WO2003106435A1 - Derives de la pyrimidin-4(3h)-one a cycles fusionnes, spn procede de preparation et ses utilisations - Google Patents

Derives de la pyrimidin-4(3h)-one a cycles fusionnes, spn procede de preparation et ses utilisations Download PDF

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WO2003106435A1
WO2003106435A1 PCT/JP2003/007677 JP0307677W WO03106435A1 WO 2003106435 A1 WO2003106435 A1 WO 2003106435A1 JP 0307677 W JP0307677 W JP 0307677W WO 03106435 A1 WO03106435 A1 WO 03106435A1
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group
ome
alkyl
ethyl
phenyl
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PCT/JP2003/007677
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Satoru Kaneko
Tsuyoshi Watanabe
Kozo Oda
Raju Mohan
Edwin J. Schweiger
Richard Martin
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Sankyo Company, Limited
X-Ceptor Therapeutics, Inc.
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Priority to AU2003238157A priority Critical patent/AU2003238157A1/en
Publication of WO2003106435A1 publication Critical patent/WO2003106435A1/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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof that exhibit excellent anti- arteriosclerotic and anti-inflammatory activity. This is due to the ability of said derivatives to improve lipid metabolism disorders and/or through their regulation of the production of inflammatory mediators, both being based on the ability of these derivatives to regulate liver X receptors (LXR).
  • LXR liver X receptors
  • the present invention further relates to pharmaceutical compositions comprising fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, preferably pharmaceutical compositions for the treatment and/or prevention of arteriosclerosis including that derived from the diseases described below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines such as chronic rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, septicaemia, psoriasis and osteoporosis, autoimmune diseases such as systemic lupus erythematosus, ulcerative colits, and Crohn's disease, cardiovascular diseases such as ischemic heart diseases and cardiac failure, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications such as retinopathy, nephropathy, neuropathy and coronary diseases, obesity, nephritis, hepatit
  • the present invention further relates to the use of fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof in the preparation of pharmaceutical compositions, preferably pharmaceutical compositions for the treatment and/or prevention of the diseases described above.
  • the present invention further relates to a method for the treatment and/or prevention of diseases, preferably the diseases described above, which method comprises administering a pharmaceutically effective amount of a fused-ring pyrimidin-4(3H)-one derivative or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal, preferably a human.
  • the present invention further relates to a process for the preparation of fused-ring pyrimidin-4(3H)-one derivative or a pharmacologically acceptable salt or ester thereof.
  • Cardiovascular diseases including heart diseases, cerebrovascular diseases and renal diseases, caused by hypertension, hyperlipidemia and hyperglycemia, for example, are a major social problem in industrialized countries.
  • heart diseases, cerebrovascular diseases and renal diseases were second, third, and eighth respectively in the list of causes of death in 1999, and the mortality rates per 100,000 head of population caused by these diseases were 120.4, 110.8, and 14.1, respectively (Vital statistics of Japan 1999, volume 1; Health and Welfare Statistics Association).
  • anti-hypertensive agents In an attempt to treat and prevent these cardiovascular diseases, anti-hypertensive agents, anti-hyperlipidemic agents and anti-diabetic agents have been used for the treatment of hypertension, hyperlipidemia, and hyperglycemia respectively
  • ⁇ - and ⁇ - Blockers, diuretics, calcium antagonists, ACE inhibitors, A-II receptor antagonists and so forth have been clinically used as anti-hypertensive agents
  • HMG-CoA reductase inhibitors, anion exchange resins, probucol, fibrates and so forth have been clinically used for the treatment of hyperlipidemia
  • insulin, sulfonylureas, metformin, glitazones, and so forth have been clinically used as anti-diabetic agents.
  • a direct risk factor of vascular diseases such as cardiac diseases, cerebrovascular disorders and renal diseases is arteriosclerosis associated with hyperplasia of the arterial walls.
  • This hyperplasia is characterised by the formation of plaques due to accumulation of oxidized LDL-cholesterol (LDL-C) on the artery walls (Ross, R., Annu. Rev. Physiol., 1995, 57, 791-804: Steinberg, D., J. Biol. Chem., 1997, 272, 20963-20966).
  • LDL-C oxidized LDL-cholesterol
  • LXR nuclear receptor superfamily
  • the LXR has two kinds of isoform, LXR ⁇ and LXR ⁇ .
  • the highest levels of LXR ⁇ in mammals are found in the liver, with lower amounts found in the kidney, small intestine, spleen and adrenal gland.
  • LXR ⁇ has been found in most organs and tissues of the body.
  • Transcriptional activity of LXR has been shown to be regulated by oxidized sterols in macrophages located in the vessel walls.
  • LXR induces expression of ATP Binding Cassette Transporter- 1 (ABCA1) and Apolipoprotein E (ApoE), which facilitates cellular cholesterol efflux from vessel walls and reverse cholesterol transport to the liver. Furthermore, LXR also induces expression of ABCA1 in the small intestine, which reduces absorption of cholesterol. Additionally, LXR ⁇ is a transcription factor in the liver which regulates expression of Cytochrome P450 7A (CYP7A), the rate-limiting enzyme for synthesis of bile acid from cholesterol, which facilitates catabolism of cholesterol to bile acid and bile acid excretion.
  • CYP7A Cytochrome P450 7A
  • medicaments that modulate LXRs may be expected to be useful in the treatment and/or prevention of arteriosclerosis, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia and/or lipid-related diseases.
  • Atherosclerosis is also regarded as a chronic inflammatory disease (Ross, R., N. Engl. J. Med., 1986, 314, 488-500). Recently it has been reported that LXR also plays an important role in controlling immune function by regulating expression of inflammatory mediators such as nitric oxide synthase, cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6) (Mangelsdorf, D. J., Tontonoz, P. et. al., Nat. Med., 2003, 9, 213-219). Thus LXR ligands may be expected to suppress initiation and progression of arteriosclerosis due to their anti-inflammatory effects in addition to improvement of lipid metabolism.
  • COX-2 cyclooxygenase-2
  • IL-6 interleukin-6
  • LXR modulators can reduce chemically induced dermatitis in animal model (Fowler, A. J. et. al., J. Invest. Dermatol, 2003, 120, 246-255). Therefore LXR modulators are expected to be useful in the treatment of a wide variety of inflammatory diseases.
  • the inventors have conducted an investigation on the synthesis and pharmacological activities of fused-ring pyrimidin-4(3H)-one compounds in order to discover compounds that exhibit excellent binding affinity against LXR. As a result, it has been found that the compounds of formula (I) described below exhibit excellent binding affinity against LXR and the present invention has thus been completed.
  • the present invention provides fused-ring pyrimidin-4(3H)-one derivatives and pharmacologically acceptable salts and esters thereof that exert excellent anti- arteriosclerotic and anti-inflammatory activity due to their ability to improve lipid metabolism disorders and/or through their regulation of the production of inflammatory mediators, both effects being based on the ability of these derivatives to regulate the nuclear receptor, liver X receptors (LXR).
  • LXR liver X receptors
  • the present invention further provides pharmaceutical compositions comprising fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof as an active ingredient, preferably pharmaceutical compositions for the treatment and/or prevention of arteriosclerosis including that derived from the diseases described below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines such as chronic rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, septicaemia, psoriasis and osteoporosis, autoimmune diseases such as systemic lupus erythematosus, ulcerative colits, and Crohn's disease, cardiovascular diseases such as ischemic heart diseases and cardiac failure, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications such as retinopathy, nephropathy, neuropathy and coronary diseases, obesity, nephritis, hepatitis,
  • the present invention further provides the use of fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof in the preparation of pharmaceutical compositions, preferably pharmaceutical compositions for the treatment and/or prevention of the diseases described above.
