, chymase activity is enhanced prior to fibrosis (Jpn. J. Pharmac).
ol. , 85 (Suppl 1), 183 (200
1)). However, it was still unclear whether it is possible to suppress tissue fibrosis by suppressing chymase activity in the tissue. Also, WO01 / 62292
The publication discloses prevention or treatment of fibrosis using a quinazoline derivative.

[0012]

As described above, an effective therapeutic agent for fibrosis has not yet been developed, and only a symptomatic therapeutic agent for a tissue whose function is deteriorated by fibrosis is used. Is. Therefore, a therapeutic or preventive agent for tissue fibrosis is desired. In particular, since fibrosis can occur in all tissues of the whole body, there is a strong demand for a therapeutic or prophylactic agent that can be applied to any tissue and that can be orally administered.

[0013]

Means for Solving the Problems The present inventors have found that a compound which is widely distributed in the body by oral administration or the like and selectively inhibits chymase becomes a therapeutic or prophylactic agent for tissue fibrosis without side effects. The present invention has been completed as a result of thorough consideration and thought through an animal model.

That is, the present invention relates to the following (1) to (14). (1) The following formula (II)

[0015]

[Chemical 3]

A therapeutic or prophylactic agent for tissue fibrosis, which comprises a compound having a pyrimidone skeleton represented by and having chymase inhibitory activity, or a pharmacologically acceptable salt thereof as an active ingredient. (2) General formula (I)

[0017]

[Chemical 4]

[In the formula, R0 represents an aryl group, R1 may be substituted with a hydrogen atom, a C1-C6 alkyl group, a C1-C6 acyl group, or a monocyclic aromatic group (C1-C).
6) alkyloxycarbonyl group, (C1 to C6) alkylsulfonyl group optionally substituted with an aryl group,
(C1 to C6) which may be substituted with an aryl group represents an alkylaminosulfonyl group or a saturated heterocyclic carbonyl group, D represents an oxygen atom or —NH—, and m represents an integer of 0 to 3 , R2 represents an optionally substituted (C1-C6) alkyl group] or a therapeutic or prophylactic agent for tissue fibrosis, which comprises a pharmacologically acceptable salt thereof as an active ingredient. .

(3) The aryl group in R0 is (C1 to
C6) an alkyl group or a phenyl group which may be substituted with a halogen atom, and a (C1-C6) alkyloxycarbonyl group which may be substituted with a monocyclic aromatic group in R1 is a (C1-C6) alkyloxy group. A carbonyl group or a pyridyl (C1-C6) alkyloxycarbonyl group, which may be substituted with an aryl group (C
1-C6) is an alkylsulfonyl group in which an alkylsulfonyl group is substituted with a phenyl group, and is optionally substituted with an aryl group (C1-C6) An alkylaminosulfonyl group is substituted with a phenyl group (C1-
C6) is an alkylaminosulfonyl group, the saturated heterocyclic carbonyl group is a saturated heterocyclic carbonyl group having an oxygen atom, and may have a substituent in R2 (C6).
1 to C6) alkyl group is a (C1 to C6) alkyl group,
(C1 to C6) alkyloxy (C1 to C6) alkyl group, (C1 to C6) alkyl group substituted with an aryl group, substituted with a heterocyclic oxy group having a nitrogen atom (C
1 to C6) The therapeutic or prophylactic agent for tissue fibrosis according to (2) above, which is a (C1 to C6) alkyl group substituted with a heterocyclic group having a nitrogen atom.

(4) The saturated heterocyclic carbonyl group having an oxygen atom in the saturated heterocyclic carbonyl group of R1 is a tetrahydrofuroyl group, and the (C1-C6) alkyl group which may have a substituent of R2 The (C1-C6) alkyl group substituted with an aryl group is a (C1-C6) alkyl group substituted with a phenyl group, and the (C1-C6) alkyl group substituted with a heterocyclic oxy group having a nitrogen atom is A (C1-C6) alkyl group substituted with a 6-membered heterocyclic oxy group having a nitrogen atom, wherein the (C1-C6) alkyl group substituted with a heterocyclic group having a nitrogen atom has a nitrogen atom. Substituted with a ring group (C1-C6)
The therapeutic or preventive agent for tissue fibrosis according to the above (3), which is an alkyl group. (5) R0 is a phenyl group or a (C1 to C6) alkylphenyl group, R1 is a hydrogen atom, a (C1 to C6) alkyloxycarbonyl group, a (C1 to C6) acyl group,
A phenyl (C1-C6) alkylsulfonyl group, a pyridyl (C1-C6) alkyloxycarbonyl group, a phenyl (C1-C6) alkylaminosulfonyl group or a (C1-C6) alkyl group, and m is 0 or 1. The therapeutic or preventive agent for tissue fibrosis according to (2) above, wherein R2 is a pyridyloxy (C1-C6) alkyl group.

