WO2003007964A1

WO2003007964A1 - Remedial or preventive agent for cardiopathy or aneurysm containing chymase inhibitory compound

Info

Publication number: WO2003007964A1
Application number: PCT/JP2002/007269
Authority: WO
Inventors: Mizuo Miyazaki; Keiichi Kamoshita; Yoshikazu Sukenaga; Yoshikazu Suzuki
Original assignee: Nippon Kayaku Kabushiki Kaisha
Priority date: 2001-07-18
Filing date: 2002-07-17
Publication date: 2003-01-30

Abstract

A remedial or preventive agent for cardiopathy or aneurysm which contains as the active ingredient either a compound having the partial skeletal structure represented by the general formula (I) and having chymase inhibitory activity or a pharmacologically acceptable salt of the compound. The drug is characterized by being capable of orally administered.

Description

Description Treatment or prophylactic agent for cardiac dysfunction or aneurysm using chymase inhibitor compound

The present invention relates to a therapeutic or prophylactic agent for cardiac dysfunction or aneurysm, which comprises a compound having a pyrimidone skeleton as a partial structure and particularly effectively inhibiting chymase activity in vivo by oral administration or the like. Background art

Diseases caused by cardiovascular disorders have been increasing in number in recent years, and have become the leading cause of death. Various diseases due to circulatory disorders are known, and among them, cardiac dysfunction caused by ischemia due to impaired blood flow, for example, angina pectoris, myocardial infarction, cardiac hypertrophy, heart failure, arteries and heart failure Aneurysms, which are bulges (capsules) formed in the body, are the major pathologies.

The renin-angiotensin-aldosterone system exists as a blood pressure regulating mechanism in the body, and it is known that angiotensin II acts on peripheral sites in this system and exhibits a strong pressor action. This angiotensin II is produced when angiotensinogen produced in the liver passes through angiotensin I and is degraded by angiotensin-converting enzyme (hereinafter referred to as ACE), which acts systemically. It is believed that. However, in recent years, molecules involved in this system have been expressed in various tissues, and it has become clear that angiotensin II exists and works independently of systemic ones in tissues. Angiotensin II in these tissues is believed to be involved in tissue remodeling, such as hypertrophy of cardiomyocytes in the heart, rather than pressor response.

In clinical practice, low concentrations of ACE inhibitors that do not affect blood pressure have been shown to be somewhat more effective than other anti-chronic heart failure drugs (Dah 1 of et al., Am. J. Hyperten s., 5, 95-: L 10 (1992)), and its action is described, for example, by John Ston et al. In Am. He art J., 126, 756-760 (1993) l As reported in, a lesser but incomplete suppression of angiotensin II in tissues rather than systemic angiotensin II.

On the other hand, Urata et al. Reported in J. Biol. Chem., 265, 22348-22357 (1990) that angiotensin II in human heart tissue is produced by chimase rather than ACE. I have. Based on the clinical effects of ACE inhibitors and angiotensin II · type 1 receptor (AT1R) antagonists, inhibiting cardiac tissue angiotensin II can prevent or prevent various heart disorders and chronic disorders. Although they have been shown to be treated, these ATIR antagonists fail to distinguish between angiotensin II, which is involved in systemic pressor response, and tissue-specific angiotensin II, and lower blood pressure In addition, ACE inhibitors cannot completely suppress the production of tissue angiotensin II, and show only incomplete effects. Aneurysms, on the other hand, are localized bulges (capsules) that form in the walls of arteries and the heart. The artery plays an important role as a transport route to send blood from the heart to each tissue, and has a structure rich in vascular smooth muscle cells and extracellular matrix to withstand the pressure of the blood sent out by the heart. When structural destruction occurs, resistance to arterial pressure diminishes at the site and the wall expands with each systole, resulting in localized bulging of the artery. The causes of such an aneurysm, which is a localized bulge (capsule), are various, such as congenital factors, infection, collagen disease, arteriosclerosis, and trauma, and the resulting blood vessels extend to all parts. ing.

When an aneurysm is formed, it can erode and compress surrounding tissues, which can be severely painful if it is to nerves. Also, a widespread thrombus in the aneurysm blocks downstream blood circulation, leading to serious injury. However, the most dangerous conditions are when the resistance of the blood vessel wall continues to decrease or when the internal pressure increases due to the formation of a thrombus inside, and if such a condition continues, the aneurysm will progress and expand, and eventually It can rupture and cause severe, sometimes fatal, internal bleeding. Therefore, if an aneurysm is found, it is surgically removed if possible. If surgical treatment is not possible, treatment is needed to regress or maintain the durability of the arterial wall so that it does not rupture, but no effective drug has been known so far.

There are various causes of aneurysms, but they continue to follow It has not been clarified whether the decrease in resistance is induced and the arteries expand. Therefore, to protect vulnerable sites in blood vessels, attempts have been made to suppress angiotensin II by using an antihypertensive ACE inhibitor.

In tissues such as human blood vessels, chymase is known to exist as an angiotensin II producing enzyme in addition to ACE (Tak ai et al., CI inn. Chim. Acta, 265). , 13-20 (1997)). Furthermore, the present inventors examined the expression of these enzymes in ruptured aneurysm lesions, and revealed that the expression of both ACE and chymase was enhanced (Jochuka et al., Journal of the Japanese Surgical Society, No. 10 Vol. 2, No. 2, 243 (2001)).