  • the present invention further provides a method for the treatment and/or prevention of diseases, preferably the diseases described above, which method comprises administering a pharmaceutically effective amount of a fused-ring pyrimidin-4(3H)-one derivative or a pharmacologically acceptable salt or ester thereof to a warm-blooded animal, preferably a human.
  • the present invention further provides a process for the preparation of fused-ring pyrimidin-4(3H)-one derivatives or pharmacologically acceptable salts or esters thereof.
  • A represents a C 6 -C ⁇ 4 aryl group or a 5- to 7-membered heteroaryl group
  • R 1 , R 2 and R 3 are the same or different and each represents a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a halogen atom, a carboxy group, a carbamoyl group, a mercapto group, a C ⁇ -C 6 alkyl group, a C ⁇ -C 6 alkyl group substituted with from 1 to 7 halogen atoms, a C 2 -C 7 alkylcarbonyloxy group, a Cj-C ⁇ alkoxy group, a Ci-C ⁇ alkylthio group, a C ⁇ -C 6 alkylsulfinyl group, a C ⁇ -C 6 alkylsulfonyl group, a C ⁇ -C 6 alkylamino group, a di(C ⁇ -C 6 alkyl)amino group (wherein the alkyl groups are the same or different), a C 2 -C alkylcarbonylamino group
  • R 4 and R 5 are the same or different and each represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a mercapto group, a C ⁇ -C 6 alkyl group, a C ⁇ -C 6 alkyl group substituted with from 1 to 7 halogen atoms, a C ⁇ -C 6 alkoxy group, a C 2 -C alkoxycarbonyl group or a C ⁇ -C 6 alkylthio group;
  • X represents a hydrogen atom, a hydroxyl group, a halogen atom, a C ⁇ -C 6 alkoxy group or a C ⁇ -C 6 alkoxy group substituted with from 1 to 7 halogen atoms;
  • Y represents a C ⁇ -C 6 alkyl group, a C ⁇ -C 6 alkyl group substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined below), a C 3 -C ⁇ o cycloalkyl group, a C 3 -C ⁇ 0 cycloalkyl group substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined below), a 5- to 9-membered heterocyclyl group, a 5- to 9-membered heterocyclyl group substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined below), a C ⁇ -Cio aryl group, a C 6 -C ⁇ o aryl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined below), a C 4
  • a cycloalkylgroup that is substituted with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a haloalkylsulfonylammo group and is optionally further substituted with from 1 to 6 groups selected from substituents ⁇ ;
  • a cycloalkylalkyl group the alkyl moiety of which is substituted at the 1 -position thereof with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a haloalkylsulfonylammo group, said cycloalkylalkyl group optionally being further substituted with from 1 to 6 groups selected from substituents ⁇ ;
  • a heterocyclylalkyl group the alkyl moiety of which is substituted at the 1 -position thereof with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group or a haloalkylsulfonylammo group, said heterocyclylalkyl group optionally being further substituted with from 1 to 6 groups selected from substituents ⁇ ;
  • an aralkyl group the alkyl moiety of which is substituted at the 1 -position thereof with an amino group, an alkylamino group, a dialkylamino group, an alkylcarbonylamino group, an alkoxycarbonylammo group, an alkylsulfonylamino group, a haloalkylsulfonylammo group, an N-(alkylcarbonyl)-N-(alkyl)amino group, an N-
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a pharmacologically active compound together with a carrier or diluent therefor, wherein said pharmacologically active compound is a compound of formula (I) as defined above or a pharmacologically acceptable salt or ester thereof. More particularly, it provides such a composition for the treatment and/or prevention in a warm-blooded animal, which may be human of a disease that is treatable and/or preventable by the modulation of LXR function in said warm-blooded animal.
  • said composition is for the treatment and/or prevention in a warm-blooded animal, which may be human of a disease selected from the group consisting of arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • said composition is for the treatment and/or prevention in a warmblooded animal, which may be human of a disease selected from the group consisting of arteriosclerosis, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines and diabetes mellitus. Most preferably, said composition is for the treatment and/or prevention in a warm-blooded animal, which may be human of arteriosclerosis.
  • the present invention further provides a compound of formula (I) as defined above or a pharmacologically acceptable salt or ester thereof for use as a medicament.
  • the present invention also provides the use of at least one compound of formula (I) as defined above or a pharmacologically acceptable salt or ester thereof in the manufacture of a medicament for the treatment and/or prevention in a warm-blooded animal, which may be human of a disease that is treatable and/or preventable by the modulation of LXR function in said warm-blooded animal.
  • said disease that is treatable and/or preventable by the modulation of LXR function in said warm-blooded animal is selected from the group consisting of arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • said disease is selected from the group consisting of arteriosclerosis, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines and diabetes mellitus. Most preferably, said disease is arteriosclerosis.
  • the present invention also provides a method for the treatment and/or prevention in a warm-blooded animal, which may be human of a disease that is treatable and/or preventable by the modulation of LXR function in said warm-blooded animal, which comprises administering to said warm-blooded animal an effective amount of a compound of formula (I) as defined above or a pharmacologically acceptable salt or ester thereof.
  • said disease that is treatable and/or preventable by the modulation of LXR function in said warm-blooded animal is selected from the group consisting of arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid- related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • arteriosclerosis including that derived from the diseases defined below, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid- related diseases, inflammatory diseases mediated by inflammatory cytokines, autoimmune diseases, cardiovascular diseases, cerebrovascular diseases, renal diseases, diabetes mellitus, diabetic complications, obesity, nephritis, hepatitis, cancer and Alzheimer's disease.
  • said disease is selected from the group consisting of arteriosclerosis, atherosclerosis, arteriosclerosis derived from diabetes mellitus, hyperlipidemia, lipid-related diseases, inflammatory diseases mediated by inflammatory cytokines and diabetes mellitus. Most preferably, said disease is arteriosclerosis.
  • a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmacologically acceptable salt or ester thereof and at least one pharmaceutically active agent selected from the group consisting of HMG-CoA reductase inhibitors, ACAT inhibitors, angiotensin II inhibitors and diuretic agents, together with a carrier or diluent therefor.
  • said pharmaceutically active agent is a HMG-CoA reductase inhibitor.