(6) R0 is a phenyl group, R1 is a hydrogen atom, a (C1-C6) acyl group or phenyl (C1
To C6) alkylaminosulfonyl group, and D is -N
H-, m is 0, R2 is pyridyloxy (C
1 to C6) The therapeutic or prophylactic agent for tissue fibrosis according to the above (2), which is an alkyl group. (7) The therapeutic or prophylactic agent for tissue fibrosis according to the above (6), wherein R1 is a formyl group, acetyl group or benzylaminosulfonyl group, and R2 is a 2-pyridyloxypropyl group.

(8) The compound represented by the general formula (I) is
2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N-
[2,3-Dioxo-1-phenylmethyl-6- (2-
Pyridyloxy)] hexylacetamide, 2- (5-hydroxymethyl-6-oxo-2-phenyl-1,6-
Dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide, 2- (5-acetylamino-6-oxo-2- Phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide or 2- (5-benzylaminosulfonyl) Amino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-
The therapeutic or prophylactic agent for tissue fibrosis according to the above (2), which is phenylmethyl-6- (2-pyridyloxy)] hexylacetamide.

(9) The compound represented by the general formula (I) is
2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N-
[2,3-Dioxo-1-phenylmethyl-6- (2-
Pyridyloxy)] hexylacetamide or a pharmacologically acceptable salt thereof, The therapeutic or prophylactic agent for tissue fibrosis according to the above (2). (10) The therapeutic or preventive agent for tissue fibrosis according to any one of (1) to (9) above, wherein the tissue fibrosis is fibrosis accompanied by an increase in chymase activity. (1) to (10) above, which is fibrosis occurring in tissues of lung, bladder, kidney, heart or liver
The therapeutic or preventive agent for tissue fibrosis according to any one of 1.

(12) The therapeutic or prophylactic agent for tissue fibrosis according to the above (11), wherein fibrosis is induced by a chemical substance. (13) The therapeutic or prophylactic agent for tissue fibrosis according to the above (12), wherein the chemical substance is bleomycin or a derivative thereof, and the fibrosis is pulmonary fibrosis. (14) An oral pharmaceutical preparation for treating or preventing tissue fibrosis, which comprises the compound according to any one of (2) to (9) above or a pharmacologically acceptable salt thereof as an active ingredient.

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a compound having a pyrimidone skeleton having a diketone moiety represented by the above formula (II) and having chymase inhibitory activity, or a pharmacologically acceptable salt thereof is used as an active ingredient. A therapeutic or preventive agent for tissue fibrosis. The chymase as referred to in the present invention belongs to a chymotrypsin type protease among serine proteases, is a cytotoxic enzyme (protein) accumulated in secretory granules in mast cells and released by stimulation. The inhibitory activity of chymase can be measured by a known method, for example, International Publication WO98 / 09949 and International Publication WO9.
It can be measured by the method disclosed in 9/41277. Having chymase inhibitory activity means having an IC ₅₀ of 100 nM or less, preferably 50 nM or less, and particularly preferably 20 nM or less in the measuring method of the publication.

The tissue fibrosis referred to in the present invention includes all commonly known fibrosis including the above-mentioned fibrosis. Fibrosis is the loss of tissue parenchymal cells and the deterioration of tissue function due to chemical stress such as drugs, excessive pressure load, and stress such as inflammatory reaction. Excessive migration of fibroblasts that occurs in the process of compensating for this And the subsequent rigidification accompanied by functional impairment of tissues due to the synthetic deposition of intercellular matrix proteins,
The induction stimulus and the site of onset are not particularly limited. More specifically, examples thereof include fibrosis of internal organs such as lung, bladder, kidney, heart, and liver.For example, fibrosis of lung caused by side effect of bleomycin administration and fibrosis of bladder caused by interstitial cystitis. In order to prevent the tissue fibrosis, the above formula (II)
The present invention also includes prophylactic administration of a compound having a pyrimidone skeleton represented by

Further, the present invention is a therapeutic or prophylactic agent for tissue fibrosis, which comprises a compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. In the general formula (I), R0 represents an aryl group. Examples of the aryl group include a phenyl group which may have a substituent, more preferably a (C1-C6) alkyl group or a phenyl group which may be substituted with a halogen atom, and further preferably a phenyl group. It is a base.

Examples of the (C1 to C6) alkyl group as the substituent include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group and s.
ec-butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-amyl group, n-hexyl group, 1,2-dimethyl-butyl group and the like,
Methyl group, ethyl group, n-propyl group, n-butyl group,
A (C1-C4) alkyl group such as a tert-butyl group is preferred. Examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like. Examples of the phenyl group substituted with a (C1 to C6) alkyl group include a tolyl group, a xylyl group, and the like, and specific examples include a 3,4-dimethylphenyl group, and a phenyl substituted with a halogen atom. Examples of the group include a fluorophenyl group, preferably a 2-fluorophenyl group.