However, in animal studies performed by Liao et al., ACE inhibitors were effective in aneurysm models, but angiotensin II receptor antagonists were ineffective (J. Vasse. Surg., 33 , 1057-1064 (2001)). That is, it is suggested that the effect of the ACE inhibitor may not be mediated by suppression of angiotensin II production, and thus the role of chymase in ruptured aneurysms remains unknown.

In general, many proteases including matrix metalloprotease (hereinafter abbreviated as MMP) are considered to be involved in the destruction of the vascular wall structure. In the case of an aneurysm, in particular, MMP-9 (or dielatine) is used. Is important, as demonstrated by an experiment by Pyo et al. (J. Clin. Invest., 105, 1641-1649 (2000)). In addition, the experimental results of Thormp son and others using clinical samples (J. Clin. Invest., 96, 318-326 (1995)) and the analysis results of McMi 11 an and others (Circulati on, 96, 2228-2232 (1997)), it is clear that many MMP-9 are also found in human aneurysm tissues. MMPs are biosynthesized as precursors and undergo limited degradation to express their activity, but the activity of chymase in the activation process of MMP-9 has not yet been clarified.

Therefore, the involvement of chymase in aneurysms has not been clarified so far, and the effect of chymase inhibitors on aneurysms has been completely unknown.

At present, there is no known effective pharmacotherapy for the progression and rupture of aneurysms. Disclosure of the invention

The present inventors have found that a compound that selectively inhibits chymase in vivo treats, ameliorates or prevents cardiac dysfunction, and in particular, treats, ameliorates or prevents cardiac dysfunction caused by impaired blood flow. Using an animal model, the present inventors have found that the present invention has an effect of effectively suppressing the progress and rupture of an aneurysm, and have completed the present invention.

That is, the present invention relates to the following (1) to (13).

(1) The following formula (I)

A therapeutic or preventive agent for cardiac dysfunction or aneurysm, comprising a compound having a partial skeleton structure represented by and having chymase inhibitory activity or a pharmaceutically acceptable salt thereof.

(2) The compound of the above (1) is represented by the general formula (II)

[Wherein, 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-C6) A (C 1 -C 6) alkylsulfonyl group, which may be substituted with aryl group or aryl group (C 1 -C 6) alkylaminosulfonyl group or saturated heterocyclic group, which may be substituted with aryl group And R represents an oxygen atom or —NH—, and m represents an integer of 0 to 3. R 2 represents a (C 1 -C 6) alkyl group which may have a substituent or a (C 1 -C 6) alkyloxy group which may have a substituent. ]

The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to (1), which is a compound represented by the formula:

(3) The aryl group in R 0 of the general formula (II) is a phenyl group which may have a (C 1 to C 6) alkyl group or a halogen atom as a substituent, and the monocyclic aromatic group in R 1 The (C 1 -C 6) alkyloxycarbonyl group which may be substituted with a group is a (C 1 -C 6) alkyloxycarbonyl group or a pyridyl (C 1 -C 6) alkyloxycarbonyl group, (C 1 -C 6) alkylsulfonyl group is a (C 1 -C 6) alkylsulfonyl group substituted with a phenyl group, and may be substituted with an aryl group (C 1 -C 6) C6) an alkylaminosulfonyl group in which an alkylaminosulfonyl group is substituted with a phenyl group; a C1-C6 alkylaminosulfonyl group, wherein the saturated heterocyclic carbonyl group is a saturated heterocyclic carbonyl group having an oxygen atom; May have (C 1 -C 6) alkyl group substituted with (C 1 -C 6) alkyl group, (C 1 -C 6) alkyloxy (C 1 -C 6) alkyl group, or aryl group The (C1-C6) alkyl group substituted with a heterocyclic oxy group having a nitrogen atom or the (C1-C6) alkyl group substituted with a heterocyclic group having a nitrogen atom; Agent for treating or preventing cardiac dysfunction or aneurysm.

(4) The saturated heterocyclic carbonyl group having an oxygen atom in the saturated heterocyclic carbonyl group of R 1 is a tetrahydrofuroyl group, and may have a substituent of R 2 (C

(C1-C6) is a (C1-C6) alkyl group substituted with an aryl group in the alkyl group, and a (C1-C6) alkyl group substituted with a phenyl group, and is a heterocyclic oxy group having a nitrogen atom. A substituted (C1-C6) alkyl group is a (C1-C6) alkyl group substituted with a 6-membered heterocyclic oxy group having a nitrogen atom, and has a nitrogen atom. The heart device according to (3), wherein the (C1-C6) alkyl group substituted with a heterocyclic group is a (C1-C6) alkyl group substituted with a 6-membered heterocyclic group having a nitrogen atom. An agent for treating or preventing dysfunction or aneurysm.

(5) In formula (II), R0 is a phenyl group or a (C1-C6) alkylphenyl group, R1 is a hydrogen atom, (C1-C6) alkyloxycarbonyl group,

(C 1 -C 6) acyl group, phenyl (C 1 -C 6) alkylsulfonyl group, pyridyl (C 1 -C 6) alkyloxycarbonyl group, phenyl (C 1 -C 6) alkylaminosulfonyl group or ( (C1 to C6) an alkyl group; m is 0 or 1; and R2 is a pyridyloxy (C1 to C6) alkyl group. Agent.

