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

Remedial or preventive agent for cardiopathy or aneurysm containing chymase inhibitory compound Download PDF

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Publication number
WO2003007964A1
WO2003007964A1 PCT/JP2002/007269 JP0207269W WO03007964A1 WO 2003007964 A1 WO2003007964 A1 WO 2003007964A1 JP 0207269 W JP0207269 W JP 0207269W WO 03007964 A1 WO03007964 A1 WO 03007964A1
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Prior art keywords
group
substituted
aneurysm
phenyl
cardiac dysfunction
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PCT/JP2002/007269
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French (fr)
Japanese (ja)
Inventor
Mizuo Miyazaki
Keiichi Kamoshita
Yoshikazu Sukenaga
Yoshikazu Suzuki
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Nippon Kayaku Kabushiki Kaisha
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Priority claimed from JP2001218654A external-priority patent/JP2003034649A/en
Priority claimed from JP2001300954A external-priority patent/JP2003104894A/en
Application filed by Nippon Kayaku Kabushiki Kaisha filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO2003007964A1 publication Critical patent/WO2003007964A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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.
  • Cardiovascular disorders 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.
  • ACE angiotensin-converting enzyme
  • Aneurysms 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.
  • 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.
  • an aneurysm 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.
  • chymase 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)).
  • 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.
  • MMP-9 matrix metalloprotease
  • 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.
  • 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.
  • the present invention relates to the following (1) to (13).
  • 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.
  • 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)
  • R represents an oxygen atom or —NH—
  • 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:
  • 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-C
  • 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.
  • 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.
  • 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
  • D is —NH—.
  • 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).
  • R 1 is a formyl group, an acetyl group or a benzylaminosulfonyl group
  • R 2 is a 2-pyridyloxypropyl group according to the above (5) or (6), A therapeutic or prophylactic agent.
  • 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
  • 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.
  • FIG. 1 shows changes in the survival rate after hamster myocardial infarction during administration of the chymase inhibitor compound according to the present 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.
  • 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.
  • R 0 represents an aryl group.
  • 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.
  • halogen atom examples 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 virazylbutoxy
  • 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
  • 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.
  • (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.
  • 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.
  • 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.
  • 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.
  • R0 is a phenyl group or a (C1-C6) alkylphenyl group
  • 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 is an oxygen atom or —NH—
  • m is 0 or 1
  • R 2 is pyridyloxy (C1 to C6) )
  • An alkyl group is an oxygen atom or —NH—
  • m is 0 or 1
  • R 2
  • R0 is a phenyl group
  • 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.
  • R0 is a phenyl group
  • R1 is a formyl group, an acetyl group or a benzylaminosulfonyl group
  • m is 0, and R2 is a 2-pyridyloxypropyl group.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • a compound having chymase inhibitory activity when 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.
  • 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.
  • 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.
  • the active ingredient is usually contained in an amount of 0.1 to 30% by weight, preferably 1 to 10% by weight.
  • 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.
  • 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.
  • 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.
  • Example 2 Cardioprotective effect of compounds in hamster infarcted heart
  • Example 1 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.
  • 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.
  • LVSP left ventricular systolic pressure
  • LVEDP left ventricular end diastolic pressure
  • Control group water administration group
  • Compound administration group Normal heart **
  • 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.
  • 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.
  • 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).
  • 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;
  • a therapeutic and ameliorating agent or a prophylactic agent that effectively suppresses the progression and rupture of an aneurysm.

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

明 細 書 キマーゼ阻害化合物を用いた心臓機能障害又は動脈瘤の治療剤又は予防剤 技術分野  Description Treatment or prophylactic agent for cardiac dysfunction or aneurysm using chymase inhibitor compound
本発明は、 ピリミドン骨格を部分構造として有し、 特に経口投与等により生体 内で有効にキマーゼ活性を阻害する化合物を用いた、 心臓機能障害又は動脈瘤の 治療剤又は予防剤に関する。 背景技術  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
循環器障害に起因する疾病は、 近年その患者数が増加傾向にあり、 更に死亡原 因としても上位を占めるに至っている。 循環器障害による疾病は種々知られてい るが、 中でも血流障害等による虚血等の原因により起こる心臓の機能障害、 例え ば狭心症、心筋梗塞、心肥大、心不全等や、動脈や心臓等に形成される膨らみ（嚢） である動脈瘤は主要な病態である。  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.
レニン—アンジォテンシン一アルドステロン系は体内の血圧調節機構として存 在し、 アンジォテンシン I Iはこの系において末梢部位に働き強い昇圧作用を示 すことが知られている。 このアンジォテンシン I Iは、 肝臓で作られるアンジォ テンシノーゲンがアンジォテンシン Iを経由し、 アンジォテンシン変換酵素 （以 下、 AC Eと記す） により分解されることで産生され、 全身性に作用すると考え られている。 しかし、 近年各組織においてもこの系に関わる分子が発現されアン ジォテンシン I Iが組織内において全身性のものとは別に独立して存在し働いて いることが明らかとなった。 こうした組織内のアンジォテンシン I Iは昇圧反応 よりむしろ、 例えば心臓においては心筋細胞の肥大等の組織リモデリングに関与 していると考えられている。  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.
臨床において、 血圧に影響を及ぼさない低濃度の AC E阻害薬が他の抗慢性心 不全薬に比較して多少有効であることが示されているが（Da h 1 o f等、 Am. J. Hyp e r t e n s., 5， 95〜： L 10 (1992))、 その作用は例えば J o h n s t on等が Am. He a r t J.， 126, 756〜 760 (1993) l に報告した通り、 全身性のアンジォテンシン I Iではなく組識内のアンジォテン シン I Iを不完全ではあるが抑制することによる。 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.
一方、 Ur a t a等はヒト心臓組織におけるアンジォテンシン I Iは、 ACE よりもむしろキマ一ゼで産生されていることを J . B i o l .Chem., 265, 22348〜22357 (1990) に報告している。 ACE阻害薬やアンジォ テンシン I I · 1型受容体 （AT 1 R) 拮抗薬の臨床効果から、 心臓組識のアン ジォテンシン I Iを抑制することで様々な心臓障害やその慢性期の障害が予防又 は治療されることが示されているが、 それら ATI R拮抗薬は、 全身性の昇圧反 応に関わるアンジォテンシン I Iと組織特異的なアンジォテンシン I Iを区別す ることができず、 血圧低下等の副作用を伴い、 又、 ACE阻害薬では組織アンジ ォテンシン I Iの産生を完全には抑制できず、 不完全な効果しか示さない。 一方、 動脈瘤は動脈や心臓の壁等に形成される限局性の膨らみ （嚢） である。 動脈は心臓から各組織へ血液を送り出す輸送路として重要な働きをしており、 心 臓が送り出す血液の圧力に耐えるため血管平滑筋細胞や細胞外基質に富んだ構造 となっているが、 その構造の破壊が生じた場合、 その部位では動脈圧への抵抗が 減弱し心収縮毎に壁が拡張するようになり、 この結果、 動脈の限局的な膨らみを 生じる。 このような限局性の膨らみ （嚢） である動脈瘤を引き起こす原因は、 先 天的要因、 感染症、 膠原病、 動脈硬化、 外傷等様々であり、 又、 その生じる血管 も全ての部位に亙っている。  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.