R1 is substituted with a hydrogen atom, a C1 to C6 alkyl group, a C1 to C6 acyl group, an optionally substituted (C1 to C6) alkyloxycarbonyl group or an aryl group. May be (C1-C6)
An alkylsulfonyl group, a (C1-C6) alkylaminosulfonyl group which may be substituted with an aryl group, or a saturated heterocyclic carbonyl group. Examples of the C1 to C6 alkyl group include (C1 to C6) as the above substituents.
Examples thereof include the same groups as the alkyl group, and the same group as the (C1 to C4) alkyl group as the above substituent is preferable.

Examples of the C1 to C6 acyl group include formyl group, acetyl group, propionyl group, butyryl group,
Examples thereof include isobutyryl group and valeryl group, and formyl group and acetyl group are particularly preferable. Examples of the monocyclic aromatic group substituting the (C1 to C6) alkyloxycarbonyl group include a phenyl group, a pyridyl group, a pyrimidyl group, a pyrazyl group, a pyridazyl group, a furyl group and a pyrrolyl group, and a pyridyl group is preferable. . Also, (C1 to C6)
Examples of the (C1-C6) alkyl in the alkyloxycarbonyl group include (C1-C6) as the above-mentioned substituent.
6) The same groups as the alkyl groups can be mentioned, and the same groups as the (C1 to C4) alkyl groups as the above substituents are preferable.

It may be substituted with a monocyclic aromatic group (C
1 to C6) alkyloxycarbonyl group, for example, methoxycarbonyl group, ethoxycarbonyl group, n-
Propoxycarbonyl group, n-butoxycarbonyl group,
tert-butoxycarbonyl group, n-pentyloxycarbonyl group, sec-pentyloxycarbonyl group,
2,2-Dimethyl-propoxycarbonyl group, n-hexyloxycarbonyl group, 1,2-dimethyl-butyloxycarbonyl group, pyridylmethoxycarbonyl group, pyridylethoxycarbonyl group, pyridylpropoxycarbonyl group, pyridylbutoxycarbonyl group, pyrimid Examples thereof include a dilmethoxycarbonyl group, a pyrimidylpropoxycarbonyl group, a pyrazylmethoxycarbonyl group, a pyrazylbutoxycarbonyl group, a pyridazylmethoxycarbonyl group, a furylmethoxycarbonyl group and a pyrrolylethoxycarbonyl group, and preferably methoxycarbonyl. Base,
(C1-C4) alkylalkyloxycarbonyl groups such as ethoxycarbonyl group and tert-butoxycarbonyl group, pyridyl (C such as pyridylmethoxycarbonyl group)
1 to C4) alkyloxycarbonyl group.
Specific examples of the (C1-C6) alkyloxycarbonyl group which may be substituted with a monocyclic aromatic group include a 4-pyridylmethoxycarbonyl group.

Examples of the aryl group substituting the (C1 to C6) alkylsulfonyl group include the same groups as the aryl group of R0, and a phenyl group is preferable. Also,
(C1 to C6) in the alkylsulfonyl group (C1 to
Examples of the C6) alkyl group include the same groups as the (C1 to C6) alkyl group as the substituent, and the same groups as the (C1 to C4) alkyl group as the substituent are preferable. It may be substituted with an aryl group (C1-
Examples of the C6) alkylsulfonyl group include a benzylsulfonyl group, a phenethylsulfonyl group, a phenylbutylsulfonyl group, and the like, and a benzylsulfonyl group is preferable.

Examples of the aryl group substituting the (C1 to C6) alkylaminosulfonyl group include the same groups as the aryl group of R0, and a phenyl group is preferable. Further, in the (C1-C6) alkylsulfonyl group, (C
Examples of the 1-C6) alkyl group include the same groups as the above-mentioned (C1-C6) alkyl group as the substituent,
The same group as the (C1-C4) alkyl group as the above-mentioned substituent is preferable. Optionally substituted with an aryl group (C
Examples of the 1-C6) alkylaminosulfonyl group include a (C1-C6) alkylaminosulfonyl group substituted with a phenyl group, and a phenyl group such as a benzylaminosulfonyl group, a phenethylaminosulfonyl group or a phenylpropylaminosulfonyl group. Replaced by (C1
To C4) alkylaminosulfonyl group is preferable, and benzylaminosulfonyl group is more preferable.

The saturated heterocyclic carbonyl group is preferably a 5- or 6-membered saturated heterocyclic carbonyl group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, for example thiolyl. Carbonyl group, dioxanylcarbonyl group, oxothianylcarbonyl group, dithiazinylcarbonyl group, oxathiolylcarbonyl group, pyrrolidinocarbonyl group, piperidylcarbonyl group, 4-alkyl-piperazinylcarbonyl group,
Morpholyl carbonyl group, tetrahydrofuroyl group and the like, a saturated heterocyclic carbonyl group having an oxygen atom is preferable, a saturated 5-membered heterocyclic carbonyl group containing an oxygen atom such as a tetrahydrofuroyl group is more preferable, and particularly, Three
-Tetrahydrofuroyl group is preferred.