  • Preferred classes of compounds of the present invention are those compounds of formula (I) and pharmacologically acceptable salts and esters thereof wherein:
  • R 1 , R 2 and R 3 are the same or different and each is a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a carboxy group, a carbamoyl group, a C 1 -C 4 alkyl group, a C ⁇ -C alkyl group substituted with from 1 to 5 halogen atoms, a Cj-C alkoxy group, a Cj-C 4 alkylthio group, a C ⁇ -C alkylamino group, a di(C ⁇ -C 4 alkyl)amino group (wherein the alkyl groups are the same or different), a C 2 -C alkylcarbonylamino group, an N-(C -C alkylcarbonyl)-N-(C ⁇ -C 4 alkyl)amino group, a C 2 -C 5 alkoxycarbonyl group
  • R 1 , R 2 and R 3 are the same or different and each is a hydrogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a fluorine atom, a chlorine atom, a bromine atom, a carboxy group, a carbamoyl group, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a pentafluoroethyl group, a methoxy group, an ethoxy group, an isopropoxy group, a methylthio group, an ethylthio group, an isopropylthio group, a methylamino group, a dimethylamino group, an acetylamino group, an N-methylacetylamino group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylcarbamoyl group, or a dimethyl carb
  • R 1 , R 2 and R 3 are the same or different and each is a hydrogen atom, a hydroxyl group, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or an acetylamino group, or R 1 and R 2 may be taken together to form a methylenedioxy group;
  • R 3 is a hydrogen atom
  • R 4 and R 5 are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a Cj-C 4 alkyl group, a C ⁇ -C 4 alkyl group substituted with from 1 to 5 halogen atoms, a C ⁇ -C 4 alkoxy group, a C 2 -C 5 alkoxycarbonyl group, or a C ⁇ -C 4 alkylthio group;
  • R 4 and R 5 are the same or different and each is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, a methylthio group or an ethylthio group;
  • R 4 and R 5 are the same or different and each is a hydrogen atom, a chlorine atom, a methyl group or a methoxy group;
  • each of R 4 and R 5 is a hydrogen atom
  • X is a hydrogen atom, a hydroxyl group, a C ⁇ -C 4 alkoxy group, or a C]-C 4 alkoxy group substituted with from 1 to 5 halogen atoms;
  • X is a hydrogen atom, a hydroxyl group, a methoxy group or a trifluoromethyloxy group
  • X is a hydroxyl group
  • Y is a C ⁇ -C 6 alkyl group or a Cj-C 4 alkyl group substituted with from 1 to 5 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined above);
  • Y is a C ⁇ -C 5 alkyl group or a C]-C 3 alkyl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ocl defined below);
  • Y is an ethyl group, a propyl group, a butyl group, an isopropyl group, a sec- butyl group, a 3 -pentyl group, a trifluoromethyl group, a dichloromethyl group, a 1- bromoethyl group, a 1-chloroethyl group, a diethylaminomethyl group or a diisopropylamino methyl group;
  • Y is a C 3 -C 6 cycloalkyl group or a 5- to 9-membered heterocyclyl group
  • Y is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a piperidyl group, a perhydroazepinyl group or a perhydroazocinyl group;
  • Y is a C 6 -C ⁇ o aryl group or a C 6 -C ⁇ o aryl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ⁇ l defined below);
  • Y is a phenyl group, a 1-naphthyl group or a 2-naphthyl group;
  • Y is a C 4 -C ⁇ 3 cycloalkylalkyl group, a C 4 -C ⁇ 3 cycloalkylalkyl group substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined above), a (5- to 9-membered heterocyclyl)- (C ⁇ -C 3 alkyl) group or a (5- to 9-membered heterocyclyl)-(C ⁇ -C 3 alkyl) group substituted with from 1 to 7 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined above);
  • Y is a (C 3 -C ⁇ o cycloalkyl)methyl group or a (5- to 9-membered heterocyclyl)mefhyl group;
  • Y is a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, a 2-thienylmethyl group, a 1 -pyrrolidinylmethyl group, a 1- piperidylmethyl group or a 1-perhydroazepinylmethyl group;
  • Y is a C -C ⁇ 4 aralkyl group or a C -C ⁇ 4 aralkyl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ⁇ defined above);
  • Y is a (C 6 -C ⁇ o aryl)methyl group, a (C 6 -C ⁇ o aryl)ethyl group, a (C 6 -C ⁇ o aryl)methyl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ⁇ l defined below) or a (C 6 -C ⁇ o aryl)ethyl group substituted with from 1 to 4 substituents (said substituents are the same or different and are selected from substituent group ⁇ l defined below);
  • Y is a benzyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group or a benzyl group which is substituted with from 1 to 4 substituents on the phenyl moiety (said substituents are the same or different and are selected from substituent group ⁇ 2 defined below);
  • A is a phenyl group, a naphthyl group or a pyridyl group
  • A is a phenyl group; wherein substituent group ⁇ l represents a group consisting of a halogen atom, an amino group, a C ⁇ -C 6 alkylamino group and a di(C ⁇ -C 6 alkyl)amino group (wherein the alkyl groups are the same or different); substituent group ⁇ l represents a group consisting of a fluorine atom, a chlorine atom, a bromine atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec- butyl group, a tert-butyl group, a trifluoromethyl group, a pentafluoroethyl group, an acetyloxy group, a propionyloxy group, a methoxy group, an ethoxy group, an is
  • R 1 , R 2 and R 3 selected from (1) to (3), R 3 selected from (4), R 4 and R 5 selected from (5) to (8), X selected from (9) to (11), Y selected from (12) to (24), and A selected from (25) to (26) are also preferred.
  • the "halogen atom" in the definitions of R , R , R 3 , R 4 , R 5 , X, substituent group ⁇ and substituent group ⁇ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and preferably it is a fluorine atom or a chlorine atom.
  • C 6 -C ⁇ 4 aryl group in the definition of A in formula (I) is an aromatic hydrocarbon group having from 6 to 14 carbon atoms and may be, for example, a phenyl, indenyl, naphthyl, phenanthryl or anthryl group; and preferably it is a phenyl group.
  • the "5- to 7-membered heteroaryl group" in the definition of A in formula (I) is a 5- to 7-membered heteroaromatic group containing from 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may be, for example, a furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyradinyl group; and preferably it is a pyridyl group.
  • the "Ci-Ce alkyl group” in the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , Y, substituent group ⁇ and substituent group ⁇ in formula (I) is a straight or branched chain alkyl group having from 1 to 6 carbon atoms and may be, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a t-pentyl group, a 1-methylbutyl group, a hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1-ethylbutyl group or a 2-ethylbut
  • the "C ⁇ -C 6 alkyl group substituted with from 1 to 7 halogen atoms" in the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and substituent group ⁇ in formula (I) is a C ⁇ -C 6 alkyl group as described above which is substituted with from 1 to 7 halogen atoms as described above and may be, for example, a trifluoromethyl group, a trichloromethyl group, a difluorome hyl group, a dichloromethyl group, a dibromomethyl group, a fluoromethyl group, a 2,2,2-trifluoroethyl group, a 2,2,2-trichloroethyl group, a 2- bro oethyl group, a 2-chloroethyl group, a 2-fluoroethyl group, a 2-iodoethyl group, a 3- chloropropyl group, a 4-fluorobutyl group
  • C 2 -C alkylcarbonyloxy group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is a carbonyloxy group (-COO-) the carbon atom of which is substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, a pentanoyloxy group or a hexanoyloxy group; it is preferably a C 2 -C 5 alkylcarbonyloxy group such as an acetyloxy group, a propionyloxy group, a butyryloxy group or an isobutyryloxy group; and more preferably it is an acetyloxy group.
  • C C 6 alkoxy group in the definitions of R 1 , R 2 , R 3 , R 4 .