動脈瘤が形成された場合、 周辺組織を侵食 ·圧迫することがあり、 それが神経 に対するものである場合にはひどい痛みを伴うこととなる。 又、 瘤内に広範な血 栓が生じると、 その下流の血行を閉塞させ重篤な障害に至る。 しかし、 最も危険 な状態は血管壁の抵抗が減弱し続けた場合や内部で血栓形成が進んで内圧が大き くなつた場合であり、 そうした状態が続くと動脈瘤が進行して拡大し、 やがて破 裂し、 重篤な、 時には致命的な内出血を起こすことになる。 従って、 動脈瘤が発 見された場合には可能であれば外科的に取り除かれる。 外科的処置が不可能な場 合は、 それを退縮させるか若しくは破裂に至らないよう動脈壁の耐久性を維持さ せる治療が必要であるが、 これまでに有効な薬剤は知られていない。  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.
動脈瘤を引き起こす原因は様々あるが、 それらに引続きどのような機序で血管 抵抗の減弱が導かれ動脈が拡張してゆくかについても解明されていない。 そのた め血管の脆弱な部位を保護することを考え、 降圧薬である AC E阻害薬の使用に よるアンジォテンシン I Iの抑制が試みられている。 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.
ヒトの血管等の組織において、 AC E以外にアンジォテンシン I I産生酵素と してキマーゼが存在していることが知られている （Tak a i等、 C I i n. C h im. Ac t a, 265, 13— 20 (1997))。 更に、 本発明者等は破裂 性動脈瘤病変におけるこれらの酵素の発現を検討し、 AC Eおよびキマーゼ共に その発現が亢進していることを明らかにした （常深等、 日本外科学会誌、 第 10 2巻第 2号 243頁 （2001))。  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)).
しかしながら L i a o等が行った動物実験では、 ACE阻害薬は動脈瘤モデル に有効であったもののアンジォテンシン I I受容体拮抗薬は無効であった （J. Va s e. Su r g., 33, 1057 - 1064 (2001))。 即ち、 ACE阻 害薬の効果はアンジォテンシン I Iの産生抑制を介していない可能性が示され、 従って破裂性動脈瘤におけるキマーゼの役割は依然不明である。  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.
又、 一般に血管壁の構造の破壊にはマトリックス金属プロテアーゼ （以下 MM Pと略す） を始めとする多くのプロテアーゼが関与しているとされ、 動脈瘤の場 合、 特に MM P— 9 (又はジエラチネ一ス Bと呼ばれる） が重要でることが Py o等の実験 （J. C l i n. I nve s t., 105, 1641 - 1649 (20 00)) により示されている。又、 臨床サンプルを用いた Th omp s o n等の実 験結果 （J. C l i n. I nve s t., 96， 318— 326 (1995)) や McM i 1 1 a n等の解析結果 （C i r c u l a t i on, 96， 2228 -2 232 (1997))から、 ヒトの動脈瘤組識にも多くの MMP— 9が認められる ことが明らかとなっている。 MMP類は前駆体として生合成された後、 限定分解 を受けてその活性が発現されるのであるが、 MMP— 9の活性化プロセスにおけ るキマーゼの働きも未だ明確になっていない。  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.
従って、 これまでにキマ一ゼの動脈瘤への関与は明確になっておらず、 キマー ゼ阻害剤の動脈瘤に対する効果も全く不明であった。  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.
現在、 動脈瘤の進行 ·破裂に対する有効な薬物療法は知られていない。 発明の開示 At present, there is no known effective pharmacotherapy for the progression and rupture of aneurysms. Disclosure of the invention
本発明者等は、 生体内で選択的にキマーゼを阻害する化合物が心臓の機能障害 を治療 ·改善又は予防、 特に血流障害に起因する心臓の機能障害を治療 ·改善又 は予防する作用、 及び動脈瘤の進展および破裂を有効に抑制する作用を有するこ とを動物モデルを用いて見出し、 本発明を完成するに至った。  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.
即ち、 本発明は、 次の （1) 〜 （13) に関するものである。  That is, the present invention relates to the following (1) to (13).
( 1 ) 下記式 （ I )  (1) The following formula (I)
Figure imgf000006_0001
Figure imgf000006_0001
で表される部分骨格構造を有し且つキマーゼ阻害活性を有する化合物又はその薬 理学上許容される塩を含有する心臓機能障害又は動脈瘤の治療剤又は予防剤。 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) 上記 （ 1 ) の化合物が、 一般式 （I I)  (2) The compound of the above (1) is represented by the general formula (II)
Figure imgf000006_0002
Figure imgf000006_0002
[式中、 R0はァリール基を示し、 R1は水素原子、 C 1〜C6のアルキル基、 C 1〜C6のァシル基、 単環芳香族基で置換されていてもよい （C 1〜C6) ァ ルキルォキシカルポニル基、 ァリール基で置換されていてもよい （C 1〜C6) アルキルスルホニル基、 ァリール基で置換されていてもよい （C 1〜C6) アル キルアミノスルホニル基又は飽和複素環力ルポ二ル基を示し、 Dは酸素原子又は — NH—を示し、 mは 0〜 3のいずれかの整数を示す。 R 2は置換基を有してい てもよい（C 1〜C 6)アルキル基又は置換基を有していてもよい（C 1〜C 6) アルキルォキシ基を示す。] [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. ]
で表される化合物である上記 （1) に記載の心臓機能障害又は動脈瘤の治療剤又 は予防剤。 The therapeutic or prophylactic agent for cardiac dysfunction or aneurysm according to (1), which is a compound represented by the formula:
(3) 一般式 （I I) の R 0におけるァリール基が、 置換基として （C 1〜C6) アルキル基又はハロゲン原子を有していてもよいフエニル基であり、 R1におけ る単環芳香族基で置換されていてもよい （C 1〜C6) アルキルォキシカルボ二 ル基が （C 1〜C6) アルキルォキシカルボニル基又はピリジル （C 1〜C6) アルキルォキシカルポニル基であり、 ァリール基で置換されていてもよい （C 1 〜C6) アルキルスルホニル基がフエニル基で置換された （C 1〜C6) アルキ ルスルホニル基であり、 ァリール基で置換されていてもよい （C 1〜C6) アル キルアミノスルホニル基がフエニル基で置換された （C 1〜C6) アルキルアミ ノスルホニル基であり、 飽和複素環カルボニル基が酸素原子を有する飽和複素環 カルボニル基であり、 R 2における置換基を有していてもよい （C 1〜C6) ァ ルキル基が（C 1〜C6) アルキル基、 （C 1〜C6) アルキルォキシ （C 1〜C 6) アルキル基、 ァリール基で置換された （C 1〜C6) アルキル基、 窒素原子 を有する複素環ォキシ基で置換された （C 1〜C6) アルキル基又は窒素原子を 有する複素環基で置換された （C 1〜C6) アルキル基である上記 （2) に記載 の心臓機能障害又は動脈瘤の治療剤又は予防剤。  (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) R 1の飽和複素環カルポニル基における酸素原子を有する飽和複素環カル ポニル基がテトラヒドロフロイル基であり、 R 2の置換基を有していてもよい（C (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