D is an oxygen atom or --NH--, m is an integer of 0 to 3, m is preferably 0 to 2,
More preferably, D is an oxygen atom and m is 1, or D is -N.
In H-, m is 0. R2 is a (C1-C6) alkyl group which may have a substituent. Examples of the (C1-C6) alkyl group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group. Group, sec-pentyl group, tert-amyl group, n
-Hexyl group, 1,2-dimethyl-butyl group and the like, and (C1-C4) alkyl groups such as methyl group, ethyl group, n-propyl group, n-butyl group and tert-butyl group are preferable.

Having a substituent in R2 (C1 to C
6) As the alkyl group, for example, a (C1 to C6) alkyloxy (C1 to C6) alkyl group, a (C1 to C6) alkyl group substituted with an aryl group, and a heterocyclic oxy group having a nitrogen atom are substituted ( C1 to C6) alkyl group,
Substituted with a heterocyclic group having a nitrogen atom (C1-C6)
Examples thereof include alkyl groups. (C1-C as a substituent
6) As the alkyloxy group, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n
Examples include -butyloxy group and tert-butyloxy group.

Examples of the aryl group in the (C1-C6) alkyl group substituted with an aryl group include a phenyl group which may have a substituent, and more preferably an unsubstituted phenyl group. Preferred aryl (C1
To C6) alkyl groups include, for example, benzyl group, phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group,
Phenyl-substituted (C1-C4) alkyl groups are more preferred. Particularly preferably, a phenethyl group and a phenylpropyl group are mentioned. Substituted with a heterocyclic oxy group (C1-
As the heterocyclic oxy group in the C6) alkyl group, a heteroaryloxy group is preferable, and examples thereof include a pyridyloxy group, a pyrimidyloxy group, a pyrazyloxy group, a pyridazyloxy group, a furyloxy group and a pyrrolyloxy group, and a heterocyclic oxy group having a nitrogen atom. Groups are preferred,
A 6-membered heterocyclic oxy group having a nitrogen atom such as a pyridyloxy group is preferable.

Substituted with a heterocyclic oxy group (C1-C
6) Examples of the alkyl group include a pyridyloxymethyl group, a pyridyloxypropyl group, a pyrimidyloxymethyl group, a pyrimidyloxypropyl group, a pyrazyloxymethyl group, a pyrazyloxybutyl group, a pyridazyloxyethyl group. , A heteroaryloxy (C1-C6) alkyl group such as a furyloxymethyl group and a pyrrolyloxyethyl group, and a 6-membered heterocyclic oxy (C1 having a nitrogen atom)
To C6) alkyl groups are preferred, and pyridyloxy (C1-C6) alkyl groups such as pyridyloxypropyl groups are particularly preferred. Specifically, for example, a 2-pyridyloxypropyl group is preferable.

Examples of the heterocyclic group in the (C1-C6) alkyl group substituted with a heterocyclic group include a morpholinyl group, an oxodihydropyridinyl group, a piperidinyl group, a piperazinyl group and a dioxanyl group. Morpholinyl group, 2-oxo-1,2-dihydropyridine-
A 1-yl group is preferable, and a 6-membered heterocyclic group having a nitrogen atom as a hetero atom such as a 2-oxo-1,2-dihydropyridin-1-yl group is more preferable. Examples of the (C1-C6) alkyl group substituted with a heterocyclic group include a pyridylmethyl group, a pyridylpropyl group, a pyrimidylmethyl group, a pyrimidylpropyl group, a pyrazylmethyl group, a pyrazylbutyl group, a pyridazylethyl group, a furylmethyl group and a pyrrolylethyl group. Group, 2-oxo-1,2-dihydropyridin-1-yl-methyl group and the like, and 2-oxo-
The 1,2-dihydropyridin-1-yl-methyl group is preferred.

A preferable combination of R0, R1, D, m and R2 is, for example, R in consideration of the strength of action.
0 is a phenyl group or a (C1-C6) alkylphenyl group, R1 is a hydrogen atom, a (C1-C4) alkyloxycarbonyl group, a (C1-C6) acyl group, a phenyl (C1-C6) alkylsulfonyl group, pyridyl (C1
To C4) alkyloxycarbonyl group, phenyl (C1
To C6) alkylaminosulfonyl group or (C1 to C)
6) It is an alkyl group, D is an oxygen atom or -NH-, m is 0 or 1, and R2 is a pyridyloxy (C1-C6) alkyl group. R0, R1, D,
As a more preferable combination of m and R2, R0 is a phenyl group and R1 is a (C1 to C6) acyl group or phenyl (C1 to C6) in consideration of actions in humans.
Is an alkylaminosulfonyl group, D is -NH-, m is 0, and R2 is pyridyloxy (C1-C).
6) It is an alkyl group. As a more preferable combination of R0, R1, D, m, and R2, R0 is a phenyl group, R1 is a formyl group, an acetyl group or a benzylaminosulfonyl group, and D is- NH-, m is 0, and R2 is a 2-pyridyloxypropyl group.