  • R 5 , X, substituent group and substituent group ⁇ in formula (I) is a hydroxy group in which the hydrogen atom is substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group, an s-butoxy group, a tert-butoxy group, an n-pentyloxy group, an isopentyloxy group, a 2-methylbutoxy group, a neopentyloxy group, an n-hexyloxy group, a 4-methylpentyloxy group, a 3-methylpentyloxy group, a 2-methylpentyloxy group, a 3,3-dimethylbutoxy group, a 2,2-di
  • C ⁇ -C 6 alkylthio group in the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , substituent group and substituent group ⁇ in formula (I) is a mercapto group substituted with a - C_ alkyl group as described above and may be, for example, a methylthio group, an ethylthio group, an n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, an s-butylthio group, a tert-butylthio group, an n-pentylthio group, an isopentylthio group, a 2-methylbutylthio group, a neopentylthio group, a 1- ethylpropylthio group, an n-hexylthio group, an isohexylthio group, a 4-
  • the "Ci-C 6 alkylsulfinyl group" in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is a sulf ⁇ nyl group (-SO-) which is substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, a methanesulfinyl group, an ethanesulfinyl group, an n-propanesulfinyl group, an isopropanesulfinyl group, an n-butanesulfinyl group, an isobutanesulfinyl group, an s-butanesulfinyl group, a tert- butanesulfinyl group, an n-pentanesulfmyl group, an isopentanesulfinyl group, a 2- methylbutanesulfinyl group, a neopenta
  • C ⁇ -C 6 alkylsulfonyl group in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is a sulfonyl group (-SO -) substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, an isopropanesulfonyl group, an n- butanesulfonyl group, an isobutanesulfonyl group, an s-butanesulfonyl group, a tert- butanesulfonyl group, an n-pentanesulfonyl group, an isopentanesulfonyl group, a 2- methylbutanesulfonyl group, a neopentanesulfon
  • C ⁇ -C 6 alkylamino group in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is an amino group substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, an isobutylamino group, an s-butylamino group, a tert-butylamino group, an n-pentylamino group, an isopentylamino group, a 2-methylbutylamino group, a neopentylamino group, a 1-ethylpropylamino group, an n-hexylamino group, an isohexylamino group, a 4- methylpentylamino group
  • the "di(C ⁇ -C 6 alkyl)amino group" in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is an amino group substituted with two C ⁇ -C 6 alkyl groups as described above which may be the same or different and may be, for example, a dimethylamino group, a methylethylamino group, a diethylamino group, a di(n-propyl)amino group, a diisopropylamino group, an N-(n-propyl)-N-ethylamino group, a di(n-butyl)amino group, a diisobutylamino group, a di(s-butyl)amino group, a di(tert-butyl)amino group, a di(n-pentyl)amino group, a diisopentylamino group, a di
  • C 2 -C 7 alkylcarbonylamino group in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is a carbonylamino group (-CONH-) the carbon atom of which is substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a pentanoylamino group or a hexanoylamino group; preferably it is a C 2 -C 5 alkylcarbonylamino group such as an acetylamino group, a propionylamino group, a butyrylamino group or an isobutyrylamino group; and more preferably it is an acetylamino group.
  • N-(C 2 -C 7 alkylcarbonyl)-N-(C ⁇ -C6 alkyl)amino group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is an amino group substituted with a - C 6 alkyl group as described above and a C 2 -C 7 alkylcarbonyl group as described below and may be, for example, an acetyl(N-methyl)amino group, an acetyl(N-efhyl)amino group, an acetyl(N-propyl)amino group, an acetyl (N-butyl) amino group, an acetyl(N- pentyl)amino group, an acetyl(N-hexyl)amino group, a pro ⁇ ionyl(N-mefhy ⁇ )amino group, a propionyl(N-ethyl)amino
  • the "C 2 -C 7 alkoxycarbonylamino group" in the definition of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is a carbonylamino group (-CONH-) the carbon atom of which is substituted with a C ⁇ -C 6 alkoxy group as described above and may be, for example, a methoxycarbonylamino group, an ethoxycarbonylamino group, an n- propoxycarbonylamino group, an isopropoxycarbonylamino group, an n- butoxycarbonylamino group, an isobutoxycarbonylamino group, an s- butoxycarbonylamino group, a tert-butoxycarbonylamino group, an n- pentyloxycarbonylamino group, an isopentyloxycarbonylamino group, a 2- methylbutoxycarbonylamino group, a neopentyloxycarbonylamino group, an
  • N-(C 2 -C 7 alkoxycarbonyl)-N-(C]-C6 alkyl)amino group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is an amino group substituted with a Ci- C 6 alkyl group as described above and a C 2 -C 7 alkoxycarbonyl group as described below and may be, for example, a methoxycarbonyl(N-methyl)amino group, an ethyoxycarbonyl(N-methyl)amino group, an n-propoxycarbonyl(N-methyl)amino group, an isopropoxycarbonyl(N-methyl)amino group, an n-butoxycarbonyl(N-methyl)amino group, an isobutoxycarbonyl(N-methyl)amino group, an s-butoxycarbonyl(N- methyl)amino group, a tert-butoxycarbonyl(N-methyl)
  • the "Ci-C ⁇ alkylsulfonylamino group" in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is an amino group substituted with a C_- C 6 alkylsulfonyl group as described above and may be, for example, a methanesulfonylamino group, an ethanesulfonylamino group, an n-propanesulfonyl amino group, an isopropanesulfonylamino group, an n-butanesulf onyl amino group, an isobutanesulfonylamino group, an s-butanesulfonylamino group, a tert- butanesulfonylamino group, an n-pentanesulfonylamino group, an isopentanesulfonylamino group, a 2-methylbutanesulfony
  • N-(C ⁇ -C 6 alkylsulfonyl)-N-(C ⁇ -C6 alkyl)amino group in the definitions of R 1 , R , R and substituent group ⁇ in formula (I) is an ammo group substituted with a C ⁇ -C 6 alkyl group as described above and a C ⁇ -C 6 alkylsulfonyl group described above and may be, for example, a methanesulfonyl(N-methyl)amino group, a methanesulfonyl (N- ethyl)amino group, a methanesuIfonyl(N-pro ⁇ yl)amino group, an ethanesulfonyl(N- methyl)amino group, an n-propanesulfonyl(N-methyl)amino group, an isopropanesulfonyl(N-methyl)amino group, an n-butanesul
  • C ⁇ -C 6 haloalkylsulfonylammo group in the definitions of R 1 , R 2 , R 3 , substituent group ⁇ and substituent group ⁇ in formula (I) is a C ⁇ -C 6 alkylsulfonylamino group as described above the alkyl group of which is substituted with from 1 to 7 halogen atoms as described above and may be, for example, a trifluoromethanesulfonylamino group, a trichloromethanesulfonylamino group, a difluoromethanesulfonylamino group, a dichloromethanesulfonylamino group, a dibromomethanesulfonylamino group, a fluoromethanesulfonylamino group, a 2,2,2-trifluoroethanesulfonylamino group, a 2,2,2- trichloroethanesulfulf
  • N-(C ⁇ -C 6 haloalkylsulfonyl)-N-(C ⁇ -C6 alkyl)amino group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is an N-(C ⁇ -C 6 alkylsulfonyl)-N-(C ⁇ -C 6 alkyl)amino group as described above in which the alkylsulfonyl moiety is substituted with from 1 to 7 halogen atoms as described above and may be, for example, a trifluoromethanesulfonyl(N-methyl)amino group, a trifluoromethanesulfonyl(N- ethyl)amino group, a trifluoromethanesulfonyl(N-propyl)amino group, a trichloromethanesulfonyl(N-methyl)amino group, a difluoromethan
  • C -C 7 alkylcarbonyl group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is a carbonyl group (-CO-) substituted with a C ⁇ -C 6 alkyl group as described above and may be, for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pentanoyl group, a pivaloyl group, or a hexanoyl group; preferably it is a C 2 -C 5 alkylcarbonyl group such as an acetyl group, a propionyl group or a butyryl group; and more preferably it is an acetyl group.