(6) R 0 in the general formula (II) is a phenyl group, R 1 is a (C 1 -C 6) acyl group or a phenyl (C 1 -C 6) alkylaminosulfonyl group, and D is —NH—. And m is 0, and R2 is a pyridyloxy (C1-C6) alkyl group, the therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to the above (2).

(7) R 1 is a formyl group, an acetyl group or a benzylaminosulfonyl group, and R 2 is a 2-pyridyloxypropyl group according to the above (5) or (6), A therapeutic or prophylactic agent.

(8) The compound represented by the general formula (II) is 2- (5-formylamino-6-year-old kiso 2-phenyl-1,6-dihydropyrimidine-11-yl) — N— [2,3 —Dioxo— 1-phenylmethyl-6- (2-pyridyloxy)] hexylamide, 2- (5-acetylamino-6-oxo-12-phenyl-1,6-dihydropyrimidin-1-yl) 1 N- [2,3-Dioxo- 1-phenylmethyl_ 6- (2-pyridyloxy)] hexylasemidamide or 2_ (5-benzylaminosulfonylamino-1-6-oxo-1 2-phenyl_1,6-dihydropyrimidine 1- (yl) 1N- [2,3-dioxo1-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide as described in (2) above, for treating a cardiac dysfunction or an aneurysm; Prophylactic agent.

(9) When the compound represented by the general formula (II) is 2- (5_formylamino-6-year-old oxo1-2-phenyl-1,6-dihydropyrimidine-1-yl) —N— [2 , 3 The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to the above (2), which is dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylasemid. (10) The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to any one of (1) to (9) above, wherein the cardiac dysfunction is a cardiac dysfunction caused by a blood flow disorder.

(1 1) The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to any one of (1) to (9) above, wherein the cardiac dysfunction is angina pectoris, myocardial infarction, cardiac hypertrophy, or heart failure. .

(12) The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to any one of the above (1) to (9), wherein the aneurysm is an abdominal aortic aneurysm.

(13) The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to any one of (1) to (12) above is an oral preparation, wherein (1) to (12) The therapeutic or prophylactic agent for aneurysm according to any one of the above. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows changes in the survival rate after hamster myocardial infarction during administration of the chymase inhibitor compound according to the present invention. BEST MODE FOR CARRYING OUT THE INVENTION

The present invention relates to a compound having a partial structure represented by the general formula (I) containing a pyrimidone skeleton and having chymase inhibitory activity or a pharmacologically acceptable salt thereof (hereinafter sometimes referred to as the present compound) as an active ingredient It is a therapeutic or prophylactic agent for cardiac dysfunction or aneurysm. The compound is not particularly limited as long as it has a partial skeleton structure represented by the general formula (I) and has a chimase inhibitory activity, but is preferably represented by the general formula (II) Compounds.

The chymase referred to in the present invention is a cytotoxic enzyme (protein) that belongs to a chymotrypsin-type protease in serine proteases, is accumulated in secretory granules in mast cells, and is released by stimulation. is there. The chymase inhibitory activity can be measured by a known method, for example, by the method disclosed in WO98 / 09949 or WO99 / 41277, and for example, a synthetic substrate (succinyl. Leucyl, leucyl, noryl, tyrosyl, methyl cumarylamide) Or a method using angiotensin I can be used. Having chymase inhibitory activity means, for example, that the IC 50 is 100 nM or less, preferably 50 nM or less, particularly preferably 20 nM or less in the measurement method of the publication. is there. Since chymase varies depending on the animal species, the inhibitory activity against chymase in the animal to which it is applied is preferably within the above range.

The cardiac dysfunction referred to in the present invention is particularly a cardiac dysfunction caused by impaired blood flow, and is specifically caused by myocardial ischemia caused by impaired blood flow caused by thrombus or thickening in blood vessels. It indicates angina pectoris, myocardial infarction, and heart failure and hypertrophy when it enters the chronic phase.

The aneurysm referred to in the present invention includes all conditions usually referred to as aneurysms. Aneurysms are classified in various ways according to their location, their cause, or their shape.For example, classification according to their location includes abdominal aortic aneurysm, anastomotic aneurysm, cerebral aneurysm, wall wall aneurysm, renal aneurysm And thoracic aortic aneurysm, etc., and the classification by cause is as follows , Fungal aneurysm, syphilitic aneurysm, etc., and classification according to shape includes saccular aneurysm, mulberry aneurysm, mural aneurysm, etc., but are not particularly limited in the present invention. Not done.

In addition, treatment of aneurysm desirably leads to regression of the aneurysm, but once formed, the aneurysm usually progresses, and what is important in treatment does not cause the aneurysm to rupture Control. Therefore, preventing the progression of arterial aneurysms so as not to lead to rupture and preventing further weakening of the blood vessel wall are also included in the treatment.

In the acetoamide derivative represented by the general formula (II) in the present invention, R 0 represents an aryl group. Examples of the aryl group include a phenyl group which may have a substituent, and more preferably a phenyl group which may have a (C 1 -C 6) alkyl group or a halogen atom as a substituent. And more preferably an unsubstituted phenyl group.

Examples of the (C 1 -C 6) alkyl group as a 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 a sec— Butyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-amyl group, n-hexyl group, 1,2-dimethyl-butyl group, etc .; (C1-C4) alkyl groups such as _propyl, n-butyl, tert-butyl and the like are preferred.