The general formula (I) used in the present invention is as follows.
Representative examples of the compounds represented by are specifically shown in Table 1, but the present invention is not limited to these compounds. In Table 1, Ph
Means a phenyl group, Boc means a tert-butoxycarbonyl group, Ac means an acetyl group, and Me means a methyl group.

Table 1

Among these compounds, more preferable ones are, for example, Nos. 3, 4, 8, 9, 10, 11, 15, 16, 1.
7, 18 and 19 are mentioned, and more preferable are:
For example, No. 10 (2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-phenylmethyl-
6- (2-pyridyloxy)] hexylacetamide),
No. 11 (2- (5-acetylamino-6-oxo-2-
Phenyl-1,6-dihydropyrimidin-1-yl)-
N- [2,3-dioxo-1-phenylmethyl-6-
(2-Pyridyloxy)] hexylacetamide), No.1
5 (2- (5-benzylaminosulfonylamino-6-
Oxo-2-phenyl-1,6-dihydropyrimidine-
1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide), No. 18 (2- (5-hydroxymethyl-6-oxo- 2-Phenyl-1,6-dihydropyrimidine-1-
Yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide)
Nos. 10 and 11 are particularly mentioned. As is apparent from the above, the feature of the present invention lies in that a compound having a pyrimidone skeleton structure represented by the above formula (II) and having chymase inhibitory activity is used for the treatment or prevention of tissue fibrosis. .

The compound used in the present invention may be a pharmacologically acceptable salt thereof. In the case of a basic compound, for example, a salt with a carboxylic acid, a sulfonic acid, a mineral acid or the like is a salt of an acidic compound. In this case, for example, salts with alkali metals, alkaline earth metals, organic bases and the like can be mentioned. Examples of the carboxylic acid, sulfonic acid, mineral acid and the like include acetic acid, adipic acid, benzoic acid, citric acid, fumaric acid, aspartic acid, lactic acid, malic acid, palmitic acid, salicylic acid, tartaric acid, benzenesulfonic acid, camphorsulfonic acid, Toluenesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like can be mentioned. Examples of the alkali metal, alkaline earth metal, organic base and the like include lithium, sodium, potassium, calcium, magnesium, barium, tetramethylammonium, tetrabutylammonium and the like.

The compound used in the present invention is an optically active substance,
Alternatively, it includes all racemates, diastereomers, mixtures of diastereomers, individual enantiomers to mixtures of enantiomers. Further, unless otherwise specified, the bonding position of the substituent and the like include all position isomers that can be bonded. Further, various polymorphisms such as solvates such as hydrates and tautomers of solvates are also included in the compound used in the present invention. The series of compounds represented by the general formula (I) in the present invention include the international publication WO98 / 09949 and the international publication WO99 / 41.
It is manufactured by the manufacturing method disclosed in Japanese Patent Publication No. 277, but is not limited to those methods.

Further, the present invention is an oral pharmaceutical preparation for treating or preventing tissue fibrosis, which comprises a compound having a pyrimidone skeleton represented by the above formula (II) and having chymase inhibitory activity as an active ingredient. Particularly preferred is an oral pharmaceutical preparation for treating or preventing tissue fibrosis, which comprises the compound represented by the general formula (I) as an active ingredient.

In the present invention, when a compound having the pyrimidone skeleton represented by the above formula (II) and having chymase inhibitory activity is used, it may be used alone or mixed with an excipient or a carrier for injection, tablets, granules. , Fine granules, powders, capsules, patches, patches, ointments, sprays, solutions, sustained-release preparations, etc., which are administered orally or parenterally or directly applied to organs Although there are administration methods such as K, oral administration is preferred. As excipients or carriers, additives that are pharmaceutically acceptable are selected, and their type and composition depend on the administration route and administration method. For example, in the case of injection, generally, salt, glucose, mannite-
Sugars such as starch and the like are desirable, and in the case of oral preparations, starch, lactose, crystalline cellulose, magnesium stearate and the like are desirable. The administration is systemically administered orally or parenterally, and if necessary, a method in which the compound effectively reaches and acts on the affected area such as direct application to an organ by an ointment or a spray is selected. Oral administration is preferred.

The content of the present compound in the preparation varies depending on the preparation, but is usually 0.1 to 100% by weight, preferably 1 to 98% by weight. For example, in the case of an injectable preparation, it is usually recommended to prepare an injectable solution containing 0.1 to 30% by weight, preferably 1 to 10% by weight of the active ingredient. In the case of oral agents, they are used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with additives. Capsules, tablets, granules and powders are generally 5-10
It contains 0% by weight, preferably 25 to 98% by weight of the active ingredient. The dose is determined according to the age, weight, symptoms, etc. of the patient, but the therapeutic dose is generally 1 to 100 mg by parenteral administration.
/ Kg · day, 5 to 500 mg / kg · day by oral administration. When used as a solution, it is used at a concentration of 10 to 1000 nM.