  • C 2 -C 7 alkoxycarbonyl group in the definitions of R 1 , R 2 , R 3 , R 4 , R 5 and substituent group ⁇ in formula (I) is a carbonyl group (-CO-) substituted with a C ⁇ -C 6 alkoxy group as described above and may be, for example, a methoxycarbonyl group, an • ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, a n- butoxycarbonyl group, an isobutoxycarbonyl group, an s-butoxycarbonyl group, a tert- butoxycarbonyl group, an n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a 2-methylbutoxycarbonyl group, a neopentyloxycarbonyl group, an n-hexyloxycarbonyl group, a 4-methylpentyloxycarbonyl group,
  • C 2 -C 7 alkylaminocarbonyl group in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is a carbonyl group (-CO-) substituted with a C ⁇ -C 6 alkylamino group as described above and may be, for example, a methylaminocarbonyl group, an ethylaminocarbonyl group, an n-propylaminocarbonyl group, an isopropylaminocarbonyl group, an n-butylaminocarbonyl group, an isobutylaminocarbonyl group, an s-butylaminocarbonyl group, a tert-butylaminocarbonyl group, an n-pentylaminocarbonyl group, an isopentylaminocarbonyl group, a 2- methylbutylaminocarbonyl group, a neopentylaminocarbonyl group, a 1- e
  • the "di(C ⁇ -C 6 alkylaminocarbonyl group" in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is a carbonyl group (-CO-) substituted with a di(C ⁇ -C 6 alkyl)amino group wherein the alkyl groups may be the same or different as described above and may be, for example, a dimethylaminocarbonyl group, a methylethylaminocarbonyl group, a diethylaminocarbonyl group, a di(n- propyl)aminocarbonyl group, a diisopropylaminocarbonyl group, an N-(n-propyl)-N- ethylaminocarbonyl group, a di(n-butyl)aminocarbonyl group, a diisobutylaminocarbonyl group, a di(s-butyl)aminocarbonyl group, a di(
  • the "C 1 -C 4 alkylenedioxy group" in the definitions of R 1 , R 2 , R 3 and substituent group ⁇ in formula (I) is an alkylenedioxy group having from 1 to 4 carbon atoms and may be, for example, a methylenedioxy group, an ethyl ene- 1,2-dioxy group, a 1- methylmethylenedioxy group, a ropylene-l,3-dioxy group, a 1-methyl ethylene- 1,2- dioxy group, a 2-methylethylene-l,2-dioxy group, a 1-ethylmethylenedioxy group, a butylene-l,4-dioxy group, a 1-methylpropyl ene- 1,3 -dioxy group, a 2-methylpropylene- 1,3-dioxy group, a 3-methylpropylene-l,3-dioxy group, a l-ethylethylene-l,2-dioxy group, a 2-ethyl
  • the "Ci-C ⁇ alkoxy group substituted with from 1 to 7 halogen atoms" in the definitions of X, substituent group ⁇ and substituent group ⁇ in formula (I) is a Cj-Ce alkoxy group as described above substituted with from 1 to 7 halogen atoms as described above and may be, for example, a trifluoromethoxy group, a trichloromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a fluoromethoxy group, a 2,2,2-trifluoroethoxy group, a 2,2,2- trichloroethoxy group, a 2- bromoethoxy group, a 2-chloroethoxy group, a 2-fluoroethoxy group, a 2-iodoethoxy group, a 3-chloropropoxy group, a 4-fluorobutoxy group, a 6-iodohexyloxy group,
  • the "C 3 -C ⁇ o cycloalkyl group" in the definition of Y in formula (I) may be, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclohepthyl group, a norbornyl group or an adamantyl group; preferably it is a C 3 -C 6 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; and more preferably it is a cylcobutyl group or a cyclohexyl group.
  • the "5- to 9-membered heterocyclyl group" in the definition of Y in formula (I) is a 5- to 9-membered heterocyclic group containing from 1 to 4 atoms selected from a group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may be, for example, an unsaturated heterocyclic group such as a furyl group, a thienyl group, a pyrrolyl group, an azepinyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a 1,2,3-oxadiazolyl group, a triazolyl group, a tetrazolyl group, a thiadiazolyl group, a pyranyl group, a pyridyl group, a pyridazinyl group, a pyr
  • C 6 -C ⁇ o aryl group in the definitions of Y and substituent group ⁇ in formula (I) is an aromatic hydrocarbon group having from 6 to 10 carbon atoms and may be, for example, a phenyl group, an indenyl group, a naphthyl group, a phenanthryl group or an anthryl group; preferably it is a phenyl group or a naphthyl group; and more preferably it is a phenyl group.
  • C 4 -C ⁇ 4 cycloalkylalkyl group in the definition of Y in formula (I) is a C ⁇ -C alkyl group substituted with a C 3 -C ⁇ o cycloalkyl group as described above and may be, for example, a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylme hyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a cyclohexylpropyl group, a cyclohexylbutyl group, a cyclohepthylmethyl group, a norbornylmethyl group or an adamantylmethyl group; preferably it is a C 4 -C 8 cycloalkylalkyl group such as a cyclopropylmethyl group,
  • the "(5- to 9-membered-heterocyclyl)-(C ⁇ -C 4 alkyl) group” in the definition of Y in formula (I) is a C 1 -C 4 alkyl group substituted with a 5- to 9-membered heterocyclyl group as described above and may be, for example, a furylmethyl group, a thienylmethyl group, a pyrrolylmethyl group, an azepinylmethyl group, a pyrazolylmethyl group, an imidazolylmethyl group, an oxazolylmethyl group, an isoxazolylmethyl group, a thiazolylmethyl group, a thienylmethyl group, an isothiazolylmethyl group, an 1,2,3- oxadiazolylmethyl group, a triazolylmethyl group, a tetrazolylmethyl group, a thiadiazolylmethyl group, a pyranylmethyl group, a pyridylmethyl
  • C 7 -C ⁇ aralkyl group in the definition of Y in formula (I) is a C ⁇ -C 6 alkyl group as described above substituted with a C 6 aryl group or a C 1 -C 4 alkyl group substituted with a C 9 -C 10 aryl group and may be, for example, a benzyl group, an 1- naphthylmethyl group, a 2-naphthylmethyl group, an indenylmethyl group, a 1-phenethyl group, a 2-phenethyl group, a 1 -naphthyl ethyl group, a 2-naphthylethyl group, a 1- phenylpropyl group, a 2-phenylpropyl group, a 3-phenylpropyl group, a 1-naphthylpropyl group, a 2-naphthylpropyl group, a 3-naphthylpropyl
  • C 7 -C ⁇ 4 aralkyloxy group in the definition of substituent group ⁇ in formula (I) is a hydroxy group substituted with a C 7 -C ⁇ 4 aralkyl group as described above and may be, for example, a benzyloxy group, an 1 -naphthylmethyloxy group, a 2- naphthylmethyloxy group, an indenylmethyloxy group, a 1- ⁇ henethyloxy group, a 2- phenethyloxy group, a 1 -naphthyl ethyl oxy group, a 2-naphthyl ethyloxy group, a 1- phenylpropyloxy group, a 2-phenylpropyl oxy group, a 3-phenylpropyloxy group, a 1- naphthylpropyloxy group, a 2-naphthylpropyl oxy group, a 3-naphthylpropyloxy group
  • the compound of formula (I) of the present invention or a pharmacologically acceptable ester thereof has a basic group
  • the compound can be converted to a salt by reacting it with an acid
  • the compound of formula (I) of the present invention or a pharmacologically acceptable ester thereof has an acidic group
  • the compound can be converted to a salt by reacting it with a base.
  • the compounds of the present invention encompass such salts. Where said salts are to be used for a therapeutic use, they must be pharmacologically acceptable.
  • Preferred examples of the salts formed with a basic group present in the compound of formula (I) of the present invention include inorganic acid salts such as hydrohalogenated acid salts (e.g. hydro chlorides, hydrobromides and hydroiodides), nitrates, perchlorates, sulfates and phosphates; organic acid salts such as C ⁇ -C 6 alkanesulfonates optionally substituted with fluorine atoms in which the C]-C 6 alkyl moiety thereof is as defined above (e.g.
  • Preferred example of the salts formed with an acidic group present in the compound of formula (I) of the present invention include metal salts such as alkali metal salts (e.g. sodium salts, potassium salts and lithium salts), alkali earth metal salts (e.g. calcium salts and magnesium salts), aluminum salts, iron salts, zinc salts, cupper salts, nickel salts, and cobalt salts; amine salts such as inorganic amine salts (e.g. ammonium salts) and organic amine salts (e.g.