Examples of the halogen atom include fluorine, chlorine, bromine, iodine and the like. (C 1 -C 6) The phenyl group substituted by an alkyl group includes, for example, a tolyl group and a xylyl group, and the phenyl group substituted by a halogen atom includes, for example, a fluorophenyl group.

R 1 may be substituted with a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 acyl group, or a monocyclic aromatic group (C 1 -C 6) alkyloxycarbonyl group, aryl A (C 1 -C 6) alkylsulfonyl group which may be substituted with a aryl group, a (C 1 -C 6) alkylaminosulfonyl group or a saturated heterocyclic carbonyl group which may be substituted with a aryl group.

Examples of the C1-C6 alkyl group include the same groups as the (C1-C6) alkyl group as the substituent, and the same as the (C1-C4) alkyl group as the substituent. Groups are preferred.

Examples of the C1 to C6 acyl group include a formyl group, an acetyl group, a propionyl group, a butyryl group, an isoptyryl group, and a valeryl group. A formyl group and an acetyl group are particularly preferable.

Examples of the monocyclic aromatic group substituted for the (C 1 -C 6) 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. Groups are preferred. The (C 1 -C 6) alkyl in the (C 1 -C 6) alkyloxycarbonyl group includes, for example, the same groups as the above-mentioned (C 1 -C 6) alkyl groups as the substituents. A group similar to the (C1-C4) alkyl group as the group is preferable.

Examples of the (C 1 -C 6) alkyloxycarbonyl group which may be substituted by a monocyclic aromatic group include, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl 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 A pyrimidylmethoxycarbonyl group, a pyrimidylpropoxycarbonyl group, a virazylmethoxycarbonyl group, a virazylbutoxycarbonyl group, a pyridazylmethoxycarbonyl group, a furylmethoxycarbonyl group, a pyrrolylethoxycarbonyl group, and the like. And preferably a pyridyl (C1-C4) alkoxycarbonyl such as a (C1-C4) alkyloxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group. Group, and the like.

Examples of the aryl group substituted with the (C 1 -C 6) alkylsulfonyl group include, for example, the same groups as the aryl group for R 0, and a phenyl group is preferable. Examples of the (C 1 -C 6) alkyl group in the (C 1 -C 6) alkylsulfonyl group include the same groups as the above-mentioned (C 1 -C 6) alkyl group as the substituent. The same groups as the (C 1 -C 4) alkyl group are preferred.

Examples of the (C 1 -C 6) alkylsulfonyl group which may be substituted with an aryl group include a benzylsulfonyl group, a phenethylsulfonyl group and a phenylbutylsulfonyl group, with a benzylsulfonyl group being preferred.

Examples of the aryl group to be substituted with the (C 1 -C 6) alkylaminosulfonyl group include the same groups as the aryl group for R 0, with a phenyl group being preferred. Examples of the (C 1 -C 6) alkyl group in the (C 1 -C 6) alkylaminosulfonyl group include, for example, the same groups as the above-mentioned (C 1 -C 6) alkyl group as the substituent. The same groups as the (C 1 -C 4) alkyl group are preferred.

Examples of the (C 1 -C 6) alkylaminosulfonyl group which may be substituted with a aryl group include, for example, a (C 1 -C 6) alkylaminosulfonyl group substituted with a phenyl group, and a benzylaminosulfonyl group, A (C 1 -C 4) alkylaminosulfonyl group substituted with a phenyl group such as an ethenylaminosulfonyl group or a phenylpropylaminosulfonyl group is preferred, and a benzylaminosulfonyl group is more preferred. The saturated heterocyclic carbonyl group is, for example, 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, dithiadiylcarbonyl group, oxathiolylcarbonyl group, pyrrolidinocarbonyl group, piperidylcarbonyl group, 4-alkyl-1-piperazinylcarbonyl group, morpholyl A saturated heterocyclic carbonyl group having an oxygen atom is preferred; a saturated 5-membered heterocyclic carbonyl group containing an oxygen atom such as a tetrahydrofuroyl group is more preferred; and particularly 3-tetrahydrofuroyl group. A floor group is preferred.

D is an oxygen atom or —NH—, m is any integer of 0 to 3, m is preferably 0 to 2, and more preferably D is an oxygen atom and m is 1, or D is —NH_ and m is m. Is 0.

R 2 is a (C 1 -C 6) alkyl group which may have a substituent or a (C 1 -C 6) alkyloxy group which may have a substituent. (C 1 -C 6) alkyl groups include, for example, methyl group, ethyl group, n-propyl group, i_propyl group, n-butyl group, i-butyl group, sec-butyl group, tert-butyl group, n —Pentyl group, sec-pentyl group, tert-amyl group, n-hexyl group, 1,2-dimethyl-butyl group, etc., and methyl group, ethyl group, n_propyl group, n-butyl group And a (C1-C4) alkyl group such as a tert-butyl group.

Examples of the (C 1 -C 6) alkyl group having a substituent in R 2 include (C 1 -C 6) alkyloxy (C 1 -C 6) alkyl groups, (C 1 -C 6) alkyl groups substituted with aryl groups, (C 1 -C 6) alkyl groups substituted with a heterocyclic oxy group having a nitrogen atom, and (C 1 -C 6) alkyl groups substituted with a heterocyclic group having a nitrogen atom.