1〜C6) アルキル基におけるァリール基で置換された （C 1〜C6) アルキル 基がフエニル基で置換された （C 1〜C6) アルキル基であり、 窒素原子を有す る複素環ォキシ基で置換された （C 1〜C6) アルキル基が窒素原子を有する 6 員複素環ォキシ基で置換された （C 1〜C6) アルキル基であり、 窒素原子を有 する複素環基で置換された （C 1〜C6) アルキル基が窒素原子を有する 6員複 素環基で置換された （C 1〜C6) アルキル基である上記 （3) に記載の心臓機 能障害又は動脈瘤の治療剤又は予防剤。 (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) 一般式 （I I) における R0がフエニル基又は （C 1〜C6) アルキルフ ェニル基であり、 R 1が水素原子、 （C 1〜C6) アルキルォキシカルボニル基、 (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〜C6) ァシル基、 フエニル （C 1〜C6) アルキルスルホニル基、 ピリ ジル （C 1〜C6) アルキルォキシカルボ二ル基、 フエニル （C 1〜C6) アル キルアミノスルホニル基又は （C 1〜C6) アルキル基であり、 mが 0又は 1で あり、 R 2がピリジルォキシ （C 1〜C6) アルキル基である上記 （2) に記載 の心臓機能障害又は動脈瘤の治療剤又は予防剤。 (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) 一般式 （I I) における R 0がフエニル基であり、 R 1が （C 1〜C6) ァシル基又はフエニル （C 1〜C6) アルキルアミノスルホニル基であり、 Dが — NH—であり、 mが 0であり、 R2がピリジルォキシ （C 1〜C6) アルキル 基である上記 （2) に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。  (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がホルミル基、 ァセチル基又はべンジルアミノスルホニル基であり、 R2が 2—ピリジルォキシプロピル基である上記 （5) 又は （6) に記載の心臓 機能障害又は動脈瘤の治療剤又は予防剤。  (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) 一般式 （I I) で表される化合物が、 2— （5—ホルミルアミノー 6—才 キソー 2—フエエル— 1, 6—ジヒドロピリミジン一 1一ィル） — N— [2, 3 —ジォキソ— 1—フエ二ルメチルー 6—（2—ピリジルォキシ）]へキシルァセ夕 ミド、 2— （5—ァセチルァミノ— 6—ォキソ一2—フエニル一 1， 6—ジヒド 口ピリミジン一 1—ィル） 一N— [2, 3—ジォキソー 1—フエニルメチル _ 6 - (2—ピリジルォキシ）] へキシルァセ夕ミド又は 2 _ (5—ベンジルアミノス ルホニルァミノ一 6—ォキソ一 2—フエニル _ 1 , 6—ジヒドロピリミジン一 1 —ィル） 一 N— [2， 3—ジォキソ一 1—フエ二ルメチルー 6— （2—ピリジル ォキシ)]へキシルァセタミドである上記（2) に記載の心臓機能障害又は動脈瘤 の治療剤又は予防剤。  (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) 一般式 （I I) で表される化合物が、 2— （5_ホルミルアミノー 6—才 キソ一2—フエ二ルー 1, 6—ジヒドロピリミジン— 1—ィル） —N— [2, 3 ージォキソ— 1—フエ二ルメチルー 6 - (2—ピリジルォキシ）]へキシルァセ夕 ミドである上記 （2) に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。 (10)心臓機能障害が血流障害に起因する心臓機能障害である上記（ 1 )〜（ 9 ) のいずれか 1項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。 (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) 心臓機能障害が、 狭心症、 心筋梗塞、 心肥大、 心不全である上記 （1) 〜 （9) のいずれか 1項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。 (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) 動脈瘤が腹部大動脈瘤である上記 （1) 〜 （9) のいずれか 1項に記載 の心臓機能障害又は動脈瘤の治療剤又は予防剤。 (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) 上記 （1) 〜 （12) のいずれか 1項に記載の心臓機能障害又は動脈瘤 の治療剤又は予防剤が、 経口製剤であることを特徴とする上記 （1) 〜 （12) のいずれか 1項に記載の動脈瘤治療又は予防剤。 図面の簡単な説明  (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
第 1図は、 本発明に係るキマーゼ阻害化合物投与時の、 ハムスター心筋梗塞後 の生存率の推移である。 発明を実施するための最良の形態  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
本発明は、 ピリミドン骨格を含む前記一般式 （I) で表される部分構造を有し 且つキマーゼ阻害活性を有する化合物又はその薬理学上許容される塩 （以下場合 により本化合物という） を有効成分とする心臓機能障害又は動脈瘤の治療剤又は 予防剤である。 本化合物としては、 前記一般式 （I) で表される部分骨格構造を 有し且つキマ一ゼ阻害活性を有する化合物であれば特に制限は無いが、 好ましく は前記一般式 （I I) で示される化合物が挙げられる。  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.
本発明でいうキマーゼとは、 セリンプロテア一ゼの中のキモトリブシンタイプ のプロテア一ゼに属し、 肥満細胞中の分泌顆粒に蓄積され、 刺激によって放出さ れる細胞障害性の酵素 （蛋白質） である。 キマーゼの阻害活性は公知の方法で測 定可能であるが、 例えば国際公開 WO 98/09949号公報や国際公開 WO 9 9/41277号公報において開示した方法で測定され、 例えば合成基質 （サク シニル ·ロイシル ·ロイシル ·ノ リル ·チロシル ·メチルクマリルアミド） を用 いる方法又はアンジォテンシン Iを用いる方法等を用いることができる。 キマー ゼ阻害活性を有するとは、 例えば該公報の測定方法において I C 5 0が 1 0 0 n M以下のものであり、 好ましくは 5 0 n M以下であり、 特に好ましくは 2 0 n M 以下である。 キマーゼは動物種により異なるので、 適用する動物におけるキマー ゼに対する阻害活性が上記の範囲にあることが好ましい。 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.
本発明でいう心臓機能障害とは、特に血流障害に起因する心臓機能障害であり、 具体的には血栓や血管内肥厚が原因となって起こる血流障害による心筋虚血によ つてもたらされる狭心症や心筋梗塞、 更にそれが慢性期に移行した場合の心不全 や心肥大を示す。  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.
本発明でいう動脈瘤には、 通常、 動脈瘤といわれる病態は全て含まれる。 動脈 瘤はその発生部位、 その原因、 又はその形状により様々に分類され、 例えば、 発 生部位による分類としては、 腹部大動脈瘤、 吻合性動脈瘤、 脳動脈瘤、 心壁動脈 瘤、 腎動脈瘤、 胸大動脈瘤等が挙げられ、 原因による分類としては、 ァテローム 硬化性動脈瘤、 細菌動脈瘤、 蔓性動脈瘤、 先天性脳動脈瘤、 解離性動脈瘤、 拡張 性動脈瘤、 塞栓性動脈瘤、 真菌性動脈瘤、 梅毒性動脈瘤等が挙げられ、 形状によ る分類としては、 嚢状動脈瘤、 桑実状動脈瘤、 壁在性動脈瘤等が挙げられるが、 本発明においては特に限定されない。  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.
又、 動脈瘤の治療とは望ましくは動脈瘤の退縮を導くものであるが、 一度形成 された動脈瘤は進行することが通常であり、 治療上重要なことは動脈瘤を破裂に 至らしめないようコントロールすることである。 よって、 破裂に導かないよう動 脈瘤の進行を防ぐこと並びに血管壁の更なる脆弱化を防ぐこともその治療に含ま れる。  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.