  • t-octylamine salts dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycinealkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamme salts, N,N'- dibenzylefhylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzylphenethylamine salts, piperazine salts, tetramethylammonium salts and tris(hydroxymethyl)aminomethane salts); and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates and aspartates. Alkali metal salts are particularly preferred.
  • the compounds of formula (I) and pharmacologically acceptable salts and esters thereof of the present invention can sometimes take up water upon exposure to the atmosphere or when recrystallized to absorb water or to form a hydrate and such hydrates are also included within the scope of the present invention. Additionally, certain other solvents may be taken up by the compounds of the present invention to produce solvates, which also form a part of the present invention.
  • the compounds of formula (I) of the present invention sometimes contain one or more asymmetric centres, and can therefore form optical isomers (including diastereoisomers).
  • each of said isomers and mixture of said isomers are depicted by a single formula, i.e. the formula (I). Accordingly, the present invention covers both the individual isomers and mixtures thereof in any proportion, including racemic mixtures.
  • esters of the compounds of formula (I) are compounds of formula (I) in which a hydroxyl group or a carboxy group of said compound of formula (I) is modified by the addition of a protecting group using conventional techniques well-known in the art (see, for example, "Protective Groups in Organic Synthesis, Second Edition", Theodora W. Greene and Peter G.M. Wuts, 1991, John Wiley & Sons, Inc.).
  • this protecting group there is no particular restriction on the nature of this protecting group, provided that, where the ester is intended for therapeutic purposes, it must be pharmacologically acceptable, i.e. the protecting group must be capable of being removed by a metabolic process (e.g. hydrolysis) on administration of said compound to the body of a live mammal to give a compound of formula (I) or a salt thereof.
  • the pharmacologically acceptable esters are pro-drugs of the compounds of formula (I) of the present invention.
  • the ester of the compound of formula (I) of the present invention is intended for non-therapeutic purposes (e.g. as an intermediate in the preparation of other compounds), then the requirement that said ester is pharmacologically acceptable does not apply.
  • an ester of a compound of formula (I) of the present invention is pharmacologically acceptable can be easily determined.
  • the compound under investigation is intravenously administered to an experimental animal such as a rat or mouse and the body fluids of the animal are thereafter studied. If a compound of formula (I) or a pharmacologically acceptable salt thereof can be detected in the body fluids, the compound under investigation is judged to be a pharmacologically acceptable ester.
  • the compounds of formula (I) of the present invention can be converted to an ester, examples of which include a compound of formula (I) in which a hydroxyl group present therein is esterified.
  • the ester residue may be a general protecting group where the esterified compound is to be used as an intermediate or a protecting group which is capable of being removed by a metabolic process (e.g. hydrolysis) in vivo where the esterified compound is one which is pharmacologically acceptable.
  • the general ester protecting group referred to above is an ester protecting group which is removable by a chemical process such as hydrolysis, hydrogenolysis, electrolysis or photolysis.
  • Preferred examples of such a general protecting group used to synthesise a compound of formula (I) in which a hydroxyl residue therein is modified include the following: (i) aliphatic acyl groups, examples of which include alkylcarbonyl groups having from 1 to 25 carbon atoms, examples of which include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methyl- penta
  • (C ⁇ -C 6 alkoxy)methyl groups which comprise a methyl group which is substituted with a C ⁇ -C 6 alkoxy group as defined above, examples of which include methoxymethyl, 1,1-dimethy 1-1 -methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl groups,
  • C ⁇ -C 6 alkoxylated (C ⁇ -C 6 alkoxy)methyl groups which comprise a (C ⁇ -C 6 alkoxy)mefhyl group as defined above in which the alkoxy moiety thereof is substituted with a Ci-C ⁇ alkoxy group as defined above, examples of which include 2- methoxyethoxymethyl groups, and halogeno (C ⁇ -C 6 alkoxy)methyl groups which comprise a (C ⁇ -C 6 alkoxy)methyl group as defined above in which the alkoxy moiety thereof is substituted with at least one halogen atom, examples of which include 2,2,2-trichloroethoxymethyl and bis(2- chloroethoxy)methyl groups; (viii) substituted ethyl groups, examples of which include
  • C ⁇ -C 6 alkoxylated ethyl groups which comprise an ethyl group which is substituted with a C ⁇ -C 6 alkoxy group as defined above, examples of which include 1-ethoxyethyl and 1 -(isopropoxy)ethyl groups, and halogenated ethyl groups such as 2,2,2-trichloroethyl groups; (ix) aralkyl groups as define above, examples of which include
  • C ⁇ -C 6 alkyl groups as defined above which are substituted with from Lto 3 aryl groups as defined above, examples of which include benzyl, 1 -naphthylmethyl, 2- naphthylmethyl, diphenylmethyl, triphenylmethyl, 1 -naphthyldiphenylmethyl and 9- anthrylmethyl groups, and
  • C ⁇ -C 6 alkyl groups as defined above which are substituted with from 1 to 3 aryl groups as defined above in which said aryl moiety is substituted with at least one substituent selected from the group consisting of C ⁇ -C 6 alkyl groups as defined above, C ⁇ -C 6 alkoxy groups as defined above, nitro groups, halogen atoms and cyano groups, examples of which include 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl- benzyl, 4-methoxybenzyl, 4-methoxyphenydiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl and 4-cyanobenzyl groups;
  • alkenyloxycarbonyl groups which comprise a carbonyl group which is substituted with an alkenyloxy group having from 2 to 6 carbon atoms, examples of which include vinyloxycarbonyl and allyloxycarbonyl groups;
  • aralkyloxycarbonyl groups which comprise a carbonyl group which is substituted with an aralkyloxy group (which is an oxygen atom substituted with an aralkyl group as defined above), in which the aryl moiety thereof may optionally be substituted with one or two substituents selected from C ⁇ -C 6 alkoxy groups as defined above and nitro groups, examples of which include benzyloxyearbonyl, 4-mefhoxybenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and 4-nitro-benzyloxycarbonyl groups;
  • (xii) ester forming residues of a Cj-Cio sulfonic acid such as a methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl or toluenesulfonyl group;
  • a Cj-Cio sulfonic acid such as a methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl or toluenesulfonyl group
  • an ester with an mono- or di-(C ⁇ -C 6 alkyl) ester of carbonic acid such as monomethyl carbonate, dimethyl carbonate, monoethyl carbonate, diethyl carbonate, monopropyl carbonate or monobutyl carbonate;
  • the ester group which is capable of being removed by a metabolic process (e.g. hydrolysis) in vivo is one, which on administration to the body of a live mammal is removable by a metabolic process (e.g. hydrolysis) to give a compound of formula (I) or a salt thereof.
  • a protecting group as an ester residue include the following: (i) l-(acyloxy)-(C ⁇ -C 6 alkyl) groups, examples of which include
  • 1 -(aliphatic acyloxy)-(CpC 6 alkyl) groups which comprise a C ⁇ -C 6 alkyl group as defined above which is substituted with an alkylcarbonyloxy group having from 1 to 6 carbon atoms, examples of which include formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1- propionyloxyethy], 1 -butyryl oxyethyl, 1 -pivaloyloxyefhyl, 1 -valeryloxyethyl, 1 - isovaleryloxyethyl, 1-hexanoyloxyethyl, 1-formyloxypropyl.