As the (C 1 -C 6) alkyloxy group and the (C 1 -C 6) alkyloxy group as the substituent, for example, a (C 1 -C 6) alkyloxy group having the same group as the above (C 1 -C 6) alkyl group bonded thereto A (C 1 -C 6) alkyloxy group to which the same group as the (C 1 -C 6) alkyl group as the substituent is bonded is preferable. Preferred alkyloxy groups include, specifically, for example, a methoxy group, an ethoxy group, (C1-C4) alkyloxy groups such as n-propoxy group, isopropoxyl group, n-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 (C 1 -C 6) alkyl groups include, for example, benzyl, phenyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl and the like. C 4) Alkyl groups are more preferred. Particularly preferred are a phenethyl group and a phenylpropyl group.

The heterocyclic oxy group in the (C 1 -C 6) alkyl group substituted with the heterocyclic oxy group is preferably heteroaryloxy. For example, a pyridyloxy group, a pyrimidyloxy group, a pyrazyloxy group, a pyridazyloxy group, a furyloxy group, A heterocyclic oxy group having a nitrogen atom is preferable, and a 6-membered heterocyclic oxy group having a nitrogen atom such as a pyridyloxy group is preferable.

Examples of the (C1-C6) alkyl group substituted with a heterocyclic oxy group include a pyridyloxymethyl group, a pyridyloxypropyl group, a pyrimidyloxymethyl group, a pyrimidyloxypropyl group, and a virazyloxy group. Heteroaryloxy (C1-C6) alkyl groups such as a methyl group, a virazyloxybutyl group, a pyridazyloxetyl group, a furyloxymethyl group and a pyrrolyloxetyl group. And a 6-membered heterocyclic oxy (C1-C6) alkyl group having a nitrogen atom, and a pyridyloxy (C1-C6) alkyl group such as a pyridyloxypropyl group is particularly 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. A 6-membered heterocyclic group having a nitrogen atom as a hetero atom, such as a morpholinyl group and 2-oxo-1,2-dihydropyridine-1-yl group, and a 2-oxo-1,2-dihydropyridine-11-yl group; Is more preferred.

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, 2-oxo-1,2-dihydropyridine-11-yl-methyl group and the like, and examples thereof include 2-oxo-1,2-dihydropyridine-1-, such as a virazylmethyl group, a pyrazylbutyl group, a pyridazylethyl group, a furylmethyl group, a pyrrolylethyl group, An yl-methyl group is preferred.

As a preferable combination of R0, R1, D, m, and R2, considering the strength of action, for example, R0 is a phenyl group or a (C1-C6) alkylphenyl group, and R1 is hydrogen. Atom, (C1-C4) alkyloxycarbonyl group, (C1-C6) acyl group, phenyl (C1-C6) alkylsulfonyl group, pyridyl (C1-C4) alkyloxycarbonyl group, phenyl (C 1 to C6) alkylaminosulfonyl group or (C1 to C6) alkyl group, D is an oxygen atom or —NH—, m is 0 or 1, R 2 is pyridyloxy (C1 to C6) ) An alkyl group.

As a more preferable combination of R0, R1, D, m, and R2, considering the action in humans, R0 is a phenyl group, and R1 is a (C1-C6) acyl group or a phenyl (C1 CC 6) an alkylaminosulfonyl group, D is —NH—, m is 0, and R 2 is a pyridyloxy (C 1 -C 6) alkyl group.

As a more preferable combination of R0, R1, D, m, and R2, considering oral absorbability, R0 is a phenyl group, R1 is a formyl group, an acetyl group or a benzylaminosulfonyl group; Is —NH—, m is 0, and R2 is a 2-pyridyloxypropyl group.

Hereinafter, typical examples of the compound represented by the general formula (II) used in the present invention are specifically shown in Table 1, but the present invention is not limited to these compounds. In Table 1, Ph represents a phenyl group, Boc represents a tert-butoxycarbonyl group, Ac represents an acetyl group, and Me represents a methyl group. Compound number R0 R1 D m R2

Ph t-Boc NH OMe Ph H NH O e

14 Ph NH Me Compound number R0 R1 D m R2

Among these compounds, more preferred are, for example, Nos. 3, 4, 8, 9, 10, 11, 15, 16, 17, 18, and 19, and more preferred are, for example, No. 10 , 11, and 15 and particularly No. 10. As is clear from the above, a compound having a partial skeleton structure represented by the general formula (I) and having a chymase inhibitory activity, more preferably a compound represented by the general formula (II) is used for treating cardiac dysfunction. The characteristics of the present invention are that it is used as an improving or preventing agent, particularly for treating cardiac dysfunction caused by impaired blood flow, and is used as an improving or preventing agent and a therapeutic or preventing agent for aneurysms. You. When treating cardiac dysfunction or aneurysm using the present compound, an effective amount of the present compound may be administered to an affected warm-blooded animal (including human), and cardiac dysfunction or aneurysm is prevented. In this case, an effective amount of the compound may be administered to warm-blooded animals (including humans) having pathological risk factors such as hypertension before the onset of the disease.