The compounds used in the present invention have low toxicity,
In addition, all compounds are characterized by low toxicity accumulation after continuous administration. For example, when the compound was orally administered to rats at a dose of 1 mg / kg once a day for 4 weeks, no signs of toxicity were observed, and 2- (5-formylamino-6-oxo-2 was used. -Phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)]
The compound of hexylacetamide (Compound No. 10) was orally administered to rats at a dose of 100 mg / kg once a day for 2 weeks without showing any signs of toxicity.

[0050]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited thereto.

Example 1 Effect of chymase inhibitor using collagen-3 as an index in bleomycin-induced pulmonary fibrosis model (hamster) (A) Preparation of pulmonary fibrosis model Per 14 male hamsters (6 weeks old) 10 mg /
kg of bleomycin was administered intratracheally. A physiological saline solution was intratracheally administered to 9 animals in the control group. (B) Compound administration The bleomycin-administered hamsters were divided into 2 groups, 6 were treated with the chymase inhibitor compound and 8 were not treated with the compound. 3 days before bleomycin administration to 3 days before pneumonectomy
30 mg / kg of 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [suspended in 0.5% sodium carboxymethylcellulose solution for 1 day. 2,3-dioxo-1
-Phenylmethyl-6- (2-pyridyloxy)] hexylacetamide (Compound No. 10) was orally administered once daily. The non-administration group was orally administered with 0.5% sodium carboxymethylcellulose solution in the same amount as the compound administration group.

(C) Measurement of collagen / 3 mRNA mRNA was extracted from the collected lung tissue by the AGPC method, and collagen / 3 mRNA was detected by the Northern plot method.
The detection probe was ³² P-dCTP-labeled mouse collagen-3 cDNA (Liau et al., J. Bio).
l. Chem. , 260, 531 (1985)). The detected collagen-3 mRNA band is bas
It was quantified by 2000 and shown as a ratio to the control group.

[0053]   Table 2   Amount of collagen-3 mRNA in lung tissue   Group collagen / 3 mRNA relative amount Control group (saline solution, placebo) 1.000 ± 0.079 Compound non-administration group (bleomycin, placebo) 1.277 ± 0.077 Compound administration group (bleomycin, compound No. 10) 0.818 ± 0.145 The results are expressed as mean value ± standard deviation.

(D) Results The expression of collagen-3 mRNA increased with pulmonary fibrosis caused by bleomycin administration was significantly suppressed by the administration of chymase inhibitor to the same degree as in the control group. The agent was shown to inhibit the synthesis of proteins that form tissue fibrosis.

Example 2 Effect of chymase inhibitor by pathological analysis in bleomycin-induced lung fibrosis model (hamster) (A) Preparation of lung fibrosis model 0.5 mg / mouse of 20 male hamsters (110 to 130 g) Bleomycin was administered intratracheally. (B) Compound Administration The bleomycin-administered hamsters were divided into two hamsters each divided into two groups, a chymase inhibitor compound-administered group and the compound non-administered group. For the administration group, 30 mg / kg of 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-) suspended in a 0.5% sodium carboxymethylcellulose solution for 21 days from the day of bleomycin administration. 1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide (Compound No. 10) was orally administered once daily.
The non-administration group was orally administered with 0.5% sodium carboxymethylcellulose solution in the same amount as the compound administration group.

(C) Pathological analysis On the 28th day after the administration of bleomycin, lungs were removed from each hamster and fixed with 10% formalin neutral phosphate buffer.
The tissue was made into a paraffin section, stained with Azan, and then photographed with a digital camera (DP11 manufactured by Olympus Corp.). Image-analysis program Image-Pro (Mediacy)
The stained fibrotic area was measured by using BERNETICS. Table 3 Effect of administration of this compound on fibrotic area in lung section Group Fibrotic area (mm ² ) Control group (bleomycin, placebo) 14.319 ± 6.167 Compound administration group (bleomycin, compound No. 10) 9. 095 ± 5.440 Results were expressed as mean ± standard deviation.

(D) Results Although a clear fibrotic image was observed in the lungs 28 days after the administration of bleomycin, the size of the fibrotic portion was reduced by the administration of the chymase inhibitor. This indicates that chymase inhibitors suppress tissue fibrosis.

Reference Example Analysis of Tissue Distribution of this Compound (A) Administration of Compound and Collection of Tissue 0.5% to male SD rats (0.25 kg to 0.35 kg)
1 mg / kg of 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1 suspended in sodium carboxymethylcellulose solution -Phenylmethyl-
6- (2-pyridyloxy)] hexylacetamide (Compound No. 10) was orally administered. After administration of the compound 1,
After 3, 8, 18, and 24 hours, three rats were each anesthetized with ether, and blood, heart, abdominal aorta, lung, liver, kidney, abdominal skin, and abdominal muscle were collected. (B) Extraction of Compound The collected tissue was minced with scissors on ice, and homogenized by adding 67% acetonitrile aqueous solution corresponding to 4 times the wet weight. The blood was made into plasma and 2 volumes of acetonitrile were added and stirred. All samples are 12
After centrifugation at 000 rpm for 10 minutes, the supernatant was used as a compound extract.

