WO2003007964A1 - Remede ou agent preventif de cardiopathie ou d'anevrysme contenant un compose d'inhibition de la chymase - Google Patents

Remede ou agent preventif de cardiopathie ou d'anevrysme contenant un compose d'inhibition de la chymase 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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English (en)
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/ja
Priority claimed from JP2001300954A external-priority patent/JP2003104894A/ja
Application filed by Nippon Kayaku Kabushiki Kaisha filed Critical Nippon Kayaku Kabushiki Kaisha
Publication of WO2003007964A1 publication Critical patent/WO2003007964A1/fr

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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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Epidemiology (AREA)
  • Hospice & Palliative Care (AREA)
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Abstract

L'invention porte sur un remède ou un agent préventif de la cardiopathie ou de l'anévrysme contenant comme principe actif soit un composant ayant une structure squelettique partielle représentée par la formule générale (I) et ayant une activité d'inhibition de la chymase, soit un sel pharmaceutiquement acceptable du composé. Le médicament est caractérisé par son administration orale.
PCT/JP2002/007269 2001-07-18 2002-07-17 Remede ou agent preventif de cardiopathie ou d'anevrysme contenant un compose d'inhibition de la chymase WO2003007964A1 (fr)

Applications Claiming Priority (4)

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JP2001-218654 2001-07-18
JP2001218654A JP2003034649A (ja) 2001-07-18 2001-07-18 心臓機能障害の改善剤または予防剤
JP2001300954A JP2003104894A (ja) 2001-09-28 2001-09-28 動脈瘤治療剤または予防剤
JP2001-300954 2001-09-28

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WO2007139230A1 (fr) 2006-05-31 2007-12-06 Asubio Pharma Co., Ltd. Anneau hétérocycliques à 7 éléments, son procédé de production et ses utilisations pharmaceutiques
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
US8924578B2 (en) 2003-06-06 2014-12-30 Siemens Aktiengesellschaft Method for transmitting messages in an MMS-based communication system

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JPH1053579A (ja) * 1996-06-24 1998-02-24 Fujisawa Pharmaceut Co Ltd 新規アセトアミド化合物
WO1998009949A1 (fr) * 1996-09-06 1998-03-12 Nippon Kayaku Kabushiki Kaisha Nouveaux derives d'acetamide et inhibiteurs de protease
WO1998018794A1 (fr) * 1996-10-25 1998-05-07 Yoshitomi Pharmaceutical Industries, Ltd. Nouveaux composes d'amide heterocycliques et leur utilisation a des fins medicinales
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WO2000010605A2 (fr) * 1998-08-20 2000-03-02 Senju Pharmaceutical Co., Ltd. Prophylaxie ou remedes pour la perturbation circulatoire de l'oeil
WO2001032214A1 (fr) * 1999-11-01 2001-05-10 Suntory Limited Inhibiteurs diriges contre le depot de lipides dans les vaisseaux, contenant des substances inhibant la chymase
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8924578B2 (en) 2003-06-06 2014-12-30 Siemens Aktiengesellschaft Method for transmitting messages in an MMS-based communication system
US7888348B2 (en) 2004-12-02 2011-02-15 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
EP2463268A1 (fr) 2004-12-02 2012-06-13 Daiichi Sankyo Company, Limited Acides aromatiques aminométhyl-substitués comme intermédiaires pour la préparation de composés 1,4-diazépan-2,5-dione inhibant la chymase
US8507714B2 (en) 2004-12-02 2013-08-13 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof
WO2007139230A1 (fr) 2006-05-31 2007-12-06 Asubio Pharma Co., Ltd. Anneau hétérocycliques à 7 éléments, son procédé de production et ses utilisations pharmaceutiques
US8049006B2 (en) 2006-05-31 2011-11-01 Daiichi Sankyo Company, Limited 7-membered ring compound and method of production and pharmaceutical application thereof

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