本発明における前記一般式 （I I ) で表されるァセトアミド誘導体において、 R 0はァリール基を示す。 ァリール基としては、 例えば置換基を有していてもよ いフエニル基が挙げられ、 より好ましくは置換基として （C 1〜C 6 ) アルキル 基又はハロゲン原子を有していてもよいフエニル基であり、 更に好ましくは無置 換のフエニル基である。  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.
置換基としての （C 1〜C 6 ) アルキル基としては、 例えばメチル基、 ェチル 基、 n—プロピル基、 i—プロピル基、 n _ブチル基、 i —ブチル基、 s e c— ブチル基、 t e r t—ブチル基、 n—ペンチル基、 s e c—ペンチル基、 t e r t—アミル基、 n—へキシル基、 1， 2—ジメチルーブチル基等が挙げられ、 メ チル基、ェチル基、 n_プロピル基、 n—ブチル基、 t e r t—ブチル基等の（C 1〜C4) アルキル基が好ましい。 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.
ハロゲン原子としては例えばフッ素、塩素、臭素、 ヨウ素等が挙げられる。 （C 1〜C 6) アルキル基で置換されたフエニル基としては、 例えばトリル基、 キシ リル基等が挙げられ、 ハロゲン原子で置換されたフエニル基としては例えばフル オロフェニル基が挙げられる。  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は水素原子、 C 1〜C6のアルキル基、 C 1〜C6のァシル基、 単環芳香 族基で置換されていてもよい （C 1〜C6) アルキルォキシカルボ二ル基、 ァリ ール基で置換されていてもよい （C 1〜C6) アルキルスルホニル基、 ァリール 基で置換されていてもよい （C 1〜C6) アルキルアミノスルホニル基又は飽和 複素環カルポニル基である。  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.
C 1〜C 6のアルキル基としては、 例えば上記置換基としての （C 1〜C 6) アルキル基と同様の基が挙げられ、 上記置換基としての （C 1〜C4) アルキル 基と同様の基が好ましい。  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.
C 1〜C 6のァシル基としては、 例えばホルミル基、 ァセチル基、 プロピオ二 ル基、 プチリル基、 イソプチリル基、 バレリル基等が挙げられ、 ホルミル基、 ァ セチル基が特に好ましい。  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.
(C 1〜C6)アルキルォキシカルポニル基に置換する単環芳香族基としては、 例えばフエニル基、 ピリジル基、 ピリミジル基、 ピラジル基、 ピリダジル基、 フ リル基、 ピロリル基等が挙げられ、 ピリジル基が好ましい。 又、 （C 1〜C6) ァ ルキルォキシカルボニル基における （C 1〜C6) アルキルとしては、 例えば上 記置換基としての （C 1〜C6) アルキル基と同様の基が挙げられ、 上記置換基 としての （C 1〜C4) アルキル基と同様の基が好ましい。  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.
単環芳香族基で置換されていてもよい （C 1〜C6) アルキルォキシカルボ二 ル基としては、 例えばメトキシカルポニル基、 エトキシカルポニル基、 n—プロ ポキシカルボニル基、 n—ブトキシカルボ二ル基、 t e r t—ブトキシカルボ二 ル基、 n—ペンチルォキシカルポニル基、 s e c—ペンチルォキシカルポニル基、 2， 2—ジメチループロポキシカルポニル基、 n一へキシルォキシカルボニル基、 1, 2—ジメチルーブチルォキシカルポニル基、ピリジルメトキシカルポニル基、 ピリジルエトキシカルボニル基、 ピリジルプロポキシカルポニル基、 ピリジルブ トキシカルポニル基、 ピリミジルメトキシカルボニル基、 ピリミジルプロポキシ カルボ二ル基、ビラジルメトキシカルボニル基、ビラジルブトキシカルボ二ル基、 ピリダジルメトキシカルポニル基、 フリルメトキシカルボニル基、 ピロリルエト キシカルポニル基等が挙げられ、 好ましくはメトキシカルポニル基、 エトキシカ ルポニル基、 t e r t—ブトキシカルボニル基等の （C 1〜C4) アルキルォキ シカルボニル基、 ピリジルメトキシカルボニル基等のピリジル （C 1〜C4) ァ ルキルォキシカルボニル基が挙げられる。 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.
(C 1〜C6) アルキルスルホニル基に置換するァリール基としては、 例えば R0のァリール基と同様の基が挙げられ、 フエニル基が好ましい。又、 （C 1〜C 6) アルキルスルホニル基における （C 1〜C6) アルキル基としては、 例えば 上記置換基としての （C 1〜C6) アルキル基と同様の基が挙げられ、 上記置換 基としての （C 1〜C4) アルキル基と同様の基が好ましい。  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.
ァリール基で置換されていてもよい （C 1〜C6) アルキルスルホニル基とし ては、 例えばべンジルスルホニル基、 フエネチルスルホニル基、 フエニルブチル スルホニル基等が挙げられ、 ベンジルスルホニル基が好ましい。  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.
(C 1〜C 6) アルキルアミノスルホニル基に置換するァリール基としては、 例えば R0のァリール基と同様の基が挙げられ、 フエニル基が好ましい。又、 （C 1〜C6) アルキルアミノスルホニル基における （C 1〜C6) アルキル基とし ては、 例えば上記置換基としての （C 1〜C6) アルキル基と同様の基が挙げら れ、 上記置換基としての （C 1〜C4) アルキル基と同様の基が好ましい。  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.
ァリール基で置換されていてもよい （C 1〜C6) アルキルアミノスルホニル 基としては、 例えばフエニル基で置換された （C 1〜C6) アルキルアミノスル ホニル基が挙げられ、 ベンジルアミノスルホニル基、 フエネチルアミノスルホニ ル基、 フエニルプロピルアミノスルホニル基等のフエニル基で置換された （C 1 〜C4) アルキルアミノスルホニル基が好ましく、 ベンジルアミノスルホニル基 がより好ましい。 飽和複素環カルボニル基としては、 例えば酸素、 窒素及び硫黄からなるグルー プから選択される 1から 4個の複素原子を含む、 5又は 6員環の飽和複素環カル ボニル基が好ましく、例えばチオリルカルポニル基、ジォキサニルカルボニル基、 ォキソチア二ルカルポニル基、 ジチアジ二ルカルポニル基、 ォキサチォリルカル ポニル基、 ピロリジノカルポニル基、 ピペリジルカルボニル基、 4一アルキル一 ピペラジニルカルポニル基、 モルホリルカルポニル基、 テトラヒドロフロイル基 等が挙げられ、 酸素原子を有する飽和複素環カルポニル基が好ましく、 テトラヒ ド口フロイル基等の酸素原子を含む飽和 5員複素環カルボニル基がより好ましく、 特に 3—テトラヒドロフロイル基が好ましい。 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は酸素原子又は—NH―、 mは 0〜 3のいずれかの整数であり、 mは 0〜2 が好ましく、 より好ましくは Dが酸素原子で mが 1、 又は Dが— NH_で mが 0 である。  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は置換基を有していてもよい （C 1〜C6) アルキル基又は置換基を有し ていてもよい （C 1〜C 6) アルキルォキシ基である。 （C 1〜C 6) アルキル基 としては、 例えばメチル基、 ェチル基、 n—プロピル基、 i _プロピル基、 n— ブチル基、 i—ブチル基、 s e c—ブチル基、 t e r t—ブチル基、 n—ペンチ ル基、 s e c—ペンチル基、 t e r t—ァミル基、 n—へキシル基、 1， 2—ジ メチル—プチル基等が挙げられ、 メチル基、 ェチル基、 n_プロピル基、 n—ブ チル基、 t e r t—プチル基等の （C 1〜C4) アルキル基が好ましい。  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.