  • (C]-C 6 alkoxy)carbonyloxyalkyl groups which comprise a C ⁇ -C 6 alkyl group as defined above or a cycloalkyl group as defined above which is substituted with a (C]-C 6 alkoxy)carbonyloxy group which comprises a carbonyloxy group substituted with a - C 6 alkoxy group as defined above or a cycloalkoxy group, examples of which include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymefhyl, cyclohexyloxycarbonyloxym ethyl, cyclohexyloxycarbonyloxy(cyclohexyl)methyl, 1 - (methoxycarbonyloxy)ethyl, 1 -(e
  • phthalidyl groups which comprise a phthalidyl group which may optionally be substituted with a substituent selected from the group consisting of lower alkyl groups as defined above and lower alkoxy groups as defined above, examples of which include phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups;
  • (x) 1 -(acyloxy)alkoxycarbonyl groups which comprise a lower alkoxycarbonyl group as defined above in which the lower alkoxy moiety is substituted with an aliphatic acyloxy group as defined above or an aromatic acyloxy group as defined above, examples of which include pivaloyloxymethyloxycarbonyl groups.
  • Bz represents a benzyl group
  • Car represents a carbamoyl group
  • cBu represents a cyclobutyl group
  • cHx represents a cyclohexyl group
  • COOMe represents a methoxycarbonyl group
  • cPn represents a cyclopentyl group
  • cPr represents a cyclopropyl group
  • diEtCar represents a N,N-diethylcarbamoyl group
  • diMeCar represents a N,N-dirnethylcarbamoyl group.
  • diMeN represents a dimethylamino group
  • diMePro represents a 2,2-dimethylpropanoylamino group
  • diMeTcr represents a N,N-dimethylthiocarbamoyl group
  • diPrCar represents a N,N-diisopropylcarbamoyl group
  • Et represents an ethyl group
  • Fur represents a furan-3-yl group
  • Hx represents a hexyl group
  • iPr represents an isopropyl group
  • Isox represents an isoxazol-3-yl group
  • Me represents a methyl group
  • MeEtCar represents a N-methyl-N-ethylcarbamoyl group
  • MeEtN represents a methylethylamino group
  • Mor represents a morpholin-1-yl group
  • Mtdo represents a methylenedioxy group
  • Nap represents a naphthyl group
  • Oxa represents an oxazol-2-yl group
  • pentaFPh represents a pentafluorophenyl group
  • Ph represents a phenyl group
  • Pip represents a piperidin- 1-yl group
  • Pr represents a propyl group
  • 2-Pyr represents a 2-pyridinyl group
  • 3-Pyr represents a 3-pyridinyl group
  • 4-Pyr represents a 4-pyridinyl group
  • Pyrd represents a pyrrolidin-1-yl group
  • Pyrm represents a pyrimidinyl group
  • Pyzi represents a pyrazinyl group
  • Pyzo represents a pyrazol-2-yl group
  • t-Bu represents a t-butyl group
  • 2,2,3,3-tetraMe-cPr represents a 2,2,3,3-tetramethylcyclopropyl group
  • Tfm represents a trifluoromethyl group
  • Thiz-2 represents a l,3-thiazol-2-yl group
  • Thiz-4 represents a l,3-thiazol-4-yl group
  • Thiz-5 represents a l,3-thiazol-5-yl group
  • H H OH cPn -650 2-AcNH H H OH cHx -651
  • 2-AcNH H H OH -(CH 2 )-cPr -652 2-AcNH H H OH -(CH 2 )-cBu -653
  • 2-AcNH H H OH -(CH 2 )-cPn -654 2-AcNH H H OH -(CH 2 )-cHx -655
  • 2-AcNH H H OH -(CH 2 ) 2 -cPn -658 2-AcNH H H OH -(CH 2 ) 2 -cHx -659
  • 2-AcNH H H OH -(CH 2 ) 3 -cPr -660 2-AcNH H H OH -(CH
  • the preferred compounds in the exemplified compounds described above are the compounds of Exemplification compound number : 1-2, 1-4, 1-8, 1-10, 1-13, 1-14, 1-17, 1-18, 1-22, 1-26, 1-32, 1-45, 1-48, 1-54, 1-70, 1-76, 1-92, 1-98, 1-114, 1-120, 1-136, 1-142, 1-180, 1-186, 1-202, 1-208, 2-2, 2-3, 2-4, 2-5, 2-6, 2-9, 2-10, 2-29, 2-30, 2-31, 2-32, 2-61, 2-63, 2-96, 2-101, 2-102, 2-188, 2-193, 2-194, 2-280, 2-285, 2-286, 2-372, 2-377, 2-378, 2-464, 2-469, 2- 470, 2-556, 2-561, 2-562, 2-740, 2-745, 2-746, 2-832, 2-837, 2-838, 3-4, 3-7, 3-8, 3-9, 3-10, 3-11, 3-13, 3-15, 3-16, 3
  • the compounds of formula (I) in the present invention can be prepared by methods A to Q described below.
  • R 1 , R 2 , R 3 , R 4 , R 5 , A, X and Y are as defined above;
  • R a represents a C ⁇ -C 6 alkyl group;
  • R b represents a C ⁇ -C 6 alkyl group or a C ⁇ -C 6 alkyl group substituted with from 1 to 7 halogen atoms;
  • R c and R d are the same or different and each represents a hydrogen atom or a C ⁇ -C 6 alkyl group, or R c and R taken together with the nitrogen atom to which they are attached form a saturated heterocyclic group containing a nitrogen atom;
  • R e represents C ⁇ -C 6 alkyl group;
  • L represents a leaving group;
  • n represents an integer from 1 to 6;
  • Prot a represents an amino protecting group;
  • Prot b represents a hydroxy protecting group;
  • Hal represents a halogen atom.
  • the leaving group L is not particularly limited provided that it can be substituted in a reaction by a nucleophilic reagent.
  • Suitable leaving groups include, for example, a hydroxy group; a halogen atom as described above; a lower alkylsulfonyloxy group such as a methanesulfonyloxy group or an ethanesulfonyloxy group; a halogenated lower alkylsulfonyloxy group such as a trifluoromethanesulfonyloxy group; an aromatic sulfonyloxy group, which is for example, an arylsulfonyloxy group such as a benzenesulfonyloxy group, a lower alkylated arylsulfonyloxy group such as a p- toluenesulfonyloxy group, or a halogenated arylsulfonyloxy group such as a p- chlorobenzene
  • the amino protecting group in Prof is not particularly limited provided that it can protect an amino group in a reaction.
  • a protecting group is a group which can be removed by a chemical reaction such as hydrogenolysis, hydrolysis, electrolysis and photolysis and may be, for example, an aliphatic acyl group, examples of which include an alkylcarbonyl group such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pentanoyl group, a pivaloyl group, a valeryl group, an isovaleryl group, an octanoyl group, a lauroyl group, a palmitoyl group or a stearoyl group, a halogenated lower alkylcarbonyl group such as a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group or a trifluoroacety
  • the hydroxy protecting group Prot b is not particularly limited provided that it can protect a hydroxy group in a reaction.
  • a protecting group is a group which can be removed by a chemical reaction such as hydrogenolysis, hydrolysis, electrolysis and photolysis and may be, for example, an aliphatic acyl group, examples of which include an alkylcarbonyl group such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pentanoyl group, a pivaloyl group, a valeryl group or an isovaleryl group, a (lower alkoxy)-(lower alkyl)carbonyl group such as a methoxyacetyl group, or an unsaturated alkylcarbonyl group such as an (E)-2-methyl-2-butenoyl group; an aromatic acyl group, examples of which include an arylcarbonyl group such as a benzoyl
  • Protection of an amino or hydroxy group with the above described protecting groups or removal of these protecting groups can be accomplished according to standard methods (described in, for example, T.H.Green et al., Protective groups in organic synthesis, JOHN WILEY & SONS, INC.).