(C) Detection of Compound The compound was detected by its inhibitory activity against purified inkymase in vitro. For inkymase, Kido et al., Anal. Biochem. , 137, 449 (19
A sample prepared from a dog heart was used with reference to the method reported in 84). Appropriate amount of tissue extract sample and inukymase solution were added with 5 mM ethylenediaminetetraacetic acid and 10 mM.
The mixture was mixed in 100 mM potassium phosphate buffer (pH 8.0) containing μM leupeptin, and treated at 25 ° C. for 3 hours.
Thereafter, angiotensin-1 having a final concentration of 0.1 mM was added, and the mixture was reacted at 25 ° C for 1 hour. The enzymatic reaction was stopped by adding 50% trichloroacetic acid, and HPLC analysis was performed using a C18 reverse phase column to measure the amount of angiotensin-2 produced. A quantitative curve was prepared from the amount of angiotensin-2 measured by adding Compound No. 10 at various concentrations in the same measurement system instead of the sample, and the compound concentration in each sample was calculated. The calculated compound concentration includes the case where an active metabolite is generated by in vivo metabolism. The unit is the equivalent amount of unchanged compound ng eq / g or ng e
It was q / ml.

(D) Results Plasma concentrations are shown in FIG. 1, heart and aortic concentrations are shown in FIG. 2, lung, liver and kidney concentrations are shown in FIG.
As shown in FIG. 4, the concentrations in muscle and skin were almost the same as those in plasma in each tissue, and the compounds were maintained for a long time. Therefore, it is shown that the present compound is rapidly absorbed into blood by oral administration and is effectively distributed to tissues. They are expected to permanently inhibit tissue chymase, and it is considered that the present compound is effective for fibrosis of various tissues by oral administration once or twice a day. The above results show that the orally administered compound is widely distributed in the living body and can treat or prevent tissue fibrosis of various organs, and is effective for many fibrosis in human clinical practice. Is expected to be.

Example 3 Formulation Example 50.0 mg of 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1] -Phenylmethyl-
Low-substituted hydroxypropylcellulose 80.0 mg, lactose 57.0 mg, hydroxypropylcellulose 2.0 mg, and magnesium stearate 1 to 6- (2-pyridyloxy)] hexylacetamide (Compound No. 10). The mixture was mixed at a ratio of 0.0 mg and encapsulated in No. 3 capsule to obtain an oral capsule.

[0062]

INDUSTRIAL APPLICABILITY According to the present invention, it has a pyrimidone skeleton and high selectivity for chymase, and has a strong inhibitory activity. In particular, it has a competitive inhibitory activity for chymase, is absorbed by oral administration, and is widely distributed in tissues. Or a compound characterized by exhibiting an effective chymase inhibitory activity in vivo, for example, a treatment for tissue fibrosis containing as an active ingredient a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof, or A preventive agent, for example, a therapeutic or preventive agent for fibrosis of lung, bladder, kidney, heart, liver and the like is provided.

[0063]

[Brief description of drawings]

FIG. 1 Time-dependent changes in the concentration of this compound in plasma

FIG. 2 Time-dependent changes in the concentration of the compound in the heart and aorta

[Fig. 3] Time course of concentration of the present compound in lung, liver and kidney

FIG. 4 Time-dependent changes in the concentration of this compound in muscle and skin

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 13/12 A61P 13/12 43/00 111 43/00 111 C07D 239/42 C07D 239/42 Z 401 / 12 401/12 401/14 401/14 405/12 405/12 (72) Inventor Tetsuya Matsumoto 2-333 Kitabukuro-cho, Saitama City, Saitama (72) Inventor Ryoichi Suzuki 3-13-8 Tabata, Kita-ku, Tokyo Term (reference) 4C063 AA01 AA03 BB09 CC29 CC73 DD12 DD29 EE01 4C086 AA01 AA02 BC42 GA02 GA07 GA08 MA01 MA04 MA52 NA14 ZA36 ZA59 ZA75 ZA81

Claims (14)