The compound used in the present invention may be a pharmacologically acceptable salt.In the case of a basic compound, for example, in the case of a salt with a carboxylic acid, a sulfonic acid, a mineral acid, or the like, or in the case of an acid compound Examples thereof include salts with alkali metals, alkaline earth metals, organic bases and the like. Examples of carboxylic acid, sulfonic acid, mineral acid, etc. include acetic acid, adipic acid, benzoic acid, cunic acid, fumaric acid, aspartic acid, lactic acid, malic acid, parilemitic acid, salicylic acid, tartaric acid, benzenesulfonic acid, camphorsulfone Acid, tolue Sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like. 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 compounds used in the present invention include optically active substances, racemates, diastereomers, or mixtures of diastereomers, and all of individual enantiomers to mixtures of enantiomers. Unless otherwise specified, the bonding positions of the substituents include all bondable positional isomers. Furthermore, various polymorphisms such as solvates such as hydrates and tautomers of solvates are also included in the compounds used in the present invention. A series of compounds represented by the above general formula (II) in the present invention are disclosed in International Publication WO98 / 09949 and International Publication WO99 / 41277. However, the present invention is not limited to these methods.

Further, the present invention relates to an oral method for treating or preventing cardiac dysfunction or aneurysm comprising a compound having a partial skeleton structure represented by the general formula (I) and having a chimase inhibitory activity as an active ingredient. It is a pharmaceutical preparation. Preferred compounds having the partial skeleton structure represented by the general formula (I) and having chymase inhibitory activity include the compounds represented by the general formula (II).

When a compound having chymase inhibitory activity is used in the present invention, it may be used alone, or as a mixture with a contrast agent or carrier, for injection, tablet, granule, fine granule, powder, capsule, patch, ointment. , A spray, a solution, a sustained-release preparation, etc., and orally or parenterally directly to the affected area, but oral administration is preferred. Pharmaceutically acceptable additives are selected as additives such as contrast agents or carriers, and the type and composition of the additives are determined by the administration route and administration method. For example, in the case of an injection, sugars such as salt, glucose, and mannitol are generally desirable, and in the case of oral preparations, starch, lactose, crystalline cellulose, magnesium stearate and the like are desirable.

In addition to systemic administration by oral or parenteral administration, a method is selected in which the compound effectively reaches the affected area and acts, such as a method using a catheter or the like and direct administration to the affected area during surgery. However, oral administration is particularly preferred. The compound in the formulation The content 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 injection, the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight. In the case of oral preparations, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with additives. Capsules, tablets, granules and powders generally contain 5 to 100% by weight, preferably 15 to 99% by weight, more preferably 20 to 98% by weight of active ingredient. The balance is a pharmaceutical additive. The dosage depends on the age, body weight, symptoms, etc. of the patient, but the therapeutic dose is generally 1 to 1 mg / kg / day for parenteral administration and 5 to 500 mg / kg / day for oral administration. When used in a solution, use at a concentration of 10 to: L 000 nM. The compounds used in the present invention are characterized by low toxicity and low toxicity accumulation by continuous administration. For example, when this compound is orally administered to a rat at a dose of lmgZkg once a day for 4 weeks, no signs of toxicity are observed, and 2- (5-formylamino-6-oxo-) is not observed. 2-Fuel — 1—6-Dihydropyrimidine-1-yl) 1-N— [2,3-Dioxo-1 1-phenylmethyl-6- (2-pyridyloxy)] hexylasemidamide (Compound No. 10) Was administered orally to rats at a dose of 10 OmgZkg once a day for 2 weeks without any signs of toxicity. Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Effect of chymase inhibitor on survival rate after hamster myocardial infarction (A) Method

A male hamster (6 weeks old) purchased from Japan SLC was anesthetized by intraperitoneal administration of 35 mg gZkg of pentobarbital, and then thoracotomy was performed. After awakening, they were bred normally and the hamster survival rate was observed. Three days before coronary artery ligation, the compound-administered group received 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine_1-yl) suspended in 0.5% carboxymethylcellulose. ) 1 N— [2,3-dioxo 1-phenylamine Tyl-6- (2-pyridyloxy)] hexylacetamide (Compound No. 10) 30 mg / kg was orally administered once a day by sonde. The control group received the same amount of water. (B) Result

FIG. 1 shows the change in the number of surviving hamsters up to 14 days after infarction due to administration of Compound No. 10 or water. In the control group to which only water was administered, 11 out of 18 animals died, while in the group to which Compound No. 10 was administered, only 3 out of 17 animals died. That is, the mortality rate after 14 days of infarction was significantly reduced from 61.1% in the control group by oral administration of water alone to 17.6% in the compound No. 10 group, and cardiac dysfunction was improved. Was done. Example 2 Cardioprotective effect of compounds in hamster infarcted heart

Although an improvement in mortality was observed in Example 1, whether the compound of the present invention has a cardioprotective effect was examined using an infarcted heart.

(A) Method

The left coronary artery was ligated as in Example 1. Similarly, 30 mg / kg of Compound No. 10 or water was orally administered every day from 3 days before the infarction. Three days after the infarction, a force neuron was inserted into the hamster artery under anesthesia, and the blood pressure (MABP) was measured with a pressure measurement amplifier. After that, open the chest under artificial respiration, insert a catheter into the left ventricle from the apex, and measure left ventricular systolic pressure (LVSP) and left ventricular end diastolic pressure (LVEDP) with a pressure transducer. + DP dt (contraction change rate of left ventricular pressure) and one dP / dt (expansion change rate of left ventricular pressure) were measured by a differentiating unit. Heart rate (HR) was measured with a heart rate monitor based on the pulse wave of left ventricular pressure.