R 2における置換基を有する （C 1〜C6) アルキル基としては、 例えば （C 1〜C6) アルキルォキシ （C 1〜C6) アルキル基、 ァリール基で置換された (C 1〜C6) アルキル基、 窒素原子を有する複素環ォキシ基で置換された （C 1〜C 6) アルキル基、 窒素原子を有する複素環基で置換された （C 1〜C6) アルキル基等が挙げられる。  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.
(C 1〜C6) アルキルォキシ基及び置換基としての （C 1〜C6) アルキル ォキシ基としては、 例えば上記 （C 1〜C6) アルキル基と同様の基が結合した (C 1〜C6) アルキルォキシ基が挙げられ、 上記置換基としての（C 1〜C 6) アルキル基と同様の基が結合した （C 1〜C6) アルキルォキシ基が好ましい。 好ましいアルキルォキシ基としては、 具体的に例えばメトキシ基、 エトキシ基、 n—プロポキシ基、 イソプロボキシル基、 n—ブチルォキシ基、 t e r t—プチ ルォキシ基等の （C 1〜C4) アルキルォキシ基が挙げられる。 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.
ァリール基で置換された （C 1〜C 6) アルキル基におけるァリール基として は、 例えば置換基を有していてもよいフエニル基が挙げられ、 より好ましくは無 置換フエニル基である。 好ましいァリール （C 1〜C6) アルキル基としては、 例えばべンジル基、 フエネチル基、 フエニルプロピル基、 フエニルブチル基、 フ ェニルペンチル基、 フエ二ルへキシル基等が挙げられ、 フエニル置換 （C 1〜C 4) アルキル基がより好ましい。 特に好ましくは、 フエネチル基やフエニルプロ ピル基が挙げられる。  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.
複素環ォキシ基で置換された （C 1〜C 6) アルキル基における複素環ォキシ 基としてはへテロァリールォキシが好ましく、 例えばピリジルォキシ基、 ピリミ ジルォキシ基、 ピラジルォキシ基、 ピリダジルォキシ基、 フリルォキシ基、 ピロ リルォキシ基等が挙げられ、 窒素原子を有する複素環ォキシ基が好ましく、 ピリ ジルォキシ基等の窒素原子を有する 6員複素環ォキシ基が好ましい。  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.
複素環ォキシ基で置換された （C 1〜C6) アルキル基としては、 例えばピリ ジルォキシメチル基、 ピリジルォキシプロピル基、 ピリミジルォキシメチル基、 ピリミジルォキシプロピル基、 ビラジルォキシメチル基、 ビラジルォキシブチル 基、 ピリダジルォキシェチル基、 フリルォキシメチル基、 ピロリルォキシェチル 基等のへテロアリールォキシ （C 1〜C 6) アルキル基が挙げられ、 窒素原子を 有する 6員複素環ォキシ （C 1〜C6) アルキル基が好ましく、 ピリジルォキシ プロピル基等のピリジルォキシ （C 1〜C6) アルキル基が特に好ましい。 複素環基で置換された （C 1〜C6) アルキル基における複素環基としては、 例えばモルホリニル基、 ォキソジヒドロピリジニル基、 ピペリジニル基、 ピペラ ジニル基、ジォキサニル基等が挙げられ、 4_モルホリニル基、 2—ォキソ— 1， 2—ジヒドロピリジン— 1ーィル基が好ましく、 2—ォキソ— 1, 2—ジヒドロ ピリジン一 1—ィル基等のへテロ原子として窒素原子を有する 6員複素環基がよ り好ましい。  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.
複素環基で置換された （C 1〜C6) アルキル基としては、 例えば、 ピリジル メチル基、 ピリジルプロピル基、 ピリミジルメチル基、 ピリミジルプロピル基、 ビラジルメチル基、 ピラジルブチル基、 ピリダジルェチル基、 フリルメチル基、 ピロリルェチル基、 2—ォキソ一 1, 2—ジヒドロピリジン一 1一ィル—メチル 基等が挙げられ、 2—ォキソ— 1， 2—ジヒドロピリジン— 1—ィル—メチル基 が好ましい。 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.
R0、 R l、 D、 m、 R 2の好ましい組み合わせとしては、 作用の強さを考慮 すると、例えば R 0がフエニル基又は（C 1〜C 6)アルキルフエニル基であり、 R 1が水素原子、 （C 1〜C4) アルキルォキシカルボニル基、 （C1〜C6) ァ シル基、 フエニル （C 1〜C6) アルキルスルホニル基、 ピリジル（C 1〜C4) アルキルォキシカルポニル基、 フエニル （C 1〜C6) アルキルアミノスルホニ ル基又は （C 1〜C6) アルキル基であり、 Dが酸素原子又は— NH—であり、 mが 0又は 1であり、 R 2がピリジルォキシ （C 1〜C6) アルキル基である。  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.
R0、 R l、 D、 m、 R 2のより好ましい組み合わせとしては、 ヒトでの作用 を考慮すると、 R0がフエニル基であり、 R 1が （C 1〜C6) ァシル基又はフ ェニル（C 1〜C 6)アルキルアミノスルホニル基であり、 Dが— NH—であり、 mが 0であり、 R 2がピリジルォキシ （C 1〜C6) アルキル基である。  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.
R0、 R l、 D、 m、 R 2の更に好ましい組み合わせとしては、 経口吸収性を 考慮すると、 R0がフエニル基であり、 R 1がホルミル基、 ァセチル基又はベン ジルアミノスルホニル基であり、 Dが— NH—であり、 mが 0であり、 R2が 2 -ピリジルォキシプロピル基である。  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.
以下に、 本発明で使用される一般式 （I I) で表せる化合物の代表例を表 1に 具体的に示すが、 本発明はこれらの化合物に限定されない。 なお、 表 1中 Phは フエニル基を、 B o cは t e r t—ブトキシカルボニル基を、 Acはァセチル基 を、 Meはメチル基を意味する。 化合物番号 R0 R1 D m R2 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
Figure imgf000016_0001
Figure imgf000016_0001
Ph t-Boc NH OMe Ph H NH O e  Ph t-Boc NH OMe Ph H NH O e
Figure imgf000016_0002
Figure imgf000016_0002
14 Ph NH Me 化合物番号 R0 R1 D m R2 14 Ph NH Me Compound number R0 R1 D m R2
Figure imgf000017_0001
これらの化合物のうち、 より好ましいものとしては、 例えば No.3、 4、 8、 9、 10、 11、 15、 16、 17、 18、 19が挙げられ、 更に好ましいものとしては、 例えば No.10、 11、 15が挙げられ、特に No.10が挙げられる。上記から明らかなように、 一般式 （I ) で表される部分骨格構造を有し且つキマーゼ阻害活性を有する化合 物、 更に好ましくは一般式 （I I ) で表される化合物を心臓機能障害の治療 ·改 善剤又は予防剤、 特に血流障害に起因する心臓機能障害の治療 ·改善剤又は予防 剤に使用する点及び動脈瘤の治療剤又は予防剤に使用する点に本発明の特徴があ る。 本化合物を用いて心臓機能障害又は動脈瘤を治療する場合は、 罹患している 温血動物 （ヒトを含む） に本化合物を有効量投与すればよく、 又、 心臓機能障害 又は動脈瘤を予防する場合は高血圧等の病態危険因子を有する温血動物 （ヒトを 含む） に、 発病前に本化合物を有効量投与すればよい。
Figure imgf000017_0001
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.