[Claims] 1. The following formula (II): A therapeutic or prophylactic agent for tissue fibrosis, comprising a compound having a pyrimidone skeleton represented by and having a chymase inhibitory activity, or a pharmacologically acceptable salt thereof as an active ingredient. 2. A compound represented by the general formula (I): [In the formula, R0 represents an aryl group, R1 represents a hydrogen atom, C
1-C6 alkyl group, C1-C6 acyl group, monocyclic aromatic group-substituted (C1-C6) alkyloxycarbonyl group, aryl group-substituted (C1-C6) An alkylsulfonyl group, an (A1-C6) alkylaminosulfonyl group which may be substituted with an aryl group, or a saturated heterocyclic carbonyl group, D represents an oxygen atom or -NH-, and m is any of 0 to 3 Of R2 may have a substituent (C
1 to C6) which represents an alkyl group] or a pharmacologically acceptable salt thereof as an active ingredient, a therapeutic or prophylactic agent for tissue fibrosis. 3. The aryl group for R0 is (C1 to C6).
It is a phenyl group which may be substituted with an alkyl group or a halogen atom, and the (C1-C6) alkyloxycarbonyl group which may be substituted with a monocyclic aromatic group in R1 is a (C1-C6) alkyloxycarbonyl group. Alternatively, it is a pyridyl (C1-C6) alkyloxycarbonyl group, which may be substituted with an aryl group (C1-C6).
6) Alkylsulfonyl group is a (C1-C6) alkylsulfonyl group substituted with a phenyl group, which may be substituted with an aryl group (C1-C6) Alkylaminosulfonyl group is substituted with a phenyl group (C1 ~ C
6) an alkylaminosulfonyl group, a saturated heterocyclic carbonyl group is a saturated heterocyclic carbonyl group having an oxygen atom, and may have a substituent in R2 (C1
To C6) alkyl group is a (C1 to C6) alkyl group,
1 to C6) alkyloxy (C1 to C6) alkyl group,
(C1-C6) alkyl group substituted with an aryl group, substituted with a heterocyclic oxy group having a nitrogen atom (C1-C6)
6) The therapeutic or prophylactic agent for tissue fibrosis according to claim 2, which is a (C1-C6) alkyl group substituted with an alkyl group or a heterocyclic group having a nitrogen atom. 4. The saturated heterocyclic carbonyl group having an oxygen atom in the saturated heterocyclic carbonyl group of R1 is a tetrahydrofuroyl group, and the aryl of the (C1-C6) alkyl group optionally having a substituent of R2. A (C1 to C6) alkyl group substituted with a group is a (C1 to C6) alkyl group substituted with a phenyl group, and a (C1 to C6) alkyl group substituted with a heterocyclic oxy group having a nitrogen atom is a nitrogen atom. A 6-membered heterocyclic ring substituted with a 6-membered heterocyclic oxy group having an atom and a (C1-C6) alkyl group substituted with a heterocyclic group having a nitrogen atom has a nitrogen atom The therapeutic or prophylactic agent for tissue fibrosis according to claim 3, which is a (C1-C6) alkyl group substituted with a group. 5. R0 is a phenyl group or a (C1 to C6) alkylphenyl group, R1 is a hydrogen atom, and (C1 to C6).
6) alkyloxycarbonyl group, (C1 to C6) acyl group, phenyl (C1 to C6) alkylsulfonyl group,
A pyridyl (C1-C6) alkyloxycarbonyl group,
A phenyl (C1-C6) alkylaminosulfonyl group or a (C1-C6) alkyl group, wherein m is 0 or 1
And R2 is a pyridyloxy (C1-C6) alkyl group, The therapeutic or prophylactic agent for tissue fibrosis according to claim 2. 6. R0 is a phenyl group, R1 is a hydrogen atom, a (C1-C6) acyl group or phenyl (C1-C6).
6) an alkylaminosulfonyl group, and D is -NH-
, M is 0, R2 is pyridyloxy (C1
The therapeutic or preventive agent for tissue fibrosis according to claim 2, wherein C6) is an alkyl group. 7. The therapeutic or prophylactic agent for tissue fibrosis according to claim 6, wherein R1 is a formyl group, acetyl group or benzylaminosulfonyl group, and R2 is a 2-pyridyloxypropyl group. 8. A compound represented by the general formula (I) is 2-
(5-formylamino-6-oxo-2-phenyl-
1,6-dihydropyrimidin-1-yl) -N- [2,
3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide, 2- (5-hydroxymethyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-
1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide, 2- (5-acetylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1
-Yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide or 2- (5-benzylaminosulfonylamino-6)
-Oxo-2-phenyl-1,6-dihydropyrimidin-1-yl) -N- [2,3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide. The therapeutic or preventive agent for tissue fibrosis according to 2. 9. A compound represented by the general formula (I) is 2-
(5-formylamino-6-oxo-2-phenyl-
1,6-dihydropyrimidin-1-yl) -N- [2,
The therapeutic or prophylactic agent for tissue fibrosis according to claim 2, which is 3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide or a pharmacologically acceptable salt thereof. 10. The therapeutic or prophylactic agent for tissue fibrosis according to any one of claims 1 to 9, wherein the tissue fibrosis is fibrosis accompanied by an increase in chymase activity. 11. The tissue fibrosis is fibrosis that occurs in lung, bladder, kidney, heart or liver tissue.
The therapeutic or preventive agent for tissue fibrosis according to any one of 1. 12. The therapeutic or prophylactic agent for tissue fibrosis according to claim 11, wherein the fibrosis is induced by a chemical substance. 13. The therapeutic or prophylactic agent for tissue fibrosis according to claim 12, wherein the chemical substance is bleomycin or a derivative thereof, and the fibrosis is pulmonary fibrosis. 14. An oral pharmaceutical preparation for the treatment or prevention of tissue fibrosis, which comprises the compound according to any one of claims 2 to 9 or a pharmacologically acceptable salt thereof as an active ingredient.