  • Step A-1 is a process for preparing a compound of formula (I) by the reaction in the presence of a base of a compound of formula (II) which can be prepared according to method T described below, is a known compound or can easily be prepared from a known compound, a compound of formula (III) which is a known compound or can be easily prepared from a known compound, and a compound of formula (IN) which can be prepared according to methods R or S described below, is a known compound, or can be easily prepared from a known compound.
  • the solvent employed is not particularly limited provided that it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ester such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; a nitrile such as acetonitrile or isobutyronitrile; an amide such as formamide, N,N-dimethylformamide, N,N-dimethylacet
  • the reagent employed may be a phosphonic acid triester such as triphenyl phosphite or trimethyl phosphite, and preferably it is triphenyl phosphite.
  • the base employed may be, for example, N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamme, N- methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5- diazabicyclo[4,3,0]non-5-ene (DBN), l,4-diazabicyclo[2,2,2]octane (DABCO) or 1,8- diazabicyclo[5,4,0]undec-7-ene (DBU); and preferably it is pyridine.
  • base may not be added.
  • the reaction temperature varies depending on the solvent, the starting materials, the reagent and the like, and is usually in a range from 20°C to 150°C; preferably it is from 50°C to 120°C.
  • the reaction time varies depending on the solvent, the starting material, the reagent, the reaction temperature and the like, and is usually in a range from 1 to 24 hours; preferably it is from 1 to 8 hours.
  • the desired compound of this step can be isolated from the reaction mixture by a conventional method: the desired compound can be, for example, obtained by 1) addition of water and an organic solvent immiscible with water such as benzene, diethyl ether, ethyl acetate or the like, to the reaction mixture, 2) extraction of the desired compound from the resulting mixture, 3) washing of the organic layer with water, 4) drying the organic layer over a desiccant such as anhydrous magnesium sulfate or the like, and 5) removal of the organic solvent.
  • the desired compound thus obtained, if necessary, can be further purified by a conventional technique such as recrystallization, reprecipitation or silica gel column chromatography.
  • the desired compound of this step can be used in a reaction of a further step without purification.
  • Step B-l is a process for preparing a compound of formula (NI) by the reaction in the presence or absence of a coupling reagent of a compound of formula (II) which can be prepared according to method T described below, is a known compound, or can be easily prepared from a known compound, and compound of formula (N) which is a known compound or can be easily prepared from a known compound.
  • the reaction in this step is accomplished via two alternatives routes: (B-la) in which the reaction is performed in the presence of a coupling reagent when the group L is a hydroxyl group, and (B-lb) in which the reaction is performed in the absence of a coupling reagent when the group Lis other than a hydroxyl group.
  • the coupling reagent employed may be:
  • a carbodiimide compound such as 1,3-dicyclohexylca ⁇ bodiimide, 1,3- diisopropylcarbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide or the like; a combination of the carbodiimide compound as described above with a base as described below; or a combination of the carbodiimide compound as described above with an ⁇ -.
  • hydroxy compound such as N-hydroxysuccinimide, 1-hydroxybenzotriaziole or N-hydroxy-5- norbornen-2,3-dicarboximide;
  • a carbonate compound such as N,N'-disuccinimidyl carbonate, diethyl pyrocarbonate, di-2-pyridyl carbonate or S,S'-bis(l-phenyl-lH-tetrazol-5-yl)dithiocarbonate;
  • a phosphonic chloride compound such as N,N'-bis(2-oxo-3- oxazolidinyl)phosphonic chloride
  • an oxalate compound such as N,N'-disuccinimidyl oxalate, N,N'-diphthalimidyl oxalate, N,N'-bis(5-nornbornen-2,3-dicarboximidyl) oxalate, l,l'-bis(benzotriazolyl) oxalate, l,l'-bis(6-chlorobenzotriazolyl) oxalate or l, -bis(6-trifluoromethylbenzotriazolyl) oxalate;
  • an N-(lower alkyl)-5-arylisoxazolium-3'-sulfonate compound such as N-ethyl-5- phenylisoxazolium-3 ' -sulfonate
  • a diheteroaryl diselenide compound such as di-2-pyridyl diselenide
  • a 2-halogeno-l-(lower alkyl)pyridinium halide such as 2-chloro-l- methylpyridinium iodide or 2-bromo-l-ethylpyridinium chloride;
  • an imidazole compound such as l,l'-oxazolyldiimidazole or N,N'- carbonyldiimidazole;
  • a phosphate compound such as phenyl dichlorophosphate or a polyphosphate ester
  • a halogenosulfonyl isocyanate compound such as chlorosulfonyl isocyanate
  • a halogenosilane compound such as trimethylsilyl chloride or triethylsilyl chloride
  • N,N,N',N'-tetra(lower alkyl)halogenoformamidium chloride compound such as N,N,N' ,N' -tetramethylchloroformamidium chloride.
  • the coupling reagent is a carbodiimide compound or an imidazole compound; and more preferably it is 1,3-dicyclohexylcarbodiimide or N,N'- carbonyldiimidazole.
  • the solvent employed is not particularly limited provided that it does not inhibit the reaction and dissolves the starting materials to some extent.
  • the solvent may be, for example, an aliphatic hydrocarbon such as hexane or heptane; an aromatic hydrocarbon such as benzene, toluene or xylene; a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; an ester such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate or diethyl carbonate; an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or di(ethylene glycol) dimethyl ether; a nitrile such as acetonitrile or isobutyronitrile; or an amide such as
  • the base employed may be, for example, an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate; an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate; or an organic base such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamme, N-methylpiperidine, pyridine, 4- pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4- mefhylpyridine, quinoline, N,N-dimethylaniline or N,N-diethylaniline; preferably the base employed is an organic base; and more preferably it is triethylamine, diisopropylethylamine or pyridine.
  • the reaction temperature varies depending on the solvent, the starting material, the reagent and the like, and is usually in a range from -20°C to 120°C, preferably from 0°C to 120°C.

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Abstract

L'invention porte sur de nouveaux composés de formule (I) et leurs sels et esters pharmacocompatibles pouvant moduler la fonction LXR et présentant de ce fait une excellente activité anti-artériosclérotique et anti-inflammatoire. Dans ladite formule: A représente aryle ou hétéroaryle; R1, R2 et R3 sont identiques ou différents et représentent chacun hydrogène, hydroxyle, nitro, cyano, amino, halogène, carboxy, carbamoyle, mercapto, alkyle, haloalkyle, alkylcarbonyloxy, alkoxy, alkylthio, alkylsulfinyle, alkylsulfonyle, alkylamino, dialkylamino, alkylcarbonylamino, N-(alkylcarbonyl)-N-(alkyl)amino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, alkylsulfonylamino, N-(alkylsulfonyl)-N-(alkyl)amino, haloalkylsulfonylamino, N-(haloalkylsulfonyl)-N-(alkyl)amino, alkylcarbonyle, alkoxycarbonyle, alkylaminocarbonyle ou un groupe dialkylaminocarbonyle, ou R1 et R2 sont ensemble alkylènedioxy; R4 et R5 sont identiques ou différents et représentent chacun hydrogène, hydroxyle, amino, halogène, mercapto, alkyle, haloalkyle, alkoxy, alkoxycarbonyle ou alkylthio; X représente hydrogène, hydroxyle, halogène, alkoxy ou haloalkoxy; et Y représente un alkyle facultativement substitué, cycloalkyle, hétérocyclyle, aryle, cycloalkylalkyle, hétérocyclylalkyle ou un groupe aralkyle.
PCT/JP2003/007677 2002-06-18 2003-06-17 Derives de la pyrimidin-4(3h)-one a cycles fusionnes, spn procede de preparation et ses utilisations WO2003106435A1 (fr)

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