本発明で使用される化合物は、 その薬理学上許容される塩であってもよく、 塩 基性化合物の場合は例えばカルボン酸、 スルホン酸、 鉱酸等との塩が、 酸性化合 物の場合は例えばアルカリ金属、 アルカリ土類金属、 有機塩基等との塩が挙げら れる。 カルボン酸、 スルホン酸、 鉱酸等としては、 例えば酢酸、 アジピン酸、 安 息香酸、 クェン酸、 フマール酸、 ァスパラギン酸、 乳酸、 リンゴ酸、 パリレミチン 酸、 サリチル酸、 酒石酸、 ベンゼンスルホン酸、 カンファースルホン酸、 トルェ ンスルホン酸、塩酸、臭化水素酸、硫酸、 リン酸等が挙げられる。アルカリ金属、 アルカリ土類金属、 有機塩基等としては、 例えばリチウム、 ナトリウム、 力リウ ム、 カルシウム、 マグネシウム、 バリウム、 テトラメチルアンモニゥム、 テトラ プチルアンモニゥム等が挙げられる。 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.
本発明で使用される化合物は光学活性体、 あるいはラセミ体、 ジァステレオマ 一、 あるいはジァステレオマーの混合物、 個々のェナンチォマーからェナンチォ マーの混合物までを全て包含するものである。 又、 置換基の結合位置等は特に限 定しない限り、結合可能な位置異性体すベてを含む。更に、水和物等の溶媒和物、 溶媒和物の互変異性体等のように様々な多型も本発明で使用される化合物に含ま れる。 本発明における上記一般式 （I I ) で表される一連の化合物群は、 国際公 開 WO 9 8 / 0 9 9 4 9号公報や国際公開 WO 9 9 / 4 1 2 7 7号公報において 開示された製造法によって製造されるが、 それらの方法に限定されるものではな い。  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.
又、 本発明は、 前記一般式 （I ) で表される部分骨格構造を有し且つキマ一ゼ 阻害活性を有する化合物を有効成分とする心臓機能障害又は動脈瘤の治療又は予 防用の経口医薬製剤である。 好ましい前記一般式 （I ) で表される部分骨格構造 を有し且つキマーゼ阻害活性を有する化合物としては、 前記一般式 （I I ) で表 される化合物が挙げられる。  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).
本発明においてキマーゼ阻害活性を有する化合物が用いられる場合は、 単独又 は賦影剤あるいは担体と混合して注射剤、 錠剤、 顆粒剤、 細粒剤、 散剤、 カプセ ル剤、 貼付剤、 軟膏剤、 スプレー剤、 溶液剤、 徐放剤等の製剤とし、 経口的に、 若しくは非経口的に直接患部に投与する等の方法があるが、経口投与が好ましい。 賦影剤又は担体等の添加剤としては薬剤学的に許容されるものが選ばれ、 その種 類及び組成は投与経路や投与方法によって決まる。 例えば注射剤の場合、 一般に 食塩、 グルコース、マンニトール等の糖類が望ましレ^経口剤の場合、でんぷん、 乳糖、 結晶セルロース、 ステアリン酸マグネシウム等が望ましい。  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.
投与は経口的に若しくは非経口的に全身性に投与される他、 カテーテル等を用 いたり手術中に体内の患部に直接投与する方法等、 患部に有効に化合物が到達し 作用する方法が選ばれるが、 特に経口投与が好ましい。 製剤中における本化合物 の含量は製剤により種々異なるが通常 0. 1〜100重量％、 好ましくは 1〜9 8重量％である。 例えば注射剤の場合には、 通常 0. 1〜30重量％、 好ましく は 1〜10重量％の有効成分を含むようにすることがよい。 経口剤の場合には、 添加剤とともに錠剤、 カプセル剤、 散剤、 顆粒剤、 液剤、 ドライシロップ剤等の 形態で用いられる。 カプセル剤、 錠剤、 顆粒、 散剤は一般に 5〜100重量％、 好ましくは 15〜99重量％、 更に好ましくは 20〜98重量％の有効成分を含 む。 残部は医薬用添加剤である。 投与量は、 患者の年令、 体重、 症状等により決 定されるが、 治療量は一般に、 非経口投与で 1〜1 O OmgZkg · 日、 経口投 与で 5〜500mg kg ' 日である。 溶液で用いる場合は、 1 0〜： L 000 n Mの濃度で用いる。 本発明で使用する化合物は低毒性であり、 又、 いずれの化合 物も連続投与による毒性の蓄積性が小さいことが特徴的である。 例えば、 本化合 物をラッ卜に lmgZk gの投与量で 1日 1回、 4週間経口投与しても何ら毒性 の徴候はみられず、 又、 2— (5—ホルミルアミノー 6_ォキソ—2—フエエル — 1— 6—ジヒドロピリミジン一 1—ィル） 一 N— [2, 3—ジォキソ一 1—フ ェニルメチルー 6— (2—ピリジルォキシ）] へキシルァセ夕ミド （化合物 No. 10) の化合物をラットに 10 OmgZkgの投与量で 1日 1回、 2週間経口投 与しても何ら毒性の徴候はみられなかった。 実施例 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
以下に本発明を実施例にて更に詳しく説明するが、 本発明はこれらに限定され るものではない.  Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
実施例 1 ハムスター心筋梗塞後の生存率に対するキマーゼ阻害化合物の効果 (A) 方法 Example 1 Effect of chymase inhibitor on survival rate after hamster myocardial infarction (A) Method
日本 SLCより購入した雄ハムスター （6週齢） をペントバルビタール 35m gZkg腹腔内投与により麻酔を施した後に開胸し、 左冠動脈を結紮して胸部を 縫合し心筋梗塞モデルとした。 覚醒後は通常飼育し、 ハムスターの生存率を観察 した。 冠動脈結紮 3日前より化合物投与群には 0. 5%カルボキシメチルセル口 ースに懸濁した 2— (5—ホルミルァミノ— 6_ォキソ—2—フエニル— 1, 6 —ジヒドロピリミジン _ 1一ィル） 一 N— [2, 3—ジォキソ一 1—フエニルメ チル— 6— （2—ピリジルォキシ）] へキシルァセタミド （化合物 No.10) 30m g/kgを 1日 1回ゾンデにより経口投与した。対照群には同量の水を投与した。 (B) 結果 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