(B) Result

Table 2.Effect of orally administered Compound No. 10 on hamster heart function 3 days after infarction

Control group (water administration group) Compound administration group Normal heart **

— DP / dt 1440 ± 189 2080 ± 200 3100 234 mmHg / s)

+ dP / dt 1960 ± 180 2960 ± 715 * 4330 ± 141 (mmHg / s)

LVEDP 5.5 ± 1.5 3.9 ± 1.4 * 4.33 ± 0.558

(mmHg)

LVSP 82.5 ± 6.29 115 ± 5.59 150 ± 6.45

(mmHg)

MABP 87.5 ± 3.77 95.8 Sat 4.38 112 Sat 3.70

(mmHg)

HR 325 ± 11.5 360 ± 17.2 423 ± 24.6

(beats / min) Significantly improved function compared to infarct control group (P <0. 05)

As a control, the value of a normal heart measured in another experiment was shown.As shown in the experimental results, it was revealed that the administration of the chymase inhibitor compound prevented the damage of myocardial infarction and caused the hamster heart to function in a near normal state. . From Examples 1 and 2, it is remarkable that the administration of the chymase-inhibiting compound significantly improved the mortality after hamster myocardial infarction, and the chymase-inhibiting compound suppressed the cardiac dysfunction caused by the cardiovascular disorder due to myocardial infarction. It was shown to be useful for improving the prognosis and preventing the progression of the disease to heart failure. Example 3 Test Using Hamster Aortic Aneurysm Model

(A) Method

An aortic aneurysm model was created in a hamster with reference to the method of Origuchi et al. (Int. Ang iol., 17, 113-119 (1998)). That is, a 20-week-old male hamster was opened, and a gauze in which elastase (20 OUZml) was infiltrated around the abdominal aorta was left for 20 minutes. After removal of the gauze, the abdomen was sutured, reared for 2 weeks, reopened, and the aorta was removed. The group with no treatment with Eras evening was similarly treated with gauze infiltrated with physiological saline for 20 minutes. In this system, from 2 days before Eras evening treatment to the day before vascular extraction, 2- (5_formylamino-6-oki) So-2-phenyl-1,6-dihydropyrimidine-1-yl) — N— [2,3-Dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide (Compound No. 10) A suspension of 30111 in 0.1% methylcellulose (1 ml) was orally administered once daily at a dose of 3 Omg / kg. In the Eras evening-untreated group and the control group, only 0.1% methylcellulose was orally administered continuously once a day during the same period. The aortic diameter was measured when Erasase or physiological saline was treated, and the aortic diameter was measured again two weeks later. The blood vessel diameter after two weeks with respect to the blood vessel diameter at the time of treatment was expressed as a percentage, and this was defined as an arterial diameter hypertrophy rate and used as an index of aneurysm.

In addition, in order to examine not only the system of the entire artery but also the actual thickness of the blood vessel wall, the cross-sectional area of the vascular media was determined from the extracted blood vessels, and the ratio to the blood vessel diameter was determined by the following equation. Media ratio = (media area) / (aortic diameter) ²

(B) Result

As shown in Table 3, the vascular media was diluted by the treatment with Elass Juice, resulting in an enlarged arterial diameter. These changes were significant as compared with the group not treated with Eras Yuze, and an aneurysm was formed by Eras Yuze treatment. These changes were significantly suppressed in the group to which this compound was orally administered daily, compared to the control group not to receive this compound (P <0.05 by Student's t-test). These results indicate that oral administration of the present compound suppressed the thinning of the vascular media and the formation of aneurysms, promising the effect of treating aneurysms in clinical practice.

Table 3 Degree of vascular hypertrophy and media thinning

Arterial diameter hypertrophy rate (%) Media ratio

Eras evening treatment 120 ± 2.2 0.165 ± 0 009

(5)

Elastase treatment 183 ± 6.6 0.062 ± 0.006

(10 animals) (control group)

Eras evening treatment

Administration of this compound 154 ± 3.6 0.097 Sat 0.009

(12) Example 4 Formulation example

50. Omg of 2- (5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl) _N_ [2,3-dioxo-1-1-phenylmethyl-6- (2- Pyridyloxy)] hexylacetamide (Compound No. 10), mixed with 80.Omg of low-substituted hydroxypropylcellulose, 57.Omg of lactose, 2.Omg of hydroxypropylcellulose and 1.Omg of magnesium stearate, Oral capsules were obtained by enclosing in No. 3 force capsules. Industrial applicability

According to the present invention, a compound having a partial structure containing a pyrimidone skeleton and inhibiting chymase in a living body with high selectivity and effectiveness, for example, a compound represented by the general formula (II) or a pharmacologically acceptable compound thereof A therapeutic or ameliorating or preventing agent for cardiac dysfunction using a salt as an active ingredient, which can act on the living body by oral administration or the like, especially a therapeutic or ameliorating or prophylactic agent for cardiac dysfunction caused by impaired blood flow; And a therapeutic and ameliorating agent or a prophylactic agent that effectively suppresses the progression and rupture of an aneurysm.