化合物 No.10又は水投与による梗塞後 14日までの生存ハムスター数の変化を 第 1図に示した。 水のみ投与の対照群では 18匹中 1 1匹が死亡したが、 化合物 No.10の投与群では死亡は 17匹中 3匹のみであった。 即ち、 水のみの経口投与 による対象群では 61. 1%であった梗塞 14日後の死亡率が、 化合物 No.10の 投与群では 17. 6%にまで有意に低下し、 心臓機能障害が改善された。 実施例 2 ハムスター梗塞心における化合物の心筋保護作用  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
実施例 1で死亡率の改善を認めたが、 本発明化合物が心筋保護作用を有するか 梗塞心臓を用いて、 その機能を調べた。  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) 方法  (A) Method
実施例 1と同様に左冠動脈を結紮した。 同様に梗塞 3日前より 30mg/kg の化合物 No.10又は水を連日経口投与した。梗塞 3日後麻酔下にハムスター類動 脈に力ニューレを挿入し、 圧測定用アンプにて血圧 （MABP) を測定した。 そ の後、 人工呼吸下で開胸し、 心尖部よりカテーテルを左心室へ挿入し、 圧トラン スデューサ一にて左室収縮期圧 （LVSP) 及び左室拡張末期圧 （LVEDP) を測定し、 微分ユニット装置にて +dP d t (左室圧の収縮変化速度） 及び一 dP/d t (左室圧の拡張変化速度） を測定した。 心拍数 （HR) は左心室圧の 脈波により心拍計にて測定した。  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) 結果  (B) Result
表 2 梗塞 3日後のハムスター心臓機能に対する経口投与された化合物 No.10の 作用 Table 2.Effect of orally administered Compound No. 10 on hamster heart function 3 days after infarction
対照群 （水投与群） 化合物投与群 正常心臓 **  Control group (water administration group) Compound administration group Normal heart **
— dP/dt 1440 ±189 2080 ±200 3100士 234 mmHg/s) — DP / dt 1440 ± 189 2080 ± 200 3100 234 mmHg / s)
+ dP/dt 1960 ±180 2960±715* 4330±141 (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 LVEDP 5.5 ± 1.5 3.9 ± 1.4 * 4.33 ± 0.558
(mmHg) (mmHg)
LVSP 82.5±6.29 115±5.59 150±6.45 LVSP 82.5 ± 6.29 115 ± 5.59 150 ± 6.45
(mmHg) (mmHg)
MABP 87·5±3.77 95.8土 4.38 112土 3.70 MABP 87.5 ± 3.77 95.8 Sat 4.38 112 Sat 3.70
(mmHg) (mmHg)
HR 325±11.5 360±17.2 423 ±24.6 HR 325 ± 11.5 360 ± 17.2 423 ± 24.6
(beats/min) 梗塞対照群に対して有意に機能を改善した （P<0. 05) (beats / min) Significantly improved function compared to infarct control group (P <0. 05)
比較対照として別実験で測定した正常心臓の値を示す 実験結果が示す通り、 キマーゼ阻害化合物の投与によりハムスターの心臓は、 心筋梗塞によるダメージを免れ正常に近い状態で機能することが明らかとなった。 実施例 1及び 2から、 キマーゼ阻害化合物の投与によりハムスター心筋梗塞後 の死亡率が有意に改善されたことは顕著であり、 キマーゼ阻害化合物が心筋梗塞 による心臓血管障害に起因する心臓機能障害の抑制及びその予後改善と心不全へ の病態進行阻止に有用であることが示された。 実施例 3 ハムスター大動脈瘤モデルによる試験  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) 方法  (A) Method
Or i g u c h iらの方法（I n t. Ang i o l ., 17, 1 13— 1 19 (1 998)) を参考にしてハムスターで大動脈瘤モデルを作成した。即ち、 20週齢 の雄性ハムスターを開腹し、 腹部大動脈周囲にエラスターゼ （20 OUZm l) を浸透させたガーゼを 20分間放置した。 ガーゼを摘出した後に腹部を縫合し、 2週間飼育し、 再度開腹して大動脈を摘出した。 エラス夕ーゼ無処置群には生理 食塩液を浸透させたガーゼで 20分間同様に処置した。 この系において、 エラス 夕ーゼ処理 3日前から血管摘出前日まで、 2— (5_ホルミルアミノー 6—ォキ ソ— 2—フエニル— 1, 6—ジヒドロピリミジン一 1—ィル） — N— [2, 3— ジォキソ— 1—フエ二ルメチルー 6 - (2 _ピリジルォキシ）]へキシルァセタミ ド （化合物 No.10) 30111 の0. 1%メチルセルロース （1ml) 懸濁液を 3 Omg/kgの投与量で一日一回連続経口投与した。 エラス夕ーゼ無処置群およ び対照群には 0. 1 %メチルセルロースのみを同期間一日一回連続経口投与した。 エラス夕ーゼ又は生理食塩液を処理する際に大動脈径を測定し、 2週間後に再 度大動脈径を測定した。 処理時の血管径に対する 2週間後の血管径を百分率で表 し、 これを動脈径肥大率とし動脈瘤の指標とした。 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.
又、 動脈全体の系だけでなく実際の血管壁の厚さを検討するため、 摘出した血 管より血管中膜の断面積を求め、その血管径に対する割合を次の式により求めた。 中膜比率 = (中膜面積） / (大動脈径） 2 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) 結果  (B) Result
表 3に示す通り、 エラス夕一ゼ処理により血管中膜は希薄化し、 その結果動脈 径は肥大していた。 これらの変化はエラス夕ーゼ無処置群に比べて有意であり、 エラス夕一ゼ処理により動脈瘤が形成されていた。 本化合物を連日経口投与した 群では、 本化合物を投与しない対照群と比べて、 これらの変化が有意に抑制され た （スチューデント t一検定により P<0. 05)。 これらの結果は、 本化合物の 経口投与が血管中膜の希薄化を抑制し動脈瘤の形成を抑制したことを示しており、 臨床における動脈瘤治療の効果を十分期待させるものである。  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.
表 3 血管肥大と中膜希薄の程度 Table 3 Degree of vascular hypertrophy and media thinning
動脈径肥大率 （％) 中膜比率  Arterial diameter hypertrophy rate (%) Media ratio
エラス夕ーゼ無処置 120 ± 2. 2 0. 165 ± 0 009Eras evening treatment 120 ± 2.2 0.165 ± 0 009
(5匹） (5)
エラスターゼ処理 183 ± 6. 6 0. 062±0. 006Elastase treatment 183 ± 6.6 0.062 ± 0.006
( 10匹） （対照群) (10 animals) (control group)
エラス夕ーゼ処理 Eras evening treatment
本化合物投与 154± 3. 6 0. 097土 0. 009Administration of this compound 154 ± 3.6 0.097 Sat 0.009
(12匹） 実施例 4 製剤例 (12) Example 4 Formulation example
50. Omgの 2— (5—ホルミルァミノ— 6_ォキソ—2—フエ二ルー 1, 6—ジヒドロピリミジン一 1—ィル） _N_ [2, 3—ジォキソ一 1一フエニル メチル—6— (2—ピリジルォキシ）] へキシルァセタミド （化合物 No.10) に対 して、低置換度ヒドロキシプロピルセルロース 80. Omg、乳糖 57. Omg、 ヒドロキシプロピルセルロース 2. Omgおよびステアリン酸マグネシウム 1. Omgの割合で混合し、 3号力プセルに封入して経口カプセル剤を得た。 産業上の利用可能性  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
本発明により、 ピリミドン骨格を含む部分構造を有し且つ生体内で高選択的に 又有効にキマーゼを阻害する化合物、 例えば一般式 （I I) で表される化合物又 はその薬理学上許容される塩を有効成分として用いる、 経口投与等により生体に 作用させ得る、 心臓の機能障害の治療 ·改善剤又は予防剤、 特に血流障害に起因 する心臓の機能障害の治療 ·改善剤又は予防剤、 及び動脈瘤の進展および破裂を 有効に抑制する治療 ·改善剤又は予防剤を提供する。  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

請 求 の 範 囲 The scope of the claims
Figure imgf000024_0001
Figure imgf000024_0001
で表される部分骨格構造を有し且つキマーゼ阻害活性を有する化合物又はその薬 理学上許容される塩を含有する心臓機能障害又は動脈瘤の治療剤又は予防剤。 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. 請求の範囲第 1項の化合物が、 一般式 （I I) 2. The compound according to claim 1 has the general formula (II)
Figure imgf000024_0002
Figure imgf000024_0002
[式中、 R0はァリール基を示し、 R 1は水素原子、 C 1〜C6のアルキル基、 C 1〜C6のァシル基、 単環芳香族基で置換されていてもよい （C 1〜C6) ァ ルキルォキシカルポニル基、 ァリール基で置換されていてもよい （C 1〜C6) アルキルスルホニル基、 ァリール基で置換されていてもよい （C 1〜C6) アル キルアミノスルホニル基、 又は飽和複素環力ルポ二ル基を示し、 Dは酸素原子又 は— NH—を示し、 mは 0〜 3のいずれかの整数を示す。 R 2は置換基を有して いてもよい （C 1〜C6) アルキル基又は置換基を有していてもよい （C 1〜C 6) アルキルォキシ基を示す。] [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. ]
で表される化合物である請求の範囲第 1項に記載の心臓機能障害又は動脈瘤の治 療剤又は予防剤。 2. The therapeutic or preventive agent for cardiac dysfunction or aneurysm according to claim 1, which is a compound represented by the formula:
3. 一般式 （I I) の R0におけるァリール基が、 置換基として （C 1~C6) アルキル基又はハロゲン原子を有していてもよいフエニル基であり、 R 1におけ る単環芳香族基で置換されていてもよい （C 1〜C6) アルキルォキシカルボ二 ル基が （C 1〜C6) アルキルォキシカルボニル基又はピリジル （C 1〜C6) アルキルォキシカルボニル基であり、 ァリール基で置換されていてもよい （C 1 〜C6) アルキルスルホニル基がフエニル基で置換された （C 1〜C6) アルキ ルスルホニル基であり、 ァリール基で置換されていてもよい （C 1〜C6) アル キルアミノスルホニル基がフエニル基で置換された （C 1〜C6) アルキルアミ ノスルホニル基であり、 飽和複素環カルボニル基が酸素原子を有する飽和複素環 カルポニル基であり、 R 2における置換基を有していてもよい （C 1〜C6) 7 ルキル基が（C 1〜C 6) アルキル基、 （C 1〜C 6) アルキルォキシ （C 1〜C 6) アルキル基、 ァリール基で置換された （C 1〜C6) アルキル基、 窒素原子 を有する複素環ォキシ基で置換された （C 1〜C6) アルキル基又は窒素原子を 有する複素環基で置換された （C 1〜C6) アルキル基である請求の範囲第 2項 に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。  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. R 1の飽和複素環カルポニル基における酸素原子を有する飽和複素環カルボ ニル基がテトラヒドロフロイル基であり、 R 2の置換基を有していてもよい （C 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
1〜C6) アルキル基におけるァリール基で置換された （C 1〜C6) アルキル 基がフエニル基で置換された （C 1〜C6) アルキル基であり、 窒素原子を有す る複素環ォキシ基で置換された （C 1〜C6) アルキル基が窒素原子を有する 6 員複素環ォキシ基で置換された （C 1〜C6) アルキル基であり、 窒素原子を有 する複素環基で置換された （C 1〜C6) アルキル基が窒素原子を有する 6員複 素環基で置換された （C 1〜C6) アルキル基である請求の範囲第 3項に記載の 心臓機能障害又は動脈瘤の治療剤又は予防剤。 (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. 一般式 （I I) における R 0がフエニル基又は （C 1〜C6) アルキルフエ ニル基であり、 R 1が水素原子、 （C 1〜C 6)アルキルォキシカルポニル基、 （C 1〜C6) ァシル基、 フエニル （C 1〜C6) アルキルスルホニル基、 ピリジル (C 1〜C6) アルキルォキシカルポニル基、 フエニル （C 1〜C6) アルキル アミノスルホニル基又は（C 1〜C 6)アルキル基であり、 mが 0又は 1であり、 R2がピリジルォキシ （C 1〜C6) アルキル基である請求の範囲第 2項に記載 の心臓機能障害又は動脈瘤の治療剤又は予防剤。 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. —般式 （I I) における R 0がフエニル基であり、 R 1が （C 1〜C6) ァ シル基又はフエニル （C 1〜C6) アルキルアミノスルホニル基であり、 Dがー NH—であり、 mが 0であり、 R 2がピリジルォキシ （C 1〜C6) アルキル基 である請求の範囲第 2項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。  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. R 1がホルミル基、 ァセチル基又はべンジルアミノスルホニル基であり、 R 2が 2—ピリジルォキシプロピル基である請求の範囲第 5項又は第 6項に記載の 心臓機能障害又は動脈瘤の治療剤又は予防剤。 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. 一般式 （I I) で表される化合物が、 2— (5—ホルミルアミノー 6—ォキ ソ一 2—フエニル一 1, 6—ジヒドロピリミジン一 1—ィル） 一 N— [2, 3 - ジォキソ— 1—フエ二ルメチルー 6—（2 _ピリジルォキシ）]へキシルァセタミ ド、 2— (5—ァセチルァミノ一 6—ォキソ _2_フエニル _ 1, 6—ジヒドロ ピリミジン— 1一ィル） — N— [2, 3—ジォキソ— 1 _フエニルメチル— 6— (2 _ピリジルォキシ）]へキシルァセタミド又は 2— (5—ベンジルアミノスル ホニルァミノ一 6—ォキソ _ 2 _フエ二ルー 1, 6—ジヒドロピリミジン一 1― ィル） — N— [2, 3—ジォキソ— 1—フエニルメチル— 6 _ (2—ピリジルォ キシ）]へキシルァセタミドである請求の範囲第 2項に記載の心臓機能障害又は動 脈瘤の治療剤又は予防剤。  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. 一般式 （I I) で表される化合物が、 2— (5—ホルミルアミノー 6—ォキ ソ一 2—フエ二ルー 1， 6—ジヒドロピリミジン一 1 Γル） 一 N— [2, 3— ジォキソ— 1—フエニルメチル— 6—（2—ピリジルォキシ）]へキシルァセタミ ドである請求の範囲第 2項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。 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. 心臓機能障害が血流障害に起因する心臓機能障害である請求の範囲第 1項 〜第 9項のいずれか 1項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。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. 心臓機能障害が、 狭心症、 心筋梗塞、 心肥大、 心不全である請求の範囲第 1項〜第 9項のいずれか 1項に記載の心臓機能障害又は動脈瘤の治療剤又は予防 剤。 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.
1 2 . 動脈瘤が腹部大動脈瘤である請求の範囲第 1項〜第 9項のいずれか 1項に 記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。  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.
1 3 . 請求の範囲第 1項〜第 1 2項のいずれか 1項に記載の心臓機能障害又は動 脈瘤の治療剤又は予防剤が、 経口製剤であることを特徴とする請求の範囲第 1項 〜第 1 2項のいずれか 1項に記載の心臓機能障害又は動脈瘤の治療剤又は予防剤。  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.
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