Claims

The scope of the claims

2. The compound according to claim 1 has the general formula (II)

[Wherein, 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-C6 ) May be substituted with an alkyloxycarbonyl group or an aryl group (C 1 -C 6) alkylsulfonyl group or may be substituted with an aryl group (C 1 -C 6) alkylaminosulfonyl group or saturated Represents a heterocyclic group, D represents an oxygen atom or —NH—, and m represents an integer of 0 to 3. R 2 may have a substituent (C 1 to C 6) may have an alkyl group or a substituent (C 1 to C 6 6) Indicates an alkyloxy group. ]

2. The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to claim 1, which is a compound represented by the formula:

3. The aryl group in R0 of the general formula (II) is a phenyl group which may have a (C1 to C6) alkyl group or a halogen atom as a substituent, and the monocyclic aromatic group in R1 The (C 1 -C 6) alkyloxycarbonyl group which may be substituted with a (C 1 -C 6) alkyloxycarbonyl group or a pyridyl (C 1 -C 6) alkyloxycarbonyl group, (C 1 -C 6) alkylsulfonyl group is a phenyl group-substituted (C 1 -C 6) alkylsulfonyl group, which may be substituted by an aryl group (C 1 -C 6 ) An alkylaminosulfonyl group in which an alkylaminosulfonyl group is substituted with a phenyl group, a saturated heterocyclic carbonyl group is a saturated heterocyclic carbonyl group having an oxygen atom, and the substituent in R 2 is May have ( (C 1 -C 6) alkyl substituted with (C 1 -C 6) alkyl, (C 1 -C 6) alkyloxy, (C 1 -C 6) alkyl or aryl group 3. A (C1-C6) alkyl group substituted with a heterocyclic oxy group having a nitrogen atom or a (C1-C6) alkyl group substituted with a heterocyclic group having a nitrogen atom. The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to 1.

4. The saturated heterocyclic carbonyl group having an oxygen atom in the saturated heterocyclic carbonyl group of R 1 is a tetrahydrofuroyl group and may have a substituent of R 2 (C

(C1-C6) is a (C1-C6) alkyl group substituted with an aryl group in the alkyl group, and a (C1-C6) alkyl group substituted with a phenyl group, and is a heterocyclic oxy group having a nitrogen atom. A substituted (C 1 -C 6) alkyl group is a (C 1 -C 6) alkyl group substituted by a 6-membered heterocyclic oxy group having a nitrogen atom, and substituted by a heterocyclic group having a nitrogen atom ( 4. The therapeutic agent for cardiac dysfunction or aneurysm according to claim 3, wherein the (C1-C6) alkyl group is a (C1-C6) alkyl group substituted with a 6-membered complex ring group having a nitrogen atom. Or a prophylactic agent.

5. In the general formula (II), R 0 is a phenyl group or a (C 1 -C 6) alkylphenyl group, R 1 is a hydrogen atom, (C 1 -C 6) alkyloxycarbonyl group, (C 1-C6) acryl group, phenyl (C1-C6) alkylsulfonyl group, pyridyl (C1-C6) alkyloxycarbonyl group, phenyl (C1-C6) alkylaminosulfonyl group or (C1-C6) 3. The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to claim 2, wherein m is 0 or 1, R 2 is a pyridyloxy (C 1 -C 6) alkyl group.

6. —R 0 in the general formula (II) is a phenyl group, R 1 is a (C 1 -C 6) acyl group or a phenyl (C 1 -C 6) alkylaminosulfonyl group, and D is —NH— 3. The therapeutic or preventive agent for heart dysfunction or aneurysm according to claim 2, wherein m is 0, and R 2 is a pyridyloxy (C 1 -C 6) alkyl group.

7. The cardiac dysfunction or artery according to claim 5, wherein R 1 is a formyl group, an acetyl group or a benzylaminosulfonyl group, and R 2 is a 2-pyridyloxypropyl group. An agent for treating or preventing aneurysms.

8. The compound represented by the general formula (II) is 2- (5-formylamino-6-oxo-1-2-phenyl-1,6-dihydropyrimidine-11-yl) -1-N— [2, 3-dioxo-1-phenylmethyl-6-(2 _ pyridyloxy)] hexyl acetamide, 2-(5-acetylamino-6-oxo _2_ phenyl _ 1, 6-dihydropyrimidine-11-)-N- [2,3-Dioxo-1-phenylphenyl-6- (2-pyridyloxy)] hexylacetamide or 2- (5-benzylaminosulfonylamino-1 6-oxo_2-2-phenyl-1,6-dihydropyrimidine-1 1- 3. The therapeutic agent for cardiac dysfunction or arterial aneurysm according to claim 2, which is N- [2,3-dioxo-1-phenylmethyl-6_ (2-pyridyloxy)] hexylacetamide. Prophylactic agent.

9. The compound represented by the general formula (II) is represented by the formula: 2- (5-formylamino-6-oxo-1-2-phenyl-1,6-dihydropyrimidine-11 mol) 1 N— [2, 3. The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to claim 2, which is 3-dioxo-1-phenylmethyl-6- (2-pyridyloxy)] hexylacetamide.

10. The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to any one of claims 1 to 9, wherein the cardiac dysfunction is a cardiac dysfunction caused by impaired blood flow.

1 1. Claims in which the cardiac dysfunction is angina, myocardial infarction, cardiac hypertrophy, or heart failure Item 10. The therapeutic or preventive agent for heart dysfunction or aneurysm according to any one of Items 1 to 9.

12. The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to any one of claims 1 to 9, wherein the aneurysm is an abdominal aortic aneurysm.

13. The therapeutic or prophylactic agent for cardiac dysfunction or arterial aneurysm according to any one of claims 1 to 12 is an oral preparation. Item 3. The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to any one of Items 1 to 12.